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10/15/92

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Animal research at Stanford: How do we know it's done humanely?

STANFORD -- 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 f r 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 b asis: 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 bee n 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 - an d 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 discussions go beyond local committees. Stanford psychology professor Russell Fernald sits on a National Institutes of Health peer review panel - the next step up in seeking approval of a research grant. Questions about pro per animal use and appropriate numbers now come up in peer review, he said.

"Attention to these issues has raised people's consciousness. It has improved the lot of some animals," Fernald said.

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 le ast 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 tot al 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. (See separate story).

Most in agreement

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 ver tebrate from fish to rats to monkeys. Panel members conduct unannounced inspections of all animal facilities twice a year. (See separate story).

The panel reports to the president of the university through the Dean of Research.

  • 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 c are 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 mistreatme nt.
  • 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 St anford gets a degree of oversight that makes even minor mistreatments difficult to hide.

The actions behind the words: 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 th e U.S. Department of Agriculture and to funding agencies. It may trigger an investigation of the whole research institution.

However, critics doubt that panels will do this.

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 anima l-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 o ccur 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.

"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.

Fewer than two dozen research projects each year require committee intervention once they are under way. Stanski, who is professor and chair of Stanford Medical School's Department of Anesthesia, said the committee's most impor tant function is not police work but helping researchers design protocols that meet humane treatment standards. It is the panel's job to interpret the growing maze of laws and regulations governing laboratory animals.

"We look for what is the spirit, not just the letter of the law," he said. "We have a responsibility both to the animals and to the researchers."

His panel consists of nine voting members, including four scientists who use animals in research and one who does not, a veterinarian (Hamm) representing the laboratory-animal staff and two community members with no Stanford ti es. In addition to Stanski and Hamm, the Stanford-affiliated members are: Daniel Bernstein, associate professor of pediatrics; C. George Fitzgerald, director of chaplaincy services; E. William Hancock, professor of cardiovascular medic ine; David Maurice, professor of ophthalmology; and Susan McConnell, assistant professor of biological sciences. The community members are veterinarians R.L. Collinson of Mountain View, and Beryl Mell of Palo Alto.

Their link with the researchers is Kathy McClelland, research compliance officer with the Office of Sponsored Projects. She keeps track of how each research project at Stanford complies with animal research and other regulation s.

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 - ano nymously 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."

The committee members work with McClelland and animal-subjects coordinator Valerie Fratus to keep paper-pushing to a minimum. (See separate story). Still, they must volunteer long hours for work that does not always endear them to their colleagues. While some scientists say they get genuine help from the committee's work, others complain about the paperwork, and some get angry when research is delayed. One reportedly called Stanski a "vigilante."

"It is not always a thankful job," Stanski said. "But someone has to do it, and it has to be done well."

With administrative help from the Office of Sponsored Projects and some prescreening by Hamm and the department's other veterinarians, the members review every new research protocol, every change or renewal, and every continuin g 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; for some, that passage comes after consultation with vets and conside rable redesign of the research method. The committee concentrates extra effort on new research designs where it is not clear what the animals will experience.

"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 sm all: "Some institutions wouldn't even put them in this category."

Every person who uses animals for teaching must come in person before the full committee at least once a year. Hamm said only a few projects each year use animals for teaching, and these are monitored even more closely than res earch projects. An example are the teaching protocols necessary for physician training - for example, to teach a surgeon a technique that would be dangerous to learn on a human patient. In such cases, the operation is performed with th e animal under anesthesia, and it dies without ever recovering consciousness.

Stanski said Stanford officials take humane treatment very seriously.

"They're willing to make tough decisions, and they're willing to spend money on staff and facilities," he said. "If the institutional response was, 'this really doesn't matter,' why would I get involved?"

A recent letter sent to all faculty who use laboratory animals from David Korn, dean of the School of Medicine, and Robert Byer, dean of research, underscores that support.

"Meticulous attention to the regulations that govern the use of animals in experimental research is not optional," they wrote. "Failure to observe [the regulations] can result in very severe penalties indeed, not only to the in dividuals at fault but to the entire institution."

Is the panel a "rubber stamp?"

Not a chance, said 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."

Mell said he makes an exception for this panel because of its commitment to animal welfare - and because it has the independence to act on its decisions. That independence, he said, "is the reason I'm still on this committee af ter eight years. The president of Stanford couldn't override our decision if he wanted to."

The scientists

"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 suffer ing.

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 was the chair of the Medical S chool ethics committee that wrote a 1988 report on the principles of animal research, published in the New England Journal of Medicine. He wrote a 1991 editorial in the Western Journal of Medicine calling for a national commission to d efine a moderate position on animal research 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 nu mbers? Will I be using the animals humanely?

It is applying those principles to a specific research project that keeps the animal care panel - and the scientists - busy.

In Stanski's own research, for example, 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 electrode s.

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 in vestigator 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."

