Latin American Perspectives on Scientific Research by Fernando Lolas

Latin American Perspectives on Scientific Research

Latin American Perspectives on Scientific Research By

Fernando Lolas and Eduardo Rodriguez

Latin American Perspectives on Scientific Research By Fernando Lolas and Eduardo Rodriguez This book first published 2020 Cambridge Scholars Publishing Lady Stephenson Library, Newcastle upon Tyne, NE6 2PA, UK British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Copyright ÂŠ 2020 by Fernando Lolas and Eduardo Rodriguez All rights for this book reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the copyright owner. ISBN (10): 1-5275-4109-6 ISBN (13): 978-1-5275-4109-2

TABLE OF CONTENTS

Foreword .................................................................................................. vii Section I: Ethics of Research Training and Research Integrity Chapter 1 .................................................................................................... 3 Ethics of Research Training: A Latin American Experience Introduction........................................................................................... 3 Program aims ........................................................................................ 4 Curricular development in research ethics â&#x20AC;&#x201C; a culture-sensitive approach .......................................................................................... 5 Approaches and experiences ............................................................... 12 Evaluation of program and outcomes ................................................. 17 Lessons learned â&#x20AC;&#x201C; the future of ethics training within the research enterprise in Latin America ........................................................... 18 A network for the advancement of a biocentric ethics ........................ 19 Chapter 2 .................................................................................................. 23 Research Misconduct and Integrity in Latin America Introduction......................................................................................... 23 Research misconduct .......................................................................... 25 Motivations for research misconduct .................................................. 27 Research integrity in Latin America ................................................... 30 Mechanisms to promote research integrity ......................................... 37 Conclusion .......................................................................................... 40 Section II: Chapters Issues in Genomic Research Chapter 3 .................................................................................................. 49 Social, Ethical and Legal Attitudes towards Genomic Research in Latin America Introduction......................................................................................... 49 Advances in genomic research in Latin America................................ 51 Social representations of genomic research by Latin American stakeholders ................................................................................... 53 Latin American publications: Social, legal and ethical issues ............ 57

Table of Contents

Media Role.......................................................................................... 65 Bioethics role ...................................................................................... 66 Conclusions......................................................................................... 68 Chapter 4 .................................................................................................. 75 Informed Consent Content for Genetic Research Using Biological Samples Stored in Biobanks: Latin American Context Ethical Issues Introduction......................................................................................... 75 Ethical issues related to informed consent for genetic research using biological samples and data stored in biobanks ................... 77 International Guidance ........................................................................ 86 Latin American Biobanks ................................................................... 90 Conclusion .......................................................................................... 92 Chapter 5 .................................................................................................. 97 Ethical Issues in Genome Editing using CRISPR/Cas9 System Introduction......................................................................................... 97 Function and origin of the CRISPR/CAS9 System............................. 98 Applications of the CRISPR/CAS9 System ...................................... 100 Ethical issues..................................................................................... 104 Bioethical issues ............................................................................... 113 Conclusion ........................................................................................ 116 Section III: Mental Health Chapter 6 ................................................................................................ 125 Ethical Issues in Mental Health Research Introduction....................................................................................... 125 Values in Mental Health Research .................................................... 127 Principles of Bioethics in Mental Health research ............................ 128 The importance of culture in psychiatric research ............................ 129 The role of Social Determinants in Mental Health ........................... 132 Research with nootropics .................................................................. 135 Legal Concerns with the non-therapeutic use of nootropics ............. 136 Ethical constraints with the non-therapeutic use of nootropics ......... 136 Glossary .................................................................................................. 143

FOREWORD

This collection of readings in ethics of research from the Interdisciplinary Center for Studies on Bioethics at the University of Chile aims at presenting some information and perspectives derived from its work. The topics cover issues of research integrity, ethics of research education and ethical issues in specific research fields, especially genomics and mental health. The main emphasis is on the Latin American context, although global issues are also considered. The book aims to contribute to training in research ethics considering the need to include ethics of research in curricular fields in universities and implementing mechanisms to safeguard research integrity.

SECTION I: ETHICS OF RESEARCH TRAINING AND RESEARCH INTEGRITY

CHAPTER 1 ETHICS OF RESEARCH TRAINING: A LATIN AMERICAN EXPERIENCE

Abstract This chapter reviews the experience in training Latin American professionals in the ethics of biomedical and psychosocial research at the Interdisciplinary Center for Studies on Bioethics (CIEB Spanish acronym) of the University of Chile, aided by a grant from Fogarty International Center (FIC) â&#x20AC;&#x201C; National Institutes of Health from 2002 to 2011 (1, 2). The network formed by faculty and former trainees has published extensively on issues relevant in the continent and has been instrumental in promoting new master-level courses at different universities, drafting regulations and norms, and promoting the use of bioethical discourse in healthcare and research.

Introduction The Interdisciplinary Center for Studies on Bioethics of the University of Chile was established in 1993 at the oldest and largest university in Chile (founded 1842). It was appointed WHO Collaborating Center in Bioethics in 2007. Partnership with the Pan American Health Organization (PAHO), Regional Office of the World Health Organization (WHO), led to the development of master programs in bioethics at different Latin American institutions (University of San Marcos, Lima, Peru, Instituto TecnolĂłgico de Santo Domingo, Dominican Republic, University of Cuyo and University of Cordova, Argentina, among others) and to substantial contributions to other institutions (Fundacion Santa Fe de Bogota, Colombia, Academia Nacional Mexicana de Bioetica, as examples). Its activities, which are supported by foundations and public institutions, have brought together experts from diverse professional backgrounds and its publications have been used in many different settings. CIEB has participated in training experiences all over the continent. Among its most successful projects are those supported by the Fogarty International Center-

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NIH. Throughout the years, scholars and researchers have been able to participate in training experiences. The Center has developed several lines of research at the interfaces between socio-cultural studies, religious beliefs, and health-related behavior, and has been instrumental in promoting bioethics. The main periodical publication, the well-established journal Acta Bioethica publishes papers in Spanish, Portuguese, and English (indexed in Scielo, Latindex, Science Citation Index, Social Science Citation Index, Lilacs). Other publications include a series of books, textbooks prepared by former NIH Fogarty Trainees, and monographs, as well as DVDs and webbased materials freely available at http://www.uchile.cl/bioetica. The master-level international program of the ethics of biomedical and psychosocial research of the Interdisciplinary Center for Studies on Bioethics of the University of Chile has selected professionals and academics from Latin America and the Caribbean. Topics covered have been diverse and recruitment of trainees has encouraged multidisciplinary professions and differences in outlooks. Throughout the years, with different emphases, the main goal has been to help increase the number of persons familiar with the ethics of research in the biomedical and psychosocial disciplines and to foster the development of training programs at different institutions of the continent. The program has trained Latin American professionals to assume leadership positions, to produce research with ethical sustainability, collaborate with the formulation of ethics of research regulations in their home countries and participate in ethical review committees at their home institutions.

Program aims 1) To train Latin American professionals in the ethics of biomedical and psychosocial research in an interdisciplinary way. 2) To provide participants with appropriate knowledge of Bioethics Reasoning, Responsible Conduct of Research, Research Ethics in Anthropological and Social Foundations of Cultural Diversity in Research Practices, Publication Methods and Research Tools. 3) To acquaint trainees with dialogical methods, mediation and negotiation in solving bioethical dilemmas and decision-making in scientific ethical review committees.

Ethics of Research Training: A Latin American Experience

4) To maintain and expand a cadre of professionals able and willing to assume leadership positions in bioethics education and research policies in their institutions and countries. 5) To develop skills for formulating public policies and regulations on research ethics. 6) To prepare trainees to address ethical and social issues related to scientific research in the context of international activities and crosscultural environments. 7) To enhance critical thinking and responsible identification with the conditions in the countries and institutions that enable meaningful participation in the international scenario of globalized science. 8) To form a network of persons and institutions that can enter into responsible discussion and implementation of public policies in health and research in Low and Middle Income Countries (LMIC) of Latin America helping to reduce the â&#x20AC;&#x153;know-do gapâ&#x20AC;? by demonstrating the relevance of research and evidence-based decisions for policy formulation and ethical sustainability.

Curricular development in research ethics â&#x20AC;&#x201C; a culture-sensitive approach Despite improvements in research output in the biological, social, and medical sciences, several problems remain with ethical underpinnings that justify training in research bioethics in the Region of South and Central America. Some aspects relevant to a training program in research ethics were identified and provided the rationale for this training program. The following were highlighted:

1. The 10/90 gap Enhancements in global health status have mostly benefited developed countries. The lack of equity occurs not only in health coverage but also in research investment. Financial resources for research are insufficient in Latin American countries. In 1999, the Global Forum for Health Research analyzed data about expenditures in health research and found that less than 10% of the budget is expended on research on health problems that account for 90% of the global disease burden, the so-called 10/90 gap. Latin American countries have low scientific research production. Brazil is the

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only country in the region that invests more than 1% of its gross domestic product on scientific research. The Global Forum for Health Research recommends that developing countries should carry out more research since scientific productivity increases economic development and more budget could be used in healthcare (3). An increase in research output must be accompanied by enhancement of ethical oversight.

2. Globalization and resource-poor countries The current trend is toward the globalization of clinical trials and other health research sponsored by industry in multi-centric studies, with a shift in sites towards emerging regions, including Latin America (4). One of the advantages is that the cost of conducting research is less in developing countries than in advanced countries. Furthermore, resource-poor countries often have large patient pools for diseases without treatment, which ensures rapid recruitment and reduction of the time needed to complete time trials. As a social responsibility, public awareness about the need for ethical control of research has increased. The following problems must be taken into account (4, 5): 1. In order to assure valid and accurate results in multi-centric studies, proceedings must be identical in all sites. 2. Genuine informed consent (informed and voluntary) must be obtained, but the task is difficult since often the populations of developing countries are not prepared to understand the complex medical and research language. 3. Difficulties with confidentiality and privacy measures, since data are often maintained in an overseas coordinating center. 4. The use of placebos as a comparison when there is no comparative drug available and where the standard of care for a particular disease in many developing countries is no treatment. Some commentators argue that subjects should receive the best method available worldwide. 5. Reporting adverse events equally in all sites. In phase IV of clinical trials often the mechanisms of pharmaco-surveillance fail in developing countries. 6. Difficulties in monitoring and safety procedures. 7. Guaranteeing benefits for the communities where the research is performed. 8. Variation in the interpretation of regulations by the different scientific ethical review committees of participating sites, often requesting changes that have to be reconsidered by all sites.

Ethics of Research Training: A Latin American Experience

9. Often research sponsorship is driven by economic interest and may not reflect the needs of host developing countries.

3. The know-do gap Another aspect that merits consideration is the translation of knowledge into practice, the so-called â&#x20AC;&#x153;know-do gapâ&#x20AC;?. While information derived from research-based evidence is available on many health-related issues, its translation into policy and practical measures is delayed in developing countries or only appropriated by a minority of the population which has the means to do so and that looks for the highest possible standard derived from scientific progress (6). Equitable distribution of the benefits derived from scientific research needs ethical reflection by the scientific community, policymakers, and the public at large. The bridge between research and public health requires not only the publication of results but also the employment of social strategies to reach the disadvantaged.

4. Research: cultural implications and responsible conduct Research is structured within a cultural process so that the way it is carried out is influenced by context. In developing countries, some activities may be classified as research, but they would not qualify as such in developed countries. In our experience with trainees, research was confused with other activities, such as surveillance in industry-guided clinical trials; social science research projects were not considered in need of ethical evaluation due to their presumed low risk. Social demand for research (as different from need or desire) continues to be low in Latin America, as reflected in resource allocation, social recognition, and employment opportunities. The different valorization of research in different societies is due to tradition, belief, social rewards, administrative and institutional arrangements for its accomplishment, and, finally, the definition of research itself. Besides the different meanings that the word research has in different languages, there is also the different approach of the expert communities in the human and the natural disciplines, and the social implications of results (7). In view of the importance of ethical considerations when conducting research, particularly when it involves human participants, it is noteworthy that the differences in social environments that make research possible or the availability of financial and institutional support have not been given proper attention. Most of the projects in Low and Middle-Income Countries seem to take for granted that this social practice is similarly conceived all

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over the world. Under this assumption, it is difficult to conceive that ethically relevant problems are similarly conceived in different settings. The acritical imposition of norms and procedures that find acceptance in highly scientifically minded societies make it difficult to respect differences that influence the very definition of what constitutes ethical scientific practice. Given the assumption that values such as dignity, autonomy, and justice – as examples – may be similarly constructed, the universality of their concrete representation faces some constraints that remain unchallenged. The homogeneity of the research enterprise across societies and the aspiration to have a universally applicable model may be questioned, although a universal method might be used (8). Responsible conduct of research is also culturally bounded. For example, risks assessment varies with context, the same can be said of safeguarding confidentiality, avoidance of stigmatization or protection from harm. In this context, experiences of training face-to-face in the cultural community where research is going to take place are important. CIEB’s training program confronted trainees with real-life examples of research in specific contexts and/or in response to felt needs of populations and institutions. The special emphasis given to public health topics and anthropological analysis was dictated by the priorities of healthcare systems on the continent and the multicultural, pluralistic environments in which researchers must act.

5. Social roles: clinician and/or researcher The scarcity of healthcare personnel, professional traditions, and restricted funding provoke confusion between the roles of caregiver and researcher in many Latin American settings. The “therapeutic misunderstandings” (9, 10) or confusion between the roles of a therapist or treating physician and the role of researcher, is common in countries with weak research capabilities. Subjects often expect that the researcher is giving them adequate personalized treatment for their condition. The different contextual interpretation of guidelines in other cultures and discrepancies between researchers from different countries/traditions/professions causes cultural differences.

Ethics of Research Training: A Latin American Experience

Table 1.1 Role of Physician as a caregiver and as a researcher (compiled by the authors) Research

Clinical practice

Goals

Systematic research involving human beings to generate generalized knowledge

Diagnosis and treatment for healthcare needs

Activities

Probe a hypothesis to reach a conclusion

Improve the health of patients with the probability of success

Subjects

The individual subject may benefit or not since the goal is the common good

The individual patient expects a direct benefit

6. International collaboration issues The international collaboration between developed countries and Latin America requires improving local capacity in research together with sound ethical oversight systems, good quality training, and awareness of the needs and expectations of the populations. Even if they are not at the forefront of research, the expanded vision of our trainees about the situation in Latin America and the awareness of the goals of research in its proper context have helped improve the translation of evidence-based facts into valuebased actions. An ethically competent researcher is also a socially competent professional, sensitive to the needs of the communities where the research results obtained and outcomes are expected to benefit. These notions are embedded in the idea of the ethical sustainability of research outcomes, which implies responsible conduct of the research, the integrity of sound data gathering and data-organizing processes and affordability of evidence-based interventions (11, 12). Several documents (13) reveal that healthcare professionals and biological and biomedical researchers continually confront tension between the advancement of scientific knowledge and the protection of research participants. Improper research conducts at Latin

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American institutions demand the need to train professionals and promote research integrity in them (14, 15).

7. Human diversity: challenge and opportunity Research ethics curricula face the challenge of diversity in multiethnic and multicultural contexts in Latin America. Culturally and ethnically different groups increasingly demand participation in public policies and involvement in research and decision-making. The indigenous population is numerous, usually fragmented in small groups, the average is 8% in Latin America, but varies widely. Some countries such as Bolivia (80%), Guatemala (60%) and Peru (40%) have large populations (16). Language diversity is a factor that hinders research, especially in social studies and public health. There are more than one thousand different indigenous languages. The globalization trend is changing the way of life of these populations very rapidly. Social progress has helped to reduce poverty and has improved access to basic services including health, but the benefits to the indigenous populations are lower, being more represented among the extremely poor (17). In Latin America, there are still people without access to healthcare services mainly due to social inequalities. The region has experienced fast and complex epidemiological changes in recent decades, combining increasing rates of non-communicable diseases and injuries, and keeping many existing endemic and emerging diseases uncontrolled. The poor and indigenous populations also experience stigmatization or adverse social judgment. There have been reactions against genomic research of indigenous populations, for example, opposing the collection of blood samples used for DNA characterization (18). There is a need for a “culture fair” approach to data gathering and interpretation when doing research in order to respect dignity or request consent. In order to achieve an ideal of justice and right relationships with proper use of power relations, the context where research is taking place must be evaluated, looking for “ethical sustainability”. This notion suggests that any change in attitudes, goals, and practices must be based on sound argument and endure over time. The training program developed by CIEB has worked on an “ethically sustainable” research agenda in a globalized context by training groups of professionals able to participate as researchers, policymakers, advisors to legislators, and mentors for new generations of academics. Professionals thus trained look to assume positions of leadership in addressing the ethical and social issues of global health research. It is recognized that ethical

Ethics of Research Training: A Latin American Experience

oversight of research is best performed locally, thus avoiding mistrust and dependence.

8. Research accountability As international experience shows, major problems in the ethics of the research enterprise arise from an undue concentration on products (publications, money, prestige), disregarding processes (interactions between research participants, sponsors, researchers). It is at this level that serious flaws in accountability have been observed in researchers of scientifically alphabetized countries. This is all the more worrisome in researchers from less-developed-countries, who enter into contacts and interactions with their peers in advanced nations and feel immune to criticism as members of an intellectual elite. The issue of accountability (holding research actors responsible for their actions) is increasingly important in international health research as cooperation among parties involves a large number of stakeholders with varying degrees of power and influence (19). Researchers in Latin America represent a privileged minority and many of them feel that ethical oversight may hamper or limit their contribution to science and technology. Most Latin American countries rely largely on external funding and donors to initiate and sustain long-term research efforts. Despite limited resources, the critical mass of Latin American researchers has produced significant scientific contributions in specific fields (20). Research in poor-resource settings, both in Low and MiddleIncome Countries and in industrialized countries, demands the establishment of training programs for professionals conversant with ethical standards and respect for human dignity. All along, the emphasis on accountability of researchers and research has been a permanent feature of our training effort. The idea is to integrate ethical reflection in the complex academic world taking into consideration that there are numerous administrative and structural obstacles to be solved in the Latin American context.

9. Role of bioethics in training The interdisciplinary group learning strategy of the program followed the deliberative method of bioethics. Concepts presented were subjected to the exchange of points of view according to personal experiences. Different arguments were respected while also trying to reach consensus by identifying common grounds which depart from cultural and educational

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background conditioning. In the deliberative method, the different interests rather than being subjected to a process of exchange are universalized, participants are enriched in their relationships and different values are respected (21). The different ethical theories were also learned according to schools of thought including how to argue with a philosophical base. The idea was to interact between the bioethics dialogical method and social and cultural values and philosophical reflection (22). Building up interfaces between institutions, professional groups, community-based organizations, and biopsychosocial health professionals is the very essence of the bioethical approach, with its emphasis on dialog and procedure above belief and philosophical persuasion (23).

Approaches and experiences The training period at CIEB was mainly devoted to work in small groups (around five multidisciplinary trainees per year) under the leadership of a faculty member, avoiding any resemblance to an asymmetrical relation of the type mentor-trainee or tutor-trainee. This structure of the program allows personalized learning in order to acquire the required skills, with time to reflect outside the usual workload. The covert dimension of the curriculum was to illustrate practically the dialogical nature of the bioethical enterprise and the development of bioethical discourse through open manifestation of ideas. Care was taken so that each year promotion had sufficient professional variety (16 different professions in the 10 years) and different countries of origin to enhance interdisciplinary reflection. CIEB trainees came from the following countries: Mexico, Colombia, Argentina, Chile, Peru, Nicaragua, Bolivia, Ecuador, Honduras, El Salvador, Brazil, Paraguay, Uruguay, Dominican Republic, Guatemala, and Venezuela.

Ethics of Research Training: A Latin American Experience

Table 1.2: CIEB Fogarty Trainees 2003-2011 (compiled by the authors) Countries

Professions

Contributions

Mexico – 8 Chile – 8 Colombia – 7 Argentina – 6 Peru – 5 Nicaragua – 3 Ecuador – 3 Bolivia – 2 Honduras – 2 El Salvador – 1 Brazil – 1 Uruguay – 1 Dominican Republic – 1 Guatemala – 1 Venezuela - 1 Total: 50 Men: 16 Women: 34

Medicine – 18 Dentist – 8 Lawyer – 4 Pharmacy – 3 Chemistry – 3 Nurse – 2 Sociology – 2 Philosophy – 2 Microbiology –2 Obstetrician – 1 Biology – 2 Psychology 2 Veterinary – 1 International Relations – 1 Epidemiology -1

Program Research Projects: 50 Additional Research Projects: 14 Publications Articles: 54 Books, chapters: 52 Web: 22 Online Virtual Modules: 6 Web Bulletins: 3 Web Sites: 3 Health Research Policies and Regulations: 26 Country ethics of research workshop interventions: 19 Development of Training programs in the ethics of research: 20 Creation of new Scientific Ethical Review Committees: 8 Participation in Scientific Ethical Review Committees: 27 Participation in National Bioethics Commissions: 6 Honors: 7 Presentations at Conferences: 103

Faculty members of the program were also from different disciplines and a horizontal dialog was promoted between trainees and faculty. The development of trainees’ leadership skills, ethical attitudes, communication and problem-solving skills, and ability to design and evaluate research ethically was emphasized. The role of faculty was not just to provide knowledge, but also to advise trainees by tutoring and promoting collaborative deliberation (24). Trainees were exposed to a wide range of content and training experiences. Courses were offered on the philosophical foundations of ethics, the history of bioethical thinking, the applications of bioethical discourse to research questions, statistical reasoning as it pertains to ethical formulation of methods, bioethical problems arising in medical and psychosocial research, qualitative and quantitative research methods, health economics, institutionalization of bioethics, structure and functions of ethics committees, anthropology and bioethics, and other topics selected on the basis of personal interests and available teaching resources. Trainees

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participated in sessions of research ethics committees and had the opportunity to interact with international scholars visiting the CIEB and were requested to select a topic to be dealt with in-depth as a final exercise. These essays were presented in evaluation sessions and graded, and constituted publications in accredited journals or presentations at seminars, workshops, or congresses, attendance at which was sometimes covered by special allowances from the program. Trainees participated also in writing grant proposals, debating ethics of research cases by applying the deliberative argumentation of bioethics and they gave lectures at conferences. When the training period was completed, participants were requested to write formal and publishable papers and to prepare an activity in their home country or at their institution of origin, to which a faculty member was invited. Thus, continuity of effort was assured and support from the home institution assessed. Conceptual approaches 1) The Comparative Approach focuses on two or more objects of analysis in order to uncover relationships and evaluate similarities and differences, emphasizing the temporal and territorial aspects of societies with different levels of development and cultural history. By comparing ethical systems in different countries, ways of overcoming obstacles and improving ethical oversight of research are discovered and tried. Cases discussed throughout the training period and those collected afterward are considered in this perspective. 2) The Pluralistic Approach focuses on the object of analysis from different perspectives and different theoretical frameworks, emphasizing key aspects of argumentation and deliberation. The idea is to provide information on the different schools of thought which have addressed the interrelationships involved in bioethics. A key dimension of the â&#x20AC;&#x153;hidden agendaâ&#x20AC;? of the training program is to emphasize openness and tolerance for different outlooks. 3) The Transdisciplinary Approach is oriented to identify and differentiate the interactions and intersections of bioethical and social variables. The objective is to map the semantic spaces of the objects of study which require an interdisciplinary analysis, maintaining a pre-eminent interest on inter-disciplines in order to emerge with knowledge transcending the traditional fields of disciplines.

Ethics of Research Training: A Latin American Experience

4) The Applied Approach is oriented towards the formulation, management, execution and evaluation of research from a bioethical perspective, and its personal and social implications in the different contexts in which trainees will act. The simultaneous use of these approaches allows interaction and exchange among trainees from different cultural backgrounds. As experience demonstrates, issues arising in the training program are inherently interdisciplinary and multidisciplinary. The program strives to take account of different points of view, cultural background, and professional skills. Key aspects: Information, knowledge, competencies, and attitudes are four key aspects of the program activities. Information refers to basic facts and figures needed for an opinion on a given subject matter. Knowledge is organized information in relation to specific applications, outcomes, or goals. [The text of the Helsinki Declaration is information. Its comprehension and application to a given problem constitute knowledge]. The distinction is important for using ethical guidelines and declarations which, divorced from concrete frameworks, may well be meaningless. Competencies are social skills deemed important for ethical deliberation and decision-making. Patient listening, tolerance for diversity, recognition of personal biases and dogmas, consideration of group dynamics, argumentation techniques, the opportunity for interventions, and others, are considered for each educational objective. Attitudes are potential ways of behaving and reacting. Unlike competencies, they may not be directly observable in current behavior. Subtle evaluation is needed. Frequently, they can be assessed only after the effects of training are incorporated into routine thinking and acting. Attitudes are best evaluated by their consequences upon long-term behavior patterns. Trainees acquire specific leadership attitudes related to work in collaboration and are able to participate in discussion groups with an improved ability to critical thinking. Among the guiding principles implemented, the following can be mentioned (1):

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 Methodical pluralism. “Solutions” given by different disciplines to ethical dilemmas depend on methods, that is, ways of formulating, interpreting, and solving problems. The power of a profession derives from its being able to identify “real” problems and provide appropriate solutions. The teaching of statistical methods, participant observation, qualitative and quantitative approaches to data acquisition and presentation were aimed at reinforcing the idea that no good science (in the ethical sense of good) can be obtained without careful attention to method. In addition, the multi-leveled and complex nature of scientific/ethical problems was underscored by stressing different approaches to problems.  Perspectivism. Not to be confused with moral relativism, the presentation of different perspectives is essential in creating an adequate environment for democratic and fact-producing dialog. This included openness to all facts related to a problem or to decision-making, illustrating a “culture of dialog” that is the essence of bioethical practice in committees and commissions. Deliberation was pursued in an attempt to generate conclusions that are well grounded on argument.  Open-mindedness. This ideal of interaction was sought after by encouraging manifestation of personal preferences and emotionladen material related to case analyses. Success was measured by requesting a personal evaluation from trainees after the completion of the face-to-face period.  Cultural sensitivity. The interdisciplinary nature of our effort was accompanied by the effort to underscore what is meant by a truly transcultural approach. Contact with anthropological thinking was provided by professional anthropologists who illustrated their methods and data with examples drawn from the cultural and the health fields. Their methods and approaches were considered valuable by trainees and helped to create awareness of the multiethnic and multicultural character of Latin American societies. The relevance of this knowledge for culturally fair bioethics was stressed at every point.  Attitudinal change. Although an ambitious goal not always easy to attain, it was expected that after the training period, attitudes toward problems, ethical dilemmas, and current or possible solutions could undergo changes. Again, this was reflected in self-evaluations made by trainees and faculty and was the subject matter of testimonies collected after the experience was finished.

Ethics of Research Training: A Latin American Experience

ď&#x201A;ˇ Improvement of communication skills. Trainees were exposed to a variety of approaches aimed at improving written and oral communication, and special training sessions were devoted to the design and development of websites, listserv lists, slide presentations, oral reports, and written materials. This was essential given the different training experiences of participants and the need to represent ideas and attitudes to wider audiences. This portion of the training experience also served to highlight moral problems associated with scientific communication and thus introduce participants to a crucial aspect of research integrity. ď&#x201A;ˇ Tolerance and the ability to listen. Although implicit, the notion that a crucial competence necessary for the successful implementation of bioethical discourse is tolerance and the capacity to listen to discrepant or adversary views was reinforced throughout the training period and was continued in the aftermath of the face-to-face experience when networking activities at the home institution were supported and followed.

Evaluation of program and outcomes A complete impact assessment may require an extended time to complete and should probably consider aspects well beyond immediate effects on research ethics. The multiplying effects of the experience through the work and effort of participants need years to show manifest outcomes in research practice, policymaking, and committee work. Faculty members served as tutors and provided advice and support to trainees throughout the training period and afterward. The evaluation consisted of written reports and feedback to participants on their degree of commitment, collaboration with the long-term goals of the program, and written productions. Individuals participating in the program provided feedback on their perceptions and accomplishments at the end of each term and their opinions proved valuable for reformulating aims and methods. Their publications attest to a wide range of interests and issues. The program itself was modified in accordance with suggestions and ideas provided by participants. At the institutional level, the effects can be summarized in the development and implementation of training programs, ethics committees, and structure modifications. The following list summarizes the contributions of trainees (total 50):

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Research projects: 64 Publications: 54 articles, 52 book chapters, 22 Web publications Websites development: 3 Health research norms: 26 Ethics of research programs at home institutions: 20 Creation of new scientific ethical review committees: 8 Participation as members in scientific ethical review committees at home institutions: 27 Participation in National Bioethics Commissions: 6

At the national level, the effects are more difficult to estimate. They depend in part on the personal influence each trainee may have in his/her local environment and the recognition of the importance of research ethics by officials and the public.

Lessons learned â&#x20AC;&#x201C; the future of ethics training within the research enterprise in Latin America As important as written materials, in and by itself a good demonstration of success and impact is the fact that both faculty and former trainees established an enduring collaboration which resulted in network programs and continued support. The impact and relevance of the program is framed in a context of realistic expectations, critical evaluation of different cultural inputs, and hands-on experience. Sharing knowledge, attitudes, and responsibilities ensures the two main values of the overall Fogarty program: appropriateness to the context and long-term sustainability. One important lesson learned from the experience was that the ethics of the research program did make a difference in the careers and outlook of participants. Many of them were able to install and develop ethical review committees and improve ethical oversight in their environments, but they also reported difficulties associated with their contribution. This fact shows that the incorporation of competent human capital into the institutions depends on appropriate conditions in the countries of origin. Individual factors and institutional variables account for different outcomes. It has been important to maintain contact and develop networking activities that reinforce the sense of leadership derived from the successful completion of the training experience. The experience was also valuable for faculty members. Interactions were not always easy, but everybody benefited from the effort, in ways that were

Ethics of Research Training: A Latin American Experience

sometimes unexpected. The interfaces with juridical systems, knowledge of funding procedures for research, the disclosure of sometimes hidden or unknown prejudices were results from the experience of interacting with professionals. There is still some mistrust of ethical oversight which may be due to faulty implementation, lack of adequate development of scientific ethical review committees or vested interests. The effort is worthwhile, the project has been rewarding to carry on, and the need is still growing.

A network for the advancement of biocentric ethics (1) The experience gathered throughout the years has demonstrated that an ethical approach to science and technology, in the current state of the development of disciplines, by necessity must incorporate specialized knowledge, be based on deliberation and dialog, and depend on an organic and cohesive community. This community includes researchers, policymakers, politicians, administrators, students, and lay people. Since research is a cultural process shaped by expectations, hopes, and practices, it cannot be examined in isolation from other aspects of social life. In point of fact, ethical oversight of research cannot be treated independently of the â&#x20AC;&#x153;ethical levelâ&#x20AC;? of the community at large. Political and administrative corruption, if present in a country and accepted as normal, cannot be irrelevant for the establishment of sound scientific practices. A sustainable effort depends critically on the establishment and maintenance of communities: Epistemic communities (or cultures), Practice communities and Moral communities. These communities do not necessarily overlap, although it might be expected that the moral one embraces the others and includes knowledge and its applications. Biocentric ethics is not simply another form of applied ethics. It represents a change in the paradigmatic construction of the moral universe. Not only does it go beyond classical anthropocentrism in the formulation of moral imperatives, it is knowledge of how to produce, expand, and apply knowledge. It is also an indication that the very foundation of welfare and progress includes a joint consideration of goals and means. Goals are formulated as culture and civilization. Means are legitimated by discursive practices respecting persons, living beings, and environment, accepting diversity and agreeing on basic principles of commonality. In order to achieve this long-term goal, adapted to the historical peculiarities of a world region, our contribution depends on dialog and common discourses. Research ethics is just a part of culture, and culture is life in common. The establishment of a network of users of bioethical discourse has been an important mission of CIEB and

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will continue to be in the future. Thanks are to be expressed to the institutions that make it possible (especially the University of Chile) and to the funders (NIH Fogarty, the Alexander von Humboldt Foundation, among others).

References 1. 2.

3. 4. 5.

6. 7. 8. 9. 10. 11. 12. 13. 14. 15.

Lolas F., Rodriguez E. “Ethics in psychosocial and biomedical research – A training experience at the Interdisciplinary Center for Bioethics (CIEB) of the University of Chile”. Acta Bioethica 2012; XVIII (1): 9-56. Rodriguez E.Aspectos cualitativos del aprendizaje en el Programa de Ética de la Investigación Biomédica y Psicosocial del Centro Interdisciplinario de Estudios en Bioética de la Universidad de Chile. Acta Bioethica 2012; XVIII (1): 57-62. Hesketh T. The 10/90 Report on Health Research 2003-2004 Global Forum for Health Research. Helping Correct the 10/90 Gap, Geneva, 2004. Ervin A-M, Taylor HA, Meinert CL, Ehrhardt S. Evidence gaps and ethical review of multicenter studies: Empirical research is needed to guide federal policy. Science (New York, NY). 2015; 350(6261): 632-633. Meert KL., Eggly S., Dean JM., Pollack M., Zimmerman J., Anand KJS., Newth CJL., Willson DF., Nicholson C. “Ethical and Logistical Considerations of Multicenter Parental Bereavement Research”. Journal of Palliative Medicine. 2008; 11(3): 444-450. Santesso N., Tugwell P. “Knowledge translation in developing countries” .J Contin Educ Health Prof. 2006 Winter; 26(1):87-96. Henk AMJ., ten Have (ed). Bioethics Education in a Global Perspective. Dordrecht: Springer, 2015. Lolas F. Bioética en la Universidad de Chile. Anales de la Universidad de Chile, Sexta Serie 1998; 8:13–18. Horng S., Grady C. “Misunderstanding in Clinical Research: Distinguishing Therapeutic Misconception, Therapeutic Misestimating, & Therapeutic Optimism”. IRB: Ethics and Human Research 2003 Jan-Feb; 25(1):11–16. Koepsell, David. Scientific Integrity and Research Ethics: An Approach from the Ethos of Science. Cham: Springer, 2017. Lolas, F. “Public health and social justice. Toward ethical sustainability in healthcare and research”. Acta Bioethica (Santiago) 2003; 9 (2): 189-194. Lolas, F. “Bioethical sustainability. Towards a value-based epistemic community in the life sciences and healthcare.” In UNESCO (Paris) National Bioethics Committees in action. UNESCO, Paris, 2010:113-115. Homedes N., Ugalde A. A review and Critique of International Ethical Principles. Research Ethics Forum, 2014:7-53. Rodriguez E., Lolas F. “The topic of research integrity in Latin America”. Bioethikos 2011; 5 (4): 362-368. Rodriguez E.,Lolas F. “Promotion of research integrity in Latin American Research Institutions”. Bioethics Update 2016 (2):115-24.

