Volume VIII Issue ii

Volume VIII Issue ii

Research Ethics and Enhancement

Also inside:

Conversations with David Perlman and Jennifer Walter Gun Control and Mental Health Surrogate Motherhood

Penn Bioethics Journal The Penn Bioethics Journal (PBJ) is the nation’s premier peer-reviewed undergraduate bioethics journal. Established in 2004, the Journal provides a venue for the contributions of undergraduates to bioethics. The PBJ, embracing the interdisciplinary focus of bioethics, reviews and publishes reports of empirical research and analysis of previous work -- addressing debates in medicine, technology, philosophy, public policy, law, theology and ethics, among other disciplines. The biannual Journal also features news briefs and editorials reviewing current bioethical issues, as summarized by our undergraduate editorial staff. Undergraduate editors and authors have a unique opportunity to get involved with the peer-review process through the collaborative and rigorous review and preparation of the PBJ. With an audience ranging from scholars in the field to a broader public seeking unbiased information, the Penn Bioethics Journal scholastically involves all undergraduates interested in the extensive field of bioethics.

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Archived editions of the Journal and information about the submission process can be found on our website: http://bioethicsjournal.com The editorial staff also promotes bioethics by hosting campus-wide events through formal lectures, case study presentations, public debates, debriefing of current bioethical issues and student-led conversations.

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PBJ

Pe n n B i o e t h i c s J o u r n a l

Editor In Chief Anand Muthusamy Publisher Kathleen Sun Managing Editors Klyde Breitton Lucy Chen Lili McKinley Ruchita Pendse Sudesh Raju Aditi Verma Associate Editors Osama Ahmed Mohammad AlMagweshi Christopher Ataksuka Diana Blidarescu Shayan Cheraghlou Laura Cosgrove Imran Cronk Samantha Freedman Elana Furman Andy Guo Audrey Harnagel Jacquelyn Kemmer Ellen Kim Kurt Koehler Georgio Legerme Nicholas Lim Robin Lo Eileen Mayro Loren Miller Tim Shinn Shashank Sirivolu Hannah Victor Andrew Wadley Abby Worthen Grace Wu Garrett Young Ahmed Yousef Samir Zaman Nikolai Zapertov Timothy Zhou Faculty Advisor Jonathan Moreno, Ph.D.

Questions or Comments?

Please direct all inquiries to the Editor in Chief at bioethicsjournal@gmail.com

Contents Letter from the Editor in Chief Anand Muthusamy

Bioethics in Brief

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Gun Control and Mental Illness

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Denmark’s Precautionary Approach to Antibiotic Resistance

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Surrogate Motherhood, Disability, and Abortion in the Case of “Baby S”

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Adolescent Organ Donation at the Children’s Hospital of Philadelphia

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Environmental Applications of Synthetic Biology

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Interviews Adolescent Care and Health Policy – A Conversation with Jennifer K. Walter

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Q&A with David Perlman

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Articles The Potential of Epigenetic Therapy and the Need for Elucidation of Risks

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Monetary Compensation of Research Subjects: The Shortfalls of Research Standards in Preserving Autonomy

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Genetic Enhancement: Definitions, Methodologies, and the Effect of Parental Attitudes

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Josh Tycko, Danielle Fields, Daniel Cabrera, Mahamad Charawi, Bradley Kaptur, University of Pennsylvania

Shivam Amin, University of South Alabama

Sarah Mayes, University of Virginia

Letter from the Editor Dear Readers, Bioethics is a burgeoning field that has gained more attention with recent advances in the life sciences and political movements shaping healthcare law.

This issue of the Penn Bioethics Journal focuses on the ethics of medical research and human enhancement to address particular links between science and healthcare outcomes.

Penn Bioethics Journal

Volume VIII Issue ii

Typically, basic science addresses a range of interesting problems without a strict agenda or need to immediately prove its utility. However, recent budget cuts have restricted the work of the National Institutes of Health, among other scientific organizations. In this environment especially, pressing societal problems raise questions about the priorities in scientific research. Recent trends have emphasized clearly demonstrating the medical applications of basic life science research. Considerations for the safety of research subjects and future patients impose additional constraints on research. Two pieces enclosed discuss the promise of synthetic biology while considering how the new associated risks demand stringent clinical trials. Our first feature article discusses the limitations of the Belmont Report, the standard guidelines for conducting biomedical research, in informing institutional review boards.

Furthermore, a newly adopted medical technology raises questions of how various agents will adapt their behavior. Our second feature article analyzes the parent-child relationship in different cases of genetic enhancement.

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This issue also addresses current bioethical issues outside medical research, such as surrogate motherhood, adolescent organ transplantation, the fight against antibiotic resistance, and the role of mental health in gun control measures. These topics are notable not only for their timeliness, but also for their implications for other practices including but not limited to scientific research and clinical practice.

I thank our editors and authors for their work in compiling this issue. I am also grateful for the strength of the bioethics community across many departments at the University of Pennsylvania. The turnout at the National Undergraduate Bioethics Conference last April at Georgetown University demonstrated a strong interest in an undergraduate bioethics community across the country. Looking forward to the next conference, we are continuing to develop and share practices to promote undergraduate bioethics. The Penn Bioethics Journal will continue to serve as an open, international forum for undergraduates across all disciplines to discuss bioethics.

Anand Muthusamy Editor in Chief University of Pennsylvania C’14

Anand Muthusamy Editor in Chief

Bioethics in Brief

Bioethics in Brief

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Gun Control and Mental Illness

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The results of the Newtown shooting sparked a debate about gun control and mental illness that catalyzed significant political activity. The ethics of gun control and mental health provisions strain a balance between individual privacy and societal safety. Of special concern is the degree to which information about mentally ill patients should be disclosed to prevent dangerous individuals from obtaining firearms.

On one hand, patient confidentiality is critical for treatment; however, others argue that a national database is especially useful for firearm regulation. The information required for the database is readily accessible and the number of individuals the system can screen is high (Mowbray 2002). In a world with complete information symmetry, this solution appears to be ideal as suspect individuals can be monitored while others can more freely purchase firearms.

However, before the symmetry of information is even considered, the effectiveness of the information must be assessed. First, many individuals already illegally purchase weapons and may be further encouraged to turn to the illegal dealers (Mowbray 2002). Second, increased background checks may only serve to penalize law-abiding gun owners while increasing the cost to the government for perhaps a marginally effective system (Kapur 2013). Third, those who voluntarily seek treatment are most likely not the ones interested in purchasing firearms for an ulterior motive (Swanson 2013). These three points not only question the meaningfulness of a database but also warrant a discussion of unintended side effects in collecting information.

Disclosure of personal information further exposes patients to stigma, which may hinder them from seeking mental healthcare. The increase in untreated mental illnesses not only adversely affects patients, but also may result in increased criminal activity. Jeffrey Swanson, a professor of psychiatry and behavioral sciences at Duke University, studied the correlation between policy action and subsequent criminal behavior of the mentally ill (Webster 2013). Swanson considered two groups: the mentally ill with a criminal history and the mentally ill without one. When aggregating both of these groups, policy appeared to have no significant effect on decreasing violent crimes by the mentally ill as a whole (Webster 2013). However, analyzing the two separate groups individually yielded more decisive results. Regulation did decrease the risk of future violence for patients without criminal records. However, for those with criminal records, the more restrictive gun control policy, surprisingly, increased the likelihood of future violent crimes by a staggering 60 percent (Webster 2013). Swanson suggests that increased stigma and stronger regulations affect the individual’s desire to reach

out for medical attention when under scrutiny. Specifically, patients with criminal history especially feel judged and persecuted, thinking that they have more to lose or hide.

Without that patient-doctor confidentiality, these patients are less likely to trust in a medical institution that appears to have not just their interest but also society’s interest at heart (Mowbray 2002). Therefore, while it is critical to have some form of background check or regulation in society, the intent should be on helping and reducing the number of mentally ill, rather than solely focusing on preventing people from obtaining weapons (Webster 2013).

Dean Rohrer

The Obama administration’s recent proposals regarding gun control and mental health care represent society’s next steps. Specifically, the administration seeks 23 stipulations that converge in two specific executive orders: the first closes loopholes in the current background check system and the second keeps surplus military weapons off the streets (White House 2013). The Obama administration plans to target mental illness by allocating $235 million in the 2014 fiscal budget proposal to three distinct areas: training for teachers in public schools, education for medical physicians, and alleviation for schools with violent history (Kliff 2013). The overlap of the two proposals provides a focus and sense of priority in the nation to address mental health concerns.

However, while the gun control proposals and mental health budget are steps forward, the most critical component of all these stipulations remains understated: the need for enforcement, which brings with it the power of suspicion

Bioethics in Brief (Devers 2013). Implementing policy necessitates training and heightened awareness, which reinforces strong stereotypes (Link 1999). The stigma of the mentally ill and the stigma of criminals permeate through society as individuals attempt to carry out the very laws that try to resolve this ingrained stereotype. Ultimately, people need to bring the best interests of others to the forefront and communicate a desire to genuinely help. By demonstrating this true interest in the success of the involved individuals, the issue of gun control and mental illness in society may finally begin to resolve itself (Corrigan 2002).

-Aditi Verma, University of Pennsylvania Corrigan, P. W., Rowan, D., Green, A., Lundin, R., River, P., UphoffWasowski, K., et al. 2002. Challenging two mental illness stigmas: personal responsibility and dangerousness. Schizophrenia Bulletin. 28(2), 293–309.

Devers, C. E., T. Dewett, Y. Mishina, and C. A. Belsito. 2013. A General Theory of Organizational Stigma. Organization Science 20(1): 154-171.

Kliff, Sarah. 2013. Obama’s Proposed Budget to Seek $235 Million for New Mental Health Programs. Washington Post. N.p.

Link, B. G., J. C. Phelan, M. Bresnahan, A. Stueve, and B. A. Pescosolido.

1999. Public Conceptions of Mental Illness: Labels, Causes, Dangerousness, and Social Distance. American Journal of Public Health 89(9): 1328-1333.

Mohney, Gillian. 2013. Obama Budget Includes $235 Million For Mental Health Care. ABC News. ABC News Network, Moorhead, Molly. 2013. A Summary of the Manchin-Toomey Gun Proposal. PolitiFact. Tampa Bay Times.

Mowbray, Carol T. 2002 Mental Health and Mental Illness: Out of the Closet? Social Service Review 75.1 135-79. Print.

Obama Announces 23 Executive Actions, Asks Congress to Pass Gun Laws. 2013. Web log post. CNN. CNN News.

Swanson, Jeffrey, PhD. 2013. Mental Illness and New Gun Law Reforms: The Promise and Peril of Crisis-Driven Policy. The Journal of American Medical Association 309(12): 1233-1234.

The White House, Office of Press Secretary 2013. FACT SHEET: New Executive Actions to Reduce Gun Violence. The White House.

The White House. 2013. Now Is the Time. Rep. The White House.

Webster, Daniel W., and Jon S. Vernick. 2013. Reducing Gun Violence in America Informing Policy with Evidence and Analysis. Baltimore: Johns Hopkins UP. Wilkie, Christina. 2013. NRA: Background Check Deal ‘A Positive Development,’ But Still Oppose Compromise Plan. The Huffington Post. TheHuffingtonPost.com.

Denmark’s Precautionary Approach to Antibiotic Resistance

Penn Bioethics Journal Volume VIII Issue ii

In 1928, when Sir Alexander Fleming discovered suggesting that exposure to prevalent antibiotics is a catalyst penicillin for use as an antibiotic, the medical field changed for developing antibiotic resistance (Forslund 2013). These radically. Patients no longer had to fear scarlet fever or and other studies support Denmark’s findings that lower death from infected wounds. Since then, many antibiotics antibiotic use may result in lower antibiotic resistance, even have been developed and are now highly available. However, when considering off-target effects. with the growing use of antibiotics, bacteria have become Despite these findings, many individuals in the increasingly resistant to such drugs. Pathogens build agricultural industry have expressed concern regarding resistance to antibiotics by evolving their genomes, a process bans on antibiotics. Withholding certain banned antibiotic that can outpace drug development. Antibiotic resistance treatments may unintentionally cause withdrawal symptoms threatens global health by increasing the possibility that in the animals. These symptoms would then need to be bacterial genes will confer resistance to medicine used as treated with other unbanned antibiotics. This situation treatment against disease. might lead to no appreciable change in overall antibiotic Responding to this concern in the 1990’s, Denmark resistance, since antibiotics would just be given later rather initiated the ban of antibiotic use for promoting growth in than earlier (Casewell 2003). livestock. The ban was critical because at the time antibiotics Such concerns may ultimately be unfounded. The World were used so prevalently that bacteria were almost completely Health Organization found that the ban on antibiotics in immune to the drugs. For example, in 1995 when the ban Denmark did not significantly harm farmers’ income or of Avoparcin was implemented, increase animals’ health risk.

