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The Ethics of Animal ResearchExploring the Controversy$

Jeremy R. Garrett

Print publication date: 2012

Print ISBN-13: 9780262017060

Published to MIT Press Scholarship Online: August 2013

DOI: 10.7551/mitpress/9780262017060.001.0001

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Ethical Issues Concerning Transgenic Animals in Biomedical Research

Ethical Issues Concerning Transgenic Animals in Biomedical Research

Chapter:
(p.169) 10 Ethical Issues Concerning Transgenic Animals in Biomedical Research
Source:
The Ethics of Animal Research
Author(s):

David B. Resnik

Publisher:
The MIT Press
DOI:10.7551/mitpress/9780262017060.003.0010

Abstract and Keywords

This chapter explores the scientific objection that we should curtail or stop using animals in research because animal species are often not good models for human physiology, pathology, toxicology, or behavior. It assumes that some types of animal research are permissible. It provides some recommendations for biomedical research. It addresses the three principles of human treatment of animals in research: replacement, reduction, and refinement. This chapter suggests that transgenic animals should experience no more pain or distress when used in research than normal animals experience when used in research.

Keywords:   animal research, animal species, biomedical research, human treatment, replacement, reduction, refinement, transgenic animals

Transgenic Animals and the Scientific Critique of Animal Research

There are two basic arguments against using nonhuman animals in biomedical research: a moral argument and a scientific one. According to the moral argument, we should not use animals in biomedical research because the value of the knowledge gained from animal experimentation does not justify the harm inflicted on animals (Singer 1990) or because animal have rights that are violated when we experiment upon them (Regan 1983). This chapter will not address the moral arguments against using animals in biomedical research, as these are addressed elsewhere in this book. Instead, I will assume that some types of animal research are permissible, including research that involves genetic engineering, provided that investigators take appropriate steps to minimize harm to animals (LaFollette and Shanks 1996).

According to the scientific argument, we should curtail or stop using animals in research because animal species are often not good models for human physiology, pathology, toxicology, or behavior. While animal experiments can sometimes yield important knowledge relevant to human well-being, the usefulness of such knowledge has been greatly exaggerated. Moreover, some results obtained from animal experiments can be misleading. At the very least, the usefulness of animal models in biomedicine should not be assumed without detailed empirical support (see LaFollette and Shanks 1996 and Nuffield Council on Bioethics 2005, for a review of moral and scientific arguments).

One of the ways of answering the scientific critique of using animals in biomedical research is to genetically engineer better animal models. In the 1970s, geneticists, cytologists, and microbiologists developed recombinant DNA techniques, which allowed them to delete or insert specific genes in bacteria. In the 1980s, these methods were extended to laboratory (p.170) animals. By the 1990s, biomedical scientists were able to modify the genomes of many different animal species, including rodents, cows, sheep, insects, fish, and primates. According to proponents of this approach to using animals in research, genetically engineered (or transgenic) animals can contribute to our understanding of the basic biological mechanisms and processes found in all mammalian species, and can also improve our understanding of the human diseases. For example, one popular method of understanding the function of a particular gene is to develop a mouse strain where the gene has been artificially removed, or a knockout mouse (Austin et al. 2004). By observing effects of the deletion of the gene on the mouse, one can infer its role in that animal species, and then predict that it has a similar role in other species. Scientists can also develop mouse strains with genes artificially added to study diseases, or knockin mice. For example, researchers have developed mouse strains with genes that confer resistance to factors that normally lead to increases in body fat, such as age and increased caloric intake (Rossmeisl et al. 2004).

An increasingly common method for understanding human disease is to develop a mouse with genes that predispose it to developing the disease. For example, many different mouse strains—otherwise known as oncomice—have been developed with genes that predispose them to develop various forms of cancer (Kerbel 1998). In some strains, researchers have knocked out genes that help mammals fight cancer, such as the p53 tumor suppressor gene; in other cases they have knocked in genes that can induce specific types of cancer, such as lung cancer (Kwak, Tsei, and DeMayo 2004). By studying how drugs affect tumors in mice, researchers can learn how they may affect tumors in human beings.

While transgenic animal models may contribute greatly to our knowledge of basic biological mechanisms and processes and our understanding of human health and disease, they also raise a variety of different ethical issues, ranging from traditional concerns about animal welfare and technology transfer to more recent concerns about producing animal-human chimeras. This chapter will explore these issues and offer some recommendations for biomedical researchers.

