Introductory history and issues, and animal welfare in the context of stem cell research


Miriam_Rothschild.jpg
"Looking back at the first half of my life as a zoologist I am particularly impressed by one fact: none of my teachers, lecturers, or professors with whom I came into contact … none of the directors of laboratories where I worked, and none of my co-workers ever discussed with me, or each other in my presence, the ethics of zoology. No one ever suggested that one should respect the lives of animals in the laboratory or that they, and not the experiments, however fascinating and instructive, were worthy of greater consideration."
- Dame Miriam Rothschild, DBE, FRS (Dame of the British Empire, Fellow of the Royal Society; 1908 - 2005), British natural scientist and author with major contributions to zoology, entomology, botany. (Animals and Man, 1986, p. 50)


“If a procedure is considered painful in humans, it should be assumed to be painful in laboratory animals, regardless of their age or species.”
- National Research Council 2009


“Animals in the millions are, to misuse the words of an old Arlo Guthrie song, ‘injected, inspected, detected, and infected’….”
- The New York Times, December 20, 2011, p. D1


“We owe much to laboratory animals, and that debt can best be repaid by good treatment and keeping painful experiments to a minimum.”
- Former U.S. Senator Bob Dole (Congressional Record (1985, Dec 17)
US Government Printing Office, Washington, DC)


“We need a boundless ethic that includes animals, too.”
- Albert Schweitzer, quoted by primatologist Jane Goodall in the Preface to
The Encyclopedia of Animal Rights and Animal Welfare (Bekoff, 2010)



Introduction


Animals are vital to research. Advances in science and medical research rarely can occur without using animals. Millions of animals are used annually in laboratories, teaching facilities, naturalistic research settings, and other contexts. They may be purpose-bred in special facilities, or acquired in other ways (see below).

Animals used in research are very diverse, from:
  • invertebrates, such as tiny fruit flies (drosophila) and nematode worms, and others; to
  • vertebrates, from tiny zebra fish, to mice and rats, cats and dogs, large farm animals such as pigs, to several kinds of primates, from tiny marmosets to large macaque monkeys and chimpanzees, and others.

In this Supplement, we will give a brief historical perspective, and an overview of a range of bioethical animal welfare and animal rights issues raised by the use of animals in biomedicine and stem cell science in particular. We shall see that while some use of animals is decreasing, and sometimes is improving, use of certain animal species is greatly increasing in stem cell and transgenic science. Given the diversity of animals used, policies and concerns about what constitutes humane care often are also diverse. Fundamentally, they all should be comfortably housed and fed, humanely handled, spared pain and suffering as much as possible, and not sacrificed for cruel or frivolous reasons.

What is the difference between animal rights and animal welfare?


These are representative definitions: The difference between animal welfare and animal rights can be explained briefly as below:

Animal welfare denotes the desire to prevent unnecessary animal suffering (that is, whilst not categorically opposed to the use of animals, wanting to ensure a good quality of life and humane death).

Animal rights denotes the philosophical belief that animals should have rights, including the right to live their lives free of human intervention (and ultimate death at the hands of humans). Animal rightists are philosophically opposed to the use of animals by humans (although some accept 'symbiotic' relationships, such as companion animal ownership). Source.

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Historical overview of the use of animals in research


Animals have been experimented on since at least the beginnings of medicine in ancient Greece and Rome, at first mostly to satisfy curiosity
For an extensive and very interesting discussion of pre-modern animal experimentation, see (Guerrini 1989; Monamy 2000)
about anatomy (Monamy 2000). Until anesthesia was used in medicine in the 19th century, all vivisection was conducted on awake animals. By the 17 century, animal experimentation was on the rise. Descartes declared that animals, lacking our higher thought processes, were essentially automatons devoid of feeling and therefore not able to sense pain.

Unconstrained use of animals for scientific experimentation was not seen as ethically problematic until the later 1700s. By the later 18th century, Jeremy Bentham (1748 – 1832), an English jurist, philosopher, legal and social reformer, challenged the prevailing Cartesian view. He stated, “The question is not, can they reason? Nor, can they talk? But can they suffer?” (Baumans 2004).