Research and application

Stuart Goodman and Randall Morris are scientists who have a rare opportunity; they can see the results of their research in the lives of the patients they have helped as doctors.

Morris stops his patients' own bodies from destroying themselves. As a transplant immunologist in Stanford's cardiothoracic surgery program, he designs drug therapies that prevent transplant recipients from rejecting new hearts and lungs.

Until recently, only four main anti-rejection drugs were produced in the 40-year history of transplantation, and they do not always work. Now there are six new ones in clinical trials, and as director of Stanford's Kovik Labora tory for Transplant Immunology, Morris has had a hand in discovering and developing all of them. Eventually, these drugs may have an impact beyond transplants - on diabetes, arthritis and other autoimmune diseases.

Goodman, an orthopedic surgeon, replaces diseased hips, knees and other joints with metal and plastic devices that must work well, without pain, for decades. Most of his patients are adolescents and elderly persons.

He recalls the story of some of the first total hip replacements, in England, which used space-age plastic and metallic materials that were expected to wear very well. In the unique environment of the body, however, tiny bits o f the material flaked off and caused such serious inflammation that most patients had to have new hip transplants.

"If it had been tested in animals, that wouldn't have happened," Goodman said.

This is why he studies biomaterials: his patients need better prostheses, and he will not change to a new material until he's sure it's safe.

"We owe it to the public to do our homework on anything we implant," he said.

Both scientists must use animals. Morris cannot model an entire immune system in a petri dish; Goodman cannot see on a computer how the body will react to a foreign object like an artificial hip.

First, though, both start their search on computers, and use cell cultures to screen for toxicity. Morris does a database search and gets on the phone to learn everything that is so far known abut new drugs so he doesn't duplic ate other scientists' work. Goodman measures cadavers to get data for a newly-designed joint, then works with biomechanical engineers and their computer models to test its biomechamics.

Once they begin using animals, the scientists start with the least invasive procedure and add complexity step by step. At each more complex stage, partly because they know more, they use fewer animals.

For example, Goodman begins by implanting his biomaterials in the bones of rabbits. It is a relatively painless procedure, and animals that show an adverse reaction are euthanized and studied intensively to find out why. New bi omaterials that pass this test are used to make an artificial knee, designed so the rabbits hop normally.

The knee-replacement rabbits are used to test how the bone and soft tissue react to the implant under a load, and how the implant functions in a living, moving organism. Goodman is now confident that some of the materials will make better prostheses.

In comparison to humans, however, rabbits do not put much weight on their knees, and extra weight could mean a serious difference in damage inside the body. So his next tests will be with sheep.

Designing his research protocol, Goodman relied on the veterinarians from the Department of Comparative Medicine to help him choose the right species to get a great deal of clinical, histological and radiological data with few animals. Plans for housing, surgery, anesthesia and post-operative care also gained from veterinary staff advice.

His protocol still raised a round of questions from the animal-care panel.

"Some were good suggestions that I incorporated into my plan," he said.

Others sent him to the veterinarians to find out what is known about the best way to handle sheep.

"There are so many hurdles you have to go through," he said. "You really have to have a clean protocol."

Goodman said he is confident that his animals do not suffer much pain, but he does not like having to see them euthanized at the end of the experiment.

"We're trained to save. It's hard for doctors to see a life lost," he said.

"Still, these materials must work. Some of the total joint replacements I do are on adolescents. Those young people need to walk, to go through their lives without pain."

To test anti-rejection drugs, Morris must find out if they prevent rejection of a transplanted heart. His animals keep their own hearts; he simply adds a second one somewhere in the body, which rapidly develops blood vessels an d begins beating.

An operation is not a pleasant experience, even with anesthetics and painkillers.

"I would be the first to say, if I were an animal I would not volunteer for this," Morris said.

"There's a tension between what you do to the animal and what you need to do, and it should be calibrated. Preliminary ideas should be weeded out in experiments that are not difficult for the animal. If the experiment makes an immediate difference, if patients' lives are at stake, then more discomfort is justified."

Morris has achieved his remarkable rate of new drug discoveries by starting with drugs that already are known and that his data search shows to have potential immune-system effects. A drug that looks promising is first tested i n a simple procedure, placing mouse-heart tissue behind an adult mouse's ear. The mouse is injected with an anti-rejection drug; if it shows no signs of swelling and edema, that drug passes one step in the trial.

The behind-the-ear transplant is very minor for the mouse, and seems to cause little discomfort, Morris said. The next step - a heart transplanted into a rat's abdomen, with all the blood vessels connected - is major surgery, t hough the rats appear to recover nicely with good nursing care.

Drugs that pass both tests promise to be good immunosuppressants with few apparent side effects. But a drug that works in a rat cannot just be injected into a human transplant patient: The immune systems, and the body sizes, ar e still too different. At the wrong dosage, the new drug - intended to save a patient whose earlier immunosuppressant drugs were failing - might only make the situation worse.

