Princeton Journal of Bioethics - 2006

Vol. VI,I Spring 2004

Volume VIII Spring 2006

PJB Princeton Journal of Bioethics

Dedicated to the discussion and contemplation of issues at the intersection of technology and society.

The Princeton Journal of Bioethics

The Princeton Journal of Bioethics Ashvin Kamath ‘06 Amar Trivedi ‘07 Anuj Nadadur ‘07 Editors-in-Chief Vinay Shah ‘09 Layout Editor Rachel Rizal ‘09 Managing Editor Tashfin Huq ‘09 Business Manager

Copyright 2006 by the Princeton Journal of Bioethics.

All rights reserved.

Cover Design: Jared Serwer ’98 Bioethics Emblem: Darryl Bledsoe ‘98

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Technical Review Board The Technical Review Board was created to review the student writing thereby ensuring the accuracy and quality of the Journal. We would like to extend our appreciation to these professionals who donated their time and expertise to our endeavor.

Katherine Benesch, J.D., MPH Partner, Duane Morris LLP, Princeton, NJ Carl Feldbaum, J.D. President, Biotechnology Industry Organization (BIO), Washington, D.C. Peter Singer Professor of Philosophy and Faculty of the Center for Human Values, Princeton University David Gresham Postdoctoral Researcher, Botstein Lab. Lewis-Sigler Institute for Integrative Genomics, Princeton University.

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The Princeton Journal of Bioethics Volume VII, Spring 2004

Foreword Ashvin Kamath ‘06 Amar Trivedi ‘06 Anuj Nadadur ‘07 Princeton University

Contents

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Questionable Boundaries: Ethical Implications of Research on Human-Nonhuman Chimeras Jana Loeb Brown University

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Though the notion of engineering a new organism from multiple species, including human, may initially seem only to be the dream of mad scientists, many scientists are in fact looking to chimeras as a way to research stem cells and human development. But pushing species boundaries raises profound questions regarding ethical boundaries. Primarily, ethical questions regarding chimeras examine what the creation and use of such organisms says about our humanity, and what status we should ascribe to an organism that might be part human. In this paper I will examine these issues. I will begin by giving background on chimeras and research involving multiple species, and focus my paper on human-nonhuman chimeras, primarily those where the host organism is nonhuman. I will introduce some current philosophical viewpoints regarding this research. Then I will analyze those viewpoints and propose that features we value as indicative of moral agency should not be ascribed to human-nonhuman chimeras, as this assignment threatens to render ambiguous that which we value highly.

Present Obligations to Future People: A Strictly 22 Ethical Argument For Mandatory Pre-Implantation Genetic Screening Jake Hartman Duke University

Pre-implantation Genetic Screening (PGS) and Pre-implantation Gene Therapy (PGT) represent two reproductive technologies which promise to significantly increase in use in the coming years. Despite this, a complete analysis of the ethical challenges presented by these advances has been notably absent. In this piece, I attempt to rectify this shortcoming. I propose that the focus on parental rights in discussions of reproductive freedom have been somewhat misguided, and that the advent of these new technologies warrant a shift in ethical focus to the rights of future persons. Working under a framework of both person-affecting and non-personaffecting harm principles, I demonstrate that concerns for the rights of future persons suggests that PGS and PGT should be implemented on a mandatory basis for genetic diseases and disabilities which inhibit “normal species function.”

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An Argument in Favor of Objective Scientific Journal Publication Practice: Proposed Changes to Contemporary Journal Practice Matthew Kelly Brown University

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BiDiL and the Business of Race Vinay Shah Princeton University

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Contemporary scientific practice is, in large ways, influenced by scientific prestige. Prestige allocation is determined based upon an evaluation of a number of independent variables, including an individual’s publication history in scientific journals. Here, I begin with a discussion of scientific prestige (Section I), then examine the use of publication history as a determinant for scientific prestige allocation (Section II), arguing that scientific journals ought to be required to maintain standards of objective publication practice, thus ensuring that one variable upon which prestige-allocation is based remains objectively reliable. Five requirements for objective publication practice are proposed. In section III, I present several case studies that suggest that scientific journals are in violation of these requirements.

Last June the FDA gave Nitromed, Inc. approval to produce and market BiDil for the treatment of heart failure in “self-identified black patients.” Notably, it is the first drug in the United States to be based on a patent for which the novelty is the observed benefit of the drug in a particular racial or ethnic group. It is also the first drug approved by the FDA for use only in a racially specified patient group. According to a controversial paper published by BiDil proponents Jay Cohn and Peter Carson, the drug is generally more effective in treating African-Americans than Caucasian patients. Much of the discussion surrounding the drug has revolved around whether BiDil truly has clinically significant differential effects in AfricanAmerican and European-American subgroups. But an aspect of the BiDil story that has received insufficient attention is the precedent that was set in procuring patent protection and regulatory approval for the drug. By imprecisely and incompletely discussing race in order to gain intellectual property rights which could not otherwise have been obtained, BiDil’s sponsors have outlined a dubious new method by which pharmaceutical companies can gain commercial advantage.

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The articles herein do not reflect the views of the Princeton Journal of Bioethics or its affiliates.

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Foreword

On behalf of the staff of the Princeton Journal of Bioethics, we are pleased to present you with the eighth issue of the Journal.

In order to explore a diverse set of issues, we have selected a range of papers including the following: the implications of engineering human-nonhuman chimeras, the moral obligations involved in pre-implantation genetic screening, the ethics behind scientific journal publication practice, and the consequences of new heart failure drugs. We hope that you find these issues stimulating and representative of the wide field of bioethics.

One of the former goals of the Journal was to become completely independent of the Princeton Bioethics Forum. We are pleased to announce that we have been successful in this endeavor.

We wanted to do this in order to establish a journalistic tradition independent of outside affiliation and also to have more flexibility in management. We would like to thank the Forum for all support from previous years and for their commitment to promoting awareness and interest within the field of bioethics.

The Journal is completely the work of undergraduate students who submit their work to the Princeton Journal of Bioethics Editorial Board. We then edit, layout, and publish the work of undergraduate submissions from around the country. Our fine tradition of finding the best undergraduate work in bioethics for publication depends upon these submissions, and we therefore encourage you to submit papers relevant to bioethical issues. Having said this, we could not achieve our goals without the expertise and guidance from the Technical Review Board. These established experts ensure the accuracy and quality of the Journal. We would also like to thank the Politics Department at Princeton without whose generous support this year’s publication would not have been possible.

Thank you for your continued support and interest in the Princeton Journal of Bioethics. We hope that the Journal provides you 6

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with new perspectives and material to ponder, debate, and discuss.

It is only through sustained dialogue and awareness that progress in bioethics can be made, and we invite you to become an active participant in this exciting and progressive field.

Sincerely, Ashvin Kamath ‘06 Amar Trivedi ‘06 Anuj Nadadur ‘07 Editors-in-Chief

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Questionable Boundaries: Ethical Implications of Research on Human-Nonhuman Chimeras Jana Loeb Brown University

Though the notion of engineering a new organism from multiple species, including human, may initially seem only to be the dream of mad scientists, many scientists are in fact looking to chimeras as a way to research stem cells and human development. But pushing species boundaries raises profound questions regarding ethical boundaries. Primarily, ethical questions regarding chimeras examine what the creation and use of such organisms says about our humanity, and what status we should ascribe to an organism that might be part human.

In this paper I will examine these issues. I will begin by giving background on chimeras and research involving multiple species, and focus my paper on human-nonhuman chimeras, primarily those where the host organism is nonhuman. I will introduce some current philosophical viewpoints regarding this research. Then I will analyze those viewpoints and propose that features we value as indicative of moral agency should not be ascribed to human-nonhuman chimeras, as this assignment threatens to render ambiguous that which we value highly.

In classical Greek mythology, a chimera was a fantastical creature with a lion’s body, a goat’s head, and a serpent’s tail. Conceptions of chimeras are everywhere in literature and the arts, from unicorns to centaurs. But today, expanding frontiers of science and medical technology have made such mythical creatures a reality. Though the notion of engineering a new organism from multiple species, including human, may initially seem only to be the dream of mad scientists, many scientists are in fact looking to chimeras as a way to research stem cells and human development. But pushing species boundaries raises profound questions regarding ethical boundaries. Primarily, ethical questions regarding chimeras examine what the creation and use of such organisms says about our humanity, and what status we should ascribe to an organism that might be part human.

In this paper I will examine these issues. I will begin by giving background on chimeras and research involving multiple species, and focus my paper on humannonhuman chimeras, primarily those where the host organism is nonhuman. I will introduce some current philosophical viewpoints regarding this research.

Then I will analyze those viewpoints and propose that features we value as indicative of moral agency should not be ascribed to human-nonhuman chimeras, 8

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as this assignment threatens to render ambiguous that which we value highly.

Despite its ancient mythological definitions, the chimera of today’s world is defined generally as “a single organism composed of a mixture of materials from two or more organisms possessing distinct genetic backgrounds.” Chimeras are distinctly different from hybrids, which are the offspring of parents from different species. Mules are naturally-occurring hybrids of horse and donkeys, but scientists can also engineer hybrids, as they have done with the “geep,” the offspring of a sheep and a goat. Chimeras are also not made of mosaic DNA; that is, they do not have multiple species’ DNA in their cells. Rather, different cells, tissues, organs, or systems of the organism’s body are that of another species. There are multiple manifestations of this. Tissues or organs from one species can be transplanted into another. Or, an organism from one species can have a fully functioning body system from a different species. This can occur in both human and nonhuman animals. Human skin tissue or bone can be engineered in mice to examine development and disease. Organs or tissues from nonhuman animals can also be transplanted into humans, such as pig heart valves, which are commonly used in heart surgeries today without ethical outcry.

More imaginative ways of utilizing this technology have, however, caused much greater ethical concern. In 2005, the U.S. Congress introduced the Human Chimera Prohibition Act. The bill prohibits chimera research and development, but defines chimeras in such a way so as to make a specific statement about which applications of the technology should be prohibited. The bill, introduced

by Senator Sam Brownback (R-KS), defines chimeras as any of the following: (A) a human embryo into which a nonhuman cell, or any component part of a nonhuman cell, has been introduced; (B) a human embryo that consists of cells derived from more than 1 human embryo, fetus, or born individual; (C) a human egg that has been fertilized by a nonhuman sperm; (D) a nonhuman egg that has been fertilized by a human sperm; (E) a human egg into which a nonhuman nucleus has been introduced; (F) a nonhuman egg into which a human nucleus has been introduced; (G) a human egg or a nonhuman egg that otherwise contains haploid sets of chromosomes from both a human and a nonhuman life form; (H) a nonhuman life form engineered such that human gametes

Nicole Kopinski, “Human-Nonhuman Chimeras: A Regulatory Proposal on the Blurring of Species Lines.” Boston College Law Review, 45 (May 2004) 619.

Though horses and donkeys do not naturally seek each other as mates, they do not need scientific intervention to breed and have a mule offspring.

By definition, a human with a pig heart valve constitutes a chimera, though our most common conception of chimeras is that of we typically view chimeras as non-human animals with human cells, tissues, or organs.

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There are some foreseeable applications of chimeras that would be expressly prohibited by this bill. Some scientists have proposed engineering human germ lines in mice and using the gametes for in vitro fertilization techniques.

Through this process, mice would be capable of producing human eggs or sperm. These gametes could then be used with in vitro fertilization techniques to create a fertilized human embryo, which would then be implanted in a human. The resulting individual would be fully human, but the sperm and egg used to create that individual would have been harvested in mice. Other forms of engineering which are arguably less outlandish, such as using bovine ova for somatic cell nuclear transfer (due to the scarcity of human ova donors), are also prohibited. The bill could also be interpreted to prohibit some important applications of human embryonic stem (hES) cell technology. An understanding of early embryonic development is critical to understanding the applications of stem cell technologies, but ethical boundaries prevent scientists from exploring past primitive streak (14 days) in human embryos. Studying hES cell development in a nonhuman host would allow this type of research to continue, but it might prove difficult to step around the definition of chimeras proposed by the Senate bill.

The bill does not seem to prohibit the use of pig heart valves in humans, an example of a nonhuman organ or tissue transplanted into a human which seems to have no ethical strings attached. On the reverse side, the bill restricts—but does not prohibit—human to nonhuman transfers of genes, cells, tissues, organs, or systems. Provision (I) is particularly concerned with this, and prohibits engineering parts of the human nervous system in nonhuman animals.

The background assumption of such a restriction is two-fold. First, the prohibition assumes that there is something different or special about human nervous tissue as opposed to other types of human body systems, such as engineered hemoglobin in pigs or human immune systems in mice.

Second, the provision assumes that this distinction of human nervous tissue is not only distinct from other human body systems, but also so pivotal to the human species that to engineer it in nonhuman animals would be unethical.

These assumptions introduce the central ethical problem of chimeras.

United States Congress. Human Chimera Prohibition Act. (Washington, D.C.: S 659 IS), 2005.

Jason Scott Robert and Françoise Baylis, “Crossing Species Boundaries.”

American Journal of Bioethics, 3, no.3 (2003): 1-15.

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Chimera research forces the question of what, exactly, makes us human. If we ascribe that entity to nonhuman animals, what status do they have compared to us? In order to examine these questions of species boundaries and human nature, we must first understand what types of boundaries exist. In their provocative paper about chimeras, Jason Scott Robert and Françoise Baylis attack this question in an attempt to formulate ethical arguments about certain types of chimeras. First, they examine specific species classifications that exist and discuss arguments against them. One such classification is that two species are distinct if they do not “successfully interbreed.” Though this distinction can prove helpful in certain contexts, it does not apply to organisms which breed asexually. Though a variety of explanations of species boundaries have been invoked, biologists agree that there is no firm definition of species, and that the boundaries we perceive are not nearly as static as we imagine.

In spite of biological arguments, however, the notion of species boundaries certainly feels like reality. Furthermore, the notion that our species, homo sapiens sapiens, is distinct from others is especially fixed in our collective consciousness. Though we might not be able to answer the question of what makes us homo sapiens sapiens, we certainly “know a human when we see one.” This cultural attachment to our species boundary carries with it an underlying assumption that humans are distinct, exceptional in some way, compared to nonhuman species. It is this attachment to which we appeal when we express ethical concern regarding chimera research. Despite what evolutionary biologists might say about species boundaries, an unambiguous line of humanness must exist, even only culturally, if crossing it is so problematic.

