ANIMAL RESEARCH FOR ANIMALS

ANIMAL RESEARCH FOR ANIMALS

Bruce H. Ewald and Douglas A. G r e g

Virginia-Maryland Regional College of Veterinary Medicine Virginia Tech

Blacksburg, Virginia 24061

INTRODUCTION

There are several means by which research on animals benefits other animals. Common laboratory animals and domesticated species are used frequently in veterinary research. This research is designed to understand the normal structure and function of animals, determine the etiology and pathogenesis of abnormal conditions, and provide pharmaceuticals and biologics for animals. Animal research designed to answer human medical problems is another way research has benefited animals. Both veterinary and medical research will be reviewed in this article.

Since animals were studied to provide insight into the physiology of human organ systems, more is now known about animals than humans. Renal excretory mechanisms have been extensively studied in the dog and rat. Considerably more information is available about the structure and function of the brain of the cat, rat, and primate than of humans.

This review will focus on research in several areas including: carcinogenesis, animal models, reproduction, disease, parasitology, and clinical techniques. There are many other research areas including nutrition, immunology, and behavior that have also aided animals. The criteria used to select the specific examples within the six research areas were based upon the economic impact and the number of animals affected. Examples of basic, applied, recent, and historical research were selected. Soave' in a previous review of this subject emphasized the benefits of cardiovascular research to animals.

Benefits for animals are attained through various means and the means often are difficult to ascertain. Researchers conducting studies for animals review published articles for information on basic concepts, techniques, or descriptions of disease entities, and apply these ideas directly to animals. Veterinarians work- ing with other biomedical researchers often recognize possible applications of the research to animals. Biomedical researchers in need of animal models may seek the assistance of veterinarians in finding populations of animals with naturally occurring diseases. In these varied ways some of the most modem methods of treatment have first been used in veterinary medicine to relieve suffering in animals.

CARCINCGENESIS

Cancer researchers have used normal animals for experimental studies but they have also extensively used naturally occurring conditions in animals. Jacob Furth utilized the chicken with lymphoid leukosis to provide evidence that a transmissible filterable agent was the cause of this type of leukemia. Peyton Rous3 of Rockefeller University was able to transmit avian fibrosarcoma with cell-free

48 0077-8923/83/0406-0048 $01.7512 0 1983, NYAS

Ewald & Gregg: Research for Animals 49

filtrates and it was this type of research that earned him a Nobel Prize. It even- tually became evident that the conditions of fibrosarcoma and lymphoid leukosis are caused by the same agent. This earlier work concerning the viral oncology of leukosis and fibrosarcoma in chickens led to studies determining that a filterable agent was the cause of Marek’s Disease, a lymphoproliferative disease, which appeared in 1949 and 1950 in the United States. Sevoian4 in 1%2 was able to transmit the disease with regularity. It was not accepted that a herpes virus was the primary cause of Marek’s disease until other research on Burkitts lymphoma and herpes virus saimiri indicated the role of herpes virus in leukemia. The earlier development of tissue culture methods and later viral propagation by Enders5 made it possible for Churchill and Biggs to develop a live, attenuated virus vaccine for Marek’s disease. It has been estimated that the economic benefit of this vaccine to the poultry industry was more than $460 million in 1%5 to 1974 or more than $160 million for 1974.6 A disease that once caused considerable deaths in chickens is no longer a concern. Obviously this is an instance where cancer research has benefitted animals, prior to the final benefit to humans.

Leukemia research has also aided the study of the bovine leukemia complex. This condition is the most common neoplasm of dairy cattle. Based on the similar early work of Bittner’ on the “milk factor,” it has been shown that this virus can be transmitted in milk to calves. Immunologic diagnostic tests have been developed to identify affected animals and presently vaccines are being tested to control bovine leukemia virus with lymphoid suspension cultures.

