special report » Utility and Morality: Contemporary Tradeoffs

Using Monkeys to Understand and Cure Parkinson Disease

Research with nonhuman primates is essential to medical progress and will still be necessary for the foreseeable future. Almost all research scientists agree that animal research is critical to understanding basic biology, discovering new treatments for human (and animal) diseases, and maximizing the safety of new medicines while minimizing their harm to humans. All but two of the Nobel prizes in medicine awarded over the last one hundred years have depended on animal research,[1] and the list of modern medicines, vaccines, and other treatments, as well as basic science discoveries, is so extensive that it could not be adequately covered in even a huge volume.[2] Increases in average life span in the last century are the result of improved public health measures, and many diseases may be related to lifestyle choices. But animal research has contributed to understanding these factors and to the development of vaccines and lifesaving treatments. The philosophical debate regarding the benefits and moral costs of animal research has also filled many volumes by ethicists and philosophers. The major arguments against the use of animals in medical research have been explicitly refuted by a few brave scientists,[3] as well as implicitly by the vast majority of the working biomedical science community.

My contribution to this discussion is to provide a personal perspective on my decision if, when, and how to use monkeys in research experiments on Parkinson disease. I do not claim to speak for all scientists. Many of them prefer not to speak on this issue because people with strongly held opposing beliefs have been willing to engage in distortion of the facts, violence, and intimidation as a way of advancing their views. Universal and unequivocal support for animal research is reflected in collective statements by all of the major medical and scientific organizations, which state, in summary, that the benefits to humans are worth the cost of some animals, as long as humane animal welfare guidelines are met.

I have great empathy and respect for animals, but I also accept the fact that the careful selection and use of animals in experiments to understand biology or to improve medicine is justified, even though this often represents a significant harm to them.

As a physician researcher, I have been working for many years to understand and cure Parkinson disease. I became a physician in order to cure, alleviate, and understand diseases and to “do good” if possible. As prescribed in the Hippocratic Oath, I also want to do “no harm.” In the real world of medicine, however, these categories are subject to probability—prescribing the right medicine to treat a disease sometimes leads to a harmful, even fatal, side effect, such as an allergic reaction, and harm is done. Balancing the risks and benefits is necessary to arrive at a reasonable course of action, and sharing the information with patients so that they can help decide what should be done is now the standard of medical practice. Similarly, sharing the risks and benefits of animal research with the general public is important for future patients (a group that will include nearly everyone at some point) to make an informed choice about the medicine of the future. I do research with monkeys to understand a serious, debilitating, and often fatal disease (a probable good) knowing that the use of some monkeys will certainly be harmful to them. But studies in monkeys will increase the probability of a benefit—as well as minimize the extent of harms from those treatments—to patients if and when the treatments are tested.

What are the criteria for conducting research on monkeys? There must be a potential scientific or medical benefit of the research, and useful knowledge from the monkey research should be likely and unobtainable from alternative approaches. Basic research to understand diseases is ultimately as important as research with specific treatment goals. Rodents and other mammals are excellent models of many physiological processes and diseases in humans, but the central nervous system and higher brain functions are sufficiently different that monkey experiments are often essential for progress with neuropsychiatric and brain-related problems. Parkinson disease represents a research problem for which monkey studies can be justified. It is a poorly understood and often fatal disease affecting millions of people worldwide for which there are only palliative treatments. We know that a small population of neurons in the brain that produce the neurotransmitter dopamine dies prematurely, leading to the signs and symptoms of the disease, which include resting tremor, slow movement, rigidity, postural instability, and other motor problems. L-Dopa, a drug that increases dopamine concentrations in critical brain areas, mitigates many of the motor problems, but unfortunately does not always control all the symptoms. The drug also has diminished effects over time and often causes unacceptable side effects, such as hallucinations or incapacitating, abnormal movements.

A number of models are useful to understand the disease and test potential therapies. They include cells in a culture dish, genetically modified fruit flies, and rats with dopamine systems destroyed by a neurotoxin to induce some signs of Parkinson disease. But each of these models has limitations and may not predict results in humans. The brain systems responsible for dopamine function that underlie Parkinson disease differ between rats and humans. The rat model responds consistently to some drugs that have effects against Parkinson disease in patients, but it also responds to other drugs that have no effect.[4] A different compound, MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), was tested in rats and was not found to have any deleterious effects, although when tested in patients, it made them worse. It was later discovered that MPTP actually destroys dopamine neurons in humans and monkeys and reproduces nearly every reported effect of Parkinson disease in monkeys.[5] Accidental exposures of humans to MPTP simulate Parkinson disease almost completely, confirming that monkeys exposed to MPTP are a reasonable model for studying the condition in humans.

