Of mice, and pigs, rabbits, frogs, dogs, cats, sheep, chickens, monkeys, zebra fish, armadillos, and men


by Lillian Kim

Inside a nondescript building at Emory, there is a door behind which you can just make out the sounds of soft grunting. Behind the door are about a dozen pale pink pigs housed in a row of large steel pens, two or three pigs to a 40-square-foot pen. When visitors enter, the animals amble to the front of their crates and snuffle good-naturedly at the proffered hands. These pigs smell surprisingly clean -- but then, how many city-bred folk know what pigs are supposed to smell like? With their sleek bodies and bright eyes, they present a picture of porcine health, and the veterinarian confirms that they are, quite literally, in the pink.

The pigs serve a variety of purposes. Some are used to develop surgical interventions for uterine fibroids and gastric reflux. A few are assigned to studies of atrial fibrillation and research in islet cell transplantation for the treatment of diabetes. Others are used to train physicians and surgeons on advanced trauma life support procedures, radiological diagnostics, and organ harvesting, as well as minimally invasive surgery.

Pigs are needed for these studies because their organs are large and fairly similar to those of humans. More important, though, they are needed because their lives can be sacrificed. The pigs are anesthetized, and their bodies cut open. Most don't wake up.

No simple answers



The advent of genetically modified mice
has revolutionized biomedical research
and made it possible to reduce the number
of higher-order species used. More than
32,000 mice now are used in animal stud-
ies at Emory, most of them housed in
ventilated cages that are inspected daily,
says Neville Whitehead, animal research
facility manager.

The answer most readily given to the question of why scientists use animals in research is that they hope to save human lives and improve human health. But questions remain. Are animals in fact good models for human biology and disease? Can't we use alternative methods to achieve medical advances without animal research? Must we use highly intelligent animals such as monkeys and apes? Is it right to use unwanted cats and dogs that otherwise would be euthanized by the pound or pigs that would be turned into bacon?

These are the questions asked by animal rights activists who would halt all animal research. They are the same questions scientists ask of themselves in an ongoing dialogue within the research community, a dialogue that will continue as long as there are animals in research.

Not all animal advocacy groups rigidly oppose animal experimentation. The Humane Society of the United States recognizes that animal research has helped advance scientific knowledge and medical practices and names as its goals the reduction and eventual elimination of pain and distress in laboratory animals.

At the other end of the spectrum, though, are groups like In Defense of Animals (IDA) and People for the Ethical Treatment of Animals (PETA), which deny that animal research has any value. They argue that it is unethical for humans to eat animals or even consider them property, much less use them in biomedical research. Some even have compared researchers who work with animals to Nazi doctors who performed atrocious experiments on humans in concentration camps during the Holocaust. (The irony is that because of those experiments, the Nuremberg Code was adopted and specifically states that experiments involving humans "should be designed and based on the results of animal experimentation....")

Impassioned and sometimes eloquent advocates for both perspectives have endlessly explored the question of whether man has the ethical right to experiment on animals but have not bridged the ideological impasse. What it comes down to is this: Some of us hold that human life has greater value than animal life. Some make no such distinction.

"They accuse us of being 'specists,'" says psychologist and Yerkes Associate Director Tom Gordon, referring to the term "speciesism" that animal rights advocates have coined to draw a parallel with racism. "Well, we are. Our ethics and our morals tell us that all human life is distinct and special."

By no means do scientists cavalierly exploit this privileged status, however, as he and many other researchers emphasize. They point out that they use animals only in limited circumstances and under strict regulation. But the critical factor driving animal research, the justification scientists invoke time and again, is that sometimes there is no other way to learn certain things. Certainly medical advances have occurred without animal-based research. But researchers say such advances are only happy accidents unless we know how and why they work.

"There is simply no way that we are even within decades of being able to replace the complexity of a living organism with a tissue culture dish or a silicon chip," says Robert Rich, executive associate dean of the Emory School of Medicine. "I can't conceive of medical research that does not involve animals."

Understanding the process

Federal law mandates testing experimental drugs and vaccines in animals before testing them on humans.