The interest in human leukemia research has led to investigations of leukemia in the cat. Hardy, a veterinarian, has been involved in these studies in collabora- tion with Old and this research has resulted in the development of an indirect fluorescent test for the feline oncomavirus cell membrane antigen (FOCMA).n Both horizontal and vertical transmission of leukemia virus in cats has been demonstrated and it has been a significant problem, not only in catteries, but for the individual pet owner. A vaccine is now available for feline leukemia. This is but one facet of feline leukemia virus research and is an example of a veterinarian participating in a biomedical research program who has been able to rapidly transfer the most recent developments to practical application in veterinary medicine.

ANIMAL MODELS

There have been many abnormal conditions described in humans that were later observed in animals. The description of abnormal conditions, subsequent research, and the development of diagnostic criteria have made it much easier to diagnose these conditions in animals. Dr. Harvey Cushing in 1932y described the clinical manifestations of tumors of the pituitary, a condition that now bears his name. Cofiin and Munson lo first described this condition in dogs in 1953 and now it is a syndrome easily recognized by veterinarians. We now realize that Cushing’s syndrome can either be a result of pituitary tumors or primary adrenal hyperfunc- tion. An adrenocorticolytic agent, mitotane (0 ’ p ‘DDD) was developed for chemotherapy of adrenocortical cancer in humans. This agent is now used for the treatment of Cushing’s syndrome in the dog. It should be noted that the drug is more effective in dogs since humans are more resistant to the cytotoxic effects of DDD on the adrenocortex.

Hemophilia has long been recognized as a pathologic condition in humans.

50 Annals New York Academy of Sciences

Research in human medicine has shown the multiplicity of factors that can cause this condition. This research enabled the identification of hemophilia A in a family of dogs in 1946.” In 1970, Dodds l 2 identified canine von Willebrand’s disease that was the same as that described in humans by von Willebrand l3 in 1946. This work has led to a greater awareness, improved treatment, and prevention of this condition in animals. Brinkhous et al. l4 proved the hereditary basis for hemophilia A in dogs. The recognition of hereditary transmission of disease in animals generally results in a greater benefit to animals than to humans. The identification of an undesirable genetic trait usually results in the elimination of affected animals from the genetic pool, since animal breeders are generally very intent on removing any undesirable genes from their population.

Animals with abnormal conditions are commonly used in research as animal models for the condition occurring in humans. An example of this is the extensive list of animals available that have thrombotic and hemorrhagic disorders. Colonies of animals maintained by individuals such as Brinkhous and DoddsI5 have made it possible to study these conditions in humans. A circular beneficial pathway is established in which both humans and animals are aided.

Another example of a condition that was first recognized in humans for which a treatment was developed is canine cystinuria. This condition was identified as early as 1908 by Garrod“’ and in 1936 Brand and CahillI7 described this condition in the dog. Frimpter, Thouin, and EwaldIR in 1%7 utilized penicillamine, which had been developed for humans, to control this condition in animals. This treatment has provided a means of preventing the development of cystinuric cystic calculi.

There are many other examples of conditions first found in humans, later in animals which now serve as animal models for human disease and are helping to eliminate or control these conditions in humans. These include pyruvate kinase deficiency resulting in hemolytic anemia, systemic lupus erythematosis, farmers lung, esophageal aclasia, hyperthermia, Ehlers-Danlos syndrome, Klinefelter’s, and lysosomal storage diseases. Extensive descriptions of these conditions have been published.lg

REPRODUCTION

The area of reproductive research has always been of importance to agriculture. Artificial insemination, embryo transfer, and now in v i m fertilization are only a few examples. The treatment of infertility and reproductive problems such as pyometra and even ovariohysterectomy in pet animals are based on an understanding of endocrine control of the reproductive organs. Drugs such as prostaglandin, oxytocin, estrogens, and gonadotrophins, which have been developed and primarily studied in rabbits and rats, are commonly used in veterinary medicine.

Embryo transfer in cattle has been estimated to be a $20 million a year industry. This has permitted increasing the reproductive rate of desirable cows, exportation of embryos, and obtaining progeny from infertile COWS.^" The procedure involves inducing follicular development and superovulation with gonadotrophins. In addi- tion, prostaglandins are administered to terminate the luteal phase, thereby allow- ing ova to be collected at any time. Normally the animal is then artificially insemi- nated and the ova are recovered from the uterus six days after estrus.