Ethics of Research Training: A Latin American Experience 16. 17.

18. 19. 20. 21. 22. 23. 24.

Minority Rights Group International. World Directory of Minorities and Indigenous Peoples. Overview; 2007. Online. UNHCR Refworld, available at: http://www.unhcr.org/refworld/docid/4954ce5723.html. German F., Schwartz-Orellana, SD., Zumaeta-Aurazo M., Costa DC., Lundvall JM., Viveros-Mendoza MC., Lucchetti LR.,Moreno-Herrera LL., Sousa LDC. 2015. Indigenous Latin America in the twenty-first century: the first decade (English). Washington, D.C.: World Bank Group. http://documents.worldbank.org/curated/en/145891467991974540/Indigen ous-Latin-America-in-the-twenty-first-century-the-first-decade. Kari_OcaDeclaration, Rio de Janeiro, 1992; Santa Cruz de la Sierra Declaration, Bolivia,1994 Ukupseni Declaration, Panama, 1997. http://www.prodiversitas.bioetica.org/doc33.htm Bruen C., Brugha R., Kageni A., Wafula F. “A concept in flux: questioning accountability in the context of global health cooperation”. Globalization and Health. 2014: 10:73. Barreto S., Miranda J.et al. “Epidemiology in Latin America and the Caribbean: current situation and challenges”. Int J Epidemiol. Apr 2012; 41 (2): 557-571. Hinman LM., Ethics: A pluralistic approach to moral theory. Belmont, CA: Wadsworth; 2004. Lolas, F. Bioethics. Moral dialog in life sciences. Editorial Universitaria, Santiago de Chile, 1999. Boud D., Cohen R., Sampson J. (eds.) Peer Learning in Higher Education. London: Kogan Page; 2001. Habermas J. Conciencia moral y acción comunicativa. Barcelona: Península; 1985.

CHAPTER 2 RESEARCH MISCONDUCT AND INTEGRITY IN LATIN AMERICA

Abstract This chapter reflects on the need to establish high standards in research integrity and monitoring mechanisms in Latin American Research Institutions in order to have an accurate science and for transferring research results to public policies, health promotion, and social progress. Most Latin American Research Institutions do not have an established system to detect and denounce research misconduct. The following problems are covered: the integrity of publications, reporting of scientific research misconduct, motivations for research misconduct, definitions of research integrity, scientific ethical review committees functioning, international multi-centric clinical trials monitoring and norms for scientific integrity and ethical oversight. The following mechanisms to promote research integrity are proposed: to promote a culture to enhance good research practices; to establish norms to maintain responsible conduct of research; to establish monitoring proceedings, and to establish mechanisms of support to confront demands of research misconduct.

Introduction Researchers and reviewers have the obligation to create, implement and inform about research results with honesty and integrity Research misconduct is one of the greatest problems that the scientific community faces since scientific progress is based on previous studies and when they are inadequate, the whole process must be started again. Research misconduct has enormous consequences which affect public trust in science. Scientific development is based on studies carried out by qualified professionals, who also must be ethically competent by respecting research

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subjects. The value of a research proposal is evaluated under scientific merit and ethical principles by competent peers and representatives of the community who must not have concrete or immediate interest in one result over another. In order for research involving human beings to be ethical, there are requisites which must be analyzed in order to respect and protect subjects, unnecessary risks must be avoided, subjects must be recruited with justice, there must be adequate informed consent procedures and confidentiality of personal data must be ensured. Bioethical thinking was initiated in response to criticism of the disregard for human dignity and rights in relation to research involving human beings. Bioethics became institutionalized in the U.S. and Europe in the form of norms, regulations, and corporate bodies (commissions and committees, IRBs) entrusted with their interpretation and application. A constructive contribution of Latin America requires sound oversight systems and science of high quality. Research quality depends on integrity and responsible conduct, but different conceptualizations between countries may affect collaboration. Translation of research evidence into public policies demands that researchers be aware of their role in a globalized scientific community and interact with their peers internationally at a comparable level of ethical competency. The â&#x20AC;&#x153;know-do gapâ&#x20AC;?, the discrepancy between knowledge and action, must be reduced not by imitation but through the realization of the social consequences of research. For many years, problems in research integrity have been discussed and detected throughout the world, and hence there is a need to promote good research practices in order to improve research quality. The numerous examples of research misconduct reported globally have questioned the efficacy of the scientific community to self-regulate and the ability of regulatory agencies to guarantee research integrity (1). This is paramount since precise and credible data are necessary in order to transfer scientific evidence to public policies and healthcare practice. There are holes in the efficacy of the review process. Biomedical and psychosocial research is required to undergo ethical review, either through national laws, professional codes of conduct or as a condition of sponsors, institutions, research agencies, or publishers. However, according to JNCI editor Barnett Kramer, ethical reviews and referees for journals typically examine study design and treatment of subjects, but it is difficult to determine whether the primary and raw data initially used in research studies are true (2).

Research Misconduct and Integrity in Latin America

In the U.S., the problem with research integrity has been recognized for a long time. An estimate of the scope of the problem may be found in a study questionnaire sent to NIH-funded PIs revealing that if the 167 scientists who had observed misconduct in the study were multiplied by the entire mass of scientific researchers the NIH supports, â&#x20AC;&#x153;the number of scientists observing incidents of suspected research misconduct in that population would be about 4650 incidents per year (3).â&#x20AC;? Studies of retracted publications on PubMed show that the main cause of retraction was misconduct (>65%), and the leading reasons were plagiarism, data management, data falsification/fabrication and compromise of the review process due to conflict of interest (4, 5). On the other hand, most Latin American countries do not have an established system for detecting and denouncing research misconduct, thus, it is difficult to know the frequency and scope of research misconduct in research institutions. But, there is a growing concern and mistrust of scientific enterprise among the population due to the denunciation of abuses and lack of ethical supervision in clinical research (6). Therefore, there is a need to establish mechanisms to guarantee research integrity. The ethics of the biomedical and psychosocial research program of the Interdisciplinary Center for studies on bioethics (CIEB) of the University of Chile over the last ten years has trained Latin American professionals (50 trainees) to assume active leadership in teaching, evaluating, designing and conducting ethically sustainable research, collaborating in the formulation of ethics of research regulations and the formation of scientific ethical review committees. Besides implementing institutional programs on responsible conduct of research, one of the fruits of such activities has been to collect data related to research integrity in Latin America, which we convey in this chapter (6, 7).

Research misconduct A scientist has the personal responsibility to research with honesty and objectivity while collaborating with a research team and also has social responsibilities to society, research subjects, sponsors, other researchers and to publish results (8). When responsibilities are not specified, the possibility of transgressions occurring increases. The Committee on Publication Ethics defines research misconduct as a violation of ethical and scientific standards in research professional practice

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(9). Research misconduct may occur at any stage of a research process, such as in the proposal, actual research, review or publication of results. Any member of the research team may commit misconduct, whether principal investigator, a collaborator, a technician or a field worker. There is research misconduct when a person doing or publishing research intends to deceive others by making them believe that a scientific result is true when in reality it is not. Therefore, research misconduct involves not only an omission or an act but also a deliberate intention to deceive (10). Typically, research misconduct includes fabrication, plagiarism, and falsification when proposing, carrying out or reporting research results (11, 12). Fabrication consists of reporting invented (partially or completely) data not obtained by experimentation. Falsification refers to the manipulation of research data, equipment or processes, or changing or omitting research results which affect the accuracy of the study. Plagiarism refers to appropriating ideas, processes, results or words of others without giving appropriate credit. In addition to these flagrant research faults, there is growing concern over the existence of conflict of interests in the research enterprise which may introduce biases in presenting and analyzing results. There is conflict of interest when a secondary interest (money, prestige, family care, and social promotion, political or religious beliefs) may prevail over what is considered primary interest (knowledge, teaching, research, promoting healthcare and subject well-being) compromising moral conduct when carrying out a study or when disseminating results (13). Furthermore, there is a long list of research misconduct practices in which there is need to pay attention to a precise and exact science, such as (14, 15): • • • • •

Not fulfilling protocol steps approved by a scientific ethical review committee Negligence in preventing avoidable risk or damage to humans, experimental animals or the environment Breaking confidentiality without authorization Lack of credit to research data of others which contradict own results Not including or giving appropriate credit to authorship

Research Misconduct and Integrity in Latin America

• • • • • • • • • •

Hiding methodology or results in details so that others will not be able to repeat the experiment Inadequate research design Inadequate record keeping Giving false information to the public Taking advantage of the peer review process to put obstacles in the way of the research of a competitor Ignoring specific vulnerabilities due to cultural factors of the studied population Circumventing certain minor aspects of human-subject requirements Overlooking others' use of flawed data or questionable interpretation of data Serious persistent negligence Accepting conclusions under subjective assumptions

Motivations for research misconduct In the past in the international setting, the alarm about scientific misconduct of cases such as the Tuskegee study of syphilis paid attention to the inhuman treatment of research subjects in the name of advancement of scientific knowledge but currently intentional misconduct appears to be associated with personal reasons, such as reactions to a negative work environment, or personal gain, either for reputation or financial gain (16, 17). There are many possible motivations behind research misconduct. The different roles in research may influence the kind of misbehavior. For example, a principal investigator may be pressed to publish or to obtain financing, a post-doc may be in a hurry to finish his/her study, field workers or research collaborators may be lazy, careless or unprepared to fulfill the research protocol. The following motivations have been reported:

1. Institutional causes The environment in the workplace may influence motivation. Insecurity and bad relations among research team personnel may cause negative attitudes towards research, not taking the work done seriously, being careless and employing little effort to improve it (18, 19). Institutions may press researchers to produce results in publications and financing. This is usually exerted to evaluate their performance and to gain

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promotion (20, 21). The lack of institutional support, and when research process norms are considered unfair, may lead to research misconduct in a collective way (22). Lack of communication or institutional management and insufficient supervision may also influence research misconduct (18).

2. Personal motivations The Office of Research Integrity of the United States found in a review of reported cases of research misconduct the following personal motivations: insufficient time, excessive workload, stress, wanting to fulfill supervisor expectations, lack of support, insecurity, frustrations, having personal problems, difficult tasks or looking for success (18).

3. Financial motivations According to Antes and collaborators, most studies that link individual factors to ethical decisions are related to financial gain (23). Some examples of this are psychosocial research studies where social inequalities are used as a resource to select study populations, due to their easier access and management, without taking into consideration that the studies may damage the populations, with the only goal to publish and gain financing (10). Obtaining profit by preferring a research result may affect the responsible conduct of research. A systematic review of the relationship between financial support origin and the result of a study and the level of evidence shows an association between industry sponsoring, the existence of financial conflicts of interest and a low level of evidence (24). Publications financed by private industry tend to report results preferred by the sponsor (25).

4. Ideology Ideology consists of personal or social structural ideas that shape expectations, actions, and goals by which reality is interpreted. Ideology introduces bias in interpretation and may influence how results are evaluated and presented in the publication, and it may even lead to research misconduct (26). In the field of biotechnology, for example, it is apparent that ideology influences the way results are presented. On one side, scientists linked to industry present idealistically the use of genetically modified organisms under a liberal economic ideology. On the other side, ecologists present data under the ideology of a sacred nature. Both sides do not engage in dialog and do not take into account the position of the other.

Research Misconduct and Integrity in Latin America

5. Social motivations In low-income countries, local field workers may feel subversion due to social reasons in protest against situations of unequal employment, labor injustice, excessive workload and low socioeconomic conditions. This may influence their relationship with researchers of developed countries thereby provoking inadequate management data and even fabrication (27). The field worker considers that he is being unfairly treated thus affecting his/her dignity, and subversion may be a form of defense or empowerment of the weak and fabrication becomes a way to show who is deciding results (28). When the field worker is treated with respect and is paid adequately, the situation changes, and the field worker becomes more efficient. Some research malpractices may be related to cultural factors, such as lack of understanding of local scientific norms in the case of foreign students who have been educated in a different way (29). Others, based on data from the Office of Research Integrity in the U.S., in which many of those found guilty of research misconduct are foreign researchers, consider that they come from a different culture where the end rather than the means is emphasized (30).

6. Psychological motivations An individual character may influence ethical decision-making (31). Persons with psychological problems may be too emotional and experience anxiety. Narcissists in particular have difficulty with personal integrity (32), since they have the need to be admired and to have power, lack empathy and behave egotistically by taking advantage of others (33). The research environment may strengthen the ego tendency due to competition and the need to be respected by colleagues and students. They may feel that they are experts and think that nobody will be able to discover their manipulations. The researcher with narcissistic tendencies may absolutely believe that his/her hypothesis is the true answer in spite of research data. The so-called â&#x20AC;&#x153;messianic complexâ&#x20AC;? has been argued as inducing research misconduct due to favoring a belief or particular theory thinking that they may be saviors in solving specific problems (34).

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Table 2.1: Research misconduct motivations (compiled by the authors) Personality problems

Social

Work environment

Pressures

Dishonest character

Subversion

Lack of time

Economic

Frustrations

Ideology

Lack of supervision

Prestige

Messianic complex

Lack of training

Institutional conflicts

Requirement for publishing

Research integrity in Latin America Latin American institutions have advanced in recent years by incorporating ethics in research committees and norms for carrying out research involving human beings but there is still much to be done to develop accurate research oversight mechanisms. In the case of research integrity, it is apparent that there is a lack of mechanisms for denouncing and for probing their veracity. In research, informed consent is accepted as a requisite for subject participation, but often the practice is reduced in many cases to signing a document which is internationally required, but without regard to respecting the process that the subject truly understands the study. Often researchers have little understanding of what they should include in informed consent: risks and benefits are poorly defined, inclusion and exclusion criteria for subjects are not defined, and the language used is too technical. Because of the difficulty in denouncing and probing veracity it is difficult to know the prevalence. Furthermore, when some cases are denounced, institutional directors minimize the facts or hide them to avoid being discredited. In the case of publications, there are limits related to lack of policies to safeguard ethical issues by many editorial committees of Latin American journals and the information about these topics is very limited (35). For plagiarism, there are sporadic reports of editors retracting a publication and some institutions have incorporated the policy to ban students from a program for plagiarism (36, 37). A study in Medline databases by Stretton and collaborators shows that plagiarism is more common in lower income countries than in developed countries (38). In Peru, there is a high frequency of plagiarism in thesis publications of university students and this leads to many denouncements (39, 40). A study

Research Misconduct and Integrity in Latin America

in Brazil shows that there are disagreements on what should be regarded as plagiarism; is it a matter of counting the words that are copied and then drawing a line under it or just verbatim copying with the intention to deceive the reader about who is the real author, involving theft of intellectual property (41). Furthermore, Brazilian researchers considered that copying a text was less serious than copying data and they also recognized that writing in English, a language they do not master, influences the tendency to copy texts (41). Lack of clear rules for preventing plagiarism contributes to exacerbating the problem (42). Most Latin American countries lack â&#x20AC;&#x153;offices of research integrityâ&#x20AC;? where denounces can be made for scientific misconduct, although in some countries they are emerging, such as in Colombia, where there is a Commission for intellectual property and a government agency for denounces. In the following paragraphs, we describe some conditions which merit the need to organize research integrity offices in Latin American countries (6): A) Publications Many Latin American scientific journals are not integrated into the science citation index system, they do not contain guidelines for ethical considerations, and they do not follow international uniform recommendations, such as the International Committee of Medical Journals Editors. Thus, for example, in an analysis of scientific Brazilian journals, only 21% contained instructions about the use of informed consent, ethical principles and the requirement to be approved by a scientific ethical review committee (43). In an attempt to correct this situation several journals have elaborated editorial ethical codes (44). Some journals have incorporated retraction due to research misconduct. Revista MĂŠdica de Chile, for example, has retracted articles due to redundant publications, plagiarism, and lack of recognition of conflicts of interest or forging (45). Retractions are slowly being incorporated in other countries as well, such as Peru, Brazil, and Argentina (46-48). B) Public-based registration of protocols The obligation to register clinical trials has been fulfilled in Latin America since 2003 by incorporating them into LATINREC of the Cochrane web (http://www.latinrec.org). Pharmaceutical trials register phase II and III trials carried out in Latin America in the U.S national web (http://www.

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clinicaltrials.gov). The problem is that often these databases are not used by scientific ethical review committee members to know if protocols were previously presented and rejected in other countries before approving a new trial. C) Limitations of Scientific Ethical Review Committees The following problems have been identified: 1) Lack of monitoring mechanisms due to time restrictions of members and lack of funding or mechanisms to pay monitors. 2) Lack of sufficient infrastructure and funding to carry out activities and excessive workload of members to carry out their function adequately. 3) Some committees do not have all the required members, often there is not an adequate member representing the community. 4) In some countries, committees have no authority to interrupt a clinical trial that presents serious adverse events. 5) Most scientific ethical review committees do not oversee informed consent procedures such as an adequate degree of literacy and understanding by subjects and verifying lack of pressure to consent before forms are signed (49). 6) In some academic institutions, thesis protocols of research involving human beings presented by students are only evaluated by tutors, not by a scientific ethical review committee, since it is considered an academic exercise, but human subjects are involved with little ethical supervision. 7) Lack of culture and structure for Scientific Misconduct Reporting. Whistle blowing reprisals are a problem with denounces. When scientific misconduct is revealed by colleagues, many times they do not denounce them due to the lack of confidence in the mechanisms to solve these issues both for denouncing and judging them. In Colombia, even though there are mechanisms, there is a reticence to denounce due to fear of reprisals (50). Furthermore, the regulatory agency INVIMA (National Institute for Drugs and Food Surveillance) has tried to regulate clinical research but does not have the necessary structure and financing to carry out this task. In Ecuador, there is an Honor Tribunal for presenting denounces, but its decisions are not binding. Nonetheless, there are cases of publicly denounced corruption related to the management of the healthcare service and research. In Argentina, there have

Research Misconduct and Integrity in Latin America

been cases of violations of the norms without punishment for several years (51). These are currently corrected with the creation of the regulatory agency ANMAT (National Administration of Drugs, Food and Medical Technology). A case with international impact was denounced at Hospital Naval Pedro Mallo in Buenos Aires with physician Luis Garre, who was the principal investigator of a clinical trial with the experimental drug Cariporide developed by Aventis Pharma. Garre falsified informed consent documents and electrocardiograms with the aim to include patients in the research protocol, taking advantage of the research fee paid by Pharma for each patient participating in the protocol. Since patients did not receive the right treatment, some died (52). Some cases denounced in the Dominican Republic by one of the CIEB trainees show the lack of experience some countries have in dealing with research oversight (6). The National Bioethics Committee CONABIOS approved a study using UV light irradiation as therapy for patients living with HIV/AIDS, carried out by researchers with no experience in this type of therapy, without provision for training and no plan for safety tests and quality control. Other cases show that some research protocols involving human beings are not reviewed by scientific ethical review committees. For example, in 2007, a researcher declared to have attempted to find a cure for AIDS without having submitted his research protocol to CONABIOS as is requested by the General Health Law. The Public Health Secretary confiscated the experimental drug which was not registered in the Agency for Drugs and Pharmacy, closed the laboratory and punished the physician (53). Although infrequent, a case was denounced in Chile for not complying with the norm for approval of protocols by a scientific ethical review committee; it involved an international study carried out without proper informed consent. The GENADIO project, a collaboration of the Universities of Glasgow (Scotland), Chile and Concepcion, Chile, aimed to find causal relations between health state and nutrition, lifestyles and environment, including genetic studies. As part of the methodology, blood samples were taken from persons of the indigenous Mapuche community to study the prevalence of obesity and diabetes, but they were not informed that the samples were going to be analyzed by genetic sequencing. The Mapuche Parliament Koz rejected the project due to lack of approval by regional authorities and for lack of a guarantee prohibiting genetic manipulations (54). In Guatemala, there are cases of researchers, denounced by a CIEB trainee (6), that carry out the same research with different sponsors with few changes, for the sole purpose of having a salary. Often patients are coerced

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by offering them free treatment with an experimental drug, knowing that they do not have access to regular treatment because of poor economic conditions. D) Problems with definitions The definitions of research integrity have some degree of ambiguity. Standard definitions of misconduct-fabrication, falsification, and plagiarism (ORI) or integrity – “the fundamental principle that scientists be truthful and fair in the conduct of research and the dissemination of research results” (CRI) do not cover miscellaneous examples. Broad definitions of research misconduct need to be narrowed to include conducts “that are not generally part of normal practice in science, where a single performance of this act is sufficient to be labeled as misconduct, and that the intent to deceive is implicit in the act itself (55).” Conflicts of interest are another example of an ambiguous area in research ethics. Cultural differences in Latin America with respect to developed countries merit a specific analysis for the region. E) The increase of Multi-centric International Research International clinical trials have grown in the last decade in Latin American countries due to the interest of pharmaceutical companies in improving costeffectiveness; enhancing patient recruitment and enrollment capability. The creation of research regulatory agencies and a system of ethical oversight by local ethical review committees have contributed to the increase in clinical trials. International contract research organizations have also contributed to the promotion of clinical research (56). Research is increasingly performed in international networks, but complex issues have to be taken into account in order to provide adequate ethical oversight. Cultural factors influence the way ethical oversight is performed and how research practice is performed. Developing countries may not have the same rigorous standards in ethical oversight as those of developed countries due to “poor funding and lack of properly trained staff” (57). Latin American countries offer large patient pools for diseases, thus ensuring rapid recruitment and reduction of time for completing trials, but regulations are weak and lack of qualified policymakers and scientists creates an imbalance between what is offered to communities and the actual benefits in terms of manpower development or economic support (58). Often, the agency of vulnerable individuals, populations and groups is not sufficiently addressed in the ethical review process with consideration to the low scientific literacy and the pressing need for health treatment (59). Issues of conflicts of interest, data management, publication, and authorship, are not given proper

Research Misconduct and Integrity in Latin America

attention and local researchers have little participation as authors (60-62). Hyder et al. have reported more preoccupation for confidentiality on the part of the U.S. IRBs (Institutional Review Boards equivalent to scientific ethical review committees) than the host country IRBs (63). The identification of adverse events in clinical trials may be influenced by cultural factors causing underreporting (64). F) Lack of sufficient regulation for scientific integrity and ethical oversight Many countries in Latin America lack an organized system for denouncing, preventing and punishing research misconduct. They do have regulations for ethical oversight in health research, but they lack sufficient qualified professionals to conduct an ethical evaluation. Countries like Argentina, Brazil, Chile, Colombia, Costa Rica, Mexico, Nicaragua, Peru, and Venezuela comply with norms, codes and policies for ethical oversight, but they do not focus on the ethical review of protocols or on monitoring the research process. The following problems have been identified: 1) In some countries, scientific ethical review committees are created for approving or rejecting research protocols but they lack a system for accreditation. 2) In general, regulatory agencies lack enough funding for monitoring activities and sufficient infrastructure to guarantee the fulfillment of norms in Good Clinical Practices (65). 3) Some Latin American countries need to create a public national register of previous research. 4) In some countries, there are national bioethics commissions, but there is confusion about their role and formation, due to political interference. G) Conflicts of interest Conflicts of interest may be defined as a situation in which a secondary interest (Money, prestige, care of family, social promotion, traveling, political or religious beliefs) prevail over the primary interest (advancing knowledge, service, teaching, research, healthcare promotion, well-being of research subjects) compromises moral conduct when carrying out a project or writing a report (66). Due to the increase in research financed by private companies, the links between professionals and companies have increased,

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so that the risk for an economic type of conflict of interest is high. In Latin American countries there are often too few specialized professionals in healthcare fields and they have low salaries, which increases the likelihood of being tempted by financial gain. Financial conflicts of interest may consist of: being a consultant, having company shares, job offers, incentives, patents, among others. Conflicts of interest may cause bias by affecting the mental state of researchers and cause them to lack objectivity in interpreting and collecting results. Biases may influence the way research questions are selected, how the research is designed, how subjects are selected, how adverse events are reported and how data are published. However, the existence of a conflict of interest only implies the potential for bias and risk to compromise research integrity, but it is different from research misconduct since this implies the evidence of a fault committed (67). There are ways to prevent falling into bias or research misconduct when there are conflicts of interest such as supervision or double-blind design in clinical trials, for example. The first strategy consists of transparency when declaring conflicts of interest. This is requested by editors when publishing in international research journals (68) and by country regulations. But in Latin America, the practice of declaring conflicts of interest has only been introduced recently and is being implemented slowly. Table 2.2: Negative consequences of research misconduct for: (compiled by the authors) Persons

Sponsors

Researchers

Institutions

-Risk of damage, death, an adverse event in research involving human beings for subjects -Indirect risks for subjects due to postponing or discontinuing healthcare treatment -Lack of confidence in science in general

-The accuracy of data is compromised -Delay in approving a product -More research and additional financing

-Retraction or correction of publications -Fired from institution or status decrease -Lack of financial support -Ending of a career

-Suspension, closing, legal allegations

Research Misconduct and Integrity in Latin America

Mechanisms to promote research integrity In order to prevent scientific misconduct, researchers must build a professional moral character, practice honesty in advancing knowledge and have a sense of social responsibility. But the mechanisms to promote research integrity fall also to research institutions since the environment affects the researcherâ&#x20AC;&#x2122;s behavior. Institutions must comply with norms for ethics oversight, and train professionals in responsible conduct of research, diminish institutional pressures and comply with support mechanisms. The following mechanisms may help to promote research integrity (7):

1. Promoting a culture to enhance good research practices Training in the responsible conduct of research should be required for scientists carrying out research in order to safeguard them from research misconduct and affirm the values of honesty, accuracy, and objectivity, and avoid biases. In general, honesty, efficiency, and objectivity are highly valued by scientists (69), but pressures to publish and ambitions may influence research misconduct. While researchers as individuals are the main focus of preventing research misconduct, the institutional environment is also important. At the institutional level, relationships and power differences among colleagues are important, since reporting misconduct may be difficult due to fear of professional repercussions (70). The culture to be built is not only institutional. Society as a whole also affects the researcherÂ´s behavior. When there is no culture of transparency or of confronting moral misbehaviors in the society in general, research misconduct tends not to be reported. The development of this culture depends on educational, social and political factors, such as: values and attitudes transmitted, sufficient financing and support for ethics of research training, a system for monitoring, regulations to protect research subjects, transparency and accuracy in reporting research results, as well as a positive work environment (71).

2. Norms to maintain responsible conduct of research Lack of institutional policies for research integrity has been associated with the recurrence of retractions (72). Research institutions should provide management norms to promote responsible conduct of research, in this way minimizing the risk of misconduct. Norms must be in accordance with country regulations covering quality control, safety measures, safeguarding

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privacy and confidentiality, risk management, resources management and rules for respecting research subjects. Research materials and data must be managed according to legal requirements and contractual agreements with norms about safety, maintenance, storage conditions and availability for auditing or transfer to other institutions or abroad. Institutions are particularly important for providing safe facilities for storage of research data and records. The management structure must specify the roles, responsibilities, and liabilities of all involved in research, with provisions for the retention of data and research materials. Intellectual property rights must be protected with specific norms for assigning rights. In collaborative research between institutions, there must be norms for agreements on financial management issues, intellectual property, authorship and publications, scientific ethical review approval, the ownership of data and equipment. Furthermore, institutions must have written norms about the management of conflict of interest, including rules for full disclosure in order to prevent biases in research results.

3. Monitoring proceedings Monitoring research when it is carried out is an effective way to ensure compliance. Institutions must comply with supervision mechanisms. One way consists of empowering ethical review committees to carry out monitoring activities, which requires training the members and budgeting for expenses incurred. Another way is to hire specialized groups for monitoring and charge the research sponsor with the expenses. Currently, most institutional ethical review committees do not carry out monitoring visits due to lack of financing of this activity by the research enterprise: Furthermore, members of ethical review committees lack time and training. In general, committees only carry out the ethical review of proposals before the commencement of the study and when they receive information on adverse events and sometimes of changes in research procedures (73). For this possibility to be effective, scientific ethical review committees must be professionalized and accredited. Monitoring activities may include (7): -

Supervising the progress of the study Guaranteeing that research staff members know their obligations and the regulations applied to the study

Research Misconduct and Integrity in Latin America

Guaranteeing that research staff members fulfill the research protocol Guaranteeing that the research site has the necessary equipment and materials to carry out the study Supervising the process of informed consent and appropriate respect for research subjects Guaranteeing the accuracy of data and their safety to safeguard confidentiality

Monitoring procedures may be replaced by auditing, but in countries where there is a regulatory agency, generally it audits a few clinical trials, but there is no auditing for other types of research.

4. Mechanisms of support to confront demands of research misconduct In order to promote research integrity in Latin American institutions, support mechanisms must be provided to manage allegations fairly, with written norms of procedures for presenting and verifying them. Scientists who commit research misconduct may face sanctions which may hamper their career; sanctions include being fired, not receiving further research funding or incurring a negative professional stigma (74). Therefore, there is an institutional obligation and responsibility to carry out the procedures in a fair way. The system of allegations must be structured with offices where allegations can be presented, staff are available to verify them and management can maintain records of processes carried out (7). A legal advisor may help prepare necessary evidence, advise on how to question witnesses or make suggestions when the problem is not related to research misconduct. It is important that the officer designed for verification must not have conflicts of interest with the parties and the institution must give him authority to obtain relevant documents. There must also be a mechanism for disciplinary actions in agreement with institutional requirements for employees should allegations be verified (19). The person denounced must have the opportunity to defend himself and the possibility of appealing. A statement must be written explaining the allegation, contain the report that verifies the claim and the reasons for taking disciplinary actions. Where publications or public records have been disseminated, corrections must be made and publications retracted. If the allegation has no basis, the institutions must

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look for a way to restore the reputation of the researcher who has been denounced.

Conclusion Lack of confidence in the scientific enterprise may damage social development, public health, and healthcare progress. Scientific knowledge is built on previous studies and research designs, and when these are found to be inaccurate, the whole process becomes stagnant. Clearly, ensuring research integrity requires building an institutional framework which currently does not exist in most Latin American institutions. The first difficulty is the lack of resources for financing, but in the long term, it may be argued that to build a framework to guarantee accuracy in science saves time and money by increasing credibility and avoiding repeat flawed experiments. Some challenges which must be focused on in order to promote research integrity are: -

To design transparency indicators on research integrity in research institutions and a methodology to evaluate those indicators. To design and implement courses and workshops for training researchers and students in university curricula about ethical issues and the practice of responsible conduct of research. To promote a culture that allows minimizing scientific misconduct risks in research development. To develop monitoring mechanisms. To create networks for disseminating the ethics of research programs. To promote the interest of researchers in the ethics of research issues.

Research in Latin America requires not only ethical codes and guidelines, but respect for subjectâ&#x20AC;&#x2122;s rights particularly and a true commitment to the research process by researchers, sponsors, subjects and scientific ethical review committees. Research integrity will only come alive with public debate and reflection about scientific advances, while preserving human dignity and autonomy.

Research Misconduct and Integrity in Latin America

References 1. 2. 3. 4. 5.

6. 7. 8.

9. 10. 11. 12. 13. 14. 15.

16. 17.

Aultman JM. “Abuses and Apologies: Irresponsible Conduct of Human Subjects Research in Latin America”. Journal of Law, Medicine and Ethics 2013; vol. 41, no. 1:353-368. Vastag B. “Cancer Fraud Case Stuns Research Community, Prompts Reflection on Peer Review Process.” Journal of the National Cancer Institute 2006; 98(6):373–376. ORI, Gallup Organization. Final Report: Observing and Reporting Suspected Misconduct in Biomedical Research, 2008. Campos-Varela I. and Ruano-Raviña A. “Misconduct as the main cause for retraction. A descriptive study of retracted publications and their authors”. Gac Sanit. 2018 Jun 5. pii: S0213-9111(18)30072-4. Moylan, EC., and Kowalczuk, MK. “Why articles are retracted: a retrospective cross-sectional study of retraction notices at BioMed Central”. BMJ 2016; Open, 6(11), e012047. http://doi.org/10.1136/bmjopen-2016012047. Rodriguez E., Lolas F. “The topic of research integrity in Latin America”. Bioethikos 2011; 5 (4): 362-368. Rodriguez E., Lolas F. “Promotion of research integrity in Latin American Research Institutions”. Bioethics Update 2016; 2:115-24. Motallebifard A., Navehebrahim A., Mohabbat H., Sadin A. “Diagnosis and scientific framework development of peer review: A qualitative approach”. Journalism Library Science and Information Science and Information Technology 2013; 22(3): 73-84. Committee on Publication Ethics (COPE).“Guidelines on good publication practice”. Clinical Oncology 2000; vol.12, no. 4: 206-12. Jaffer U. and Cameron AE. “Deceit and fraud in medical research”. International Journal of Surgery 2006; vol. 4, no. 2: 122-6. U.S. Department of Health and Human Services, Office of Research Integrity, Fed.Reg.76262. Pimple KD. “Six domains of research ethics. A heuristic framework for the responsible conduct of research”. Sci Eng Ethics 2002; vol. 8, no. 2: 191205. Thompson DF. “Understanding financial conflicts of interest”. New England Journal of Medicine 1993; vol. 329: 573-576. Sponholz, G. “Teaching scientific integrity and research ethics”. Forensic Science International 2000; 113(1): 511-514. Council of Science Editors (2012). “Description of research misconduct”. https://www.councilscienceeditors.org/resource-library/editorialpolicies/white-paper-on-publication-ethics/3-1-description-of-researchmisconduct/ Martinson BC., Anderson MS., Crain AL., de Vries R. “Scientists’ perceptions of organizational justice and self-reported misbehaviors”. Journal of Empirical Research in Human Research Ethics 2006; 1:51–66. Giles J. “Breeding Cheats”. Nature 2007; 445:242–243.

