A United States federal law, signed August 26 by president George Bush, makes it an offence to break into animal research facilities in that country. The Enterprise Protection Act of 1992 offers new protection to animal researchers and their facilities by imposing stiff federal penalties on those who commit violent and unlawful acts as a means of protesting animal research. At Stanford University in Palo Alto, California, one of the major animal research facilities in the United States, controversy over animal treatment continues. Joel Shurkin of Stanford's news bureau is author of a series of articles that were made available as news releases last week. Excerpts follow. ----- I was not afraid of the needle. Some of the first-graders squirmed and cried, but I took a deep breath and looked away. The injection was over before I knew it, just as Mom had promised. Thus began this reporter's experience as a research animal. This was one of the first batches of the polio vaccine, which would spare tens of thousands of my generation from life in an iron lung. The makers of the vaccine believed it had been sufficiently tested, but something went wrong with the batch I received. Some of the children contracted polio from it. The anguish to their families -- and the terror for parents like mine whose children escaped a close call -- led to a public uproar. The polio mistake is one of the reasons the U.S. government requires a tier of tests in at least three different species of animals before a new drug is tested on humans. It is one reason that thalidomide, the painkiller that caused birth defects, was never prescribed to American mothers -- it had not been tested on enough species. The polio virus would still be crippling American children if scientists had not learned to understand it with research using animals. Hundreds of thousands of other people have escaped early death from pneumonia or dysentery or infected battle wounds thanks to antibiotics that were tested in animals before they were given to humans. If researchers had not been able to study the function of the kidneys in animals, there would have been no dialysis to save Steve Lewis' life, the year he was a college sophomore and both of his kidneys failed on an adverse reaction to antibiotics. The kidney transplant he received three years later would have been a science fiction fantasy. Lewis, 25, is a Palo Alto physical therapy aide who has applied for medical school, a dream he said would have been impossible without the transplant and the immunosuppressant drugs that keep him from rejecting his new kidneys. Because he may need new drugs if his system develops resistance to the current ones, he relies on animal research for his future. "It would take an incredibly long time to figure out what immunosuppressants work, to figure out what is the right dosage, if you had to start on humans," Lewis said. 'They [animal activists] talk about cell culture but there is no way to know what [a drug] would do to the body as a whole. "There is no way to know that unless you try it on the whole animal." Animal research has made possible vaccines and drugs against such killer diseases as measles and tuberculosis, insulin for diabetes, pacemakers for hearts, drugs that fight cancer, painkillers, antidepressants, hip replacements and heart surgery. At Stanford, scientists could not have made heart and lung transplants, giving decades of life to some patients, without first testing the method on animals. Other Stanford scientists created the SCID-hu mouse, with an immune system that mimics a human's and is being used to study AIDS. Among questions left unanswered that require animals for a solution: how to treat killers like cancer, atherosclerosis, cystic fibrosis and AIDS; what to do against the parasitic diseases that afflict one quarter of humankind; and how to treat arthritis, trauma and strokes. And animal research benefits animals other than humans. A visiting scholar at Stanford is studying immunotherapy that may pave the way for kidney transplants for cats. Parvovirus, canine distemper and feline leukemia virus are a few of the pet-killers that are now preventable because of research done in other animals. Lewis has joined a Palo Alto-based group, CLEAR, or Citizens for Life, Education and Research, that works to clear up public misunderstanding of animal research. He said he joined "when I found out that people were trying to completely abolish animal research, not just improve what was done badly. "That seems ridiculous when there are so many benefits from it," he said. ----- A profound change in the way scientists conduct research using animals took hold nationally in 1985 when Congress updated the Animal Welfare Act to require virtually every researcher who uses animals to plan ahead for their humane care and handling. The rules say that no scientist can ask for federal funds for research using animals until the proposal first has been approved by a committee of fellow faculty and community members. The committee says yea or nay on a single basis: whether or not the study will meet humane use and care regulations. The National Institutes of Health require these powerful review panels for research on all animals, including rats and mice, at NIH-funded biomedical institutions. Stanford University is one of several institutions