The first embryo transfer work was designed to answer a basic scientific question as to whether the phenotype of the embryo was influenced by the uterine


environrnent.*l These embryo transfers were performed by Walter Heape in 1891 in rabbits, and it is interesting to note that he anesthetized these animals with chloroform, which had been first used in medicine in 1847. Research on pituitary hormones in animals permitted Pincus to use gonadotrophic hormones to induce superovulation in the rabbit.** The first artificial insemination in research was performed by Spallanzani in dogs.*’ Since that time, considerable research (much of it on animals) has studied sperm maturation as a part of birth control research. Even though prostaglandins were first discovered in human semen, extensive animal research was conducted to realize all the varied activities of these com- pounds, such as their luteolytic effect. Prostaglandin is also used in a condition of dogs called pyometra when surgical correction is not possible.

DISEASE

Medical science has historically been closely linked with animal disease research. As early as the 18th century when Rinderpest, a highly fatal plague of cattle was sweeping across Europe and killing millions of cattle, medical institu- tions were called upon to stop the onslaught of this and other devastating epidemic diseases, such as anthrax and foot-and-mouth disease. This period brought with it the development of the first veterinary schools and the beginning of comparative medical research into the cause and prevention of many diseases. One of the first great veterinary-physicians, Edward Jenner (1749- 1843), not only discovered that cowpox vaccination effectively protected humans from smallpox, which has led to the recent eradication of this disease from the world, but also published observations on hydatid disease and canine distemper.**

Many great discoveries were made during the 19th century that were the result of animal and basic research into diseases that plagued both humans and animals. Work by Chamberland, Roux, and Pasteur led to the first chemically attenuated vaccine for anthrax that protected sheep from this disease.‘* This discovery led the way to the control of many diseases, both bacterial and viral, through the use of heat or chemical attenuation. Pasteur has been credited with much of the early work on attenuated vaccines. Probably his most notable work was on rabies, which he was able to attenuate through passage in rabbits. Pasteur also tested his vaccine on dogs before attempting to use it on humans. For nearly a century, Pasteur’s vaccine was the only treatment available for rabies in humans.

Before the turn of the century, animal research brought major developments in bacterial disease control. The physician, Jean Villemin, and the veterinarian, Jean-Baptiste Chauveau, proved that tuberculosis (TB) was transmissible both by inoculation and by ingestion in rabbits and guinea pigs.= The physcian, Robert Koch, introduced tuberculin as a cure for tuberculosis after his discovery that it cured a guinea pig with a subcutaneous TB lesion.23 However, the true value of tuberculin as a diagnostic agent was discovered by the veterinary microbiologist, Bernhard Bang. This discovery was made using cattle, but has been equally important in the diagnosis of tuberculosis in man. Through the use of the tuberculin test in cattle and a strict eradication program, tuberculosis is now a rare disease in North America and most of Europe. Another interesting benefit of bovine research on tuberculosis was the development of the vaccine, Bacillus of Calmette and Guerin (BCG), named after the physician and veterinarian who developed it for use in cattle. Its value, however, has been in its worldwide use as an immuniz- ing agent in human medicine, not only for tuberculosis but to boost the immune response to certain kinds of cancer.


At the turn of the century, another major contribution from animal research was being made in the area of bacterial diseases. Daniel E. Salmon, a veterinarian in charge of the new Bureau of Animal Industry (BAI) (later to be the U.S. Department of Agriculture), isolated the first salmonella organism from swine and produced the first bacterin against Salnionella cholerasuis, which protected pigeons from experimental infection.’4 As a result of this early success in animal research, we now control many human and animal diseases through the use of bacterins. In fact, typhoid fever is controlled today in much of the world with a bacterin very similar to that of Salmon’s. Bacterins are used widely in veterinary medicine to control epidemic bacterial diseases of livestock. These diseases include Pasteurella pneumonia, leptospirosis, anthrax, blackleg, malignant edema, and fowl cholera.