42 18. 19. 20. 21. 22. 23.

24. 25.

26. 27. 28. 29.

30. 31. 32.

33.

Chapter 2 Mark S., Davis MS., Morris M., Diaz S. “Causal factors implicated in research misconduct: Evidence from ORI case files”. Science and Engineering Ethics 2007; 13: 395-414. Morrison RS. “Disreputable science: Definition and detection”. Journal of Advanced Nursing 1990; 15(8): 911-913. Goodstein DL. “On Fact and Fraud: Cautionary Tales from the Front Lines of Science”. New Jersey: Princeton University Press, 2010. Office of Research Integrity. Available at http://ori.hhs.gov/content/handbooks-and-guidelines. True G, Alexander L B, et al. “Misbehaviors of front-line research personnel and the integrity of community-based research”. J. Empir. Res. Hum. Res. Ethics JERHRE 2011; 6 (2), 3-12. Antes A., Brown P., Murphy S., Waples E., Mumford M., Connelly S., Devenport L. “Personality and Ethical Decision-Making in Research: The Role of Perceptions of Self and Others”. Journal of Empirical Research in Human Research Ethics 2007; 2(4):15–34. Amiri AR., Kanesalingam K., Cro S., Casey AT. “Does source of funding and conflict of interest influence the outcome and quality of spinal research”? Spine J 2014. Feb;14(2):308-314. Bailey CS., Fehlings MG., Rampersaud YR., Hall H., Wai EK., Fisher CG. “Industry and evidence-based medicine: Believable or conflicted? A systematic review of the surgical literature”. Can J Surg 2011. Oct;54(5):321-326. Goodstein DL. On Fact and Fraud: Cautionary Tales from the Front Lines of Science. New Jersey: Princeton University Press, 2010. Kingori P., Gerrets R. “Morals, morale and motivations in data fabrication: Medical research fieldworkers views and practices in two Sub-Saharan African contexts”. Soc Sci Med 2016 Oct; 166:150-159. Scott JC. Weapons of the Weak: Everyday Forms of Peasant Resistance, Yale University Press, New Haven, 1985. Meyer WM. and Bernier Jr., GM. “Potential cultural factors in scientific misconduct allegations”. In N. H. Steneck and M. D. Scheetz (Eds.), Investigating research integrity: Proceedings of the first ORI research conference on research integrity 2002, Rockville, MD: Office of Research Integrity. Davis MS. “The role of culture in research misconduct”. Account Res. 2003 Jul-Sep;10(3):189-201. Vastag B. “Cancer Fraud Case Stuns Research Community, Prompts Reflection on Peer Review Process”, Journal of the National Cancer Institute 2006; 98(6):373-376. Mumford MD. and Helton, WB. “Organizational influences on scientific integrity”. In N. H. Steneck & M. D. Scheetz (Eds.), Investigating research integrity: Proceedings of the first ORI research conference on research integrity2002, Rockville, MD: Office of Research Integrity. Diagnostic and statistical manual of mental disorders, Fifth Edition. https://doi.org/10.1176/appi.books.9780890425596

Research Misconduct and Integrity in Latin America 34. 35. 36. 37. 38.

39. 40. 41. 42.

43.

44. 45. 46. 47. 48.

49.

Lock S. “Fraud in medical research”. Journal of the Royal College of Physicians of London 1997; 31(1): 90–94. Palacios M. “Mortalidad evitable de manuscritos científicos”. Editorial. Colombia Médica 2010 Abril-Jun; Vol 41(No. 2). Reyes H., Palma J., Andersen M. “Ética de las publicaciones en revistas médicas”. Revista Médica de Chile 2007; 135:529–533. Guillén Fonseca M. Información. Revista Cubana Enfermería. 2006;22(1) Rojas Ochoa F. Publicación duplicada o redundante [editorial] Revista Cubana Salud Pública 2006; 32(4). Stretton S., Bramich NJ., Keys JR., Monk JA., Ely JA., Haley C., Woolley MJ., Woolley KL. “Publication misconduct and plagiarism retractions: a systematic, retrospective study”. Current Medical Research and Opinion 2012; 28 (10): 1575-1583. Saldana-Gastulo J., Quezada-Osoria C., Pena-Oscuvilca A., et al. “Alta frecuencia de plagio en tesis de medicina de una universidad publica peruana”. Rev Peru Med Exp Salud Publica 2010; 27: 63-7. Huamani C., Mayta-Tristan P., Rodriguez-Morales AJ. “Irregularidades eticas en la investigacion estudiantil”. An Fac Med (Lima) 2008: 69:146. Vasconcelos S., Leta J., Costa L., Pinto A., Sorenson MM. “Discussing plagiarism in Latin American science. Brazilian researchers begin to address an ethical issue”. EMBO Reports. 2009; 10(7): 677-682. Vasconcelos S. “Aumento do plágio em produções científicas preocupa pesquisadores em todo o mundo. O Estado de S. Paulo”. Universidad Federal Rio de Janeiro 2011. http://saude.estadao.com.br/noticias/geral,aumento-do-plagio-emproducoes-cientificas-preocupa-pesquisadores-em-todo-o-mundo,692874. Trajano S., Müller S., Pereira Hamilton R., Oliveira Reinaldo A., Hossne William S. “Análisis de los aspectos éticos de la investigación en seres humanos contenidos en las instrucciones a los autores de 139 revistas científicas brasileñas”. Acta bioethica 2000 Dic;6(2):293–307. Palacio M. Editorial “La obligación del editor en relación con el fraude científico” Colombia Médica 2008 Enero-Mar; Vol. 39(Nº 1). Reyes B., Humberto. “Ethical problems in scientific publications”. Revista médica de Chile 2018; 146(3): 373-378. Mayta-Tristan P., Curioso WH. “Polı´tica editorial ante la deteccio´ n de una publicacio´ n redundante”. Rev Peru Med Exp Salud Publica 2009; 26: 5-8. Pereira JH., de Oliveira JS., Canduri F., et al. “Interaction of shikimic acid with shikimate kinase”. BiochemBiophys Res Commun 2004; 325: 10-17. Retraction in: BiochemBiophys Res Commun 2005; 334: 967. Barboza M., Duschak VG., Cazzulo JJ., et al. “Presence of sialic acid in Nlinked oligosaccharide chains and O-linked N-acetylglucosamine in cruzipain, the major cysteine proteinase of Trypanosoma cruzi”. Mol BiochemParasitol. 2003; 127: 69-72. Retraction in: Mol BiochemParasitol 2003; 129:215. Palacio M. Editorial “La obligación del editor en relación con el fraude científico” Colombia Médica 2008 Enero-Mar; Vol. 39(Nº 1).

44 50. 51. 52. 53. 54. 55. 56. 57. 58.

59. 60. 61. 62. 63. 64. 65. 66. 67. 68.

Chapter 2 Cardozo de Martinez CA. “Retos y dificultades de los Tribunales Disciplinarios”. En Boletin Tribunal Nacional de Etica en Odontología. www.tribunalnacionaldeetica.org. Giardinelli M. “La pobreza del lenguaje es parte de la tragedia argentina (Reportaje)”. LaNación.com. 2004 May; Available in: http://www.lanacion.com.ar/650334. DeYoung Karen, Nelson Deborah. “Latin America is ripe for Clinical Trials and Fraud”. The Body Hunters Washington Post 2000 Dec; A01. SESPAS “someterá a la justicia al doctor Báez Acosta”. 2007 Monday July; elviajero.com.do/nacionales/sespas-sometera-a-la-justicia-al-doctor-baez. Parlamento de Koz Koz. Panguipulli. 2008. Feb. 20. Grinnel F. “Ambiguity in the practice of science”. Science 1996; 272:333. Rettig RA. “The industrialization of clinical research”. Health Aff. (Millwood) 2000; 19(2): 129-146. Nuffield Council on Bioethics. The Ethics of Research Related to Healthcare in Developing Countries. London, UK: 2002. Heitman E, Petty J. “Preparing students to navigate cross-national differences in the research environment”. (Ch. 15) In: Anderson MS., Steneck NH., (eds.) International Research Collaborations: Much to be Gained, Many Ways to Get in Trouble. Routledge, New York: 2010: 201–214. London L. “Ethical Oversight of Public Health Research: Can Rules and IRBs Make a Difference in Developing Countries?” American Journal of Public Health 2002; 92, no. 7: 1079-1084. Drane J., Fuenzalida H. “Medical ethics in Latin America: a new interest and commitment”. Kennedy Institute of Ethics Journal 1991; (4):325–338. Serrano D., Linares AM. “Principios éticos de la investigación biomédica en seres humanos: aplicación y limitaciones en América Latina y el Caribe”. Bol. Oficina Sanit. Panam. 1990; 108(5/6):489-499. Lavados M., Salas S. “Problemas éticos en los proyectos de investigación biomédica presentados al Comité de Ética de la Escuela de Medicina de la Universidad Católica de Chile”. Rev. Méd. Chile 1997; 125:1011–1018. Hyder AA., Wali SA., Khan AN., Teah NB., Kass NE., Dason L. “Global Research Ethics. Ethical review of health research: a perspective from developing country researchers”. Journal of Medical Ethics 2004; 30:68-72. Ptak LR. “The globalization of clinical research”. Journal of Pharmacy Practice 1996; 6:418. Thompson DF. “Understanding financial conflicts of interest”. New England Journal of Medicine 1993; 329: 573-576. Kassirer JP., Angell M. “Financial conflicts of interest in Biomedical Research”. New England Journal of Medicine, 1993; 329: 579. Drazen JM., Van Der Weyden MB., Sahni P., Rosenberg J., Marusic A., Laine C et al. Uniform Format for Disclosure of Competing Interests in ICMJE Journals. Published at www.nejm.org October 13, 2009. Office of Inspector General, U.S. Department of Health and Human Services. The Globalization of Clinical Trials: A Growing Challenge in

Research Misconduct and Integrity in Latin America

69. 70. 71. 72. 73.

74.

Protecting Human Subjects. Washington, D.C: DHHS; 2001: 10. (http://oig.hhs.gov/oei/reports/oei-01-00-00190.pdf) Stenek NH. Introduction to the Responsible Conduct of Research 2006. http:/ori.hss.gov/education/products/RCRintro/ Geller G., Boyce A., Ford DE., Sugarman J. “Beyond ‘compliance’: the role of institutional culture in promoting research integrity”.Acad Med. 2010 Aug;85(8):1296-302. Rodriguez Yunta E. “Cultura ética e investigación en salud”. Acta bioethica 2005; vol.11, no.1: 11-22. Fanelli D., Costas R., Larivière V. “Misconduct Policies, Academic Culture and Career Stage, Not Gender or Pressures to Publish, Affect Scientific Integrity.” PLoS ONE 2015; 10(6): e0127556. Leon-Correa, FJ. Etica Clinica y Comites de Etica en Latinoamerica, FELAIBE, Fundación Ciencia y Vida, Santiago de Chile, 2011: 1-327. http://www.bioeticachile.cl/felaibe/documentos/libros/congreso/FELAIBE %20Comites.pdf. National Academy of Sciences, National Academy of Engineering (U.S.) and Institute of Medicine (U.S.) Committee on Science, Engineering, and Public Policy. On Being a Scientist: A Guide to Responsible Conduct in Research: Third Edition. Washington (D.C): National Academies Press (U.S.); 2009. RESEARCH MISCONDUCT. Available from: https://www.ncbi.nlm.nih.gov/books/NBK214564/

SECTION II: CHAPTERS ISSUES IN GENOMIC RESEARCH

CHAPTER 3 SOCIAL, ETHICAL AND LEGAL ATTITUDES TOWARDS GENOMIC RESEARCH IN LATIN AMERICA

Abstract The present chapter reflects on social representations of genomic research and its applications. Several issues are addressed: little access to prevention and therapeutic methods, lack of equity in health benefits, commercialization of gene sequences through patents which leads to commercial exploitation of underdeveloped countries, the possibility of physical or psychological damage or genetic discrimination, the possibility of genetic modifications or abortion for eugenic reasons, anxiety or hostility towards genomic modifications, the necessity of safeguarding confidentiality, risks and benefits of the use of genetically modified organisms, legal restrictions and regulations of access to genetic information.

Introduction Genomics is defined as the study and use of genomic information and technologies, coupled with other biological approaches and computational analyses, to advance our understanding and knowledge of genes and genome function. Since the release of the draft sequence of the human genome (1, 2), many advances in human health have been developed in relation to genomics, leading to new conceptualizations of health. Thanks to the development of next-generation DNA sequencing (NGS) technologies (3), the human genome has been mapped in many individuals. Identification of the genes and DNA sequence variants that underlie inherited susceptibility to rare and common human diseases has led to fundamental advances in understanding the molecular basis of these diseases. "Genomic medicine" has been developed using genomic information and technologies to determine disease risk and predisposition, diagnosis and prognosis, and the selection and prioritization of therapeutic options (4). With the new

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genetic tools, it is possible to identify the underlying genetic determinants for every disease, get insights into the pathology and etiology of the disease, and look for appropriate treatment and ways of preventing the disease. The high-throughput sequencing and sequence-capture technologies have provided new opportunities to study Mendelian disorders through exome sequencing and whole genome sequencing (5). Data from Genome-wide association studies (GWASs) which compare populations that have a particular disease with control groups without the disease in order to identify genetic differences have enabled the identification of a large number of disease genes underlying common diseases (6). Identification of the disease gene in single-gene disorders has increased knowledge about disease development, enabling precise molecular diagnosis; and, in a small number of cases, given rise to new targeted therapies. The stratified or personalized use of medicines employs pharmacogenetic or pharmacogenomic tests (7), to stratify a patient group according to their predicted responsiveness to a particular treatment. Stratified use of medicines helps to improve the effectiveness of treatments by targeting individuals who will respond well to a particular treatment based, for example, on genetic tests, or by excluding individuals who are predicted to have an adverse reaction to treatments. The possibility of knowing the genetic constitution of individuals opens up a range of ethical, legal and social issues. Persons can be characterized by their genes and DNA sequence, which can give information, for instance on paternity and health status, making them susceptible to discrimination and stigmatization (for example: stereotyping, showing prejudice, increasing health insurance fees, employers avoiding hiring someone). There are numerous bioethical issues to take into account in order to satisfy research needs and guarantee data protection. Issues of privacy and safeguarding confidentiality and differences in the understanding and perception of risks are culturally determined (8). Personal genomic information has become an important tool for decision-making related to health and behavior. Genetic testing may diagnose current disease states at all stages of development, carrier status for transferring certain genetic traits to offspring or may predict late-onset disorders related to specific mutations in persons without symptoms of disease (9). Genetic tests raise serious issues related to health treatment, policies for public health and social access related to who will be informed and how the tests will be implemented (10). There is also concern over the potential impact on public health of the growing tendency to offer genetic tests directly to consumers through the internet because of their little predictive power and the information delivered that affects health and genetic risks without consultation to healthcare professionals that interpret

Social, Ethical and Legal Attitudes towards Genomic Research in Latin America

results (11, 12). Personal identifiers or community/population identifiers may cause problems in safeguarding confidentiality over sensible issues which risk the possibility of social stigmatization or discrimination. Furthermore, living organisms are used as models for fighting infections by making them more resistant, or studying diseases, and for developing genetically modified organisms to improve crops and cattle or as bioreactors to produce products of human therapeutic value. The biotechnological industry is growing enormously due to the creation of genetically modified organisms, and profits from patenting. The present reflection is based mainly on data on the social representations of genomic research and its applications obtained through interviews with scientists, legislators, lawyers, students from journalism and engineering careers and civilians in four countries: Argentina, Chile, Mexico and Peru and on data originating from the biomedical and legal literature in these countries as part of a project supported by the U.S. Department of Energy (Grant DE-FG02-02ER63435) (13-17). The issues raised by genomic research can have major social, legal, political, economic and cultural repercussions which can involve not only specialists but lay people as well.

Advances in genomic research in Latin America In general, there is an impression that Latin American countries are not prepared to respond to the explosive development of genomics and genetic engineering which has taken place in developed countries. There is little interest in most Latin American governments for research in this area since they believe that other priorities are more important. As a result, Latin American countries act mostly as consumers with the added problem of the little information that lay civilians possess. There is also a lack of legal norms to regulate this field in general. This contributes to the generation of a certain anxiety since there are fears that certain issues raised by the expansion of genomic research could be manipulated and used for the interests of a few. In general, developing countries are left behind in biotechnology and genomic medicine development, but there are some exceptions in Latin America such as Brazil, Cuba, Argentina and Mexico in the development of genomics. Cuba has linked biotechnology to its healthcare sector. Brazil represents the biggest market in Latin America. Argentina is moving

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towards being a force in Latin America in the transgenic market. Mexico has recognized the potential for genomics in addressing public health issues. Brazil has 71 Biotechnological Companies, most working on transgenics and some have developed genetically engineered healthcare products, such as insulin, vaccines, kits for diagnosis and immunization; since 1998 the Human Genome Project for Cancer has functioned under the sponsorship of the Ludwig Institute of the United States and the Foundation for Research Protection at Sao Paulo (Fundaciรณn de Amparo a la Investigaciรณn del Estado de Sao Paulo FAPESP) (18). Brazil created the Genomic Institution ONSA in 1997, which unites several laboratories. The first development was sequencing the first Latin American microbial genome, the bacteria Xylella fastidious (19). Furthermore, several projects have been initiated which link universities and research institutions with regional agriculture and health problems. Examples are the sequencing of Chromobacterium violaceum, a human pathogen; the sequencing of Herbaspirillumseropedicae of farm value; the sequencing of RNA transcripts of human cancers; and the sequencing of RNA transcripts of the disease caused by Leishmania chagasi (20). An example in Cuba has been the development of the first human vaccine with a synthetic antigen for meningitis B. The vaccine against Hemophilus influenza type B (Hib) infection made in Cuba is a much cheaper and safer product than other existing vaccines. This was possible due to the commitment and involvement of government bodies, public research institutions, universities and the health system (21). Argentina has used its Intellectual Property Rights laws to develop the pharmaceutical sector for competition in the global marketplace and constitutes an example of a developing country moving forward in creating national guidelines, approval procedures and research institutes to evaluate the risks of genetically modified organisms. Argentina has sequenced the genome of Trypanosoma Cruzi. The country commercializes genetically modified organisms and complies with technology for genetic diagnosis of human diseases. The Campomar foundation performs research on the genetics of cancer. The Laboratory BioSidus S.A. produces biotechnological proteins with human health value. Genomic medicine has become a priority for the Mexican government as a means of finding new strategies to tackle common diseases. Thus, in 2003, Mexico launched a plan to develop a genomic medicine program which led to the establishment of the Institute of Genomic Medicine and a National

Social, Ethical and Legal Attitudes towards Genomic Research in Latin America

Platform for Genomic Medicine which has modified the healthcare system (22). As a result of this program, Mexico has genotyped over 1200 people from different regions of the country and studied possible relationships between genetic make-up and health problems with greater burden, such as macular degeneration, hypertension, obesity, infectious diseases, cancer, diabetes and cardiovascular diseases, with the potential to reduce healthcare costs. Chile has also favored the development of genomic research, which is coordinated by the National Commission for Science and Technology. Several universities, as well as biotechnology companies, participate in research, producing genetically modified organisms in agriculture. Examples are potatoes which are genetically modified for resistance to viral and bacterial diseases, such as Erwinia caratovora; development of a bacterial strain Corynebacterium glutamicum which overproduces trehalosa. Chile is also working on the genetic characterization of current and antique indigenous populations, studying mummies, and also specific mutations and genetic markers for particular diseases, such as cystic fibrosis, diabetes, and cancer (23, 24). Genomic research in Peru is coordinated by the National Council of Science and Technology with an International Center for Genetic Engineering and Biotechnology. Even though there are low resources, genomic research in Peru has studied genetic markers of disease resistance, such as diabetes type II, mental disorders and Mendelian diseases of the Peruvian population in collaboration with foreign institutions.

Social representations of genomic research by Latin American stakeholders The following considerations are highlighted on the social representations of genomic research and its applications obtained through interviews with scientists, legislators, lawyers, students and civilians in four countries: Argentina, Chile, Mexico and Peru (13): Biomedical researchers appreciate more the benefits of the human genome project, but they see or experience the lack of governmental support for research. They point out the falsehood of genetic reductionism or determinism which overvalues the role of genes causing practically all human behaviors. Human beings cannot be reduced to their genetic constitution, without considering the influence of the physical, cultural and social environment. Also, they advise genetic counseling when taking

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health decisions related to genomic tests, since these are difficult decisions which may generate anxiety. University students worry about the lack of equity in access to genomic medicine in the population and the instrumentation of human beings. Lawyers and legislators are worried about the regulation of genetic information because of its possible manipulation by power interests, of possible eugenic selection of embryos (elimination due to their genetic constitution) and of possible genetic discrimination by health insurers and employers. They consider that genetic information may give rise to social stigmatization since persons will be characterized as sick by their genetic constitution without manifestation of the disease, and this information may be used by employers and insurers to discriminate by increasing insurance fees or not employing those most susceptible to disease. They worry about how access to genetic information is controlled and the mechanisms of counseling. Lay civilians fear that genetic manipulation may take away God's role in human creation since new babies would be designed according to human will not by natural means. Commercialization of genetic products for agriculture, for example, is seen as negative by all groups since it will benefit mostly the international biotechnological companies and not local farmers. Table 3.1 Degree of worry about the use of genetic information according to issue (High>20%; Low <10%) (compiled by the authors) Issue

Lawyers

Scientists

Civilians

Students

Discrimination Enhancement Power (instrumentation) Inequity Godâ&#x20AC;&#x2122;s Role Lack of support Eugenics Lack of information

High Middle High

High Middle Middle

Low Low Middle

Low Middle Middle

High None Low Middle Middle

High None High Low Low

Low Middle Low None Middle

Middle Low Low None Low

Social, Ethical and Legal Attitudes towards Genomic Research in Latin America

In general, human reproductive cloning is negatively valued by all groups. It is associated with lack of singularity, since clones will be genetically identical to their parental nucleus; a form of manipulation or using human beings as means to an end (role in society defined before the clone is born); as a source of power by using clones for example for war or as servants; or as altering human behaviors by making clones more aggressive or having psychological problems; some lawyers and legislators see it as an instrument of power, which should be prohibited since certain genotypes would be chosen by those who take decisions using clones for purposes such as war or as means for an end, while others consider that it needs to be regulated. Among lay civilians, influenced by what they see in the media, they believe that a human clone does not have a soul because it would be a replication of a being already in existence and that a clone is an exact copy of a person including his/her personality and conscience. Therapeutic cloning (the use of clones for culturing embryonic stem cells and posterior organ transplantation), however, is seen as beneficial for its potential in organ transplantation by some scientists, but others criticize it indicating that this technique manipulates human beings by using them just as a source of organs. Biomedical researches and lawyers worry about the commercial mentality associated with genetic research and the fact that it may lead to an increase in the gap already existing between developed and underdeveloped countries. In biotechnology, there are worries due to the commercialization control of a few companies, the fact of patenting living beings and because of the alteration of the natural equilibrium. Nevertheless, researchers see benefits in the generation of transgenics for increasing productivity and enhancement of properties for cattle and agriculture, such as vigor, duration, nutrition, and plague resistance. Lay civilians and university students tend to consider genetically modified organisms as dangerous for health, especially for inducing cancer, and as artificial, which is equated to lack of trustworthiness for consuming them. With respect to participating in genomic research as subjects, most respondents would accept being enrolled in a study when the study has a therapeutic component, maybe because it has a chance to benefit them. Researchers are interested as well in scientific advancement and would accept more genetic enhancement for reasons related to beauty and intelligence. Reasons given for refusing to participate in genomic research are: fear of instrumentation or being treated like guinea pigs, fear of physical damage, lack of knowledge of what it means to be a research subject,

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acceptance of oneself and oneâ&#x20AC;&#x2122;s weaknesses so that no change in genetic content is necessary, or lack of previous studies being made on humans. Table 3.2 Degree of acceptance as genomic research subject according to purpose (high > 20%; low <10%) (compiled by the authors) Issue

Lawyers

Scientists

Civilians

Students

Treatment Enhancement Knowledge Against Nature Acceptance of oneself (no change)

High Low Low Low High

High High High None High

High Low Low Middle Middle

High Middle Low Low High

Content analysis of verbal behavior in interviews using the Gottschalk and Gleser method (25) can measure levels of anxiety and hostility. Data from our group (13) show an inverse relationship between the level of anxiety and the level of knowledge. The group which produces the greatest level of total anxiety is that of the retired lay civilians who have very little knowledge of genomics, followed by lay civilians, university students, lawyers, and legislators. Biomedical researchers have the least anxiety. Mutilation, guilt and shame anxieties present the greatest levels. Mutilation is associated mainly with the fear of being subjected to genetic manipulations which will affect health. Guilt is mostly associated with moral disagreement towards certain forms of genetic manipulation such as cloning or eugenics. Shame refers mainly to lack of knowledge about genetic research and to personal private information which should not be shared by others, but it is not explicitly disapproved. With respect to hostility levels, external hostility is most present in lawyers and legislators associated with aggressive behavior occurring in solving litigations and in their worries for genetic discrimination. Lay retired civilians present the greatest level of inner hostility towards themselves because of feeling not worthy. They also show the greatest ambivalent hostility of others to them because of feeling discriminated against or disrespected by others, probably associated with their situation of lack of social support in general in Latin America. Retired civilians may feel discriminated against and they lack self-esteem.

Social, Ethical and Legal Attitudes towards Genomic Research in Latin America

Latin American publications: Social, legal and ethical issues The application of genomic research can have social, legal and ethical consequences, both in personal and familial spheres and also in broader collective spheres which can affect societies and communities.

1. Personal, familial and social issues It is expected that knowledge of the human genome will offer new ways for prevention, diagnosis, and treatment of diseases with a hereditary component. There are many possible advances in genomic medicine. However, presently there are no preventive or safe therapeutic measures for most hereditary diseases in contrast with the development of the diagnostic and predictive capacity of genetic probes (26). This raises the issue that some genetic information may be unwanted by some individuals since it will generate unnecessary anxiety due to lack of preventive or therapeutic solutions. Even though genomic research and its applications are positively viewed, it is recognized that there are manipulations contrary to human dignity and fundamental human rights which demand regulation by legal norms and sanctions. It is feared that the idea of genetic determinism and the power of genetic technology may engender the myth of perfect health leading to abuses in developing countries with poor resources and low understanding of the real power of genetics (27). There are also concerns related to the resurgence of eugenics, like the practice of eugenic abortion and embryo selection, for other than medical purposes (28, 29). Genetic modifications, in general, carry greater risks than benefits. For example, with respect to somatic gene therapy, there is a high risk associated with the intervention, thus it is recommended only for serious diseases without a cure. Among the risks pointed out are: interference with normal genes, induction of cancer, short time activity of genes introduced, induction of mutations and viral infections (30). Caution is expressed for genetic modifications in the germ-line, be it for therapeutic reasons or for enhancement, since it may alter the integrity of human genetic patrimony by introducing undesired alterations and because of lack of consent for future generations (26, 31, 32). On the other hand, if the technique is perfected it might be beneficial in helping to eradicate diseases for future and present generations (33, 34). Genetic modifications leading to enhancement are viewed as non-ethical since their use in the present cultural

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circumstances will aggravate social differences due to their restricted access to those who can afford it. Even though genomic research and its applications are positively perceived by Latin American publications, it is recognized that there are genetic manipulations contrary to human dignity and fundamental human rights, which demand regulation through legal norms and sanctions. The creation of human and animal hybrids and human reproductive cloning is negatively perceived, so there should be regulation, criminalization, and penalization (35). Among the problems carried out by human cloning, the following are highlighted: lack of freedom, being manipulated by design, problems with personal identity, power and control by those who create the clones, problems with family and social relations, manipulation of womenÂ´s gestation (36-40). Nevertheless, scientists point out that an absolute clone is impossible since there is other genetic information in the cytoplasm and epigenetic factors that contribute to differences between clones (41). The biography of a person may produce differences in personality due to the plasticity of the central nervous system. Therapeutic cloning is more accepted if there are applications for health (42, 43). Embryonic cells may be used with the purpose of treating diseases, but their detractors consider that a human being is being used as an instrument to create an organ reservoir for another. Another topic refers to the privacy of genetic data since this information can be used as an instrument of power by third parties (44). The protection of genetic information implies that only the person from whom it is derived can authorize the use. The principle of autonomy must prevail unless there is a criminal cause or risk of damage to others, in which case a court order can overrule the confidentiality of the data. The tendency today is that health and personal data are maintained in electronic records. This constitutes an advance, but sensible data must be safeguarded by confidentiality agreements. Informed consent is required for any genetic test. In genomic studies, researchers must establish clearly who will have access to the information and what the uses of the sample taken will be, including possible future research. The individual genetic information poses peculiar characteristics as it may be partially shared by family members, race or ethnic group. There is a risk associated with the divulging of genetic information due to the possibility of social stigmatization and genetic discrimination. Regulations are needed to prescribe the way in which genetic information, including informed consent and sanctions for inadequate disclosure of information will be used, while also establishing

Social, Ethical and Legal Attitudes towards Genomic Research in Latin America

exceptions for invading privacy, for example, criminal liability by court request (45). Among the negative consequences of lack of privacy is the possibility of genetic discrimination, particularly in the area of health insurance and employment. There is concern that employers may avoid hiring workers with particular diseases based on genetic tests or that insurers may establish their fees based on the results of genetic tests (46, 47). However, the reality in Latin America is that currently there are very few court cases due to genetic discrimination and there is little danger of adverse selection in Latin America with respect to the customer knowing more than the insurance company. Nevertheless, legislators suggest regulating against employers and insurers requiring genetic tests (48). Employers and insurers should be prohibited from requesting genetic tests prior to contractual agreements. In general, the genetic information on diseases is considered a sensible issue, subjected to confidentiality norms. For safeguarding confidentiality, it has been recommended that genetic data be kept separate from medical records until security systems are developed (49). Another important aspect of confidentiality of genetic data refers to, on the one hand the patientâ&#x20AC;&#x2122;s "right to know" which involves access to all genetic information referring to one's health and on the other hand, the "right to ignore" especially when there is no treatment or preventive measures for a particular disease, as it may generate unnecessary anxiety (50). The decision to know or to ignore belongs to each patient. Even though genomic information is considered a shared human patrimony, personal genetic data must be considered the property of the person from whom information has been taken, so he/she decides who can have access to the data (44). States must recognize and respect that personal genetic information belongs to the individual from whom it has been extracted; otherwise, there is a risk of manipulation (51) As technology has evolved and become more cost-effective, genetic testing services have been introduced in Latin America (52-54). The market for genetic tests has increased, but there is little protection for consumers. A socially responsible transfer of such technologies to Latin America requires handling a number of social challenges: (1) Large inequalities in income and medical literacy. (2) A rapidly growing demand for private healthcare due to large cuts in the public healthcare sector. (3) Consent procedures may be less stringent in the private sector due to a lack of regulation.

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(3) Public institutions have increasing difficulty in curbing malpractices by growing commercial entities. (4) Strong public demand to have access to over-the-counter medical products. (5) There is a different readiness to disclose information when such disclosure can help to avoid fraud. (6) There are a low number of genetic counselors so that the counseling is mostly done by a physician.

2. Indigenous populations issue Consent to collect biological samples from indigenous groups is a sensitive issue due to their vulnerability and the value they give to body parts, especially blood samples (55). Furthermore, there is generally a requirement to ask for consent from elderly leaders. Several problems arise: how informed consent has been obtained since the concept and purpose is difficult to understand by many indigenous populations, who will own the genetic samples, how intellectual property rights of indigenous people will be protected since there are no international policies or regulations governing the trade of human genetic materials, and who will profit from the commercialization of products derived from the samples. Several declarations of indigenous populations in Latin America manifest opposition to the collection of blood samples used for DNA characterization (56). In Chile research with blood samples taken from the Mapuche led to a protest by ethnic leaders (57). The studies carried out in Mexico to determine genetic variation and susceptibility to diseases of Mestizo populations were highly questioned due to their little applicability for the health of Mexicans and because of political differences in funding research (58).There have been complaints that samples of Brazilian ethnic groups are sold by the U.S. Coriell Institute of Medical Research (59).

3. Pharmacogenomic issues Pharmacogenomics may be used to improve speed and efficiency in drug development. Drug safety and efficiency studies are complemented with exploratory genomic tests to identify biomarker predictors of drug response, which avoids having to use those with drug resistance or low response in tests.