that had been requiring this kind of approval for many years, even for research that received no government funding at all. As the committees gained power and responsibility, most scientists initially expected little change. They said they had always taken good care of their animals to ensure good research results. Still, looking back on the days before the animal-care panels had much clout, Stanford immunologist Randall Morris saw a difference. "In those days," he said, "you owned the rat and you did what you wanted." Now -- to the benefit of science as well as animals, Morris said -- each new research idea requires a written plan that spells out how the animals will be treated to avoid pain and suffering. The result: Scientists now sit down to discuss in detail the concepts of humane treatment to which most subscribe in principle. The review panel asks if they are using an appropriate species, in the fewest possible numbers -- and if they could do the experiment without using animals at all. They must plan ahead to reduce the animals' pain and maintain their comfort. The new laws do not satisfy many animal rights advocates. They point to dramatic cases of animal abuse that were reported in past decades and say that such things could happen again. Though animal-care panels must include at least one public representative, the critics complain that most panel members are the scientist's colleagues, who might rubber-stamp bad research proposals and turn a blind eye to mistreatment. "There is a constituency with an enormous stake in preserving the status quo," said Lise Giraud, a librarian emerita from Stanford and co-director of research with the San Rafael-based animal-rights protest group, In Defense of Animals. Stanford has one of the largest animal research programs among biomedical research universities, along with others such as Harvard and Johns Hopkins University. More than 500 research and teaching projects involving animals are approved each year at Stanford, mostly in the School of Medicine. At any given time, approximately 230 research groups are working with animals. About 80,000 rats and mice are used in a typical year, along with 2,600 rabbits and a total of 1,600 other large animals, such as dogs, cats, pigs, sheep and monkeys. A partial list of the benefits from such research at Stanford includes Dr. Norman Shumway's pioneering heart and lung transplant work; treatments for Hodgkin's disease and other lymphomas, and the development of a mouse with a human immune system that can be used to model AIDS. Nonetheless, activists like Giraud have picketed and campaigned against the program for years, most recently to demand disclosure of the name of a researcher who broke the rules. How can the community be assured that Stanford's research animals are well cared for and guarded against mistreatment? Interviews with scientists, workers in research labs, animal-care workers, activists and government officials -- as well as inspections of how research animals live and are handled -- found agreement among all but the activists: * Stanford's Administrative Panel for Laboratory Animal Care (A-PLAC) has considerable clout, with veto power not only over federally funded projects but over every research and teaching project involving animals, and every vertebrate from fish to rats to monkeys. Panel members conduct unannounced inspections of all animal facilities twice a year. * The university invested $30 million in animal care in the 1980s, replacing antiquated facilities with new state- of-the-art buildings and consolidating most animals in one place. The 45-person animal husbandry and veterinary care staff keeps animals healthy, trains scientists in good handling techniques and helps develop new methods to obtain data with less impact on animals. * Trained staff see all animals daily. Staff members are trained to report even minor signs of animal illness or discomfort. Vets take care of illness; top staffers and A- PLAC committee members investigate reports of mistreatment. * Looking over Stanford's shoulder are 15 federal, state and local regulatory agencies. Facilities undergo several complete outside inspections each year. * In spite of the growing web of government regulations they must enforce, scientists say the committee and the veterinary staff generally manage to improve research, not hinder it. Associate Professor Thomas Hamm Jr., the university's chief veterinarian and founding chair of the Department of Comparative Medicine, has presided over the changes of the past eight years and is now leaving to take a position at North Carolina State University. Under his direction, the university invested in a philosophy that excellent animal care means better research. The first to admit that no system is perfect, Hamm points out that animal research at Stanford gets a degree of oversight that makes even minor mistreatments difficult to hide. At Stanford, serious misuse of animals has meant that research was stopped. At every research institution, the presiding veterinarian and the animal-care panels have the authority to take away an investigator's animals for violating humane use practices. A suspension of animals has to be reported to the U.S. Department of Agriculture and to funding agencies. It may trigger an investigation of the whole research institution. Stanford has