After the development of cell culture techniques in the early part of this century and the demonstration by Enders> that viruses could grow, multiply, and be enumerated, many major viral disease breakthroughs followed. Cell culture techniques did not replace the use of animals in disease research, but opened the door to basic research on the identity of viruses and allowed for accurate qualitative and quantitative observations of viruses. The effect a virus has on an animal still remains a fundamental feature of all disease and immunologic research.

The number of live, modified-live, attenuated, and killed vaccines that have been developed in the past twenty years are too numerous to list. However, many major epidemic viral diseases of man and animals can be successfully controlled through the use of vaccines. Certainly, some vaccines have broader spectra or longer lasting immunity than others. Also, success in producing effective vaccines against some virus types, such as the herpes group or cytoplasmic viruses, has been limited. These problems will remain a fertile area for future immunologic research.

Extensive chromosomal studies in animals and microbes were preliminary to another new and powerful tool of disease research that has the potential of revo- lutionizing the pharmaceutical and‘biologics industry. DNA recombinant technology has yielded a new vaccine for foot-and-mouth disease as recently announced by the Plum Island Animal Disease Center of the U.S. Department of Agriculture (USDA). This is the first effective vaccine to be produced using microbial expression of recombinant DNA. The virus-free vaccine contains a short segment of sterile purified protein that had been shown in 1975 to be the antigenic component of the virus coat.25 It should be noted that although this vaccine was produced in a matter of months, it required many years of basic research and animal testing in mice, guinea pigs, swine, and cattle to determine which viral protein component produced an immune response in animals. Other viruses with known antigenic subunits that may be candidates for this type of technology include human hepa- titis B ,26 canine parvovirus, infectious bovine rhinotracheitis, transmissible gas- troenteritis of swine, and pseudorabies.

PARASITOLOGY

Probably one of the most notable historic events of parasitic research was the discovery of the first arthropod vector of disease. This discovery dates back to 1888 during the early days of the Bureau of Animal Industry (BAI). For 100 years prior to this time, cattle in the southern states had been plagued by a wasting disease. Little was known of the disease except that it seemed to follow in the wake of cattle drives from Texas, thus the name Texas Cattle Fever.


In 1888 the BAI physician and early microbiologist, Theobald Smith, deter- mined that these cattle were infected with a protozoan parasite of the red blood cells (Piroplusmu big em in^).^' Cattlemen had begun to suspect that ticks were the cause of the disease, and a strong proponent of this theory was BAI veterinarian, Fred L. Kilbourne, who carefully devised an experiment with ticks and cattle to test this theory. With an understanding of the life cycle of the Texas fever tick worked out by his colleague, Cooper Curtice, also a BAI veterinarian, Kilbourne was abie to prove that infected adult ticks as well as their offspring could transmit piroplasmoskZ7

The success of Kilbourne's experiment on the transmission of Texas Cattle Fever had a direct effect on human health and disease control. It was at this time that the U S . had undertaken the construction of the Panama Canal that the French had twice attempted and failed, primarily due to Yellow Fever. Kilbourne's work provided medical scientists with the necessary lead to determine that mosquitos were the vector of Yellow Fever.'* The subsequent mosquito control program in Panama made possible the completion of the Panama Canal. In other studies, the role of arthropods in diseases such as malaria, typhus, bubonic plague, encepha- lides, and anaplasmosis were quickly elucidated. Vector control programs or vaccination for these diseases now prevent them from becoming epidemic in most of the world where they still exist.

More recently, medical research on another arthropod-transmitted zoonotic disease has benefitted horses when there was a disease threat to this U.S. livestock industry. In this turnabout, the USDA was able to acquire human vaccine attenuated in guinea pig heart cells for Venezuelan Equine Encephalomyelitis (VEE) from the U.S. Army Medical Research and Development Command.'Y This vaccine had been developed and stockpiled in the event that the military would need it. In 1!371,2.8 million doses of human VEE vaccine were administered to horses in 19 states and the District of Columbia to prevent this disease from becoming established in our equine population.

Frequently major discoveries in the field of medicine are not the direct result of a single piece of applied research, but encompass a broad base of basic research that offers the important key to solve a problem. This was the case in the control of the screw-worm parasite (Cochliomyiu hominivorux) from the United States, in which basic research on insect genetics played an important role.