Animal Welfare and the Three Rs

Almost all scientists who conduct experiments on animals agree that it is important to take appropriate steps to protect and promote the welfare of the animals used in research. In 1959, William Russell and Rex Burch articulated three principles of human treatment of animals in research (p.171) that have come to be known as the Three Rs: replacement, reduction, and refinement (Russell and Burch 1959). These principles, which represent an attempt to formulate rules for minimizing the total amount of pain and distress experienced by research animals, have had a great of influence over animal research regulations and guidelines. The principle of replacement holds that one should replace animal models with other models—such as cells, tissues, and computer models—whenever scientifically possible. The principle of reduction states that one should attempt to reduce the total number of animals used in experimentation, provided that reducing the number of animals used does not undermine scientific validity. The principle of refinement holds that one should refine experimental techniques to minimize animal pain and suffering and maximize animal welfare (Zurlo, Rudacille, and Goldberg 1996).

Reduction

In theory, genetic modification has the potential to reduce the overall number of animals used in research, since transgenic animal models may offer greater precision and efficacy than traditional animal models (Schuppli, Fraser, and McDonald 2004). For example, suppose Experiment A uses 100 oncomice to determine that a new drug has statistically significant effects on tumor growth, whereas Experiment B uses 500 traditional mice to demonstrate the same result. In this case, Experiment A would save 400 mice.

The real world is much more complex than this simple example, however. First, one must consider all of the animals that are required to develop a transgenic strain. Several hundred mice may be required to develop a single transgenic mouse strain, depending on the type of mutation sought (Williams, Flaherty, and Threadgill 2003; Cohen and Buning 2003). If it takes 400 mice to develop the strain used in Experiment A, then there is no net savings in animals. Second, one must also consider the impact that transgenic animals have on the entire research enterprise. Transgenic animals have opened up new areas of investigation, which can increase the total number of animals used in research. Indeed, there is some evidence that genetic modification is reversing a thirty-year trend toward reducing the number of animals used in research (Schuppli, Fraser, and McDonald 2004).

Some of the new areas of investigation include mammoth research projects involving millions of animals and hundreds of researchers. According to some estimates, the knockout mouse project, which aims to create mouse strains corresponding to the approximate number of 25,000 (p.172) genes in the mouse genome, would use approximately ten million mice (Williams, Flaherty, and Threadgill 2003). The leaders of the knockout mouse project hope to understand the function of each of the 25,000 or so mouse genes by creating an animal strain lacking each of these different genes. Since almost 99 percent of mouse genes have human homologs, understanding mouse genetics and genomics can provide researchers with valuable insights into human genetics and genomics (Austin et al. 2004). Other new areas include modeling human diseases in animals. While about three thousand different genetic diseases in humans are caused by mutations in only a single gene, most human diseases with a genetic basis are caused by dozens of different genes. Thousands of mice might be required to study all of the genes involved in complex diseases, such as type 2 diabetes.

Replacement

Genetic modification may help researchers replace animals with other models, such as cell or tissue models. Researchers have used genetic manipulation techniques to develop transgenic animal cell lines from normal cells as well as from transgenic animals. Scientists can use these altered cell lines to study biochemical reactions and pathways, cellular processes, cell signaling, cell differentiation, and embryonic development (Wobus and Boheler 2005). Transgenic cells models offer many advantages over normal cell models, because researchers can control some of the different properties of transgenic cells. For example, to understand how a particular gene controls cell metabolism, researchers can create transgenic cells that lack the gene and observe its affects on those cells. One of the goals of the knockout mouse project is to develop cell lines corresponding to the 200 different tissues types in the mouse (Austin et al. 2004).

Refinement

One of the most difficult ethical issues related to transgenic animals in biomedical research concerns the potential pain and distress experienced by the animals. In some cases, genetic modification may increase rather than decrease the pain and distress experienced by animals. First, insertion or deletion of genes may result in harmful mutations to the animal. If genes randomly integrate into the genome, unanticipated adverse effects may result, including the disruption of normal gene expression (Schuppli, Fraser, and McDonald 2004). Genetic deletions can also have adverse effects, especially when the deleted gene plays an important role in metabolism, development, respiration, or neuromuscular activity. Researchers should (p.173) take great care to understand and minimize the potential adverse effects of genetic modifications when creating transgenic animals (Nuffield Council on Bioethics 2005).