“This situation might lead to no Rather, the ban reduced 72.7% of broiler’s chickens had glycopeptide-resistant E. faecium appreciable change in overall antibiotic human health risk (Chan (GRE), a bacterium found in 2012). As a result, other the broiler’s fecal collection resistance, since antibiotics would just be countries have followed (Aarestrup 2001). Following the given later rather than earlier.”

Denmark’s ban on antibiotics ban in 2000, that figure fell to and agricultural model.

5.8% (Aarestrup 2001). Similar Denmark is a remarkable results were found after the ban of other antibiotics, such as example for efficiently banning antibiotics in agriculture Virginiamycin and Erthomycin (Aarestrup 2001). since the agricultural industry across the country is set up in Additionally, the European Molecular Biology a uniform manner (Aarestrup 2001).

Laboratory recently released a study that investigated All over the world, countries are pushing for legislation 252 metagenomes and found that resistance is highest for against antibiotic resistance. In Australia, there is a current antibiotics that are highly available and used in animals, push to fight antibiotic resistance by actively working to stay

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Bioethics in Brief ahead of the evolution of antibiotic strains. The Office of the Chief Scientists of Australia released a paper that urged scientists to develop more effective antibiotics and vaccines to fight growing antibiotic resistance in bacteria (Prasad and Smith 2013). In the United States, there are also new movements. U.S. Representative Louise Slaughter (D-NY) wrote to Nature in August 2013 that she has been striving to pass legislation to ban the use of eight medically important classes of antibiotics currently used in agriculture. Her piece was in response to several articles published in Nature: “MRSA: Farming up Trouble,” “Antibiotic Resistance: The last resort,” and “Antibiotic Threat” (Slaughter 2013).

Supplementing Representative Slaughter’s concern that treating livestock with antibiotics increases humans’ risk of acquiring an antibiotic resistant infection is a new study released by Johns Hopkins University that used data from a major health system, the Geisinger Health System. This study showed that exposure to swine manure, which contains antibiotic resistant bacteria, resistance genes, and antibiotics, increases an individual’s risk of contracting MRSA (Casey 2013). Especially as we see growing evidence of antibiotic resistance, it is time the United States takes action to reduce resistance in our own country.

Despite worries of limited antibiotic use leading to decreased animal quality of life, the evidence supports that banning antibiotics for use in agriculture reduces the possibility of infectious bacteria evolving into something

more dangerous. Antibiotics still are “magic bullets” for specific ailments, and in order to protect their effectiveness, we must both carefully use and continually develop drugs to outpace the development of resistance.

-Lilian McKinley, University of Pennsylvania Aarestrup, F.M., A.M. Seyfarth, H. Emborg, K. Perdersen, R.S. Hendriksen, F. Bager. 2001. Effect of Abolishment of the Use of Antimicrobial Agents for Growth Promotion on Occurrence of Antimicrobial Resistance in Fecal Enterococci from Food Animals in Denmark. Antimicrobial Agents and Chemotherapy 45(7): 2054-2059.

Casewell, Mark, et. al. 2003. The European ban on growth-promoting antibiotics and emerging consequences for human and animal health.

Journal of Antimicrobial Chemotherapy (52): 159-161.

Casey, John, et. al. 2013. High-Density Livestock Operations, Crop Field Application of Manure, and Risk of Community-Associated Methicillin-Resistant Staphylococcus aureus Infection in Pennsylvania.

JAMA Internal Medicine. E1-E11.

Chan, Margaret. 2012. Antimicrobial Resistance in the European Union and the World. WHO. Forslund, Kristoffer, S. Sunagawa, J.R. Kultima, D. Mende, M. Arumugam, A. Typas, P. Bork. 2013. Country-specific antibiotic use practices impact the human gut resistome. Genome Research (23): 1163-1169.

Prasad, Simon and Phillipa Smith. 2013. Meeting the Threat of Antibiotic Resistance: Building a New Frontiline Defense. Occasional Paper Series (7): 1-4.

Slaughter, Louise. 2013. Antibiotics: Support US policy change. Nature 500: 400.

Wharam, Barney and L. Lazarou. 2013. Ethical considerations in an era of mass drug administration. Parasites and Vectors 6(1): 234.

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Surrogate Motherhood, Disability, and Abortion in the Case of “Baby S”

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Perhaps one of the most interesting (and morally to prostitution. They disapprove of surrogacy because women ambiguous) bioethical news stories to have surfaced this are offering their bodies for financial gain (Anderson 2000). year is the case of “Baby S.” The story began with a surrogate This case also raises the issues of commodification of mother, Crystal Kelley, who decided to bear the baby of a children when financial incentive for abortion is involved, mother who could not bear children. However, an ultrasound whether abortion can be right in certain cases, and whether showed that the fetus had serious defects, and that the baby such abortions encourage eugenics and artificial selection of would only have a “25% chance of [leading] a ‘normal life’” “better” children. Finally, this case problematizes agency and (Cohen 2013). The parents decided that terminating the its implications. Can a surrogate mother violate the desires pregnancy would be the most ethical course of action, but of biological parents by birthing a child the parents no longer Kelley disagreed. Legal disputes want for medical reasons? And followed, with the parents if the surrogate mother does “This case also raises the issues of follow through with birthing an offering $10,000 to abort the fetus and refusing to raise the commodification of children when financial unwanted child, do the parents have an obligation to support child if it were born. Ultimately, Kelley fled to Michigan in incentive for abortion is involved, whether the child?

Developing a philosophical search of adoptive parents who abortion can be right in certain cases, and framework to fairly evaluate the would provide a loving home whether such abortions encourage eugenics ethics of this story is challenging for the child. The child was born disabled and given to an and artificial selection of ‘better’ children.” indeed. Recent work by noted Oxford philosophers Julian adoptive mother. Eventually, Savulescu and Guy Kahane the biological parents too came have publicized one framework in particular to assess such to support the decision and now regularly visit Baby S. Though this dispute was resolved, it raised a staggering cases: the Principle of Procreative Beneficence (PB). This number of bioethical issues. With regards to the ethics of principle states that though the disabled can still lead happy surrogacy itself, some critics compare surrogate motherhood lives, couples should choose the best outcome regarding their

Bioethics in Brief possible children. Parents should support selection against disability whenever selection is possible and better outcomes likely exist. The principle argues that “[the] reason to select the child with better prospects is that the child [is likely to] benefit more than the other would by being caused to exist” (2009).

According to PB, Kelley should have accepted abortion and helped the couple conceive another child without expected disabilities. However, the case of Baby S involves some issues not considered by Savulescu and Kahane, such as monetary concerns and legal issues in “kidnapping” Baby S. Furthermore, PB overall does not consider the societal implications of its directives—namely, that only those with the education and resources to consider selective abortion can do so. PB provides a highly relevant framework to inform choices in selective abortion of the disabled, but it is not complete in assessing this case.

The case of Baby S provides a good example of bioethics being applied to a real situation with real consequences. This case also illustrates that few real life situations are as simple as the assumptions employed by PB. The case of Baby S

demonstrates that we cannot just consider core issues of an ethical dilemma one at a time—they are all intertwined. That said, frameworks such as PB are still essential to making informed decisions. Just as this system informs the ethics of selective abortion, others consider the monetary, legal, and societal implications. As bioethics grows as a field, we may expect to see future frameworks that take all such matters into consideration so that future medical decisions may have more comprehensive ethical guidance in situations such as the case of Baby S. -Klyde Breitton, University of Pennsylvania Anderson, E.S. 2000. Why Commercial Surrogate Motherhood Unethically Commodifies Women and Children: Reply to McLachlan and Swales. Health Care Analysis 8: 19-26.

Cohen, E. 2013. Surrogate offered $10,000 to abort baby. CNN. Available at http://www.cnn.com/2013/03/04/health/surrogacy-kelley-legalbattle/index.html?iref=allsearch.

Savulescu, J. and Kahane, G. 2009. The Moral Obligation to Create Children with the Best Chance of the Best Life. Bioethics 23(5): 274290.

temple.edu/centers/cbuhp | facebook.com/cbuhp cbuhp@temple.edu

Volume VIII Issue ii

Temple University’s MA in Urban Bioethics, offered through the CBUHP, trains students in the ethics and values of health, health care delivery, and health law and policy underlying the urban context of density, diversity, and inequalities. Coursework is practical, methodological, and theoretical. The degree is designed for Temple graduate students and area professionals who face, or will soon face, the complexities and disparities of urban health, and want specialized training in the ethics, values, and politics of health care in our increasingly multi-dimensionally diverse society.

Penn Bioethics Journal

Center for Bioethics, Urban Health, & Policy

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Bioethics in Brief

Penn Bioethics Journal

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Adolescent Organ Donation at the Children’s Hospital of Philadelphia

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In June 2013, Sarah Murnaghan, a 10-year-old girl situation worsening, her parents used their resources to sue suffering from cystic fibrosis, was admitted to the Children’s in court to amend the rules and to allow their daughter Hospital of Philadelphia (CHOP) in desperate need of a to be placed atop the adult waiting list and to receive the lung transplant. In the current framework of organ donation, transplant. The Department of Health and Humans services adolescent patients are placed on a waiting list behind adult reviewed the appeal and eventually it was decided by a single patients; hence, adolescent patients have a low success rate judge to give Sarah a temporary ten day period to receive a in obtaining organ donations. The reasoning behind this rule transplant after which the national policy will be reinstated. is based on the fact that children’s bodies are still growing, Though children across the nation are in need of organ and the organ transplantation often needs to be performed transplants, Sarah’s family’s resources are ultimately what again. With Sarah Murnaghan’s worsening condition, her allowed her to be was pushed to the top of the waiting list. parents mounted a suit that resulted in a local judge ordering This case raises serious questions in equity and justice within the Organ Procurement and bioethics. Can children only Transplantation Network to compete for organ transplants “Can children only compete for organ if their families have the add her to the top of the adult waiting list. CHOP surgeons transplants if their families have the economic and political means were then required to resize fight the federal law? Why economic and political means to fight the to the adult donor lungs and take should one girl be able to a portion to transplant into federal law?” obtain the transplant while Sarah’s body. With the successful many other patients within transplantation, Sarah has slightly below 50% chance of CHOP still are waiting on the adolescent waiting list? Is it surviving past one year, but significantly less chance of equitable that families with resources can circumvent the law surviving past five years. Hence, transplants for adolescent for a temporary time while others must wait for the national patients suffering from cystic fibrosis and other diseases policy to be reviewed? Is it fair that a patient can receive a delve deep into the bioethical issues of organ transplantation transplant when national studies indicate that the adolescent and equity. has a greater chance of mortality than surviving past five Sarah was not alone in her predicament: an estimated years? Or rather, is the system unjust and are Sarah’s parents 30,000 American children suffer from cystic fibrosis, a rare starting a national conversation about allowing children in genetic disorder. The disease causes cells to produce excessive need of transplants to receive them more fairly in the future? mucus, sweat, and digestive juices that clog passageways Now, Sarah has received her lung transplant is recouping throughout the body, most notably in the respiratory and at home in Delaware County and has bright hopes. Since digestive systems. The thickened mucus damages the airways, her transplant in June, she has shown 0% lung rejection causing coughing and difficulty of breathing. This mucus and does not need to breathe through an oxygen machine. also serves as a breeding site for bacteria and fungi that She is relearning how to walk making progress. Through increase the risk of infections such as sinusitis, bronchitis, an emotional legal and medical process, Sarah has shown and pneumonia. Additionally, mucus restricts the passage of bravery. However, it also raises issues that should be digestive enzymes to the small intestine, inhibiting digestion. thoughtfully considered by bioethicists to better deal with In combination, these complications lead to systemic failure cases similar to Sarah’s in the future. that requires organ transplants (NIH 2013).