Rich's statement may surprise those unfamiliar with the biomedical research process and the key role of animal research.

Many people know about clinical trials, human studies of experimental treatments required by the US Food and Drug Administration for approval. Less well known is that federal law also mandates that experimental drugs and vaccines be assessed in animals before entering human testing, to determine that they are safe and promising enough to warrant the enormous ethical, logistical, and economic challenges of human trials.

Yet more obscure is the fact that clinical trials represent only the very end of a development process that draws from an enormous body of research, including many animal studies.

The core of all research is basic science, which seeks to learn about the functions of organisms at molecular, cellular, and system levels. Without understanding the body's mechanisms and processes, it is impossible to determine the effects of disease and injury and how to treat them. Using animals, scientists can analyze and manipulate these functions in ways not feasible in humans.

"Sometimes you need to do studies in animals just to understand the basic cell biology, not really for any specific disease," explains immunologist Rafi Ahmed, who uses transgenic and knockout mice, in which certain genes have been manipulated, to study how the immune system develops and functions. He aims to better understand the immune system and to use that knowledge to help create improved vaccines and therapies. Already other Emory researchers are translating such findings into applications, including new types of vaccines for infectious diseases and better ways to prevent organ rejection in transplant recipients.

Basic science research with animals also leads to advances in surgical procedures. A notable example is pallidotomy, a treatment for the tremor, stiffness, and slowness that are the hallmarks of Parkinson's disease. For decades, the procedure, in which a neurosurgeon destroys part of the basal ganglia structure of the brain, gave wildly erratic results; some patients showed remarkable improvement, others little or none.

By studying the brains of monkeys, scientists discovered that only a part of the basal ganglia controls motor function, which explained why haphazardly targeted pallidotomies failed. Based on these findings, neurologists Jerrold Vitek and Mahlon DeLong pinpointed the procedure more precisely, greatly improving results.

"Without that animal work, we wouldn't have made the procedure more consistent," Vitek says. "We wouldn't even know why it worked."

The translation of basic science into concrete medical advances isn't usually immediate. It may take years, even decades, for human applications to derive from a scientific finding, which is why scientists say it is unwise to dismiss experiments that don't hold the ready promise of practical returns.

This is one of the criticisms animal rights activists direct against Stuart Zola, the newly appointed director of the Yerkes Regional Primate Research Center at Emory. A neuroscientist, Zola specializes in memory formation and memory problems, specifically amnesia.

In studies with monkeys at the University of California at San Diego, Zola conclusively identified brain structures that play important roles in memory function. While he isn't working toward a particular therapy or intervention, his findings provide insight into the memory loss that characterizes numerous conditions, including brain injury, Alzheimer's disease, chronic stress, normal aging, and depression.

In other research, Paul Plotsky uses mice, rats, and monkeys in his stress neurology laboratory to study the biological basis of depression and other mental disorders. He examines early-life risk factors like abuse or neglect that cause permanent, measurable changes in brain chemistry, resulting in greater vulnerability to psychiatric disorders in adulthood, such as major depression and post-traumatic stress.

Neuroscientists Tom Insel, Larry Young, and Jim Winslow of the Center for Behavioral Neuroscience are studying a specific gene for the hormone oxytocin that appears to control social behavior in mice and voles. At the Yerkes Field Station in Lawrenceville, primatologist Frans de Waal observes the social dynamics of groups of chimpanzees.

It's important to note that some behavioral studies are necessarily invasive as well as observational. For instance, Plotsky implants electrodes and dialysis fibers into the brains of some animals to assess the release of neurochemicals during behavioral tests. At present, he must also dissect brains to measure brain chemicals and gene expression until more sensitive neuroimaging techniques become available.

"I absolutely hate killing animals, even rats and mice," Plotsky says. "I'd love the day to come when we can reduce the use of these animals. But cell culture is not a replacement. While I think information from cell lines is critical, it's not going to help us understand how networks of cells in the brain interpret environmental events."

Human stand-ins

The list of medical advances in which animal research played a key part is so long and varied - ranging from the polio vaccine developed using monkeys to insulin developed with dogs - that a full catalog would take up this entire publication.