reported several suspensions to the government, according to Hamm. Details of the incidents are not released to the public, he said, because panel business is confidential and because of perceived danger from animal- rights extremists. The suspensions "just show we're doing our job," Hamm said. Most incidents are resolved after the research team takes training in better animal handling practices; the experiment is usually allowed to start up again under close monitoring. In two cases, Hamm said, animal use was stopped permanently. In a February 1992 investigation of one incident, Agriculture Department inspector Homer Malaby reported to his superiors, "Stanford University did all that could be expected to preclude a situation like this, and when it did occur they took appropriate action to correct it and to preclude any recurrence." In an interview, Malaby said that Stanford also does well in the Agriculture Department's twice-a-year surprise inspections. "They have a system of monitoring things," he said. "They can pick up problems before they even occur." Most problems don't lead to suspended research, said Donald Stanski, chair of the animal-care panel and chair of Stanford Medical School's Department of Anesthesia. "When things are going wrong, we detect it early and solve it quickly," he said. A confrontation with a principal investigator can be the most difficult part of the job, but usually it ends well, with an agreement to get better training for members of the scientist's lab. Kathy McClelland, research compliance officer with the Office of Sponsored Projects, keeps track of how each research project at Stanford complies with animal research and other regulations. She also acts as an ombudsperson of sorts for the animals. A telephone number is posted in every animal facility and on every protocol application; anyone who sees evidence of mistreatment can call and report the incident -- anonymously if that is one's preference. McClelland checks on the facts, takes questions to the A-PLAC panel if they can't be adequately answered, and reports back to each caller, "sometimes to people whose names I don't even know." Committee members review every new research protocol, every change or renewal, and every continuing protocol at least once a year. They turn back many protocols, sometimes more than once, for the scientist to clarify or change animal handling plans. Most protocols eventually pass review. "We get into discussions about what indicates pain," Stanski said. "It can be difficult to define -- the animal does not have the ability to describe what can be a subjective process." In most cases, the answer is for the researcher to specify when and how drugs will be given to relieve what might be painful. Or the plan will specify how the scientists will monitor a tumor and give euthanasia before it grows painfully large. One or two projects a year, usually involving fewer than 75 animals, fit into category E: pain cannot be alleviated because the painkillers would invalidate the results. According to Hamm, in most cases the amount of pain is small: "Some institutions wouldn't even put them in this category." Is the panel a "rubber stamp?" Not a chance, said veterinarian Beryl Mell, one of the panel's two public members. Mell, in Stanski's words, is "ferociously independent"; he said one of the reasons he runs a solo veterinary practice is because "I hate committees." "There is no point in saying that animals do not suffer," researcher Thomas Raffin said. "Animals have feelings, and their lives have value." However, he said, there is an ethical principle of humane treatment that allows animals to be used by humans but obligates the person to use them only when necessary -- and then to do everything possible to minimize their suffering. Raffin, who studies tumor necrosis factor using guinea pigs, is chief of pulmonary and critical care medicine at the Stanford Medical Center and co-director of the Center for Biomedical Ethics. He said scientists should ask themselves four questions if they believe they must use animals for research: Have I sought alternatives? Am I proposing to use the appropriate species? Am I proposing to use the fewest possible numbers? Will I be using the animals humanely? In Stanski's own research he has faced many of the questions he asks others. He works with rats because they are a small species, but still large enough to conduct delicate surgery to place catheters and electrodes. After recuperating, the rats are tested to measure subtle effects of drugs on the brain and cardiovascular system. To produce successful, valid results, the work requires calm, gentle handling of the rats. So, Stanski and his research associates learned new techniques from the veterinary staff. It is part of his obligation as a principal investigator to make sure that each new graduate student or postdoctoral fellow follows the protocol; Stanski's rule is that they must be taught by his lab's animal supervisor before they are allowed to participate in the work. "It's like practicing medicine," he said. "You need someone skilled to train you." ----- A troupe of juvenile squirrel monkeys gathered at Seymour Levine's side of their cage until a stranger came into the room. Then they fled, flowing over one another along the springy bars and into the next cage where they could