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3 Benefits Derived from the Use of Animals 1 Animal studies have been an essential component of every field of medical research and have been crucial for the acquisition of basic knowledge in biology. In this chapter a few of the contributions of such studies in biomedical and behavioral research will be chroni- cled. These descriptions should be viewed within the context of the vast improvements In human health and understanding that have oc- curred in the past 150 years. For example, since 1900 the average life expectancy in the United States has increased by 25 years (U.S. Na- tional Center for Health Statistics, 1988~. This remarkable increase cannot be attributed solely to animal research, as much of it is the result of improved hygiene and nutrition, but animal research has clearly been an important contributor to improved human health. Despite the many advances and the projected results that will come through the use of anunals, some individuals question the value of using animal models to study human disease, contending that the knowledge thus gained is insufficiently applicable to humans. Although experiments performed on humans would provide the most relevant information (and are used in clinical research conducted on humans when appropriate), it is not possible by commonly accepted ethical aIld moral standards or by law to perform most experiments on humans initially. It IS true that not every experiment using animals yields immediate and practical results, but the advances that will be described in this chapter provide evidence that this 27

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28 USE OF LABORATORY ANIMALS means of research has contributed enormously to the welI-being of humankind. POLIO As a result of the acquisition of information and the development of techniques achieved through the use of animals, poliomyelitis is no longer a major threat to health In the United States. The number of cases of paralytic polio in the United States has declined as a result of vaccinations from 58,000 in 1952 to only 4 in 1984 (Office of Technology Assessment, 1986~. Unfortunately, polio is still a major threat to health where the vaccine is not used. Indeed, in a number of African, Asian, and South American countries, the incidence of the disease has been rising, despite the availability of the vaccine (Cockburn and Droz~ov, 1970~. An estimates! 500,000 cases occur around the world each year (Salk, 1983~. The use of rhesus monkeys for the study of polio began when Landsteiner and Popper (1909) showed that injection of spinal cord material from patients dying of polio caused paralysis in the ani- mals. FIexner and Lewis (1909) promptly confirmed this result. To learn how to immunize monkeys to protect them against infection, researchers first used live virus, then formalin-inactivated virus from infected brain suspensions, and eventually modified live virus. A ma- jor breakthrough occurred when Enders, Weller, and Robbers (1949) showed that the virus could be propagated in cultured cells of non- neural origin. That set the stage for mass production of viruses that could be made into formalin-~nactivated Salk vaccine or the modified liv~virus Sabin vaccine (Salk, 1983~. Although the use of monkeys in polio research has decreased considerably, they are still essential to the production of both live and killed polio vaccines, which are routinely produced in monkey kidney cell cultures. The live vaccine is tested for neurovirulence in monkeys, and the killed vaccine is routinely tested for safety in monkeys. ACQUIRED IMMUNE DEFICIENCY SYNDROM1: The recent emergence of acquired immune deficiency syndrome (AIDS) as a major health threat exemplifies not only the unpre- dictability of research needs, but also the criticality of animals in research. The similarity of sirn~an AIDS, identified in rhesus mon- keys at two primate centers, to human AIDS has allowed the disease

