Human-nonhuman chimeras in embryonic stem cell research.

• Author: Munzer, Stephen R.

TABLE OF CONTENTS I. INTRODUCTION II. FOUNDATIONS: AN APPROACH TO MORALITY AND MORAL APPRAISAL III. MORALITY AND HUMAN-NONHUMAN CHIMERAS A. Six Cases B. A Proposed Moral Framework and Its Defense C. The Analysis of Cases D. Revisiting the Moral Framework IV. FROM ETHICS TO SOCIAL POLICY A. General Considerations B. Social Policy in Commission Reports V. CHIMERAS AND THE LAW A. Regulation B. Should Human-Nonhuman Chimeras Ever Be Patentable? VI. CONCLUSION I. INTRODUCTION

Myths of different cultures speak of creatures that combine species. In Greek mythology, we find the Chimera, a fire-breathing she-monster represented either as having a lion's head, a goat's body, and a serpent's tail, or as having a lion's body and head with a goat's head rising from the back. (1) The Chimera created havoc and inspired terror until Bellerophon slew it. (2)

The big "C" Chimera of lore has given way to the small "c" chimeras of laboratories. In contemporary scientific parlance, the term chimera applies to various entities that contain cells from two or more individuals of the same or different species. (3) Chimeras differ from transgenic plants and animals in that the latter have genes from two or more species. (4) Examples of chimeras include: (1) a cross between a male of one species and a female of another species; (5) (2) a fetus that results from the fusing of fraternal twins; (6) and (3) nonhuman animals that contain selected human cells, tissues, or organs. (7)

Creating and using the third type of chimera would have significant benefits. Human-nonhuman chimeras could, for example, be effective testing models for future therapies. The Food and Drug Administration ("FDA") requires that any new drug or therapy undergo extensive testing in animals before allowing human trials to commence. (8) Pharmaceutical companies spend a great deal of money conducting pre-clinical trials on each new drug. Still, the main reason drugs fail to be approved is that they are found to be unsafe or ineffective in human beings, even though they perform well in animal studies. (9) Thus, conventional animal models are often inadequate for testing pharmaceutical safety and effectiveness. Nonhuman animals that carry "humanized" organs or tissues are likely to demonstrate a more human response to new drugs and therapies than their unmodified brethren. (10) In addition to their use as testing models, chimeras potentially could be employed to "farm" human organs and tissues; those organs and tissues could then be transplanted into human beings. (11) Such organs and tissues are likely to have a lower risk of rejection than tissues or organs provided by an unrelated donor, particularly if they are grown using the patient's own stem cells. (12) Furthermore, human-nonhuman chimeras created using human embryonic stem cells ("hESCs") may prove useful in testing the pluripotency (13) of existing hESC lines, in overcoming immunological barriers to xenotransplantation, (14) and in preventing cross-species viral diseases. (15)

Many scientists believe that putting hESCs or their differentiated derivatives into an adult animal, if done at the right time, is unlikely to affect radically the resulting chimera's appearance or cognitive abilities, while still affording the opportunity for experimental control of the chimera and the chance to observe cellular behavior. (16) In fact, scientists can create human-nonhuman chimeras in many ways. For example, scientists can insert hESCs or their differentiated derivatives into enucleated animal ova, blastocysts, embryos, fetuses, or adults. (17) They can also reverse the order by inserting nonhuman embryonic stem cells ("ESCs") or their derivatives into human enucleated ova, blastocysts, embryos, fetuses, or adults. Some believe that, in such experiments, an animal embryo or fetus would be more likely than an adult animal to become "humanized"--that is, to become less like a nonhuman animal and more like a human being. (18) And some think that the earlier in gestation one introduces the human stem cells, the more humanized the animal is likely to become. (19) Yet because different animals have different gestation periods, it is hard to decide when is "too young" and when is "old enough." In part for these reasons, most stem cell researchers in the United States currently shy away from putting hESCs into animal blastocysts even though there is no legal prohibition against doing so. (20)

It requires little imagination or political attunement to see why the topic of human-nonhuman chimeras is hotly debated. First, such chimeras contain a mix of cells from human and nonhuman species, which some people regard as contrary to God's will, immoral, or at least imprudent. (21) Second, human-nonhuman chimeras are linked to the abiding controversy over hESC research. (22)