Possibly better animal models are being developed as a result of new knowledge about several genes associated with Parkinson disease. At the present time, however, the monkey with MPTP-induced Parkinson disease is the best model we have and can predict benefits and side effects of new treatments. The species of monkey we use, Clorocebus sabaeus, is not endangered in the West Indies, and its closely related “parent” species, Chlorocebus aethiops, is widespread in Africa, with an estimated population in the millions.

Finally, there are considerable data supporting the main hypothesis of my work—that the dopamine neurons destroyed by Parkinson disease (or experimentally by a neurotoxin) could be replaced by neurons derived from fetal brain tissue, stem cells, or gene manipulations that would lead to therapeutic dopamine release and symptom relief.[6] We don’t know, however, whether the cells would survive, develop, and connect properly in an adult brain affected by Parkinson disease. It is necessary, therefore, to test potential therapies in an animal model that simulates the conditions of the disease as closely as possible.[7]

When should the research be done? The first steps in research with animals should begin with the simplest animals that are appropriate. There are economic—and, some would say, moral—reasons that experiments should progress with models up the phylogenetic scale where possible. Extensive neural tissue transplantation studies were first done in rodents, showing that cells survived. Monkeys should not be used without knowing the results from studies in simpler biological systems, although, as in the case of MPTP, rodent studies do not always predict what would happen in monkeys or humans.

For cell replacement therapy, using dopamine precursor cells derived from fetal brain tissue, stem cells, or from other adult cell sources such as skin, it is important that the potential treatment be well characterized. We should know what types of cells they are and what they become in culture, what genes and proteins they express, how neurons are activated electrophysiologically, and what neurotransmitters and other chemicals they release. Then they should be tested in the best Parkinson disease model to see if they survive a new environment, what cells they become, where they go, and if they relieve the signs and symptoms of the disease.

The fact that monkeys are genetically closer to humans than are rats increases the probability that predictions from monkey experiments will be correct. But this closeness also makes their use of greater concern. At some point after enough research has been done in monkeys, humans also have to be studied to find out the potential benefits and harms of the treatment. The fact that this is so does not diminish the importance of what is learned from the animal experiments. Far more harm would be done to humans if the animal experiments were not done first. When, exactly, enough preliminary research has been done to move to human trials is often a controversial point, and scientists tend to argue for more animal and safety studies.

How should the research be conducted? When animal use is necessary, it should be carried out humanely and with concern for the comfort, general health, and well-being of the animals by scientists and staff who are qualified and trained to do the work successfully. These concerns have been codified in the Animal Welfare Act and the Guide for the Care and Use of Animals in the United States and in similar documents in other countries. Scientists, physicians, and veterinarians drafted these regulations not only for the well-being of the animals, but because they are necessary to ensure that research with the animals is valid. Animals are provided with veterinary care, cages that are large enough for them to move about, adequate food and water, an environment free of pain and with minimal stress, and conditions that are as natural as possible for their species. Proper anesthetics are used for procedures that might cause pain, along with analgesics thereafter. At the end of experiments, animals often must be killed to harvest tissues such as brain specimens that provide critical outcome measurements. These “sacrifices” are done humanely, using the same drugs that a veterinarian uses to put cats and dogs to sleep. If there are exceptions to any of these guidelines, such as research on pain, or the withholding of palliative treatments, these must be justified scientifically. The study plan and procedures must be reviewed and approved by an independent committee of experts for each institution that is constituted and operates according to rules that eliminate conflict of interest to ensure that the plan is properly carried out and the animals are cared for.

The best experimental designs should be used, with random assignment of treatment groups, controls for as many variables as possible, and blinding of evaluations to eliminate investigator bias. The fewest animals should be used that are necessary to accept or reject the study hypothesis according to the method that modern science uses to make progress.[8]  The reality is that most experiments conducted in accordance with the scientific method could be described as failures, but this does not mean that they are without value. They rule out important negatives that lead to incremental knowledge and then, often after many years, to a successful new treatment. When new discoveries are made, they have to be replicated. That is not a “waste of animals” or duplication of effort, but how modern science works. Independent replication is how we confirm what is true. I have summarized the conditions for the use of monkeys in the table.

Moral and ethical issues. The morality and necessity of medical research with animals are linked with the ethics of human research and medical practice. The ethical prescriptions and proscriptions as outlined in the Declaration of Helsinki in 1964 (and modified through 2008)[9] require a number of practices, many of which have been codified into the laws of many countries and are regulated in the United States by the Food and Drug Administration. These guidelines prescribe that humans should not be exposed to unknown risks or to risks without potential benefits. This usually requires that substances and potential treatments be tested in animals for efficacy and safety. It is certainly true that animal research does not predict human responses perfectly. This depends upon how accurate the animal model is and how similar or identical the particular animal system used is to humans. So research on human subjects is also always necessary. It is often necessary to do new animal experiments after human clinical trials to improve understanding or resolve problems before arriving at the most successful therapy.