The larva of the screw-worm fly is a flesh-eating parasite that infects wounds of warm-blooded animals. As the southwest United States was being settled in the 1880s, the population of cattle and screw-worms increased until the screw-worm became the major predator on newborn calves.3o A USDA entomologist, E. F. Knipling, initiated the concept of screw-worm control through the use of sterile males as early as 1937, when he discovered that female screw-worms were monogamous. It was not until 1950 when basic genetic research into radiation effects on the chromosomes of drosophila by Muller gave Knipling the key to successfully sterilize male flies by rad ia t i~n .~ ' With this technique, a successful eradication was accomplished in 1954-1958 in Florida. The cost of eradicating screw-worms from Florida was $10.6 million with an estimated annual savings of $20 million. The program was then extended to the rest of the U.S. with similar success by 1%6. Since 1981, the control program has been expanded deep into Mexico with hopes of eradication in this country as well. As a result of this successful program in the U S . , work is now under way to similarly control the tsetse fly, house fly, and mo~qui to .~ ' Such research could have inestimable benefits for disease control everywhere in the world.

While considering recent accomplishments of animal research and parasitol-


ogy, the unraveling of the complex life cycle of toxoplasmosis should be men- tioned. Since it was first recognized in 1908, this protozoan has been seen in 200 species of animals, and as early as 1939 had been incriminated as the cause of perinatal neurologic disorders in humans.3' In the 1940s toxoplasmosis was reported in most domestic animals and by 1957 was implicated in perinatal mortality in Despite these reports, and other reports showing that one half of the tested human population of New York City had antibodies to toxoplasmosis by the age 40,34 little was known about the mode of transmission of this disease. It was only through transmission studies in which mice were fed the feces of cats which had been fed toxoplasma cysts, that this mode of transmission was first under-

It was not long before the infective form in cat feces was identified as the coccidian oocyst of Isospora bigemina, a parasite that had long been recognized in cats. It is now known that cats and certain other felidae are the primary hosts of this parasite and that all other species are infected with an intermediate merozoite-like form of Isospora bigemina. It was only through the contributions of many animal researchers in both the medical and veterinary fields that these two organisms, Toxoplasma gondii and Isospora bigrmina, were found to be two forms of the same agent.

Another area of parasitology that relies heavily on experimental animals is in the development of antiparasitic drugs. It is not surprising that nearly all antiparasitic drugs that are developed are first tested on animal models, not only for ethical reasons, but for safety and economic reasons as well. Though many antiparasitic drugs are tested in vitro, it is still necessary to study the host-parasite-drug interac- tions to determine what indirect effect the drug may have on the host-parasite relationship.

One outstanding example of this indirect effect, as well as being a prime example of cross-currents in biomedical research, is the antifilarial drug diethylcarbamazine. This drug was developed after World War I1 out of a search for a treatment for filariasis, which infected over 15.000 U.S. troops in the Western Pacific. The search was carried out using in vim microfilaria as well as filarial- infected cotton rats and dogs.36 Of the various piperazine derivatives tested, diethylcarbamazine proved to be the most effective microfilaricide in vivo. It is worth noting that this drug would not have been found by in vitro testing alone because it has no visible effect on filarial worms. However, the drug sensitizes the surface of microfilaria in such a way that they become easily phagocytized by the fixed macrophages of the reticuloendothelial Though this drug's value in treating filariasis in humans was discovered through the use of heartworm (Dirofilaria immitis)-infected dogs, its value as a prophylactic or therapeutic drug for this disease was not immediately recognized. This is mainly due to the fact that the drug did not always kill the adult heartworms in early trials. Today this drug is used as the drug of choice throughout the United States as a prophylactic treatment for dogs living in heartworm endemic areas. Its value is in the prevention of the development of adult heartworms by eliminating the microfilaria before they develop into adults.