While Sarah was not alone in her need for transplantation, -Sudesh Raju, University of Pennsylvania she received special treatment, which raises equality and judicial issues within bioethics. Currently, children in the CBS News. Web. 7 Sept. 2013. <http://philadelphia.cbslocal. com/2013/08/26/sarah-murnaghan-to-leave-chop-after-lungU.S. are only eligible to receive organs from other child transplants/>. donors (under 12 years) and have lower priority than adults NBC. Web. 7 Sept. 2013. http://www.nbcphiladelphia.com/news/ on the waitlist for adult organs (12 years and above). This local/221150671.html>. policy is rooted in biological constraints: adolescents grow CNN. Web. 7 Sept. 2013. http://www.cnn.com/2013/08/26/health/sarahmurnaghan-update/index.html after the operation and the transplant needs to be resized. In NIH. Web. 7 Sept. 2013. <http://www.nhlbi.nih.gov/health/health-topics/ addition, there is a less than a one in three chance of survival topics/cf/>. for lung transplantation past 10 years. There is not a high Klugman, Craig. 6 June 2013. “Bioethics.net.” Bioethicsnet Blog. Bioethics. prevalence of child donors, especially for lung transplants, so Sarah had been waiting for over six months. With her

Bioethics in Brief

Environmental Applications of Synthetic Biology through the process of conjugation, potentially spreading modifications in an uncontrolled way (Sanderson 2009).

Some environmentalists also worry that if synthetic biology is used to help solve problems like reducing greenhouse gas levels, other necessary public policy steps will not be taken because people will assume scientific advancements will take care of the problem (Callaway 2013). Additionally, there is

the possibility that animals affected by genetic modification may be harmed. For example, the insertion of the fungal resistance gene in the R. silius frogs could have unforeseen negative consequences for the frogs themselves and for other organisms that interact with them, especially their predators.

While remaining wary of these concerns and others that were discussed, biologists, environmentalists, and ethicists alike are optimistic about the potential for synthetic biology to make meaningful—and safe—contributions to the field of environmental science.

-Ruchita Pendse, University of Pennsylvania

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Callaway, Ewen. 2013. Synthetic biologists and conservationists open talks.

Nature 496: 281.

Sanderson, Katharine. “Synthetic biology gets ethical.” Nature. 12 May 2009. Web. <http://www.nature.com/news/2009/090512/full/ news.2009.464.html> United States. Presidential Commission for the Study of Bioethical Issues.

Synthetic Biology. 2010. Web. <http://bioethics.gov/taxonomy/term/1>.

Penn Bioethics Journal

In 2010, President Barack Obama convened the newly formed Presidential Commission on Bioethical Issues to evaluate the field of synthetic biology. Synthetic biology aims to modify the genome of organisms to endow them with specific qualities, which are often transferred from genes of other organisms or synthesized in labs. The commission, comprised of leading scientists, ethicists, and public policy experts, spent months hearing the testimonies of numerous experts in relevant fields to determine whether this developing field posed significant biological, ethical, or ecological risks. While the commission acknowledged potential for harm, it outlined potential benefits of synthetic biology and encouraged individual scientists to be responsible when conducting research (United States 2010).

The field has since continued taking shape, and in midApril 2013, the University of Cambridge in England held a meeting of synthetic biologists and conservationists to discuss how synthetic biology could be used to benefit the planet. One such proposed application of synthetic biology is to genetically endow susceptible frogs with resistance to chytridiomycosis, a fungal disease that threatens some amphibians with extinction. Already, it is likely that this fungal disease contributed to the recent extinction of Rheobatrachus silius, a species of frog last seen in the wild three decades ago (Callaway 2013). In May of 2013, Australian scientists revealed they were close to cloning R. silius, and many biologists believe that adding genetically engineered chytridiomycosis immunity is necessary to ensure survival of the cloned species (Sanderson 2009).

Another recent example of what synthetic biology can accomplish is the development of genetically modified Escherichia coli bacteria. These bacteria move into plant roots and stimulate the production of auxin, a plant growth hormone. Roots of plants with these bacteria were found to be longer, resulting in greater water retention in soil.

This discovery has potential for preventing desertification, the loss of vital soil nutrients that causes the degradation of fertile land (Callaway 2013).

However, skeptics worry that synthetic biology could have unintended consequences. One major concern is the spreading of engineered genes into populations that were not meant to be modified. While genetically engineered bacteria may be able to help regulate pollution, bacteria can efficiently pass their genetic information to other bacterial cells

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Interview

Adolescent Care and Health Policy – A Conversation with Jennifer K. Walter Jennifer K. Walter is an Assistant Professor of Pediatrics at the Children’s Hospital of Philadelphia at the University of Pennsylvania’s Perelman School of Medicine. As a clinical lecturer, she has taught the ethics and procedures for carrying out pediatric medicine. Dr. Walter earned her MS in Health and Health Care Research at the University of Michigan and her MD and PhD in Philosophy at Georgetown University. The Penn Bioethics Journal spoke with Dr. Walter about the unique challenges for bioethics in pediatric care, the theory behind healthcare policy, and her own professional trajectory.

Penn Bioethics Journal

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Bioethics of Care for Adolescents

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Penn Bioethics Journal: What are the unique challenges of providing ethically appropriate care for adolescents?

Jennifer K. Walter: When caring for competent adult patients, providers have responsibilities to adequately inform patients about their health conditions and guide them through decision-making. Ultimately, however, competent adults can choose to ignore medical advice and make their own decisions about whether to continue to receive care. Adolescents are not yet considered legally capable of making decisions about their own care, unless they have been legally emancipated. However, they possess many, if not all of the capacities to make decisions for themselves that do not substantially change when they become the age of majority, 18 years old in most states. Therefore, when adolescents express a strong opinion about their care that is different from their parent’s wishes for them it is important to engage them in a discussion about why they are making that choice and the potential consequences of their decision.

Some ethicists have argued that parents should maintain the right to override their adolescent’s choices in serious illness if they are refusing care, because this preserves the child’s opportunity to survive the illness and exercise their autonomy in the future.1 PBJ: What is the physician’s obligation to protect the autonomy of adolescent patients?

JKW: Physicians have an obligation to support the development of capacities for autonomy, or self-governance, for adolescent patients because these capacities should be nurtured in the relationships adolescents have with others.

Decisions made while ill have a significant impact on all patients, including children, and having control over some of these decisions impacts how individuals understand themselves and the kind of control they have over their own bodies. Adolescents may not yet have legal control over consenting for treatment, but it is expected that outside of emergency situations, assent, or the child’s agreement to proceed, should be sought by healthcare providers to acknowledge the burgeoning autonomy of children and adolescents.2

PBJ: Why are goals of care conversations important in providing good care?

JKW: When a child has a serious or chronic illness, data from parents demonstrate that they want honest, timely information about their child’s condition3,4 and want to participate in choosing between different treatment options.

These conversations discuss what goals or hopes parents have for their child and how they would like to prioritize different care options. Only by engaging families in these discussions about what they value most can we as health care providers offer truly family centered care. In fact, the American College of Critical Care Medicine recommends that these kinds of conversations happen with patients and families within 24-72 hours of patients being admitted to intensive care units.5 PBJ: How do you assess the quality of these conversations?

JKW: There is a whole body of research that assesses the quality of communication in healthcare and quantifies everything from the amount of time that different members of a conversation speak, the number of empathetic statements used, and even different aspects of nonverbal communication. Most of this research relies upon at least audio taping of conversations (or video taping in cases that assess nonverbal communication) and a standardized scoring system that is applied to the interaction.6,7 PBJ: What are some of the barriers for providers that prevent them from engaging families in goals of care conversations?

JKW: In the interviews I’ve done with pediatric oncologists and intensive care doctors, they describe several barriers to having frank conversations with patients and families about prognosis and goals of care.

First, often there is significant medical uncertainty, and providers do not want to be inaccurate about a bad prognosis and

Adolescent Care and Health Policy upset families unnecessarily. Also, they want to preserve a patient’s or family’s hope for recovery, so they may not be as frank as they could be. Finally, physicians in the hospital are often caring for patients that they do not have a long term relationship with, so they find it challenging to share bad news with them because they believe it would be better heard from a trusted provider who is not as readily available.

These all contribute to delaying goals of care conversations.

PBJ: What were the conclusions of your study?

JKW: I completed a study in the pediatric intensive care unit (PICU) where I examined how long after admission to the PICU that a physician documented having a goals of care conversation with the patient or family. I found that only 1/3 of the sickest patients admitted to the PICU had goals of care conversations documented, which means that even if other conversations were occurring, the information of what they covered was not easily accessible to their colleagues who cared for those patients later. I also looked to see whether there was variation in how often conversations were documented by different patient diseases categories and discovered that oncology patients were most likely to have had a conversation documented. I also found that patients with a cardiovascular diagnosis went longer from admission to the documentation of a conversation. These differences demonstrate that different subspecialties may have different thresholds for documenting these kinds of conversations.8

Healthcare Policy

Deliberative Democracy, Bioethics, and Policy Making

Professional Experience

PBJ: Please explain your academic trajectory. How did your interests in philosophy develop and lead to medicine?

JKW: I have wanted to be a physician since I was about 7 years old, but when I started college my parents encouraged me to major in whatever I enjoyed, since I could complete my premed requirements at the same time. I fell in love with philosophy and the way it taught me to critically think about many different aspects of life. I thought my training in philosophy would end when I started medical school, but then I learned about the program at Georgetown that paired both a PhD in Philosophy with a medical degree. I don’t believe the program still exists, but Edmund Pellegrino, who started the program, was a visionary in recognizing that clinicians who were bioethicists have a unique understanding of bioethical challenges and the potential solutions to those dilemmas.

PBJ: How does your knowledge of philosophy, and bioethics in particular, inform your day-to-day practice as a physician?

JKW: Because of my training in philosophy, I developed the ability to recognize how individual behaviors or institutional policies perhaps could have a larger impact on how we as health care providers fulfilled our ethical obligations to care for patients. For example, I realized that when physicians avoided the difficult conversations with families and patients

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PBJ: How does ACA ignore discussions of equality?

JKW: The ACA, while doing many important things to expand access to health care to millions of Americans who are currently uninsured, has largely focused on improving the quality of care, while not emphasizing the importance of ensuring that all Americans receive similarly high quality care. In our article, we argued that this approach of ensuring “equality-in-quality” will improve health in important ways.

Empirical evidence for this approach can be found in vaccine policies that worked to prioritize improving vaccination rates among impoverished children and thereby reducing the disparity in vaccination by this group, which lead to improved immunity for the entire community.11

PBJ: How do bioethicists impact policies? What are examples of particular individuals and their work?

JKW: Bioethicists have impacted political policies in several areas. US Presidents have appointed a group of ethicists to a Council on Bioethics, which under Obama is known as the Presidential Commission for the Study of Bioethical Issues.

The previous chairs included ethicists Edmund Pellegrino and Leon Kass and the current chair of this Commission is Amy Gutmann. These Councils have significant influence in describing the ethical issues around public policy issues like stem cell research, newborn screening and our responsibilities to the aging members of society. Additionally, bioethicists like Ezekiel Emanuel have been influential in the design of the Affordable Care Act and have advocated for wider access to health care in the US.

Penn Bioethics Journal

PBJ: How would the concept of “equality” function in healthcare policy?

JKW: In terms of healthcare policy, equality refers to a reduction in the disparities of health outcomes and kinds of care offered to different classes of patients. There is significant evidence that there are health disparities based on race, gender and class in the US.9,10 Many theories of justice defend an equality of opportunity, which would include access to health care that treats all like patients alike, regardless of race, class, gender or education.

PBJ: Are there any real world examples of successes in decision making for bioethical issues utilizing deliberative democracy?

JKW: Deliberative democracy is an ideal described in political philosophy of how citizens would respectfully discuss social and political issues in terms accessible to other citizens while holding each other accountable to the decisions agreed upon. There are some examples of how this process can be approximated in smaller scale discussions about public issues, but unfortunately, it has not been achieved by any government at a large scale level. “Choosing Healthplans All Together” is a deliberative democratic exercise which has been successful in allowing citizens to deliberate about just healthcare systems.12

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Adolescent Care and Health Policy

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because those were uncomfortable to have, they could also be failing to meet their obligation to ensure patients have the information they need to make decisions about their care.