One famous example is organ transplantation. Before performing the first successful human organ transplant in 1954, Harvard surgeon Joseph E. Murray performed kidney transplants in dogs. Today, nearly a half century after Murray's Nobel Prize-winning work, Emory transplant specialists Christian Larsen and Thomas Pearson are working toward preventing organ rejection in transplant recipients without lifelong immunosuppressive therapy, which leaves patients dangerously susceptible to infections. The researchers use in vitro (laboratory) methods as well as mice and nonhuman primates.

Those opposed to animal research say using animals to replicate human diseases and conditions constitutes "bad science." They argue that animal biology differs too greatly from human biology to be comparable.

An oft-cited example of an animal research failure is thalidomide, the drug that caused thousands of European babies to be born with severely deformed limbs. Tests of thalidomide in rodents and rabbits did not find such birth defects.

The failure lay not in the use of animals but in the choice of species. The rodent studies had indicated that rats metabolized thalidomide differently from humans. Tests in baboons conducted after the birth defects started showing up found the drug caused the same defects in baboon infants. Animal studies had, in fact, provided a vital clue.


©2002 XPLANE.com

Criticism of animal research is harshest when researchers use animals to study diseases unique to humans, like AIDS.

The development of any vaccine is scientifically arduous and extraordinarily expensive, but AIDS has magnified those challenges because of the nature of HIV, which invades and destroys the very immune cells that a vaccine needs to enlist. Researchers have had to rethink vaccine strategies and create entirely new types of vaccines. And because these vaccines are new, researchers strongly feel they must be studied in animals -- specifically nonhuman primates. "Because HIV infection is fundamentally different from all other infections for which successful vaccines have been developed, new vaccine approaches attempt to activate particular arms of the immune system in ways that were not essential for earlier vaccine successes," explains AIDS physician and researcher Mark Feinberg. "The most promising strategies for the development of an AIDS vaccine employ concepts that have never been used in humans, so it is neither ethical nor appropriate to evaluate new types in humans before they are first shown to be safe and able to elicit the desired immune responses in rodents and nonhuman primates."

But HIV generally does not cause infection in nonhuman primates, except chimpanzees. While some chimps at Yerkes have progressed to AIDS several years after being infected with HIV, they are the exception. The long latency period of HIV infection in chimpanzees, similar to that of humans, makes them unsuitable for HIV studies with an accelerated timeline. As a result, AIDS researchers have turned to rhesus macaque monkeys.

While HIV does not infect macaques, its close cousin, simian immunodeficiency virus (SIV), does. To study AIDS vaccines in monkeys, researchers created a hybrid virus, SHIV, which combines SIV's ability to infect monkeys with some of HIV's genes. AIDS researchers acknowledge that SHIV doesn't perfectly parallel HIV. But they emphasize it's a very good model.

"Our vaccine effectively controls SHIV in monkeys, and we believe the human version of the vaccine will effectively control HIV in people," says virologist Harriet Robinson, whose DNA-based vaccine will move to clinical trials in 2002. "Without the monkey data, we would not take our vaccine forward into humans."

Care and use of research animals

Some of us hold that human life has
greater value than animal life. Some make no such distinction.

As a principle, scientists use the lowest order animals and the fewest animals appropriate for a particular study. For early stages of research, researchers generally use mice and rats. Of the roughly 35,000 experimental animals at Emory, about 32,000 are mice, many of which have been genetically engineered.

In addition to mice, Emory's animal facilities house on average some 3,000 nonhuman primates, 90 frogs, 50 rabbits, 50 dogs, 20 cats, a dozen pigs, and a room full of inch-long zebra fish, which no one tries to count. On rare occasions, a few sheep or chickens are brought into the colony. Interestingly, there are only a few guinea pigs; the animal whose name is shorthand for experimental subject has been supplanted by its smaller rodent cousins.

All the animals are either bred by Emory or purchased from licensed animal breeders specializing in research animals. Emory stopped acquiring cats and dogs from animal shelters a few years ago because of public opposition to the practice. But scientists point out that this policy change has not necessarily solved the ethical quandary: cats and dogs are being bred for research purposes while unwanted cats and dogs are euthanized every day.