Social, Ethical and Legal Attitudes towards Genomic Research in Latin America

In Latin American countries there are practical problems in the application of information gathered in pharmacogenomic studies. Several issues hamper application, such as (60): a) Lack of sufficient clinical laboratories available to carry out tests in a rapid and cost-effective way. b) Insufficient healthcare professionals able to interpret results of tests and associated clinical pharmacology. c) Doubts whether insurance or healthcare systems will subsidize the tests. In general, a population with low income does not have access to genetic tests. The low healthcare budget determines other priorities. d) Lack of information about pharmacogenomic genes in the population of Latin America in general, especially of the variety of ethnic groups in the region. e) Lack of governmental support. f) Post-marketing surveillance of drug response may pose problems in controlling unknown adverse events if clinical trials are performed in smaller more targeted patient populations since there will be less available data about potential adverse drug reactions in the general population when the drug is made available (61). Genotyping as a criterion for inclusion and exclusion may lead to those excluded losing benefits and less participation of populations with the genotype of low response. Selecting populations may establish categories of persons or groups which may be subjected to stigmatization or discrimination. Furthermore, the pharmaceutical industry may be reluctant to develop medicines for small groups of patients. Currently, rare diseases are grouped into “orphan medicines” due to the lack of interest for investment. Pharmacogenetics may extend the number of orphan medicines by stratifying the patient population into genetic base subgroups. The proponents of personalized medicine pretend that the reduction of costs in clinical trials by using genomic information to select those less susceptible to adverse effects but including minorities may increase the expenses in drug development (62).

4. Genetically modified organisms – issues There are objections to the commercialization of genetically modified organisms since the tendency is to use the genetic richness of Latin American natural products for patenting new organisms in developed countries. This can have negative effects on Latin America´s agriculture

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since plant patents can be used to restrict access by biotechnological companies and change farming practices. There is excessive control by biotechnological companies and in general, genetically modified organisms have advantages over conventional crops due to their special properties, such as greater vigor and resistance to insects or to bacterial infections. It is argued that biotechnological companies use genetic material from Latin American countries to create genetically modified organisms and commercialize them by taking advantage of their minimal regulatory mechanisms. Biotechnology has come under sharp criticism and media focus for its potential negative impacts and contingent risks due to its potentiality to change the course of nature and life. Questions are raised by the use of the new biotechnology applications such as whether it will assure sustainable development, affect biodiversity and environmental ecology, create new diseases, or whether the genetically modified organisms are made to suit market needs rather than to help the poor. Many biotechnological companies from developed countries may use developing countries to test crops designed for the needs of developed countries, not necessarily those of the developing countries. This is more serious when the lack of controls to protect the environment in many developing countries is considered. Although there is interest in Latin American countries in developing better crop yields, achieving nutrition needs and for reducing the need to spray pesticides, the biotechnological companies tend to play down the difficulties that countries may have in managing the environmental risks posed by genetically modified organisms. Patenting organisms and their DNA promotes the concept that life is a commodity and the view that living beings may be considered as â&#x20AC;&#x153;gene machinesâ&#x20AC;? to be exploited for profit. Patents derive from concepts of individual innovation and ownership, which may be foreign to cultures which emphasize the sharing of community resources and the free exchange of goods and knowledge. Genomic technologies by their very nature represent a challenge to existing values and systems and induce changes in traditional concepts of nature. There are worries about the possible effect of a decrease in biodiversity because of the use of genetically modified organisms in agriculture. The causes of this decrease are many, but in relation to the current system are related to the substitution of traditional varieties with high genetic diversity by transgenic seeds with a high degree of uniformity (63). An example of this is what is happening in Argentina, where the agricultural production system has become dominated by the transgenic crop Roundup Ready soybean. This crop is resistant to the herbicide glyphosate and relies on

Social, Ethical and Legal Attitudes towards Genomic Research in Latin America

repeated herbicide applications to control weeds. But nature finds ways to evolve around it. Already, strains of Roundup-resistant weeds have appeared in Argentina, requiring ever-heavier doses of the herbicide, which kill off microbes and degrade soil quality. Heavy herbicide applications and widespread planting of Roundup Ready soybeans have also led to increases in pest and disease severity. The rate at which forests in Northern Argentina are being turned into soy plantations is 3-6 times higher than the world average. This massive destruction of forests has sparked violence and protests by agrarian families and is changing the local climate to a semidesert causing both droughts and flooding (64). Monoculture makes a country very vulnerable to environmental changes. Furthermore, Argentina has faced pressures from Monsanto to pay royalties for the use of the transgenic soybean, claiming to be the only holder of patents for the soybean, even though this patent has not been recognized in Argentina. Monsanto has threatened Argentina with a fine of 15 dollars for each ton of soybeans exported to Europe. In Argentina, farmers have the right to keep and reuse seeds, established by the law for seeds. Since 1999 Monsanto has a norm expressed by its distributors to charge a percentage for reusing seeds (“extended royalties”). Due to the pressures of Monsanto, the Minister for Agriculture of Argentina presented a law proposal for “global royalties”, called Funds for Technological Compensation. By this mechanism, the government applies taxes to farmers to safeguard the interests of multinational companies. Due to the protest of farmers, this law has not passed, but Monsanto threatens to charge greater fees in the ports of exportation entry. Another issue is that transgenic soybeans have passed through smuggling from Argentina to Paraguay and Brazil. Monsanto has managed to ensure that in these countries the transgenic soybeans have been legalized and royalties paid (65). Another important point is that part of the advocacy done by environmentalist groups and the fears expressed by the civil society are focused on arguments that are not always scientifically sound. The idea of rejecting genetically modified organisms because of being artificial or that human beings act against the sacred laws of nature by introducing genetic modifications cannot be sustained. If we were to follow this ideology we could not consume most of the world's cattle and crop production, since human beings have manipulated animal and plant genomes for many centuries forming hybrids, inducing mutations and selecting varieties artificially. In a poll carried out by FAO in Latin America, it was found that civilians have a negative perception of transgenic food due to lack of knowledge on how they are generated, lack of confidence toward biotechnological international companies, fear of unknown innovations, lack of confidence toward

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regulatory measures and the threat to biodiversity (66). Countries look for safeguards to avoid the commercialization of unsafe crops. In Montreal, in January 2000 a biosafety protocol was signed. It governs transgenic world trade so that any country has the right to deny the commercialization of certain transgenics if there is reasonable scientific evidence of risk to health or environmental damage. Nevertheless, it is not clear if these rights will enter into conflict with the free market defended by the World Trade Organization. However, there are some studies which show possible toxic risks or adverse effects on health because of consuming transgenic food (67). Some of the potential adverse effects identified are allergy, resistance to antibiotics, lack or modification of the nutritious value of food, the presence of toxic components, the emergence of new non-treatable diseases and possible damage to wild species (68, 69). There is, therefore, an ethical exigency for guaranteeing test trials for every transgenic introduced in the market. Some technologies are viewed as not respecting nature. An example is a terminator genetic engineering technology that causes plants to release a fatal toxin in the second generation of seed, so they cannot reproduce themselves, introducing infertility (70). Genetically engineered fish and shellfish pose additional ecological risks since aquatic organisms have the capacity to survive in nature, moving easily from the controlled environment to the wild. In Chile, for example, there is concern over the possible industrial use of a transgenic salmon with growth hormone, which grows much faster than wild salmon, which may compete with native species supplanting them and deploying ecosystems by high-grade food consumption (71). The arguments for and against transgenics are based on visions of the new technology from widely different ethical perspectives, involving scientists, philosophers, commerce, politicians, journalists, religious and lobby groups and the public. These arguments involve values and the controversies have polarized society into proponents and opponents, with once seemingly trustworthy and ethically sound scientists being viewed with suspicion by many. In the polemics, differing beliefs intervene, questioning topics such as the role of God and the sacred attribution to nature; and also, power relationships, such as the immense power of biotechnological companies and the ownership of life forms through patents.

Social, Ethical and Legal Attitudes towards Genomic Research in Latin America

With respect to the patenting of human genes, legal, ethical and intellectual legitimacy are at the center of conflicting debates (36, 72) arguing that the current tendency to patent human gene sequences has resulted in the progressive loss of limits between invention and discovery, and is opposed to the principle of non-commercialization of the body and its parts. Bergel considers that this practice manipulates human genetic information with commercial interests, while others agree with the patenting of human genes on the basis that it can further innovation (73). But the countries which possess the technology and are governed by a comprehensive patent system control and dominate the market and are appropriating information that is shared by all human beings. Table 3.3 Perceived effects of genomic research (compiled by the authors) Human cloning

Transgenics

Genetic tests

-Singularity loss

-Ecological disequilibrium

-Discrimination

-Instrumentation -Behavior problems -Prohibition

-Biodiversity decrease -Health damage -Bio-safety problems

-Stigmatization -Eugenics -Inequality -Confidentiality break

Media role New technological advancements have modified the role of information in society giving it extra power and responsibility. Although there is public awareness of genomic issues, it is misleading due to the lack of formal education on genomics and of information based on real facts. Media may treat genomic issues in a sensationalist way, provoking a misbalance between the media agenda and public needs. This leads to a lack of citizen consciousness over some threats that genetic material faces and the health risks that it involves and other threats that are over exaggerated; thus, some authors suggest that important aspects of genetics such as toxic effects for the environment which affect humans are not considered public health needs due to lack of media coverage (74). Media may portray an additional charge of imagination to scientific facts. For example: movies presenting human clones as aggressive, Jurassic park presenting the resurgence of extinct

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species. Transgenics have been presented emotively, with talk of "Cashing in on Hunger", "Demon Seeds", "Terminator Technology" and "Frankenstein Foods" (75). Rather carelessly presented accounts of genetic engineering developments by the media have aroused concern that human health will be adversely affected by the consumption of transgenic crops and products derived from them (76). On the other hand, other press reports seem to favor industry interests. Transgenic use appears without risks and enhancement characteristics are viewed positively, while scientific reports on possible negative effects on the environment are not presented (77). Media provide information in a horizontal or vertical way, horizontally provoking dialog through the internet in which all may intervene equally but with knowledge gaps; and vertically expressing the views of experts and the voices of those with a special interest which may manipulate the direction of thinking. The internet is used by non-governmental organizations to raise awareness on abuses and injustices committed by the use of transgenic food which may be useful in some instances, but in others, it may provoke negative attitudes towards transgenic food consumption without critical thinking. Since there are myths appearing in the media which may distort the public analysis, it is critical to focus the discussion on a wide scoping and integrative perspective, engaging the scientific community, together with other public sectors in a debate associated with the positive and negative aspects of new discoveries around the human genome and the use of transgenics. This is imperative since the scientific advances do not by themselves cause the social problems; rather they are caused by the decisions that society takes in terms of how technological advances are used.

Role of bioethics Bioethics has a role in clarifying the complex topics of social consequences derived from problems with the use of genomic research products and information. The bioethical debate over the present and prospective applications of genetic research and the social consequences of access to genetic information must be based on a rational background derived from scientific data and philosophical reflection. Clearly, lack of knowledge and reflection creates anxiety. Therefore, it would be helpful to improve information about these issues in a critical way at all levels of society. The

Social, Ethical and Legal Attitudes towards Genomic Research in Latin America

globalization of information and the information given by the media about genetic issues increase the possibility of encouraging public participation in bioethical debates on these issues. But public debate is limited by lack of knowledge, the sensationalism of media portrayals and the fundamentalism of religious beliefs. There are also interest power groups which manipulate the debate with their own ideology. Therefore, we recommend the need to educate lay people on genomic issues and the social implications, clarifying in particular the real and tangible benefits and risks of biotechnology. There is a real need to avoid or clarify conflicting issues such as the natural/artificial split, since some popular press tends to equate artificial to evil. Bioethics represents an adequate instrument for the critical analysis of scientific activity. We consider that bioethics should not be a discourse only for experts, but the ideal medium to achieve exchange between laypersons and experts. Bioethics is dialogical par excellence, understanding dialog as an exchange of opinions among those affected as equals. Law, as a normative system has the function to safeguard order and propriety in society, which points towards its justification by principles and arguments based on morals in order to be accepted. Bioethics reflection has a role in pointing out areas in need of regulation. For example, there is need for legal regulation in order to control the possibility of arbitrary genetic manipulations contrary to human dignity. There is also little regulation for the introduction of genetically modified organisms; some are still under evaluation for safety and nevertheless, they are introduced as if their safety were already established. While there are no reports of these organisms producing cancer or causing physical damage in human beings, there are questions to be answered; questions such as the impact on biodiversity or the possible transfer of genes from one species to others with properties not wanted in wild plants such as resistance to herbicides or to insects or microorganisms. Bioethics has the role not only of applying the four core principles to clinical cases under an interpersonal perspective in genomic medicine but to see the issue of genomics as a social issue. Topics such as ownership and patents, genetic manipulation, allocation of resources, public policies for regulating genetic manipulations in humans and living beings require the involvement and reflection of the whole society (78). The globalization of genetic banks is creating new concerns over group interests since genetic information has

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effects beyond individuals and may modify the meanings associated with the terms ‘individual’ and ‘community’. Concepts such as solidarity, benefit sharing, equity, public participation, and collective identity need to enter into the bioethics debate (79). The issue of responsibility towards future generations is a new challenge in genomics derived from the genetic technological progress which makes it possible to introduce genetic variations affecting future generations, which calls for bioethical reflection. Hans Jonas has reflected on this principle, which affects not only humans but also all living beings (80). The increasing power of biotechnology has created concern raising the issue of responsibility, in the sense that with greater power there is greater responsibility for avoiding evil and channeling technology towards good goals (81). Responsibility means reflecting on the actions to be taken, balancing risks and benefits for social development. Human beings have great power over nature thanks to biotechnology; life can be manipulated and altered deeply. The principle of responsibility of Hans Jonas implies at least two duties: that future generations will have an environment and biodiversity comparable to the present one; and that the genetic identity of human beings will not be altered (82). Rules for decision-making must consider how ignorant we are of the consequences that may be posed for ecology of the uncontrolled introduction of genetically modified organisms. On the basis of the principle of nonmaleficence, this issue creates obligations in terms of environmental and healthcare policies in order to avoid, as far as possible, the worsening of genetic endowment (83). Care must be taken to limit the slippery-slope tendency whereby acceptance of one controversial technology inevitably leads to acceptance of more and more, the benefits of which become progressively less certain, which calls for a definition of acceptable and unacceptable activities and the setting of limits (84).

Conclusions Even though Latin American research on genomics is limited, there are programs and local initiatives in collaboration with developed countries. Advances in genomic diagnosis have been introduced in Latin American countries, but there is inequity in access to the technology. Health therapeutic benefits are still limited. Some Latin American countries are producing transgenics, mainly Argentina and Brazil; Chile produces transgenics only for international commerce. The most pressing social demands are inequity and the imposition of the international biotechnological companies. There is no interest in human

Social, Ethical and Legal Attitudes towards Genomic Research in Latin America

genomic enhancement and reproductive cloning. Regulation to avoid genetic discrimination and stigmatization is valued, but currently, there are deficiencies in confidentiality protective measures. The human genome is considered a juridical good that must be protected. There is little regulation of the introduction of genetically modified organisms. There are issues which should be regulated, such as the protection of biodiversity or introducing genes from one species to others with properties not wanted in wild plants such as resistance to herbicides or to insects or microorganisms. Bioethical reflection clarifies the complex social consequences of access to genetic information of individuals and may play a role in the dialog between scientists, legislators, and civilians. In the migration of knowledge from the laboratory to society, the media has a role in influencing the way civilians understand these topics, for which further education is necessary.

References 1. 2. 3. 4.

5. 6. 7. 8.

Lander ES., Linton LM., Birren B., Nusbaum C., et al. ”Initial sequencing and analysis of the human genome”. Nature2001;409:860–921. Venter JC., Adams MD., Myers EW., Li PW.et al. “The sequence of the human genome”.Science 2001;291:1304–1351. Ansorge WJ. “Next-generation DNA sequencing techniques”. National Biotechnology 2009;25:195-203. Manolio TA., Chisholm RL., Ozenberger B., Roden DM., Williams MS., Wilson R., Bick D., Bottinger EP., Brilliant MH., Eng C., Frazer KA., Korf B., Ledbetter DH., Lupski JR., Marsh C., Mrazek D., Murray MF., O'Donnell PH., Rader DJ., Relling MV., Shuldiner AR., Valle D., Weinshilboum R., Green ED., Ginsburg GS. “Implementing genomic medicine in the clinic: the future is here”. Genet Med. 2013 April; 15(4): 258-267. Gilissen C., Hoischen A., Brunner HG., Veltman JA. “Unlocking Mendelian disease using exomesequencing”.Genome Biology2011; 12(9): 228. Donnelly P. “Progress and challenges in genome-wide association studies in humans”. Nature.2008;456:728-731. Johnson JA. “Pharmacogenetics in clinical practice: how far have we come and where are we going?” Pharmacogenomics. 2013 May; 14(7): 835-843. Haddow G., Laurie G., Cunningham-Burley S., Hunter KG (2007). “Tackling community concerns about commercialization and genetic research: a modest interdisciplinary proposal”. Social Sciences and Medicine 64:272-282.

70 9.

10.

11. 12. 13.

14.

15. 16.

17. 18. 19. 20. 21.

Chapter 3 Institute of Medicine (U.S.) Committee on Assessing Genetic Risks; Andrews LB, Fullarton JE, Holtzman NA, et al., editors. Assessing Genetic Risks: Implications for Health and Social Policy. Washington (D.C): National Academies Press (U.S.); 1994. 2, Genetic Testing and Assessment. Available from: https://www.ncbi.nlm.nih.gov/books/NBK236037/ Institute of Medicine (U.S.) Committee on Assessing Genetic Risks; Andrews LB, Fullarton JE, Holtzman NA, et al., editors. Assessing Genetic Risks: Implications for Health and Social Policy. Washington (D.C): National Academies Press (U.S.); 1994. 8, Social, Legal, and Ethical Implications of Genetic Testing. Available from: https://www.ncbi.nlm.nih.gov/books/NBK236044/ Covolo L, Rubinelli S, Ceretti E, Gelatti U. “Internet-Based Direct-toConsumer Genetic Testing: A Systematic Review”. Ed. Gunther Eysenbach. Journal of Medical Internet Research 2015; 17.12: e279. Bunnik, EM., Janssens, ACJW., and Schermer, MH. “Informed Consent in Direct‐to‐Consumer Personal Genome Testing: The Outline of A Model between Specific and Generic Consent”. Bioethics2014; 28(7), 343-351. Rodriguez E, Valdebenito C, Misseroni A, Fernández L, Outomuro D, Schiattino I, Ferrer M, Lolas F. “Social, ethical and legal attitudes towards genomic research in four Latin American countries”. Electronic Journal of Biotechnology December 2005; 8(3). Available from: http://www.ejbiotechnology.info/content/vol8/issue3/full/9/index.html. Rodriguez E, Valdebenito C., Misseroni A., Fernández L., Outomuro D., Schiattino I., Lolas F. “Percepciones Sociales sobre Genómica en Cuatro Países Latinoamericanos. ImplicacionesÉticoLegales”, Derecho y Genoma (2004) 21: 141-164. Lolas, F., Rodriguez E., Valdebenito C. “El Proyecto del Genoma Humano en la Literatura Biomédica en cuatro países Latinoamericanos”. Acta Bioethica 2004; X: 167-180. Schiattino I., Silva C., Lolas F., Valdebenito C., Rodriguez E., “Percepciones y estados emocionales sobre el proyecto genoma humano en actores sociales seleccionados en la Región Metropolitana, Chile”, Revista Chilena de Salud Pública 2005; 9: 154-161. Schiattino I., Silva C., Lolas F., Valdebenito C., Rodriguez E. “Descripción de las percepciones sobre el proyecto genoma humana en Chile, Perú, Argentina y Mexico”. Rev Quirón 2005, v 36: Nº1/3 Bisang R., Campi M., Cesa V. “Biotecnología y Desarrollo”. Comisión Económica para América Latina y el Caribe (CEPAL) 2009: 73-74. Simpson, AJ., et al., “The Genome Sequence of the Plant Pathogen Xylella fastidiosa. The Xylella fastidiosa Consortium of the Organization for Nucleotide Sequencing and Analysis”. Nature, 2000, 6792: 151-157. Simpson Andrew JG., “Genomics in Brazil”. Research Coordination, Pan American Health Organization (online), 2001, Portable Document Format, Internet: http://www.paho.org/english/hdp/HDR/ACHR-02-Simpson.PDF. Thorsteinsdóttir H., Daar AS., Sáenz TW., Singer PA. “Building a Biopharmaceutical Innovation System in Cuba: Growth Through Linkages”.

Social, Ethical and Legal Attitudes towards Genomic Research in Latin America

22. 23.

24.

25.

26.

27. 28. 29. 30.

31. 32. 33. 34. 35.

In: Mytelka LK., (ed). Building (bio)pharmaceutical innovation systems in developing countries. Maastricht, The Netherlands: Institute for New Technologies (INTECH), United Nations University, 2009. Sanchez GJ. “Developing a Platform for Genomic Medicine in Mexico”. Science 2003; 300: 295-296. Rocco PP., Morales GC., Moraga VM., Miquel PJF., Nervi OF., Llop RE et al. “Composición genética de la población chilena: Distribución de polimorfismos de DNA mitocondrial en grupos originarios y en la población mixta de Santiago”. Rev. méd. Chile 2002 Feb; 130(2): 125-131. Rotthammer F., Moraga VM., Rivera M., Santoro MC., Standen GV., García F., Carvallo P. “Análisis de ADNmt de restos esqueletales del sitio arqueológico de Tiwanaku y su relación con el origen de sus constructores” Chungará (Arica), Chile, v. 35, n. 2, jul. 2003. Available in <http://www.scielo.cl/scielo.php?script=sci_arttext&pid=S071773562003000200006&lng=es&nrm=iso>. Rodriguez E., Valdebenito C., Misseroni A., Fernández L., Outomuro D., Schiattino I., Ferrer M., Lolas F. “Social, ethical and legal attitudes towards genomic research in four Latin American countries”. Electronic Journal of Biotechnology December 2005; 8(3). Available from: http://www.ejbiotechnology.info/content/vol8/issue3/full/9/index.html. Gottschalk L., Lolas F. “The Gottschalk-Gleser Content Analysis Method of Measuring the Magnitude of Psychological Dimensions: Its Application in Transcultural Research”, Transcultural Psychiatric Research Review 1989; 26: 83-111. Rodriguez-Yunta E., “Terapia génica y principios éticos”. Acta Bioethica, 2003, vol. 9, no. 1: 69-79. Vergès Claude. “Genética y Bioética en América Latina”. Acta Bioethica. 2004 10(2): 155-166. Santos, MA. “Aspectos científicos de los principales avances de la genética humana. El Impacto Social de la Manipulación Genética”. Humanistas9 (1997): 16-27. Bandeira Flavia Miranda Gomes de Constantino, Gomes Yara de Miranda, Abath Frederico Guilherme Coutinho. “Saúde pública e ética na era da medicina genômica: rastreamentos genéticos”. Rev. Bras. Saude Mater. Infant. 2006; 6(1): 141-146. Austin-Ward ED and Villaseca GC. “La terapia génica y sus aplicaciones”. RevistaMédica de Chile, 1998, vol. 126, no. 7: 838-845. Giorgiutti, ED. “Aspectos éticos de la terapia génica”. Medicina (Buenos Aires), 1998, vol. 58, no. 2: 228-238. Cruz-Coke, R. “Historia de la genética latinoamericana en el siglo XX”. RevistaMédica de Chile, 1999, vol. 127, no. 12: 1524-1532. Valenzuela CY. “Ética científica de la terapia génica de individuos. Urgencia de la cirugía génica del AND”. Revista Médica de Chile, 2003, vol. 131, no. 1: 1208-1214. Saez-Capel J. “Es de Total Necesidad Tipificar Penalmente los Actos Relativos a la Manipulación Genética con el Fin de Clonar Seres Humano”s.

36. 37. 38. 39. 40. 41. 42. 43. 44. 45.

46.

47.

48.

49.

Chapter 3 In: Jornadas Nacionales de Bioética y Derecho. (1º, 22 - 23 August 2000, Buenos Aires, Argentina). Asociación de Abogados de Buenos Aires. 2000. Available from: Internet: http://www.aaba.org.ar/bi170p32.htm. Bergel SD. “Aspectos Éticos y Jurídicos del Proyecto Genoma Humano: Patentamiento de Genes y Secuencias”. Medicina (Buenos Aires), 2000, vol. 60, no. 4: 729-730. Mancini R. “Consideraciones bioéticas sobre la clonación”. RevistaChilena de Neuropsiquiatría 1997; 35: 425-429. Kottow M. “Investigación, clonación y personas”. Revista Chilena de Neuropsiquiatría 1997; 35: 421-423. Vial JdeD. “El significado de la clonación. El Impacto Social de la Manipulación Genética”. Humanitas 1997; 9: 7-15. Pallavicini J. “Significado existencial del clon. El Impacto Social de la Manipulación Genética”. Humanitas 1997; 9: 36-43. Lolas F. “La clonación de humanos: aproximación ética”. En: Fundación Fernando Fueyo Laneri. Derecho, Bioética y Genoma Humano. Santiago de Chile: Editorial Jurídica de Chile; 2003: 145-156. Arranz J., Ariza X., Ruidor E., et al. “Reflexiones preliminares sobre una aplicación científico-médica de actualidad: la clonación”. Acta Bioethica 2003; 9(1): 81-91. Subiria R., Perales A., Wagner P. et al. Pronunciamiento de la Academia Nacional de Medicina sobre "clonación humana". Anales de la Facultad de Medicina, Universidad Nacional Mayor de San Marcos 2002; 63: 73-81. Schramm F. “Perspectivas sanitarias prometedoras del clonaje humano”. Acta Bioethica 2003; 9(1):93-104. Kurczyn PV. “Proyecto del Genoma Humano y las Relaciones Laborales. Cuadernos del Núcleo de Estudios Interdisciplinarios” en Salud y Derechos Humanos. Diagnóstico Genético y Derechos Humanos, UNAM, 2002, vol. 3. Available from Internet: http://info.juridicas.unam.mx/publica/salud/cuad3/kurczyn.htm. Alvarez RM. “El Contrato del Seguro y el Proyecto del Genoma Humano”. Cuadernos del Núcleo de Estudios Interdisciplinarios en Salud y Derechos Humanos. Diagnóstico Genético y Derechos Humanos, UNAM, 2002, vol. 3. Available from Internet: http://info.juridicas.unam.mx/publica/salud/cuad3/alvarez.htm. Kuyumdjian P. “Proyecto del Genoma Humano y Derecho a la Intimidad”. In: Jornadas Nacionales de Bioética y Derecho. (1º, 22 - 23 August 2000, Buenos Aires, Argentina). Asociación de Abogados de Buenos Aires. 2000. Available from: Internet: http://www.aaba.org.ar/bi170p23.htm. Badillo A., Elisa M. “Seguros y Discriminación con Bases Genéticas”. Cuadernos del Núcleo de Estudios Interdisciplinarios en Salud y Derechos Humanos. Diagnóstico Genético y Derechos Humanos, UNAM, 2002, vol. 3. Available from Internet: http://info.juridicas.unam.mx/publica/salud/cuad3/badi.htm. Arriberre R. “El Deber de Información y la Confidencialidad en la Genética. Aportes para una Legislación que Preserve la Intimidad de la Persona y Evite

Social, Ethical and Legal Attitudes towards Genomic Research in Latin America

50. 51. 52. 53. 54. 55.

56. 57.

58. 59.

60. 61. 62. 63. 64. 65.

la Discriminación”. In: Jornadas Nacionales de Bioética y Derecho. (1º, 22 - 23 August 2000, Buenos Aires, Argentina). Asociación de Abogados de Buenos Aires. 2000. Available from internet: http://www.aaba.org.ar/bi170p24.htm. Zanlungo MS., Arrese JM and Rigotti RA. “Medicina molecular: presente y future”. Revista Médica de Chile, 1999, vol. 127, no. 8: 982-988. Fajreldin V. “Problemas bioéticos de la investigación biomédica con pueblos indígenas de Chile”. Acta Bioethica 2010; 16(2): 191-197. Concha, H., “Consideraciones en Torno al Diagnóstico Genético y su Impacto en el Estado de Derecho”, Cuaderno del Núcleo de Estudios Interdisciplinarios en Salud y Derechos Humanos UNAM 2002; 3. Chavarri-Guerra Y., Blazer KR., Weitzel JN. “Genetic Cancer Risk Assessment for Breast Cancer in Latin America”. Rev Invest Clin. 2017 MarApr; 69(2):94-102. Toro J., Cardenas S., Fernando Martinez C., Urrutia J., Diaz C. Multiple sclerosis in Colombia and other Latin American Countries. Multiple Sclerosis and Related Disorders, 2013; 2 (2):80-89. Parsam VL., Kannabiran C., Honavar S., Vemuganti GK., Ali MJ. “A comprehensive, sensitive and economical approach for the detection of mutations in the RB1 gene in retinoblastoma”. J Genet.2009; 88(4):517– 527. Kari_Oca Declaration, Rio de Janeiro, 1992; Santa Cruz de la Sierra Declaration, Bolivia,1994UkupseniDeclaration, Panama, 1997. http://www.prodiversitas.bioetica.org/doc33.htm Mercurio, 22 de Febrero 2008, Santiago, Chil.Silva-Zolezzi I., HidalgoMiranda A., Estrada-Gil J., Fernández- JC., Uribe-Figueroa L., Contreras A., Balam-Ortiz E., del Bosque-Plata L., Velazquez-Fernández D., Lara C., Goya R., Hernandez-Lemus E., Davila C., Barrientos E., March S., JimenezSanchez G. “Analysis of genomic diversity in Mexican Mestizo populations to develop genomic medicine in Mexico”. Proceedings National Academy of Science U S A.2009 May 26; 106(21): 8611–8616. http://www.coriell.org/ Quiñones Luis, Roco, Ángela, Cayún Juan P, Escalante, Paula, Miranda Carla, Varela Nelson, Meneses Francisca, Gallegos Bastián, Zaruma-Torres Fausto, and Lares-Asseff Ismael. (2017). “Clinical applications of pharmacogenomics”. Revista médica de Chile, 145 (4): 483-500. Rodriguez E.“Ética en innovación tecnológica y farmacogenómica”. Acta Bioethica 2009 Monografía; 2: 265-282. Wertz D.C. “Ethical, legal and social issues in pharmacogenomics”. Pharmacogenomics J 2003; 3:194-6. FAO The State of the World' Plant Genetic Resources 1999. http://apis.ufl.edu. Silvia Ribeiro. Monsanto y la soya Argentina. 2009; http://www.etcgroup.org/es/materiales/publicaciones.html?pub_id=64. http://www.ric.fao.org/redes/redbio/default.htm.

74 66. 67. 68. 69. 70. 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82.

83.

Chapter 3 Roig JLD and Gómez M. “Riesgos sobre la Salud de los Alimentos Modificados Genéticamente: Una revisión bibliográfica.” Revista Española de Salud Pública, 2000, vol. 74, no. 3: 255-261. Reyes MS and Rozowski JN. “Alimentos Transgénicos”. Revista Chilena de Nutrición, 2003, vol. 30,no. 1: 21-26. Paparini A. and Romano-Soica V. “Public Health Issues Related with the Consumption of Food Obtained from Genetically Modified Organisms”. Biotechnology Annual Review, 2004, vol. 10, no. 1: 85-122. SIMAS Comunicación para el desarrollo rural (2007). “Terminator: Las semillas suicidas son semillas homicidas”. http://www.simas.org.ni/simasnoticia/359. Gustavo Gonzalez, “Alerta en Chile ante el super salmón”. http://www.tierramerica.net/2001/0812/articulo.shtml. Madrid R. III. “Cuestiones Jurídicas. En: Proyecto del Genoma Humano: Presente y Perspectivas Futuras”. Humanitas, 1999, vol. 15: 20-24. Bergel SD “Los Derechos Humanos entre la Bioética y la Genética”. Acta Bioethica 2002; vol. 8, no. 2: 315-329. Prieto González EA. “Deterioro genómico y manipulación genética: Dessequilibrio en la prioridad de las agendas pública”. Acta bioethica2007 Nov; 13(2): 223-231. Robinson J. “Ethics and Transgenic Crops: a Review”. Electron. J. Biotechnol. 1999 Ago; 2(2): 5-6. Anon. “Seeds of discontent”. The Economist 20th February 1999: 93-95. Maccioni RB., Muñoz JP., “Maccioni C. Dimensiones bioéticas de la investigación sobre el genoma human”. Acta bioethica 2004;10(1): 75-80. Kottow Miguel H. “Public health, genetics and ethics”. Rev. Saúde Pública 2002 Oct; 36(5): 537-544. Chadwick Ruth. “Genomics, Public Health, and Identity”. Acta bioethica 2003; 9(2): 209-218. Jonas H. El Principio Responsabilidad, Barcelona, Círculo de Lectores/Herder, 1995. González G. Derechos humanos. La condición humana en la sociedad tecnológica, Madrid, Tecnos, 1999: 79-94. Jonas H. El principio de responsabilidad. Ensayo de una ética para la civilización tecnológica,1979. Neri D. “On the concept of eugenics: preliminaries to a critical appraisal”. Cad. Saúde Pública. Available from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0102311X1999000500004&lng=en. Weil, V. Biotechnology and ethics: a blueprint for the future. Biotechnology: social impact and quandaries, 1996. http://www.biotech.nwu.edu/nsf/weil.htm.