Two events spurred increased animal experimentation by the later 19th century: the discovery of anesthetics, and the publication of Darwin's Origin of Species. Anesthesia provided a means to reduce animal suffering. The theory of evolution intimately linked human beings to animals in the larger biological framework.

Rene Descartes (1596-1650)


French philosopher and mathematician extraordinaire. René Descartes is often mentioned as “the Father of Modern Philosophy.”
He was also celebrated for his famous dictum, “cogito ergo sum” (English: I think, therefore I am; or I am thinking, therefore I exist; French: Je pense, donc je suis). For Descartes, animals had no interior life that suggested they deserved protection from the worst abuses. Like other philosophers of his time, he believed that animals lack rationality, self-consciousness, and autonomy.

Today, we are aware that animals, especially higher mammals, have their own consciousness, and we are less likely to assume lack of sentience even though they lack higher thought. Moreover, our appreciation of their moral status has improved, given that we recognize that they share psychological and mental similarities with infants and disabled human beings, and feel pain much as we do. Animals increasingly have been shown to have species-guided complex cognitive, social, and emotional capacities (Babara 2001).


Thought question


Australian philosopher and noted animal rights advocate Peter Singer has written: “All the arguments to prove man’s superiority cannot shatter this hard fact: in suffering the animals are our equal.”


Agree or disagree? Why?



See this interview with Peter Singer on the ideas of personhood, speciesism, and pain by Ethic Bites.

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The rise of modern laboratory animal science and the regulation of animal research


The increase in animal experimentation and development of many standardized experimental animal models that occurred over the 20th century helped to propel the rise of modern biomedicine (Baumans 2004).

Multidisciplinary laboratory animal science arose in the 1950s. It concerned itself with the nature and quality of animal experiments and the welfare of laboratory animals. Along with growing attention to the welfare of laboratory animals, regulations and animal ethics committees were developed in many countries (Baumans 2004). Institutional committees known as IACUCs (Institutional Animal Care and Use Committees) now strictly regulate acquisition, housing, care, and use of all species of lab animals.

Baumans asserts that the reduction in use of animals from the 1970s until approximately 1995 can be accounted for by growing animal rights and welfare concerns and activities, increased regulation, and efforts to find non-animal models. Furthermore, Baumans indicated that the increasing use of animal in biomedicine since 1995 can be accounted for by the rapid rise in the use of genetically modified animals, in particular very large numbers of rodents (Baumans 2004).

The National Research Council


The National Research Council, one of the most authoritative institutional sources for laboratory animal standards in the US, has issued three reports in recent years:
  • Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research (2003)
  • Recognition and Alleviation of Distress in Laboratory Animals (2008)
  • Recognition and Alleviation of Pain in Laboratory Animals (2009).

Together these reports offer very detailed guidance concerning how to manage laboratory animals so as to minimize pain and distress. For further information, see the National Research Council's site here.

Rats and mice as the dominant modern lab animal “models”


By far, the animals most experimented upon in research are rodents of the taxonomic Family Muridae (hence “murine model”), the true mice and rats; and in much lesser numbers, other types of rodents, such as guinea pigs, rabbits, and others. Mice are widely considered the prime model for studying inherited human disease; they share 99% of their genes with humans (Wellcome-Trust-Sanger-Institute 2002). Knock-out and knock-in mice are those in which genes have been de-activated or inserted, respectively, affording researchers two powerful and intensively used models. More recently, rats are being genetically engineered for many types of biomedical research paradigms (i.e., a knock-out rat).

Murine animals are highly convenient to use in research protocols. They are:
  • small
  • easily handled
  • easy and inexpensive to house and feed
  • have a short lifespan
  • reproduce easily and prolifically in the laboratory environment
  • are biologically suitable in a very wide variety of experiments that can yield meaningful outcomes and results.