peer back through a window, a garland of curious eyes and golden furry limbs. Levine has worked with squirrel monkeys for about 20 years. Their high neuroendocrine levels and social behavior make them a good model to study psychosocial aspects of stress. They require first-class care because they are notoriously difficult to breed in captivity. "One of the fundamental indicators of the health of any colony is how well they breed," Levine said. Levine's monkeys breed so successfully that it has been 10 years since he studied a wild monkey. Some of his older monkeys are given to researchers elsewhere, on a highly selective basis. "I have to see their protocols first," Levine said, "and they have to come here to train." This is not the image of Levine that animal-rights activists portray. "To them I'm the devil incarnate." Activists have targeted him for protests because his studies of stress sometimes included separating infants and mothers for six to 24 hours at a time; protesters have tried to link him to much longer-term mother deprivation experiments conducted elsewhere in the past. Levine's monkeys live in the sort of colony housing that most primate experts believe best simulates wild living. Lately, he has been testing an idea that some animal activists lobbied to make mandatory on the theory it would make caged monkeys happier: a puzzle feeder, so the monkeys have the challenge of foraging for food as if in the wild. The puzzle feeder has 80 holes the monkeys reach into, to find food hidden in wood shavings. Hidden observers recorded the monkeys' behavior, and frequent weigh-ins made sure each was getting enough food. After two weeks of having to forage, the monkeys showed a disintegration of their normal highly social behavior. The animals usually spend large amounts of time huddling and touching one another. But something -- perhaps the uncertainty of food availability -- stopped the huddling behavior, even when the monkeys were sleeping. Levine found higher levels of the stress hormone cortisol in female monkeys during two weeks of having to forage. The nursing infants of foraging mothers had higher stress-hormone levels as well. And their play with other infants was markedly reduced. Levine said he does not know whether other species of monkeys find puzzle feeders stressful. Stanford scientists count on the animal-care facility to keep their animals in peak health. They also count on a security system that does its best to protect them from an incident like the March 1992 Animal Liberation Front fire at Michigan State University, which destroyed two scientists' data and a cumulative 40 years of work. It doesn't take long in a conversation with top staffers of the Department of Comparative Medicine to find that they are rankled by the animal-rights movement. The threat of violence is worrisome, they say, but what really hurts are the continued misrepresentations and exaggerations of non-violent animal protesters, who use a few, years-old examples of animal abuse in scattered locations to paint a picture of torture and terrible suffering being carried on in every lab today. Sometimes those assumptions are picked up by the general public. When Stanford's suspension of a researcher's animal privileges was reported by the Associated Press last winter, veterinarian Heidi Hamlen and animal-care manager Reese Zasio both got calls from friends. "My sister called and asked, 'Are you torturing animals?'" Hamlen said. "I said they'd have to do it over my dead body." "We have people come from all over the world to see how this place works. Our animals are better cared for than human patients in some other countries. Most people really don't realize the job we do." Veterinarian Joanne Blum, associate director of comparative medicine, oversees the animal husbandry and veterinary care staff. She said the goal is to make sure sick animals are treated and -- if at all possible -- saved. This make sense for humane and scientific reasons: Each animal lost is a loss of research data. No one can obtain an animal without going through Hamm's staff. Almost no researchers keep animals in their laboratories -- "I had to prove I knew far more about caring for fish than they did," said psychologist Russell Fernald, who breeds some fish in aquariums. Staff are trained in animal-handling techniques and in polite ways to pass them on to inexperienced scientists: "Here, let me handle that," is the phrase that Zasio teaches to his workers. Staff and researchers alike concede that living alone in a cage -- sometimes for m any years -- is not a normal life for any animal. Even with good care and pain relief, the treatments being tested are sometimes uncomfortable and probably confusing to the animals. How do they fare under these circumstances? "Look at the way that the animals act," Hamm said. "If they're frightened, they'll cower in the back of the cage. If they come up to you to play, they're not being mistreated." In three visits to the underground animal buildings, no cowering animals were visible. Large, healthy rabbits sniffed at a visitor through the bars of cages large enough for some hopping room; they are part of a colony that has blood taken from ear veins about once a month for immunology tests. Male monkeys displayed aggressively at the bars of their cages. Mice nestled together in soft