Second, pain and distress may be impossible to avoid when creating transgenic animals to model human diseases. Diseases inevitably produce signs, symptoms, and malfunctions that lead to pain and distress in animals, such as difficulty breathing, paralysis, toxicity, immune reactions, diarrhea, vomiting, tumors, sores, and so on. In the last two decades, scientists have created animal models of many different human diseases, including diabetes, hepatitis, acquired immunodeficiency syndrome, morbid obesity, anorexia nervosa, alcoholism, Parkinson’s disease, Huntington’s disease, atherosclerosis, cystic fibrosis, Lesch-Nyhan’s disease, polio, autoimmune diseases, hypertension, and various forms of cancer (Nuffield Council on Bioethics 2005). In some cases, it may be possible to use analgesia, anesthesia, and euthanasia to minimize animal pain and distress. However, the techniques used to minimize pain and distress may conflict with scientific goals by (1) affecting variables that researchers want to measure, such as the ability to move or eat; (2) interfering with experimental medications administered to the animal; or, in the case of euthanasia, (3) requiring the destruction of an animal before an experiment has been completed. For example, tumors can cause considerable pain and distress to oncomice, especially if they are allowed to grow too large. The Animal Care and Use Committee (ACUC), which approves animal research protocols, may require the researchers to euthanize the animal at some predetermined point to prevent unnecessary pain and distress. However, researchers may want to keep the animal alive beyond this point, in order to gather valuable data. Additionally, researchers may not want to administer anesthesia or analgesia to these animals, since these drugs may interfere with the anti-cancer drugs or experimental procedures. Thus, using transgenic animals to study human diseases can present an ethical conflict between the need to minimize pain and distress to the animal and the desire to gather scientific evidence (Salvi 2001).

To deal with the inevitable tension between animal welfare and scientific goals, researchers must anticipate how genetic manipulations will affect the animal, and they must carefully monitor animals. They should also develop appropriate methods of anesthesia, analgesia, and euthanasia to minimize pain and distress. Researchers should also be able to explain why they need to use a particular type of transgenic animal, and how using that animal will contribute to our understanding of biomedical science or human health and disease. Ideally, transgenic animals should experience (p.174) no more pain or distress in experimentation than animals that have not been genetically engineered (Rollin 1995). However, this goal may be difficult to achieve because many of the diseases modeled in animals inevitably cause considerable pain and distress. Unless researchers discover a way to create animals that do not experience pain or distress, there will always be a tension between protecting animal welfare and promoting scientific research when using transgenic animals in research.

Chimeras

A chimera is an organism containing organs, tissues, cells, or genes from two or more different organisms or species. Researchers have created many different types of chimeras to understand biological processes and mechanisms and study diseases, such as goats with human DNA, chicken embryos with human embryonic stem cells, and mice with human neuronal stem cells (Robert and Baylis 2003; Weiss 2005). Chimeras are becoming increasingly common in medicine as well. Indeed, all human beings that receive organ transplants are chimeras. Increasingly, human beings are receiving replacement parts from other species, such as pig heart valves. Researchers are developing pigs with human DNA that codes for a protein found on the surfaces of human cells, to help overcome the tissue rejection that occurs in xenotransplantation. Some day transgenic pigs may help to eliminate the shortages of organs needed for transplantation (Hammer 2004).

While animal-human chimeras can have important uses in biomedical research and clinical medicine, they also raise some novel moral issues. Because these organisms undermine traditional (or commonsense) conceptions of clear demarcations between human and animal species, they also challenge our moral and legal frameworks concerning the treatment of animals (Robert and Baylis 2003). Most moral codes and laws place a higher value on human life than on animal life: human beings have moral and legal rights; animals do not. But how should we treat an organism with significant human body parts, such as a transgenic monkey with an enlarged brain or a transgenic pig with humanlike organs? Although most transgenic animals will not be very humanlike, we need to consider how we should treat animals with significant human characteristics or parts. Should we treat quasi-human animals like humans, like animals, or like something nonhuman and non-animal? What would be the basis for our moral obligations to quasi-human animals? One might argue that we should not create quasi-human transgenic animals, such as those in H. G. (p.175) Wells’s book, The Island of Dr. Moreau, unless we are prepared to treat them like human beings. Treating humanlike chimeras as less than human would, in effect, enable us to create strains of subhumans for research or other purposes.

Because society is not currently prepared to deal with the moral and legal ramifications of quasi-human animals, researchers should adopt a voluntary moratorium on genetic modifications to animals that would make them quasi-human. Researchers should also define the term “quasi-human” (or some similar phrase) so that this moratorium would have some clear limits. For example, mice with human skin cells or human metabolic genes should not be considered quasi-human, and research using these animals should not raise any novel ethical problems. However, transgenic animals with humanlike cognitive, emotional, or behavioral characteristics would be closer to humans than would be mice with a few human cells or genes, and therefore would raise some difficult ethical questions. The National Academy of Sciences (2005) has recommended some limitations on embryonic stem-cell research involving animal-human chimeras.

Technology Transfer and Patenting

Transgenic animals can be important research tools. Sharing data, methods, and research tools can help to promote progress in science and technology (Shamoo and Resnik 2009). To promote sharing in science, many journals now require that authors deposit data in public databases as a condition of publication (Science 2011). The National Institutes of Health (NIH) requires that researchers who receive NIH funding make data, reagents, and other research tools, such as transgenic animals, reasonably available to other researchers following publication (NIH 2004).