This avoidance and lack of communication could actually be disrespectful and not acknowledge the patient and family’s autonomy. This concern led me to consider the system level barriers that prevent providers from having those conversations and find ways to help providers live up to those obligations in a way that is authentic and compassionate.

work requires true experts in different fields to be in discussion with each other about novel solutions to problems and problem-solving.

PBJ: Conversely, how does your experience as a physician give you a unique perspective within the bioethics community?

JKW: Philosophers and other ethicists are incredibly skilled at solving puzzles and separating out the individual threads of an argument to distinguish the different things at stake in a moral dilemma. However, because they don’t live in the clinical world, they may not understand the large distance between ethical issues that have been resolved theoretically, but still on a day to day basis are challenges. There is significant consensus on issues like the reasons for and importance of obtaining informed consent. However, the practice of informed consent is still incredibly murky and imperfect. My experience of actually practicing medicine, offers a new perspective on how to translate what appears to be a simple solution to the complicated real world reality of that lived challenge.

1. Ross L. Children, families and health care decision-making. New York: Oxford University Press; 1998.

2. Walter JK. Supporting Her Autonomy: The Obligations of Guardians and Physicians in Adolescents’ Refusals of Care. Journal of Clinical Ethics. 2012;23(1):56-59.

3. Shudy M, de Almeida M, Ly S, et al. Impact of pediatric critical illness and injury on families; a systematic literature review.

Pediatrics. 2006;118(S3):S203-219.

4. Meert KL, Eggly S, Pollack M, et al. Parents’ perspectives on physician-parent communication near the time of a child’s death in the pediatric intensive care unit. Pediatr Crit Care Med. Jan 2008;9(1):2-7.

5. Davidson J, Powers K, Hedayat K, et al. Clinical practice guidelines for support of the family in the patient-centered intensive care unit: American College of Critical Care Medicine Task Force 2004-2005. Crit Care Med. 2007;35(2):605-622.

6. Curtis J, Engelberg R. Measuring success of interventions to improve the quality of end-of-life care in the intensive care unit.

Critical care medicine. 2006;34(11 Suppl):S341-347.

7. Roter DL, Stewart M, Putnam SM, Lipkin M, Jr., Stiles W, Inui TS. Communication patterns of primary care physicians.

JAMA : the journal of the American Medical Association. Jan 22-29 1997;277(4):350-356.

8. Walter JK, Rosenberg A, Feudtner C. Tackling taboo topics: how to have effective advanced care planning discussions with adolescents and young adults with cancer. JAMA Pediatrics.

2013;11:1-3.

9. 2010 National Healthcare Disparities Report. Rockville, MD: Agency for Healthcare Research and Quality;2011. 11-0005.

10. Medicine Io. Toward Health Equity and Patient-Centeredness: Integrating Health Literacy, Disparities Reduction, and Quality Improvement: Workshop Summary. Disparities Reduction, and Quality Improvement: Workshop Summary 2009.

11. Davis MM, Walter JK. Equality-in-Quality in the Era of the Affordable Care Act. JAMA. 2011;306(8):872-873.

12. Goold SD, Biddle AK, Klipp G, Hall CN, Danis M. Choosing Healthplans All Together: A Deliberative Exercise for Allocating Limited Health Care Resources. Journal of Health Politics, Policy and Law. 2005;30(4):563-602.

PBJ: How can undergraduate education be improved to enable students to pursue interdisciplinary studies in fields like the life sciences, humanities, healthcare management, and related fields that eventually affect patient outcomes?

JKW: I benefited from attending a true liberal arts school where I both was required to take many classes in the humanities and social sciences, while still completing my science requirements for medical school. I think the universities which offer a broad curriculum, like the one I was exposed to at Loyola Chicago, gives students an opportunity to be exposed to different methodologies and bodies of literature which offer cognitive flexibility when confronting new problems and recognition that different disciplines may be encountering similar problems methodologically and can share resources in solving problems. True interdisciplinary

-Interview and questions by Anand Muthusamy, University of Pennsylvania -References and responses written by Jennifer K. Walter

References

Interview

Q&A with David Perlman The Penn Nursing senior lecturer speaks on his interactive bioethics thriller, The Organ Farm The next science fiction thriller might just be based on a recent book by University of Pennsylvania School of Nursing senior lecturer David Perlman. The Organ Farm, an interactive eBook offered on Kindle, tells the story of a secret operation that offers end-of-life care in exchange for donated organs. Not everyone’s reading of the story is necessarily the same though—the book is written in a choose-your-own-adventure style, with crucial choices along the way. The Penn Bioethics Journal sat down with Perlman to discuss the book’s premise, future prospects, and implications for society.

Penn Bioethics Journal: How did you become interested in ethics?

David Perlman: I actually have a book on that. It talks about how I got into the field—mainly, I was watching relatives die and how poorly that was managed back in the day. We’ve done a much better job nowadays, but there are still a lot of myths about dying and end of life care.

PBJ: So tell me a little bit about the premise behind The Organ Farm.

DP: It’s set in the future, when we have the confluence of

It’s also an interactive novel, which means you get to make

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PBJ: What about fiction-writing?

DP: I’ve always been interested in science fiction. In terms of writing, I tried to practice my hand in undergrad and thought about getting a creative writing degree and making less money than you do as a philosopher, but I said I can do this on a part-time basis just for fun. I’ve always written, whether it is scholarly stuff or fiction. The computer and I have always been one.

The book lays out the premise that there are these people who will knock on your door and say, “The government can no longer provide support, what do you want us to do? We can offer them terminal sedation to ease their death or you can take over paying this on some kind of private mechanism.”

We still have an organ shortage.

There’s this surgeon in the military, and he gets the bright idea to take advantage of this health policy issue, and he buys up the old Guantanamo Bay medical facility in Cuba.

He finds people in this permanent vegetative state and offers to the family to maintain their loved one in perpetuity for something in exchange—a kidney.

They also want to expand—why can’t we also get women who have this condition who still are of reproductive viability and use them to grow babies for people who can’t have them? It gets really creepy. I fictionalized all of this, but at the end of the book, there’s an essay about how we’re one venture capitalist away from an organ farm coming true.

Penn Bioethics Journal

The other [reason] is that ever since I was a young kid, I wanted to be a cardiothoracic surgeon. The joke answer is I found out that doctors usually have to wear ties, and I hate neckties. But the real answer is that when I was in undergrad, I was taking more and more philosophy classes and became interested in the intersection.

several different things. We’ve had major healthcare reform in the US. We’ve realized that we have to make cost cuts, and one of those that’s natural to think about is we spend a billion dollars a year taking care of patients in a permanent vegetative state.

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Q&A with David Perlman your own choices throughout, which is a remnant of my childhood. The idea I had for the book technically was all the way back in 1993, but as a country, I don’t think we were really ready until Terri Schiavo, where we had this come into public consciousness.

PBJ: You mentioned that you wanted to expand the series in the future. What’s coming up?

DP: I already have a prequel and a sequel planned. The prequel will be a series of character sketches, and they’ll all meet in the end. And spoiler alert, there’s room for a sequel in one of the branches of the ending.

PBJ: How did you come up with all the different choices?

DP: The first thing you have to do is map it all out. It became like I was programming a computer software. If this happens, then this. But it was really fairly easy to do with hyperlink technology. Hyperlinking is a nice way of having it be crossplatform.

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PBJ: You offered to give readers who send in feedback a free book and a donation to a non-profit. How have people responded?

DP: People who have responded—it’s a handful right now—have said that they really like this book, so I’m giving it away to people for free who’ve said that they would [send feedback]. I just made my first donation to Kivva.org because someone finally sent me a question and an answer, and I put it on the Facebook page. I’m not looking to get rich by any stretch of the imagination, although I do have plans for a screenplay. As long as I can get someone interested in Hollywood, I think this would be a really cool idea.

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PBJ: Would that also be interactive?

DP: I’m hoping people would be able to do it via their cell phones or clickers. I’ve thought about the novel and turning it into a screenplay, and I have people I’d love to play certain parts. For the Latino woman who gets a transplant, I’d love to have Jessica Alba because I really liked her in the series Dark Angel. For the black male surgeon, I’d like Will Smith because he’s a homeboy from West Philadelphia.

PBJ: What do you want readers to learn from the choices they make in the interactive novel?

DP: The feedback that I’ve had from readers is that what they’ll do is sit down first and use their gut instinct, but then they’ll go back and explore the various options, so it’s almost like getting 15 books in one. I hope that when they make those choices, they’re also reflecting on why a character might choose that. But it’s also designed as a page-turner.

It’s just like any other science fiction movie or book that has scientific and societal implications. Gattaca doesn’t talk about ethics, but if you look behind, we really are talking about what we do value as a species.

PBJ: You mentioned health policy reform as one of the reasons for the book. Where do you think we are as a country in terms of all the recent healthcare reform?

DP: I don’t think you can really be involved in healthcare and in ethics and not support some kind of universal access.

We’re the only industrialized nation that doesn’t have some kind of system. We’ve seen whole-scale attempts to revise our system in the past 50 years fail. What we have today is largely an incremental change, and I think that works best for our country. It’s not necessarily what I would support, but something’s better than nothing. We have a long ways to go in terms of health and social policy. I became a new dad and saw what it was like for working moms, and we encourage people to have kids and then we don’t offer them the support they need to raise them.

PBJ: Why did you choose organ donation as one important issue?

DP: It lent itself to where I was headed. At the time, I had just finished reading the book Coma, which talks about body snatchers. It just seemed to make sense. One of the goals of the book is to get people to think about these kinds of issues. I tell my students, “Have you had a discussion with your family member about what you might want to do if something untoward were to happen to you?” Very few people have thought about it, especially 18 to 22 year olds.

You think you’re invincible, but you really should be thinking about those issues.

PBJ: Do you think university students should have to take an ethics requirement?

DP: It depends on which students. Before we send anyone out into the world, you know, it’s like Socrates said, “The unexamined life is not worth living.” You don’t want people to be robots and do their jobs without thinking about what they’re doing. You have to know what the ethical demands are for your particular discipline. But what I’d really like to see is to have [ethics] integrated into various facets of the curriculum. What you don’t want is people to think of the ethics course as separate from their discipline. You should always be thinking about those things because you’re going to run into them in real life.

-Interview and questions by Lucy Chen, University of Pennsylvania

Article

The Potential of Epigenetic Therapy and the Need for Elucidation of Risks

Josh Tycko, Danielle Fields, Daniel Cabrera, Mahamad Charawi, Bradley Kaptur‡ Epigenetic phenomena are known to be a root cause of many common diseases. To date, the FDA has approved four epigenetic therapies that show promising results for prolonging lives of terminal cancer patients. However, there is a relative lack of knowledge about long-term epigenetic effects, especially those that affect future generations. We propose a heightening of standards for epigenetic therapy: therapies should be targeted to specific genes in specific cells and cannot affect the germline and patients’ epigenomes should be sequenced before and after treatment. Moreover, further research should be performed to answer questions about transgenerational epigenetic effects, to analyze the effects of altered epigenomes in the long term, and to develop superior assays for screening epigenomes. We highlight current research in the field, including the work of the Penn iGEM group.

Epigenetics Background

Epigenetic Diseases

‡ University of Pennsylvania, Penn iGEM 2013

Fundamental Advantages. The aforementioned epigenetic roots of disease are attractive targets for therapy.

Aberrant DNA methylation patterns are more easily reversible than genetic mutations. In the case of cancer, epigenetic therapy coaxes tumor cells to return to a healthy state, rewiring their methylation patterns so the cells express genes that halt their cancerous uncontrolled growth.

Traditional chemotherapy strategies, on the other hand, aim to kill cancer cells and are fundamentally more toxic to patients since healthy cells are also harmed.

Recent Successes. There have been some exciting clinical successes with the first generation of epigenetic therapies. To date, four epigenetics treatments have been approved by the FDA for use in cancer patients: Zolinza, Istodax, Vidaza, and Dacogen (Claus 2005).

The first two are histone deacetylase inhibitors and prevent histone modifications, a type of epigenetic change; the second two inhibit DNA methylation. These compounds are chemical analogues of the DNA base cytosine (“C”), and at low doses, they bind to the methyltransferases so that they don’t come into contact with the patient’s actual DNA, preventing the DNA’s methylation. At high doses, they

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Cancer. DNA methylation has been referred to as the “hallmark of cancer” (Szyf 2004). Abnormal methylation patterns throughout the genome that cause blockage of tumor suppressor genes have been linked to many types of cancer.