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BENEFITS DERIVED FROM ANIMAL USE 29 in monkeys to serve as a mode! for the human disease. In mon- keys, the virus that causes the disease has been isolated, infectibility studies have been conducted, and some exper~rnents have provided preliminary indications of the possibility of vaccine development. This animal model might prove useful for testing the efficacy and safety of vaccines and therapeutic agents developed to prevent or treat the human disease (Institute of Medicine, 1986~. Recently, a new virus called feline T-lymphotropic lentiv~rus has been discovered. It resembles morphologically the human immune deficiency virus (HIV) that causes AIDS, although differing antigeni- cally, and causes a disease naturally in cats similar to AIDS. Thus, infected cats knight prove useful as animal models for the study of certain aspects of human AIDS (Pedersen et al., 1987~. T1lANSP[ANTATION The transplantation of skin, corneas, and various internal organs could not have become a safe and standard procedure without the knowledge of the biology of transplantation i~rununology acquired through the use of experunental animals. Some 30,000 Americans now alive have transplanted kiclneys, and others survive with trans- planted hearts and livers or ret awn their sight because of corneal transplants. The treatment of burn victims was of particular unportance to the British during World War Il. and British biologist P. B. Medawar (1944) undertook to find relief for them through the transplantation of skin. For one of his models, he used freemartin cattle. A freemartin is a sexually maldeveloped female calf that is born as a twin of a nor- mal male calf; male hormones that reach it through placental vessels usually make it sterile (Billie, 1917~. Experimentation showed that skin and other tissues could be transplanted with good, lasting suc- cess between the male and freemartin twins at any stage in their lives (Anderson et al., 1961~. They were "tolerantly of each other's tissues because of prenatal exposure to each other's tissue antigens. Medawar and his colleagues sought to induce such tolerance in new- born mice. When newborns received skin transplants or received bone marrow from unrelated animals, they became forever ~toler- ant" of the new tissue (Brent et al., 1976~. That discovery signaled a new era in immunology, with wile ramifications for health and the treatment of disease not only in humans, but also in animals.

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30 . USE OF LABORATORY ANVILS Through a systematic study of the surface immune markers of spe- cially bred strains of mice, Snell and Benacerraf provided the basis for much of the understanding that has led to the success of organ transplantation (Benacerraf, 1981~. In the past, young women with chronic pyelonephritis, patients with genetic polycystic disease, and people suffering from the af- termath of streptococcal infections were ad vulnerable to chronic renal failure en c] death. Those people benefited from the invention of Artificial kidneys," which periodically washed blood and removed poisonous substances from it. The recipients of the benefit, however, had to undergo frequent, laborious, and uncomfortable procedures and had to rely on hospitals and mechanical devices. The first extensive work with renal transplantation was reported In 1955 (Hume et al., 1955~. At first, transplanted kidneys were rejected unless they were exchanged between iclentical twins. How- ever, studies in dogs showed that administration of the drug ~ mercaptopurine after transplantation would prolong the survival of a transplanted organ from an unrelated person. This use of immuno- suppressants ushered in the modern era of transplantation (StarzI and Holmes, 1964~. These compounds, having been studied first in animals and proved to be effective, are now used in human transplant recipients. The study of tissue antigens proceeded at the same time as transplantation work, first in mice and then in humans. Inbred (isogeneic) strains of mice had been created by repeated brother- sister matings. Ultimately, these strains became genetically identical, and the exchange of tissues and organs became possible. In the study of minor genetic differences between such strains, it became clear that some genes specify the cell-surface structures responsible for tissue recognition and rejection. Transplantation antigens can now be identified by tissue typing, and the most appropriate donors can be chosen for transplantation in both humans and animals. A second revolution in transplantation was ushered in by the development of cyclosporin. This i~rununosuppressive agent was first used successfully in humans in 1983, after five years of toxicity and efficacy testing in Eunice, rats, and other animals. Since it became available for heart transplantation, survival after transplantation has improved significantly (Kupiec-Weglinski et al., 1984~. Further progress is now occurring with monoclonal antibodies that seem to immobilize the cell-surface markers responsible for recognition and rejection. The hope is that such monoclonal antibodies, which have