wood shavings. Miniature pigs were glistening and clean; they are given daily hot-oil rubs to keep their skin from cracking. In the veterinary intensive-care unit, six rat cages were laid half on, half off a heated water pad; the rats inside, recovering from surgery, could lie in warm or cool bedding as they chose. Two puppies, recovering from transplants that may improve lung transplants for children, played with a veterinary nurse. In another room, a member of the world's only colony of narcoleptic dogs stood on its hind legs to bark eagerly every time someone looked through the peephole window into its room. The dogs' cages were big enough to pace in, and the room has a narrow, ten-foot space where each dog can run while its cage is being cleaned. Hamm said research had shown that dogs need no more space than this for exercise, which is now mandated by federal regulations. The dogs spend part of each year at the outdoor breeding facility, where runs are so large that the law does not require them to be taken out of their cages. To meet another requirement -- for psychological well- being of primates -- male monkeys were given cages placed so they could face, but not bully one another. Hamm said staff members are encouraged to play with the animals and find toys for them. "It's for our psychological well-being as much as anything else," he said. There are some scientists who find the oversight intrusive, the rules frustrating. Hamm has coined the term "staff abuse" for the threats and tongue-lashings his people have had to endure. "Threatening to fire you, threatening to take you to the dean, that happens daily here," he said. On the other hand, Hamm agreed that scientists should be frustrated by regulations. Many of the practices codified into law in the past decade have been used by good veterinarians for 20 years, he said. Other new rules he regards as unnecessarily rigid or capricious. "I have to enforce many regulations that don't make sense scientifically," he said. "What's hard for me is to get another scientist to do this. But I do it -- we obey the spirit and letter of the law." Hamm expects the situation to get worse as political pressures continue on politicians to add more rules. Scientists will not be able to afford many large-animal experiments, he said, so studies of the heart, lung and brain will be more difficult. Public universities will be squeezed between budget cuts and rules that require them to modernize animal facilities. Stanford may have been not just wise but lucky to invest in upgrading its animal program early, Hamm said. "This is part of the infrastructure of science, and support for infrastructure is collapsing," he said. "We are being required to do more and more at the same time that research-support dollars are decreasing." ----- Lise Giraud is an emerita librarian from Stanford's Green Library; with her husband Raymond Giraud, professor emeritus of French and Italian, she is co-director of education for the San Rafael-based group In Defense of Animals, which opposes any use of animals for research. A former president and board member of the Palo Alto Humane Society, Giraud has long been one of the severest critics of animal research at Stanford. When asked what single step Stanford could take that would make the lives of its research animals better, Giraud states her agenda clearly: "The best thing one can do for them is just not to use them [animals] at all." Giraud said that researchers submit animals to "lives of suffering and deprivation" and that no university oversight committee or government inspection system is sufficient to protect them. Animal-research decisions are made by an "old boys' and old girls' network," Giraud said. She charged that "people can cook up the most bizarre protocols and get them passed by their peers," and that Stanford officials hide animal mistreatment from the public. "I'm sure the facility is scrupulously clean," she said. "But whether it's a clean prison or a dirty prison, it's still a prison." She said that the university's Administrative Panel on Laboratory Animal Care is incapable of protecting the public interest because all its members are appointed by the president of the university. She rejected the possibility that the committee's record of stopping research is proof that it exercises real clout or succeeds in protecting animals. Pressed for specific examples of animal mistreatment, Giraud recalled charges going back as much as 20 years, but few examples from the period since the A-PLAC panel has been reviewing protocols and stopping research. She mentioned one 1987 case in which a researcher used only one of two required anesthetics while putting an endotracheal tube down a cat's throat. The research was stopped by the A-PLAC committee, and the individual, whom Giraud charged previously had done "horrible things to monkeys and cats," later left the university. Other examples that she considered abusive: cats kept on platforms over water to keep them awake; monkeys frightened by the sight of a boa constrictor outside their cages; a photo, sent to her anonymously, of a white rat apparently suspended by its tail. The first two projects occurred more than a decade ago, and the date of the third is unknown, but Giraud said that they represent the current attitude of Stanford scientists toward animals.