Could “alternatives” lead to the same or better results? Groups opposed to animal research often argue that computer models and other alternatives to animals could make animal experiments unnecessary. Alternatives to animal use are clearly desirable and researchers eagerly adopt them when they become available. But at this time we do not have good alternatives to replace the animal models in use.  A computer might be able to model a disease in some respects if we knew everything possible about it, and if the computer had all of the necessary capacities of an animal (the ability to move and to simulate the abnormal movement in Parkinson disease). But we do not have that knowledge, and to get it requires that we study animals.

 

Conditions for Using Monkeys for Biomedical Research

  1. The research should address a significant basic science or potential therapeutic question for humans or monkeys.
  2. Preliminary research should be done to support and justify the experimental approach proposed.
  3. Some research should have been done in nonprimate species to gather preliminary data and, if possible, to test the experimental design.
  4. There should be research findings to support differences between other potential animal models and monkeys or humans that would therefore support the study of monkeys and the inferiority of other animal models or alternatives to animals.
  5. The potential benefits of the research should be evaluated against the potential risks to the primate subjects.
  6. The species of monkeys used should be justified, and the use of endangered or threatened populations avoided without special justification.
  7. The number of monkeys used for the research should be justified and minimized.
  8. All animal welfare regulations should be followed, with special importance placed upon species-typical behaviors and environments unless exceptions are scientifically justified.

 

The drug industry and academic and government scientists are highly motivated for economic and ethical reasons to replace animal research if possible. Animals are expensive, experiments often take a long time, and the necessary sample of animals that must be studied is often not clear. Finally, the experiments often fail to predict the results in humans. New strategies are being adopted that are an improvement over animal experiments, such as gene arrays for toxicology studies (see “No Animals Harmed: Toward a Paradigm Shift in Toxicity Testing,” in this volume) or stem cells taken from humans with a disease to be studied in cell cultures (“disease in a dish”). None of these advances, however, resulted from targeted efforts to find “alternatives,” but from excellent basic science. Many of these alternatives depended upon animal experiments for their development or will depend on them for validation of results.

The suggestion by critics of animal research that scientists persist in animal experiments despite valid and viable alternatives is an ill-informed and intellectually and ethically insulting attack on the major scientific professional organizations, the National Institutes of Health, the Centers for Disease Control and Prevention, the U.S. Department of Agriculture, and most research universities and institutes. I do not know a single scientist who takes pleasure in inflicting pain or injury on animals. I, for one, have known and cared about all kinds of animals starting with my childhood experiences on my grandmother’s farm with cows, horses, sheep, pigs, chickens, and other domestic animals (that are often treated horribly with today’s industrialized farming conditions). I have been very attached to pet dogs and cats, and I had a monkey living in my house with my family for two years. I also have observed and interacted with numerous other animals in their native habitats and work for their conservation and protection. I have great empathy and respect for them, but I also accept the fact that the careful selection and use of animals in experiments to understand biology or to improve medicine is justified, even though this often represents a significant harm to them.

Moral status of animals. I do not accept the idea that all living creatures have equal moral status, but rather that they have graded value according to their genomic similarities with us. In this view, highly intelligent, sentient creatures such as great apes, monkeys, dolphins, whales, and elephants have relatively high moral status. We have responsibilities because of our intelligence and power to interact with all animals with kindness and compassion. We also have the responsibility to understand and cure disease in our own species and others if possible, while inflicting the least amount of harm to both humans and animals. Basic science and research for new treatments are both essential for this process. Research with monkeys aided in the development of deep brain stimulation,with benefits for some Parkinson disease patients so far, but we have more work to do for the cure.[10] If the use of monkeys leads to the cure of Parkinson disease for the 500,000 people in the United States (and millions more around the world), some of whom suffer, suffocate, and die each year, it is an acceptable moral price to pay. These are your parents, grandparents, brothers, sisters, and possibly yourself. And Parkinson disease is just one of many horrible and incurable diseases that remain to be conquered with the aid of research with animals, including monkeys.

 

D. Eugene Redmond, Jr., is professor of psychiatry and neurosurgery at the Yale University School of Medicine. He has published extensively on his team’s effort to cure Parkinson disease using cell replacements, beginning with fetal brain cells and more recently using stem cells in monkeys. His research interests are in restoring the damaged brain and spinal cord, using cellular replacements, and gene therapy. He has worked extensively with nonhuman primates on studies of anxiety, drug addiction, schizophrenia, cognition, Parkinson disease, spinal cord injury, and amyotrophic lateral sclerosis.