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BENEFITS DERIVED FROM ANIMAL USE 31 been developed and maintained in animals, will make it unnecessary to resort to complete irnrnunosuppression of a transplant recipient. This would reduce the occurrence of infection and increase the rates of survival of transplanted organs. CA]LDIOVASCUIAR-R1:NAL SYSTEMS Dogs have traditionally been used in cardiovascular-renal studies because of their relatively large size, which facilitates experimental procedures. For example, an early mode] of hypertension was pro- duced by partially occluding the renal artery in dogs. Studies of renal function that use clearance techniques in unanesthetized ani- mab are most often done in dogs. In the last two decades, however, some mutant rats have proved exceedingly valuable as animal models of human disease. The Brattleboro rat is an excellent example. It has diabetes insipidus and must drink 70 percent of its body weight in water each day. It cannot produce vasopressin, a hormone that plays an essential role in the kidneys' ability to regulate water ex- cretion and blood pressure. Research on the Brattieboro rat has greatly increased our understanding of vasopressin's role in kidney and cardiovascular function, and that understanding might lead to the development of better drugs (and drugs with fewer side effects) for the treatment of clinical disorders (Soko} and Valtin, 1982~. The development of open-heart surgery ~ but one of many exam- ple~ of the value of using laboratory animals. Working with cats and dogs, Gibbon built the forerunner of the presen~day heart-lung ma- chine (Deaton, 1974), which makes open-heart surgery possible. His research in the early 1930s included clamping off more and more of an animal's vasculature and detouring its blood through the heart-lung machine. The machine was further improved by the incorporation of a roller pump developed by DeBakey (DeBakey ~d Henly, 1961), which aDowed the entire circulation to be shunted through the ma- chine, which added oxygen to the animal's blood. The pump was first used and perfected in the animal laboratory and is now a standard, essentiad component of the heart-lung machine. As a result of these developments, more than 80 percent of infants born with congenital cardiac abnormalities now can be treated surgically and can lead normal lives. Replacement of heart valves and segments of large arteries in the treatment of valvular heart disease was made feasible by dog studies done in the late 1940s and early 1950s (Gay, 1984~. Before

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32 USE OF LABORATORY ANIMALS diseased heart erasures could be replaced in patients, scientists had to study their design and use ~ anneals. As with so many other drugs and operations, physicians and surgeons would not consider applying them to patients until they had proved safe and effective in anneals, nor would the public accept them until their safety was proved. Each decade since then has seen improvements in the design, installation, and performance of these valves and other prosthetic devices. BE cause the ideal valve has not yet been developed, research is still in progress in many laboratories to further improve its capacities. NERVOUS SYSTEM The human brain is a structure of extraordinary complexity. Each of its 200 billion neurons (nerve cello) makes a few thousand to several hundred thousand connections with other neurons, mus- cles, or glands. Neurons use large amounts of metabolic energy to carry out a host of functions: the generation and conduction of impulses; the synthesis, transport, secretion, and uptake of trance rn~tters; and the modification of structure and synaptic efficacy in response to activity and environmental perturbations (Kande} and Schwartz, 1985~. Many basic aspects of neuronal development can be studied in cell and tissue cultures, in brain slices, and in simple invertebrate neuronal systems. Computer simulations and noninvasive human studies can also provide important data on fundamental mechanisms of learning and memory. Yet there ~ no adequate substitute for animal studies in attempts to understand the complex behavioral and cognitive functions of the brain in health and disease. Movement and E unction Our understanding of the nervous system and approaches to rational therapy of its disorders could not have come about with- out animal studies initiated by the physiologist Charles Sherrington (Eccies and Gibson, 1979~. His studies on reflex mechanisms of the spinal cord in cats were continued by Eccles (1957), who described how excitatory ant! inhibitory processes work in the central nervous system. Today, neurosurgeons can remove some brain tumors with minimal damage to the motor system in part because scientists such as Sherrington discovered that localized electrical stimulation of the exposed brain of the dog COI11d elicit discrete movements of the limbs.