For instance, breast cancer generally exhibits inactivation of the gene BRCA1. In sporadic (i.e. non-familial) cases, this suppression is usually caused by hypermethylation rather than mutation of the gene (Rice 2000). In other cases, hypomethylation causes overexpression of the flap endonuclease 1 gene and lead to breast cancer in some patients (Singh 2008).

Neurological. Methylation abnormalities have been linked to a wide range of diseases. Fragile X syndrome,

Epigenetic Therapy

Penn Bioethics Journal

Introduction. The code of life is more than a sequence of As, Cs, Ts, and Gs. Muscle cells in the human heart contain the same DNA as skin cells in the foot, yet these two cell types behave in radically different ways. Both contain the DNA for over 20,000 human genes but express only the ones needed for their own form and function.

These differences in gene expression are modulated by epigenetic controls. Epigenetics refers to any heritable chemical modification of DNA that alters expression without changing genetic sequence. Neurodevelopmental disorders, immunodeficiency, cancer, and other illnesses can result when these mechanisms go awry.

Methylation.

In humans, enzymes called methyltransferases add methyl groups to short DNA sequences, called CpG sites, abundant in the genome.

Methyl groups block transcription factors (gene activators) from binding to DNA and performing their normal function. Although epigenetic factors do not change the sequence of DNA, they can affect the phenotype, the observable characteristics of the organism. Specific patterns of methylation are necessary for a cell to modulate the level of expression of each of its genes.

one of the leading genetic causes of intellectual disability, is characterized by hypermethylation, which disrupts the production of protein necessary for normal brain development. Patients suffering from this disorder are at risk for autism, ADHD, decreased IQ, infertility in females, and distorted facial features ( Jacquemont 2011).

Psychological. Epigenetic mechanisms can also impact psychological states. In an animal study, rat pups that received better maternal care in the form of licking, grooming, and arched-back nursing had lower levels of methylation at the glucocorticoid receptor gene. These rats displayed less intense responses to stressful situations than those who received poor maternal care. The researchers were able to eliminate these differences via epigenetic interference (Weaver 2004).

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The Potential of Epigenetic Therapy and the Need for Elucidation of Risks can incorporate into the DNA or RNA itself and reduce cell viability. These treatments are used, at low doses, to reverse hypermethylation in patients with myelodysplastics syndromes (MDS), a spectrum of blood cell disorders that can lead to anemia and heighted susceptibility to infections.

The drugs effectively reverse cancerous hypermethylation and return standard function to cell-cycle genes, restoring normal growth rates. However, fewer than 10 percent of patients experience a “complete response,” a total reversal from diseased to healthy bone marrow and blood (Silverman 2002).

Problems. The results of first generation epigenetic therapies are promising, but these drugs should not be seen as the ideal model for future developing therapies, especially if doctors want to treat younger patients with non-lethal epigenetic diseases. First generation drugs fail to satisfactorily address many issues. For one, they all inhibit DNA methylation processes. As previously mentioned, many cancers can be caused by low methylation levels, and would need to be treated with drugs that restore normal methylation levels (Feinberg 2004).

Second, the current drugs work by blindly affecting all genes in the genome of all the cells they encounter. One of the scientists behind the Dacogen studies noted there is a “potential for harm,” but so far the adverse events, including red blood cell suppression, diarrhea, anorexia, and others, have been deemed acceptable by the FDA (Issa 2007). It is possible that the potential for greater harm will be realized if epigenetic therapies are used on patients with a much longer expected life span than the current patient population.

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Ethical Questions

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Long Term Risk. Research has not yet fully elucidated the effects of DNA methylation (Rothstein 2009). Therapies may have off-target effects that are difficult to observe especially if they appear years after the initial therapy.

To date, approved trials have been conducted with very sick, elderly cancer patients, but research has confirmed epigenetic modifications can affect us on a longer, even transgenerational, time-scale (Rothstein 2009). Clinical trials however do not normally track side-effects ten, twenty, or thirty years after treatment. If these treatments alleviate disease in the short term but eventually cause unforeseeable epigenetic abnormalities, are they acceptable for younger patients with non-terminal diseases? Most would argue this depends on the gravity of the adverse effects—a risk/ benefit analysis similar to that performed for any drug approval should be conducted. Therefore, clinical trials must be designed to take these risks into account. Trials and follow-ups should last for a sufficient amount of time to assess these risks – on the decade time scale. On the other hand, if the drug does show an immediate benefit in the trial subjects, the ethics of delaying its medical use until the conclusion of the trial must be assessed. Certainly, trials of such durations with these looming questions would be unfavorable for the pharmaceutical investment community.

Comprehensive diagnostic tests could help balance the

need to push new drugs and ensure safe use. Methylationsensitive genome sequencing in multiple cell types for each patient would reveal potential off-target effects. This kind of personalized medicine could obviate the need of a longitudinal clinical trial. This is difficult and expensive with existing technologies, and these procedural problems must be overcome so that adequate assessment of epigenetic therapies can be performed (Laird 2010). As more research is conducted, the balance between clinical trials and personal diagnostic tests and the responsibilities of those involved must be considered.

Trans-generational Risk. The issues discussed thus far are not unique to first generation epigenetic therapies. They act blindly not only on a genomic level, but also in terms of affected cell type. We cannot exclude the possibility that these treatments will affect the epigenomes of germline cells. In fact, recent studies demonstrate that Dacogen could interfere with embryo implantation and harm the fetus if given to a pregnant woman or to a man or woman planning on having children (Ding 2012). There is evidence that epigenetic modifications can be inherited by children and even grandchildren, so doctors need to keep the health of future generations in mind (Grossniklaus 2013). The effect of epigenetic therapies on germline cells should be measured not only while the drug is being administered, but also in follow-ups after the treatment is finished. It is critical that more basic research is performed to determine the extent of transgenerational epigenetic effects. If we acknowledge that some patients will have children regardless of any warnings, we must consider if it is acceptable to have synthetically altered epigenomes in the population.

Second Generation Epigenetic Therapies Higher Standards. Continued development of first generation epigenetic therapies that affect whole genomes and any cell type should be accompanied with open acknowledgement of potential undetectable harm. To date, epigenetic therapy has been held to the same safety standards as other cancer therapies. However, as these drugs affect gene expression, the basis of our existence, it is more appropriate to hold them to the standards of gene therapies. That entails an expectation to target only the genes, pathways, and cells relevant to the disease (U.S. Food and Drug Administration).

Germline transmission of epigenetic modifications should be unacceptable. Animal model studies are always carried out before therapies are tested with humans—these must continue to be carried out rigorously before epigenetic therapies are more widely applied. In particular, researchers must consider non-mouse models as most mice can only live for around two years, which may not properly model long-term epigenetic effects. Patients’ epigenomes should be screened, so doctors can be sure the proposed therapy is relevant to the individual, just as they would sequence a patient’s genome to be sure of a genetic disease. Genome wide epigenetic sequencing has recently become feasible, although it is still difficult and somewhat error prone (Laird 2010). There is a need for further development of this

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The Potential of Epigenetic Therapy and the Need for Elucidation of Risks

Penn iGEM is an undergraduate research team that only exists because of the generous support of many individuals and companies (see http://2013.igem. org/Team:Penn). Dr. Brian Chow of Penn Bioengineering advises and directs the team. Dr. Jordan Miller of Bioengineering at Rice University also advises the team.

Spencer Glantz, Mike Magarici, Avin Veerakumar, and Dr. Orkan Telhan have also provided invaluable expertise.

Drs. Brian Chow, Benjamin Tycko, and Marisa Bartolomei reviewed and provided comments on this manuscript.

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About the Authors

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Claus, R., Almstedt, M., & Lubbert, M. 2005. Epigenetic treatment of hematopoietic malignancies: in vivo targets of demethylating agents.

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Ding, Y. B., Long, C. L., Liu, X. Q., Chen, X. M., Guo, L. R., Xia, Y. Y., et al. (2012). 5-aza-2’-deoxycytidine leads to reduced embryo implantation and reduced expression of DNA methyltransferases and essential endometrial genes. PLoS One 7(9): e45364.

Feinberg, A. P., & Tycko, B. 2004. The history of cancer epigenetics.

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Grossniklaus, U., Kelly, B., Ferguson-Smith, A. C., Pembrey, M., & Lindquist, S. 2013. Transgenerational epigenetic inheritance: how important is it? Nature Reviews Genetics 14(3): 228-235.

Issa, Jean-Pierre. Interview by Nova. Nova. Public Broadcasting System.

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Jacquemont, S., Curie, A., des Portes, V., Torrioli, M. G., Berry-Kravis, E., Hagerman, R. J., et al. 2011. Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Science Translational Medicine 3(64): 64ra61.

Kerkel, K., Schupf, N., Hatta, K., Pang, D., Salas, M., Kratz, A., et al.

2010. Altered DNA methylation in leukocytes with trisomy 21.

PLoS Genetics 6(11): e1001212.

Kondo, T., Bobek, M. P., Kuick, R., Lamb, B., Zhu, X., Narayan, A., et al. 2000. Whole-genome methylation scan in ICF syndrome: hypomethylation of non-satellite DNA repeats D4Z4 and NBL2.

Human Molecular Genetics 9(4): 597-604.

Konermann S, Brigham MD, Trevino AE, Hsu PD, Heidenreich M, Cong L, Platt RJ, Scott DA, Church GM, Zhang F. 2013. Optical control of mammalian endogenous transcription and epigenetic states. Nature 500(7436): 472-6.

Laird, P. W. 2010. Principles and challenges of genomewide DNA methylation analysis. Nature Review Genetics 11(3): 191-203.

Maeder ML, Angstman JF, Richardson ME, Linder SJ, Cascio VM, Tsai SQ, Ho QH, Sander JD, Reyon D, Bernstein BE, Costello JF, Wilkinson MF, Joung JK. 2013. Targeted DNA demethylation and activation of endogenous genes using programmable TALE-TET1 fusion proteins. Nature Biotechnology. Online publication ahead of print.

Mendenhall EM, Williamson KE, Reyon D, Zou JY, Ram O, Joung JK, Bernstein BE. 2013. Locus-specific editing of histone modifications at endogenous enhancers. Nature Biotechnology. Online publication ahead of print.

Rice, J. C., Ozcelik, H., Maxeiner, P., Andrulis, I., & Futscher, B. W. 2000. Methylation of the BRCA1 promoter is associated with decreased BRCA1 mRNA levels in clinical breast cancer specimens.

Carcinogenesis 21(9): 1761-1765.

Rothstein, M. A., Cai, Y., & Marchant, G. E. 2009. The ghost in our genes: legal and ethical implications of epigenetics. Health Matrix 19(1): 1-62.

Silverman, L. R., Demakos, E. P., Peterson, B. L., Kornblith, A. B., Holland, J. C., Odchimar-Reissig, R., et al. 2002. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. Journal of Clinical Oncology 20(10): 2429-2440.

Singh, P., Yang, M., Dai, H., Yu, D., Huang, Q., Tan, W., et al. 2008.

Overexpression and hypomethylation of flap endonuclease 1 gene in breast and other cancers. Molecular Cancer Research 6(11): 17101717.

Szyf, M., Pakneshan, P., & Rabbani, S. A. 2004. DNA methylation and breast cancer. Biochemical Pharmacology 68(6): 1187-1197.

U.S. Food and Drug Administration. “Cellular and Gene Therapy Guidances.” Last modified July 2, 2013. http:// www.fda.gov/BiologicsBloodVaccines/GuidanceCompliance RegulatoryInformation/Guidances/CellularandGeneTherapy/ default.htm.

Weaver, I. C., Cervoni, N., Champagne, F. A., D’Alessio, A. C., Sharma, S., Seckl, J. R., et al. 2004. Epigenetic programming by maternal behavior. Nature Neuroscience 7(8): 847-854.

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technology to enable the promise of personalized epigenetic treatment.

Research at Penn and Beyond. These more stringent safety standards demand the development of secondgeneration epigenetic therapeutics that are properly targeted at the genomic and cellular levels. In the past few months, we have seen promising initial published work on new tools for manipulating the genome in a careful, targeted manner.