The animals are cared for by veterinarians, animal care technicians, and enrichment specialists, according to the regulations of the Animal Welfare Act (AWA) and the National Institutes of Health (NIH). Emory also follows guidelines established by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC), an independent organization that monitors animal research institutions. Emory and Yerkes both are fully accredited by AAALAC.

In addition, as required by the Animal Welfare Act and NIH policy, Emory's institutional animal care and use committee (IACUC) reviews all studies involving animals to determine whether researchers are using animals appropriately and humanely and adhering to all regulations and guidelines. The committee consists of volunteer scientists, veterinarians, and community members.

"It's a huge amount of work," says IACUC chair Judy Kapp. "But we do it because these activities improve the sense of joint venture between the people who are responsible for the husbandry of these animals, the veterinarians, and the scientists. That's very positive."

Researchers submitting new study protocols for approval must include reviews by a veterinarian and, if nonhuman primates are involved, an animal enrichment specialist. The latter works to ensure full compliance with the AWA's provisions for the psychological well-being and enrichment of nonhuman primates.

The deliberate redundancy of federal and independent oversight aims to ensure that research animals receive the best possible care and experience minimal pain and distress. But even veterinarians say it is unrealistic to expect that discomfort in research animals can be wholly eliminated.

"If we are going to study in animals those diseases and conditions that cause pain and distress in humans, then there are going to be some animals that may be in pain or distress," says Michael Huerkamp, associate director of the division of animal resources. "We have to balance the cost of this to animals and the potential benefit to humans, while providing them the finest veterinary care that we can." He adds that such research also benefits animals by advancing veterinary medicine.

Alternative methods?

ÒScientists have an obligation to the taxpaying public to explain what they do and why they do it.Ó -- Stuart Zola

Opponents of animal research argue that nonanimal research methods, such as in vitro experimentation, computer modeling, and human clinical trials, are just as effective as animal experimentation, if not more so. Some animal rights activists even claim that animal research hampers medical progress by diverting funds and resources that could be applied to other types of studies or purposes.

These are dangerous fallacies, say advocates for animal research who argue that the term "alternative methods" is a misnomer, since such methods cannot wholly substitute for animal research. Scientists also point out that these methods always are based on information gleaned from past animal studies. Cell cultures actually require tissue taken from animals and must be sustained in serum derived from animals.

"Computer models and even cell culture lines are useful only because they are predicated on a base of knowledge that initially came from animals," Gordon says.

Without question, in vitro studies and computer modeling are vital research tools that can help identify potential approaches. But at best, these methods can only predict what might happen in vivo (in the body of an animal).

"We look at a variety of exciting strategies that look good in test tubes," Larsen says. "The vast majority of those fail. The appropriate place to figure that out is in an early mouse study. We would never be able to test those in human patients. The cost and the risk to patients just wouldn't be appropriate."

Science simply lacks the technological skill to create an artificial model, in either petri dishes or lines of computer code, capable of precisely mimicking all the incalculably complex interactions that occur within a living organism. "You cannot study how the immune system works in a test tube," says Ahmed. "We're looking at responses being made at the whole-animal level."

Ahmed, who as director of the Emory Vaccine Research Center oversees vaccine programs targeting several infectious diseases, grimaces when asked to consider attempting vaccine research without animals. "It's absolutely absurd," he says.

Animal research advocates say nonanimal research methods have three purposes: to refine tests to minimize animal pain or distress; to reduce the number of animals needed for certain tests; and to replace animals in testing whenever possible.

Scientists are quick to clarify that these principles, while valid, should not be interpreted to mean that animal research as a whole will decrease or cease altogether in the foreseeable future. On the contrary, the need for animals likely will increase.

Need animals more



Researchers Ron Boothe and Dolores
Bradley assess visual development in
rhesus monkeys, which have visual
systems identical to those of humans,
except those of monkeys develop
four times faster.