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BENEFITS DERIVE:D FROM ANIM,4L USE 33 Neurologists and neurosurgeons now examine electrical signals from the brain to diagnose and treat epilepsy, study leveb of con- sciousness, localize brain tumors, diagnose multiple sclerosis, and study learning disabilities in children. Moreover, the applications of such essential toob for diagnosis and therapy as computed axial tomographic (CAT) scans and magnetic resonance imaging (MRI) were developed with research Mornay (Kande] and Schwartz, 1985~. Behavior The study of the nervous system and behavior is one of the major frontiers of modern science. A good deal is known about the anatomy and physiology of the brain and nervous system, but much remains to be learned about it as an organized assemblage of neurons and about how it is affected by environmental stimulation. The following examples provide an idea of how anunals are used in studies of such subjects. Postnatal Development of the Visual Cortex and the Influence of Environment Hube} and Wiese} shared the Nobel Prize in 1981 for their studies of vision in cats and monkeys, including the development of visual functions ~ young annnab (Barlow, 1982~. The visual cortex of monkeys is not fully developed at birth; nerve cells are still growing and making connections with other nerve cello. In this process, normal development depends on visual stimulation during a critical period in early postnatal life. As in humans, each eye of a monkey sees a slightly different view of the same object; normal binocular vision gives the impression of depth. If early In postnatal life one eye ~ occluded, the nerve cells for that eye in the visual cortex do not develop normally. Most of the nerve cells become responsive only to the open eye, as shown in recordings from cells of the visual cortex of anesthetized animals. In normal development, the visual cortex consists of alternating bands of reactive neuron from the right and left eyes; but In a monkey with an occluded eye, the regular alternation is weakened, and most neurons react only to the normal eye. These anatomical and physiological changes are the basis of blindness in the occluded eye. Children with congenital cataracts or clouding of the ocular me- dia for other reasons demonstrate a smi~lar dependence of human

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34 USE OF LABORATORY ANIMALS vision on visual stimulation. Testing after restoration of normal vision has shown that the acuity of the previously occluded eye is re- duced; the earlier in life the eye was occluded, the greater the degree of deficit. Animal experiments have also shown that correction of strabismus (squint) by surgery should be performed early in, or cer- ta~nly before the end of, the critical period of eye-brain development to ensure normal vision (Wiesel, 1982~. The close correlation between the effects of visual deprivation observed in animals and the effects observed in the clinic suggests that they are based on similar physiological mechanisms. This correlation has been helpful in developing appropriate measures of prevention and treatment of neural eye disorders. Memory Another subject of behavioral research is memory. An estimated 5 percent of people over the age of 65 have severe limitations or even failures of memory and cognition; another 10 percent of the people over 65 have maid to moderate cognitive problems (Coyle et al., 1985~. Specific conditions, such as Korsakoff's syndrome and Alzheimer's disease, affect mental functions and can cause extreme memory Toss. Research on animate is improving the understanding of the mecha- nisms of such losses. In turn, this increased understanding has led to the discovery of some drugs that show promise of counteracting the losses. Most of the knowledge about the neurotransmitters involved in these diseases has also been derived from studies of the brains and nervous system of animals. Primates are phylogenetically closer to humans than are other marrunals. Their behaviorad capabilities are in keeping with the greater development and complexity of their brains. Primates also have age-related decrements in memory function. Generally, memory impairment with advancing age first appears as a failure of immediate memory, the recall of events that have just occurred. Transmitter chemicals of the a-adrenergic class, like clonidine, were first found to improve memory performance in macaques and aged rodents. Clonidine has now adso proved effective in improving the memory of patients with Korsakoff's syndrome. Those findings suggest a new approach to the treatment of patients with memory disorders, and they have provided a new option for clinics trials with patients suffering from Alzheimer's disease (Arnsten and Goldman-Rakic, 1985~.

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BENEFITS DERIVED FROM ANIMAL USE Pain 35 Pain is a common symptom of disease ~ humans and anunals. It ~ important that medical science develop more effective methods of pain management than are now available. Much pharmacological research has focused on the production of drugs with potent analgesic properties, and much research on pain particularly that concerned with analgesics, acupuncture efficacy, hypnosis, and so on has been carried out on human subjects for over a century. Research using ani- mals is necessary, however, if unsolved problems are to be adequately addressed. Although may experiments that study pain must involve pain for the an~rnal, researchers have developed methods that are as hu- mane as possible within the context of the experiment. For example, the slightest reflex movement of the tail of a rat or mouse is objective evidence that a noxious stimulus applied to the skin of the tail has attained threshold intensity. Reflex behavior, such as the ta~-flick, is a useful index of the comparative effectiveness of analgesics, as wed as of the effects of manipulating chern~cal messengers in the central pain pathways (Willis, 1985~. The understanding of intrinsic brain mechanisms of pain and its modification wid require the use of modern techniques for cell mark- ing and pathway tracing, immunocytochemical and microphysiolog- ical methods, and sophisticated behavioral studies. Paradoxically, many investigations of Pam can be explored in anesthetized attune. Thanks to psychophysical studies in humans that were replicated in animals, neuroscient~ts have been able to trace the nerve fibers Tom skin, muscle, and internal organs that are specific carriers of Spain signals.n With such a powerful handle on the input end of the pain system, the passage and transformation of pain signals can be ex- plored in complex neuronal organizations in anesthetized animals. It is also possible to study the central systems that control the passage of pain signals to higher levels of the central nervous system. Finally, isolation and identification of the transrrutters, structure, and other components of the neurochemical machinery of the brain involved in pain perception ant] its modification can be elucidated (Willis, 1985~. Increasing recognition that behavioral factors play a significant role in many current health problems for example, drugs and alcm ho! abuse, eating disorders, effects of stress, cardiovascular disease, and mental and psychiatric ailmentshas led to the development of animal models for experimental and biological analysis as part of the emerging field of behavioral medicine (Hamburg et al., 1982~.