Histone methylases, histone demethylases, and DNA demethylases have all been engineered to act on specific DNA sequences (Konermann 2013, Mendenhall 2013, Maedner 2013). Our research team at the University of Pennsylvania, Penn iGEM, took initial steps to complete this suite of tools by designing a novel enzyme that selectively restores methylation at specific DNA sites. More importantly, we have developed an alternative DNA methylation assay, called MaGellin, which is significantly simpler, faster, and cheaper than methylation-sensitive sequencing for applications like ours to accelerate the optimization of these tools. These efforts would not have been possible without the expert advice of the University of Pennsylvania’s epigenetics research labs. Dr. Marisa Bartolomei’s lab is actively studying how methylation patterns are transmitted across generations. Additionally, Dr. Rebecca Simmons’ lab in the Perelman School of Medicine has discovered a way to reverse epigenetic modifications including DNA methylation and prevent the onset of obesity in a rat model.

Conclusion. Epigenetic phenomena have a significant impact on the way we live and grow and can be responsible for the way we die. The need for epigenetic therapies is clear and the initial successes are promising for cancer patients, but the model for future developments is not yet set in stone.

If doctors want to treat younger patients with non-lethal epigenetic diseases, the consideration of risks must include the long term, and the decisions in the clinic must be based on data from researchers asking fundamental questions.

The proposed second generation epigenetic therapies could overcome the hurdles of restoring methylation, as opposed to only inhibiting methylation, and targeting specific genes as opposed to the entire genome. However, the issues of their delivery and cellular targeting still loom. While it will require significant effort from basic researchers to determine the relevant mechanisms to optimize the clinical strategies, the path forward is promising.

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The Scattergood Program for the Applied Ethics of Behavioral Healthcare is dedicated to applied research and scholarship in all areas of behavioral healthcare ethics. Housed at the University of Pennsylvania, in the Department of Medical Ethics & Health Policy, the ScattergoodEthics Program is a regional and national effort that welcomes all those active in the field of behavioral healthcare.

Bioethics

Life, Health, and Environment M.A. in Bioethics The NYU masterâ&#x20AC;&#x2122;s program promotes a broad conception of Bioethics encompassing both medical and environmental ethics through conferences, workshops, public lectures, and graduate courses. Students may choose to follow a health track or an environment track, and in both cases they will receive training in broader bioethical theories and application.

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Article

Monetary Compensation of Research Subjects: The Shortfalls of Research Standards in Preserving Autonomy

Shivam Amin‡

Biomedical researchers are expected to respect the autonomy of human subjects through the process of informed consent. The Belmont Report established the principle of respect for autonomy as a cornerstone of biomedical research ethics in 1979. However, researchers can find it difficult to uphold this ideal when compensating human subjects. Ambiguities in both the Belmont Report and government guidelines complicate pinpointing exactly how to preserve the autonomy of research subjects. The process of informed consent itself poses a set of problems for researchers. Specifically, the term “undue inducement,” describing a concept central to the preservation of a subject’s autonomy, is particularly vague and warrants further investigation. It is certainly possible that researchers can undermine a subject’s autonomy through the offer of a monetary payment. However, the magnitude of this problem is nearly impossible to measure because inconsistencies in policy make it extremely difficult for researchers to respect the principle of respect for autonomy in practice. Once some of these inconsistencies are resolved, researchers can then explore the underlying so-

Introduction

Inadequacies of the Belmont Report and U.S. Government Guidelines

‡ University of South Alabama, sva1002@jagmail.southalabama.edu

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In the United States, in 1979 the Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research, Report of the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, hereafter the “Belmont Report,” helped establish an ethical framework for biomedical research involving human subjects.

While the Report has no legal enforcement mechanism, the scientific community has embraced the Report’s guidelines to help resolve potential ethical dilemmas. The Belmont Report’s principles also guide institutional review boards (IRBs) and executive bodies in the US that oversee most research projects involving human subjects. IRBs are usually

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Respect for autonomy is one of the cornerstone principles of bioethics. According to Tom Beauchamp and LeRoy Walters, two leading bioethicists at the Kennedy Institute of Ethics, “personal autonomy refers to personal self-governance: personal rule of the self by adequate understanding while remaining free from controlling interferences by others and from personal limitations that prevent choice” (2003). The idea that one should respect another person’s right to decide his or her own fate is largely a product of Western culture and has become deeply ingrained in biomedical research ethics. The principle of autonomy is rooted in the Kantian conception of human beings as ends in themselves and never only as means to an end ( Johnson 2012). This paper explores the principle of respect for autonomy as it relates to the practice of monetarily compensating human research subjects.

affiliated with academic institutions and consist of at least five professionals of varying backgrounds. These individuals have the authority to approve or reject any research project in which human subjects are involved (DHHS 1993). Each major institution conducting human subject research will have at least one such IRB panel that must approve any proposal of such research.

The Belmont Report highlights three ethical principles that serve as the moral backbones for biomedical research ethics: respect for persons, beneficence, and justice (HEW 1979). Central to the principle of respect for persons is the notion that every person be treated as an autonomous individual. According to the Belmont Report, an autonomous individual is someone who is capable of making personal decisions through careful deliberation. To respect autonomy is to not obstruct this decision-making process.

The Belmont Report underscores the importance of informed consent as a way to ensure respect for autonomy.

In order to provide informed consent, a potential human research subject should be made aware of what a research project entails and be afforded the right to choose whether or not to participate in the project. Informed consent is contingent upon three factors: information, comprehension, and voluntariness. A potential research subject must be given a thorough overview of a research project in an understandable manner. Ultimately, the subject must use this understanding to voluntarily give consent to participate in the project (HEW 1979).

When voluntarily giving consent, an individual must be “free of coercion or undue influence” (HEW 1979).

The Belmont Report states that undue influence “occurs through an offer of an excessive, unwarranted, inappropriate

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or improper reward or other overture in order to obtain compliance. Also, inducements that would ordinarily be acceptable may become undue influences if the subject is especially vulnerable (HEW 1979). The problem with terms such as “excessive” and “vulnerable” is that they are vague.

At what point is an award “excessive”? In what situation is a person deemed “vulnerable”?

While the Belmont Report does not rigorously define “undue influence,” “excessive,” or “vulnerable,” it is important to note that its purpose is simply to provide a foundation of moral guidelines. It is necessary that the Belmont Report be vague so that it can adequately address a wide range of ethical quandaries. The real issue arises when IRBs consider exactly how much “vulnerable” human research subjects should be monetarily compensated. An offer of payment could unduly influence potential research subjects and compromise their autonomy, especially if they are at the lower end of the socioeconomic hierarchy. The IRB Guidebook and the Code of Federal Regulations (CFR) are meant to guide researchers in dealing with such ambiguities, but neither provides enough specifications to guide practice. The IRB Guidebook states that IRBs should provide “special safeguards” when economically vulnerable individuals or populations are involved in research that offers monetary compensation. However, the IRB Guidebook does not offer any insight into what these “special safeguards” should entail (HHS 1993). CFR Title 45 Part 46 alludes to the protection of economically disadvantaged individuals and, like the IRB Guidebook, states that special measures have to be taken when these disadvantaged individuals are monetarily compensated (PHS 2009). Yet neither of these documents elucidates exactly how these disadvantaged individuals can be protected.

Furthermore, just as the Belmont Report does not clearly define the term “undue inducement,” neither does the IRB Guidebook, which makes it difficult for IRBs to preserve individual autonomy. The Belmont Report delineates a set of ideals to build a foundation for the protection of human research subjects, but these ideals need to be expounded upon as IRBs and researchers cope with specific situations. It is difficult to reconcile the principle of respect for autonomy with the actual practice of monetary compensation if IRBs are forced to act upon a set of vague axioms. Ultimately, the vagueness of the IRB Guidebook means IRBs have little more to rely upon than the Belmont Report itself. Different IRBs often have different working understandings of the term “undue inducement,” and even within a single IRB there may not be a standard set of rules for how monetary payments should be determined (Klitzman 2013).

Obtaining Informed Consent The definitions of terms like “undue inducement” are crucial because they are meant to protect individual autonomy through the exercise of informed consent by the patient. The purpose of informed consent is to formalize the decision of an individual to be a research subject. Informed consent is more than just a signature; it is more accurately

described in CFR Title 21 as a dialogue between researcher and subject, in which the researcher ensures that the subject has a comprehensive understanding of his or her role in the project (2012). Through informed consent, researchers and IRBs try to prevent undue inducement and uphold the principle of respect for autonomy. They want each subject to understand what a trial or study entails, but they typically ignore the motives behind an individual’s decision to volunteer as a subject in the first place.

More often than not, informed consent equates to respect for autonomy. People choose to be research subjects for a variety of reasons. However, sometimes there is a need to examine the rationale behind why people choose to participate as subjects. While it is reasonable to assume monetary compensation does not threaten the autonomy of most people, this may not be true for individuals who are extremely poor.

Two types of problems can arise when socioeconomically disadvantaged individuals or populations are involved in a research project. The first is that a subject’s desire for money may supersede any risks outlined during the informed consent process, compromising that subject’s autonomy. The second problem is that socioeconomically disadvantaged individuals are susceptible to a systematic exploitation of which they may be largely unaware. For example, a drug company might conduct a human trial in an impoverished region and offer a monetary payment to all potential subjects.

The individuals of that region might feel incentivized to volunteer as research subjects, but they may never be able to afford the drug when it actually hits the market.

Consequently, this population would be systematically exploited because they would be unable to reap the benefits of the very drug they helped bring to market.

While this latter issue largely involves the principle of justice, it is also closely tied to the principle of respect for autonomy because in such a scenario, researchers would still be exploiting the socioeconomic bearings of a group of people—a specific individual may be unable to act autonomously because an offer of monetary payment has distorted his or her judgment. The common solution cited is that payments be extremely minimal or nonexistent in cases in which a project presents a greater than minimal risk (DHHS 1993). This strategy prevents a particular subject from being harmed by his or her inability to act autonomously. An overlooked step is that IRBs should not allow researchers to view monetary payments as a recruitment tool but rather as reciprocation for a subject’s time. Researchers need to consider payments as compensation for someone who has taken the time to help further a scientific endeavor and not as inducements. When researchers see monetary payments as a way simply to gain volunteers, it is more likely that they will unduly influence some participants and compromise their autonomy. In such a scenario, researchers are not acting with the intent to preserve the subject’s autonomy but rather steering a prospective subject’s judgment in a specific direction, which is exactly what the Belmont Report condemns.

Monetary Compensation of Research Subjects However, even if every research subject chooses to participate autonomously at an individual level, their autonomy may still not be respected because they may be exploited at a systemic level. This is especially true if the researching party knows that the recruited subjects will not have access to the drug they have helped develop once the study is over. New legislation may help by guaranteeing that the people of a particular region where a drug trial is conducted are offered the final product at a discounted rate. In the end, however, since it can be difficult to pinpoint systematic exploitation, IRBs, drug companies, researchers—individuals and institutions in positions of power—have to make a conscious effort to understand the social circumstances of the population in the region where a project will be carried out.

Unfortunately, government guidelines are inconsistent regarding the matter. Chapter 6 of the IRB Guidebook states that research subjects should be compensated for “their time and discomfort,” whereas the Food and Drug Administration (FDA) states that IRBs and clinical investigators should be aware that monetary compensation “is not considered a benefit, it is a recruitment incentive” (HHS 1993). To pay a subject for his or her time and discomfort makes sense— to offer payments as recruitment incentives increases the likelihood that the principle of respect for autonomy may not be upheld. These inconsistencies need to be rectified so that all researchers approach the practice of monetary compensation with a mindset that is in accordance with the IRB Guidebook and not the FDA.

Perversion of Choice

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Coercion and undue inducement are two ways researchers can potentially undermine autonomy. Because blatant coercion involves an actual threat towards a research subject, it is unlikely that a subject will ever feel threatened to participate in a research project as long as IRBs are intact (HEW 1979). However, the problem of undue influence is very real and needs to be addressed. Although there is no general consensus on what undue influence entails, Ezekiel Emanuel, an acclaimed bioethicist at the University of Pennsylvania, highlights four factors that create undue influence: 1. An Offered Good—Individuals are offered something that is valuable or desirable in order to do something.