These features of compactness and rapid turnaround in obtaining results all are reasons why small animal models of research are so favored, ubiquitous, and experimentally powerful. When a well-controlled research question can be addressed in a human clinical model, the human study usually would take years to complete and analyze.

Animal models used in stem cell research

There are three main types of animal models used in stem cell and transgenic research:

Genetically modified animals
  • “Knock-out” mice and rats are genetically engineered by researchers who have inactivated, or "knocked out," specific gene(s), replacing or disrupting the genes with exogenous DNA. The loss of native gene activity impacts the phenotype of the mouse or rat. Physical characteristics such as coat color, biochemical and physiological characteristics, and behavioral and psychological characteristics all can be altered.
  • “Knock-in” mice are animals whose genetic makeup has been altered to transfect (introduce) single or multiple genes that regulate specific proteins and introduce new physiological or behavioral characteristics.
  • Human-animal chimeras are animals having two or more different populations of genetically distinct cells that originated from different zygotes, in utero.
  • Clones are created via somatic cell nuclear transfer (SCNT) using parent DNA and a donated oocyte.
  • “Pharmed” animals are genetically manipulated animal clones that have had human genes inserted during embryological development so that they will produce human proteins in their milk, blood, and other tissues for medical and research purposes.

The particular bioethical issues raised by these specialized, purpose-bred animals will be discussed below, after reviewing core issues of lab animal welfare.

Knock-out mice


Knock-out mice have been used since 1989. Capecchi, Evans, and Smithies won the Nobel Prize for Medicine in 2007 for their invention of knock-out mice. Published knock-out mice exist for approximately 60% of mouse genes; still, a majority of common human neurological diseases do not have a knock-out mouse model.

Knock-out rats have only become economically and technically feasible recently, since about 2008. See for example this fact sheet on knockout mice of the National Human Genome Research Institute.

The cost and procurement of lab animals

Today, laboratory animal commercial facilities and research universities breed thousands of genetically specialized types of animals, mostly mice and rats. They also breed, maintain, and distribute colonies and individuals of many other types of experimental animals. These breeding enterprises have become an enormous, highly lucrative business, worth billions every year. The most reputable lab animal breeders (Class A dealers) must maintain very high standards in order to attract leading researchers.

Breeders of specialized lab mouse strains


Breeders of specialized lab mouse strains As an example of a Class A dealer, Jackson Laboratory of Bar Harbor, ME, a non-profit breeding facility, breeds many strains of specialized mice, some of them derived from strains bred at the NIH decades earlier. “JAX® Mice are the most published and well characterized mouse models in the world, and include the only fully sequenced strain, C57BL/6J” (from the Jackson Lab website, http://jaxmice.jax.org). The Jackson Laboratory can breed approximately 3000 specialized strains of mice (most are in frozen embryo state until needed). The Jackson Laboratory also publishes the Handbook on Genetically Standardized Mice, “the definitive resource for anyone around the world working with laboratory mice.”

An example of a leading commercial rodent breeding facility is the Charles River Lab.

Source: http://jaxmice.jax.org/

Unlike mice, rats, or hamsters that may cost between $2 and $10 in a pet store, specialized or purpose-bred lab mice with a specific disease such as arthritis, epilepsy, or Alzheimer’s disease cost between 10-200 times more. A genetically modified or knock-out mouse can cost from hundreds to thousands of dollars apiece (Associated-Press/Fox News 2006); see Web sites of Jackson Labs, Charles River Labs, Deltagen and similar companies).

Other mammals offer certain advantages over mice. Mice do not provide a good animal model for cardiac diseases such as atherosclerosis since they never die of this disease. Dogs are better models for atherosclerosis, as they can experience heart attacks caused by this disease. Pigs offer research advantages in studying skin diseases (as their skin is hairless like that of humans); they also are used in many physiological studies given their physiological similarities to humans. Currently, pigs are being examined as potential research animals for xenograph organ transplantation.