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36 USE OF LABORATORY ANIMALS OTHER BENEFITS FOR HUMANS The preceding examples provide a sampling of the contributions that research using animals has made to the improvement of hu- man health and the acquisition of knowledge. Many others could be cited for example, the development of medicinals such as the sul- fonamides (Hubbard, 1976~; the development of lif~support systems for premature infants (Coalson et al., 1982; deLemo~ et al., 1985; Escobedo et al., 1982~; and the increase in understanding of learning (MitIer, 1985; Paviov, 1927; Skinner, 1938; Thorndike, 1898), nonlin- guistic communication (Gardner and Gardner, 1969; Romski et al., 1984), drug abuse (Deneau et al., 1969; National Institute of Drug Abuse, 1984; Seevers, 1968), and nervous system regeneration. Many examples of such benefits are also chronicled in publications such as those by Gay (1986), Leader and Stark (1987), and Paton (1984~. BENEFITS FOR ANIMALS One might have the impression that animal research is conducted only with the aim of alleviating human suffering. The conduct of ex- tensive research in veterinary schoob and other institutions indicates that that is not the case. Most research on domestic farm animals is undertaken to increase the productivity and quality of animal products. Research ~ also undertaken to reduce the suffering and increase the overall well-being of animals, particularly companion animals. Examples include current research on Potomac fever in horses, the development of ivermect~n to eradicate parasitic diseases in a variety of animals, and the development of vaccines for feline leukemia virus and canine parvovirus. Research anned at human illnesses has also had immeasurable benefits for animals. A host of immunizations and antibiotics have proven applicable to the therapy of animal diseases (Paton, 1984~. Kidney transplantation, cardiovascular treatments, chemotherapeu- tics, and narcotics are widely applicable, as are the insights gained from genetic research (Gorman, 1988~. One example of the benefits of biomedical research for animals can be found in the propagation of endangered species. The ability to transfer embryos, eliminate parasitism, treat illnesses, and use anesthetic advances has improved the health and survival of many species. The knowledge gained from genetic studies has allowed appropriate management of species that are endangered or have disappeared in the wild. For example, the ability to identify the sex

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BENEFITS DERIVED FROM ANIMAL USE 37 of birds has been essential In the management of the whooping crane and the California condor. Research into obstacles to successful breeding in captivity has markedly reduced the need for unportation of many species, especially monkeys. For example, among nonhuman primate species used In research, there were 7,908 births in 1984 In the United States, compared with 2,198 in 1973 (Johmen and Whitehair, 1986~. SUMMARY Animal research has resulted in enormous benefits for humans and animals. The searching and systematic methods of scientific inquiry have greatly reduced the incidence of human disease and have substantially increased life expectancy. Those results have come largely through experimental methods based in part on the use of animals, as illustrated by the many examples cited in this chapter. At the same tune, much obviously remains to be learned. Fur- ther studies in such areas as cancer, heart disease, diabetes, AIDS, dementias, and the development of vaccines and chemotherapeutic agents wiB continue to require the use of animals.