2. Excessive Offer—The offered good must be so large or in excess that it is irresistible in the context.

3. Poor Judgment—The offer leads individuals to exercise poor judgment in an important decision.

4. Risk of Serious Harm—The individual’s poor judgment leads to sufficiently high probability that he or she will experience a harm that seriously contravenes his or her interests (2005).

The problem with this set of criteria is it presupposes that undue inducement is contingent upon only the consequences that result from an individual’s decision, meaning that undue inducement occurs only when a poorly

informed decision has deleterious consequences. However, the Belmont Report does not consider consequences. It states that undue inducement occurs at the moment an excessive award perverts an individual’s judgment. But according to Emanuel’s criteria, even if a subject is offered compensation so excessive that he is all but forced to accept it, he is only unduly influenced if he is likely to be harmed.

It is apparent then that only the first three conditions Emanuel outlines reflect the nature of the Belmont Report.

With that in mind, it is undoubtedly easy to link the practice of excessive monetary compensation to undue inducement and call foul play. However, it is important to note that autonomy is predicated upon choice. An individual’s autonomy is only jeopardized when a theoretical financial reward is so excessive that it renders other options too difficult to select. By feeling an obligation to accept the reward, the individual in question exercises poor judgment.

The individual is unduly influenced to participate as a subject by the coercive nature of the reward (Ashcroft 2011).

Emanuel also argues that the issue of undue inducement has largely been blown out of proportion. He makes a very interesting point when he notes, “From store sales to salary bonuses, from low interest rates to added computer memory, from scholarships to ‘free’ PDAs, we are constantly bombarded by offers of desirable things to make us change our behavior.” He goes on to argue that offering money to an individual for his or her participation in a research project is no different from the marketing schemes highlighted above and that monetary compensation is almost always just an inducement (Emmanuel 2005).

However, a monetary payment offered by a researcher is quite different from, for example, a scholarship offered by a university. The researcher is bound by a code of ethics; he or she has an obligation to protect individual autonomy. The goal of study or clinical trial can never come at the expense of the subject’s rights. A university that offers a scholarship to a prospective student is not bound by many guidelines; its purpose is, in fact, to induce that student. In the case of a scholarship, both the university and the student have a definitive goal and are bound by specific parameters: a university offers a scholarship with the primary intent of recruiting a student and a student accepts a scholarship with the primary intent of attending that university. The transaction is simple.

Regarding the case where a researcher offers a monetary payment to a potential subject, there are implications that extend beyond both the researcher and potential subject.

There are sometimes inherent risks with studies or trials, and researchers need to make sure subjects are aware of them. A monetary offer cannot undermine this process.

Researchers always have to be mindful of their obligation to fulfill the ideal of respect for autonomy, even if they are not entirely successful in this endeavor. In a normative field such as bioethics, it is often impossible for researchers to comply with absolute maxims, but these maxims are in place so that researchers are not blinded by their own interests.

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Improving Guidelines

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There must be a more uniform protocol for the practice of monetarily compensating human subjects. IRBs need better guidelines on how, when, and what to compensate individuals as currently there are too many disparities in the standards that different researchers adhere to (Klitzman 2013). It is not enough for governing bodies to simply reiterate what the Belmont Report states and to allow each IRB to develop its own “special safeguards” with nothing else to refer to (HHS 1993).

Perhaps it is not possible to construct such a firm set of guidelines right now because IRBs do not understand exactly how people are influenced by money. If that is the case, then fields such as sociology and anthropology may provide answers, and it could even be necessary for biomedical researchers to delve into the behavioral and social sciences. As long as monetary incentives and discrepancies in protocol across IRBs prevail, it will always be difficult to observe the tenet of respect for autonomy.

These other fields may allow researchers and IRBs to recognize the context in which projects are sanctioned.

Too often, disproportionate targeting of poor persons is simplified to the question of “Was the subject presented with a choice?” (Azetsop et al. 2010). However, what may be a choice for one individual may not be a choice for another. Even though it is likely impossible to truly respect the autonomy of every individual within a research setting, IRBs and researchers have to try to understand the socioeconomic underpinnings of each and every research setting so that it is less likely subjects are unduly induced (Klitzman 2005). “Excessive” rewards are contingent upon circumstance; therefore, researchers and IRBs need to investigate the environment in which a particular project is carried out so that a reasonable amount of payment can be determined. They have to do more than obtain informed consent—in order to truly respect an individual’s autonomy, researchers and IRBs have to understand the underlying circumstances of their subjects.

Conclusion

Monetary compensation is not inherently morally impermissible, and it is in fact necessary for biomedical research to advance at its current rate. However, there are clearly inconsistencies and ambiguities that make it difficult for researchers to preserve the principle of respect for autonomy when monetary payments are involved.

Government agencies need to ensure that the policies they enact are not only consistent with the tenets of the Belmont Report, but also that they explicate and not merely reiterate what is mentioned in the Belmont Report. Researchers and IRBs alike have to be aware of how informed consent can lead to systematic and individual exploitation. “Undue inducement” warrants further clarification because there is no consensus amongst IRBs on what those two words mean (Klitzman 2013). While this clarification is underway, researchers have to begin analyzing research

settings because that may be the only way to truly establish a more comprehensive and uniform set of guidelines for the practice of monetarily compensating human subjects.

Researchers and IRBs may never be able to fully actualize the principle of respect for autonomy, but acute awareness of the ways in which autonomy can be compromised and how exploitation can happen is necessary to get as close to that ideal as possible.

About the Author Shivam Amin studies philosophy at the University of South Alabama. His faculty sponsor is Ted Poston, Associate Professor of Philosophy at the University of South Alabama.

References Ashcroft, R. E. 2011. Personal financial incentives in health promotion: where do they fit in an ethic of autonomy? Health Expectations 14(2).

Azetsop, J. and Rennie, S. 2010. Principlism, medical individualism, and health promotion in resource-poor countries: can autonomybased bioethics promote social justice and population health?

Philosophy, Ethics, and Humanities in Medicine 5(1).

Ballantyne, A. 2008. Benefits to Research Subjects in International Trials: Do They Reduce Exploitation or Increase Undue Inducement? Developing World Bioethics 8(3): 178-191.

Beauchamp, T. L. and Walters, L. 2003. Contemporary Issues in Bioethics. Belmont: Wadsworth Publishing.

Emanuel, E. J. 2005. Undue Inducement: Nonsense on Stilts? The American Journal of Bioethics 5(5).

Johnson, R. 2012. Kant’s Moral Philosophy. The Stanford Encyclopedia of Philosophy (Summer 2012 Edition). Available at: http://plato.stanford.edu/entries/kant-moral/ Klitzman, R. 2013. How IRBs view and make decisions about coercion and undue influence. Journal of Medical Ethics 39: 224229.

Klitzman, R. 2005. The Importance of Social, Cultural, and Economic Contexts, and Empirical Research in Examining “Undue Inducement”. The American Journal of Bioethics 5(5):19-21.

Protection of Human Subjects, 45. C.F.R. pt. 46. 2009. Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46. html#46.111 Protection of Human Subjects, 21. C.F.R. pt. 50. 2012. Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/ CFRSearch.cfm?CFRPart=50&showFR=1&subpartNo de=21:1.0.1.1.19.2 US Department of Health, Education, and Welfare. 1979. Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Available at: http://www.hhs.gov/ ohrp/humansubjects/guidance/belmont.html US Department of Health and Human Services. 1993. Institutional Review Board Guidebook. Available at: http://www.hhs.gov/ ohrp/archive/irb/irb_guidebook.htm US Food and Drug Administration. 2010. Payment to Research Subjects- Information Sheet. Guidance for Institutional Review Boards and Clinical Investigators. Available at: http://www.fda. gov/RegulatoryInformation/Guidances/ucm126429.htm

Article

Genetic Enhancement: Definitions, Methodologies, and the Effect of Parental Attitudes

Sarah Mayes‡

A rapidly expanding understanding of genomics has introduced the possibility of genetically enhancing humans.

Nonessential genetic enhancements may be realized in three ways: screening out the bad, selecting for the good, and engineering novel traits. With respect to parental attitudes, common deontological objections to genetic enhancement—that enhancement is wrongly motivated—suggest it encourages parental hubris, restricts children’s freedoms, and commodifies children. These deontological objections fail to consider parents’ humaneness. Namely, in deciding to have a child, parents already ascribe personhood and value to this child. Enhancement merely sets an expectation for a desired outcome and does not equate to loving a child only if that outcome is achieved. Therefore, parents capable of accepting their children while encouraging them to reach their full potential may permissibly enhance their children.

Although other factors such as socioeconomic discrimination must be considered in a full discussion of the ethics of enhancement, this paper evaluates genetic enhancement solely in the context of the parent-child relationship and is meant to discuss one portion of the overall discussion of enhancement.

Introduction

Before examining the ethics of enhancement, one must necessarily distinguish enhancement from targeting disorders. Julian Savulescu, Professor of Practical Ethics at the University of Oxford, describes the essence of enhancement as “something which makes our lives better … the fulfillment of nonessential, but perhaps important, interests” (2006). Enhancement includes procedures to introduce characteristics that beneficially exceed the “norm” for a given population. In contrast, treatments bringing an individual “up to par” with the rest of the population are not considered enhancement. The qualifier “nonessential,” in contrast to “normal,” is required to distinguish enhancement from therapy. In this context, I define “nonessential enhancement” as an interruption of characteristics that a person naturally possesses and does not contribute to that person’s ability to function independently. A treatment, on the other hand, would describe a procedure that remedies a loss of normal human function that may prevent or reduce a person’s ability to function independently.

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‡ University of Virginia, skm5yd@virginia.edu

Defining Enhancement

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Parents spend incredible amounts of money, time, and effort on baseball coaching, SAT tutoring, counseling, and other modes of personal development for their children.

The life work of countless parents consists of providing a means for their children to reach their full potential as human beings. Although typically thought of in abstract, unquantifiable terms, this “potential” is thought to be partly determined by the genotype of each particular child.

What has previously been left to chance is now becoming feasibly adjustable with the rise of genetic enhancement technologies. For instance, the Genetics and Public Policy Center at Johns Hopkins University announced in 2005 that genetic modification of the germline is possible in animals but not yet in humans (Baruch et al. 2005). Researchers are pursuing the possibility of inserting new genes into human germlines. This advancement may one day allow parents to control the genetic makeup of their children and may open up a Pandora’s box of concerns. Such concerns include the inherent nature of altering the genetic makeup of children and the practical societal implications of only the affluent having the means to do so.

According to the former President’s Council on Bioethics during the Bush administration, the parent-child relationship is the locus of ethical concern and agency in larger issue of genetic enhancement (2003). The ethics of genetic enhancement not only concerns the procedure and result, but also parental agency in selecting for genetic enhancement. The ability to engineer qualities into a child may affect the manner in which the parent relates to the

child. To examine the ethical permissibility of genetic enhancement in terms of parental attitudes, I will first define “enhancement” and then establish three types of possible genetic enhancements. I then argue that common objections to genetic enhancement in regards to parental attitudes fail in a deontological framework—whether an action is right or wrong based on the motive—and given the resulting discussion on the parent-child relationship, I conclude that parents may permissibly enhance their children.

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The qualifier “nonessential” bypasses the difficulty of defining enhancement as a procedure that exceeds the norm.

The problematic nature of the qualifier “normal” is obvious: humanity is extremely diverse, and it is nearly impossible to establish a norm for most characteristics within a particular society, much less on a global scale. Michael Bess, Professor of History at Vanderbilt University, provides the example that the statistically normal IQ score in 1918 would be considered five points away from mild mental retardation when compared to the scale used in 1978 and argues the “concepts of the ‘normal’ and ‘species typical’ are fraught with ambiguities” since the definitions of “normal” are evershifting (2010).

For example, if a short individual (but not so debilitatingly short as to inhibit daily, independent activity) were to undertake a procedure in order to grow taller, such a procedure would universally be considered an enhancement using a “nonessential” definition. On the other hand, if using a “normal” definition, such a procedure would not be considered an enhancement (and instead be considered a treatment) when the individual is placed in an overwhelming population of those taller than him—but would be considered an enhancement if placed in shorter population around his own height.

The “nonessential” qualification may be applied to medical procedures to define, for example, medications for illness and hearing aids for the hearing impaired as treatments and not as enhancements because they increase or restore the ability to function independently. The introduction of genes or medications to increase the intelligence of a normal child, however, would be considered an enhancement. If instead the child’s IQ were sufficiently low to approach retardation, such gene therapies or medications would qualify as treatments.