Many dogs and cats used in medical training and in laboratories are bought from semi-regulated Class B dealers. These dealers obtain the animals from random sources that include animal shelters, a practice animal welfare organizations are trying to end. Random source animals typically are much less expensive than purpose-bred animals, and “probably endure greater degrees of stress and distress compared to purpose-bred animals” (NRC 2008). Pigs and other farm animals are obtained in a variety of ways for research or teaching, including standard agricultural and food industry sources, as well as specialized breeding.

Transgenic science

For an interesting look at cutting edge research using transgenic pigs to study diabetes and other grave illnesses, see the research of Dr. Eckhard Wolf. According to Dr. Wolf, pigs are a bridge model between mice and humans, given that porcine physiology is much closer to that of humans than that of the mouse. (Source)


Transgenic science also is being used to improve the food supply through development of animals with highly desirable characteristics. For example, see in this video how a breed of cattle, the Belgian Blue, has been developed transgenically to have unusually large muscle mass, which then can yield far more high quality meat per animal.

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Primates in research


Primates used in research are extremely expensive to buy, house, and care for. The most widely used primate model in neuroscience and other research is the Rhesus macaque (Macaca mulatta), originally captured in the wild and now bred in colonies for research (see this Primate Info Net Factsheet). One standard macaque costs approximately $3,500 (Hopkins). Chimpanzees (Pan troglodytes) also have been used, for example for behavioral or HIV research, and are even more costly at approximately $60,000 each (Hopkins); see for example Primate Research Models).

On December 20, 2011, Dr. Francis S. Collins, Director of the NIH, issued a profound and highly significant announcement, that federal funding for chimpanzee research soon will be terminated permanently. Underlying this announcement was the long-overdue appreciation of the ethical issues raised by our use of chimpanzees, given their human-like behavioral and social characteristics.

In making the announcement, Dr. Collins said that chimpanzees, as the closest human relatives, deserve “special consideration and respect,” and that the agency was accepting the recommendations released earlier in the day by an expert committee of the Institute of Medicine, which concluded that most research on chimpanzees was unnecessary.

Humane treatment of research animals: The Three R’s


Humane treatment of research animals is critical to successful research (Reinhardt 2004; National-Research-Council 2008; NRC 2008). Observing the “Three R’s: Replacement, Reduction and Refinement” (Russell and Burch 1959) is essential for the humane treatment of animals. Teaching the “Three R’s” has become the ethical standard in laboratory animal science and care in many countries. Facilities and institutions that do not teach and implement the “Three R’s” are considered sub-standard.

W.M.S. (Bill) Russell (1925–2006) and R. L. (Rex) Burch (d. 1996) and The Three R’s


Bill Russell and Rex Burch
The most widely cited guiding principles of laboratory animal science are “The Three R's” of Russell and Burch, as set out in their book, The Principles of Humane Experimental Technique: Replacement, Reduction and Refinement (first edition 1959; current edition1992). In honor of zoologist W.M.S. (Bill) Russell (1925–2006) and microbiologist R. L. (Rex) Burch (d. 1996), both of whom held numerous academic posts and were closely affiliated with the Universities Federation of Animal Welfare (UFAW) in the United Kingdom, the Humane Society of the United States recently created the Russell and Burch Award, in recognition of their efforts. For a compelling remembrance of Russell and his work with R.L. Burch, see altweb.jhsph.edu/bin/w/q/paper1.pdf).


Sources and for more information:
Russell and Burch (1959/1992);
Baumans 2004; and
altweb.jhsph.edu/resources/refinement/index.html
www.vetmed.ucdavis.edu/Animal_Alternatives/3Rs.html
www.pcrm.org/resch/pediatrics/index.html
ehp.niehs.nih.gov/members/1996/104-8/zurlo.html

Thought question


When is animal experimentation truly needed to advance knowledge and when is it not justified?

Certainly there is increasing pressure to justify animal experimentation. Using animals for medical, educational, and research training purposes is increasingly questioned, and consequently is being reduced whenever possible.