CHAPTER 4 INFORMED CONSENT CONTENT FOR GENETIC RESEARCH USING BIOLOGICAL SAMPLES STORED IN BIOBANKS: LATIN AMERICAN CONTEXT ETHICAL ISSUES

Abstract This chapter exposes ethical issues associated with informed consent content for genetic research when using biological materials in relation to Latin American biobanking practices. The following issues are reflected: informed consent information, comprehension of disclosed information, benefits determination, consent for research purposes, consent for vulnerable populations, safety procedures, transfer and disposal of data and biological samples, safeguarding confidentiality, right to withdraw, death or incapacity of participants, waiver of consent and adequate type of consent. There is a need for ethical and legal safeguards for informed consent procedures so that biobanks will not be used in any way that may harm the individual who has provided the sample or his genetic relatives or community.

Introduction There is considerable agreement on the broad aspects of what constitutes a biobank, but there is much disagreement regarding the precise definition. A broad definition of a biobank is that of being a repository of biological tissue with the intention to use the samples (1). Although there are biobanks storing non-human biological samples, the purpose of this chapter is only to include human samples. Important characteristics for being a biobank are that they comply with associated sample data and are managed according to professional standards (2). Samples may derive from the clinical setting, research projects or judiciary mandate and may come from surgery, wastes, diagnostic tests, birth products (placenta and umbilical cord), donation of gametes or embryos or biological materials from genetic research population

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studies and body parts of deceased persons. Data associated with the samples may be individual (clinical, lifestyle), familial (genealogy information or ethnic origin) or belong to a group (geographical location, language). Biobanks store human biological materials or samples for one or more research purposes, such as genetics of human diseases, studies involving environmental agents, infectious diseases, protein biology or epigenetic factors. The use of samples for genetic research may produce new knowledge for healthcare or public health decisions (3, 4). Genetic research can be done to identify gene sequences associated with inherited diseases, association studies to find correlations between diseases and genetic changes, genetic epidemiology to study the interaction of genes with the environment, those which may be used for gene therapy or enhancement and pharmacogenetic studies to study the genetic basis of the interaction of the human body with drugs used in therapy, leading to a personalized approach to healthcare. Each of these types of studies uses genetic databases in a different way and may raise different legal, ethical and social issues (5-7). Informed consent is subjected to ethical scrutiny since there are many issues involved (8, 9). Due to the advancement of genetic research, there is global interest in the use of biological samples and data, and trans-national sharing of biobank resources has increased. Collaborative genetic research may require shipment of samples between countries. Therefore, there is a growing need to harmonize biobank processes. Legal safeguards must be placed so that biobanks will not be used in any way that may harm the individual who has provided the sample or his genetic relatives or community. One complaint is that biobank research may be conducted without the knowledge or consent of those whose tissues are stored. Biological samples may be used in ways not originally intended, such as those collected for clinical reasons and subsequently used in research without notifying the donor (10-13). The scope and purpose of transferring biological samples between countries is subject to major constraints, due to legal, ethical and political framework differences (14, 15). Furthermore, biobank collaboration requires that the biological samples they receive be of a certain level of quality, which implies stringent quality control measures covering acquisition, transport, pre-analytical handling and storage of biological samples (16).

Informed Consent Content for Genetic Research Using Biological Samples Stored in Biobanks

Ethical issues related to informed consent for genetic research using biological samples and data stored in biobanks The ethical, legal and social issues involved in the necessary content of informed consent for the use of biological samples in research are very complex, but the donorâ&#x20AC;&#x2122;s wishes must be respected and international relations safeguarded. Some concerns are:

1. Informed consent information When there is research involved, biobanks should provide potential participants with sufficient information on the nature, implications and foreseeable benefits and risks (stigmatization, discrimination, intra-familial conflicts), so that they can realistically assess the implications of their participation and make informed decisions. Also, the source of the biological samples that will be collected for research must be informed. Prior to consent, there is a need for risk assessment. Perception of risks in the informed consent process affects the acceptance of research. Potential risks of genomic research are mainly of a socioeconomic nature, which may affect not only individuals but families and ethnic groups as well. There may be risks of potential stigmatization for being labeled with a particular disease, discrimination by health insurance or employers, conflicts within families, and the possibility that research may create or increment the risk of stigmatization or discrimination of groups. However, many of these risks are minimized with confidentiality measures and in general in Latin America, the risk of discrimination by health insurance or employees is very low due to limitations being able to afford the costs of genetic tests. Another issue is the need to harmonize a common language for international biobanking information procedures related to technical terms (17). Some English technical terms are translated into Spanish in different ways in Latin America countries, which may cause confusion.

2. Comprehension of disclosed information Comprehension of disclosed information in informed consent processes may be complicated in low literacy groups and in the elderly who have little education in science. The information to be provided to potential participants needs to be in simple, concise, explicit language, with consideration given to

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the different needs. Nevertheless, it is very doubtful that vulnerable populations with a low level of education in science, such as Latin American indigenous populations and illiterate groups, would be able to understand the complex issues exposed in informed consent content for the use of biological samples in research. Lack of understanding is the main barrier for proper informed consent in such populations (18, 19). Often, Latin American civil society has limited exposure to what is going on in research, depending on what media covers the issue. Particular groups may have a negative reaction to participating in research by donating their tissues if they focus on fears of stigmatization and discrimination exposed by media. Other groups may have a positive reaction to participating in research which focuses on expectations of finding new therapeutic approaches. The process of obtaining informed consent may be too difficult to explain to vulnerable populations since there are many complex issues involved. Thus, their response may be based on their little knowledge and understanding not because of having reflected on the issue.

3. Determination of benefits There is a need to clarify ownership issues with respect to biological samples stored in biobanks; issues such as intellectual property or the patentability of biological samples since there have been disputes over who has the right to control the use and distribution of biological samples and products derived from them. For example, in the case of Moore v. Regents of the University of California, the Court ruled that a tissue sample donated by a patient to a hospital is not the personal property of the patient and that individuals do not have rights to a share in the profits earned from commercial products or research derived from their cells (20). In the case of Greenberg v. Miami Children's Hospital Research Institute, the Court ruled that individuals do not own their tissue samples when researchers take them for testing (21). Greenberg claimed that the genetic probe for Canavan disease should be public without cost for laboratory use and without license cost. The Court ruled to accept the patent license but with free use in research. International commercial trade of biological samples has been questioned. There have been serious concerns about commercial and research use of stored DNA and cell lines of aboriginal groups without their consent (22). As regards transnational research, developed countries often get most benefits in the distribution of financial or other assets that result from the

Informed Consent Content for Genetic Research Using Biological Samples Stored in Biobanks

research, which is viewed with suspicion in Latin American countries and may hamper international collaboration (23).

4. Consent for research purposes Research ethics has established the right of participants to be fully informed of the objectives and procedures of research projects and the right to withdraw from a project at any time. However, biobanks may have openended scientific goals; some logistical difficulties, such as re-contacting people whose biological material and related data are stored in biobanks should be addressed when planning research, especially when this must be done many times (24-26). Circumstances for new consent should be specified when there is a secondary use of samples. If there is no new consent, the specificity of the first consent should be assessed for secondary use. However, the secondary use may be difficult to ascertain when biological samples are stored in biobanks, since it is difficult to control what will be done with them.

5. Consent of vulnerable populations There are concerns related to consent for vulnerable populations since they may have greater risks for discrimination or stigmatization. For example, the high frequency of specific diseases or genetic sequences related to social problems may stigmatize ethnic groups so that any member may be labeled as having a specific pathology or behaviors such as alcoholism, drug addiction or violence. For this reason, it is important that community leaders are involved in consent. The consent process should respect the cultural and religious beliefs and practices of participants and the community in which the research is being carried out. Latin American aboriginal leaders have opposed the collection of blood samples used for DNA characterization due to the status of blood as sacred (27). Some aborigines also consider that no part of the body should be outside when they are buried. In a study carried out by our group, it was shown that lack of understanding about the technology and implications of genetic research is associated with an increase in anxiety and hostility towards genetic experimentation in Latin America (23, 28-31). In Mexico, the National Institute of Genomic Medicine, the first of its kind in Latin America, was created to map the genome of Mexicans in order to promote preventive medicine, but since its inception it has provoked social

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controversies and rejection due to a misunderstanding of its purpose (32, 33). Table 4.1 Problems associated with genetic research using aboriginal samples (compiled by the authors) Understanding of science and research

Commercialization

Respect for autonomy

Social risks

Informed consent is difficult to obtain since the concept and purpose of genetic studies are difficult for indigenous populations to understand

-There are no international norms governing the commerce of products derived from samples

Lack of specification of the use of samples in informed consent

-Discrimination

-Generally, no benefits are derived from research by aboriginal communities

-Stigmatization -Lack of respect for their culture

Ethical concerns also arise in relation to consent for future use with children, such as whether, when and how a childâ&#x20AC;&#x2122;s assent will be obtained and procedures for possible future consent (34, 35).

6. Release of information There is controversy about the obligation of researchers to reveal information of potential importance to the future health of participants or their blood relatives. Some participants may choose to know the information and others not to know it when there is no therapy. Researchers who oppose returning results to participants assert that the purpose of research is to generate knowledge rather than to provide clinical care and those research laboratories do not necessarily operate in accordance with clinical laboratory standards (36). When there is no effective method for prevention or treatment of a specific serious disease, to reveal to the patient that he/she will suffer the disease in the future, may cause anxiety and serious emotional difficulties. In the case of predictive testing for Huntingdonâ&#x20AC;&#x2122;s disease, there have been cases of depression and attempted suicide when people know they will have this disease when they are older (37). There is only consensus that people should be offered results that could trigger interventions that are lifesaving or that could avert serious adverse health outcomes, but not for

Informed Consent Content for Genetic Research Using Biological Samples Stored in Biobanks

other situations. Consent must be asked before releasing the information. A deliberative engagement strategy may facilitate the understanding of participants (38, 39). However, this issue has not been explored in Latin America. Furthermore, in order for the research to be approved by an ethical review committee, the issue of whether information from or about family members, in addition to that provided by participants, is required for the research and this expressed informed consent needs to be addressed.

7. Safety procedures A critical issue in defining protocols for biobanking practices is the preservation of molecules and tissues for clinical and translational studies. Tissue storage temperature and the length of time that tissues and purified molecules stay frozen may directly impact preservation. In Latin America, the regulation of safety procedures and quality assurance for keeping biological samples is difficult to implement. Safety procedures are costly due to the need for personnel, equipment, processing methods and the need to monitor that frozen samples are kept at adequate temperature and liquid nitrogen levels.

8. Data and biological samples â&#x20AC;&#x201C; transfer and disposal Some participants may not wish to have their data or biological sample transferred overseas. This is not always respected due to the lack of proper consent mechanisms. Informed consent documents should inform about duration, transfer and disposal procedures (when the samples are no longer required or participants request that they be destroyed); the international transfer of data when applicable must also be included. The issue is complicated since the possibility of tracing the person from whom the sample and data were derived varies according to how the samples are linked to their donor identity in the database (40). Samples and associated information can be: A) Identifiable. The identity (or personal and unique id number) of individuals is directly attached or linked to the samples or data. B) Traceable or coded. Code is attached to them and the correspondence between code and identity is physically separated from sample and data. A limited number of people can connect the code to identity. C) Encrypted. There is a further level of protection through encryption (that is, the code is transformed into several characters that are linked

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to the code with the intervention of a third party). This third-party intervention will then be required to trace individual identity. D) Anonymized. The link has been irreversibly cut between sample/data and the individualâ&#x20AC;&#x2122;s identity. E) Anonymous. There has never been any possibility to link the sample and the attached data to a given person.

9. Safeguarding confidentiality and privacy There are concerns with the possibility of an invasion of privacy, difficulties in safeguarding confidentiality and ways to avoid discrimination and stigmatization (41, 42). Confidentiality and privacy issues raise the need for protection of databases storing genetic and health information. Information should be given by informed consent about procedures and safeguards used to protect confidentiality and privacy. Information should include data linkage procedures, including which health and other records are to be accessed, who the custodian of the biological samples will be and what the role of the data custodian will be. Privacy concerns may enter into conflict with researchers needs when there is no disposition to recruit data. The way some biobanks are established makes it difficult to report individual data due to privacy protection or because of the requirement to make data anonymous (25). Nevertheless, some genetic studies need health-associated data, or family inheritance confidentiality policies may include data encryption, coding of biological samples and data, thereby establishing limited access or varying levels of access by biobank employees, use of nondisclosure or other agreements, as well as data security practices (43). Most Latin American countries consider genetic data as private and subject to confidentiality agreements in their regulations. Genetic information possesses special characteristics which make it susceptible to private protection: permanent character, direct relation with the identity of a person, predictive capacity, provides information beyond the individual (family, ethnic group), often the diagnosis is more accessible than therapy, and there is a risk of stigmatization or discrimination. Biological samples and genetic information may be shared for proficiency testing, international research, insurance companies, law enforcement or publication of data. Therefore, there is a need to establish policies for access to biological samples and data by third parties such as insurers, employers or law enforcement agencies. The necessity for biobanks to share their resources with third parties poses potential risks for public trust, particularly if these may affect social stigmatization or discrimination. This is a sensitive

Informed Consent Content for Genetic Research Using Biological Samples Stored in Biobanks

issue for Latin America as well. The genetic data-sharing arrangement may affect the intention to participate in genetic research (44).

10. Right to withdraw Informed consent procedures should inform about the available types of withdrawal and the implications of such withdrawal; ethical guidelines for health research respect the right of patients to refuse the donation of biological samples, without affecting their treatment or eligibility to participate. Samples stored in biobanks may be destroyed if requested by donors.

11. Death or incapacity of participant Arrangements must be in place for the storage and data protection of biological samples in the event of incapacity or death of the participant.

12. Waiver of consent A research ethics committee may waive the requirement for consent in certain studies when there is minimal risk to human subjects; the waiver will not adversely affect the rights and welfare of the subjects; there is no known or likely reason for thinking that participants would not have consented if they had been asked; there is sufficient protection of their privacy; and there is an adequate plan to protect the confidentiality of data (CIOMS guidelines, 2016).

13. Adequate type of consent There are discussions about which type of consent is more suitable for biobanking. Several models of consent for use in research of materials and data stored in biobanks are considered: broad or blanket (open to any kind of research), restricted (specific informed consent for each piece of research), tiered consent (choosing among a potential use of a secondary research list) or deliberative consent (45). Biobank researchers tend to favor a broad model of consent, justifying it by referring to the potential benefits research could produce combined with the presumed low level of risk when privacy and confidentiality measures are taken (46, 47). The broad model argues for a general or generic consent, open to any kind of research, given once the tissue is procured for health issues, taking into account that many patients do not wish to be re-contacted. Scientists tend to favor broad

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consent, but not all agree on this issue (48): they consider that donors need some form of assurance that nothing unethical will be done with their samples and information (49). Public perceptions show that broad consent is unacceptable when there are other options and most people “do not favor broad consent for either research itself or for research and subsequent wide sharing of data” (50, 51). However, some persons accept broad consent (52). Some ethicists consider that broad consent is not truly informed consent, but rather a generic authorization that sacrifices the right of the donor to self-determination in favor of research interests (53). Nuffield Council guidelines consider that “participation agreements” should replace the traditional consenting procedures and that broad aims of research are acceptable under the approval of the research ethics committees and low risk for participants based on the principle of solidarity (54). Brazil favors a consent form with two mutually exclusive options: an explanation about the use of the stored material in each research study, and the need for new consent or the waiver thereof when the material is used for a new study. On the other hand, the informed consent form for biobanks must be exclusive and related to specific research (55, 56). An approach which may be useful in specific settings is to be responsive to and inclusive of the values and beliefs of biobank participants by keeping contact in a deliberative understanding (38, 39).

14. Issues in regulating biobanking Many Latin American countries lack specific national regulations for biobanking activities. In general, norms referring to international transfer of biological samples are subjected to international cooperation agreements which may need contractual warranties. These agreements may not be sensitive to some specific ethnic groups, such as indigenous populations or may enter into conflict with some countries’ national regulations. There is a need to standardize the quality of stored biological samples that are to be used in research in an efficient way and efforts have been made to establish guidelines. Some developed countries have created international networks coordinating their biological sample collections by the development of common standard operating procedures, compatible informatics systems and harmonized informed consent and material transfer policies and procedures (57-61), but there is still a lot to be covered in Latin American biobanking procedures.

- Patenting -International trade -Donors and community benefits

-Language -Scientific terminology -Aboriginals

-Research Purposes -Interventions -Risks

-Right to withdraw

-Secondary use

-Benefits

Benefitssharing

Comprehension difficulties

Scope of information

-Breaking confidentiality

Anxiety, depression

-Family

-Disposal

-Anonymous

-Anonymized

-Encrypted

-Coded

-Transfer -Right not to know

-Identifiable

-Storage

-Right to know

-Stigmatization -Discrimination

Linkage to samples

Safety procedures

Release of information

Risks

-Deliberative

-Tiered

-Restricted

-Broad

-Waiver

Consent

Table 4.2 Ethical and social issues related to informed consent content for genetic research using biological samples and data stored in biobanks (compiled by the authors)

Informed Consent Content for Genetic Research Using Biological Samples Stored in Biobanks

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International guidance In light of the legal and socioeconomic issues related to genetic research and the use of stored samples, international guidelines have been proposed. The UNESCO Universal Declaration on Bioethics and Human Rights provides broad guidance on consent, privacy, and sharing of benefits. The UNESCO Universal Declaration on the Human Genome and Human Rights (1997) has provisions relating to the status of the human genome as the common heritage of humanity and examines the fundamental rights of the individual and society that should be protected during research, but deals only with the human gene in its natural state and not with assemblages of data in biobanks. The International Declaration on human genetic data elaborated by UNESCO (2003) settles a number of rules about biological samples and on the personal data which may be collected from those samples. It establishes that the genetic data may contain information of unknown relevance at the moment of the collection of the biological samples and, that the genetic data may be culturally important for individuals or groups of people. It also states the requirements which have to be met to use biological samples preserved when genetic data are to be collected: previous, free, informed and express consent from the person concerned is required. The World Medical Association Declaration of Helsinki, ‘Ethical Principles for Medical Research Involving Human Subjects’ (1964, last revision 2008) and its Declaration of Taipei on ethical considerations regarding health databases and biobanks (2016) provides guidance to physicians and other participants in medical research involving human subjects, including research on identifiable human material or identifiable data. The Council of International Organizations of Medical Sciences (CIOMS) in its International Ethical Guidelines for Biomedical Research Involving Human Subjects (2002, 2016) contains guidelines for implementation of informed consent when biological materials are extracted for research. The Council of Europe, ‘Convention on Human Rights and Biomedicine’ (1997) deals primarily with protection, especially of human rights, in the context of the application of biology and medicine. The Council of Europe also adopted the ‘Recommendation Rec 2006(4) of the Committee of Ministers to Member States on research on biological materials of human origin’ (2006) which applies to research activities in the health field involving the removal of biological material of human origin to be stored for research use. Within this recommendation, there is also a brief section on population biobanks. The HUGO Ethics Committee, ‘Statement on Human Genomic Databases’ (2002) provides principles and recommendations for biobanks generally. The Organization for Economic

Informed Consent Content for Genetic Research Using Biological Samples Stored in Biobanks

Co-operation and Development, ‘OECD Guidelines on Human Biobanks and Genetic Research Databases’ (2009) provides principles and best practices for the establishment and management of human biobanks. The Organization for Economic Co-operation and Development, ‘Best Practice Guidelines for Biological Resource Centres’ (2007) provides guidelines for the establishment and management of access, use and security of samples and data. The International Society for Biological and Environmental Repositories, ‘2008 Best Practices for Repositories: Collection, Storage, Retrieval and Distribution of Biological Materials for Research’ provides best practices for the management of all aspects of biobanks. Nuffield Council provides two relevant reports: ‘The collection, linking and use of data in biomedical research and healthcare: ethical issues’ (2014) and ‘Solidarity: Reflections on an emerging concept on bioethics´ (2011). Here we consider some specifications of CIOMS 2002 and 2016 about requirements for informed consent for biological samples used in research. For prospective sampling, CIOMS guidelines specify that informed consent should include: -

Explanation of research purposes Explanation of risks and discomfort due to the biological sample collection procedure Explanation of the way to identify biological samples taken (personal, coding) Guarantee of voluntary participation in the study Explanation of authorization conditions for secondary use of biological samples Explanation of the right to know and how to access information about results of the study when a research subject requests it Information about possible commercial use Specification of limits to guarantee confidentiality and possible social adverse consequences due to confidentiality break Information about policies on the use of results in relation to family members and for preventing the release of information to third parties (family members, health insurance, employers) without the consent of the research subject Information about safety procedures Information about property rights for stored biological samples Information about the right to request biological sample destruction or elimination of codes, making samples anonymous

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Explanation of coding mechanisms and whether the researcher plans to destroy the biological samples after the study Information about the duration of biological sample storage Information about the sponsor financing the research project

Regarding broad informed consent for collecting and storing biological samples linked with health data, information given should specify: -

Biobank purposes Conditions and duration of storage Policies for access to biobank data Ways in which the donor can contact the custodian of the biobank and keep informed about the future use of biological samples Foreseeable uses of biological samples like whether they are limited to a defined specific study or extended to several studies fully or partially defined.

Furthermore, CIOMS guidelines specify certain conditions for waiver of consent, but under the approval of a scientific ethical review committee. This is mainly due to the fact that retrospective studies may use stored old biological samples for which it is not possible to obtain informed consent. The request of individual informed consent is waived when a scientific ethical review committee has determined that: -

There is minimal risk to human subjects The waiver will not adversely affect the rights and welfare of the subjects There is sufficient protection of their privacy There is an adequate plan to protect the confidentiality of data There is no known or likely reason for thinking that participants would not have consented if they had been asked Research design responds to an important inquiry The research will not be possible if the request for informed consent is enforced

Other aspects which must be considered when obtaining informed consent for the use of biological samples in research are: a) There is a right to know the results of genetic studies by subjects and a right not to know when there is no prevention or treatment available. Research subject must be advised about making a decision

Informed Consent Content for Genetic Research Using Biological Samples Stored in Biobanks

b) c)

d) e)

with respect to the communication of research results and how to do it. The research subject must be warned of the implications of genetic information for family members and the convenience that he/she be the one to transmit the information. To explain to the research subject the non-profit character that the donation of biological samples and information linked has and that the subject only has the right to compensation of expenses related to research participation. There are no earnings for donors because of patenting or commercial products derived from their biological samples. Use of genetic counseling for decision-making in relation to research results. Biological samples with a waiver of consent for any use must be destroyed.

The UNESCO International Declaration on Human Genetic Data (2003) points out the following ethical principles in relation to data derived from the human genome: 1) Protection against genetic discrimination 2) Protection against social stigmatization for making genetic data public 3) Right to informed consent and withdrawal with appropriate, clear and equilibrated information, specifying the uses of genetic data 4) Right to access proteomic or genetic data 5) Right not to be informed of research results 6) Right to genetic counseling when receiving results of genetic tests 7) Right to privacy and confidentiality of genetic data associated with a person, family or identifiable group 8) Right to accurate, reliable and safe procedures 9) Right to benefit sharing In order to protect human genetic data, the following must be taken into account: -

As a general rule, human genetic and proteomic data and biological samples obtained for research should not be associated with an identifiable person. Even when they are dissociated, necessary precautions must be taken to guarantee the safety of data and biological samples.

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Human genetic and proteomic data and biological samples obtained for research may only continue to be associated with an identifiable person when it is necessary for research purposes and under the condition that privacy and confidentiality are safeguarded. Human genetic and proteomic data should not be stored in a way that it is possible to identify the donor person for a longer time than necessary in order to fulfill the goals for which they were collected or recently treated. In case of waiver of consent: a) Consent could be waived by the donor unless data are not linked to an identifiable person; b) When a person waives consent, genetic and proteomic data and biological samples should not be used unless they are not linked to the donor; c) When the wishes of the donor cannot be determined or they are not feasible or they are uncertain, data and biological samples must be made anonymous or destroyed.

Latin American Biobanks Currently most biobanks in Latin America function with their own norms of consent and quality standards for use of human biological materials in research in the absence of specific country regulations, except Brazil. The Brazilian Guidelines for biobanks and biorepositories dedicated to Health Research (Brazilian Ministry of Health Ordinance 2201/11) and the National Health Council Resolution CNS 441/11 (governing the ethical analysis of research projects using human biological material) recognize and regulate mono/oligo-user and poly-user collections of human biological materials. Although these regulations do not define the term biobanks, they can be applied to them (62). Biobanks are registered at the Brazilian National Research Ethics Commission (CONEP). To be recognized as institutional biobanks, they must adopt a set of procedures to standardize the collection, storage, processing and distribution of human biological material, ensuring its quality and fitness-for-purpose and also the individual rights of donors (63). Colombia has regulations for research using biological samples in clinical trials but has no regulation for biobanks. In Chile, there are some regulations for research using human biological samples, but regulation of biobanks is not specified. The Ministry of Health has guidelines for the collection and storage of biological materials by healthcare institutions: â&#x20AC;&#x153;Guide for Surveillance Systems for Diseases Transmitted by Food and Research on Outbreaksâ&#x20AC;? (64). Furthermore, the

Informed Consent Content for Genetic Research Using Biological Samples Stored in Biobanks

National Commission for Science and Technology requires approval by scientific ethical review committees of any research with human biological materials. In the informed consent recommendations elaborated by this Commission, the following is pointed out: to inform potential subjects of the type of biological sample to be extracted, quantity of fluids to be extracted, destiny of samples, risks involved, destiny of leftover tissue, measures to guarantee confidentiality and the requirement of re-consent for new research with the biological materials: when this is not possible the decision is taken by scientific ethical review committees (65). Other countries do not have specific regulations on biobanking practices. The protection of research subjects is safeguarded by ethical review committees in research performed in the country, but donor provisions are not always fully incorporated in biobank consent, particularly when there is a transfer of biological samples to other countries. Biobanksâ&#x20AC;&#x2122; norms may be too open or too restrictive for research subjects or researchersâ&#x20AC;&#x2122; satisfaction. The matter is complicated since there are various types of biobanks: populationbased, disease-oriented, hospital- or academic-based, networked, or run by the government, non-profit organizations, or commercial companies (66). In the case of tumor tissues, there is an international Latin American network of biobanks (National Cancer Institutes Network). There are numerous bioethical issues to take into account in order to satisfy research needs and guarantee data protection of human subjects from which biological samples are taken. Personal identifiers or community/population identifiers may cause problems in safeguarding confidentiality over sensible issues which risk the possibility of social stigmatization or discrimination. The anonymity of the samples may not preclude the possibility to trace the community or population origin if the location, language or name of the ethnic group is given. Moreover, depending on the type of research it may be necessary to keep some health and environmental exposure data. Furthermore, archive samples may be used without the previous consent of a donor. The following difficulties are found in Latin America: - Large inequalities in income and science literacy. - Consent procedures may be less stringent in the private sector due to lack of regulation. - Genetic counselors may play a role in ethically and legally appropriate biobank recruitment and management strategies for genetic research (67), but this specialty is very limited in Latin American countries.

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Conclusion While interest in the use of international biological samples for genetic research has increased considerably, there are still many unresolved issues over how to handle informed consent content and enhance the understanding of risks and benefits for donated samples, particularly for vulnerable populations. There is a need for international harmonization and oversight of best practices to improve the quality of biological samples and coordination in biobanking networks. While technical and management issues of the use of biological samples that are stored in biobanks are more straightforward, ethical and regulatory practices often involve issues that are controversial and difficult to standardize since they are developed within particular contexts. Nevertheless, the issue of national regulations for biobanking in Latin America may help to clarify what can be done in the field of international and national research in respecting the donations of subjects.

References 1. 2. 3. 4. 5. 6. 7.

8. 9.

Shaw DM., Elger BS., Colledge F. “What is a biobank? Differing definitions among biobank stakeholders”. Clin Genet. 2014 Mar; 85(3): 223-7. Hewitt R., Watson P. “Defining biobank”. Biopreserv Biobank. 2013 Oct; 11(5): 309-15 Cambon-Thomsen, A., Ducournau, P., Gourraud, P. A. & Pontille, D. “Biobanks for genomics and genomics for biobanks”. Comp. Funct. Genomics 2003; 4: 628–634. Hansson, MG. & Levin, M. (eds) Biobanks as Resources for Health (Uppsala Univ., Uppsala, 2003). Elger B., Biller-Andorno N., Mauro A. and Capron AM. Ethical Issues in Governing Biobanks: Global Perspectives. Farnham, UK, Ashgate Publishing, 2008. Meslin EM., Quaid KA. “Ethical issues in the collection, storage, and research use of human biological materials”. Journal of Laboratory Clinical Medicine 2004; 144:229-34. American College of Medical Genetics, Storage of Genetics Materials Committee. ACMG statement. Statement on storage and use of genetic materials. American College of Medical Genetics Storage of Genetics Materials Committee. Am J Hum Genet. 1995;57:1499–1500. Rodriguez E., Lolas F. “The problem of informed consent content for genetic research using biological samples stored in biobanks”. Bioethikos 2012; 6 (3): 307-312 Rodriguez, E. “Ethical Issues of Consent for Genetic Research in Latin American Bio-banks”. J Clinic Res Bioeth 2015; 6: 228.

Informed Consent Content for Genetic Research Using Biological Samples Stored in Biobanks 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.

24. 25. 26. 27.

OECD. Biological Resource Centres: Underpinning the Future of Life Sciences and Biotechnology OECD code 932001041E1 (OECD, Paris, 2001). Rothstein M. “Expanding the ethical analysis of biobanks”. Journal of Law and Medicine, 2005; 33(1):89-101. Arbour, L., & Cook, D. “DNA on loan: issues to consider when carrying out genetic research with aboriginal families and communities”. Community Genetics 2006; 9: 153-160. Anderlik M. “Commercial biobanks and genetic research: ethical and legal issues.” Am J Pharmacogenomic.2003;3(3):203-15. Kiehntopf M., Krawczak M. “Biobanking and international interoperability: samples”. Hum Genet. 2011 Sep;130(3):369-76. Vaught J., Kelly A., Hewitt R. “A review of international biobanks and networks: success factors and key benchmarks”. Biopreserv Biobanking.2010;3:143-150. Rothstein M. “Expanding the ethical analysis of biobanks”. Journal of Law and Medicine 2005;33(1):89-101. Fransson MN., Rial-Sebbag E., Brochhausen M., Litton JE. “Toward a common language for biobanking”. Eur J Hum Genet 2015; Jan;23(1):22-8. Rogers W., Ballantyne A. “Special populations. Vulnerability and protection”. Elec. J. Commun. Inf. Innov. Health. Rio de Janeiro Dec. 2008; v.2, Sup. 1, p.Sup.30-Sup.40. Kottow M. “The battering of informed consent”. Journal of Medical Ethics 2004; 30:565-569. Moore v. Regents of University of California 793, p 2d 479 (Cal.1990). Greenberg v. Miami Children’s Hospital Research Inst., Inc., 264 F. Supp. 2d 1064, 1075 (SD Fla. 2003). Arbour, L., & Cook, D. “DNA on loan: issues to consider when carrying out genetic research with aboriginal families and communities”. Community Genetics 2006; 9: 153-160. Rodriguez-Yunta E., Valdebenito-Herrera C., Misseroni A., FernándezMilla L., Outomuro D. et al. “Percepciones Sociales sobre Genómica en Cuatro Países Latinoamericanos. Implicaciones Ético Legales”. Derecho y Genoma2004; 21: 141-164. Lipworth, W. and Ankeny, R. et al. “Consent in crisis: the need to reconceptualize consent to tissue banking research”. Intern Med J 2006;36(2): 124-8. Knoppers BM. “Biobanks: simplifying consent”. Nature Review Genetics 2004; 5: 485. Knoppers BM. “Consent revisited: points to consider”. Health Law Review 2005; 13: 33-38. Statement of “Kari_Oca”, Rio de Janeiro, Brazil, 1992; Statement of “Santa Cruz de la Sierra”, Bolivia, 1994; Statement of “Ukupseni Kuna Yala”, Panama 1997. http://www.prodiversitas.bioetica.org/doc33.htm

94 28. 29.

30.

31. 32. 33. 34. 35. 36. 37. 38.

39. 40. 41. 42.