Roberts and Baylis discuss some common objections to chimeras. The first is the argument from religion. The argument from religion holds that God is perfect, and God’s creations are perfect. Tampering with them, mixing them, or taking creations into our own hands nullifies the value of God’s already-perfect creations and therefore negates and denies God’s perfection. Any argument from religion is difficult to counter with a non-religious viewpoint, but Roberts and Baylis discuss some counter-arguments that relate specifically to the application of the argument from religion to chimeras. First, new species have occurred naturally, and continue to do so. This would imply that creation is presumably still going on, or was incomplete when God “stopped” creating. Another argument promotes the incomplete nature of creation and points to humans as the new creators, enacting our God-given faculties on our environment to continue

Robert and Baylis, 2003.

Ibid., 3.

Robert and Baylis, 6.

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creation in a way we see fit. This argument uses the religious argument’s own terms to promote but not to reject chimera research. Furthermore, the religious argument against chimeras might not apply to hybrids, which can occur in nature or in a controlled setting. The religious argument can ignore hybrids and accept them while prohibiting chimeras, but this seems inconsistent. If hybrids are not contrary to God’s creation, then would it not automatically follow that chimeras are also permitted?10 Perhaps the best argument against the religious opposition is that it is non-rational; it does not allow both sides to argue on terms to which they both agree. Though an argument from religion is strong enough for those who support it, it is not strong enough to apply to all sides.

Other arguments against chimeras appeal to what Roberts and Baylis call a “yuk” factor.

Other arguments against chimeras appeal to what Roberts and Baylis call a “yuk” factor.

Leon Kass has argued that chimeras tamper with what is “unspeakably profound.”11 This argument from “repugnance”12 appeals to the extreme unnatural nature of the research as enough of an objection to it. This repugnance might result from an underlying discomfort with anything that implies devaluing humans. Though the impact of chimera research on the value of humans is unknown, the threat that what we value will be thrown in flux can understandably result in a repugnant response. Robert and Baylis appeal to notions of taboo, and assignment of taboo status to anything that straddles a classification system. Classification is important for humans to feel definite, both in ourselves and in other aspects of life. When these lines are crossed, the dignity we ascribe to the categories is threatened.13 When applied to chimeras, the argument would claim that we cannot cross species boundaries because it leaves our definition of our own species, our own classification, vulnerable and devalued.

Mary Midgley also analyzes the “yuk factor” in her article, “Biotechnology and Monstrosity.”14 Midgley asserts that “feeling is an essential part of our moral life.”15 As such, we should pay attention to our emotional responses in the face of moral questions. Oftentimes we assume that emotionality suggests irrationality, and as such is isolated from a rational moral

Ibid., 7.

10 I acknowledge Professor Martin Gunderson for this insight.

11 Robert and Baylis, 7.

12 Ibid., 7.

13 Ibid., 8.

14 Mary Midgley, “Biotechnology and Monstrosity: Why We Should Pay Attention to the ‘Yuk Factor’.” The Hastings Center Report 30, no. 5 (2000) 7-15.

15 Ibid., 9.

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framework. But Midgley argues that this connection in fact provides a very meaningful framework from which to derive moral assumptions. Without this connection, argues Midgley, morals are merely theoretical. Midgley does not suggest we rely on emotions entirely, arguing that sometimes emotions which accompany moral action can be misplaced or present by “chance association.”16 Nonetheless, she does claim that feelings are an important source of moral decisions and that rationality can not, and does not act alone.

Though it is not the goal of this paper to present a wide rejection of emotivist ethics, Midgley’s stance is important to consider in light of its application to chimera research, and its wider context as a problematic basis for ethics should also be briefly discussed. Midgley is arguing that there are two ways to incorporate emotions into ethical inquiries. First, we can reject emotions altogether as harbingers of irrationality, indicative of a far too subjective framework for an attempt to derive broad ethical principles. Midgley rejects this in favor of a different relationship between morals and emotion; that they are causally linked and as such, their relationship is our guide in determining what we ought and ought not to do.

But I would argue that Midgley’s is a false dichotomy. We need not ignore emotions in our moral decisions, nor need we defer to them as the cause or source of moral decision-making. In fact, the latter viewpoint, which Midgley advocates, suggests a problematic subjectivist framework for morality.

Certainly, faith in rationality as the primary source of moral decision-making implies that all moral agents are equally capable of making rational moral decisions, an assumption which is problematic in the face of real-world evidence.

Nonetheless, rationality risks less relativism than emotion threatens. In addition to its problems of relativism and perhaps too heavy a reliance on subjective morality, Midgley’s view also ignores counter-examples. Though Midgley argues that emotions are sources of our moral calculus, she does not address the myriad situations in which our emotions and morals conflict. Oftentimes we must make a choice we know is morally correct, but our emotion alone would strongly caution or influence us against this choice. For example, we ought not to lie, even if the truth might upset the recipient. Obviously, our emotions would steer us to avoid causing emotional pain to another individual, but the moral obligation to tell the truth might override such a concern.

In Midgley’s application of her views to biotechnology, she argues that emotional response on a grand scale, such as repugnance, helps us understand that perhaps the path we are pursuing is immoral. Particularly in the case of chimeras, a widespread response of repugnance, in Midgley’s view, is indicative of crossing a problematic moral boundary. Though this objection appeals to human psychology in a meaningful way, it does not seem strong enough 16

Ibid.

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to oppose chimera research. Indeed, just because we do not like something or are not used to it does not warrant our absolute rejection of it. Just as we make small yet important moral choices when our emotions are in conflict with our action, biomedical research provides a similar situation on a larger scale. We can not opt out of an important and promising field of research solely because we do not feel comfortable with it. We must examine this discomfort and analyze its moral consequences. Taboos change, classifications change, and reserving against medically promising research for the sake of our gut response seems immature and ethically weak. Roberts and Baylis point to interracial marriage as one such example of a once-repugnant institution, the taboo on which has significantly subsided over time.17 Indeed, an emotionally repugnant response to intermarriage allowed immoral reservations against an act that obviously had no immoral consequences and was not intrinsically wrong. Intermarriage did not become morally right simply because taboos changed; rather, society recognized that emotion alone was an unfair and unfounded basis for a moral reservation. In regards to our emotional attachment to man-made classifications and taboos and our potential repugnant response to crossing such boundaries, we should ask whether protecting our classified place in the world is truly a sufficient ethical argument against chimeras. Arguably, appealing to a self-conceived notion of hierarchy—a fluid, changing one at that—can not and should not be a sufficient ethical objection.

Though Robert and Baylis do not address them, there could be Kantian objections to chimeras. If chimeras are part human, their use as means to an end raises objections from Kant’s second formulation of the categorical imperative.18 Whether the chimera has a malady for the sake of further study of the human body, or whether the chimera has a human immune system, human-nonhuman chimeras are created for the sole purpose of being used to achieve an end. Particularly problematic are cases in which chimeras are engineered to be compromised in some way. But the application of the means-ends objection depends strongly on the belief that chimeras have moral status as rational moral agents, thereby worthy and deserving of ethical treatment like any human moral agent. The question for chimeras is particularly tricky, as Kant does not claim that only humans can be rational moral agents.

Unfortunately, we can not dismiss the moral agency of chimeras simply on the basis that they are not human. This begs the question of species membership and what moral status we ascribe to creatures of ambiguous species.

Perhaps a Kantian would argue that a nonhuman animal with human neural 17 Robert and Baylis., 7.

18 Josephine Johnson, “Chimeras and Human Dignity.” American Journal of Bioethics 3, no. 3 (2003): 7.

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cells should be considered a moral agent and thus treated as an ends only, but this implies that the creature is a full moral agent. Clearly there is only one feature of the chimera that is of the human species, but can an organism that is only part human be treated as a full moral agent, therefore eligible for protection under the means-ends analysis? Here, the Kantian would have to target specific aspects of moral agency and argue from these parts to the whole.

Additionally, the Kantian might argue against chimeras on grounds against animal cruelty. With this objection, however, a Kantian must clearly define cruelty and specify which elements of chimera research result (or do not result) in such treatment. Assuming that the Kantian supports certain forms of animal research, he or she would have to ensure that the arguments against chimeras did not also extend to these more acceptable forms of research. Perhaps the Kantian could argue that altering the purity of an animal’s species by using the biomaterial of another species is cruel because it degrades the integrity of the animal in question. But this argument would reach roadblocks in the case of hybrids, and also faces problems in light of the already ambiguous notion of species boundaries.

Robert and Baylis’s own view claims not to take a stance on chimera research either in opposition or support, but rather attempts to give perspective on a frightening moral consequence to the research. Their argument maintains that transgressing our supposed species boundaries “would introduce inexorable moral confusion into our relationships with nonhuman animals and our future relationships with part-human hybrids and chimeras.”19 This appeal to moral confusion is based on the belief that membership in the human species is necessary and sufficient for moral status. This is supported by the notion that, in the case of humans, “the intention with which one is created is irrelevant to one’s moral status.”20 In contrast, “the moral status of nonhuman animals, unlike human beings, invariably depends in part on features other than species membership, such as the intention with which the animal came into being.”21 There are many different categories we could use to rank the value of animals in different contexts. In the context of our evolutionary relatives, nonhuman primates are highly valued. In the context of certain ecosystems, other animals are given a higher status. But in regards to humans, membership in the species alone is enough to grant moral status.

With chimeras, however, species membership is a grey area, and therefore it does not automatically connote moral status. It is here that moral confusion arises. Our “frameworks for attributing moral status”22 to humans and 19 20 21 22

Robert and Baylis., 9.

Ibid.

Ibid.

Ibid.

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nonhumans are distinct and can not be reconciled. So how could we possibly approach a situation in which a nonhuman animal has partially human features?

If we have no clear framework for assessing their moral status, Robert and Baylis argue, we are at a loss in regards to our relationships and obligations to these beings. Since we can not point to any biological demarcation of species, chimeras challenge our moral frameworks by straddling the line between our fixed cultural notions of species boundaries and the moral weight we place upon them.

Since we can not point to any biological demarcation

of species, chimeras challenge our moral frameworks by straddling the line between our fixed cultural notions of species boundaries and the moral weight we place upon them.

Some might argue that this blurry distinction is not relevant only to chimeras; indeed, animal rights advocates largely base their arguments in favor of the ethical treatment of animals on the grounds that specieism is unfounded.

Blurry lines exist among humans as well, as varying states of brain activity raise questions about varying states of rational moral agency.23 Unless we are willing to ascribe full moral status to chimeras because they are part human, the notion that humanness is necessary and sufficient for personhood is deeply threatened.24 Kantians address this framework by questioning the moral agency of the chimera. Additionally, a utilitarian might argue that an appropriate framework would advise weighing the extent of the chimera’s suffering against the benefit the research provides to humans.

Though Robert and Baylis argue moral confusion as a strong concern resulting from chimeras, it is not solid enough to give guidance on how and if scientists should pursue research. Namely, it does not answer any ethical question of the appropriateness of chimera research, though it does give excellent ethical perspective to the issue.25 Indeed, moral confusion has existed in history and has been resolved. But the resolution of moral confusion in the case of chimeras is not enough to direct research in an ethical way. With chimeras, we must attempt to draw a line, despite our tentative notions of species boundaries.

Though solving the question of our moral obligations to beings with ambiguous moral status is an impossible task, searching for a background principle for 23 Thank you to Prof. Martin Gnderson, Macalester College, for these insights regarding other applications of the blurred distinctions between species (Dec. 5th, 2005).

24 Robert and Baylis, 10.

25 Hilary Bok, “What’s Wrong With Confusion?” American Journal of Bioethics 3, no. 3 (2003): 25-26.

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certain types of prohibitions, like provision (I) in the Human Chimera Prohibition Act, is critical in determining how to proceed ethically. If we find a way to direct research such that beings with questionable moral status never arise, we can avoid the “inexorable moral confusion” that Robert and Baylis warn against.

Instead of pointing to the moral confusion that might arise when certain types of human tissues, such as nerve tissue, are introduced into animals, we should assess how to guide such research in the first place. Cynthia Cohen outlines how we might go about this in her response to the Robert and Baylis article.

Cohen argues that we should search for features and characteristics that are distinctly human.26 Then, we should distinguish which cells and systems of the body might impart those characteristics, and determine whether to implant those cells and tissues into nonhuman animals. Though Cohen lays out this process quite neatly, she delivers no guidance on the first part of her protocol; finding those features and characteristics which are distinctly human. Additionally, even if we do find those characteristics, we have no reason to believe they will be isolated to any one system or cell in the human body. If we determine that what makes us distinctly human is, in fact, the combination of all our unique tissues, organs, and systems, then we would likely not allow any part of the human body to be implanted in a nonhuman animal for fear it would give that animal human status.

The guideline for determining what features and characteristics make us human beings should not be focused on uniqueness. We should not look to characteristics which are distinctly human. Indeed, it would be difficult to make an argument that anything is distinctly human because it belongs only to us; the chimpanzee genome is 99% similar to the human genome, and considering that cells and tissues arise from instructions coded in an organism’s genome, it would be difficult to argue that there are many different characteristics between us and other species. After all, species boundaries are a construct, so it would be at best difficult and at worst obsolete to claim there is anything species-related that separates us on a biological level from nonhuman animals.

Because species boundaries are cognitive constructs, we should not look to what seems to separate us from other species. Rather, our guideline should be what we value about our species. In this sense, the notion of value is different from appreciation because those characteristics which we value distinguish the biological notion of humanness from the moral notion of personhood or moral agency. Though we appreciate many aspects of our species, we ascribe value to those aspects which give us moral agency. For example, hemoglobin is a critical protein of the circulatory system. Indeed, hemoglo26 Cynthia Cohen, “Creating Human-Nonhuman Chimeras: Of Mice and Men.” American Journal of Bioethics 3, no. 3 (2003): 3-5.

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bin is appreciated as an important and distinct aspect of the human body. It would be very difficult, however, to link hemoglobin to moral agency. For example, people who have lost their moral agency, such as patients in persistent vegetative states, still produce hemoglobin regardless of their compromised or moral agency. Though we appreciate those aspects of the human body that keep us alive, a higher order of respect is paid to those features which take us beyond biological humanness and into the realm of moral agency.

This demarcation should be the guideline for drawing a line for humannonhuman chimera research. A proponent of all forms of chimera research would argue that if we value some aspect of our humanity, we should be willing to allow research on these features if such research could prove helpful to humans. But by researching features of humanity that we correlate to moral agency, we are too close to using such features as a means to an end. These features have value for their contribution to moral agency and should therefore be considered ends in themselves. Additionally, research could threaten to render such valuables ambiguous. We should always avoid anything that threatens ambiguity on that which we value. If we value certain features that give humans moral agency, these valuable features should be protected from the inevitable ambiguity which would result from problematic relationships with and questionable obligations to nonhuman animals which possess these features.

