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AIDS researcher Norman Letvin says developing an HIV vaccine depends on "working in animal models." |
ANIMAL LIBERATION
Peter Singer was an Oxford philosophy student who had little interest in animals, domesticated or otherwise, until he had lunch with a vegetarian friend one day and they began talking about the use and abuse of animals. Singer was quickly converted to the cause, and within a few years became its champion. One of the pivotal events in the treatment of laboratory animals in this country and throughout the world was the publication of his manifesto, Animal Liberation, in 1975.
Just 25 years ago, some proponents of animal experimentation still held that animals' intellectual inferiority to humans meant that they could not be accorded the same rights as humans. Some argued that animals had no consciousness or memory, that they did not think as humans did. The quality and intensity of the pain felt by animals was still subject to debate. Singer, recently appointed DeCamp professor of bioethics at Princeton University's Center for Human Values, refuted the assertion of animals' inequality, pointing out that our society grants equal rights to all humans without regard to IQ or ability to function. "If the demand for equality were based on the actual equality of all human beings, we would have to stop demanding equality," he wrote. "...[T]he claim to equality does not depend on intelligence, moral capacity, physical strength, or similar matters of fact."
As for consciousness and the ability to feel pain, Singer pointed out that we have no reason to believe animals lack either one. Some of the experiments he recounts make their emotional vulnerability all too clear. In the late 1950s, for instance, psychologist Harry Harlow of the University of Wisconsin embarked on a series of experiments in which he deprived young rhesus monkeys of contact with their mothers. Young monkeys who were most completely deprived of parental contact developed very bizarre behavior, and would cling to objects that supplied the most minimal comfort, such as a scrap of terrycloth. Many of his fellow researchers considered Harlow a genius for having established the importance of interpersonal contact to normal childhood development. Singer, on the other hand, pointed out that the experiments demonstrated just how much like us monkeys really are, and he condemned the inhumanity of torturing them to obtain information that could have been elucidated in many other ways, perhaps through epidemiological studies of children who had been separated from their mothers at critical periods of development.
"You can't have it both ways," says biochemist Karin Zupko '77, an animal-rights advocate formerly with the New England Anti-Vivisection Society. "You can't say that animals are different enough from people so that it's acceptable to experiment on them, but enough like people so that the results of the experiments are valid."
MODELS FOR MEDICINE
Scientists, however, counter that you can, in fact, gather useful information about humans from animals that seem vastly different from us. They point to the many surgical experiments performed on pigs, dogs, and monkeys that have led to advances in transplantation, heart-valve replacement, and coronary artery bypass graft surgery.
"Research on live organisms is essential for medical advance," asserts Francis D. Moore '35, M.D. '39, S.D. '82, Moseley professor and surgeon-in-chief emeritus at Harvard Medical School and Brigham and Women's Hospital, respectively. As Moore has pointed out in testimony to the Massachusetts legislature and in his autobiographical book, A Miracle and A Privilege, the first successful human kidney transplant, in which Moore played a pivotal role in 1963, would not have been possible at that time without an understanding of immunology based on experiments in rats and mice. Important aspects of the surgery were developed in larger animals. "There's no substitute for it," says Moore. "Some people say you can set up a computer program to act like a dog. Well, forget it. All animals have responses that we don't understand, and there's no way to set that up on a computer."
Scientists, Says Sandi Larson, "have been trained to look at animals as tools." |
A great deal of our understanding of basic human physiology comes from experiments in large animals, like dogs and chimpanzees. Harvard physiologist Walter B. Cannon, A.B. 1896, M.D. '00, S.D. '37, for example, performed experiments on dogs for many years to understand the basic dynamics of digestion. Different animals may be selected for different purposes. A dog's prostate differs from that of a human in having only two lobes, yet dogs, like humans, can develop benign prostatic hyperplasia.
"Not all animal models are ideal, but some cases are a perfect fit," says Arthur Lage. "Mice are certainly a very good model for studying human genes. Much of the genetic makeup of the mouse is very similar to that of a human; there are large regions of shared identity." That's why, Lage explains, Harvard will probably double its use of mice over the next five years--to about 100,000 mice annually. The chief reason for this is transgenic-mouse technology--which allows the insertion and deletion of key disease genes into the mouse genome. These techniques allow researchers to study the impact of both subtle and drastic changes in the genome, and to make key predictions about how similar changes would affect humans. Mice can be bred, for example, with varying ability to express the p53 gene, which has been implicated in a wide variety of cancers. Understanding how the activity of such genes affects cancer development promises to vastly increase our knowledge of treatment and prevention.