Niclosamide (Yomesan) is an anticestodal drug developed in Germany in 1960. Its efficacy was first demonstrated in laboratory rats infected with Hymenolepsis d i r n ~ t n u t a . ~ ~ Since then, it has been used as an anticestodal agent in all domestic animals and humans and is considered the most effective agent for such infections. Unlike the history of diethylcarbamazine, this drug's value in veterinary medicine was immediately recognized and has been widely used, especially in dogs and cats. Only relatively recently has this drug been widely accepted for treatment of human


tapeworms and at present is still only available from the Center for Disease Control.

CLINICAL TECHNIQUES

Medical research on clinical techniques very often requires the use of animal models of similar size and physiology as humans. Many modem medical techniques that were first researched in animals are being applied in veterinary prac- tice. In the area of diagnostic imaging and surgical techniques some interesting current examples come to mind.

In the field of diagnostic imaging, all new methods involving any form of radiation, including sound waves, must be tested first in animals to determine their safety. As a result, diagnostic ultrasound was used experimentally in the rat, cat, and dog before it was used in humans. One of the earliest trials was conducted in 1949 by Ludwig and strut her^^^ to determine if gallstones implanted in a dog could be located with ultrasound. Today, ultrasound imaging is used routinely as an aid in the diagnosis of pregnancy in humans. Though it has not been widely used for this purpose in animals, it has been shown to be a useful aid in pregnancy diagnosis in ewes and h o r s e ~ . ~ " It is particularly useful in veterinary medicine to differentiate solid, cystic, or mineralized masses in the abdomen of animals and to diagnose cardiac abnormalities. Ultrasound imaging has even been widely used to measure the thickness of fat on meat-producing animals.'O

In the field of surgery there have been several technological advances in recent years that have been researched in animals and are now finding their place in veterinary medicine. One such technique is cryosurgery that has a long history dating back to the late 1800s when Openchowski4' used a jet of ether to freeze an area of cerebral cortex of a dog and noted the reversible changes in motor and sensory reflexes that occurred. He also reported that little hemorrhage occurred as a result of freezing. More recently, cryosurgery has been used in both human and veterinary medicine to remove tumors and warts, to cure chronic infections of the prostate in man or anal fistulas of the dog, and to remove the lens from the eye of both man and dogs. Interestingly, the most promising area now being researched with cryotherapy in humans is the relief from chronic pain and migraine headaches through selective freezing of nerves, or brain arteries in the case of migraines, which is surprisingly similar to Openchowski's early experiments on dogs. Recently, cryoanalgesia has also been used successfully to relieve chronic lameness in horses.

Probably one of the most promising new tools is the surgical laser, which has been thoroughly studied using selected animals that simulate closely human tissue responses to this new form of radiation. The animal models vary widely depending on the tissue being irradiated. To study the effects of the laser in the eye, rabbits and monkeys are used; for skin, the miniature pig, most similar to the human, is used. To study carcinogenic effects of the laser beam itself, the nude mouse is preferred. 42

The laser's most obvious values are its precision, bloodlessness, and its ability to penetrate the eye for noninvasive retinal surgery.

A unique application, which has developed out of the unusual joint efforts of cancer researchers in the well-known Roswell Park Memorial Institute and Richard Thorna, a local small-animal veterinarian, is the use of the argon laser to selectively destroy photosensitized tumor masses in pet dogs and cats.43 Animal


experimentation and clinical findings have shown that rat tumors and a number of human tumors can be selectively photosensitized by the tumor’s specific uptake and retention of exogenous hematoporphyrin derivative. When this tissue is photoradiated with the red light of the argon laser, administered through a fiber optic scope, the photosensitized tumor cells rapidly necrotize leaving minimal normal tissue damage.

Through this close relationship between a practicing veterinarian and a cancer research institution, these research findings were extended to benefit pet animals suffering from primary tumors. This animal research study furthered human cancer therapy by adding to the number of primary tumors successfully treated with the argon laser and furthered animal health by providing a new tool to the veterinarian for the treatment of animals. More relationships such as this could perhaps transcend professional boundaries and bring us into a new age of comparative medicine.

CONCLUSION

This review includes only a few examples of how animals have been helped. It is the intent of this paper to stimulate interest among people to report other examples of how biomedical research has benefited the animals who originally served as the experimental subjects.

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ANIMAL RESEARCH FOR ANIMALS

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