The explosive growth of genetic research and development of powerful biotechnological tools, such as DNA microarray "gene chip" technology, mean research will rely on animals more than ever, says Rich, who delivers this same message to scientific groups such as the Federation of American Societies for Experimental Biology, of which he is president.

"Things are going to change in a fundamental way over the next couple of decades because of the completion of the Human Genome Project," he says. "We need to understand what all these genes do. And the only way we can understand that is to use experimental animals."

Research needs will shift yet further toward rodents, especially knockout and transgenic mice. Yet large animals and nonhuman primates will continue to be critical to organ transplantation studies and neuroscience research as well as many other studies.

"Anybody who thinks that because of increases in technology we're going to be getting away from animals in research is simply wrong. Our need for animals in research is going to expand at a very rapid rate," Rich predicts.

And that means no end in sight for the animal rights campaigns that already have stepped up in intensity. Local groups have targeted individual researchers, placing their photographs and home addresses - even the name of one researcher's wife - in newspaper ads, leaflets, and websites. The spate of neighborhood leafleting has led to heightened security concerns among researchers, raised yet further by recent events. In September, a fire caused $1 million in damage at the Coulston Foundation, a New Mexico primate research facility. The Animal Liberation Front, which the FBI considers a terrorist organization, later claimed responsibility for the arson.

The IACUC distributes information packets addressing animal rights issues with every study protocol approval. But many scientists now realize it's ultimately their responsibility to educate the public about research and what is at stake. They are, after all, educators.

To that end, Emory is developing a speakers bureau, modeled on one Zola helped develop when he was at UC San Diego. Emory scientists will talk about their research in schools and to civic organizations. The speakers will focus on educating people about the entire continuum of scientific research, from basic science to clinical trials.

Scientists have an obligation to maintain a public dialogue about their work, emphasizes Zola, who was a favorite target of animal rights groups of southern California before he came to Emory. "Even if there were no issues with animal research, we still need to explain what we do, just to heighten the public's interest and excitement about science."

Other scientists are eager for the opportunity to present their research, confident that most of their listeners will prove supportive."I'm not saying we should be extolling our virtues to people," says neurologist Jerrold Vitek. "But we should be telling people what we're doing and why we're doing it. Then people can decide for themselves whether medical progress is worth the price of animal research."

Huerkamp emphasizes that it is a privilege, not a right, to use animals in research. "This is an example of the public trust, something that can be taken away if we are not responsible stewards," he says. "And that puts the onus on our scientists, on our animal care and use committees, and on our institutional leaders to be committed to doing things the best way we can."


Lillian Kim is chief of public affairs for Yerkes Research Center.


 


Many scientists who are devoted to studying a particular disease or condition attribute their zeal to a life-changing moment. For physiologist Richard Nichols, that moment occurred during the Vietnam War, when he visited a VA hospital near Boston.

"In the spinal cord unit there," Nichols recalls, "was a patient who was paralyzed from the neck down from an injury he'd received during the first World War. He was treated well, but he'd been in bed for all these years.

"In the next bed was a young man in his early 20s who had also sustained a spinal cord injury. He had just come back from Vietnam. His doctor said, 'The young guy is going to be just like the old guy in 30 years. We can make them comfortable, but that's it.'

"I decided that was unacceptable," Nichols says.

As a basic scientist, Nichols studies the manner in which the spinal cord regulates posture and balance. While the brain controls many motor functions, the spinal cord itself has some intrinsic motor capacities. Patterns of locomotion, for instance, are generated partly by spinal cord circuits that receive sensory information from the muscles. Associated circuits help keep the body upright and balanced using the same sensory information.

The circuits can be disrupted by diseases like cerebral palsy or injuries to the spinal cord or its peripheral nerves. However, in some spinal cord injuries, such as a broken neck, the circuits located at lower levels remain intact to a large extent. Because the circuits can deteriorate through long disuse, the limbs of paralyzed individuals hoping to regain mobility must be exercised regularly to maintain the feedback loop. But these circuits also may hold the key to restoring balance and upright posture in addition to movement.

"When you think about it, it's not sufficient to make your muscles go in a cyclic fashion," Nichols says. "You have to be able to stand up out of a chair and keep your balance as you go along. That is an enormous feat."