These examples demonstrate the advantages and applications of the “nonessential” qualification for enhancement in contrast to the “normal” qualification.

It should be noted that the term “nonessential” is not completely objective either—for example, daily activities that constitute an ability to support oneself independently may differ across societies—but it leaves much less room for debate and uncertainty than does “normal.” As such, “enhancement” procedures should be understood using a “nonessential” qualification. Future usage of the term “genetic enhancement” in this paper will also assume a “nonessential” qualification.

Three Forms of Enhancement

The former President’s Council on Bioethics, under the leadership of Leon Kass, described in 2003 three methods of “increasing genetic control” for parents: “(1) eliminating the bad (‘screening out’), (2) selecting the good (‘choosing in’), and (3) redesigning for the better (‘fixing up’)” (2003).

Nonessential enhancement concerns only “selecting the good” and “redesigning for the better;” these can be further divided based on different biological strategies for enhancement. With respect to “selecting the good,” two categories will be considered: (1) selecting for traits that

parents already have and (2) introducing traits that parents do not possess. “Redesigning for the better” can be understood as (3) engineering new traits and genetically inserting them into one’s DNA. Parents currently may select to pass certain traits to their child via prenatal screening, which occurs during pregnancy, and pre-implantation genetic diagnosis (PGD), which involves in-vitro fertilization (IVF). These methods are usually used to screen for specific genetic diseases and malformations and are used to assist parents in making reproductive decisions. For example, a woman pregnant with a fatally malformed or mentally retarded fetus may decide to abort the fetus, or, parents with a family history of a particular genetic disease may employ IVF in order to selectively implant only the embryos that lack the diseased genetic defect.

These particular situations do not qualify as enhancement or “selecting the good” because they do not present nonessential improvement, but rather avoid a detrimental condition. However, these same methods can also be used to select for a particular trait for nonessential enhancement. For example, a couple using PGD and IVF may choose to keep the embryos with the highest potential for aptitude based on genome analysis. Instead of leaving fate to determine which of the parental gametes will form the embryo, parents could select the best of the options they naturally produce.

Another form of “selecting the good” is introducing traits that parents do not possess but that currently exist in the human gene pool. This would involve extracting particular genetic sequences from a non-parent and inserting them into the child’s genome, whether embryonically or postnatally. Theoretically, one could imagine acquiring a gene for athleticism from an Olympian and inserting it into an embryo, resulting in a child with much more athletic potential than the genomes from only his parents would have endowed.

Finally, the engineering of traits that are not currently expressed in the human population constitutes a third category of enhancement. Such traits could provide superhuman intelligence or physical strength. Such a form of enhancement is much further from current reality than the other two but is still perhaps foreseeable in the future. It is best to keep in mind that though our current technology does not have the capability of realizing these three forms of enhancement, the dilemma of genetic enhancement should still be considered. While not discussed here, the state of today’s research suggests that genetic enhancement is very much within the realm of possibility.

Benevolent Parental Intent

As stated previously, parental attitudes offer one important set of ethical concerns that could arise with enhancement.

With “enhancement” defined and the future possibilities outlined, we come to examining the ethical permissibility of enhancement. Specifically, we deontologically examine enhancement in terms of parental attitudes and the common objections that opponents of genetic enhancement put forth.

Parental Attitudes in Genetic Enhancement Michael Sandel, a political philosopher at Harvard and leading opponent of genetic enhancement, identifies that a core problem to the parental intent to enhance is rooted in the deontological concern of parental hubris: “The problem is in the hubris of the designing parents, in their drive to master the mystery of birth . . . it would disfigure the relation between parent and child, and deprive the parent of the humility and enlarged human sympathies that an openness to the unbidden can cultivate.” In his argument, Sandel considers the child as a “gift” and points to the sinister “human disposition [enhancement] promotes” when parental hubris calls for modifying such gifts. Sandel considers that the desire for mastery is so overwhelmingly negative in principle that enhancements should not be explored (2004).

The intent to avoid human disposition toward pure power is valid and should not be brushed aside too quickly. If the goal of genetic enhancement is pure mastery for the sake of itself, then Sandel’s objections may hold weight. However, Frances Kamm, another leading Harvard philosopher, argues that “it is possible for a rational agent to have as his aim the pursuit of the good,” with “good” able to take on many meanings from increased potential for the child to succeed to even increased ethical awareness of the child (2005). Although genetic enhancements would be ethically suspect if they only constituted an end in themselves, they are not problematic in this sense when performed with good intentions. Kamm’s assertion is vital because she credits humans as capable of altruistic pursuits when enhancing children. The desire to enhance and modify a child, even when considered a “gift,” does not have to be rooted in hubris. Therefore, even on a practical level, Kamm’s deontological analysis of parental intent permits parents to use genetic enhancements.

Conservation of Children’s Freedoms

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While the ability to select for genetic traits does not imply giving parents control of their child’s destiny, parents must also know how to allow a child the freedom to nurture what characteristics he himself desires to cultivate. That is, a loving parent must love the child regardless of whether the child chooses to nurture the characteristics chosen for him.

This way, the child is not objectified. Opponents of genetic enhancement worry that if parents are allowed to essentially choose their children’s traits, parents would be encouraged to love only the childfor their desired end. This then creates a deontological fear of conditional love in which parents will judge their enhanced children based only on the child’s successes that any original enhancements were expected to bring about.

In order to examine such objections in regards to parental love, one must first define what “love” means. William May identifies two types of love necessary for a nurturing parenthood: accepting love, in which “parents need to accept the child as he is,” and transforming love, in which parents must “encourage the wellbeing of the child” by “promot[ing] the child’s excellence” (President’s Council on Bioethics, 2002). Accepting love provides the security and confidence necessary for a child to be able to improve himself, and transforming love encourages the child to do so. Even without genetic enhancements, parents accept and highlight particular aspects of their children that the children desire to “transform,” or cultivate and exhibit. As such, unconditional love, which is analogous to accepting love, implies that parents would love their child regardless of whether the child possesses a particular beneficial trait.

Unconditional love is of course desirable, and as Davis frames it, opponents of genetic enhancement would believe that unconditional love and genetic enhancement are mutually exclusive (2008). Enhancing a child regardless of whether they measure up to expectations, however, does not render parents incapable of loving unconditionally. This can be illustrated through current situations—if given the choice between having a severely disabled child and a healthy, “normal” child, most parents would of course choose the healthy child. Parents expect and desire a non-disabled child.

However, if their child wound up born disabled or was born healthy and later became disabled, the parents would still be capable of loving the child as is seen nowadays. Similarly, in a hypothetical enhancement situation, if parents create a child with the intention that he have the ability to run a three-minute mile and a car accident later renders the child unable to walk, the parents could still love the now-disabled child. As Guy Kahane and Julian Savulescu explain, parents would merely prefer the healthy child or the enhanced child but would nonetheless unconditionally love any child they have (2009).

The reason parents may unconditionally love an enhanced child regardless of expectations is that parents first and foremost desire to produce a child (Wilkinson 2010). The love of a child itself supersedes the love of any trait that the

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Beyond parental hubris, the President’s Council on Bioethics worries about “expanding parental choice and mastery over the next generation” (2003). They are concerned that each generation will tyrannically impose its ideals on the next, controlling the destiny of children in a manner that is deontologically impermissible and violating of their autonomy.

Although parents may one day select for traits that would not have been expressed without intervention, the child still does not experience any loss of freedom due to enhancement despite such a claim seeming initially counterintuitive. John Davis argues that “arranging a genetic endowment” is not problematic because by doing so, parents are essentially creating a different child after choosing to enhance (2008).

The freedom of a non-endowed/non-enhanced child to remain as such is not usurped because that child simply does not exist in the first place. Similarly, there is no “destiny” or “autonomy” to violate for a child that does not exist, and neither is the autonomy of a theoretically enhanced child violated any more than that of a child nowadays. A child already does not choose his parents, so he has no say in which genetic characteristics and what quality of parental upbringing is available to him.

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Parental Attitudes in Genetic Enhancement child may possess. And because the interests of the child come first, the role of transforming love changes with time.

At one season of the child’s life, this may include encouraging and cultivating the selected beneficial trait, whereas at other times parents may encourage different futures based on the child’s own developing desires. Whether the child exhibits the enhanced trait or not, transforming love demands that parents nurture the child with an underlying accepting love.

Avoiding a Baby Bazaar

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Finally, with the prospect of selecting traits for children comes a common deontological fear of commodification. A science-fiction scene depicts parents selecting traits from a long list to create their vision of a perfect child, making children now commodities based on the value of the selected traits. Although keeping in mind the technological infeasibility of this situation, a strong initial reaction to this picture causes many to shudder.

While this fear is frightening and legitimate, it fails to give credit to parents’ humanness for the same reasons that parental love can be unconditional. Similar to the ideas of Kahane, Savulescu, and Wilkinson, although people may initially be attracted to certain characteristics in others, the development of love finds its roots in the person himself and not in the value of those traits (Nozick 1977). The desire to be valued and attribute value to others is not based on one’s intellect, athletic ability, or physique—but rather in one’s character. Allen Buchannan, Professor of Philosophy at Duke University, concurs that selecting genetic enhancements for children would not open the door for parents to “regard their offspring as manufactured items” because human

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References Baruch, S. et al. 2005 “Human Germline Genetic Modification: Issues and Options for Policymakers” Genetics and Public Policy Center. Washington, DC. Bess, M. 2010. “Enhanced Humans vs. ‘Normal People’: Elusive Definitions”. Journal of Medicine and Philosophy 35(6): 641-655.

Buchanan, A. 2008. “Human Nature and Enhancement”. Bioethics, Malden, MA: Blackwell.

Davis, J. 2008. “Selecting Potential Children and Unconditional Parental Love”. Bioethics, 22: 258.

Kahane, G. & Savulescu, J. 2009. “The Moral Obligation to Create Children With the Best Chance of the Best Life.” Bioethics 23(5): 274-290.

Kamm, F. 2005. “Is There a Problem with Enhancement?”. The American Journal of Bioethics, 5: 3-14.

Nozick, R. 1977. Anarchy, State and Utopia. New York, NY: Basic Books.

President’s Council on Bioethics. 2003. “Beyond Therapy – General Reflections”. Beyond Therapy, chapter 6.

President’s Council on Bioethics. 2002. Council discussion of “The Birth-Mark,” Nathaniel Hawthorne, led by William F. May, Ph.D. Sandel, M. 2004. “The Case against Perfection”. Atlantic Magazine.

Savulescu, J. 2006. “Justice, Fairness, and Enhancement”. Annals of the New York Academy of Science 1093: 5.

Schwartz, P. 2005. “Defending the Distinction Between Treatment and Enhancement”. American Journal of Bioethics 5(3): 17-19.

Wilkinson, S. 2010. Choosing Tomorrow’s Children: The Ethics of Selective Reproduction. Oxford.

relationship lies much deeper (2008). Humans innately remonstrate objectification. Parents’ humanness and capacity for accepting a child regardless of expectations soundly provide assurance that certain traits do not place value on an individual’s lovability. From a deontological standpoint, therefore, the genuine nature of parental love would not be jeopardized by the prospect of genetic enhancements, and parental choice to enhance their children is not inherently problematic.

Conclusion

This paper offers an in-depth analysis of the ethical considerations that parental attitudes raise for genetic enhancements. I do not claim to offer a comprehensive answer to the question of whether genetic enhancements are ethically permissible. For example, concerns regarding socioeconomic inequalities, gender differences, and the possibility of genetic influences on human nature itself are necessary for a full exploration of the acceptability of genetic enhancements. However, it remains that genetic enhancement is deontologically acceptable in terms of parental attitudes. Parental choice to enhance is not rooted in hubris and instead can be altruistic in nature. Genetic enhancement does not limit children’s freedoms, nor does it imply conditional love or commodification of children.

Although exceptions always exist in which parents may not demonstrate expected levels of humanness, this paper demonstrates that genetic enhancement fails to violate deontological concerns in the case of the parent capable of love.

About the Author Sarah Mayes studies biology and religious studies at the University of Virginia. Her faculty sponsor is Brian Cwik, a graduate instructor in the Department of Philosophy at the University of Virginia.

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