Even though there are some good reasons for sharing transgenic animals with other researchers, sharing creates its own dilemmas. First, most scientists are interested in promoting their own careers (Shamoo and Resnik 2009). Most scientists will want to ensure that they receive proper credit for their work and some may not want to share animals with competitors. Second, even when scientists are willing to share animals with others, sharing can be an administrative hassle that uses valuable time, money, and resources. Sharing draws resources away from other scientific activities, such as experimentation and data analysis.

There are some potential solutions to the ethical conundrums related to sharing animals. First, scientists may offer to collaborate with colleagues (p.176) that request their animals, which can lead to publication and coauthorship. While this solution helps scientists to promote their careers and encourage sharing, it could lead to problems of undeserved authorship if the scientists share the animals but make no other intellectual contribution to the publication. Second, scientists could charge a fee for sharing animals to recoup some of the costs of sharing. One might argue that charging a fee for sharing transgenic animals is fair, because the recipient should bear the costs of sharing. Alternatively, scientists could sell or license their animals to a private company, which could handle requests to share. If scientists have patented their transgenic animals, they could develop licensing agreements to deal with financial and other issues relating to sharing.

Many of the transgenic animals used in research have been patented. The first patent on an organism was awarded by the United States Patent and Trademark Office (PTO) to Ananda Chakrabarty in 1980 for a genetically engineered bacterium. In 1988, the PTO awarded a patent to researchers at Harvard University and Dupont Inc. for a genetically engineered mouse. Since the 1980s, the PTO has awarded thousands of patents on organisms, cell lines, and DNA (Resnik 2004). The patenting of transgenic animals used in research raises a number of different ethical and legal issues. Some scholars, researchers, and organizations oppose all patents on living things. Opposition to patents on life stems from several sources, including (1) the belief that life is sacred and should not be treated as commodity; (2) the belief that life is not patentable because human beings do not invent life; and (3) the conviction that patents on living things will undermine research and development in biomedicine.

While it is not likely that these objections to patenting life forms will overturn current practices and policies, they may lead to changes in the patent system (or its application). Many researchers, scholars, and organizations have argued that the patents laws need to be reformed to promote innovation and discovery in biomedicine. Some of these potential reforms include: (1) guaranteeing an exemption in patent law that allows scientists to use patented organisms for research (not commercial) purposes; (2) rigorous enforcement of patent criteria to prevent abuse of the patent system; and (3) restricting the scope of patents to strike an appropriate balance of private and public control information (Resnik 2004).

Researchers working with transgenic animals should pay close attention to relevant patent laws to avoid patent infringement. When researchers use commercially available animals, they will usually sign a license agreement with the company that owns that patent on the animal. When researchers develop their own transgenic animals, they should consider whether (p.177) their research will infringe any existing patents, and whether they need to obtain a license to avoid infringement. They should also consider whether to pursue patent(s) on the animal, and, if they do, what steps they should take to protect proprietary information. In the United States, publication of information on an invention prior to patenting the invention can invalidate the patent. In other countries, publication may not invalidate the patent, but it may allow a second inventor to “steal” the invention by filing an application before the first inventor. In either case, researchers, institutions, and corporations have strong incentives to maintain secrecy when they are pursuing projects that they intend to patent, which can conflict with the ethic of openness in science (Resnik 2004).

Conclusions and Recommendations

Transgenic animal models can help researchers obtain important knowledge concerning biological processes and mechanisms and human health and disease, but they also raise a variety of different ethical issues. Researchers who use transgenic animals should be mindful of how their projects will affect the total number of animals used in research. To help reduce the total number of animals used, researchers should develop procedures and techniques that will improve the efficiency of the production of transgenic animals, and they should not undertake large projects with questionable scientific or practical value. In some situations, using existing transgenic animals will be preferable to creating new strains of animals. Researchers must also take great care to understand how genetic modifications affect the welfare of transgenic animals, and they should take measures to minimize pain and distress. Researchers must exercise good judgment when developing transgenic animals to model human diseases, since the animals will inevitably experience some pain and distress due to their diseases. Ideally, transgenic animals should experience no more pain or distress when used in research than normal animals experience when used in research. When it is not possible, for practical or scientific reasons, to prevent a transgenic animal from experiencing significant pain or distress, researchers must provide a sound justification for using that animal for research purposes. Researchers should also take great care when creating animal-human chimeras for experiments and should avoid creating any animals with significant human characteristics or parts (i.e., quasi-humans or subhumans). Finally, researchers should be mindful of technology transfer and patenting issues related to the development and use of transgenic animals. They should make transgenic animals available (p.178) to other researchers, following publication, avoid patent infringement, and decide whether (and how) to protect information that may have proprietary value.

Acknowledgment

This research was funded by the Intramural Program of the National Institute of Environmental Health Sciences (NIEHS), a branch of the National Institutes of Health (NIH). It does not represent the views of the NIEHS, NIH, or United States government.

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