Chapter 4 Lolas, F., Rodriguez, E., Valdebenito, C., Lolas, F., “El Proyecto del Genoma Humano en la Literatura Biomédica en cuatro países Latinoamericano”s. Acta Bioethica 2004; X: 167-180. Rodriguez E., Valdebenito C., Misseroni A., Fernández L, Outomuro D., Schiattino I., Ferrer M., Lolas F. “Social, ethical and legal attitudes towards genomic research in four Latin American countries. ” Electronic Journal of Biotechnology 2005; 8(3). Available from: http://www.ejbiotechnology.info/content/vol8/issue3/full/9/index.html. Schiattino I., Silva C., Lolas F., Valdebenito C., Rodriguez E., “Percepciones y estados emocionales sobre el proyecto genoma humano en actores sociales seleccionados en la Región Metropolitana, Chile”, Revista Chilena de Salud Pública 2005; 9: 154-161. Schiattino I., Silva C., Lolas F., Valdebenito C., Rodriguez E. “Descripción de las percepciones sobre el proyecto genoma humana en Chile, Perú, Argentina y Mexico”. Rev Quirón 2005; v 36: Nº1/3). Jimenez-Sanchez G. “Developing a platform for genomic medicine in Mexico”. Science2003; 300 (5617): 295-296. Jimenez-Sanchez G., Silva-Zoletti I., Hidalgo A., March S. “Genomic medicine in Mexico: Initial steps and the road ahead”. Genome Research 2008; 18 (8): 1191-1198. Holm S. “Informed consent and the biobanking of material from children”. Genomics, Society and Policy 2005; 1: 16-26. Knoppers BM., Avard D., Cardinal G., Glass KC. “Science and society: children and incompetent adults in genetic research: consent and safeguards”. Nature Review Genetics 2002; 3: 221-225. Clayton EW., McGuire AL. “The legal risks of returning results of genomics research”. Genet Med.2012;14(4):473-7. Meiser B., Dunn S. “Psychological effect of genetic testing for Huntington’s disease: an update of the literature”. Western Journal of Medicine. 2001; 174(5): 336-340. Lemke, AA., Halverson, C., & Ross, LF. (2012). “Biobank Participation and Returning Research Results: Perspectives from a Deliberative Engagement in South Side Chicago”. American Journal of Medical Genetics. Part a, 158 A (5): 1029-1037. De Vries RG., Ryan KA., Gordon L., Krenz CD., Tomlinson T., Jewell S., Kim SYH. “Biobanks and the Moral Concerns of Donors: A Democratic Deliberation”. Qual Health Res. 2018 Aug; 10:1049732318791826. Thomsen, CA. “The social and ethical issues of post-genomic biobanks”. Nature Review Genetics 2004; 5: 866-873. Corrigan, O. “Biobanks: can they overcome their controversy and deliver on their promise to unravel the origins of common disease?” Medical Education 2006; 40(6): 500-502. Godard B., Schmidtke J., Cassiman JJ., Ayme´ S. “Data storage and DNA banking for biomedical research: informed consent, confidentiality, quality issue, ownership, return of benefits. A Professional Perspective”. EUROGAPP PROJECT 1999–2000. ESHG 1; November 2002.

Informed Consent Content for Genetic Research Using Biological Samples Stored in Biobanks 43. 44.

45. 46. 47. 48. 49. 50. 51.

52.

53. 54. 55.

56. 57.

Eriksson, S., &Helgesson, G. “Potential harms, anonymization, and the right to withdraw consent to biobank research”. European Journal of Human Genetics 2005; 13: 1071-1076. Critchley C., Nicol D., Otlowski M. “The impact of commercialisation and genetic data sharing arrangements on public trust and the intention to participate in biobank research”. Public Health Genomics 2015; 18(3): 16072. Master Z., Nelson E., Murdoch B.& Caulfield T. “Biobanks consent and claims of consensus”. Nat Methods. 2012; Sep;9c(9):885-8. Sheehan M. “Can broad consent be informed consent?” Public Health Ethics 2011; 4 (3): 226-235. Master Z., Campo-Engelstein L., Caulfield T. “Scientists' perspectives on consent in the context of biobanking research”. Eur J Hum Genet. 2015; May 23(5):569-74. Master Z. “The U.S. National Biobank and (no) consensus on informed consent”. The American Journal of Bioethics 2015 Sep 2; 15(9): 63-5 Caulfield T. “Biobanks and blanket consent: The proper place of the public good and public perception rationales”. Kings Law Journal 2007; 18:209226. Simon CM., L'heureux J., Murray JC., Winokur P., Weiner G., Newbury E.et al. “Active choice but not too active: public perspectives on biobank consent models”. Genetics in Medicine 2011 Sep 1; 13(9): 821-31. Garrison NA., Sathe NA., Antommaria AH., Holm IA., Sanderson SC., Smith ME.et al. “A systematic literature review of individuals' perspectives on broad consent and data sharing in the United States”. Genetics in Medicine 2015 Nov 19; 18(7): 663-71. Sanderson SC., Brothers KB., Mercaldo ND., Clayton EW., Antommaria AH., Aufox SA.et al. “Public Attitudes toward Consent and Data Sharing in Biobank Research: A Large Multi-site Experimental Survey in the U.S.”. The American Journal of Human Genetics. 2017 Mar 2;100(3):414-27. Otlowski M., Hansson M., Dillner J., Bartram C., Carlson J., Helgesson G. “Should Donors be Allowed to give Broad Consent to Future Biobank Research?’ Lancet Oncology 2006; 7:266-269. Prainsack B. & Buyx A. Nuffield Council Report Solidarity: Reflections on an emerging concept on bioethics. http://nuffieldbioethics.org/wpcontent/uploads/2014/07/Solidarity_report_FOR_WEB_summary.pdf Marodin G., França PH., Salgueiro JB., Motta ML., Tannous GS.et al. “Alternatives of informed consent for storage and use of human biological material for research purposes: Brazilian regulation”. Dev World Bioeth 2014; 14: 127-131. National Guidelines for Biorepositories and Biobanks of Human Biological Material for. Research Purpose. Brazil Ministry of Health, 14 September 2011. NCI Best Practices for Biospecimen Resources. Table of contents. 2011 http://biospecimens.cancer.gov/bestpractices/toc/ISBER best practices for repositories. Cell Preserv Tech2008; 6:1-58.

96 58. 59. 60. 61.

62. 63. 64. 65. 66. 67.

Chapter 4 National Cancer Institute NCI Best Practices for Biospecimen Resources, 2007. Good Laboratory Practices GLP http://www.oecd.org/document/63/0,2340,en_2649_34381_2346175_1_1_ 1_1,00.html. Clinical Laboratory Improvement Amendment http://wwwn.cdc.gov/clia/ U.S. Food and Drug Administration FDA Quality System Regulation, 21 CFR 820, http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?cfrp art=820. Marodin G., França P., Rocha JCC., Campos AH. Biobanking for health research in Brazil: Present challenges and future directions. Rev Panam Salud Publica 2012; 31(6):523–8. Campos AFM, Carraro DM and Fernando Augusto Soares FA. “Tumor banking for health research in Brazil and Latin America: time to leave the cradle”. Applied Cancer Research 2017; 37:6 http://epi.minsal.cl/epi/html/software/guias/VETA/E/anexo_c.htm http://www.fondecyt.cl/comite_bioetica/consentimiento_informado.pdf[02. 11.2007]. Virani AH., Longstaff H. “Ethical considerations in biobanks: how a public health ethics perspective sheds new light on old controversies”. J Genet Couns 2015 Jun;24(3):428-32. Hawkins AK. “Biobanks: importance, implications and opportunities for genetic counselors”. J Genet Couns2010 Oct;19(5):423-9.

CHAPTER 5 ETHICAL ISSUES IN GENOME EDITING USING CRISPR/CAS9 SYSTEM

Abstract This chapter reviews ethical issues related to genome editing, specifically with the preferred current method, the CRISPR/Cas9 system. The use of genome editing gives rise to new issues in genetic modification technology due to high accessibility, ability to make precise and specific edits of DNA in living cells, ability to leave no trace so that it is not possible to know whether the change has been introduced intentionally or through natural mutation, low cost, speed of use to produce results; and potential to achieve multiple simultaneous edits. The use of the CRISPR/Cas9 system revives the need for ethical argumentation of previous social and ethical issues with humans, other organisms and the environment, and also produces new issues. Issues identified: risks of inducing mutations, genome editing in germ-line, possible use of the technique for genetic enhancement, the possibility of ecological disequilibrium for the release of edited organisms into the environment particularly in relation to gene drives, gaps in regulation, animal welfare, military or terrorist applications and the possibility of xenotransplantation between animals and humans. The following is recommended: public engagement and ethical reflection are needed to inform decision-making; safety issues and environmental risk assessment must be enhanced to ensure efficacious regulation and preventions must be taken to oversee laboratories that use CRISPR technology.

Introduction For many years it has been possible to make genome modifications using vectors and physical methods, but interventions in DNA were random and not in specific locations. For purposes of gene therapy and genome repair there has been interest in intervening and modifying the DNA of organisms by guided genome editing; i.e. to change the organism genome by introducing

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a new function or correcting a mutation in a specific location. Genome editing is defined as “the practice of making targeted interventions at the molecular level of DNA or RNA function, to deliberately alter the structural or functional characteristics of biological entities” (1). The development of new approaches has made genome editing more precise, efficient and flexible. Examples are the use of mega-nucleases; zinc finger nucleases (ZFNs) and transcription activator-like effectors nucleases (TALENs). In recent years, CRISPR/Cas9 has been chosen as the preferred method for genome editing thereby revolutionizing biotechnology and therapeutic approaches due to its high degree of fidelity, relatively simple construction and low cost (2). These characteristics make this technique attractive for use by any molecular biology lab. There is, however, a problem in that the possible uses of genome editing need careful assessment. This chapter reflects on the ethical, regulatory and social issues arising from the use of this technique. Scientific observations show concern that the technology is developing too fast with little time for assessing the ethical and safety issues associated with the use of this technology.

Function and origin of the CRISPR/Cas9 System The CRISPR/Cas system was found in nature in bacteria to function as a type of immune system that confers resistance to foreign genetic elements such as plasmids and viruses (3, 4). CRISPR refers to “clustered regularly interspaced short palindrome repeats” and consists of DNA sequences which contain short repetitions followed by short segments of spacer DNA. These sequences originate as a result of being exposed to a bacterial virus or plasmid. The Cas (CRISPR-associated) genes code for nuclease or helicase proteins associated with CRISPR repeats which have the function of cutting or unwinding DNA (5). The CRISPR system in bacteria functions by storing DNA sequences from viruses or plasmids that have invaded and when the same type of virus invades again, the bacteria are able to recognize it using the transcribed RNA sequences and to direct a Cas nuclease or helicase to cut or unwind the DNA. Cas9 was isolated from bacterium Streptococcus pyogenes (6) and is a nuclease able to cut DNA into two active cutting sites at each strand of the double helix of the DNA. Doudna and Charpentier were the first to discover that bacteria respond to invading viruses by transcribing spacers and palindrome DNA into a long RNA molecule which is cut into pieces (called crRNAs) by using trans-activating RNA (tracrRNA) and protein Cas9 (7). This bacterial immune system provided the basis for genetic engineering of human cells and other eukaryotic organisms with the ability of gene editing by combining

Ethical Issues in Genome Editing using CRISPR/Cas9 System

tracrRNA and spacer RNA into a single guideRNA mixed with Cas9 programmed to find and cut specific target DNA segments (8, 9); crRNA contains a segment able to bind tracrRNA forming a hairpin loop; Cas9 is able to modify DNA utilizing crRNA as a guide as it is able to recognize a specific site in the host DNA and cleave one or both strands of DNA. The sgRNA-Cas9 complex binds to its target and creates a double-strand break (DSB) that can be repaired by imprecise non-homologous end joining (NHEJ) or by the precise homology-directed repair (HDR) pathway, modifying or permanently replacing the genomic target sequence for the desired function. For therapeutic purposes, homologous repair which is inefficient in eukaryotic cells is more useful (10). Efficiency can be improved by using base editors which are chimera proteins composed of a DNA targeting module and a catalytic domain capable of modifying DNA bases (11).

Figure 5.1 CRISPR-Cas9 target recognition. (http://www.genecopoeia.com/resource/genome-editing-talen-or-crispr/)

The CRISPR/Cas system exists in nature as a prokaryotic immune system that confers resistance to foreign genetic elements such as plasmids and bacterial viruses (3, 4). CRISPR refers to â&#x20AC;&#x153;clustered regularly interspaced short palindrome repeatsâ&#x20AC;? consisting of short repetitions of DNA sequences followed by short segments of spacer DNA which originated as a result of

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exposure to a bacterial virus or plasmid. The Cas (CRISPR-associated) genes code for nuclease or helicase proteins associated with CRISPR repeats with the function of cutting or unwinding DNA (5). The CRISPR system functions by storing DNA sequences from invaded viruses or plasmids and when the same type of virus invades again, the system recognizes it using the transcribed RNA sequences and directs a Cas nuclease to cut the DNA. Cas9 was isolated from bacterium Streptococcus pyogenes and is a nuclease able to cut DNA in two active cutting sites at each strand of the double helix of the DNA. Doudna and Charpentier discover that bacteria respond to invading phages by transcribing spacers and palindrome DNA into a long RNA molecule which is cut into pieces (called crRNAs) by using trans-activating RNA (tracrRNA) and protein Cas9 (4). It was later discovered that the combination of tracrRNA and spacer RNA into a single guideRNA mixed with Cas9 could be programmed to find and cut specific target DNA segments, thus providing the ability of gene editing (6, 7); crRNA contains a segment able to bind tracrRNA forming a hairpin loop; Cas9 is able to modify DNA utilizing crRNA as a guide able to recognize a specific site in host DNA and cleave one or both strands of DNA. The sgRNA-Cas9 complex binds to its target and creates a double-strand break (DSB) that can be repaired by non-homologous end joining (NHEJ) or by the homology-directed repair (HDR) pathway, modifying or permanently replacing the genomic target sequence for the desired function. Generally, a plasmid is used to transfect target cells with CRIPSPR/Cas9 or a virus is used as a vector. The crRNA is designed so that Cas9 is able to bind the DNA of the cell only where editing is desired. The DNA repair template is also designed in order to overlap with the sequences on either side of the cut and code for the insertion sequence.

Applications of the CRISPR/Cas9 system The CRISPR/Cas9 system has many potential applications due to its ability to cut the DNA of any genome at any desired location by introducing the Cas9 protein and appropriate guide DNA into a cell (2, 9). The system has the ability for genome editing and gene regulation in many types of organisms facilitating the elucidation of target genes in biology and in modeling, studying or correcting diseases. Efficient genome editing has been demonstrated in multiple organisms, including bacteria, plants, insects, fish, reptiles, birds and mammals (12-15). Genome editing intervention of human cells is also possible by engineering a novel version of CRISPR/Cas9 (16).

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The CRISPR/Cas9 system can be engineered for many desired functions, including the treatment of diseases and related research by identifying the performance of defective genes in these diseases (17). CRISPR/Cas9 has been modified to program specific transcription factors to target and activate or silence specific genes (18). Compared to the previous systems, CRISPR can deactivate or eliminate a gene regulating gene expression by binding to the non-template DNA strand of the coding region blocking the transcription process without interfering with intracellular mechanisms (19). The system may be used to edit the genome of organisms to be used as models of human diseases, in which physiological and pathological processes could be studied in vivo. The ability of the CRISPR/Cas9 system to induce targeted double-strand breaks enables the creation of complex, disease-associated genomic changes, such as large chromosomal deletions, inversions, and translocations or simple ones such as deletions of individual genes (20, 21). Genome editing has the potential to treat diseases by disrupting endogenous disease-causing genes, correcting disease-causing mutations or inserting new genes with protective functions (22). Mutations that cause diseases can be “knocked out” or the function of genes may be changed by adding or replacing sections of DNA. The technique can be used to develop tissue-based treatments for cancer and other diseases (23). For example, CRISPR/Cas9 may target HIV provirus to mediate excision of the integrated viral genome or prevent cellular entry of the virus (24). The technique has also been shown to correct the mutation causing cystic fibrosis in intestinal stem cells derived from patients (25). It is expected that CRISPR/Cas9 could be used as a treatment option for neurological disorders such as Alzheimer’s or Huntington’s disease by targeting specific genes including those involved in the early onset of the disease (26-28). A mouse model has been developed to test the deleterious effects of mutations in cancer turning off the oncogenes and turning on the tumor suppressor genes (29). Cellular models of human diseases have been created using CRISPR/Cas9 (30). The CRISPR/Cas9 system can introduce DNA in the germ-line of any organism, and modify somatic genes by genomic editing. Using CRISPR/Cas9 it is possible to make genome modifications in fertilized animal eggs or embryos altering the genetic make-up of every cell in an organism so that changes will be passed to subsequent generations (31). Another idea, which might be accepted, is to recover extinct species (32).

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Furthermore, crops for human consumption may be improved with pest and disease resistance or better nutritional and other consumer qualities, with the advantage that by using CRISPR/Cas9 it is expected that the absence of foreign DNA in the final product and the introduction of genes derived from the same plant species should increase consumer acceptance improving crop quality or introducing disease resistance (33-37). Another line of research is the possibility of using genome editing to facilitate the transplantation of animal organs into people. There is a shortage of human donors for some organs such as the liver. CRISPR/Cas9 may be used to eliminate copies of retrovirus and other pathogens present in animal genomes that may harm human recipients, thus facilitating transplantation from animals (22). Furthermore, CRISPR/Cas9 in combination with induced pluripotent human stem cells may have the potential to enable the growth of human organs in pigs, creating chimera animals, with the possibility of having an unlimited supply of organs not rejected by the immune system of a human recipient (38). The use of genome editing will include interventions of essential regulators necessary for organ growth. A method called the mutagenic chain reaction or â&#x20AC;&#x153;gene driveâ&#x20AC;? based on the CRISPR/Cas9 technique can generate autocatalytic mutations to produce homozygous loss of function mutations, spreading from the chromosome of origin to a homologous chromosome in the majority of somatic and germline cells, thus changing organisms in a few generations (39). This phenomenon causes rapid changes in genetic traits spreading rapidly in a population for many generations copying themselves many times in the genome. Among other uses, gene drives could be used to control damaging invasive species preventing the spread of disease, or reverse pesticide and herbicide resistance in insects and weeds in agriculture (40). CRISPR technology using gene drives may have the potential to eradicate disease vectors and invasive species, such as malaria, zika, chikungunya or dengue by targeting wild populations of disease-transmitting organisms. For example, editing the Aedes aegypti female mosquito may render it incapable of carrying dengue disease or induce sterility in male mosquitoes thereby preventing their reproduction, or limit the lifespan of their offspring. Researchers have demonstrated that by using CRISPR/Cas9 it is possible to create a gene drive that blocks malarial transmission without affecting mosquito populations by blocking Plasmodium genes (41). Altering DNA by genome editing in human embryos is also possible. Liang and collaborators in China were the first to report DNA alterations in human

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embryos in the journal Protein & Cell (previously rejected in Science and Nature due to ethical concerns). They used abnormal human embryos previously rejected after in vitro fertilization procedures. They had limited success in correcting a mutation that causes the disease of beta thalassemia by using CRISPR/Cas9, but only some of the genes were changed, and there were off-target effects on other genes. (42). The authors stated that the technique is not ready for clinical use. The application of this technique into the zygote or early-stage embryo allows the modification of all cells of the organism, including the germ-line that can be passed to subsequent generations. Scientists are looking to eliminate disease-causing genes in the human germ-line. Table 5.1 Genome Editing Intended Applications (compiled by the authors) Human health

Genetically edited Animals

Genetically edited crops

Microorganisms

-Edit mutations to non-disease variants

-Recover extinct species

-biotic/abiotic stress reduction

-Remediation

-Enhancement of farm animals (increase muscle mass, improve nutritional quality, facilitate handling, less susceptible to disease)

-Enhanced photosynthesis

-Inactivation of disease mutations -Elimination of diseasecarrying vectors -Diagnostics and treatment

-Animal chimeras for human organ transplantations -Reverse pesticide resistance in insects -Production of therapeutic agents -Disease models

-Root architecture -Designer crops to improve productivity and nutritional quality -Reverse herbicide resistance in weeds -Production of biofuels -Production of pharmaceuticals

-Environmental cleaning -Production of pharmaceuticals

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Ethical issues The CRISPR/Cas9 system gives rise to significant social, ethical and regulatory questions (43, 44) due to its high accessibility, ability to make precise and specific edits of DNA in living cells, and the ability to leave no trace so that it is not possible to know whether the change has been introduced intentionally or through natural mutation, low cost, speed of use to produce results; and potential to achieve multiple simultaneous edits. The following issues were identified:

A. The balance of risks and benefits An important ethical issue in research is that benefits must be pursued and risks must be minimal. Benefits are related to potential therapeutic and industrial use. Great attention must be paid to risks, since they may damage living beings or the environment, including humans. The application of the CRISPR/Cas9 technique involves risks since it may produce off-target mutations, which can be deleterious, causing cell death or transformation (45, 46). This may occur when CRISPR/Cas9 cleaves DNA sequences within the genome that are homologous to the target DNA sequences, causing an unintended mutation. A high frequency of off-target effects has been found in human cells, but low frequency effects have been observed in mice and zebrafish (47, 48). One problem is that large genomes may contain multiple DNA sequences that are identical or highly homologous to the intended target DNA sequence. CRISPR/Cas9 may also cleave these unintended sequences causing mutations. Recently, it has been found that the technique also causes off-target mutations such as deletions and complex rearrangements which may pass undetected by standard methods (49). Mosaicism of the mutation(s) could be introduced when the CRISPR/Cas9 system repeatedly target genes at different stages of embryonic development (50). Efforts have been made to reduce off-target mutations, but further improvement is needed, especially for precise modifications needed for therapeutic interventions (13, 15, 51). Another important problem is the efficient safe delivery of CRISPR/Cas9 into cell types or tissues that are hard to transfect and/or infect and to improve the efficiency of homozygous knockout and homologous recombination, which is still low. The main challenge is to ensure the efficiency of genome editing while avoiding the introduction of unintended changes in the genome. Some scientists claim that the use of an engineered Cas9 protein must be so efficient that no off-target cutting is detectable across the whole genome, which has been reported in a few organisms (52, 53), but every organism

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must be tested. Furthermore, the possibility of an immune reaction in humans against the protein Cas9 used in genome editing must be tested. Another issue is whether the use of CRISPR/Cas9 may favor cancer growth. A recent report shows that p53 inhibits CRISPR/Cas9 engineering in human pluripotent stem cells (54, 55). The problem is that in order to use CRISPR/Cas9 with efficiency, the gene that codes p53 must be silenced, but lack of function of p53 is associated with cancer induction.

B. Gene drives and ecological disequilibrium The introduction of genetically edited organisms may provoke disequilibrium in ecosystems, since they may have advantages over related wild species. Furthermore, the use of gene drives could spread a trait through an entire population of organisms so rapidly that it would not be possible to prevent ecological effects if released into a natural environment. For example, a â&#x20AC;&#x153;gene driveâ&#x20AC;? was created in Drosophila, capable of driving a mutation in 97% of offspring in two generations by a mutagenic chain reaction (56). Gene drive actively copies a mutation made by CRISPR on one chromosome to its partner chromosome ensuring that all offspring and subsequent generations will inherit the edited genome. Once introduced these genetic changes are self-propagated. If released outside a laboratory, the effects will spread with every new generation. Critics contend that unanticipated secondary effects and unintended environmental consequences, such as eliminating a food source for other species, or promoting the proliferation of invasive pests may appear or the sequence inserted may mutate and target unwanted parts of the genome (57). Precautions must be taken since the gene drive method may transmit mutations, modified sequences or negative traits to the next generations, and also to related organisms even across political borders. The ecosystem may be affected by community dynamics and ecological factors. Examples are: disruptions of interactions with other species in the community, other plagues may be developed after target species disappear, rapid changes in the community from one configuration to another, effects over other species that have coevolved with the target species, development of mechanisms to neutralize the gene drive by target species, such as evolving resistance (58). The risk of broader ecosystem disruption is unknown and the duration of effects difficult to envision. Some researchers have warned about the risks and propose to implement ways of protecting against the accidental release of experimental organisms edited with gene drives (59).

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The National Academy of Sciences (60) contends that there is insufficient evidence available at this time to support the release of gene drive- modified organisms into the environment, but highly controlled field trials are possible. Laboratories must perform safety tests before releasing any edited organism into the environment with appropriate safeguards.

C. Regulatory mechanisms issues Since genetically modified organisms have been produced for a long time, the CRISPR technology may not appear to create new ethical problems, but the affordability and efficiency of CRISPR technology create legal concerns in need of effective and global regulation. In general, current regulations worldwide provide inadequate guidance and oversight for genome editing applications (61). It is not clear how the possibility of an expanded market using CRISPR/Cas9 beyond transgenics will be handled. One problem is that the efficacy of the CRISPR/Cas9 technique to obtain precise genetic modifications makes it more difficult to identify a genetically modified organism once outside the lab and also to regulate these organisms in the market. Regulations must clarify which limitations apply for the use of genome editing and for marketing them. Criteria for assessing the safety for human consumption need to be established. The degree of acceptance of enhancement must be assessed for farm animals, since they may be controversial or affect their well-being, for example, creating hornless cattle that are easier to handle (61). There is no unified guidance for the modification of non-human organisms by gene editing. Crops have long been genetically manipulated to make them less susceptible to disease and pests, more productive or more resistant to cold and dryness with the production of transgenics. Genome editing using the CRISPR/Cas9 system no longer requires the insertion of foreign DNA into the plant genome using a vector. For this reason, it has been suggested that CRISPR/Cas9edited organisms do not classify as transgenic and need different legislation (61). Genome editing of a few bases is difficult to detect, it could be confused with a natural mutation. Furthermore, the Animal and Plant Health Inspection Service (APHIS), an arm of the U.S. Department of Agriculture, has indicated that products resulting from CRISPR/Cas9 that only delete a gene or a few bases, would not be regulated because no new genetic material is integrated into the recipient genome. As a result, APHIS has received many requests for the non-regulation status of genome-edited products by academic centers and biotechnology companies, thus avoiding having to be reviewed for safety and efficacy by federal agencies. On the other hand, there is a requirement

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to register a commercial new plant variety for Plant Variety Protection to guarantee intellectual property rights for breeders. The European Union regulation currently operates in a different way, considering all genetically modified crops or animals as transgenic, regardless of whether they result from the insertion of foreign DNA or direct genome editing, and therefore they are subjected to regulation and risk assessment. The regulatory system requires testing for toxicity and allergy in order to be commercialized safely without risks for human consumption and ecological tests that the new crop will not become a weed or threaten endangered or beneficial species. There is concern about the generation and release of organisms edited by CRISPR/Cas9, particularly in relation to gene drives, which may fall under no particular regulation for direct potential harm to humans or domesticated animals. There is not enough monitoring to ensure the safety of CRISPRedited organisms by regulatory agencies. This does not foster public trust. Regulatory agencies should require that researchers demonstrate sufficient control mechanisms as a condition for using the CRISPR/Cas9 editing system. The ability to design organisms with desired characteristics using CRISPR technology at low cost might encourage many laboratories worldwide to do studies without sufficient containment mechanisms, which may result in the environmental release of modified organisms with lack of control over their spread. Long-term effects on the environment are more difficult to ascertain. Therefore, safety protocols need to be implemented by any laboratory performing genome editing studies. Public views are also important. In order to approve potential specific gene drives, safety and efficacy of performed edits must be rigorously tested and edited organisms should only be released into the environment after public consultation and appropriate consent of potentially affected populations with previous tests of ecological safety, including limits on organism viability and assessment of effects. The World Health Organization has outlined a phase testing pathway to test genetically modified mosquitoes, which may be useful for other tests. The approach is precautionary, step by step, with careful study and evaluation, and checkpoints to determine whether to move to the next phase and for enhancing their effectiveness (62). Regulation is also needed for surveillance and governance of potential biological weapons developed by genome editing. Another issue is the regulation of patenting. There are many economic interests involved. Patents for transgenic organisms with industrial use and human gene sequences for health purposes have been accepted for a long time as leading to the enormous growth of biotechnology. However, the

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practice of patenting may be subjected to litigation. An example is the controversy and frictions which occurred over patenting CRISPR/Cas9 for therapeutic use in humans. Researchers Zhang vs. Doudna and Charpentier disputed the patent of the technique for use in human cells (63). There is also a narrow line between invention and discovery for which the patenting of genome editing products are criticized. On one hand patenting raises the ethical issue that puts the emphasis on profit giving too much power to biotechnological companies, but on the other hand patenting may help regulate the field. Nevertheless, the emphasis must be to commercialize or release only safe products. The critics of the patent law regime consider that the regime favors the private interests of biotechnological companies over the public interest (64).

D. Caring for animal welfare Animals may suffer under gene editing experiments due to technical difficulties. Unintended mutations may produce loss of function of a gene, adverse events, and even fetal abnormalities. Therefore, any study to be performed requires ethical justification. Furthermore, current public attitudes reject research with non-human animals unless it is fully justified. Ethical assessment requires that research with experimental animals must consider whether experimental alternatives exist, whether the species used is appropriate, the number of animals used diminished, and methods to ameliorate or avoid suffering are used (65-67).

E. Military or terrorist applications An important ethical issue is the possibility of using the CRISPR/Cas9 editing system to synthesize and manipulate pathogens so as to make them dangerous for human health, which has been called genetically altered biological weapons. The ease and efficiency of CRISPR raise the concern that anyone with the appropriate equipment could engineer invasive species. Some researchers warn about the likelihood of terrorist groups developing neuro-weapons by genome editing which would modify neuroactive substances (68). The commercialization of CRISPR/Cas9 kits that are affordable by a greater number of users beyond traditional biotechnological companies and research institutions makes the creation and release of genetically altered pathogens a much easier task, challenging how this reality will be governed and regulated effectively (69).

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The Biological and Chemical Weapons Convention aims to prevent research which seeks to develop biological weapons. But, this Convention has limitations, since it has not been designed to address private companies or individuals, which as the technology moves forward, may enter more as producers.

F. Xenotransplantation or humanized animals The shortage of available human organs for transplantation is a worldwide problem in medicine. There have been many attempts to transplant animal organs to humans, but there are risks of infection by animal microorganisms and rejection by the immune system, a risk which increases when species are discordant. Scientists are looking to improve the possibility of transplanting organs from animals to humans using CRISPR/Cas9 genome editing technology by reducing the risks of zoonosis (transmission of microorganisms between animals and humans) and adverse immune response (70). Genetically modified pigs have been favored as resources in xenotransplantation. Multiple simultaneous editing followed by nuclear transfer cloning techniques or direct reprogramming of cells to gametes or zygotes could potentially develop organisms with suitable organs for transplantation. A recent study shows the possibility of inactivating porcine endogenous retroviruses in pig kidney cells by using CRSPR/Cas9 with the goal of producing virus-free transgenic pigs to grow organs for humans (71). But it is difficult to ascertain the complete removal of host pathogens, and there is concern that an unknown virus may potentially trigger new plagues through xenotransplantation. Another idea to be explored is to create chimera pigs unable to grow their own organs, introducing human stem cells so that these pigs grow human organs for xenotransplantation. The development of human/animal chimeras for organ transplantation may provide hope for many who have to wait valuable time for a human organ donor to become available. One problem identified, however, is that the formation of animal/human chimeras may carry human neural and germ cells (72). Chimeras have raised ethical concerns over their risk and the violation of the order of nature, producing moral confusion on how to treat the organism â&#x20AC;&#x201C; as an animal or human (72, 73). For some, chimera embryos possess the potential to develop organisms with human-derived cells or tissue, which may affect the identity of the human species, affecting its dignity. It may be argued, however, that an organism containing human cells does not convert the being into a human, nor does this affect its dignity. The human-like

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characteristics associated with the chimera are only of a biological nature, they do not affect the moral status of the animal, and the animal does not achieve consciousness. Another ethical concern is the pressure exerted to use primates as organ donors, due to their similarity to humans.

G. Application of CRISPR/Cas9 technique to human germ-line Ethical concerns have been raised regarding the possibility of genome editing in the human germ-line, since genome changes can be transmitted to the following generations, be they from gametes, a fertilized egg or from first embryo divisions. For example, there will be problems in how to implement informed consent when there are risks and the effects could be transmitted to several generations (74, 75). Until now, all therapeutic interventions in humans using genome editing have been performed in somatic cells, but the use of genome editing may facilitate experimentation in the germ-line. In general, therapeutic genome editing interventions in somatic cells are ethically acceptable, if consideration is given to balancing the risks and benefits and the use of informed consent. But experimenting in germ-line cells adds responsibility for future generations, particularly when the technique may produce mutations, side effects and unpredictable changes which will be transmitted. In light of the possibility to alter human genes, some scientists are calling for a moratorium on applying CRISPR/Cas9 to the human germ-line, since they do not see the technique as developed enough for any clinical use in making inheritable changes to humans (76). UNESCO in the Universal Declaration on the Human Genome and Human Rights had recommended in 1997 a moratorium for intervening in the human germ-line genetically due to the risks involved for future generations. Recently, in 2015, the International Summit on Human Gene Editing, which gathers members of the national scientific academies of America, Britain, and China, discussed the ethics of germ-line modification, and decided that altering gametocytes and embryos to generate inheritable changes in humans is irresponsible in the present state of the genome editing technique. In addition, they agreed to initiate an international forum where these concerns would be continuously addressed, and regulations in research harmonized across countries (77). The U.S. National Institute of Health issued a statement, calling for a moratorium, banning NIH-funded research into genomic editing of human embryos (78). However, some countries are already accepting interventions in the germline. In February 2016, British scientists were given permission by

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regulators to genetically modify human embryos by using CRISPR/Cas9 and related techniques only for research (79, 80). The Nuffield Council on Bioethics accepts ethical gene editing to avoid inherited diseases, provided interventions are secure and consistent with the welfare of future persons (81). Furthermore, the National Academies of Sciences, Engineering, and Medicine in its document Human Genome Editing: Science, Ethics, and Governance Report of 2017 accepts clinical trials using heritable genome editing (82) but only under a robust and effective regulatory framework encompassing: -

the absence of reasonable alternatives; restriction to preventing a serious disease or condition; restriction to editing genes that have been convincingly demonstrated to cause or to strongly predispose to that disease or condition; restriction to converting such genes to versions that are prevalent in the population and are known to be associated with ordinary health with little or no evidence of adverse effects; the availability of credible preclinical and/or clinical data on risks and potential health benefits of the procedures; ongoing, rigorous oversight during clinical trials of the effects of the procedure on the health and safety of the research participants; comprehensive plans for long-term, multigenerational follow up that still respect personal autonomy; maximum transparency consistent with patient privacy; continued reassessment of both health and societal benefits and risks, with broad ongoing participation and input by the public; and reliable oversight mechanisms to prevent extension to uses other than preventing a serious disease or condition.