Chimeras are extremely useful and helpful as biotechnological tools for learning more about human development and disease. Their problematic species status and questionable moral status makes their classification as ‘tools’ very difficult. Many arguments exist against using chimeras, from religious objections to Kantian concerns. Practical concerns in the chimera debate, such as patenting, can also help us frame the ethical issues. Human beings can not be patented because of the 13th amendment, so patenting a chimera with human characteristics would imply that the chimera is not human. By the same token, refusing to award a patent might imply that the chimera is human “enough” to warrant concern over a patent. One of the most difficult obstacles in the chimera debate is the moral confusion that arises from the questionable status of these organisms. Because human-nonhuman chimeras are indeed part human, their creation requires us to examine just how much human makes a human. Indeed, such quantification seems to degrade humanity. Instead of quantifying aspects of our species, we should qualify them by looking to what we value as necessary for moral agency in humans. Then we should aim to protect those valuable features from the ambiguity that would necessarily arise if we attributed those features to nonhuman animals. This allows us to build a 18

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ledge on an otherwise slippery slope. Certain arguments against chimeras are not compelling enough to warrant a ban on the research, but clarifying what type of research is appropriate will allow us to pursue scientific advances that can save human lives without confusing their value with that of other species.

Acknowledgements

Special thanks to Professor Martin Gunderson, Macalester College; Professor Jeffrey Poland, Brown University; the Brown University Program in Biomedical Ethics; and the Brown University De par tment Underg raduate Group for Biomedical Ethics.

Works Cited Bok, Hilary. “What’s Wrong With Confusion?” American Journal of Bioethics 3, no. 3 (2003): 25-26.

Cohen, Cynthia. “Creating Human-Nonhuman Chimeras: Of Mice and Men.” American Journal of Bioethics 3, no. 3 (2003): 3-5.

Greely, Henry T. “Defining Chimeras…and Chimeric Concerns.” American Journal of Bioethics 3, no. 3 (2003): 17-20.

Iwasaka, Ryan M. T., “From Chakrabarty to Chimeras: The Growing Need for Evolutionary Biology in Patent Law.” The Yale Law Journal 109, No. 6 (2000): 1505-1534. Discusses the patent case of Diamond v.

Chakrabarty and appeals to evolutionary biology to solve questions of patents on living organisms.

Johnston, Josephine. “Chimeras and ‘Human Dignity.’” American Journal of Bioethics 3, no. 3 (2003).

Kamage, Andrea J. and Heider, Julie A., “Patently Immoral? The Debate Over Beings With Mixed Genetic Components Rages On.” The National Law Journal 27, no. 40 (2005). Discusses the implications of chimeras in patent law.

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-------, “So What, Exactly, Is ‘Human’?” Legal Times, June 20, 2005. An extension of the above article, also discusses the implications of chimeras in patent law.

Karpowicz, Phillip. “In Defense of Stem Cell Chimeras: A Response to ‘Crossing Species Boundaries.” American Journal of Bioethics 3, no.

3 (2003): 17-19.

Knowles, Lori P., “Stem Cell Policy: Where Do We Draw the Lines?” New England Law Review 39 (2005): 623.

Kopinski, Nicole E. “A Regulatory Proposal on the Blurring of Species Lines.” Boston College Law Review 45 (2004): 619.

Midgley, Mary. “Biotechnology and Monstrosity: Why We Should Pay Attention to the ‘Yuk Factor’.” The Hastings Center Report 30, no. 5 (2000) 7-15.

National Research Council, BLS, BHSP. Guidelines For Human Embryonic Stem Cell Research. Washington, D.C.: National Academies Press, 2005. A pamphlet for biotechnology researchers and engineers.

Introduces the ethical questions of chimera research and advises against breeding chimeras.

Robert, Jason Scott and Baylis, Françoise. “Crossing Species Boundaries.”

American Journal of Bioethics, 3, no. 3 (2003): 1-15. Argues that the primary concern in chimera research is the possibility of moral confusion, as we are unsure of our obligations or relationship to these beings.

Rollin, Bernard E. “Ethics and Species Integrity.” American Journal of Bioethics 3, no. 3 (2003): 15-17.

United States Congress. Human Chimera Prohibition Act. (Washington, D.C.: S 659 IS), 2005. Law prohibiting chimeras, also provides a detailed definition of chimeras such that all fitting under the definition are prohibited.

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Present Obligations to Future People: A Strictly Ethical Argument for Mandatory Pre-implantation Genetic Screening Jake Hartman Duke University

Pre-implantation Genetic Screening (PGS) and Pre-implantation Gene Therapy (PGT) represent two reproductive technologies which promise to significantly increase in use in the coming years. Despite this, a complete analysis of the ethical challenges presented by these advances has been notably absent. In this piece, I attempt to rectify this shortcoming. I propose that the focus on parental rights in discussions of reproductive freedom have been somewhat misguided, and that the advent of these new technologies warrant a shift in ethical focus to the rights of future persons. Working under a framework of both person-affecting and non-person-affecting harm principles, I demonstrate that concerns for the rights of future persons suggests that PGS and PGT should be implemented on a mandatory basis for genetic diseases and disabilities which inhibit “normal species function.�

With the dawn of the genetic revolution behind us, the time has come to shift our focus to the future. In the history of modern science and technology, the pace of progress has outstripped legal and ethical analysis, leaving legislators scrambling to assemble a piecemeal policy to tackle unanticipated issues.

In the case of genetic technological advancement, we have a rare opportunity to investigate the foreseeable challenges of rapidly advancing abilities. Preimplantation screening and gene therapy represent two such advancements.

In this paper, I will investigate the issues surrounding both Pre-Implantation Genetic Screening (PGS) and Pre-Implantation Gene Therapy (PGT) in terms of modern ethical theories and propose potential ethical and legal prescriptions for coping with the future uses of these technologies.

Framework for the Argument

To undergo a true ethical evaluation, a number of limitations must be instated to allow for functional analysis. The first of these limitations is the necessity of universal healthcare. Before any issue of future medical treatment may be evaluated, equal access must be available to have any hope of satisfying conditions of distributive justice . As such, in the ensuing argument, I will be assuming a society with legitimate universal healthcare. By this, I do not intend to suggest a medical utopia, but rather a case in which there is universal access

Jordaan, 598-599.

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to technologies such as PGS and PGT, as well as appropriate levels of care surrounding such procedures. Another limitation placed on this argument will be to limit the discussion to treatment of diseases with the intention of avoiding the discussion of genetic enhancement . This limitation will be founded upon the recently disputed Treatment/Enhancement boundary as discussed

by Buchanan . To overcome the apparent challenge of setting this boundary, I will rely on the concept of Normal Species Function (NSF) . This is to say, in determining whether or not a procedure represents a treatment or an enhancement, treatment will be defined as follows: Any procedure which involves eliminating a disease which would interfere with the normal function of the species will be considered a treatment. As such, any procedure aimed at altering an individual to function above and beyond normal species function will be considered, for the purposes of this argument, an enhancement, and therefore not a subject of inquiry.

As PGS and PGT potentially involve manipulation or elimination of human embryos, it is clear that a great deal of ethical analysis will hinge on the status of the embryo. It has been claimed that life begins at conception, and that an embryo’s status as a human life entitles it to all of the rights typically accorded persons . The first component of this claim, that an embryo is a human organism, is relatively uncontested. Nonetheless, it is considerably less clear that the accordance of the status of “human being” to an embryo necessarily assigns the embryo all of the moral rights typically accorded to a person . To deny an embryo the same rights as a person, there must be some distinction drawn between an embryo and a “person”. One potential criterion for this distinction is on account of numerical identity. Prior to day 14 of gestation, an embryo is comprised solely of undifferentiated, totipotent cells. At any time in development prior to the differentiation of cell types, any cell from the zygote may be removed and will develop into a fully functional human being. Conversely, in this same period, two genetically unique zygotes may fuse to form a single person . Persons, as we traditionally think of them, do not share this property. If a friend or coworker were to spontaneously divide, we

While genetic enhancement is, without question, an issue of concern for medical ethics and society at large, limitations of space dictate that I put this question aside for this paper.

Jordaan, 112-115.

Kamm, 360-361.

Kuhse and Singer, 65.

Morgan, 146.

Kuhse and Singer, 66-67.

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would think this quite strange indeed. As the zygote possesses this potential which persons do not, specifically in its transient identity, it seems that they are not true persons. The other significant disconnect between the person and the embryo is equally significant. As humans, we tend to think of human life as being somehow sacred, and worth protecting. This sacredness is traditionally not attributed to other forms of life. If there is something specific to human beings that makes human life sacred and different from the life of other animals, it surely must be consciousness . This is to say that the reason that rights are attributed to humans and not animals is that humans are sentient, self-aware beings. With few exceptions, no one is prepared to seriously defend the idea that an embryo, a mass of undifferentiated cells, is sentient or self aware. This being the case, it seems that it would be faulty to attribute personhood, and the rights that accompany it, to an embryo . This distinction is essential in evaluating the ethics of PGS and PGT, and has been established repeatedly10. From this point forward, I will use the term embryos with the understanding that I am referencing an entity with a non-personal moral status.

Cases of Interest

The two cases of interest for this evaluation are Pre-Implantation Genetic Screening (PGS) and Pre-Implantation Gene Therapy (PGT). In PGS, a number of eggs are fertilized in-vitro and each zygote allowed to divide multiple times. At this point, a single cell from each embryo is extracted and undergoes genetic testing for any potential genetic diseases or disabilities. Once this information has been acquired, the parents are able to select which embryo or embryos will be implanted and carried to term. In PGT, the same process occurs, except instead of selecting one of the embryos and discarding the other, any afflicted embryo may be treated with a genetic vector which excises the gene leading to the disease or disability and replaced by a gene which would accord the embryo normal species function.

PGS and PGT are typically discussed as very different cases. The reason behind this is that, presumably, PGS results in the choice between creation of one individual or another, whereas with PGT, a parent would only be treating the same potential individual. This idea is called into question somewhat by an extension of the so-called zygote principle. The zygote principle essentially

Ibid, 69-70.

Ibid, 70-71.

10 In addition to the above references, see Glannon (2000), Kamm (1992) and Shenfield et al (2001) for more.

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states what is often assumed in pre-implantation and prenatal cases, specifically that the identity of a given human being is contingent on the combination of a unique pair of egg and sperm. Were another zygote to have been formed as a result of the fusing of a different egg or sperm, the individual who resulted would be different11. In the case of PGS, the choice made is clearly between unique gamete pairs and therefore, by the zygote principle, between unique potential persons. In PGT, the same zygote is used, but this may nonetheless be insufficient to claim true identity. It seems illogical to say that the person with Tay-Sachs who would arise from the unaltered zygote is the same as the person who would arise were the zygote to undergo gene therapy. Furthermore, the one component which is theoretically continuous in same-zygote cases, the genome, would be altered to some degree. Whether the person resulting from an embryo which undergoes PGT is the same person is a question of some merit, but this distinction may be irrelevant in the framework of this argument as such.

Ethical Foundation for the Argument

Until now, the vast majority of ethical evaluations about the use of pre-implantation technologies have been focused on the rights of potential parents and in assuring that those rights would not be violated by any compulsory testing or action. One of the most valued rights in an open society is the procreative autonomy of individuals, and I believe that this is the reason that protecting these rights has been the primary focus of ethical inquiry to date.12 The act of procreation is itself unique from other prized individual rights, as the act itself involves the creation of a new individual with rights. This being the case, despite the historical focus on parental rights, this section will focus primarily on what rights, if any, the future individual has or will have, as well as how those rights may limit parental rights.

The ethical implications of nearly any action generally rely first and foremost on the harm principle. Simply stated, the harm principle sets the minimum condition for an action to be ethical, specifically that the action must do no harm to another person. A number of descriptions of harm have been proposed in the discussion of obligations to embryos and to future people.

Moral harm can be done, according to Dworkin, by frustrating the interests of a person, by which he means restricting the “opportunity to redeem his ambi11 12

Gavaghan, 250-251.

Jordaan, 587.

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tions or otherwise lead a full and flourishing life.”13 Frustrations of this sort may arise as a result of premature death, leaving one’s investments, both personal and natural, unrealized. It may also occur by other forms of limitation, such as those due to handicaps or poverty.14 Yet another form of harm that may be imposed upon a person, especially a future person, is a form of harm resulting from the equivalent of a broken promise or obligation.15 In these cases, harm results from the failure of the parent to fulfill the “promise” entailed in the creation of another person, specifically that the future person would not have its newfound interests frustrated upon coming into existence.16 While the individual in question may not exist at the time the “promise” is made, creation of an individual is a unique case, as the act of choosing to create entails, by its very essence, the creation of rights. The final type of harm to be considered is in cases of wrongful life. In cases of this sort, the contention is that the quality of life is so low that the individual is actually worse off than had he/she not existed17. These cases are usually quite extreme, and the contention of wrongful life is typically only made in cases where the individual lives a very short life with nearly constant suffering. The idea of what constitutes a life worth living is significant in many accounts of the ethical implications in PGS and PGT cases.

The challenge of evaluating harm in PGS and PGT cases is that, at the time a decision is made, there is no person in existence to be harmed.

The challenge of evaluating harm in PGS and PGT cases is that, at the time a decision is made, there is no person in existence to be harmed.

Since harm is contingent on the existence of an object to be harmed, it seems that it is irrational to discuss harm being done to as of yet unrealized entities.

It was this problem that Derek Parfit recognized and named The Non-Identity Problem.18 Parfit provides a number of examples which illustrate the problem at hand. In one such problem, Parfit suggests a situation in which a 14 year old girl has become pregnant. The girl knows that if she has the child, she will not be able to provide it with a good start in life, and may be unable to even provide the basic necessities of life. She also knows that, if she were to wait a few years, she might have a child that she can give a good start in life and provide for 13 14 15 16 17 18

Dworkin, 89-90.

Ibid, 89.

Kamm, 141-142.

Woodward, 821.

Buchanan et al, 225-226.

Buchanan, 351-379.

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adequately. Setting aside the moral concerns of abortion momentarily, it seems that common sense dictates that the girl would be acting immorally if she were to have the child when she could choose to wait. Despite this inclination, it seems that she cannot be acting against the interests of the child, since the only options for that child are to be born in less than ideal conditions, or to never exist at all. Whom does she harm in choosing to have the first child instead of choosing to wait? To answer this question, Parfit suggests a new approach to cases of non-identity. To address cases of seeming non-identity, Parfit relies on what he considers a “wide, comparative principle.”19 This principle strays from traditional ways of thinking of harm, as it considers not harm done to individuals, but rather the comparative good in two different situations. This approach is referred to as the non-person-affecting harm principle.