Philip Leder '56, M.D. '60, Andrus professor of genetics and head of the medical school's department of genetics, who pioneered the technology, points out that transgenic mice have been used to test the safety and efficacy of new therapeutics; to detect biohazards; and to advance our knowledge of cancer. Yet he concedes this widely embraced methodology has yet to produce new therapies itself. "It's impossible as yet to bring it home to lives of patients," he says, "because the development of diagnostics and therapeutics takes time."
There are many areas, however, where a direct connection between animal research and patient welfare can be argued. In the field of AIDS, for instance, research on animals has been making important contributions to the basic understanding, prevention, and treatment of this life-threatening disease.
In 1981, Norman Letvin '71, M.D. '75, received a call that would change his life. It concerned an epidemic of mysterious deaths, all caused by unusual pathogens and cancers, such as pneumocystis carinii pneumonia, cytomegalovirus, and rare lymphomas. But the patients suffering from these infections were not humans, but laboratory monkeys.
We now recognize these so-called "opportunistic infections" as signals of the presence of the human immunodeficiency virus (HIV) that causes AIDS. But at that time, the disease was just being recognized in humans, the term "AIDS" itself was unknown, and the cause of all these infections was still a frightening mystery.
Letvin, now professor of medicine at Harvard, says HIV probably began as a relatively harmless virus that infected some species of African monkeys. When it crossed species lines, it did so in several directions, spreading simultaneously into both human and additional non-human primate populations. In these new populations, the infection had much more serious consequences than in the African monkeys: it was lethal. But to Letvin, the realization that a parallel syndrome was occurring in man and monkeys was a tremendous opportunity.
"A great deal of effort has been expended on trying to find rodent and rabbit models for studying HIV infections, but they have not proven terribly useful," Letvin notes. "The only way we can see what happens in the first few minutes, hours, and days after infections--questions that are essential to answer in order to develop an HIV vaccine--is by working in animal models. We are forced to work in these models if we want to answer these questions." (The number of monkeys needed for such an experiment, he hastens to point out, is relatively small: usually about six.)
In Letvin's experiments, monkeys are inoculated with candidate vaccines against HIV. After a brief period during which the vaccine draws a response from the host monkeys' immune system, the animals are inoculated with a strain of immunodeficiency virus that brings on an AIDS-like disease. Periodic blood samples are taken to monitor their white blood cell counts and viral replication. An experimental model that causes the monkeys to get sick is more informative, Letvin explains, because even if the vaccine doesn't prevent infection, it may slow the course of the disease enough to be useful.
"There's little question that exciting animal data is a major drive for the initiation of human studies," Letvin says. "It's not a gatekeeper, but an important piece of a complex puzzle we use to determine whether to go forward with the long march into humans. There are hundreds of approaches one could take. If a strategy does look promising, an animal trial makes it easier to determine whether it's worth spending millions of dollars to measure its safety and efficacy in humans."
Letvin points out that an AIDS vaccine would save millions of human lives, particularly in populations where expensive treatment is not available. Thus the use of animals in research on diseases such as AIDS seems fated to continue for years to come. If the past is any indication, it will probably yield a rich crop of new medical information.
Perhaps the more accurate question then--under the circumstances--is, how much do we care about animal suffering? Is it worthwhile to consider that issue in our quest for better treatment for diseases?
THE THREE R'S
Since Peter Singer formulated his ideas, the animal-protection movement has gone from a series of staccato eruptions to a steady influence on the course of medical research. Everyone involved in the animal-research debate admits that the situation has changed considerably during the last 25 years. Ernie Prentice, a nationally recognized expert in the regulation and ethics of animal research and a member of the institutional animal care and use committee at the University of Nebraska Medical Center, can remember a time when animals were routinely subjected to painful measures without pain control. In one well-publicized experiment, pigs were burned without anesthetic; in another long-running research project, monkeys were subjected to traumatic blows to the head without analgesics. Animals progressed to the end stages of artificially induced malignancies, renal failure, and heart disease, all without any form of pain control.
"Those kinds of projects would not be permitted now. They would be unacceptable for at least two reasons," says Prentice. "One is that we now have regulations that clearly ban this kind of experimentation, and those regulations are adequately enforced to make sure that they're followed. At the same time, there is heightened ethical sensitivity among both researchers and IACUCs. If you had sat in on a meeting of an IACUC in 1985 and were able to compare the level of discussion back then with what goes on today, you would see a tremendous difference."