Currently however, the risks of hereditable unpredictable genetic mutations are greater than the possible benefits of therapy, affecting the principle of non-maleficence. The technique should be fully safe in order to try therapy in the germ-line. Furthermore, if damage were introduced, there would be a problem as to who would be liable for the damage to the following generations. Once genome editing reaches a sufficient margin of safety to allow clinical applications for preventing the development of genetic diseases, further discussion will be needed, with respect to the social, legal and ethical implications and the need of regulatory norms to avoid abuses due to germline genome editing interventions.

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H. Genome editing for enhancement of human characteristics Another ethical issue that must be discussed is the possibility of nontherapeutic interventions using genome editing. Its use in the germ-line is banned for safety reasons. But, the efficiency of the CRISPR/Cas9 technique increases the possibility to intervene in somatic cells in order to match genetics to our life interests. Many phenotypic characteristics have a genetic component, apart from the environment, which could be intervened with. For some scientists there is no moral base to restrict human beings from altering their nature, so that genome editing interventions may be a way to avoid difficulties and enhance the human way of life. For example, the technique could be used to enhance the immunological system to resist infections and cancer; to reduce the need of the body to sleep while maintaining attention capability; to increase the power of memory; to enhance performance of athletes; to prevent violent behavior; to diminish addiction; to delay aging thereby prolonging life expectancy (83, 84). In fact, there is a narrow line between enhancement, disease, and prevention for which social deliberation with public involvement is needed. Generally, gene therapy looks to improve the health of a patient for its own benefit, but it may be envisioned that in the future the technique could be used to enforce eradication of social problems; for example, the criminal justice system could mandate genome editing of genes related to violence for repeat offenders or violent dangerous criminals (85). If the intervention is done during development it is questionable whether parents or guardians should be allowed to decide the future characteristics of offspring for non-health reasons. Socially, there would be a problem if some populations or individuals were to be enhanced genetically and thus have an advantage over others. The main social risk is to produce categories of persons according to characteristics, some would be more worthy than others giving rise to discrimination and stigmatization. Equity would be very difficult to achieve, more at international level since the access to genome technology is only possible for those with resources, most probably social differences would increase. However, The Nuffield Council on Bioethics ethically accepts gene editing for enhancement provided interventions are secure and they do not increase disadvantage, discrimination or division in society (86).

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Table 5.2 Ethical, social and legal issues (compiled by the authors) Risks

Environment

Regulation

Human germ-line interventions

Human enhancement interventions

-Of target effects

-Ecological disequilibrium

-Regulation of marketing

-Damage to future generations

-On target mutations

-Unknown environmental effects

-Safety laboratory measures

-Group Disadvantages or social divisions

-Effects on animal well-being Mosaicism

-Patenting -Development of biological weapons

-Modifying human nature -Unknown long-term effects

-Discrimination -Stigmatization -Increased inequalities

-Power of Biotechnological companies

Bioethical issues Bioethics reflection favors a horizontal discourse between experts and lay people, which demand transparency in the information about the benefits and risks of genome editing organisms. The following governing principles consider the way scientific ethical review committees may evaluate genome editing interventions (82): 1) The principle of autonomy, which acknowledges and respects the capacity of individuals to take personal decisions. Under this principle, it is important to consider: information that must be provided in the process of informed consent, ways of protection of privacy and confidentiality. 2) The principle of respect for the dignity of persons, which recognizes the personal dignity of individuals. This principle considers that every person has equal moral value regardless of genetic qualities. Under this principle it is important to consider: how to prevent abusive forms of eugenics and avoid stigmatization and discrimination. 3) The principles of beneficence and non-maleficence, or promoting well-being, which means enhancing benefits and preventing harm to those affected. Under these principles it is important to consider:

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observations aimed at minimizing risks and potential harm and maximizing potential benefits, issues of ensuring a reasonable balance of risk and benefit for any application of genome editing, issues of protection for vulnerable populations and protections against induced harm. It is relevant to consider the precautionary principle set out in the Rio Declaration on Environment and Development (Principle 15) which requires that reasonable measures should be taken to anticipate potential serious and undesirable consequences to the environment even without scientific proof. The principle of justice or fairness, which encompasses impartiality and equitable distribution of risks and benefits under distributive justice. Under this principle, it is important to consider: fair selection of participants, appropriate distribution of risks and burdens on one hand and broad and equitable access to benefits. The principle of due care for people enrolled in genome editing procedures, which requires proceeding carefully and deliberately, and only when supported by sufficient and robust evidence. Under this principle, it is important to consider: cautious procedures, appropriate supervision and ways that allow frequent reassessment in light of future advances and cultural opinions. The principle of responsible science, which requires adherence to the highest standards of research in accordance with international and professional norms. Under this principle it is important to consider: high quality experimental design and analysis, appropriate review and evaluation of protocols and resulting data and correction of false or misleading data or analysis. Care must also be taken with respect to conflicts of interest so that decisions must be guided by the idea of the common good and not by financial interests. The principle of transnational cooperation, which supports a commitment to collaborative approaches to research and governance while respecting different cultural contexts. Under this principle, it is important to consider: respect for differing national policies, coordination of regulatory standards and procedures whenever possible, and transnational collaboration and data sharing among different scientific communities and responsible regulatory authorities. The principle of respecting cultural values and transparency in information about new developments. Under this principle, it is important to consider: mechanisms of communication of scientific breakthroughs to the public, cultural values that must be protected, public engagement in policymaking.

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Animal experimentation requires that experimental organisms do not suffer unnecessarily, especially when working with sentient living beings. Bioethical reflection considers the human being as able to transform nature, but nature also has the power to modify human beings and any damage inflicted ends up also affecting human beings (87). Interference with the balance of nature is particularly relevant when releasing modified organisms into the environment. Natural processes build stable ecosystems which may lose their balance under human intervention with potential damage. There are some discussions regarding technological interventions to modify the genome of organisms since modifying their way of life may affect their intrinsic value. Having intrinsic value means that organisms are ends in themselves regardless of whether they are useful as means to other ends. The possession of an intrinsic value generates the moral duty of humans as moral agents to protect organisms or at least refrain from damaging them. One position holds that it is wrong to intervene in organisms artificially and the other position holds that respect for non-human organisms imposes limits over human interventions (88). Some scientists question whether intervening directly in the genome is different from other ways of manipulating nature, such as selective breeding of plants and animals, and it is generally thought that the difference lies in the role in inheritance and the potential scale, seriousness, and unpredictability of effects (1). Beliefs and the sacredness of nature also form part of the discussion, and there are power struggles in controlling the economic power of patents. The global culture imposes a society moved by profit in which the use of natural resources has no limit while there are benefits, but there is responsibility with possible risks involved. Furthermore, there is a responsibility to future generations. Hans Jonas has reflected on the principle of responsibility for future generations, affecting not only human beings, but all living beings. We have a responsibility to ensure that future generations will have an environment that is at least as biodiverse as the present one (89). Human beings have great power over nature with the genome editing technique and are responsible for taking the risks into account. Ethically, there should be limits to human intervention. And it should be remembered that living beings are not just objects, subject to appropriation. It is important to have an inclusive public sphere in which to engage society in discussions about genome editing. The ethical, legal and social debate in relation to genome editing is particularly necessary for international forums

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where consensus may be achieved between civilians, genome researchers, experts in bioethics, religious scholars, industrialists, sociologists and policymakers (90). Public engagement can help to frame and define the risks of gene drive-modified organisms and provide input into practical decisionmaking and policy issues related to genome editing. The outcomes of public engagement may be as crucial as the scientific outcomes to decisions about whether to release a gene drive-modified organism into the environment. Engagement requires effort, attention, resources, and advanced planning.

Conclusion While the use of the CRISPR/Cas9 system in genome editing may have many potential beneficial applications, there are ethical, social and regulatory problems that are not yet fully resolved and which should not be overlooked. Adequate regulation must oversee the prohibition of using CRISPR/Cas9 with the intent of damaging others or the possibility of laboratories that lack adequate containing mechanisms working with the technique. Safety issues and environmental risk assessment must be enhanced to ensure efficacious regulation and precautions must be taken to oversee laboratories that use CRISPR technology. Commercialization of genome edited products must be regulated. Furthermore, ecological risk assessments are not sufficiently well developed to release organisms carrying gene drives. Public engagement and expert opinions over the social, ethical and legal implications of using the genome editing technique are needed to inform decision-making in relevant issues, such as taking into account the nonmaleficence and precautionary principles in risk assessment, creation of human-animal chimeras for organ transplantation, safety issues to avoid ecological impairment, germ-line interventions in humans or the possible use of the technique for genetic enhancement.

References 1. 2. 3.

Nuffield Council on Bioethics. Genome editing: an ethical review. http://www.nuffieldbioethics.org. 2016. Zhu LJ. “Overview of guide RNA design tools for CRISPR/Cas9 genome editing technology”. Front Biol 2015; 10: 289-296. Barrangou R., Fremaux C., Deveau H., Richards M., Boyaval P., Moineau S., Romero DA., Horvath P. “CRISPR provides acquired resistance against viruses in prokaryotes”. Science 2007; 315 (5819): 1709-1712.

Ethical Issues in Genome Editing using CRISPR/Cas9 System 4. 5. 6. 7. 8. 9.

10. 11. 12. 13. 14. 15. 16.

17. 18. 19.

117

Marraffini LA., Sontheimer EJ. “CRISPR interference limits horizontal gene transfer in staphylococci by targeting DNA”. Science 2008; 322 (5909): 1843-1845. Jansen R., Embden JD., Gaastra W., Schouls LM. “Identification of genes that are associated with DNA repeats in prokaryotes.”Molecular Microbiology2002; 43 (6): 1565-1575. Pennisi E. “The CRISPR craze”. Science 2013; 341 (6148): 833-836. Doudna J., Charpentier E. “The new frontier of genome engineering with CRISPR/Cas9”. Science 2014; 346. Jinek M., Chylinski K., Fonfara I., Hauer M, Doudna JA., Charpentier E. “A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity”. Science 2012; 337 (6096): 816-821. Hsu PD., Scott DA.,Weinstein JA., Ran FA., Konermann S., Agarwala V., Li Y., Fine E J.,Wu X., Shalem O., Cradick TJ., Marraffini LA., Bao G., Zhang F.“DNA targeting specificity of RNA-guided Cas9 nucleases”. Nat Biotechnology 2013; 31(9): 827-832. Rouet P., Smith F. and Jasin M. “Expression of a site-specific endonuclease stimulate homologous recombination in mammalian cell”. Proc. Natl Acad. Sci. U.S.A. 1994; 91, 6064-6068. Eid A., Alshareef S., Mahfouz MM. “CRISPR base editors: genome editing without double-stranded break”. Biochemical Journal. 2018; 475(11): 19551964. Chen L., Tang L., Xiang H., Jin L., Li Q., Dong Y., Wang W. and Zhang G. “Advances in genome editing technology and its promising application in evolutionary and ecological studies”. GigaScience 2014; 3:24. Cong L., Ran FA., Cox D., Lin S., Barretto R., Habib N., Hsu PD., Wu X., Jiang W., Marraffini LA., Zhang F. “Multiplex genome engineering using CRISPR/Cas systems”. Science 2013; 339(6121): 819-823. Mali P., Esvelt KM., Church GM., “Cas9 as a versatile tool for engineering biology”. Nature Methods 2013; 10 (10): 957-63. Ma Y., Zhang L., Huang X. “Genome modification by CRISPR/Cas9”. FEBS J. 2014; 281(23):5186-93. Hendel A., Bak RO., Clark JT., Kennedy AB., Ryan DE., Roy S., Steinfeld I., Lunstad BD., Kaiser RJ., Wilkens AB., Bacchetta R., Tsalenko A., Dellinger D., Bruhn L., Porteus MH. “Chemically modified guide RNAs enhance CRISPR-Cas genome editing in human primary cells”. Nature Biotechnology 2015; 33: 985-989. Jamal M., Ullah A., Ahsan M., Tyagi R., Habib Z., Khan FA., Rehman K. “Treating Genetic Disorders Using State-Of-The-Art Technology”.Curr Issues Mol Biol. 2018; 26: 33-46. Larson MH., Gilbert LA., Wang X., Lim WA., Weissman JS., Qi LS. “CRISPR interference (CRISPRi) for sequence-specific control of gene expression”". Nature Protocols 2013; 8 (11): 2180-2196. Shalem O., Sanjana NE., Hartenian E., Shi X., Scott DA., Mikkelsen TS., Heckl D., Ebert BL., Root DE., Doench JG., Zhang F. “Genome-scale

118

20. 21. 22. 23. 24. 25.

26. 27. 28. 29. 30.

31. 32. 33. 34.

Chapter 5 CRISPR/Cas9 knockout screening in human cells”. Science 2014; 343 (6166): 84-87. Blasco RB., et al .“Simple and rapid in vivo generation of chromosomal rearrangements using CRISPR/Cas9 technology”. Cell reports 2014; 9(4):1219-1227. Choi PS., Meyerson M. “Targeted genomic rearrangements using CRISPR/Cas technology”. Nat Commun. 2014; 5:3728. Rath D., Amlinger L., Rath A., Lundgren M. “The CRISPR-Cas immune system: Biology, mechanisms and applications”. Biochimie 2015; 117: 119128. Cain L., Fisher AL., Huang H., Xie Z. “CRISPR-mediated genome editing and human diseases”. Genes and Diseases 2016; 3 (4): 244-251. Saayman S., Ali SA., Morris KV., Weinberg MS. “The therapeutic application of CRISPR/Cas9 technologies for HIV”. Expert Opin Biol Ther.2015;5(6):819-830. Schwank G., Koo BK., Sasselli V., Dekkers JF., Heo I., Demircan T., Sasaki N,.Boymans S., Cuppen E., van der Ent CK., Nieuwenhuis EE., Beekman JM., Clevers H. “Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients”. Cell Stem Cell 2013; 13(6):653-658. Rohn TT., Kim N., Isho NF., & Mack, JM. (2018). “The Potential of CRISPR/Cas9 Gene Editing as a Treatment Strategy for Alzheimer’s Disease.” Journal of Alzheimer’s Disease & Parkinsonism, 8(3): 439. Shin JW., Kim KH., Chao MJ., Atwal RS., Gillis T., et al. “Permanent inactivation of Huntington’s disease mutation by personalized allelespecific CRISPR/Cas9”. Hum Mol Genet. 2016;25:4566-4576. Kolli N., Lu M., Maiti P., Rossignol J., Dunbar GL. “CRISPR-Cas9 mediated gene-silencing of the mutant Huntington gene in an in vitro model of Huntington’s disease”. Int J Mol Sci. 2017:18. Chin A. “CRISPR/Cas9 Therapeutics: A Technology Overview”. Oxford Biotechnology 2015. Freedman BS., Brooks CR., Lam AQ., Fu H., Morizane R., Agrawal V., Saad AF., Li MK., Hughes MR., Werff RV., Peters DT., Lu J., Baccei A., Siedlecki AM., Valerius MT., Musunuru K., McNagny KM., Steinman TI., Zhou J., Lerou PH., Bonventre JV. “Modeling kidney disease with CRISPRmutant kidney organoids derived from human pluripotent epiblast spheroids. ”Nature Communications2015; 6: 8715. Maggio I., Gonçalves MA. “Genome editing at the crossroads of delivery, specificity, and fidelity”. Trends Biotechnol. 2015; 33 (5): 280-291. Shapiro B.” Mammoth 2.0: will genome engineering resurrect extinct species?” Genome Biology2015; 16(1): 228. Shan Q., Wang Y., Li J., Zhang Y., Chen K., Liang Z., Zhang K., Liu J., Xi JJ., Qiu JL. et al. “Targeted genome modification of crop plants using a CRISPR-Cas system.” Nat Biotechnol 2013; 31: 686-688. Xie K. and Yang Y. “RNA-guided genome editing in plants using a CRISPR-Cas system”. Mol Plant 2013; 6: 1975-1983.

Ethical Issues in Genome Editing using CRISPR/Cas9 System 35. 36. 37. 38.

39. 40. 41.

42.

43. 44. 45. 46. 47. 48. 49.

119

Fen Z., Zhang B., Ding W., Liu X., Yang DL., Wei P., Cao F., Zhu S., Zhang F., Mao Y. and Zhu JK. “Efficient genome editing in plants using a CRISPR/Cas system”. Cell Res 2013; 23: 1229-1232. Mao Y., Zhang H., Xu N., Zhang B., Gou F. and Zhu JK. “Application of the CRISPR-Cas system for efficient genome engineering in plants”. Mol Plant 2013; 6: 2008-2011. Schaeffer SM., Nakata PA. “CRISPR/Cas9-mediated genome editing and gene replacement in plants: Transitioning from lab to field”. Plant Sci. 2015; 240:130-142. Feng W., Dai Y., Mou L., Cooper DKC., Shi D. and Cai Z. “The Potential of the Combination of CRISPR/Cas9 and Pluripotent Stem Cells to Provide Human Organs from Chimaeric Pigs”. Int. J. Mol. Sci. 2015; 16(3): 65456556. Gantz VM. and Bier E. “The mutagenic chain reaction: A method for converting heterozygous to homozygous mutations”. Science 2015; 348:442-444. Esvelt KM. “Concerning RNA-guided gene drives for the alteration of wild populations”. eLife 2014; 17: e03401. Gantz VM., Jasinskiene N., Tatarenkova O., et al. (2015).“Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi”. Proceedings of the National Academy of Sciences 2015; 112(49):E6736-43.112(49):E6736-43. Liang P., Xu Y., Zhang X., Ding C., Huang R., Zhang Z., Lv J., Xie X., Chen Y, Li Y, Sun Y, Bai Y, SongyangZ., Ma W., Zhou C., Huang J. “CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes”. Protein Cell2015; 6 (5): 363-72. Rodriguez E. “Ethical issues in genome editing using CRISPR/Cas9 system”. Journal of Clinical Research and Bioethics 2016; 7: 266. Rodriguez E. “Ethical issues in genome editing for non-human organisms using CRISPR/Cas9 system”. Journal of Clinical Research and Bioethics 2017; 8 (2): 300. Hwang WY., Fu Y., Reyon D., Maeder ML., Tsai SQ., Sander JD. “Efficient genome editing in zebrafish using a CRISPR-Cas system”. Nature Biotechnology 2013; 31: 227-229. Yang H., Wang H., Shivalila CS., Cheng AW., Shi L., Jaenisch R. “One step generation of mice-carrying reported and conditional alleles by CRISPR/Cas-mediated genome engineering”. Cell 2013; 154: 1370-1379. Fu, Y., Foden, JA., Khayter, C., Maeder, ML., Reyon, D., Joung, JK. and Sander, JD. “High-frequency off-target mutagenesis induced by CRISPRCas nucleases in human cells”. Nat Biotechnology 2013; 31: 822-826. Zhang X-H., Tee LY., Wang X-G., Huang Q-Sand., Yang S-H. “Off-target Effects in CRISPR/Cas9-mediated Genome Engineering”. Molecular Therapy Nucleic Acids 2015; 4: e264. Kosicki M., Tomberg K., Bradley A. “Repair of double-strand breaks induced by CRISPR–Cas9 leads to large deletions and complex rearrangements”. Nat. Biotechnol. 2018 Sep; 36(8): 765-771.

120 50. 51.

52. 53. 54.

55. 56. 57. 58. 59. 60.

61.

62.

Chapter 5 Wang H. et al. “One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering”. Cell 2013; 153: 910918. Hsu PD., Scott DA., Weinstein JA., Ran FA., Konermann S., Agarwala V., Li Y., Fine EJ., Wu X., Shalem O., Cradick TJ., Marraffini LA., Bao G.and Zhang F. “DNA targeting specificity of RNA-guided Cas9nucleases”. Nat Biotechnol 2013; 31: 827-832. Kleinstiver BP., Pattanayak V., Prew MS., et al. “High-fidelity CRISPRCas9 nucleases with no detectable genome-wide off-target effects”. Nature 2016; 529(7587): 490-95. Slaymaker IM., Gao L., Zetsche B., et al. “Rationally engineered Cas9 nucleases with improved specificity”. Science 2016; 351(6268): 84-8. Ihry RJ., Worringer KA., Salick MR., Frias E., Ho D., Theriault K, Kommineni S., Chen J., Sondey M., Ye C., Randhawa R., Kulkarni T., Yang Z., McAllister G., Russ C., Reece-Hoyes G., Russ C., Reece-Hoyes J., Forrester W., Hoffman GR., Dolmetsch R., Kaykas A. “p53 inhibits CRISPR-Cas9 engineering in human pluripotent stem cells”. Nature Medicine 2018; 24: 939-946. Haapaniemi E., Botla S., Person J., Schmierer B., Taipale J. “CRISPR–Cas9 genome editing induces a p53-mediated DNA damage response”. Nature Medicine 2018; 24: 927-930. Gantz VM. and Bier E. “The mutagenic chain reaction: A method for converting heterozygous to homozygous mutations”. Science 2015; 348(6233): 442-4. Oye, KA., Esvelt K., Appleton E., Catteruccia F., Church G., Kuiken T., Lightfoot SB., McNamara J., Smidler A., Collins JP. “Regulating gene drives”. Science 2014; 345:626-628. Ledford H. “CRISPR, the disruptor.”Nature News 2015; 522 (7554): 20-24. Esvelt KM. “Concerning RNA-guided gene drives for the alteration of wild populations”. eLife 2014; 17: e03401. National Academies of Sciences. Engineering, and Medicine. Gene Drives on the Horizon: Advancing Science, Navigating Uncertainty, and Aligning Research with Public Values. Washington, D.C: The National Academies Press, 2016. Caplan AL., Parent B., Shen M., et al. “No Time to Waste—the Ethical Challenges Created by CRISPR: CRISPR/Cas, Being an Efficient, Simple, and Cheap Technology to Edit the Genome of Any Organism, Raises Many Ethical and Regulatory Issues beyond the Use to Manipulate Human GermLine Cells”. EMBO Reports 2015; 16.11: 1421-1426. WHO (World Health Organization). The Guidance Framework for Testing Genetically Modified Mosquitoes. 2014. [April 19, 2016]. (World Health Organization, Programme for Research and Training in Tropical Diseases).http://apps.who.int/iris/bitstream/10665 /127889/1/9789241507486_eng.pdf?ua=1

Ethical Issues in Genome Editing using CRISPR/Cas9 System 63. 64. 65. 66. 67. 68. 69. 70. 71. 72. 73. 74. 75.

76. 77.

78.

121

Smith-Willis H. and San Martín B. “Revolutionizing genome editing with CRISPR/Cas9: patent battles and human embryos”. Cell and Gene Therapy Insights 2015; 1(2): 253-62. Piccioto S. “Private rights vs. public interests in the TRIPS agreement”. Proceedings of the Annual Meeting (American Society of International Law) 2003; 97: 167-72. Blakemore C., Clark JM., Nevalainen T., Oberdorfer M., Sussman A. “Implementing the 3Rs in neuroscience research: a reasoned approach”. Neuron2012; 75 (6): 948-950. Russell WMS., Burch RL. The Principles of Humane Experimental Technique. Methuen; London: 1959. National Research Council. Guide for the Care and Use of Laboratory Animals. National Academies Press; Washington D.C: 2011. www.nap.edu. DiEuliis D., Giordano J. “Why Gene Editors Like CRISPR/Cas May Be a Game-Changer for Neuroweapons”. Health Security 2017; 15(3): 296-302. Pope SM. “Impact of Gene Editing Tools, Like CRISPR/Cas9, on the Public Health Response to Disease Outbreaks”. Disaster Med Public Health Prep. 2017 Apr; 11(2): 155-159 Fung RK., Kerridge IH. “Gene editing advance re-ignites debate on the merits and risks of animal to human transplantation”. Intern Med J. 2016; Sep;46(9):1017-22. Niu, D., Wei, H.-J., Lin, L., George, H., Wang, T., Lee, I.-H., … Yang, L. “Inactivation of porcine endogenous retrovirus in pigs using CRISPRCas9”. Science (New York, N.Y.) 2017; 357(6357): 1303-1307. Hermerén G. “Ethical considerations in chimera research”. Development 2015; 142(1):3-5. Hyun I. “From naïve pluripotency to chimeras: a new ethical challenge?” Development 2015; 142(1):6-8. Billings PR., Hubbard R., Newman SA. “Human germ-line gene modification: a dissent.” Lancet 1999; 353(9167):1873-1875. Frankel MS., Chapman AR. American Association for the Advancement of Sciences. Human Inheritable Genetic Modifications. Assessing Scientific, Ethical, Religious and Policy Issues 2000, http://www.aaas.org/spp/dspp/sfrl/germline/main.htm: 1-82. Lanphier E., Urnov F., Haecker SE., Werner M., Smolenski J. “Don't edit the human germ-line”. Nature 2015; 519 (7544): 410-411. Steven O. (Ed.). Committee on Science, Technology, and Law; Policy and Global Affairs; National Academies of Sciences, Engineering, and Medicine. International Summit on Gene Editing 2015. http://www.nap.edu/catalog/21913/international-summit-on-humangeneediting-a-global-discussion. Collins F. Statement on NIH funding of research using gene editing technologies in human embryos. The NIH Director – National Institutes of Health (NIH) 2015. http://www.nih.gov/about-nih/who-we-are/nih-director/ statements/statement-nih-funding-research-using-geneeditingtechnologies-human-embryos.

122 79. 80.

81. 82. 83.

84. 85. 86. 87. 88. 89. 90.

Chapter 5 Gallagher J. “Scientists get 'gene editing' go-ahead”. BBC News (BBC) 2016. http://www.bbc.com/news/health-35459054. Cheng M. “Britain approves controversial geneediting technique”. AP News 2016, http://bigstory.ap.org/article/fdda5bf9f0314b748c7438c9659da83a/britainapproves-controversial-geneediting-technique. Nuffield Council on Bioethics. Report on human genome editing, 2018. National Academies of Sciences, Engineering, and Medicine. Human Genome Editing: Science, Ethics, and Governance. Washington, D.C: The National Academies Press, 2017. Camporesi S., Maugeri P. “Genetic Enhancement in Sports: The Role of Reason and Private Rationalities in the Public Arena.” Cambridge quarterly of healthcare ethics: CQ: the international journal of healthcare ethics committees. 2011; 20(2):248-257. So D., Kleiderman E., Touré SB., Joly Y. “Disease Resistance and the Definition of Genetic Enhancement”. Frontiers in Genetics. 2017; 8:40. Polcz S. and Lewis A. “CRISPR/Cas9 and the Non-Germ-line NonControversy”. Journal of Law and the Biosciences 2016: 1-13. https://wwwcdn.law.stanford.edu/wp-content/uploads/2016/06/jlb.lsw016.full_.pdf. Nuffield Council on Bioethics. Ideas about naturalness in public and political debates about science, technology and medicine, available at: http://nuffieldbioethics.org/project/naturalness/the-findings/. 2015. Velayos C. “La dimensión moral del ambiente natural: ¿Necesitamos una nueva ética?” Editorial Comares; Granada: 1996. Jamieson, D. Morality’s Progress: Essays on Humans, Other Animals, and the Rest of Nature, Oxford: Clarendon Press, 2002. Jonas H. El Principio de Responsabilidad. Barcelona: Círculo de Lectores/Herder; 1995. Shinwari ZK., Tanveer F., Khalil AT.“Ethical Issues Regarding CRISPR Mediated Genome Editing”. Curr Issues Mol Biol. 2018; 26: 103-110.

SECTION III: MENTAL HEALTH

CHAPTER 6 ETHICAL ISSUES IN MENTAL HEALTH RESEARCH

Abstract As in other fields of medicine, ethical analysis and reflection in mental healthcare can center on many different activities. The aim is always to generate behavior in accordance with individual beliefs, societal customs, cultural norms, and respect for human dignity. The following ethical issues are reflected: the role of ethical review committees, risks and safety assessment, dependence, coercion, fair and equitable inclusion, heterogeneity, values morally relevant (honesty, authenticity, personal identity, fairness, social consequences), non-therapeutic use of nootropics (pharmacological cognitive enhancers).

Introduction The elusive term mental health has replaced psychiatry as the core topic of research associated with individual well-being, madness, behavioral problems, and social stress. Mental health refers to well-being, prevention of mental disorders, therapy and rehabilitation of persons affected by mental disorders. The exact definition of the term is a matter of debate, as reflected in the influential Lancet series epitomized as â&#x20AC;&#x153;no health without mental healthâ&#x20AC;? (1). Irrespective of the vagueness in the scope of the term and the evident tautology implicit in the designation, some of the most pressing needs in global health research pertain to psychological and behavioral disorders. World Health Organization data show that mental health disorders continue to be one of the health problems that have a major impact on peopleâ&#x20AC;&#x2122;s quality of life and on budget costs for individuals, society and healthcare systems (2). According to the World Health Organization (WHO), 32% of all years-lived-with disability is due to neuropsychiatric conditions, most commonly unipolar depression (11.8%), alcohol abuse (3.33%), bipolar depression (2.4%) and dementia (1.6%).

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This is particularly true in Low and Middle-Income Countries (LMIC) or, taken more generally, in resource-poor settings (RPS). The need for better services, equitable access, trained personnel and regulated interactions between private and public institutions demands that evidence-based interventions based on sound research results, adequate and culture fair knowledge production and affordable practices at the community and individual levels. Mental health is neglected in country health budgets and research faces difficulties. The “one-size-fits-all approach” imposed by Western views on mental illnesses and psychiatric care ignores the “multiple models” of health and healing existing in different cultures and supports the notion that the “ethic” approach supported by most Westerntrained researchers and its biomedical foundation is the only acceptable one to tackle problems associated with knowledge production and delivery of services. This “social projection” or “false consensus bias” results in obvious disregard for the axiological dimensions of diagnosis, prognosis, and treatment (3). The complex interactions between ethics, politics, and technology in the practice of biomedical research are seldom addressed in standard publications (4). The editors of psychiatric journals give preference to empirical data obtained through scientifically rigorous methods. While evidence-based interventions are welcome, the value-based nature of the psychiatric research enterprise tends to be forgotten. In the field of mental health research, ethical competence may be equated with cultural competence (5) since it is an acknowledged fact that sociocultural determinants are critical in shaping the illness experience, service demand, and even the definition of what properly constitutes mental health in a positive sense (6). Research is an activity that changes the human capital and the conceptual background of a profession. Research is, in and by itself, an autonomous activity. Being a researcher implies adherence to certain rules of conduct beyond those that must be honored by practitioners and defenders of the profession. If a common ethos is said to exist, in the case of researchers this ethos must be qualified by certain conditions. Almost all modern professions owe their prestige to the existence of an accepted knowledge base demanding specialized studies, appropriate socialization in the rules of gathering facts, generating information and creating valid, generalized and reliable knowledge. It is this knowledge base that gives professionals the certitude of being accepted as experts by the population at large. It is based on their prestige and the trust deposited in them by society (7).

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Values in mental health research (7) The mental health field is more exposed to forgeries, false claims of miraculous achievements or cures or wonderful feats of the imagination than most other fields. Expectations are so high that people would like to have happiness, health, and wealth just by resorting to the mental health professional. In order to be socially useful, scientific knowledge must be constructed in accordance with certain values. Values are those features of activities and things that confer them meaning in a given context. In psychology, we find instrumental and moral values. Among the instrumental values, that is, those guidelines that ensure the quality of knowledge, certainly the most important ones are truthfulness, integrity, and respect for peers. These values, and many others of their kind are the backbone of good research practice. Moral values, on the other hand, refer to qualities that complement instrumental considerations. If these can be considered a means to achieve ends, true moral values are ends in themselves. A long tradition of research involving human beings has demonstrated that moral values have not always guided research practices. Sometimes, in the name of science, human dignity was ignored, sordid practices were allowed and suffering was imposed upon innocent or defenseless people. The first moral imperative in research is technical. Any project not sufficiently grounded on an accepted tradition of inquiry or insufficiently formulated leads to the loss of time, money, and human life. A research protocol without adequate consideration of previous work, faulty research design, or improper handling of data is already unethical, even before it starts. But beyond the instrumental values that ensure technical quality, moral values, those permanent invariants of Western culture so laboriously achieved and perpetuated, are the key to the social standing of the profession, the respect it deserves, and the trust necessary for achieving acceptable ends. Sound methodology, exigent training, and appropriate certification by accredited bodies are preconditions for a good appreciation of a modern profession. In addition, cultural factors must be taken into account. This is better considered from the standpoint of social relevance. A true response to social demands is always in consonance with the expectations and characteristics of the populations it claims to serve. This is not easy to

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discern in an era of globalization, but everyone knows what is appropriate and what is not in the place where he or she works. This is also a moral imperative. Without research based on sound instrumental and moral values, a profession is not really a profession with a future in a postmodern world. It is just a trade, devoid of the true background that modern developments are so much in need of. In the training of future professionals, some of them must be reserved for the activity we call research: the renovation of manpower and ideas through the creation of valid, generalized and reliable knowledge.