A non-person-affecting principle of harm has no trouble contending with the type of case Parfit suggests. In the case of the 14 year old girl, all other things being equal, it would be better that a child be born with a good start in life than without one. Whether children have a right to a “good start” in like (which Woodward contends they do not)20 will be addressed in the next section. In reference to concerns with this example, Kamm proposed a more extreme case which highlights what is important in utilizing impersonal ethical considerations. In Kamm’s proposed case, a woman is told that if she becomes pregnant immediately, that child will be born mentally retarded. On the other hand, if the woman waits only a few months to become pregnant, the child will be born with normal intelligence21. In this case, it is again apparent that no direct harm may be caused to the child that would be born were she to become pregnant immediately, given that there is no person yet in existence with the potential to be harmed and considering the fact that, despite its disabilities, the retarded child’s life would be worth living. Nevertheless, it seems that the woman would be making an unethical decision were she to opt to become pregnant immediately and bear the retarded child. In this case, a comparative approach yields an ethical evaluation in line with common sense. Specifically, the woman would be acting immorally not in harming one potential person or another, but in the sense that things would be better were she to have a child of normal mental health. Even in the more extreme iteration, many find this analysis difficult to accept.

Woodward suggests that Parfit’s denial of the use of person-affecting considerations is incorrect. Instead, Woodward proposes instead that person19 20 21

Woodward, 804.

Woodward, 815.

Kamm, 125-126.

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affecting principles, properly construed, can be applied to cases of future individuals in a logically sound manner. Woodward’s contention is that, in cases such as those proposed by Parfit, the decisions in question are directly tied to the existence of certain persons as opposed to others. As a result, the impact of those decisions on the persons that will come to exist are ethically relevant.22 Woodward and Kamm argue similar points in claiming that the creation of a person represents a promise or obligation of sorts. Assume that, in the case of the 14 year old girl, there are some rights that persons do possess which the potential near-future child would be deprived of. Woodward claims that, in this situation, “the reason that a certain course of action would be wrong is that it would involve the creation of rights and obligations that would probably or inevitably be violated.”23 It is important to note that Woodward does not suggest that the potential persons have any rights de novo, but rather that those rights become relevant once the decision resulting in their creation is made.

The last general ethical concern which must be addressed is the question of what rights a person may have in beginning life. As noted, Woodward contends that there is no right to a “good start” of any particular sort.24 Kamm has proposed an alternate requirement, that of “The minima.” Kamm’s claim is that creation is immoral in cases in which it is unlikely that the resultant person would be given some minima, specifically some number of years to life during which he/she would have some welfare.25 In this discussion, however, Kamm also takes into account parental responsibilities to the newborn in terms of care.

For the purposes of this discussion, the idea of a “decent genetic minimum,” may be more appropriate, as it focuses solely on genetic obligations to future persons. The “genetic decent minimum” functions as a baseline which requires that we “use advances in genetic intervention to prevent or ameliorate the most serious disabilities that limit an individual’s opportunities.”26 This concept sets the bar for the kind of obligations parents might have to future offspring, bearing striking resemblance to the normal species function concept, but with the addition of a prescriptive element.

The “decent genetic minimum” and Kamm’s “minima” represent not only the rights that a person has in being born, but also the limitations on parental autonomy. These conceptual baseline obligations are, I believe unquestionably, the primary ethical concern in cases of reproductive freedom. If a parent’s reproductive autonomy may remain without violation of the future rights of 22 23 24 25 26

Woodward, 804-831.

Ibid, 821.

Ibid, 815.

Kamm, 132.

Buchanan et al., 81.

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potential persons, then the parents’ reproductive rights ought to be the second tier of concern for any ethical inquiry. However, in any case where respect to parental autonomy includes a violation of the rights of a future person, parental autonomy must be disregarded in deference to the rights of the future child.

Extrapolated into cases of PGS and PGT, this would mean that no embryo may be implanted if found to have a disease or disability which would limit that child’s opportunities unless that disease or disability is removed by PGT. This conclusion is supported by numerous others who have investigated this problem27, 28, 29, though the degree to which a disability must limit that child’s opportunities is rarely agreed upon. Some have claimed that the only cases in which such action should truly be compulsory are those cases in which the child’s life would not be worth living.30 This requirement seems too moderate in light of the considerations of harm previously discussed. I am far more inclined to side with Kamm, Jordaan and Glannon in the claim that, in the case where there is a choice between a healthy embryo and an unhealthy embryo (one that fails to meet the NSF criterion), there should be absolutely no option to implant the unhealthy embryo. I hold that this requirement can and should be carried further. If the first obligation of society is to the future person, and the best way to ensure that future people are not subject to frustrations of their interests as a result of genetic disease or disability is by PGS and PGT, then it follows that parents should be obligated to reproduce utilizing in-vitro technology, with the limitation that only embryos meeting the NSF requirement may be implanted.31 This conclusion may seem harsh, but I believe that it follow logically from the preceding argument. If, as a society, our primary obligation is truly to the future persons we create (as I believe it must be), then the sacrifices entailed in ensuring the health of the next generation should be made willingly.

Objections to Pre-Implantation Genetic Screening and Gene Therapy

Numerous objections have been raised against both PGS and PGT on a variety of different grounds. Religious groups have claimed that these technologies are immoral on the grounds that they constitute “playing God” or that they are “unnatural.” From a purely ethical standpoint, use of these technologies has been objected to on the grounds that the elimination of embryos with dis27 Jordaan, 596-601.

28 Buchanan, 230-236.

29 Kamm, 273-276.

30 Kamm, 375.

31 At this point, I’d like to make it clear that I am only referring to a limitation on reproduction as such, and do not suggest that there ought to be restrictions on sex, sexuality, marriage, etc.

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abilities or diseases discriminates against the disabled and thereby stigmatizes the group of individuals who are being selectively prevented from existing. The final common argument against PGS and PGT is that, by selectively removing certain traits from the population, these technologies are eugenic in both their aims and practice and are therefore wrong. I contend that none of these arguments is substantially founded, and that none of the aforementioned arguments represent a compelling reason to avoid the use of these technologies or to avoid a compulsory program of screening such as the one that I propose.

The first and most common argument against the use of reproductive technologies in general is that such technological application is the equivalent of “playing god” and is therefore immoral.32

The first and most common argument against the use of reproductive technologies in general is that such technological application is the equivalent of “playing god” and is therefore immoral.

Holtug delineates a number of different meanings of this argument. The first two contentions are purely metaphysical: that we are doing what is God’s alone to do and/or that we are doing some which is unnatural.33 The second argument I will set aside for further consideration later. As to the first objection, the argument that these technologies usurp God’s prerogative is logically unsound.

If it were the case that it were God’s choice who will be created, then there are only two possible ways to treat procreation. In one case, parents violate this prerogative every time they choose to have a child, as that may not be the combination of gametes that God had in mind. In the other, it is God who guides when the parents procreate, and therefore is able to determine who will and will not exist.34 With either of these formulations of the God’s prerogative objection, it is either the case that every parent violates this prerogative with every procreation, or it is the case that no parent violates the prerogative, as God has the ultimate say. If it is the former, than the fact that this new technology violates God’s prerogative is essentially irrelevant, as is would not be a new or unique situation but rather a byproduct of human procreation. In the latter case, there is no reason to believe that an omnipotent being, if he disapproved of this form of procreation specifically, would be unable to prevent parents from choosing to do so.35 32 33 34 35

Holtug, 158.

Ibid.

Ibid.

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The third and forth iterations of the “playing God” argument claim that human decisions on who will or will not exist are often made for the wrong reason or that humans cannot properly predict the outcomes of actions such as gene therapy.36 In regards to the third iteration of the objection, there is simply no reason to believe this is the case. While quality of life predictions may be inadequate to properly assess whether one person or another ought to come into existence, I have yet to see a compelling argument for believing that a severely disabled person would live a better life than another child, born into the same family, of adequate health. In the absence of such a counterargument, I am compelled to believe that our judgments, rough though they may be, are still substantially adequate to make sound choices in this regard. The fourth argument holds a bit more water that the previous three. This argument is less an argument about playing God, and more an iteration of the Law of Unforeseen consequences. The Law of Unforeseen consequences essentially states that, for every human action, there is at least one consequence which was not anticipated.37 The standard response to objections couched in these terms is that, while there may be negative unforeseen consequences, the potential benefit of implementing treatments like gene therapy to eliminate severe genetic disorders outweighs the possibility of negative unforeseen outcomes.38 Given the various failures and inconsistencies of the objections based on ‘playing God,’ I am inclined to concur with Holtug and conclude that none of them is sufficiently compelling to restrict the use of PGS or PGT on these grounds.

The next major set of objections to the use of PGS and PGT rely on the claim that reproductive technologies are “unnatural” and therefore wrong.

There are two major forms of the objection from naturalness. The first is that it is against human nature, and the second that it is contrary to the “natural processes of life.”39 The first version of this objection, as Jordaan points out, is utterly unfounded. As humans, our most differentiating trait as a species is our ability to alter nature. This ability to manipulate nature lies at the very foundation of what separates humans from animals. To claim that this essential quality of humanness is, somehow, against human nature, is essentially meaningless.40 The second iteration of this objection, that it is against the natural processes of objections relating to metaphysically tenuous entities. While space prohibits further exploration of this problem, forthcoming work will delineate exactly why objections of this sort must fail from a purely logical standpoint.

36 Holtug, 158.

37 Owen Flanagan. Interview by Jake Hartman, 1 December 2005.

38 Holtug, 159.

39 Jordaan, 590.

40 Ibid.

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life, bears further examination. The flaw in this objection lies in an unspoken premise of the argument; that all things natural are intrinsically good.41 If this were true, there are a wide variety of practices which ought not occur. Hottois provides an excellent example in examining this flawed premise. If it were the case that we attribute intrinsic good to all things natural, we would be acting immorally in curing diseases, relieving pain, and truly in all medical endeavors, as such practices seek to eliminate things that occur naturally.42 Clearly, this is not the way we regard all natural entities and processes. A further problem with this objection can be seen in the actions taken historically in the name of preventing “unnatural” actions. As both Holtug and Jordaan observe, interracial relationships were commonly considered “unnatural” in the United States for hundreds of years, and there are still groups today that claim homosexuality to be “unnatural.”43,44 While deplorable uses of an objection do not necessarily discredit the objection itself, these various forms of ignorance should not be ignored when considering claims of this sort. The reverence shown for processes viewed as “natural” is often tied to the concept of “sentimental morality,” the idea that moral judgments can be found in one’s “gut feelings.”45 I am inclined to concur with Jordaan in his assessment that such judgments are a product of laziness or inability to form a rational argument in support of one’s preconceived value judgment, and that any judgment derived from such a framework is worthless in any intelligent discussion of ethics.46

The third major class of objections to PGS and PGT are based on the claim that, by choosing not to implant embryos with certain diseases or disabilities, society devalues living individuals with those conditions, essentially stigmatizing the afflicted population. This concern has been expressed repeatedly, but most completely and clearly by David King. In his piece on PGS and disability, King claims that the practice of screening for embryos with certain conditions and preventing the implantation of those that test positive will “lessen society’s tolerance” for those with genetic disabilities and diseases.47 While this is a reasonable concern, and one which must be thoroughly considered, there is a problem in King’s equivocation between society’s treatment of embryos with a certain condition and actual living individuals with the same condition. As has been noted, there is not a mandatory connection between society’s feelings 41 42 43 44 45 46 47

Ibid.

Hottois, 787-789.

Jordaan, 590-591.

Holtug, 158.

Jordaan, 591.

Ibid.

Ibid, 181.

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about selecting the existence of a healthy new person over a disabled or diseased individual and society’s feelings about actual persons with the same condition.

As Kamm notes, wanting to prevent someone from having a disability is by no means the same as saying that we wish those who exist with that disability did not exist.48 Furthermore, if this claim is accepted, than actions to find a cure for a disease or to correct a disability would be similarly unethical, as these actions also aim to reduce the prevalence of a disability or disease.49 A related concern to this one is that research efforts to find a cure or treatment for disorders and disabilities being selectively eliminated will decrease or halt altogether. While this is a real and valid concern, there is no compelling evidence that such a result will indeed occur. As such, this concern is, for the moment, unfounded.

The final consideration in evaluating this objection is related again to the issue of primacy of rights. While it is a right of those with genetic disorders or diseases to be treated fairly, we have already seen that it is also a right of a person not to have to suffer from a disease or have his/her options in life limited as a result of disability. The question as to which of these groups has a primacy of rights has no clear answer, but I am inclined to again place primacy in the well-being of future persons. Furthermore, this concern is irrelevant if Kamm and others are correct and discrimination does not necessarily follow from the use of these technologies.

The final objection to the use of PGS and PGT is that the practice of these technologies is, in its very nature, eugenic and therefore wrong. It is hard to deny that the argument for mandatory screening and gene therapy has eugenic overtones, as it does aim to prevent the future occurrence of individuals with certain diseases and disabilities. The true question here lies in what truly constitutes eugenics, and whether eugenics itself is necessarily unethical or simply the uses of eugenics historically observed. The first step in this process is to separate true ethical arguments from simple rhetoric. Buchanan et al make an excellent observation on this point, noting: “rival parties assume that if it can be shown that someone’s views are “eugenic,”they are thereby discredited. Much energy is then spent in trying to attach the label to an opponent or avoid being labeled a eugenicist. Such exercises tend to be long on rhetoric and short on cognitive content.”50 48 49 50

Kamm, 382.

Ibid.

Buchanan et al, 10.

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I do not believe that eugenics in and of itself is conceptually immoral. However, if it is not the case that eugenics is immoral in principle, it is necessary to investigate what features of the historical invocations led to practices which are generally considered unethical. A number of theories on this count have been proposed,51 but the issue of compulsion is the most striking. Although King claims that “coercion was never an essential feature of eugenics in theory or practice,”52 I believe that coercion is not only an essential feature of the historical use of eugenics, but is the primary feature of eugenics which made its practice unethical. The reason that the actions of the US and Germany were so deplorable is not necessarily, that they aimed to improve the gene pool for future generations,53 but rather was due to the fact that, in both cases, the reproductive autonomy and even the lives of individuals were forfeited without any choice on the part of the affected individual. That so many individuals were sterilized or killed without having any say in the matter is the root of the ethical failures of past eugenic programs.