Facts and figures about animals used in research


In North America and Europe in the early 2000’s, 50 - 100 million animals have been used in laboratories (Zutphen, Baumans et al. 2001; Matheny and White 2006). The rise of biomedical research worldwide, particularly in East and South Asia, means the total number of research animals now used worldwide is much higher.

Table 1 Animal use in biomedicine, comparative percentages (Baumans, 2004)
Purpose % of all animals used
Education 1%
Heart/circulation 2%
Toxicity tests 9%
Cancer research 12%
Vaccines/biology 21%
Drug research 23%
Other research 32%
Total 100%


Animal welfare and bioethical issues related to stem cell research


Previous units of this course have already presented information about the use of animals in stem cell research and related transgenic experimental models.

Module 7 discusses bioethical concerns raised by the creation of chimeras, and presents some of the nascent recommendations for adequate monitoring of these specialized laboratory animals. Bioethical issues raised by cloning and pharming are set out in Supplement 3: Historical overview of vertebrate cloning.

Below we will say a bit more about issues raised by the use of animals in stem cell research.

There are many potential applications of stem cells being developed in the effort to cure human diseases (see Module 8). Given the very limited state of current knowledge about how stem cells might work in target human organs and systems, and the risks these procedures might pose, researching the fate of human cells in an animal has become increasingly relevant to stem cell and related transgenic research models. Among other research models, chimeras (any of embryonic, fetal, post-natal) can be used to:

These kinds of basic and applied studies make research using chimeras very compelling, even though in many cases little is known about how productive the translation from human-animal chimera outcomes might be to results for human health (see Module 7). Because of the many unique and difficult animal welfare questions and problems chimera and other stem cell and transgenic research models raise, implementing these studies should – mostly appropriately – be slowed. Many questions first must be asked so that needed guidelines and regulations then may emerge.

  • Various species of primates are increasingly are being looked at as transgenic and chimeric models. Small, tame, new world monkeys called marmosets are being developed rapidly as an attractive primate model. They can be easily raised in labs on a large scale, much like rats and mice (Sasaki, Suemizu et al. 2009; Schatten and Mitalipov 2009). Many questions are raised:
    • How should we feel about primate chimeras becoming widely used?
    • For better or for worse, many European countries (e.g., the UK, Germany) are more restrictive with respect to primate research than is the U.S., but this has had an inhibiting effect on research in Europe (Cyranoski 2006).
  • Many international drug companies are increasingly turning to protein-based therapies that are likely to provoke an immune response. As a result, many companies are looking to use primate models because a mouse model would be far less predictive of the possible human response.
  • China is striving to become the top world supplier of primates for research (Cyranoski 2006; Mandavilli 2006). Primate research costs and regulations are far less burdensome in China. Many facilities in China still do not meet various international animal welfare standards, but a few do.
    • In general, should companies be allowed to greatly increase transgenic and chimeric primate models before the US or other countries might create more regulations and primate research infrastructure?

Thought question


How should we feel about any possible expansion of primate or other animal research in China or other countries that do not have a good animal welfare record?

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General animal welfare issues and bioethical concerns


With respect to all genetically manipulated animals – clones, pharmed animals, and in particular, human-animal chimeras - there is widespread agreement that these animals should be carefully controlled to prevent their “escape” into the wider environment and animal populations, where they might reproduce or cause unforeseen problems. This implies that as animal technologies increasingly are used, vast numbers of specially engineered animals will have to be carefully housed and monitored and their distribution carefully controlled. As there are to date no international codes and regulations setting out appropriate controls over stem cell cultures, similarly there are none for the monitoring and control of chimeric animals. As this science grows, there will be an increasing need to create systematic regulations for documentation - of creation, housing, care, distribution, termination, and other aspects of the lives of chimeric animals.

Clones, pharmed animals, and especially chimeras, are not normal animals of their species. Perhaps we should be ethically concerned that during their lifetimes, if of any duration beyond fetal, they may suffer from behavioral or emotional problems from their mixed nature (see Module 7).