Increasingly, members of the protection community are taking legal steps to gain input into animal-treatment guidelines, and have found more conventional ways to exert pressure. Marc Jurnove, a member of the Animal Legal Defense Fund (ALDF), is suing the USDA for "aesthetic and recreational injuries" that he suffered when seeing the living conditions of chimpanzees and apes at a Long Island zoo. Jurnove charged that the USDA failed to adopt and enforce adequate standards for the animals' well-being, as is required by the AWA. This past September, the U.S. Court of Appeals for the District of Columbia Circuit, the nation's most influential circuit court, upheld Jurnove's right to sue. Recently, the ALDF also led animal-rights groups in successfully suing the National Academy of Sciences for access to records and to committee meetings pertaining to a guide on the care and use of laboratory animals.
Geneticist Philip Leder's transgenic mice are used to test the safety and efficacy of new medicines. |
Some major funding organizations have also embraced the animal-rights movement. The Doris Duke Charitable Foundation, with assets of $1.25 billion, is one of the 25 wealthiest philanthropies in the country. Although it funds medical research, one of its restrictions is that animals not be used as subjects. This creates a sticky situation for the board, which hopes to fund research on AIDS, cancer, heart disease, and sickle-cell anemia, areas heavily dependent on animal research in the past.
But the effort to occupy a middle ground, supporting the principles of reduction, replacement, and refinement of animal research while acknowledging its necessity, has been extremely frustrating.
Several research institutions have established centers of animal-rights advocacy. The Center for Animals and Public Policy at Tufts University and the Center for Alternatives to Animal Testing at Johns Hopkins University, for example, have tried to establish liaisons with both protectionists and researchers. "I wasn't running around throwing bombs," says Andrew Rowan, Ph.D., former director of the Tufts Center and now senior vice president of the Humane Society of the United States. "I was engaging colleagues in scientific debate without being obstreperous. People were shouting past each other." Veterinarian Peter Theran, vice president of the health and hospitals division of the Massachusetts Society for the Prevention of Cruelty to Animals and director of the MSPCA's Center for Laboratory Animal Welfare, says that his group has had to walk a fine line. "We try to maintain a rapport with both sides," he stresses. "I have to say that we often don't agree with some of the more aggressive groups, like PETA. But there's a tendency to paint the animal-welfare community with a broad brush. And that makes dialogue extremely difficult."
"When you say you're for animal welfare, you're perceived as rabid," says Joanne Zurlo of the Johns Hopkins center. "At the same time, we can't deal with groups like PETA because they believe in abolition of animal use. When we organized the first World Congress on Alternatives and Animal Use in the Life Sciences in 1993, we invited representatives from every organization to sit at the table. PETA would not join. Even the American AntiVivisection Society sent a representative, but members of the hard-line groups who were picketing outside hounded her and called her a murderer."
HUMAN LIVES, HUMANE EXPERIMENTS
The growth of the animal-protection debate has been fraught with acrimony. The results, however, go beyond the additional credibility that has been afforded animal protectionists. Scientists, too, find that they can be more open about the feelings they have or may have had for the creatures in their care, and are more free to explore alternative methods of experimentation.
"All of us, whether we're doing research on animals or not, recognize that this is something that is not optimal," Andrew Rowan says. "If society didn't feel that we needed the information, we wouldn't do research on animals. But society feels we do, and so do scientists. There's a tension between our concern about causing pain and distress and killing animals and our need for new knowledge. No one would say that the animals in research benefit from it, and in a world that was perfect we wouldn't be doing this. We're engaged in encouraging people to make animal welfare a higher priority without compromising their ability to gather information."
Neal Barnard, of the Physicians Committee for Responsible Medicine, argues that the route away from animal research should carry us toward population-based efforts like the Framingham Heart Study, in which heart researchers have closely followed the health habits and outcomes of 5,000 adults for just over 50 years. That study was a key factor in galvanizing current national efforts to lower cholesterol, combat hypertension, and encourage proper diet and exercise to reduce mortality from heart disease.
"Those areas where we struggle the most, clinically, are those where we haven't exploited good clinical research and are relying on animal models," Barnard says. "Look at cardiac defects. We don't know how they're caused because no one has done the equivalent of the Framingham study for heart defects, even though it's quite feasible. The Centers for Disease Control and organizations study these congenital abnormalities only in a very haphazard way.