This Article has three main tasks: (1) devising a framework for thinking about human-nonhuman chimeras and using that framework to analyze cases that raise moral problems; (2) building on that framework to evaluate and shape social policy; and (3) employing the framework to assess existing law and a legislative proposals. The Article mainly addresses hESC-derived human-nonhuman chimeras, but the moral, social, and legal analysis developed here also applies for the most part to human-nonhuman chimeras created without using hESCs. To keep the inquiry manageable, I assume that hESCs in a laboratory dish have no moral status that makes it wrong to use them in research and that existing regulations on the use of animals in research are morally, socially, and legally justified. (23)

My primary thesis is that the moral, social, and legal concerns about human-nonhuman chimeras are so complicated that, though one can illuminate these concerns, one cannot categorize the creation of human-nonhuman chimera as either permissible or impermissible. It is simply beyond the current state of scientific knowledge and moral thinking to formulate a set of necessary and sufficient conditions that could be used for sorting all cases into morally permissible and morally impermissible categories, without leaving any cases undecided. One can, however, shed a great deal of light on these concerns. Specifically, it is possible to create a multi-element framework that contains some sufficient conditions for morally permissible chimeras, to illuminate many cases with the framework by identifying the relevant issues and resolving them, and to use other cases to suggest ways of improving the framework.

Furthermore, with regard to social policy, I argue that one commission report by the President's Council on Bioethics, Reproduction and Responsibility is unduly narrow in concentrating chiefly on human-nonhuman chimeras created by intervening at the stage of fertilization. (24) A later report prepared by a board acting on behalf of the Institute of Medicine makes sensible recommendations on chimeras created using hESCs. (25) Finally, I consider the legal issues surrounding chimeras and contend that Congress, FDA, and/or the United States Department of Agriculture ("USDA") should regulate hESC-derived human-nonhuman chimeras. No current federal statute or regulation addresses this matter. I argue that the bills proposed by Senator Sam Brownback (R-Kan.) are helpful in some respects, but are misguided in others and remain incomplete. (26) I suggest a different regulatory approach. I also argue that some human-nonhuman chimeras should be patentable.

The inquiry takes the following path. Part II explains my approach to morality and moral appraisal. Part III develops and defends a moral framework for analyzing human-nonhuman chimeras, applies that framework to six cases, and then revisits the framework to see whether the examination of particular cases gives any reasons for adjusting it. Part IV discusses social policy. It pays critical attention to the policies embedded in two major commission reports on chimeras and suggests how improvements could be made on those reports. Part V turns to chimeras and the law. It addresses the legal regulation and patentability of human-nonhuman chimeras. Part VI concludes the inquiry.

This Article, therefore, involves a mix of the concrete and the abstract. It combines moral theory as well as practical social and legal investigation. To launch this project, I begin by first laying the foundations of my approach to moral philosophy.

2. FOUNDATIONS: AN APPROACH TO MORALITY AND MORAL APPRAISAL

   There are many competing approaches to morality and moral appraisal, and I wish to state forthrightly how my approach compares with others. Moral philosophers often distinguish between consequentialist and nonconsequentialist approaches to morality. The former holds that the morality of actions should be judged by their consequences. Prominent among consequentialist approaches are various forms of utilitarianism. In utilitarianism, the supreme goal is the promotion of "utility," which is often defined as happiness, preference-satisfaction, or the balance of pleasure over pain. (27) In contrast, nonconsequentialist approaches to morality stress one or more principles that are generally either duty-based or right-based. Approaches relying on duty-based (deontological) principles are common. Noteworthy among them is Kant's moral philosophy with its categorical imperative: "Act in such a way that you always treat humanity, whether in your own person or in the person of any other, never simply as a means, but always at the same time as an end." (28) J.L. Mackie, in contrast, argues that morality is right-based or, more precisely, that we should invent a right-based morality. (29) Other contemporary nonconsequentialist theories include the theories of Charles Fried and Alan Gewirth. (30) There are, of course, mixed ("pluralist") approaches that contain either (1) both consequentialist and nonconsequentialist principles, (2) nonconsequentialist principles that can sometimes...