Principles of bioethics in mental health research (8) Psychiatric research faces the same demands as biomedical or biological research, with the proviso, however, that it may incorporate areas that would fall on what we may loosely call "the social sciences". Such is the case, for instance, of studies on the efficacy of the psychotherapies or on the implementation of alternative models for mental healthcare, where perceptions of the subjects and participants cannot be excluded as "research noise" and therefore become part of the very interventions under study. Among other considerations, the placebo debate in psychiatry is far more complicated than in purely organic medicine (9). Perhaps the most widely known documents regarding the ethics of human research are the Declaration of Helsinki, the Belmont Report, the Council of International Organizations for Medical Science (CIOMS) Guidelines, and the European Guidelines. Key topics in all these documents are informed consent on the part of research participants, independent review of ethical aspects of the proposals, community benefits after completion of clinical trials, the distinction between research with therapeutic benefits for participants and research with the sole aim of furthering knowledge, and research with vulnerable populations or incompetent subjects. Consideration is also given to conflicts of interests, financial or otherwise, research with children and pregnant women, and the dilemmas associated with confidentiality, privacy and the dissemination of scientific or factual information. It has become customary to use the conceptual framework of principilism to address and formulate ethical dilemmas in medicine. According to this position, there exist prima facie principles, at an intermediate level between universal values and practical norms of conduct. The Belmont Report

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introduced the idea that the principles behind moral reasoning in research with human subjects can be subsumed under general headings such as autonomy, beneficence, non-maleficence, and justice. Textbooks and a wide body of literature have given currency to the usefulness of formal principles in dealing with case analysis. It should be noted, however, that the term "formal" in this context means that each of the principles may have different expressions or contents in different cultures or institutional environments. Autonomy, for example, although univocal in the grammatical sense, is different in an Islamic society and a secular community and, while highly appreciated in some regions of the world, may have a different value in others. The same holds true for justice and beneficence. This caveat does not imply relativism but suggests that some degree of cultural sensitivity is essential for an adequate understanding of the contents of each formal principle and the details of its extension and impact in a particular society. Another aspect that should be noted refers to the relative importance of the principles when applied to particular cases or situations. Although useful, codes of ethics do not indicate which principle should be given priority or preference in a given situation. More often than not, true ethical dilemmas stem from a collision between principles, that is, for instance, when to privilege autonomy over beneficence or vice versa. This is one of the tasks of an ethics committee, along with an adequate evaluation of the risks and benefits of research. Psychiatrists and other mental health professionals face the challenge of dealing with human beings in conditions of high vulnerability and establishing relationships with people who are intimate but detached. That is, a psychotherapist or clinical psychiatrist should be in possession of all relevant information about a person in order to be effective, but at the same time he or she should maintain the necessary distance in order not to assume roles different from that of a therapist (friend, lover, mentor) and keep a scientific point of view. Research in some aspects of mental health is charged with emotional undertones, but this fact should not preclude a technical stance in all matters related to design and conduct. No justification can be given for flaws in a scientific study, even if it is carried out for very humane purposes.

The importance of culture in mental health research Culture is a way of life with a particular vision of the world shared within a group of people with a common structure of beliefs, values, and behaviors (10). Culture shapes identity, a way of life and traditions giving particular

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meanings to cognition and personal relations (11). In relation to mental health, cultural factors may affect how the disease is confronted (12): 1) Culture produces identity categories and social practices which advantage some members and disadvantage others. 2) Interpretation systems may aggravate or mitigate certain risks (for example, different meanings to poverty and social exclusion). 3) Culture mediates the efficacy of health interventions at the individual and population level. 4) Culture structures health definitions, values, and priorities. Nowadays, there is a global dimension of culture which influences specific cultures around the world. Global mental health is not an unambiguous designation. It includes the notion of geographical extension, beyond national boundaries, with a possible implication for all peoples in the world. It does not have the connotation of international health, which stresses national differences and was used in the past as a label for neocolonialist postures. An interesting use of the term "global" is to employ it to cover all aspects of human life. This usage is warranted insofar as the interests of humans may vary greatly between and within national borders and populations. For some peoples, religious belief is more important than for others. Autonomy is appreciated more in some ethnic or national societies than in others. The conditions for normality may stretch from very basic notions to a highly sophisticated lifestyle. A hungry and deprived population is certainly different from a wealthy one. Thus, the "globality" of interests, conditions for happiness, and normality may be quite complex to ascertain if one abandons the utopic thought that the human organism is the same irrespective of contexts and history. Global also means integral, biopsychosocial, or holistic, with the added connotation of cultural diversity. This meaning permits a comparative and culturally sensitive consideration and a better analysis of ethical dilemmas, allowing what Sass aptly terms a "differential ethics" approach (13). Imposed "universal" notions of wellbeing fail because they do not consider this differential embodiment and embeddedness of human beings. "Health" in some quarters may leave aside aspects that in others are deemed essential. "Global health" as "integral health" captures both the universality of the claim to humanness and the particular value constellation of different individuals. It also helps to establish global as an attribute of humanity across cultures and historical periods (14).

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The historical expectation of psychiatry has been to translate clinical labels into natural entities in order to become a medical specialty relating etiology to anatomy or physiology. The reliance upon course, processes or developments instead of a real bodily lesion or phenomenon makes it almost impossible to chart similarities and compare phenomena in different contexts. The connotation of global as integral but variable, rejecting homogeneity, indicates that mental health (encompassing different and relevant aspects of life for a given human being) is, and should be, quite diverse depending upon context, culture, and tradition. The "Umwelt" of a member of an African tribe is different from the environment of a suburban dweller in New York. And global (in the sense of embracing all aspects of embeddedness) has a different meaning for these two persons. According to Kleinman (15), academic psychiatry, with its current emphasis on neuroscientific reductionism and dependence from the pharmaceutical industry, should reorient itself to a wider social horizon in order not to become irrelevant. This is all the more evident considering the small numbers of specialists in Low and Middle-Income Countries and their concentration in urban areas, not to mention language barriers for research and experiences published in languages other than English. A paradigm change, as advocated by some (16), does not solve the main issue, which seems to be a more intense involvement of other professionals and lay people in the construction of mental health, as a pursuit wider than the treatment of mental disorders. Frontier research that opens possibilities for understanding and treating disease is not possible in underdeveloped scientific communities, but its results open hopes and expectations in poor populations or lead to paradoxical restrictions on research practices. Such is the case of research on cloning, stem cell research or advanced neuroscience. Latin American and African countries, for example, reproduce regulations and legislation prohibiting some forms of research intended to protect subjects but their technical infrastructure does not permit them. Those gaps divide, and comparisons are based on an implicitly defined standard: the one developed in countries of the North and published in English. Underrepresentation of other languages in the academic corpus of current psychiatry is evident (17). The tension between the individual and the group has an impact on research practices and on the translation from laboratory to clinical work. Most of the underlying assumptions of Western science relate to individual human rights and some streams of thought contrast this position with the common good of populations. Theoretical reflection is needed to harmonize the welfare of the individual with the well-being of populations or groups. The

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argument needs to be formulated, and not only contrast individuals and national communities. In an age of globalization, individuals are embedded in successive layers of group belonging, from the nearest to the farthest. Twenty-first -century citizens do belong, simultaneously, to their local reference groups (family, national communities) and to the population of the world at large. This constellation of human relations is unprecedented in history. It is partly responsible for the feeling that all humans belong to the same space and are entitled to the same rights, irrespective of their geographical situation. While being a true and appealing assertion, it does not match the real-world circumstances of people in different regions of the world. Under the assumption that the biological body is the same, cultural differences are disregarded, ignoring the fact that even the most biological or empirical information is shaped by culture. This affects the way in which data are collected, organized, and communicated. Since tools shape thinking, instruments determine what is empirically accessible and what is not. And belief systems are pervasive components of the scientific framework. Cultural psychiatry may help to understand local variability in solving mental health problems by taking into account anthropological, psychological and sociological factors (11). Cultural factors may help in confronting disease, healing, recovery, and adaptation to disease symptoms (11).

The role of social determinants in mental health Mental health is a "neuro-cultural construction" based on nature and nurture intertwined in irrevocable ways. Neuroscience and the social sciences should arrive at the same final end (health or well-being) while differing in the means to create, promote or preserve it. The long struggle between a "mindless physiology" and a "brainless psychology" indicates the need to overcome partial reductionisms, disparate languages, and contradictory practical implications. The complement should overcome the juxtaposition of languages and techniques. It must accept that full human potential can be achieved under diverse conditions. An integrative language recognizing diversity in the context of universal humanness is necessary. The task ahead is to teach individuals that others belong to other groups and those distinctions sometimes entail differences and sometimes are arbitrary. Economic globalization created the divide between the "haves" and the "have-nots". One of its consequences has been the collapse or disruption of the social fabric in some regions of the world. The fracture of the social structures is also a disruption of the valoric world. Unemployment,

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terrorism, violence, and insecurity are some of its consequences. The "visible losers" in the globalization game show that "free trade" is sometimes "managed trade", leading to inequalities, social turmoil, and immoral behavior. Since the "right to health" is never a right to health alone (sometimes the technical jargon calls for "inter-sector approaches"), social determinants of health must be considered in mental health policies. Conceptualization of impairments, disabilities, and handicaps as "mental health problems" or "mental disorders" is a shifting target. Catalogs of illnesses and diseases vary with each new edition of standard manuals or training courses. The influence of industry and the economy in shaping the borders of normalcy and disease are a powerful inducement to create pathologies for which "solutions" are provided by industry, even if they are not felt as "problems" by the affected populations. In addition to the normative dimension associated with the word "ethics", it is undoubtedly a means for personal growth and what Cooley (18) calls "flourishing", the attainment of a full perfect human life. Virtue was understood in classical writings as personal human perfection. Although an individual enterprise, society, and institutions should provide the foundations for this achievement, in technical terms, preconditions for a good quality of life (and personal fulfillment) depend on organized group efforts. This is the traditional "ethos" of public health. Individuals may or may not attain virtues (perfections), but opportunities should be provided. A just society is one in which institutions are structured in a way that harmonizes individual rights and duties with the common good. Mental health as public or common good (19) involves a right to diversity: it should be universally attainable, uniformly possessed and not in competition with other goods. These attributes are not observed in current landscapes across the world, partly because living conditions are so diverse, and inequity or inequalities prevail. An ethical challenge involves thus a reasoned priority setting on the part of administrators, politicians, and policymakers (20). Prioritizing what makes humans human and permitting enjoyment of civilizationâ&#x20AC;&#x2122;s goods is essentially an ethical challenge, not simply a technical one. Modern ethical theorization calls for dialog and deliberation. This should be considered when establishing goals or justifying means. The "new architecture for global mental health" (21) demands ethics in this sense. Technical foundation and moral justification should go hand in hand when formulating policies. By definition, scarcity dictates the need for priority setting when striving for the achievement of common goods. But a

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rational and reasonable standard is not a matter of imposing a worldview but of accepting diversity and belief. The emphasis given to attributing the cause of mental health problems exclusively to brain dysfunctions has provoked the excessive use of psycho drugs, overdose of which may damage patients (10). Furthermore, there is a dependency on the pharma industry, while ignoring social and prevention aspects (22). In addition, the requirement of diagnostic tests has increased and the age to initiate tests is even earlier in childhood. These facts have increased mental health costs and made it difficult for developing countries to include them in the allocation of resources and some countries even lack psychiatry specialists. Mental health problems are different from other diseases in that their primary expression produces social and psychological imbalances involving multiple causalities and altering the regulation of behaviors through cognitive, emotional, perception and feeling processes (10). There are tensions between taking public health decisions based on evidence of biomedical practices and the approach of public health based on community experience which emphasizes social determinants of mental health and local priorities strengthening community resources and developing endogenous solutions (12). Studies carried out in Latin America show that socioeconomic status is related negatively with indicators of mental health disorders and lack of schooling is related to symptoms of depression, suicide attempts, and mood and anxiety disorders (23). Healthcare analysis requires taking into account four interrelated levels: historical, social, environmental, and biological and ontological, which enter into dialog a lot. Health is experimented at the biological, psychological, affective, intellectual, socio-cultural and historical level (24). The World Health Organization has created a Commission to study social determinants of health and carry out recommendations with the goal to diminish health inequalities (25). The social inequalities in health are due to unfair and avoidable differences between social, economic, demographic or geographic defined populations (26). The worst health condition of a social group has to be with having less social, economic and political power, worst living conditions and fewer opportunities and resources related to health (27-29). The study of the World Health Organization Commission shows that living conditions influence the way people get sick and die. Therefore,

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it is possible to gain a better quality of life by empowering persons and social groups and giving them resources for prevention so as to diminish unfair health inequalities (30). In mental health, poverty, unemployment, and lack of social relations increase the risk of suffering mental disorders (31). The study presents an analysis of social causes of both health and disease from a social and epidemiological perspective based on global justice (32). Health is considered a capacity and the way to obtain equity is centered in having opportunities so that the distribution of social determinants of health will allow equal opportunities for a healthy life according to the World Health Organization Commission (25). Taking into account that the social determinants of health make health inequalities visible and the need for restoring social justice as a structural tool (33), the justice principle reflection looks for equity and for diminishing discrimination in the social system.

Research with nootropics Nootropics or pharmacological cognitive enhancers are substances able to improve some cognitive functions, mood, emotions, and affectivity due to their effect on the biochemical balance of the brain (34). The use of psychotropic drugs to enhance brain function is based on clinical and experimental studies related to the treatment of neuropsychiatric disorders. Due to their effects, they have become lifestyle drugs employed by healthy individuals to enhance performance in work-related, academic, and social settings. Pharmacological interventions may improve certain mental functions beyond currently accepted medical indications, so-called â&#x20AC;&#x153;brain dopingâ&#x20AC;? (35). Reportedly, pharmacological neuroenhancement increases alertness, prevents fatigue, increases concentration, speeds up thought processes, and strengthens memory. It may also be used for other purposes, such as increasing sexual desire and attraction and attachment in romantic partnerships (36, 37). The effects may be summarized under the following categories: sensory perception, mood and emotions, motor action, communication, cognition (memory, attention, decision-making), and social and moral behavior (38). Their widespread use and the expectations associated with their effects constitute areas of concern in relation to longterm effects and accessibility to them in the social context. Intellectual enhancers range from diet, exercise, meditation, electrical stimulation, and social support. The particular character of pharmacological enhancement resides in the fact that it is easy to employ, it is backed up by

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a sound theory of brain function and may be deemed accessible without secondary or untoward effects. Expectations surrounding its effects added to the attraction of having advantages that other people cannot enjoy, demand careful analysis of the ethical and legal dimensions associated with non-therapeutic uses.

Legal Concerns with the non-therapeutic use of nootropics 1) How to control the use of non-prescribed drugs for neuroenhancement. There is no professional or social consensus regarding clinician response to the demand for nootropics when there is no diagnosis of neurological disorder (39). 2) Commercialization of nootropics for non-therapeutic uses may need the same safety requirements as those used for health reasons and be subjected to the same regulatory oversight (40). 3) The degree of availability. Nootropics may be freely available, over the counter as well as prescribed or illicit. For neurologists, the primary concern is whether the practice of off-label prescribing of nootropics may expose them to greater risk of liability for malpractice when secondary effects appear (39).

Ethical constraints with the non-therapeutic use of nootropics There are discrepancies regarding ethical constraints, related to diverse interests in improving cognitive function. The ethical discussion is polarized between conservative and liberal normative positions (41). While liberals believe that enhancement is part of human history and that it is useful in reducing suffering and promoting well-being, autonomous decisions being the most important principle (42), conservatives insist on preserving human â&#x20AC;&#x153;naturalâ&#x20AC;? functions and avoiding collateral, undesirable, physical and social effects (43). It may be argued that the use of nootropics could be unacceptable, defensible or even obligatory. Since the use of nootropics has been rising in recent years (44), benefits-risks assessment is mandatory, particularly since consumers may overemphasize benefits or minimize risks without adequate scientific information. Beneficial effects of common nootropic drugs in healthy individuals have been exaggerated (45, 46), and others may exaggerate risks, which affect decision-making. Psychiatrists may prescribe nootropics without clear-cut indications, for example, if the

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drug is considered safe and the person insists on the drug to be able to face a challenging situation (47). Similar social and moral constraints are present in all cultures: risks and safety; competition, achievement, and professional performance pressures, which occur across countries (48), including Latin America (49-51). Prescribing nootropics to improve the well-being of persons may be considered ethically permissible by professionals and society in the same way as cosmetic surgery and other interventions are prescribed to increase well-being (39). However, the discussion sometimes resembles the clash of opinions regarding doping in athletic competitions, where the use of substances is considered unfair or illegal. Overwhelming demands and stress are associated with the use of nootropics (52). Some have argued that if nootropics are shown to be safe and effective in high-responsibility professions their use could be mandatory in professions where the lives of others are at risk (i.e. surgeons, military, pilots) (53, 54). The following ethical issues are identified: 1) Risk and safety should be assessed, such as short- and long-term adverse events. Consumption of nootropics may produce undesired cognitive and personality changes (55). There are also risks of inducing or exacerbating existing illnesses, such as depression or bipolarity (56). 2) Dependence induction both physiological and psychological (57). Dependence affects autonomy since persons look for positive effects at all costs, losing freedom in their decision to consume. 3) Issues of autonomy affected by coercion: related to concerns about explicit and implicit pressures to use nootropics (55, 58, 59). Neuroenhancement in non-autonomous children, adolescents, or adults without the diagnosis of a neurological disorder is not advisable because of the fiduciary responsibility of physicians (60). Pharmacological cognitive enhancement in children has increased with the rising rates of attention deficit disorders and the prescribing of stimulant medication, which ethically should be justified when there is compelling evidence that the diagnosis is correct and the condition merits treatment (60, 61). An added problem is the vulnerability of children to coercion, limitation of their autonomy and the physicianâ&#x20AC;&#x2122;s duty to prevent misuse of medication (60). There may also be social coercion since those who do not enhance their

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brain functions may feel that they are at a disadvantage compared to those who can afford enhancers (62, 63). Furthermore, decisionmaking may be manipulated by marketing to consumers with unrealistic expectations regarding the effects of nootropic drugs in healthy individuals. 4) Issues of distributive justice: fair and equitable inclusion in light of what persons are owed or entitled to in a fair manner. Since the use of nootropics for persons without a neurological disorder is considered a lifestyle issue and not treatment, it may not be a social obligation to provide access. Those who can afford their use may be in a position that increases their chances of success in education and employment (63). 5) Moral acceptability or unacceptability including values morally relevant (example: honesty, authenticity, personal identity, fairness, and social consequences). In general, lack of fairness is related to lack of honesty and authenticity (64): the use of nootropics reduces authenticity and honesty by removing personal effort and endeavor. Competitive achievements may lose their meaning if some have an advantage over others by neuroenhancement.

References 1. Collins P., Patel V., Joestl S., March D., Insel T., Daar A. Grand challenges in global mental health. Nature 2011; 475 (7354): 27‐30. 2. World Health Organization. Mental Health Atlas 2014, www.who.int 3. Lolas F. The axiological dimensions in psychiatric diagnosis. Acta Bioethica (Santiago) 2009; 15(2):148‐150. 4. Lolas F. Medical praxis: an interface between ethics, politics, and technology. Social Science and Medicine (Oxford) 1994; 39: 1‐5. 5. Kirmayer LJ. Rethinking cultural competence. Transcultural Psychiatry 2012; 49 (2):149‐164. 6. Vaillant GE. Positive mental health: is there a cross‐cultural definition? World Psychiatry 2012; 11(2): 93‐99. 7. Lolas F. The importance of research for the development of psychological science. International Journal of Psychological Research 2015; 8(2):8-9. 8. Lolas F. Ethics in psychiatry: a framework. World Psychiatry 2006; 5(3): 185187. 9. Lolas F, Agar L, (eds). Interfaces between bioethics and the empirical social sciences. Santiago de Chile: Organización Panamericana de la Salud; 2002. 10. Suman F. Mental Health, Race and Culture. Palgrave MacMillan, 2010. 11. Kirmayer L.& Swartz L. “Culture and global mental health”. In V. Patel M. Prince A. Cohen & H. Minas (eds.), Global Mental Health: Principles and Practice. New York: Oxford University Press, 2013.

Ethical Issues in Mental Health Research

139

12. Sass HM. Differentialethik: Anwendungen in Medizin, Wirtschaft und Politik. Berlin: Lit Verlag; 2006. 13. Lolas F. Differential ethics in global mental health. JAHR. European Journal of Bioethics 2015; 6(2): 247-254. 14. Kleinman A. Rebalancing academic psychiatry: why it needs to happen-and soon. British Journal of Psychiatry2012: 201: 421-422. 15. Bracken P, Thomas O, Timimi S, Asen E, et al. Psychiatry beyond the current paradigm. British Journal of Psychiatry 2012; 201: 430-434. 16. Editorial: Language, psychiatry and globalization: the case for Spanish-speaking psychiatry. Asia Pacific Psychiatry 2010; 2: 4-6. 17. Cooley DR. Death’s values and obligations: a pragmatic framework. Dordrecht: Springer; 2015. 18. Lolas F. Salud mental global como bien público: sugerencias para la reflexión ética. Revista de Neuropsiquiatría (Lima) 2013; 76(3): 131-136. 19. Lolas F, Martin D, Quezada A. Prioridades en salud y salud intercultural. Santiago de Chile: CIEB Universidad de Chile; 2007. 20. Kirmayer LJ, Pedersen, D. Toward a new architecture for global mental health. Transcultural Psychiatry 2014; 51(6): 759-776. 21. Ingleby D. “How ‘evidence based’ is the movement for Global mental health?” Disability and the Global South, 2014; Volume 1, No. 2: 203-226. 22. Ortiz-Hernández L., López-Moreno S., Borges G. “Desigualdad socioeconómica y salud mental: revisión de la literatura latinoamerican”a. Cad. Saúde Pública,2007 June; 23(6): 1255-1272. 23. Peñaranda F. “Salud pública y justicia social en el marco del debate determinantes-determinación social de la salud”. Rev Fac NacSaludPública 2013; 31 (1): S91-S102. 24. World Health Organization, Commission on Social Determinants of Health. Towards a conceptual framework for analysis and action on social determinants of health. Geneva: World Health Organization; 2005 25. Solar O., Irwin A. “A conceptual framework for action on the social determinants of health”. Social Determinants of Health Discussion Paper 2 (Policy and Practice). Geneva: World Health Organization; 2010. 26. Phelan J., Link B., Tehranifar P. “Social conditions as fundamental causes of health inequalities: theory, evidence, and policy implications”. J Health Soc Behav. 2010; 51 Suppl: S28-40. 27. Whitehead M. “The concepts and principles of equity and health”. Int J Health Serv. 1992; 22: 429-45. 28. Malmusi D., Ortiz-Barreda G. “Desigualdades sociales en salud en poblaciones inmigradas en España: revisión de la literature”. Rev. Esp. Salud Publica 2014 Dic; 88(6): 687-701. 29. OMS-CDSS. Subsanar las desigualdades en una generación. Resumen analítico del Informe final. Ginebra, 2008. 30. Patel V., Lund C., Heatherill S., Plagerson S., Corrigal J., Funk M., Flisher A.” Social determinants of mental disorders. In E. Blas, & A. Sivasankara Kurup (eds.) Priority public health conditions: From learning to action on social”l

140

31. 32. 33. 34. 35. 36.

37. 38. 39. 40.

41. 42. 43. 44. 45.

Chapter 6 determinants of health, Geneva, Switzerland: World Health Organization. 2009:115-134. Venkatapuram, S. Global justice and the social determinants of health. Ethics and International Affairs2010; 24, 2: 1-8. López O., Escudero J., Carmona L. Los determinantes sociales de la salud. Una perspectiva desde el taller Latinoamericano de Determinantes Sociales de la Salud.2008; 4 (3): 323-325. Racine E, Forlini C. “Cognitive enhancement, lifestyle choice or misuse of prescription drugs?” Neuroethics 2010; 3:1-4. Schermer M., Bolt I., De Jongh R., Olivier B. “The future of psychopharmacological enhancements: expectations and policies”. Neuroethics 2009; 2: 75-87. Earp BD, Sandberg A. Savulescu J. “The Medicalization of Love”. Cambridge Quarterly of Healthcare Ethics 2015; 24(3):323-336. Earp BD., Sandberg A., and Savulescu J. “Natural Selection, Childrearing, and the Ethics of Marriage (and Divorce): Building a Case for the Neuroenhancement of Human Relationships”. Philosophy & Technology 2012; 25.4: 561-587. Brukamp K., Gross D. “Neuroenhancement- a controversial topic in contemporary medical ethics”. In Tech-Neuroenhancement_a_controversial_ topic_in_contemporary_medical_ethics.pdf, 2012. Larriviere D., Williams MA., Rizzo M., Bonnie RJ. “Responding to Requests from Adult Patients for Neuroenhancements: Guidance of the Ethics, Law and Humanities Committee”. Neurology 2009; 73.17: 1406-1412. Nuffield Council on Bioethics. Novel Biotechnologies: Intervening in the Brain.nuffieldbioethics.org/wp.../2013/06/Novel_neurotechnologies_report_P DF_web_0. pd, 2013. Forlini C., Racine E. “Does the cognitive enhancement debate call for a renewal of the deliberative role of bioethics?” in Cognitive Enhancement: An Interdisciplinary Perspective, Hildt E., Franke A., (eds.) (New York, NY: Springer, 2013): 173-186. Bostrom N., Sandberg A. “Cognitive enhancement: methods, ethics, regulatory challenges. Sci. Eng. Ethics 2009”; 15: 311-341. Sandel MJ. “The case against perfection: what’s wrong with designer children, bionic athletes, and genetic engineering”. Atl. Mon.2004; 292: 50-54. Partridge BJ., Bell SK., Lucke JC., Yeates S., Hall WD. “Smart Drugs ‘As Common As Coffee’: Media Hype about Neuroenhancement”. Ross JS, ed. PLoS ONE. 2011; 6(11):e28416. Repantis D., Laisney O., Heuser I. “Acetylcholinesterase inhibitors and memantine for neuroenhancement in healthy individuals: a systematic review”. Pharmacol. Res.2010; 61: 473-481. Repantis D., Schlattmann P., Laisney O., Heuser I. “Modafinil and methylphenidate for neuroenhancement in healthy individuals: a systematic review”. Pharmacol. Res.2010; 6:187-206.

Ethical Issues in Mental Health Research

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46. Ott R., Lenk C., Miller N., Neuhaus-Bühler R., Biller-Andorno N. “Neuroenhancement – perspectives of Swiss psychiatrists and general practitioners”. Swiss Med Wkly 2012; 142:w13707. 47. Forlini C., Hall W. “The is and ought of the Ethics of Neuroenhancement: Mind the Gap”. Frontiers in Psychology 2015;6:1998. 48. Batistela S., Bueno OFA., Vaz LJ., Galduróz JCF. “Methylphenidate as a cognitive enhancer in healthy young people”. Dementia &Neuropsychologia 2016; 10(2): 134-142. 49. Romero MI., Santander J., Hitschfeld MJ., Labbé M., Zamora V. “Consumo de sustancias ilícitas y psicotrópicos entre los estudiantes de medicina de la Pontificia Universidad Católica de Chile”. Revista médica de Chile 2009; 137(4): 459-465. 50. Buchanan JC., Pillon SC. “Uso de drogas entre estudiantes de medicina, tegucigalpa, Honduras”. Revista Latino-Americana de Enfermagem, 2008; 16(spe): 595-600. 51. Wolff W., Brand R. “Subjective stressors in school and their relation to neuroenhancement: a behavioral perspective on students’ everyday life ‘doping’”. Subst. Abuse Treat. Prev. Policy 2013; 8:23. 52. Maslen H., Douglas T., Kadosh RC., Levy N., Savulescu J. “The regulation of cognitive enhancement devices: extending the medical model”. J. Law Biosci. 2014; 1: 68-93. 53. GooldI., Maslen H. “Must the surgeon take the pill? negligence duty in the context of cognitive enhancement”. Mod. Law. Rev. 2014; 77: 60–86. 54. Maslen H., Faulmüller N., Savulescu J. “Pharmacological cognitive enhancement – How neuroscientific research could advance ethical debate”. Front. Syst. Neurosci. 2014; 8:107. 55. Bell E., Maxwell B., McAndrews MP., Sadikot A., Racine E. “Deep brain stimulation and ethics: perspectives from a multisite qualitative study of Canadian neurosurgical centers”. World Neurosurg. 2011;76(6):537-47. 56. Heinz A., Kipke R., Heimann H., Wiesing U. “Cognitive neuroenhancement: false assumptions in the ethical debate”. Journal of Medical Ethics 2012; 38(6):372-375. 57. Warren OJ., Leff DR., Athanasiou T., Kennard C., Darzi A. “The neurocognitive enhancement of surgeons: an ethical perspective”. J. Surg. Res. 2009; 152: 167172. 58. Schoomaker EB. “Military medical research on cognitive performance: the war fighter's competitive edge”. Aviat. Space Environ. Med. 2007; 78: B4-B6 59. Graf WD., Nagel SK., Epstein LG., Miller., Nass R., Larriviere D. “Pediatric neuroenhancement: ethical, legal, social, and neurodevelopmental implications”. Neurology 2013 Mar 26; 80(13):1251-60. 60. Gaucher N., Payot A., Racine E. “Cognitive enhancement in children and adolescents: Is it in their best interests?” Acta Paediatr2013 Dec; 102(12):111824. 61. Webb JR., Valasek MA., North CS. “Prevalence of stimulant use in a sample of U.S. medical students”. Ann Clin Psychiatry 2013; 25(1):27-32.

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62. Maier LJ., Liechti ME., Herzig F., Schaub MP. “To dope or not to dope: neuroenhancement with prescription drugs and drugs of abuse among Swiss university students”. PLoS ONE 2013; 8:e77967. 63. Fitz NS., Nadler R., Manogaran P., Chong EWJ., Reiner PB. “Public attitudes toward cognitive enhancement”. Neuroethics 2013; 7: 173-188. 64. Schermer M. “On the argument that enhancement is ‘cheating’”. J. Med. Ethics 2008; 34: 85-88.

GLOSSARY

Accuracy: Degree to which the result of a measurement, calculation, or specification conforms to the correct value or a standard. Adverse event: In pharmacology, any unexpected or dangerous reaction to a drug or vaccine. Allegation: A claim or assertion that someone has done something illegal or wrong, typically one made without proof. Biodiversity: The number and types of plants and animals that exist in a particular area or in the world generally, or the problem of protecting this. Biopsychosocial: Relating to, or concerned with the biological, psychological, and social aspects in contrast to the strictly biomedical aspects of a disease. Biorepository or Biobank: A facility that collects, catalogs, and store samples of biological material, such as urine, blood, tissue, cells, DNA, RNA, and protein from human, animals, or plants for research. If the samples are from people, medical information may also be stored along with written consent to use the samples in laboratory studies. Biosafety: The application of knowledge, techniques and equipment to prevent personal, laboratory, and environmental exposure to potentially infectious agents or biohazards. Biosafety defines the containment conditions under which infectious agents can be safely manipulated. The objective of containment is to confine biohazards and to reduce the potential exposure of the laboratory worker, persons outside of the laboratory, and the environment to potentially infectious agents. Biotechnology: The genetic manipulation of living organisms or their components to produce useful usually commercial products. Chimera: An organism that contains cells or tissues from two or more different species. Clinical trial: research in which people volunteer to test new treatments, interventions or tests as a means to prevent, detect, treat or manage various

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diseases or medical conditions. The research evaluates the effectiveness and safety of medications or medical devices by monitoring their effects on large groups of people. Confidentiality: The idea that, apart from where necessary in order to conduct the research or where legally required, all details agree with the subject should be kept private by the researcher and not disclosed to any third party. This is an important component of the professional codes of conduct within which research is conducted. Equity: Having equal opportunities. Eugenics: The study of or belief in the possibility of improving the qualities of the human species or a human population based on genetics, by such means as eliminating embryos ore fetuses with genetic defects or discouraging reproduction by persons having genetic defects or presumed to have inheritable undesirable traits (negative eugenics) or encouraging reproduction by persons presumed to have inheritable desirable traits (positive eugenics). Gene Knockout: Genetic Technique in which one of an organism's genes is made inoperative. Germ-line: The cellular lineage of a sexually reproducing organism from which eggs and sperm are derived. Also, the genetic material contained in this cellular lineage which can be passed to the next generation. Globalization: A situation in which available goods and services, or social and cultural influences, gradually become similar in all parts of the world. Herbicide: A chemical that is used to destroy plants, especially weeds. Informed Consent: Agreement or permission to do something from someone who has been given full information about the possible effects or results. Monitoring: A systematic process of observing, tracking, and recording activities or data for the purpose of measuring a program or project implementation and its progress towards achieving objectives. Information gathered through monitoring is used to analyze, evaluate for all of the components of a project or a department in order to measure its effectiveness and adjust inputs where necessary. Moratorium: A temporary prohibition of an activity.

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Mosaicism: The property or state of being composed of cells of two genetically different types. Multicentric: Research conducted at more than one medical center or clinic. Pharmaco-surveillance: Monitoring of drug safety, for example, by means of spontaneous adverse event reporting systems, case-control and cohort studies. Phenotype: The set of observable characteristics of an individual resulting from the interaction of its genotype with the environment. Placebo: A substance that has no therapeutic effect, used as a control in testing new drugs. Pluripotent cells: Cells that are self-replicating, derived from human embryos or human fetal tissue, and known to develop into cells and tissues of the organism. Privacy: Someone's right to keep their personal matters and relationships secret. Responsible conduct of research: "the practice of scientific investigation with integrity." It involves the awareness and application of established professional norms and ethical principles in the performance of all activities related to scientific research. Transdisciplinary: research efforts conducted by investigators from different disciplines working jointly to create new conceptual, theoretical, methodological, and translational innovations that integrate and move beyond discipline-specific approaches to address a common problem. Transgenic: relating to or denoting an organism that contains genetic material into which DNA from an unrelated organism has been artificially introduced. Vulnerable: adults without the capacity (relative, absolute, or temporary) to give voluntary consent and children, who are generally considered to lack capacity to decide for themselves.

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Sources: https://www.medicinenet.com/medterms-medical-dictionary https://dictionary.cambridge.org/ https://www.merriam-webster.com/medical/ https://www.aqr.org.uk/glossary https://www.research.ucsb.edu https://www.hsph.harvard.edu