To learn more about how those circuits work, Nichols studies cats. That research has made him a primary target of animal rights activists, who say Nichols conducts torturous studies that have not produced any cures. However, Nichols has accumulated substantial evidence that the spinal cord and the musculoskeletal system are responsible for maintaining posture -- evidence that will provide the basis for designing rehabilitation strategies for patients with spinal cord injury.

What Nichols does is this: He operates on a cat, severing a nerve going to a single muscle, then immediately reattaches it in the same operation. As the cat heals, the muscle regains its full strength, but the sensory information the muscles send to the spinal cord is permanently disrupted, resulting in some loss of dexterity. The barely noticeable impairment can be measured using state-of-the-art methods when the cat performs certain exercises, such as walking up and down ramps and jumping onto platforms.

Sometimes, Nichols needs to make more specific, invasive physiological measurements. To do this, he deeply anesthetizes the cat, then exposes the muscles he needs to examine. At the end of the procedure, the animal is euthanized with an overdose of anesthesia. The cat feels nothing during the entire process.

"I don't like killing animals," Nichols says. "I dislike it very much."

But he uses cats because a great deal of information about feline spinal cord and motor coordination functions compiled by scientists over the past century enables researchers today to make major findings using relatively few animals. In addition, cats will be the first to benefit from any breakthroughs derived from this research.

Using cats also allows Nichols to control confounding factors that might muddy his results; this would be impossible in a study of human subjects with varying types and degrees of spinal injury.

"We're still at the stage where we must depend primarily on animal experimentation," Nichols says, emphasizing that the cats living in his colony are thriving and healthy, with only minor impairment.

Certainly this seems the case during a recent visit to the facility where the colony is housed. As veterinarian Mike Huerkamp eases open the door to the large room where several of Nichols' cats roam freely, the cats freeze in the classic attitude any cat owner would recognize as that of cats caught with a proverbial paw in the fish bowl. Two of the cats are on the counter, pretending to ignore the faucet gushing water full blast into the sink.

"Who turned this on?" Huerkamp scolds as the pair casually jumps down to the floor to indicate their total innocence. All the cats jockey for position around his legs, gracefully swishing back and forth in figure eights. The pushier ones stand on their hind legs and paw at him.

"I find it ironic that Richard, of all people, has been targeted by the animal rights activists, because he's such a caring person," Huerkamp says, explaining that Nichols worked to ensure social housing for his cats.

To Nichols, the most disturbing aspect of the attacks is that they have entered his personal life. In 2000, an animal rights group ran ads in The Emory Wheel and Creative Loafing attacking his research. On two subsequent occasions, the group distributed leaflets in Nichols' neighborhood near Emory.

In addition, last year Nichols received a threatening e-mail from an animal rights activist who has been arrested at demonstrations around the country, including a violent 1997 protest at Yerkes. The e-mail mentioned Nichols' wife, whose name also has been listed on a local animal rights website.


One researcher's story: Seeking a new balance



Physiologist Richard Nichols
and feline friends.







Using state-of-the-art methods, scientists
measure minor impairments in cats per-
forming certain exercises. Examining
motor function in cats may help in
designing rehabilitation strategies
for patients with spinal cord injuries.

"They came into my neighborhood, invaded my privacy, and involved my family," he says.

Nichols promptly launched his own door-to-door campaign to educate his neighbors about his work and correct any misconceptions. With painstaking earnestness, he has explained how he conducts his work, what he already has accomplished, and what he hopes to learn.

"Even people in my neighborhood who are extreme animal lovers and feel uncomfortable with animal research -- after hearing about my research, they endorse what I do," he says.

And he offers this as evidence that the public as a whole will endorse animal research, once people learn how and why researchers do what they do.

In this Issue


From the Director  /  Letters

Of mice and men

Lives on the line

Our GRA connection

Moving Forward  /  Noteworthy

On point: Perspectives on bioterrorism

Coming to a helipad near you

 


Copyright © Emory University, 2002. All Rights Reserved.
Send comments to the Editors.
Web version by Jaime Henriquez.