One consideration offered in dealing with this objection is that, in fact, PGT is not a truly eugenic practice. As PGT aims not to eliminate an individual but only to prevent that future person from suffering unnecessarily, it does not represent a eugenic practice at all, but rather a new form of treatment.54 Unfortunately, applying this response to PGS is challenging if not impossible.

If it is the case that PGS is a eugenic practice, is it also the case that, as some claim, it is necessarily immoral? As noted, it is my contention that what made the previous uses of eugenics morally deplorable was not the underlying theory necessarily, but the coercive actions of the government and other institutions. If this is the case, then the mandatory nature of my proposed program must also be evaluated. While I have proposed that, ethically speaking, screening should be mandatory, as should selection of embryos meeting the NSF qualification and which would be born with a “decent genetic minimum,” I maintain that my program is not unethically eugenic, as it does not restrict who may reproduce, as historical eugenic programs did. In historical cases, the reproductive rights of individuals were not restricted, they were removed altogether. This is not the case with a program of mandatory screening and selection/treatment. As the reproductive freedoms of parents would only be limited and not removed altogether, I do not find the proposed program to be 51 Buchanan et al, 46-52.

52 King, 177.

53 This is obvious not true of the eugenic practices in Nazi Germany, where the obvious racism and discrimination did represent an additional immoral component. The motives of US eugenicists are additionally suspect.

54 Wagner, 234.

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unethical as a result of potentially eugenic implications.

Legislation and Limitations

While I have maintained that my proposed program is ethically sound in nature, this by no means precludes the possibility of abuse if such technology is not tightly regulated. For a program such as this to be functional, it must be more than an ethical theory. As seen in the case of the Cyprus program, optional screening is not effective.55 For such a program to be functional, it must be enforced by legislation. The question then arises, what diseases/disorders will be screened for? I propose that, given the future society which I have posited, only genetic disorders and disabilities which would result in a person failing to meet the NSF or “decent genetic minimum� criteria would qualify. This would mean that a number of mild disorders may be allowed, assuming that the disorder will not sufficiently frustrate the interests of the future individual.

Conclusion

As I have shown, current discussions on reproductive ethics are faulty in their failure to adequately recognize the primacy of potential rights of future persons. It follows from this that both person-affecting and non-person-affecting harm principles mandate that all reasonable steps be taken to prevent the creation of a future person with frustrated interests. As a result, from a purely ethical standpoint, Pre-Implantation Genetic Screening and Pre-Implantation Gene Therapy are not only acceptable, they should be made a requirement.

While this prescription is clearly a strong one, I contend that it follows logically from the component arguments.

I do not claim to have the final solution to the problem of when/how programs of PGS and PGT ought to be implemented. While I have proposed that a program of mandatory screening and selection is ethically sound, the stipulations on which the argument rest are numerous, and some unlikely to occur. Whether such a program should be put into practice in any society is further questionable. The outcomes of such a program do indeed seem to be valuable: the elimination of the suffering caused by genetic diseases and disorders. The true question lies in whether or not any human population is responsible enough to wield such awesome scientific power responsibly and to learn from mistakes of the past in any such uses. It is my conclusion that these complicated issues must be dealt with soon, before PGS and PGT are readily 55

Guterman, A22.

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available. If this question can be addressed before the problem is truly critical, it is possible that a great deal of legal and ethical floundering may be avoided when these technologies are readily available and easy accessible. As such, I think that scientists and ethicists worldwide need to take this issue to task and investigate whether these practices can indeed be performed ethically. If these types of decisions aren’t made now, we may find ourselves in a very precarious situation, where once again our ability has outpaced our understanding.

Works Cited Buchanan, A., Brock, D., Daniels, N., & Wilker, D. (2000) From Chance to Choice. Cambridge: Cambridge University Press.

Flanagan, Owen. Interview by Jacob Hartman, 1 December 2005.

Glannon, W. (1998). Genes, Embryos, and Future People. Bioethics, 12(3), 187-211.

Guterman, L. (2003). Choosing Eugenics: How far will a nation go to eliminate a genetic disease? The Chronicles of Higher Education, 49(34), A22.

Hanser, M. (1990). Harming Future People. Philosophy and Public Affairs, 19(1), 47-70.

Holtug, N. (1997). Altering Humans – The Case For and Against Human Gene Therapy. Cambridge Quarterly of Healthcare Ethics, 6, 157-174.

Hottois, G. (1998). Is cloning the absolute evil? Human Reproduction Update, 4, 787-789.

Jordaan, D. (2003) Preimplantation Genetic Screening and Selection: An Ethical Analysis. Biotechnology Law Report, 22(8), 586-601.

Kamm, F. M. (1992). Creation and Abortion. Oxford: Oxford University Press.

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Kamm, F.M. (2002). Genes, Justice, and Obligations to Future People. Social Philosophy and Policy, 19(2), 360-388.

King, D. (1999). Preimplantation genetic diagnosis and the ‘new’ eugenics.

Journal of Medical Ethics, 25(2), 176-182.

Kuhse, H. & Singer, P. (1990) Individuals, Humans and persons: The issue of moral status. In Embryo Experimentation. New York: Cambridge University Press.

Lippman, A. (1994). The Genetic Construction of Prenatal Testing: Choice, Consent of Conformity for Women? In Women and Prenatal Testing Columbus, OH: Ohio State University Press.

Morgan, D. (1995) The Legal Status of the Embryo and the Fetus. In Issues in Fetal Medicine, New York: St. Martin’s Press.

Parfit, D. (1984). Reasons and Persons. Oxford: Clarendon Press.

Shenfield, F., Pennings, G., Sureau, C., Cohen, J., Devroey, P., & Tarlatzis, B. The moral status of the pre-implantation embryo. Human Reproduction, 16(5), 1046-1048.

Wagner, J. (1997). Gene therapy is not eugenics. Nature Genetics, 15, 234.

Woodward, J. (1986). The Non-Identity Problem. Ethics, 96(4), 804-831.

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An Argument in Favor of Objective Scientific Journal Publication Practice: Proposed Changes to Contemporary Journal Practice Matthew Kelly Brown University

Contemporary scientific practice is, in large ways, influenced by scientific prestige. Prestige allocation is determined based upon an evaluation of a number of independent variables, including an individual’s publication history in scientific journals. Here, I begin with a discussion of scientific prestige (Section I), then examine the use of publication history as a determinant for scientific prestige allocation (Section II), arguing that scientific journals ought to be required to maintain standards of objective publication practice, thus ensuring that one variable upon which prestige-allocation is based remains objectively reliable. Five requirements for objective publication practice are proposed. In section III, I present several case studies that suggest that scientific journals are in violation of these requirements.

Section I: Examination of Scientific Prestige “My love of natural science…has been much aided by the ambition to be esteemed by my fellow naturalists.”

-Charles Darwin It is no secret that some scientists are esteemed more than others. When we say that a scientist is esteemed, we are saying something about the work he has done, the discoveries he has made, or the ideas he has thought. The scientist who has excelled in any of these tasks may be said to be “esteemed” or “prestigious.” Because scientific prestige is allocated to some scientists and not to others, and to varying degrees to some scientists, it seems fair to claim that it is a variable that exists on a spectrum and that can qualitatively measured. What’s more, there is reason to believe that the amount of scientific prestige a scientist is granted by her peers may serve as an incentive for her to excel in her role as scientist. She may strive to be viewed as prestigious by members of the scientific community (as Darwin did) or she may strive to be viewed as prestigious by individuals outside of the scientific community. Indeed, scientific prestige means something to individuals inside and outside the scientific community.

Some scholars have gone so far as to claim that the allocation of scientific prestige by and to members of the scientific community is a fundamental component of the ethos of science. Robert Merton, for example, argues that

Charles Darwin, The Autobiography of Charles Darwin,1 May 1881.

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effective, efficient scientific practice involves, “recognition and esteem [accruing] to those who have best fulfilled their roles, to those who have made genuinely original contributions to the common stock of knowledge.” The allocation of scientific prestige, therefore, has become a fundamental component of science that facilitates an efficient workforce: individuals yearn for scientific prestige, and thus increase the contributions they make to the common knowledge pool.

I have so far claimed that scientific prestige (a) is real, (b) can be qualitatively measured, (c) can be selectively allocated to individuals in different amounts, and (d) matters as an assessment criteria for individuals inside and outside of the scientific community. If scientific prestige is a variable that influences the ways scientists operate or the ways the public views science (as I will soon argue it does), we ought to question the mechanisms by which it is allocated. If prestige is allocated based upon contributions to the scientific knowledge-base, then it is necessary to examine how we evaluate contributions to the scientific knowledge-base. That is, there must be specific variables that are independent of prestige that identify scientific accomplishment (prestige, as a variable, is thus dependent upon these independent variables.)

There are a number of variables that seem to be used as indicators of scientific contribution (and therefore scientific prestige). Whether or not an individual has won one of few generally respected scientific prizes serves as one variable for an analysis of scientific contribution. To win the Nobel Prize, for example, is to essentially secure a type of scientific prestige that one would have to work very hard to tarnish. Receipt of fellowships, like awards, can additionally modulate one’s prestige ranking. Placements in academic posts at leading research institutions also serve as indicators of scientific contribution.1 Whether or not an individual is a member of respected panels or committees (e.g. science advisory panels), furthermore, may be examined for prestige allocation decisions. A final method by which scientific contribution is measured (and by which prestige is allocated) has to do with the extent to which an individual has published in the world’s leading peer-reviewed scientific journals. I will revisit this final marker of scientific contribution and prestige later in this paper.

It is important to note that scientific prestige is an institutional marker of performance that integrates into a larger institutional system. When a scientist is determined to be sufficiently prestigious, he finds it easier and perhaps more enjoyable to function within the scientific institution. In effect, the yearning to earn scientific prestige gains its motivational powers via the standards of practice utilized by the scientific community. For example, prestige is evaluated by

Robert Merton, “Priorities in Scientific Discovery: A Chapter in the Sociology of Science,” American Sociological Review 22.6 (1957): 639.

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members of the scientific institution in the determination of the placement of researchers in academic positions, and the awarding of grant/fellowship funding. The fact that scientific prestige allocation can influence decisions regarding these two activities is largely significant: the fact that certain individuals (and not others) secure academic positions can influence the nature of scientific education for future generations, and therefore influence the face of science for another generation. The fact that certain individuals (and not others) receive grant money means that these individuals will have more opportunities to influence the scientific knowledge pool and thus our perceptions of particular issues, problems, and observations. This further underscores the fact that scientists are motivated to be viewed as prestigious, and that this motivation is grounded firmly in the practices of the larger scientific community.

Thus far, I have concentrated my attention on the ways in which scientific prestige allocation can influence the motivations and behaviors of members of the scientific community. However, we also ought to examine how scientific prestige allocation can influence the perceptions of those operating outside the scientific community. If authority within the scientific community is differentiated based upon a prestige ranking, then it should come as little surprise that society would translate this differential scale of prestige into a system that more highly values the statements of prestigious scientists. My support for this claim is founded in the epistemic authority scientists enjoy: the general public is apt to accept and import the evaluations of the scientific community for a wide range of examples, including evaluations of scientists themselves. An examination of social practice reveals that this is, indeed, the case: The public is more apt to read a new book targeted at the general public when it is written by a prestigious scientist than one written by a less prestigious scientist. Likewise, a lay press media outlet is more apt to question a prestigious researcher for comments on a hot issue than they are a lesser known researcher.

I believe that reasons exist suggesting that the allocation of prestige in scientific practice may influence public perceptions of science even further: At least some (and probably most) members of our society appear to have a low saturation level for scientific information, after which they are not receptive to scientific discussions (this is a broad generalization, but one that I believe is at least sometimes true). Thus, even if a great many scientific viewpoints are represented by any given media outlet on a given day, the prestige factor may draw the public’s eye such that the opinions of those deemed more prestigious are the primary viewpoints to make it to the public’s attention. If the public

Christine Wenneras and Agnes Wold, “Nepotism and Sexism in Peer Review,” Nature 387 (1997): 341-343.

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is not receptive to extensive scientific discourse, then the viewpoints of the “prestigious individuals” may be the only viewpoints to come to the attention of some (and perhaps many) people.

I have thus far argued that scientific prestige labels exert significant influence upon decisions in both the scientific and general public spheres. For these reasons, we ought to be highly critical of the dependability of the independent variables used to measure scientific contribution and thus prestige. Put another way, the significance of scientific prestige (as measured by its impact) is an indicator of the significance of the loss of objectivity endured when prestige-granting-mechanisms go awry.

In this section, I have presented several independent variables that are examined for prestige allocation: receipt of respected awards, receipt of fellowships/grants, affiliation with respected research university, affiliation with respected panels/committees, and publication in scientific journals. Each of these should be examined critically to determine avenues for loss of objectivity.

Here, I will focus my attention on one variable upon which scientific prestige is dependent: publication history.

Section II: An Examination of an Indicator of Scientific Prestige: Publication History As in most academic disciplines, publication remains an esteemed goal coveted by the diligent researcher. If contribution to the scientific knowledge pool is the main criterion for scientific prestige (as I have argued it is), then it is not difficult to understand why a scientist’s publication history influences prestige allocation. Indeed, publication in a journal serves as the direct mechanism by which a scientist actively contributes to the knowledge-pool. Scientific journals serve as the intellectual forums for scientific idea-sharing, critique, and revision.

Therefore, the number of times an individual has published research papers in scientific journals affects the amount of prestige afforded them by the scientific community (more publications yields a higher prestige allocation).

Furthermore, individuals are not always interested in being published in “just any scientific journal.” It is more difficult to be published in some journals than others; this difficulty reflects the gradient in prestige that exists between the many scientific journals. The journals Nature and Science, for example, are widely considered to be the most prestigious of all scientific journals, whereas other more specialized journals (e.g. Atherosclerosis, Radiology, Neuroscience) are generally considered to be less prestigious. Therefore, in total, prestige via

Ibid.

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publication history is evaluated using two variables: the quality of the journals in which one is published, and the number of times an individual is published in journals. A third variable that influences prestige is the number of times an article is cited in other sources.

Because very few people can earn prestige by winning the Nobel Prize (or other prestigious scientific awards), I believe that the use of publication history may be currently used as the single-most important tool in the determination of prestige. I also believe that publication history serves as a sort of primary evaluation of prestige, and other prestige markers are themselves determined based on publication history. For example, publication history is actively used in determining whether an individual should be hired to academic posts at leading universities. Additionally, when fellowship review committees must determine to whom they will grant research dollars, publication history provides for an examination of an individual’s intellectual output and productivity over a period of time. It also represents an individual’s ability to compete with other members of the scientific community in securing publication in the most prestigious peer-review journals. Thus, publication history as a measurement of prestige can directly affect whether scientists will secure academic positions or grant money – two factors that themselves influence prestige allocation.

