Perspectives On Medical Research

Volume 5, 1995

Aping Science

A Critical Analysis of Research at the Yerkes
Regional Primate Research Center

Introduction

The Committee on Animal Models in Biomedical Research has attempted to determine what role animal models in general, and nonhuman primates in particular, play in medical discovery. Today, much of the United States' biomedical research enterprise aims to create and study animal models of human conditions. While leading science bureaucrats and scientific societies assert that animal models are integral to biomedical discovery,^1-3 critics of animal models point to their inherent limitations^4,5 and their frequently misleading results.^6-9

A model is, ideally, analogous to the system one wishes to understand.¹⁰ The value of a particular model depends, first, on the question it aims to address. To investigate basic principles of cellular function, such as the genetic code or the Krebs cycle, it would appear that cells derived from any animal would suffice. When looking at specific enzymatic activities, however, inter-species differences begin to undermine any valid extrapolation. When trying to assess organ and whole-body effects of various stimuli (such as infectious organisms, drugs, or physical trauma), inter-species differences become even more problematic for animal modelers. It may be that no animal-model system can reliably elucidate such issues for humans. In determining how an individual human responds to a particular stimulus, even other humans may not constitute adequate "models." Clinicians must often adjust medication regimens in consideration of each patient's unique physiology.

Animal-model conditions can never exactly mimic human ones; they only share certain characteristics. Yet, despite their inherent limitations, they are commonly used to investigate human physiology or pathology. While similarities do exist among many species, each has unique tissues and organ systems. Organ subsystems interact, and one organ subsystem difference between a "laboratory"-animal and humans necessarily affects others. Consequently, a stimulus applied to an animal model perturbs physiological functions in ways that cannot be predicted or fully understood, which severely undermine extrapolation of animal data to humans. Animal models of human conditions tend to provide only obvious and general information, such as "cancers kill."³ In order for an animal model to provide specific and reliable information, it must be identical to the human condition being modelled.

What role, if any, can animal models play in medical discovery? The answer to this question requires understanding the process of medical discovery.^11,12 First, scientists develop an hypothesis to explain observed phenomena. Oftentimes, an anomalous, unexpected observation forces a modification of existing theories and inspires creative thinkers to generate new hypotheses.^13,14 This can occur in a variety of ways, including clinical observation, in vitro techniques, and animal experiments. However, many of the "anomalies" observed in animal experiments merely reflect unnatural and artificial laboratory "disease" induction or effects of a stressful laboratory environment on animals.^8,15,16 Such anomalies are irrelevant to human anatomy, physiology, or pathology, and "testing" hypotheses derived from these anomalies wastes considerable time, energy, and animal lives. Only human clinical investigation is inherently reliable in that naturally occurring anomalies represent human phenomena. While animal experiments occasionally do inspire useful hypotheses about humans, they are neither an efficient nor reliable means of doing so. Indeed, many historians have found that, in many areas of inquiry regarding human physiology and pathology, anomalies first observed in human patients have been the principal sources of hypotheses.^17-22

Another element in the discovery process involves testing the hypothesis, often through experimentation. However, again, it makes no logical sense to test a theory about humans using an analogous system (nonhumans). While they may be dramatic, animal models can neither validate nor refute any hypothesis about humans. Nevertheless when scientists debate the validity of competing theories, they often cite animal studies as "evidence." In this context, animal models serve primarily as dramatic, rhetorical devices.

Animal-model data often appear compelling to scientists because the laboratory environment is "controlled." By controlling every variable except that being studied, scientists believe, they can ascertain the effect of that one variable on the entire system. However, the control is largely illusory. First, one cannot control for the inter-species differences in anatomy and physiology. This difficulty is compounded by the inherent complexity of biological systems, because all subsystems interact in ways that cannot be predicted or even fully understood.^4,5 Second, animal-experimental conditions are generally artificially induced--not parallelling human conditions--and one cannot control for these inherent differences in etiology and pathogenesis.²³ Third, unnatural laboratory environments cause animal stress, which alters important system-wide variables such as blood pressure and corticosteroid levels.²⁴ These stress-induced variables do not parallel human conditions and cannot be controlled. For these reasons, animal data cannot be reliably extrapolated to humans. Researchers may generate data valid for nonhuman animals studied in an artificial laboratory environment, but these data cannot be applied confidently to naturally occurring conditions in wild animals, let alone to humans.

Nevertheless, animal experiments are dramatic, which serves to convince the general public and funding bodies to continue its financial support. For example, Bertha Madras of the New England Regional Primate Research Center declared in the 1990 Congressional appropriations hearings, "The course of AIDS in primates is virtually identical to that of humans."²⁵ However, as discussed later in this report, there are fundamental differences between AIDS in humans and other primates. Animal experiments purporting to address prevention or treatment of AIDS cannot answer such questions for humans; at best, they can merely dramatize general theories of AIDS prevention or treatment.

The numerous species available to researchers, together with the nearly infinite possibilities for experimental manipulations, allow nearly any theory to be grippingly dramatized with animal models. For example, in 1989, Tulane University primate researchers immunized monkeys against a monkey virus that remotely resembled HIV, maintaining that this provided "unambiguous proof that a vaccine for AIDS is possible.²⁵ In truth, however, studying a vaccine that immunizes monkeys against a virus different from HIV can neither validate nor disprove the hypothesis that a human AIDS vaccine is possible. The development of an AIDS vaccine has been frustrated by the ability of HIV to undergo spontaneous genetic transformation. The Tulane researchers avoided this problem by preparing the vaccine and infecting the monkeys with the same single strain of virus, thereby skirting the central issue of genetic transformation.