That requires tests with monkeys, which have the immune system most like a human's. Morris does not like having to use monkeys.

"They're more intelligent, so they're more emotionally disturbed by what's happened to them," he said. "It's difficult for the monkeys. But if we have someone who's rejecting an organ and may die, we need these data to give the m the best chance to live."

In a sense, the human heart and lung transplant patients are the next subjects in Morris' testing sequence. If the new immunosuppresants prove safe and effective in transplant clinical trials, they may also turn out to be helpf ul to other people who have immune-system diseases, such as diabetes and arthritis.

Monkey business

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 not oriously 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," he said.

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 ex periments 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 m ake 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 unc ertainty 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 infan ts was markedly reduced.

Levine said he does not know whether other species of monkeys find puzzle feeders stressful.

Caring for the animals

The air in the corridors of RAF I and 11, Stanford's twin research-animal buildings, smells faintly of animal feed.

It does not smell like a kennel or a farmyard or a giant mouse colony, though there are rabbits, ducks, dogs and at least 50,000 mice in residence here at any one time.

The reason is a constant air-exchange system that not only cleans and filters the air, but can be temperature-adjusted for each of 97 animal rooms. A central computer and sensors in each room monitor the air exchanges, plus the reverse osmosis water-purification system and the lighting timed to each group of animals' optimum light requirements. The computer also keeps track of how often the animals' cages are taken away and replaced with clean, sterilized on es.

All of these systems in the state-of-the art facility are designed to keep animals comfortable and disease-free. The fact that RAF-I and II are built underground offers a number of advantages: energy efficiency, earthquake safe ty, greater security.

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 fi re 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 hurt s 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 i n 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."

Zasio said: "I thought [the suspension] meant we are doing our job right."

"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."

Stanford's division of laboratory animal medicine is part of the Department of Comparative Medicine in the School of Medicine. The department also includes the division of comparative pathology, reflecting a new commitment to r esearch and training in this rapidly growing veterinary specialty.

Veterinarian Joanne Blum, associate director of comparative medicine, oversees the animal husbandry and veterinary care staff. There are two other clinical veterinarians, and a veterinarian is on call 24 hours a day. There are 10 veterinary nurses - also called animal health technicians, and there is at least one on duty caring for animals - around the clock, seven nights a week, including holidays.

In addition to animal buyers, maintenance mechanics and office personnel, there are 30 to 40 supervisors and caretaking staff. They provide food and care for animals, assist scientists with surgical anesthesia, operate a diagno stic laboratory so any animal diseases can be solved on the spot before they spread. They operate the nation's only 24-hour-a-day laboratory animal intensive-care unit.

Blum 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. Veterinarians and staff members often cooperate with scientists to study and publish research on animal health. For example, Hamlen is studying snuffles, a bacterial disease that sometimes affects rabbits.

Stanford's state-of-the-art facilities are the results of decisions the university made a decade ago, Hamm said, when it temporarily lost a prestigious voluntary accreditation from the American Association for Laboratory Animal Care.

"The quality and humaneness of animal care was good here," Hamm said, looking back before 1982. "But the facilities were atrocious."

Whereas animals once were scattered in many buildings across campus, they are now housed in RAF and in five satellite facilities, including an outdoor kennel for narcoleptic dogs, a separate building where sheep are housed for biomedical research, and the 20-year-old breeding colony for squirrel monkeys.

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.

Goodman is one researcher who relies on the Comparative Medicine staff for veterinary nurses to assist in surgery and postoperative care, and for frequent monitoring to make sure his rabbits are healthy and comfortable.

"Part of my success here is because of what they've done," he said. "From the planning stages, to the experiment itself, to the postoperative care, this is a very positive and professional organization. Things get done in an or derly manner, with minor distress to the animal and a low complication rate."

Goodman said that some of the visiting scientists who have come to collaborate with him were so impressed with the lab animal staff that they took them out to lunch.

No normal life

Staff and researchers alike concede that living alone in a cage - sometimes for many 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 transp lants 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, an d 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.

It is the staff who find almost all cases of mistreatment, usually in the course of the same reporting process that detects animal illness.

On a recent morning, Hamlen checked on reporting slips from cage workers and veterinary nurses about a rabbit with ear mites, a rat with bleeding footpads and a dog with a nasal discharge. All were followed up; all were treatab le and had natural causes.

If the circumstances had been questionable, Hamlen said, the veterinarians would have pursued the matter by talking with the researchers. If there was evidence of mistreatment or if a problem could not be resolved, Hamm, Blum, Stanski and A-PLAC would become involved.

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 regar ds 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."

Not obeying could have serious consequences, Hamm said. If a federal agency found that an institution had a pattern of protocol violations, then instead of stopping one or two research projects, as Stanford has done, they could cut off all federal funding to animal research. This happened to two major research institutions several years ago.

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 wil l 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, H amm 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."

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