Seeing that scientific journals are so influential in allocations of prestige, we ought to clearly outline standards for scientific journal practice.

Seeing that scientific journals are so influential in allocations of prestige, we ought to clearly outline standards for scientific journal practice.

If publication history is to be used as an objective measure of scientific contribution (and therefore scientific prestige), then we must ensure that standards for publication practice are maintained by scientific journals.

Some may object to this claim, arguing that scientific journals are not responsible for the manners in which the scientific community relies upon their practice. Specifically, they might argue that scientific journals do not have an obligation to ensure that their practices are fit to serve as indicators of scientific contribution, and instead have only an obligation to publish scientific research as they see fit. I believe that this criticism is short-sighted. Scientific journals are sustained by a community that is bounded by norms of practice that demand objectivity be maintained. Although the scientific community is dependent upon scientific journals as an indicator of scientific contribution, this dependency is recognized and permitted by the scientific institution. The 42

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scientific institution could, conceivable, reject the use of scientific journals as a method of information dissemination (and therefore an indicator of scientific contribution). I bring this up merely to highlight the fact that scientific journals operate at the behest of the scientific community and therefore are bound by the needs of this community. If the scientific community demands objective scientific practice (and it ought to), and if scientific journal practice can influence whether or not objective scientific practice takes place (here, by affecting prestige allocation), then scientific journals ought to abide by set rules of objective practice. If journals violate requirements for objective practice, then they will introduce unreasonable harms into prestige allocation, thus posing harm to members of the scientific community and the public at large. Such harms ought not to be tolerated; thus, I believe that journals have an ethical obligation to maintain objective practice, inhering in their professional roles in prestige allocation.

The construction of a set of rules for objective publication practice ought to prevent the introduction of personal or social biases into publication protocols. I propose that the following five requirements are necessary for objective publication practices to be maintained by scientific journals. Although this list may not exhaust the requirements for objective publication practice, I believe that they address several main avenues for bias. Here, I present each requirement and follow it with a brief supporting argument: R1: The Journal must develop and implement a system for evaluation of submitted articles that allows for the critical analysis of the scientific soundness and rigor of the research and analysis of the research by the article’s author(s). The system must sufficiently prevent analysis of anything other than the soundness of scientific methods and reasoning employed (i.e. it must prevent discrimination based upon the identity of the author, the institutional affiliation of the research).

Because scientific journals receive a large number of submissions of research studies for publication, it is understood that they will be selective.

What’s more, the selective nature of scientific journals is a key element of their usefulness as indicators of scientific contribution. If publication in a scientific journal reflects contribution to the scientific community, then we ought to demand that the method of evaluating submitted articles involves an analysis of the research’s contribution to the scientific community and not some other extraneous details surrounding the research or researchers who submitted the article.

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We should therefore require scientific journals to establish evaluative methods that allow for a fair evaluation of scientific contribution. As one of the elements of scientific contribution, the journal ought to examine the rigor of the scientific methods employed, the appropriateness of the techniques, and the soundness of the reasoning/analysis of accrued data. If an insufficient evaluative method exists, then journals run the risk of allowing for social assumptions to influence acceptance practices. Journals may import biasing assumptions/observations if they consider any of the following in their evaluative methods: any characteristics that are specific to the author, such as sex, race, sexual orientation, or institutional affiliation. They may also import bias if they allow for considerations regarding personal interests researchers other than the authors may have in publishing the data. If a journal accepted an article because the brother of the editor would benefit, then this would represent an inappropriate personal bias. If the Journal rejected the article so that his brother could publish on a similar topic, we would also consider this problematic.

There is little reason to believe that authors’ characteristics are legitimate markers of a research’s rigor and soundness. Furthermore, any belief that these characteristics are indicative of scientific soundness no doubt relies upon the importation of social biases regarding particular races, sexes, etc. The same is true for institutional affiliation, whereby assumptions are made regarding researches quality based upon the academic positions held by researchers. This sort of assumption allows for academic affiliation to serve as a proxy for scientific soundness in evaluations of submitted articles. Ideas that one particular research institution “hires better researchers” can only be explained by calling upon assumptions biased by social or personal beliefs regarding that institution.

These sorts of biases are inappropriate for scientific publication, and ought to be prevented. Thus, journals ought to establish and maintain evaluative methods that satisfy R1.

R2: If the Journal chooses to publish material that has not endured the assessment system of R1, this material must be clearly distinguished from the material that has passed the assessment system.

There may be instances where it would be beneficial (for the scientific community) for a scientific journal to publish submissions that do not employ rigorous scientific proofs. It may be useful, for example, for a journal to publish letters that comment upon scientific research. These letters, however, may be pure conjecture. If a letter proposes an alternative, unsubstantiated idea that 44

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contradicts an article’s conclusion, it would be difficult for a journal to ensure that objective scientific practice led to its formation. We allow for freedom when it comes to hypothesis formation, and letters seem to be a useful venue to showcase these ideas. It is important to note that R2 allows for Journals to choose to publish material that had not endured the “soundness” assessment of R1. However, R2 does not allow for a journal to evaluate letters or review articles based upon peripheral matters, such as the characteristics of the author.

If a journal allows for submissions that have not endured the evaluative requirements of R1 to be published, they ought to be clearly distinguished from those articles that have been evaluated and accepted using R1’s requirements.

Otherwise, those who read scientific journals (members of the scientific community and the general public) will not be able to determine which articles are certifiably sound (viz. R1). If a scientific journal does not distinguish scientific articles that are objectively sound (via the standards of R1), then we have no means of knowing which articles have been deemed worthy contributions to the scientific knowledge pool and which are less rigorous critiques of these contributions.

R3: The Journal must ensure that its assessment system does not grant a more lenient soundness evaluation to articles in “hot topic” issues, where an articles status as hot topic is determined by members of the community who depend upon the Journal in understanding the reliability of a theory or the prestige of researchers.

In choosing which articles to publish, scientific journals should not sacrifice the evaluative standards outlined in R1 for articles that are more popular in the popular mind frame. To subject “hot topic” research articles to less stringent requirements merely because they are popular in a particular social, economic, or political landscape is to allow for social biases to influence publication practice. The idea that a particular topic is more interesting than another is not an objectively defensible claim. It requires that personal or social assumptions be allowed to influence important decisions regarding what does and does not constitute a worthy contribution to the scientific knowledge-base.

Although the selective publication of “hot topic” does involve the importation of social biases (i.e. the granting of legitimacy to social assumptions regarding what is “hot” and what is not), some may claim that this type of bias is acceptable for scientific journal practice. They might claim that scientific journal practice needn’t be protected from every type of bias. This objection 45

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ought to be addressed, as it relates to a larger concern of the social obligations of science.

The root of the argument against R3 holds that science is a social institution and, as a social institution, ought to conduct research that benefits the public. It is altogether possible for “hot topic� issues to be issues that the public feels are particular important or timely. According to this argument, it may be appropriate for scientific journals to modify their publication practice to highlight those topics members of society are interested in hearing about.

I take issue with this line of reasoning. For one, I believe that it is dangerous to embrace a system whereby members of society rely upon the expertise and authority of the scientific community while exerting considerable control over a cherished mechanism of prestige allocation: the scientific journal. A great deal of scientific practice is inaccessible to the general public due to the complex language, techniques, and reasoning involved. The authority the general public places in the scientific institution is therefore based upon a delicate trust that the scientific community will maintain objective research practices. By allowing for hot topic issues to receive preferential publication, we are effectively allowing for social biases to influence the prestige allocation of a number of scientists.

By allowing for hot topic issues to receive preferential publication, we are effectively allowing for social biases to influence the prestige allocation of a number of scientists

Work that is subpar via the standards of R1 may be published (thus increasing these author’s prestige allocations), and work that satisfies the standards of R1 may be rejected (thus withholding prestige allocation for the respective researchers). The general public cannot both defer to the authority of the scientific community while, at the same time, demanding that its nonscientifically-based biases factor into evaluations of scientific contribution.

If we do allow for social biases to influence scientific publication (and therefore prestige allocation), we will embrace a system whereby a demand for the importation of social biases leads to the publication of sub par research.

Prestige will be incorrectly allocated, and the scientific institution will evaluate this underserved prestige in the same way it evaluates deserved prestige. The result of the importation of social biases, therefore, will be to decrease the 46

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standards of practice of the scientific community.

Some may claim that my arguments here rob the general public of their role in the scientific process. They may, furthermore, claim that my arguments ignore the social obligation the scientific institution has. I do not believe that this is true. I believe that R3 represents a fair example of the scientific institution preventing the general public from constructing a system that would, in the long run, hurt the general public (by decreasing the standards of scientific practice, where members of society rely upon scientific practice. In short, R3 represents an instance of justified paternalism. It is a paternalism that calls upon the authority the public already places in the scientific institution.

R4: The Journal must ensure that its assessment system is not more stringent in its soundness evaluation for articles that support conclusions that are viewed as unpopular at the time of article submittal, where an article’s status as unpopular is determined by members of the community who depend upon the Journal for understanding the reliability of a theory of the prestige of researchers.

I omit an explicit argument in favor of R4 here, as the argument would be extremely similar to the argument provided above for R3.

R5: The Journal must not privilege (for publication purposes) positive findings over negative findings or vice versa.

Scientific research oftentimes seeks to establish whether or not a correlation exists between two variables. Scientists may be interested, for example, in understanding whether or not Chemical X and incidence of Disease Y are correlated with one another. If researchers determine, through rigorous and sound scientific practice, that X and Y are not correlated, then this information is just as useful as it would be if they had found that X and Y are, indeed, correlated with one another. There is simply no reason to suggest that a positive correlation between X and Y is any more useful than a negative one.

If scientific journals import a “positive vs. negative results” assumption, then they allow for their practices to be dictated by faulty reasoning. What’s more, their practices may be detrimental to scientific progress. As Sterling and Weinkam argue, this form of publication bias may allow for a series of negative findings (i.e. X and Y are not correlated) to go unpublished and unnoticed, while a change positive finding that is not reproducible is published and thus noticed.

Thus, the scientific community and general public may be made to believe that the positive correlation between X and Y is well established, despite the large 47

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quantity of previous studies that found otherwise.

Section III: Case Studies Demonstrating Violations of R1-R5

I have thus far introduced five requirements for objective scientific journal practice. If any of these requirements are violated, then scientific journals are not fulfilling their obligations to maintain objective practices. In this section of the paper, I will introduce several case studies that represent alleged violations of several of these requirements.2 Violation of Requirement 1 In contemporary scientific practice, most scientific journals (the most reputable ones) utilize a method of evaluating submitted articles that, in the very least, is meant to satisfy the standards of R1. The peer-review process is intended to create a double-blind evaluative system where individuals review anonymous research papers and provide personal opinions regarding whether or not it ought to get published.

In recent years, critics have alleged that the peer-review system is inadequate at (1) assuring consistent evaluations of the scientific soundness of particular research, and (2) preventing the importation of personal and social biases into discussions of publication. I will provide an example for each of these allegations.

In a Correspondence Article in a 1993 edition of Nature, E. Ernst et. al. presented preliminary findings that suggested that the peer review process does not provide for a dependable evaluation of scientific soundness. They presented 45 referees for scientific journals with a scientific research article and asked for each referee to independently evaluate a number of features of the study, including “scientific merit,” “statistical methods,” “methodology,” and “overall merit.” The qualitative assessments were limited to “Unacceptable,” “acceptable,” “fair,” “good,” and “excellent.” The results were staggering, as there was a general lack of consensus among the reviewers on all of the aforementioned categories. For each of these categories, some reviewers graded “unacceptable” whereas others graded “excellent.” As the authors note, “The results therefore suggest that the method of evaluating scientific papers is unreliable and open to bias and should itself be submitted to evaluation.”

Ernst and Keinbacher have also presented evidence that supports the

T.D. Sterling, W. L. Rosenbaum and J. J. Weinkam, “Publication Decisions Revisited: The Effect of the Outcome of Statistical Tests on the Decision to Publish and Vice Versa,” American Statistician 49.1 (1995): 108-112.

E. Ernst, T. Saradeth, and K.L. Resch, “Drawbacks of Peer Review,” Nature 363 (1993): 296.

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claim that national identity is allowed to influence evaluations of submitted articles. Although their research requires further validation, preliminary data shows that journals tend to publish articles written by individuals who are citizens of the country in which the journal is based. For a journal based in the United States, for example, an examination revealed that 79% of primary authors of scientific research papers were American, compared with 21% non-Americans.

These results suggest that factors other than scientific soundness/rigor are being evaluated in determinations of scientific publication.

In addition to nationalistic bias, some authors have claimed that their research has been stalled by referees of the peer review process who, after receiving an article on topic X, rush to publish their own article on topic X. This practice, again, underscores the sense of urgency fostered by the scientific institution: you not only “need” to publish, you need to publish first. What’s more, there is no reason for us to believe that behind the scenes referee maneuvers is novelty of the 21st century. Charles Darwin, whose quote regarding the yearning for esteem prompted the above discussion of scientific prestige, immediately began to think of his own personal interests upon receiving the manuscript of a young Alfred Wallace.

Thus, an analysis of the evaluative procedures in place for contemporary scientific journals reveals that Requirement 1 is not being satisfied. Our current system of evaluation does not dependably evaluate scientific soundness or rigor, nor does it prevent the evaluation of peripheral issues, such as author characteristics. We must seriously question the ability for contemporary peer review standards to satisfy Requirement 1, and suggest reforms to remedy the aforementioned violations.

Violation of Requirement 3 The third requirement in my proposal states that article submissions in “hot topic” areas ought not to receive less scrutiny in peer-review than other articles that are submitted.

I will briefly recall my argument supporting Requirement 3 here: Members of society trust the institution of science with properly evaluating prestige in its ranks and for allowing for a continuation of productive, objective research.

This authority is granted by the public due to the educational and technical requirements necessary for scientific research (and the understanding that members of the scientific community are best qualified to make these evaluations of prestige). However, the scientific community uses the publication record of

258.

E. Ernst and T. Keinbacher. “Chauvinism,” Nature 352 (1991): 560.

Trisha Gura, “News Feature - Peer Review: Unmasked,” Nature 416 (2002): 49

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individuals to determine prestige. If scientific journals selectively publish hot topic articles by lessening their standards of evaluation for these articles, they are allowing for more prestige to be allocated to the writers of these articles. If allocation of scientific prestige is influenced by subjective public interests (e.g. the latest “hot topic”), then the authority that we place in science experts may be not be justified; it may be a false authority, or an illusion of authority. In total, it is dangerous for an authoritative system (here science) to base its evaluation of prestige (and, in general, its actions) on the behaviors of the very people who seek the authority of the system.