 

Footnotes    (↵ returns to text)
  1. 1. Foundation for Biomedical Research, http://www.fbresearch.org/TwoColumnWireframe.aspx?pageid=128, accessed September 30, 2012.
  2. 2. Ibid.
  3. 3. J.H. Comrow and R. Dripps, Jr., “Scientific Basis for Support of Biomedical Science,” Science 192 (1976): 105-111; P.M. Conn and J.V. Parker, “The Animal Research War,”  Federation of American Societies for Experimental Biology Journal 22, no. 5 (2008): 1294-95; N.E. Miller, “The Value of Behavioral Research on Animals,” American Psychologist 40, no. 4 (1985): 423-40; N.E. Miller, “The Morality and Humaneness of Animal Research on Stress and Pain,” Annals of the New York Academy of Sciences 467, (1986): 402-4; D.L. Ringach, “The Use of Nonhuman Animals in Biomedical Research,” American Journal of the Medical Sciences 342, no. 4 (2011): 305-313.
  4. 4. M.E. Emborg, “Nonhuman Primate Models of Parkinson’s Disease,” Institute for Laboratory Animal Research Journal 48, no. 4 (2007): 339-55; J.R. Taylor et al., “Behavioral Effects of MPTP Administration in the Vervet Monkey: A Primate Model of Parkinson’s Disease,” in Toxin-Induced Models of Neurological Disorders, A.J. Nonneman and M.L. Woodruff, eds. (New York: Plenum Press, 1994), 139-74.
  5. 5. Emborg, “Nonhuman Primate Models of Parkinson’s Disease,” 339-55.
  6. 6. A. Björklund and U. Stenevi, Neural Grafting in the Mammalian CNS (Amsterdam, the Netherlands: Elsevier Science Publishers, 1985); L.M. Björklund et al., “Embryonic Stem Cells Develop into Functional Dopaminergic Neurons after Transplantation in a Parkinson Rat Model,” Proceedings of the National Academy of Sciences U.S.A. 99, no. 4 (2002): 2344-49; D.L. Choi-Lundberg et al., “Dopaminergic Neurons Protected from Degeneration by GDNF Gene Therapy,” Science 275 (1997): 838-41; H. Lui et al., “Generation of Induced Pluripotent Stem Cells from Adult Rhesus Monkey Fibroblasts,” Cell Stem Cell 3, no. 6 (2008): 587-90; I. Mendez et al., “Dopamine Neurons Implanted into People with Parkinson’s Disease Survive without Pathology for 14 Years,” Nature Medicine 14, no. 5 (2008): 507-9; M.J. Perlow et al., “Brain Grafts Reduce Motor Abnormalities Produced by Destruction of Nigrostriatal Dopamine System,” Science 204 (1979): 643-53; D.E. Redmond, “Cellular Replacement Therapy for Parkinson’s Disease—Where Are We Today?” Neuroscientist 8, no. 5 (2002): 457-58; D.E. Redmond, Jr., et al., “Cryopreservation, Culture and Transplantation of Human Mesencephalic Tissue into Monkeys,” Science 242 (1988): 768-71; D.E Redmond, Jr., et al., “Behavioral Improvement in a Primate Parkinson’s Model Is Associated with Multiple Homeostatic Effects of Human Neural Stem Cells,” Proceedings of the National Academy of Sciences U.S.A. 104, no. 29 (2007): 12175-80;  E.Y. Snyder et al., “Multipotent Neural Precursors Can Differentiate toward Replacement of Neurons Undergoing Targeted Apoptotic Degeneration in Adult Mouse Neocortex,” Proceedings of the National Academy of Sciences U.S.A. 94, no. 21 (1997): 11663-68; M. Wernig et al., “Neurons Derived from Reprogrammed Fibroblasts Functionally Integrate into the Fetal Brain and Improve Symptoms of Rats with Parkinson’s Disease,” Proceedings of the National Academy of Sciences U.S.A. 105, no. 15 (2008): 5856-61.
  7. 7. Redmond, Jr., et al., “Behavioral Improvement in a Primate Parkinson’s Model Is Associated with Multiple Homeostatic Effects of Human Neural Stem Cells.”
  8. 8. Ringach, “The Use of Nonhuman Animals in Biomedical Research.”
  9. 9. World Medical Association Declaration of Helsinki—Ethical Principals for Medical Research Involving Human Subjects, October 2008, http://www.wma.net/en/30publications/10policies/b3/.
  10. 10. T. Wichmann et al., “Milestones in Research on the Pathophysiology of Parkinson’s Disease,” Movement Disorders Journal 26, no. 6 (2011): 1032-41; “Parkinson’s Patient Speaks Up,” http://www.youtube.com/watch?v=uMaCiuapAW0, uploaded April 29, 2010, and accessed September 30, 2012.