Animal researchers often defend animal models on the grounds that "humans are animals." It would seem to follow, therefore, that nonhuman primate research would apply most to humans since humans are primates. Defenders of the regional primate research centers frequently argue that the "evolutionary closeness" of nonhuman primates to humans justifies these expensive facilities. This contention can be tested by determining if representative nonhuman primate research from a primate center has had significant clinical impact. Have nonhuman primate studies been useful in generating new hypotheses, or have they served mainly as rhetorical devices? If animal modelling is indeed an efficient and reliable means of biomedical discovery, then nonhuman primate research should be responsible for many clinical advances.

To address this issue, the Committee on Animal Models in Biomedical Research examined the Yerkes Regional Primate Research Center, an affiliate of Emory University in Atlanta, Georgia. Yerkes, the oldest primate center, receives about $13 million per year in federal funding²⁷ and houses over 3000 primates, over 200 of which are chimpanzees.²⁸ Of the seven regional primate research centers, Yerkes is the only one that performs experiments on great apes, which are genetically the closest relatives to humans. Yerkes should be a leader in biomedical discovery, if the 'evolutionary closeness" argument is valid.

This report first reviews the historical role of nonhuman primate research. it then assesses the value to humans of specific nonhuman primate research projects at Yerkes. Next, it considers the risks of nonhuman research. A risk-benefit assessment concludes the report, with proposals for research approaches most relevant to future public health needs.

1. Bernard C. An Introduction to the Study of Experimental Medicine. Paris, Henry Schuman, 1949.

2. American Medical Association. Use of Animals in Biomedical Research: The Challenge and Response [White Paper]. Chicago, AMA, 1988.

3. Stanford Committee on Ethics. Animal research at Stanford University: Principles, policies, and practices. New England Journal of Medicine 1988;318: 1630-1632.

3a. Gay WI (ed). Health Benefits of Animal Research. Washington DC, Foundation for Biomedical Research, 1986.

4. LaFollette H, Shanks N. Animal models in biomedical research: Some epistemological worries. Public Affairs Quarterly 1992;7(2): 113-130.

5. LaFollette H, Shanks N. Brute Science, in press.

6. Peller S. Quantitative Research in Human Biology and Medicine. Bristol, John Wright & Sons, 1981.

7. Rowan AN. Of Mice, Models, & Men: A Critical Evaluation of Animal Research. Albany, SUNY Press, 1984.

8. Wiebers DO, Adams HP, Whisnant JP. Animal models of stroke: Are they relevant to human disease? Stroke 1990;21:1-3.

9. Kaufman SR. Does vivisection pass the utilitarian test? Public Affairs Quarterly, 1995;9: 127-137.

10. Hull D. Philosophy of Biological Science. Englewood Cliffs, NJ, Prentice-Hall, 1974.

11. Kuhn T. The Structure of Scientifc Revolutions. Chicago, University of Chicago Press, 1969.

12. Poppa K. The Logic of Scientific Discovery. New York, Basic, 1959.

13. Humphreys W. Anomalies and Scientific Theories. San Francisco, WH Freeman, 1968.

14. McQuarrie I. The Experiments of Nature and Other Essays from the Porter Lectures. Lawrence, Kansas, University of Kansas Press, 1944.

15. Cohen SM, Ellwein LB. Cell proliferation in carcinogenesis. Science, 1990;249: 1007-1011.

16. Freedman DA, Zeisel H. From mouse to man: The quantitative assessment of cancer risks. Statistical Science 1988;3:3-28.

17. Good BA. Runestones in immunology. Journal of Immunology 1976; 117: 14 13-1428.

18. Good BA. Keystones. Journal of Clinical Investigation 1968;47: 1466-1471.

19. Beeson PB. The growth of knowledge about a disease: hepatitis. American Journal of Medicine 1979:67;366-370.

20. Reines BP. On the locus of medical discovery. The Journal of Medicine and Philosophy 1991;16: 183-209.

21. Reines BP. On the role of clinical anomaly in Harvey's discovery of the mechanism of the pulse. Perspectives in Biology and Medicine 1990;34: 128-133.

22.Cohen MJ, Young C. Alcoholic Rats and other Alcohol Research Using Animals. New York, National Research Information Center, 1989.

23. Medical Research Modernization Committee. A Critical Look at Animal Experimentation. New York, MRMC, 1995.

24. Barnard N, Hou S. Inherent stress--the tough life in lab routine. Lab Animal 1988; 17(6):21-27.

25. Madras BK. Testimony presented to the U.S. Congress, House of Representatives: Appropriations Subcommittee on Labor, Health and Human Services, Education and Related Agencies. Washington DC, US Government Printing Office, 1990, pp 1481-1489.

26. Hilts PJ. Tests of a vaccine in monkeys offer new hope in AIDS fight. New York Times Dec 8, 1989.

27. Annual Progress Report 1993. Yerkes Regional Primate Research Center, 1994.

28. Skolnick AA. Neuroscientist/psychiatrist takes helm at flagship primate research center. Journal of the AMA 1994;272:907-909.