Biased publication of hot topic issues, furthermore, may convince members of the public that progress is being made in particular scientific subfield or area, whereas no true progress is actually being made. Thus, selective publication practices contribute to a false sense of scientific innovation, furthering entrenching those who rely upon journals for indicators of scientific contribution. This community of individuals includes both scientists (who, presumably, read scientific journals) and the general public (who, presumably, read secondary publications that report on scientific journals).

In 2005, David Magnus argued that Nature had, effectively, lessened its standards for publication for two articles in a hot topic issue: stem cell research: The research that was announced yesterday showing the possibility of supposedly more ethical alternatives to stem cell research is a lot less substance than hype. Neither result is really very surprising (at least in mice). The knockout mouse experiment demonstrates that a gene does pretty much what we thought it does (in mice). And the other experiment shows that cells separated at an early stage of development can do pretty much what we already knew they could do.

Due to space limitations, I cannot provide a full argument in favor of Magnus’ comments here. However, his argument, though brief, successfully raises eyebrows. If Nature accepted articles for publication that were not legitimate contributions to the scientific knowledge pool (because the same information was already part of the common scientific knowledge pool), then scientific prestige may have been allocated wrongfully to scientists who did not actually contribute something worthy to the scientific knowledge pool. The general public, reliant upon scientific journals for indications of “what’s important in

David Magnus, “Bad Ethics + Boring Science = Nature Publication,” blog. bioethics.net 17 Oct. 2005.

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science,” were swept up by the presumed contributions of these two articles. As the Philadelphia News reported the day after the Nature articles were published: “Two new mouse experiments may show how to obtain human embryonic stem cells without ethical hurdles, a step that could allow federal funding for such research, scientists reported yesterday.”10 Violation of Requirement 4

In 2005, Science published an article that provided evidence suggesting that a great majority of scientists either implicitly or explicitly supported the idea that global warming is a natural phenomenon and that has been caused by the actions of humans.11 Several scientists allege that they submitted letters to Nature providing evidence that contradicts the majority standpoint on global warming issues (in response to the Roger paper), but were rejected for unclear reasons. One scientist, Benny Peiser, claims to have submitted a letter to Science that directly contradicted Roger’s findings that a consensus exists in the scientific community on the issue, only to have the letter rejected. A correspondent for Science claimed that, “The information in the letter was not perceived to be novel.”12 Therefore, Science allowed for publication an article that maintained that a consensus on global warming exists in the scientific community, while rejecting a letter that provided research explicitly rejecting the conclusions of the study.

It seems plausible to argue that Peiser’s research was, indeed, pertinent in that it employed methods very similar to the Roger study and reached differing conclusions, thus casting doubt on the reproducibility of Roger’s methodology. Science’s claims that the article was not novel is not convincing. The fact that their rejection of the letter appears completely based upon this claim (and no claim to the effect that the research itself was unsound or non-rigorous) is deeply troubling.

The point that I mean to raise here is not one about Global Warming, but rather one about the publication of contradictory findings by the scientific community.

Whether or not the reader supports Peiser’s conclusions regarding Global Warming should not factor into a discussion of whether opposing research findings ought to be made accessible to the public and to the scientific community.

Violation of Requirement 5

Easterbrook and Berlin (1991) reported that, in an examination of 287 studies, researchers found that only 15% of studies with positive results went unpublished compared with 44% of those with negative results. Furthermore, 10 “Mice studies offer some hope of expanding stem-cell research,” Philadelphia News, 17 Oct. 2005.

11 Roger A. Pielke, Jr and Naomi Oreskes, “Consensus about Climate Change?” Science 308 (2005): 952-954.

12 Robert Matthews, “Leading scientific journals ‘are censoring debate on global warming,’” Telegraph Group Limited (2005).

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the author’s found that 27% of articles with positive results were published in the most prestigious scientific journals (measured through an independently determined journal “impact factor”) compared with only 16% of those with negative findings.13

These findings are highly troubling, as they reveal that scientific journals are importing unsubstantiated assumptions (that are probably founded in or reinforced by social biases) that lead to a violation of the fifth requirement for objective scientific publication practices.

Conclusion

I have argued that scientific journals have a special role in prestige allocation for members of the scientific community, and that they must abide by set standards for objective practice. This paper represented an attempt to define several of these requirements, to argue in favor of their roles as standards for objective publication practice, and to provide several case studies examining the violation of these requirements.

I believe that the method employed in this paper must be employed on a much larger scale to determine a more complete list of requirements for objective publication practices. In the meantime, we ought to address the aforementioned violations of these five requirements. If violations of this sort are permitted to remain uncorrected, then we ought to seriously consider the sort of authority we grant publication in scientific journals as an indicator of scientific contribution and determinants of scientific prestige.

Works Cited Easterbrook, P.J., Berlin, J.A., “Publication Bias in Clinical Research.” Lancet, 13 April; 1991 337.8746.

Ernst, E. and T Keinbacher. “Chauvinism.” Nature. 352 Aug 1991: 560.

Ernst, E., T. Saradeth, and K.L. Resch. “Drawbacks of Peer Review.” Nature. 363 May 1993: 296.

Gura, Trisha. “News Feature - Peer Review: Unmasked.” Nature. 416 March 2002: 258-

260.

Magnus, David. “Bad Ethics + Boring Science = Nature Publication.” blog. bioethics.net 17 Oct. 2005.

13 P.J. Easterbrook and J.A. Berlin, “Publication Bias in Clinical Research,” Lancet, 337.8746 (1991): 867.

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<http://blog.bioethics.net/2005/10/bad-ethics-boring-science-_ 112956835293135329.html?> Matthews, Robert. “Leading scientific journals ‘are censoring debate on global warm

ing.’” Telegraph Group Limited. 2005.

Merton, Robert. “Priorities in Scientific Discovery: A Chapter in the Sociology of Sci

ence.” American Sociological Review. 22.6. Dec 1957: 635-659.

“Mice studies offer some hope of expanding stem-cell research.” Philadelphia

News. 17 Oct. 2005.

Roger A. Pielke, Jr.; and Naomi Oreskes. “Consensus About Climate Change?” Science 13 May 2005 308: 952-954.

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BiDil and the Business of Race Vinay Shah Princeton University

Last June the FDA gave Nitromed, Inc. approval to produce and market BiDil for the treatment of heart failure in “self-identified black patients.” Notably, it is the first drug in the United States to be based on a patent for which the novelty is the observed benefit of the drug in a particular racial or ethnic group. It is also the first drug approved by the FDA for use only in a racially specified patient group. According to a controversial paper published by BiDil proponents Jay Cohn and Peter Carson, the drug is generally more effective in treating AfricanAmericans than Caucasian patients. Much of the discussion surrounding the drug has revolved around whether BiDil truly has clinically significant differential effects in African-American and European-American subgroups. But an aspect of the BiDil story that has received insufficient attention is the precedent that was set in procuring patent protection and regulatory approval for the drug. By imprecisely and incompletely discussing race in order to gain intellectual property rights which could not otherwise have been obtained, BiDil’s sponsors have outlined a dubious new method by which pharmaceutical companies can gain commercial advantage.

Most Americans are well aware of the fact that the selling of pharmaceuticals is a lucrative industry. Especially after the FDA lifted the ban on radio and television promotion of prescription drugs in 1997, drug company advertising budgets have increased considerably in recent years as ads for medicines like Claritin® and Viagra® dominate the airwaves. But the considerable impact of commercial considerations on the research and development required in moving a drug from the laboratory to everyday clinical settings is less obvious. The history of a controversial new heart drug named BiDil exemplifies this point. Last June the FDA gave Nitromed, Inc. approval to produce and market BiDil for the treatment of heart failure in “self-identified black patients.” Physicians around the country began prescribing BiDil shortly thereafter. Notably, it is the first drug in the United States to be based on a patent for which the novelty is the observed benefit of the drug in a particular racial or ethnic group. It is also the first drug approved by the FDA for use only in a racially specified patient group. According to a controversial paper

United States. FDA. FDA Approves BiDil Heart Failure Drug for Black Patients. 23 June 2005. 14 Apr. 2006 <http://www.fda.gov/bbs/topics/NEWS/2005/\ NEW01190.html>.

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published by BiDil proponents Jay Cohn and Peter Carson, the drug is generally more effective in treating African-Americans than Caucasian patients.

Much of the discussion surrounding the drug has revolved around whether BiDil truly has clinically significant differential effects in AfricanAmerican and European-American subgroups. BiDil also figures prominently within a larger debate about the merits and dangers of using race as a surrogate marker in order to uncover underlying genetic differences between individuals. But an aspect of the BiDil story that has received insufficient attention is the precedent that was set in procuring patent protection and regulatory approval for the drug. By imprecisely and incompletely discussing race in order to gain intellectual property rights which could not otherwise have been obtained, BiDil’s sponsors have outlined a dubious new method by which pharmaceutical companies can gain commercial advantage.

To understand how and why BiDil was cast as a “racial” drug, it is instructive to review its history. In the early 1980s, a pair of clinical trials conducted by the Veterans Administration was the source of a new method to treat heart failure. The trials included significant numbers of both African American and Caucasian patients. In the Vasodilator Heart Failure Trial (V-HeFT I) it was established that a combination therapy of generic drugs hydralazine and isosorbide dinitrate (then administered as two separate pills) had at least some positive effect in treating heart failure . When used together the combination of drugs was referred to as H/I. Jay Cohn, the University of Minnesota cardiologist who headed V-HeFT I, applied for a patent for the novel “method” of treating heart failure with H/I in 1987, and was issued it by the United States Patent and Trademark Office (USPTO) in 1989 . Importantly, any mention of race was absent from the patent application. Presumably, H/I could be an effective therapy for heart failure in patients of all races. With the methods patent, which is set to expire in 2007, the holder had the exclusive right to market the H/I therapy for the specific use of treating heart failure. Soon thereafter, the two generics

Carson, Peter, Susan Ziesche, Gary Johnson, and Jay N. Cohn. “Racial Differences in Response to Therapy for Heart Failure: Analysis of the Vasodilator Heart Failure Trials.” Journal of Cardiac Failiure 5 (1999): 178-187.

Cohn, J N., D G. Archibald, S Ziesche, J A. Franciosa, W E. Harston, F E. Tristani, W B. Dunkman, W Jacobs, G S. Francis, K H. Flohr, S Goldman, F R. Cobb, P M. Shah, R Saunders, R D. Fletcher, H S. Loeb, V C. Hughes, and B Baker. “Effect of Vasodilator Therapy on Mortality in Chronic Congestive Heart Failure: Results of a Veterans Administration Cooperative Study (V-HeFT).” New England Journal of Medicine (1986): 1547-1552.

Cohn, Jay N. United States. United States Patent Office. US Patent # 4,868,179 Method of Reducing Mortality Associated with Congestive Heart Failure Using Hydra zine and Isosorbide Dinitrate.

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which comprised the H/I therapy were combined into a single pill called BiDil®.

It was only with the combination of hydralazine and isorbidide dinitrate into the single dose BiDil® that the drug gained significant commercial prospects. Since BiDil is a physically combined form of two generics, rather than a novel chemical compound, Cohn could not obtain a “combination of matter” patent for the drug. Thus, generic manufacturers are still free to sell hydralazine and isosorbide dinitrate individually as long as they do not physically combine the two or market them together as a therapy for heart failure.

But since it has been established in the medical literature that less complicated medicine regimens lead to improved patient compliance , it seemed logical that many doctors would rather prescribe single-pill BiDil than multiple generics. As Cohn himself remarked, “the BiDil® formulation represents a very convenient dosage form that…should lead to increased usage of this effective therapy.”

But before BiDil could be sold or marketed as a therapy for heart failure, it would have to be approved by the FDA, a test which would prove difficult to pass. The FDA would have to acknowledge that the single pill combined form was a safe and widely effective therapy for heart failure. The intellectual property rights for BiDil were transferred from Cohn to a pharmaceutical firm called Medco, which did the requisite testing in order to prepare a New Drug Application (NDA) to submit to the FDA. Medco’s NDA for BiDil, which made no mention of race, was rejected by the FDA in 1997. The FDA panel did not deny that BiDil was at least somewhat effective. The main reason that they did not approve BiDil was that the percentage of patients who benefited from the drug fell short of statistically significant level required by the FDA for new drug approval.

With the rejection of the NDA, Medco did not pursue any further opportunities with BiDil, and the intellectual property rights for the drug reverted to Cohn.

It was not until after the rejection of the NDA that race became relevant to BiDil’s development as Cohn reviewed his data one more time and the “racialization” of BiDil began. During the discussions regarding the 1997 NDA for BiDil, Cohn had remarked that “we have much data comparing the Caucasian and African-American responses [to BiDil].” In 1999, Cohn, Carson and two

Connor, J, N Rafter, and A Rodgers. “Do Fixed-Dose Combination Pills or Unit-of-Use Packaging Improve Adherence? A Systematic Review.” Bulletin of the World Health Organization (2004): 935-939.

Medco Finds BiDil Bioequivalent and Re-Acquires Rights From BoehringerManheim Pharmaceuticals Plans to Submit NDA. PR Newswire, 1996.

United States. Center for Drug Evaluation and Research, Cardiovascualr and Renal Drugs Advisory Committee. FDA. Minutes From the 80th Meeting of the Food & Drug Administration. Feb. 27-28, 1997.

Ibid.

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other researchers published the aforementioned Racial Differences in Response to Therapy for Heart Failure: Analysis of the Vasodilator Heart Failure Trails.

The paper was based on a retrospective analysis of data from V-HeFT I and II which compared responses to therapy for heart failure in white and black populations. The finding that was most heavily emphasized was that the mortality rate in the black patient population treated with H/I was significantly lower than the mortality rate in the white patient population treated with the same therapy.