The issues raised above seem like understandable concerns, and reflect new perspectives on centuries of traditional views of the relationship of man to animals and to creation. Dov Fox (2010) finds that we are in our current predicament - of dealing with the consequences of our drive toward endless experimentation and improvement - as the result of:
  • Neutralist liberalism
  • Enlightenment emphasis on human perfectibility
  • An ethic of control of nature and of enterprise (that now should be more in balance with an ethic of restraint)
  • Locke-ian promotion of liberalism as a route to personal freedom.

Scientific and public pressure is intensifying to use these animal-intensive biomedical technologies for increasingly widespread research applications. As a consequence, bioethicists and philosophers are taking a closer look at the traditional philosophical arguments supporting animal experimentation that spring, for example, from utilitarianism and liberalism, and find them wanting. Autumn Fiester critiques these arguments and proposes a new framework, called “a Presumption of Restraint,” as a guiding principle for use of animals in biomedical technology. She bases her framework on pragmatic and compassionate assessment of need (Fiester 2008).

The deep and wide-ranging questions raised by the technological manipulation of animals constitute a growing literature that cannot fully be summarized here. The reader is encouraged to further explore these topics using many of the resources and references below.

Conclusion


In reviewing a wide array of content to write this Supplement, it became clear that many institutional and professional resources are in place to guide humane animal research to a high standard of care, and that concerted efforts are being made in many quarters to Replace, Reduce and Refine the use of animals. However, animal advocates continue to report on many instances of poor care and barren living conditions as well as carelessness with the lives of animals. Many experimental procedures certainly appear cruel, may be cruel or painful by a reasonable standard, and are likely to stir emotions, especially among those who may know less of the science.

On the other hand, scientists, too, have their biases and may at times be blind to their self-justifications or other ways in which they might be faulted for their careless uses of animals. Some medical scientists, over many decades, have gone on record that they believe vivisection often does not yield scientifically and/or medically useful results. For a long list of such quotes, go to: http://www.ohsukillsprimates.com/quotes.htm, a Web site of the Coalition to Abolish Animal Testing (CAAT). A major exception might be the growing use of genetically engineered mice, for example, as these valuable animals generally are treated well, although they live unnaturally and are manipulated and humanely sacrificed.

Newer, highly productive high-tech non-animal methods may well reduce the need to use animals. One major motivation to develop new, non-animal techniques might have been missing, were it not for the critique of biomedical research posed by animal rights activists. In principle, few researchers would say they would allow or tolerate animal cruelty, yet many labs have found they need to strengthen their standards of animal care and justifications for use of animals. Most university-based Institutional Animal Care and Use Committees (IACUCs) require all investigators who propose using animals for their studies to justify that no cell-based models are available to address the research objectives they are proposing to examine.

Animal rights activists must not resort to violence and destruction of scientific property although in the past some groups have (e.g. People for the Ethical Treatment of Animals (PETA)). Even scientists who are sympathetic to animal welfare issues – and many are – often cannot speak their minds at risk of becoming associated with those who would condone violent and disruptive acts. Criminal acts, no matter how emotional the issues may become, should never be supported or tolerated. Change must come about through education, changed awareness about animals, increased compassion, and ultimately through invention and adoption of new and better techniques, as well as more enlightened legislation and regulation. While this will take time, the debate will continue and, hopefully, the picture for animals will continue to improve.

We should remember that decades and centuries ago, far fewer animals were used in research. Today, the sheer industrial scale of use of animals in laboratories, as well as for food, fur, and other purposes creates efficiencies and standardization useful for human beings, but leads to treating animals as supplies and commodities, and often not as living, sentient, feeling creatures.

At the same time, psychology and neuroscience have been making it ever clearer that higher animals share with us the ability to feel pain (as do most lower animals), and have complex social and even emotional lives and species-specific needs that rarely are met. All these characteristics make humans aware that animals are individuals and are very like us in fundamental ways. None the less, we still are confronted with our need to use and kill them. Hopefully, our increased bioethical debates and discussions, along with our greater understanding of animals, will lead to on-going improvement in our appreciation and humane use of animals.


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References


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