"Of course," he continues, "there have been some brilliant exceptions, such as the research on neural tube defects. It was found through observation of humans that these defects were associated with deficiencies in folic acid, and that by taking vitamin supplements you can reduce the risk. The same with fetal alcohol syndrome: the breakthroughs came in studying humans, not animals."
Politics frequently obscures our view of research bias, Barnard says. He has called for a Framingham-style study of the health implications of cow's milk consumption, which has been implicated in some studies as a possible cause of Type 1 diabetes in children. Barnard believes that the political strength of the dairy industry has kept such a study from becoming a reality even though some 700,000 Americans suffer from Type 1 diabetes.
Even within the scientific community, there is an increasing willingness to admit that current research methods can be improved upon. A wide variety of in vitro tests have been proposed (among them, the use of human tissue culture and in vitro cell-culture assays), as well as increased reliance on computer modeling and the creative application of human epidemiological studies. Both government and industry experts agree that if new techniques eliminate or reduce the use of animals, so much the better. "[T]he current rodent bioassay for assessing carcinogenicity costs $1 million to $3 million and requires at least 3 years to complete," reads the summary of a January 1997 meeting of the Scientific Group on Methodologies for the Safety Evaluation of Chemicals. The main topic of the meeting was the development of alternatives to animal research, and the report continues, "More efficient testing methods may reduce the time required to bring new products to the marketplace and increase the amount of useful information that can be obtained."
Most researchers recognize that the humane treatment of animals isn't only compassionate--it's also good science. Imagine trying to measure the effect of blood-pressure medication on a dog that hasn't been walked in days. We now know that animals' feelings, behavior, and emotions have a profound effect on their physiological functioning--as is the case with humans. Consequently, after strong initial opposition to the Animal Welfare Act, most researchers have come to support it.
The Humane Society of the United States represents one example of how animal protectionists can set reasonably limited goals that promote animal welfare in ways that better serve both animals and humans. "We've contacted animal care and use committees and asked them to work with us to identify techniques that cause pain and distress and figure out ways to share ways to eliminate that in research," says HSUS's Andrew Rowan. "Some of the committees are rather suspicious; they see a hidden attempt to stop all animal research. The response has been slight so far. But we think that most researchers are bright people and will understand that our primary goal is just to eliminate animal suffering wherever possible."
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"IT IS VERY EASY TO SAY IT IS WRONG TO CAUSE THE DEATH OF ANOTHER LIVING ANIMAL. THE DIFFICULTY COMES IN SAYING, 'I UNDERSTAND THAT WHAT I'M DOING IS CAUSING THE DEATH OF A LIMITED NUMBER OF ANIMALS, BUT I'M MAKING A JUDGMENT THAT THE RESULTS WILL JUSTIFY DOING THE STUDY.'"
NORMAN LETVIN |
Norman Letvin, who frequently debates animal protectionists, knows that there are many who would like to end the practice of animal research for good. Although he is ready and willing to discuss the morality and ethics of his work, he thinks that calling an end to the practice would hurt society enormously.
"It is very easy to take an absolutist position and say it is wrong to cause the death of another living animal," Letvin says. "The difficulty in what [researchers] do comes in saying, 'I understand that what I'm doing is causing the death of a limited number of animals, but I'm making a judgment that the information gained from this limited, focused experiment will yield results that will justify doing the study.' Many humans infected with viruses or suffering from cancer or heart disease enter into studies that allow the development of new therapeutics. Every day, thousands of humans say, 'It is worth it for me to be involved in those studies because, even though I probably won't benefit, others will.' In the end, the decisions I'm making with respect to experimental animals are not dissimilar."
As we walked to a new facility on Longwood Avenue, Arthur Lage reminded me that it was the former site of Angell Memorial Animal Hospital, which has since moved to Huntington Avenue in Jamaica Plain. He points out where horses were tethered in the courtyard as they waited to be seen by a veterinarian. He indicates a barely visible tower protruding from the rear roof where distempered dogs were once quarantined. "It was hard work," he recalls, somewhat wistfully, of the internship and residency he served at Angell. "But it was rewarding. You might sit up all night with a sick dog or cat, trying to save its life."
Today, Lage cannot devote as much time to saving animals' lives. Instead, as he says, he's helping save human lives through animal research, while ensuring that animals are used humanely. Embodied in his work are many of the contradictions that many of us feel when we consider the millions of animals--from mice to monkeys--that annually give their lives for human health. The use of animals in research will not end today, nor tomorrow, but opinions on the matter appear to be evolving, perhaps toward a better life for animals in the laboratory, and toward better science.