Later that same year, Cohn and Carson used these findings to apply for a patent which was strikingly incomplete in its discussion of race. The second BiDil-related patent, granted in 2000, was a methods patent for the method of using H/I to treat heart failure “in an African-American patient”.10 The grounds for the patent were as follows: “The unexpected finding of the present invention is that blacks responded more favorably than whites to the combination of at least one hydralazine compound and either isosorbide dinitrate or isosorbide mononitrate.” 11 The phrase “more favorably” is purposely vague. Traditionally, there are a number of criteria considered in assessing pharmacological response. Whether or not overall response to a drug is called “favorable” or not depends on a composite of factors, including mortality rate, hospitalization rate, and physiological response. While the overall mortality rate in the black patient group was lower than that observed in the white patient group, other measures of pharmacological response were similar in black and white patient groups. For example, decreases in the rate of hospitalization as well as increases in exercise tolerance were similar in both the white and black populations.12 But this was not the only important subtlety that was omitted. Significantly, nowhere in the document was it made clear that patient responses to BiDil, at least by the

Carson, Peter, Susan Ziesche, Gary Johnson, and Jay N. Cohn. “Racial Differences in Response to Therapy for Heart Failure: Analysis of the Vasodilator Heart Failure Trials.” Journal of Cardiac Failiure 5 (1999): 178-187.

10 Carson, Peter, and Jay N. Cohn. United States. United States Patent Office. U.S Patent # 6,465,463. Methods of Treating and Preventing Congestive Heart Failure with Hydralazine Compounds and Isosorbide Dinitrate or Isosorbide Mononitrate. Unite States Patent Office.

11 Ibid.

12 Carson, Peter, Susan Ziesche, Gary Johnson, and Jay N. Cohn. “Racial Differences in Response to Therapy for Heart Failure: Analysis of the Vasodilator Heart Failure Trials.” Journal of Cardiac Failiure 5 (1999): 178-187.

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measure of mortality, were correlated with but not necessarily caused by race.

If Cohn and Carson had been thorough and explicit in their discussion of race they wouldn’t have been able to successfully acquire the new, racespecific, patent protection. Under US patent law, a patent can be granted on either any entirely new innovation, or “any new and useful improvement” on an “existing process, machine, manufacture, composition of matter, or material.” 13 Cohn and Carson were granted the 2000 patent because the USPTO believed that using H/I to treat heart failure “in an African-American patient” constituted a “non-obvious” extension of the method described in the non-race-specific 1987 patent.14 If Cohn and Carson or their lawyers had been forced to make the patent scientifically precise, it would have read quite differently. Since differential response to the H/I combination was correlated with but not necessarily caused by race, the only completely accurate statement that could have been made with regard to response to the drug would be a tautology: that BiDil worked in individuals who seemed to respond to it best. However, the USPTO would not have been likely to grant a patent for a method of using H/I to treat heart failure “in a patient who responded to it best.” Such phraseology would have made it seem ridiculous to assert that a “non-obvious” extension of the previous concept had been discovered. Indeed, it seems like common sense to state that a drug should be given to those who respond best to it. But the identification of a particular racial group made the patent claim credible. A precise document would have noted the mortality rate in blacks treated with H/I was significantly lower than the mortality rate in whites given the same therapy and that mortality rate is an important measure of pharmacological response. But using mortality as a catch-all for response produced a much more convincing patent claim because it made the racially correlated difference seem more substantial.

A new race-specific patent was necessary in order to secure corporate support for further research and the eventual commercialization of BiDil. Near the end of their 1999 paper, Cohn and Carson remarked that “prospective trials involving large numbers of black patients are needed to further clarify their response to therapy”. 15 As is the case with any pharmaceutical, the process of developing, testing, and bringing BiDil to market was vastly expensive and 13 United States. United States Patent Office. United States Patent Code. 2006.

14 Carson, Peter, and Jay N. Cohn. United States. United States Patent Office. U.S Patent # 6,465,463. Methods of Treating and Preventing Congestive Heart Failure with Hydralazine Compounds and Isosorbide Dinitrate or Isosorbide Mononitrate. United States Patent Office.

15 Carson, Peter, Susan Ziesche, Gary Johnson, and Jay N. Cohn. “Racial Differences in Response to Therapy for Heart Failure: Analysis of the Vasodilator Heart Failure Trials.” Journal of Cardiac Failiure 5 (1999): 178-187.

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time consuming. For example, Nitromed raised $31.4 million to help finance A-HeFt, the clinical trial which was conducted with the goal of obtaining FDA approval for BiDil.16 And even though it was ended early, it still lasted 18 months.17 Thus, for a firm to justify committing the resources required to support such a process, it needs a strong economic incentive. This comes in the form of patent protection, which in the United States gives the patent holder monopoly rights over a certain device, method, process or composition of matter for a period of 20 years from the date on which a patent is filed with the USPTO.18 In the pharmaceutical industry, a firm must have both patent protection and regulatory approval from the FDA in order to possess exclusive rights to produce and/or market a certain drug for a specific purpose. Once these rights are secured the firm is almost assured some profit since it is the sole occupant of a unique market niche. Since the non-race-specific approach did not result in regulatory approval, a new patent was practically a prerequisite in order to obtain the capital needed to finance BiDilâ&#x20AC;&#x2122;s development.

It seems like common sense to state that a drug should be given to those who respond to it. But the identification of a particular racial group made the patent claim credible.

A race-specific patent also extended the duration of the drugâ&#x20AC;&#x2122;s patent protection, thereby increasing the potential for profit. The 1987 patent on using the H/I combination to treat heart failure in all patients gave the holder the exclusive right to market the H/I combination for the specific use of treating heart failure until 2007. By 1999 only 8 years of exclusivity remained.

As BiDilâ&#x20AC;&#x2122;s proponents already knew, a second attempt at gaining regulatory approval from the FDA was likely to be both lengthy and unpredictable. Indeed, it was wholly possible that the 1987 patent would expire before BiDil received FDA approval. The race-specific patent issued in 2000 gave Nitromed the exclusive right to market BiDil as a therapy for heart failure in AfricanAmerican patients until 2020. The additional 13 years of patent protection increased the value of the intellectual property rights to BiDil significantly.

16 Nitromed Press Release June 14, 2001. NitroMed Completes $31.4 Million Private Financing. Nitromed, Inc. 17 Nitromed Press Release November 8, 2004. First Heart Failure Study in African Americans Shows 43 Percent Improvement in Survival. Nitromed, Inc. Nitromed, Inc. 18 United States. United States Patent Office. United States Patent Code 2006.

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Cohn and Carson’s decision to retrospectively examine and highlight racial differences in response to BiDil was validated by the licensing of their 1999 patent to Boston-based biotech firm Nitromed Inc.; under the company’s careful guidance, the race-specific patent was successfully parlayed into racespecific regulatory approval. The lucrative new potential of BiDil allowed Nitromed to acquire $ 31.4 million in venture capital financing (Nitromed Press Release June 14, 2001), this in the middle of the 2001 recession, in order to fund the clinical trials which would be required to prepare a new NDA for FDA approval for BiDil. In March 2001, following discussions with the FDA, Nitromed received a conditional “approvability” letter from the FDA which stated that it was likely to grant race-specific approval for the drug.

19 But in order for this endorsement to be granted, the FDA told Nitromed that it would have to successfully complete a trial involving a large number of African-American subjects which conclusively showed the benefits of BiDil in this subgroup. In response, Nitromed initiated the African-American Heart Failure Trial (A-HeFT), which enrolled 1,050 African-American subjects20 but no white patients. In 2004, the spectacular success of the trial, which reported a 43 % improvement in survival and a 33 % reduction in first-time hospitalization for heart failure, led an independent safety and data-monitoring board to recommend its suspension on ethical grounds (Nitromed Press Release November 8, 2004). In June of 2005, BiDil was approved by the FDA for the treatment of heart failure in “self-identified African American” patients.21 Just as in the patent process, the drug’s sponsors made a tortured effort to emphasize the racial differences in response to BiDil in order to gain regulatory approval and commercial advantage. The paradox of a more specific “racial” mandate being more profitable than a broader one remained applicable.

If race-specific approval was granted then the 2000 patent would apply, meaning that Nitromed would have exclusive rights over BiDil until 2020. But if the FDA decided that BiDil could be efficacious for patients of all races, then the 1987 patent would apply and Nitromed’s exclusivity rights would only apply until 2007.

A-HeFT was clearly a trial designed with the sole intention of securing racespecific approval from the FDA. If Nitromed was truly interested in showing 19 Nitromed Press Release March 8, 2001. NitroMed Receives FDA Letter on BiDil® NDA, A. Nitromed, Inc. 2001.

20 Nitromed Press Release November 8, 2004. First Heart Failure Study in African Americans Shows 43 Percent Improvement in Survival. Nitromed, Inc. Nitromed, Inc. 21 United States. FDA. FDA Approves BiDil Heart Failure Drug for Black Patients. 23 June 2005. 14 Apr. 2006 <http://www.fda.gov/bbs/topics/NEWS/2005/ NEW01190.html>.

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that BiDil was more effective in blacks than in whites, they would have enrolled white patients in their study as a control and compared patient outcomes. But such a study may not have resulted in race-specific approval as it may have shown that BiDil’s benefits were not entirely race-specific. And without knowledge of any underlying pharmacogenetic markers that Nitromed researchers hypothesized would explain differential responses to the drug in different individuals, it would have been impossible for the company to select a mixed-race group of individuals who would have generally responded well to the drug. Indeed, at that point in time it was still unknown whether the differential response to BiDil was genetically based at all. After all, the drug’s differential efficacy in different populations could have been due to its alleviation of biological problems caused by social rather than genetic factors. Thus, the odds of producing the sort of conclusive data required for FDA approval were much greater if the trial was conducted with a randomly selected group of African-American patients rather than a randomly selected mix of African-American and white patients.

Predictably, now that Nitromed has secured patent protection and regulatory approval for BiDil, it seems to be seeking to broaden the market for its product. In recent months, supporters of the drug have stated that they hope BiDil is prescribed to anyone who may benefit from it, irrespective of race.22 Nitromed’s Chief Medical Officer Manuel Worcel has said, “I believe that a subset of non-African-Americans, whites, Asians, whomever, do respond to BiDil”. 23 However, this opinion is conspicuously absent from the language of BiDil’s patent, the FDA’s approval, and the label that will be seen by millions of doctors and patients. While such comments were not forthcoming in previous years, it now seems likely that though Nitromed is only technically allowed to market its drug to African-Americans, it will tacitly encourage so-called “off-label” prescription to non-blacks. Interestingly, Nitromed has recently produced timely evidence that strongly corroborates Worcel’s claim. Last month the company announced that its researchers seem to have determined which specific genotypic variations are correlated with a positive response to BiDil.24 Unsurprisingly, these variations aren’t exclusive to black patients.25 22 “Study: Heart Failure Drug Helps Black Patients.” Reuters 8 Nov. 2004. 12 Apr. 2006 <www.msnbc.msn.com/id/6435861>.

23 Davies, Kevin. “FDA Approves First “Ethnic Medicine”” Bio-IT World 24 June 2005. 15 Apr. 2006 <http://www.bio-itworld.com/newsitems/2005/06-05/06-24-05-newsbidil>.

24 Nitromed Press Release March 13, 2006. Researchers Identify Gene Variations That May Determine Which Heart Failure Patients are Likely to Benefit From Treatment with BiDil. Nitromed, Inc. 25 Ibid.

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The narrative of how BiDil came to be a “racial” drug is at once fascinating and disturbing. It is certainly a cautionary tale that speaks volumes about the influence of commercial considerations on research and development in the pharmaceutical industry. But what is unique to the BiDil story is the strategic use of race. The message currently conveyed by the language of Nitromed’s patent, the FDA’s approval, and BiDil’s label is that it is somehow an “African-American” drug. Indeed, Cohn and Nitromed had to take this race-specific approach in securing patent protection and regulatory approval for BiDil. But unless the relevance of racial variables in determining BiDil’s efficacy is more thoroughly examined and communicated, there is a distinct possibility that the drug will not be prescribed to many non-African-American patients who may potentially benefit from it. Furthermore, unless we seriously reform patent and approval guidelines so as to require a complete and precise discussion of the relevance of race in clinical findings, the BiDil story will have industry-wide consequences as other firms may be encouraged to mimic this commercial approach. At present, at least 29 medications have been identified in the medical literature as having differential effects in safety or efficacy in different populations.26 Though such claims are generally accompanied by controversy, now that a race-specific business strategy has been validated by the USPTO and the FDA, manufacturers of these drugs may very well seek to obtain race-specific patents and approval for their products. Pharmaceutical giant AstraZeneca has already been prompted to initiate new trials to assess Crestor’s efficacy in lowering cholesterol in Hispanic, African-American, and South Asian populations.27 Irrespective of the role of race in biomedical research, it has clearly begun to impact commercial strategy in the pharmaceutical industry. Further studies of this phenomenon are needed in order to revise relevant policy guidelines so as to account for this change.

Works Cited Carson, Peter, and Jay N. Cohn. United States. United States Patent Office.

U.S Patent # 6,465,463. Methods of Treating and Preventing Congestive Heart Failure with Hydralazine Compounds and Isosorbide Dinitrate or Isosorbide Mononitrate. United States Patent Office.

Carson, Peter, Susan Ziesche, Gary Johnson, and Jay N. Cohn. “Racial Differences in Response to Therapy for Heart Failure: Analysis of 26 Tate, Sarah K., and David B. Goldstein. “Will Tomorrow’s Medicines Work for Everyone?” Nature Genetics (2004): 34-42.

27 McCain, Jack. “Does Race Have a Place in Biotechnological Research?” Biotechnology Healthcare Dec. 2005: 54-62.

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the Vasodilator Heart Failure Trials.” Journal of Cardiac Failiure 5 (1999): 178-187.

Cohn, Jay N. United States. United States Patent Office. US Patent # 4,868,179. Method of Reducing Mortality Associated with Congestive Heart Failure Using Hydralazine and Isosorbide Dinitrate.

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The Princeton Journal of Bioethics Call For Papers Spring 2007 Issue

The Bioethics Forum of Princeton University requests submissions from undergraduate students for the Spring 2007 Princeton Journal of Bioethics. We encourage contributions to the national, undergraduate journal on any topic in Bioethics. Submissions in WORD format ONLY are due on or before 31 December 2006 to the address listed below. Please include two hard copies, a copy on a PC disk, and relevant contact information.

General Guidelines and Requirements

• Maximum of 3000 words, approximately 10-15 pages.

• Fully parenthetically referenced, following MLA

guidelines; please number references.

• Include name, year, academic institution, and email

or postal address.

• A clear, well-developed argument, from any discipline

relevant to Bioethics.

• Include a 100 word abstract and a 50 word biography.

Additional guidelines are available at our website (http://www. princeton.edu/~pjb). In addition to essays, we will also accept reviews of books dealing with issues in Bioethics, as well as shorter opinion pieces.

How to contact us:

E-mail Address: pjb@princeton.edu

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Vol. VI,I Spring 2004

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