Improving The Lot Of The Laboratory Animal

Sidebar: What Can Scientists Do To make Animals 'Happier' Animal rights activists have had an impact, but the biggest changes are coming from scientists themselves Why should a physicist or a chemist care about the endless public debate over the use of research animals? Almost every scientist knows the creatures are crucial for progress in biology and medicine. And scientists are fed up with the clamor being raised by folks who seem to care less about the human animal than about the lab animal. Well, it turns out that something has been quietly happening in the laboratory, something that might resolve some of the debate and which is changing the way science is done. It turns out scientists are beginning to care more about their experimental subjects, even to the point of trying to keep them "happy." (see story, page 3) At the University of Houston, for example, endocrinologists have devised high-tech radio monitors so they can throw out the traditional restraining chair for their monkeys. At the University of California, San Francisco, a physiologist has designed and built elaborate stainless-steel tanks with all the comforts of a home pond for his colony of frogs. And at the University of Virginia, researchers on opposite sides of the campus study the pituitaries and livers of the same rats to reduce by half the total number of animals used. "I believe scientists themselves are committed to the ethical issue of animals in experimentation and want to use animals in a humane fashion," says Thomas Raffin, chief of respiratory medicine at Stanford and chair of the university's committee on ethics. "There's more emphasis now on thinking about the feelings and the rights of animals, while before it was mainly a focus on science." This is a subtle shift in attitude, hard to quantify or even to document. In fact, many scientists say that they haven't noticed the change; they assume that laboratory animals have always been well cared-for, if only because healthy research subjects make good science. And it is equally difficult to sort out the underlying cause. Has the change been prompted by animal rights groups and new legislation? Or has the impetus come from within science itself, either because of a demand for healthier subjects from which to gather ever more sensitive data, or from a sense of moral responsibility? No one has a definitive answer. But what is certain, say scientists, ethicists, and lab veterinarians interviewed by The Scientist, is that animals are receiving better treatment in labs across the country. "There are changes in the mindset of the research community with respect to the use of animals," says bioethicist Arthur L. Caplan of the University of Minnesota, chief adviser to a recent Office of Technology Assessment report on laboratory animal use. "Many bench scientists have begun to think that they have a strong obligation." Witness physiologist James Hudspeth of UC-San Francisco, who studies auditory hair cells that convert sound into the electrical signals that we hear as music or speech in the brain. His work has contributed to the development of the cochlear implant, a device that stimulates auditory nerves to allow the profoundly deaf to hear. Hudspeth's research is an excellent example of refinement, reduction, and replacement, the "three Rs" touted by groups like the Scientists' Center for Animal Welfare, advocates for responsible animal research. More than a decade ago, he developed a way to study auditory hair cells in the test tube, vastly reducing the number of animal cells that he needs in order to collect data. He also has been a pioneer in using computer simulations to replace the cells entirely for some of his research. Hudspeth, however, still needs animals for his work. His choice is the frog. It has big, hardy auditory hair cells that look a lot like those in human ears. Hudspeth sacrifices his frogs and dissects out their ears, maintaining the cells in tissue culture. Then he uses electrodes to stimulate the hair bundle, "a rather beautiful set of protrusions that sticks out of the top of the cell," examining how it works and how it can be damaged. Even though his amphibians will be killed, the physiologist does everything in his power to ensure that they live in the lap of luxury. The frogs swim and bask in a veritable small-scale Malibu, three stainless steel tanks consisting of a deep-water swimming hole sloping up to a dry sunning bench. Circulating fresh water reduces bacteria and skin disease, the caged frog's worst enemies. For food, the frogs often receive live crickets - T-bone steak to amphibian gourmets. No one requires Hudspeth to provide his frogs with more than a galvanized tub of water to swim in. The scientist could ignore the skin diseases, which have nothing to do with ears - though at $5.00 a frog, the tanks have long since paid for themselves by reducing losses. But practical considerations aside, a special tone creeps into Hudspeth's voice when he talks about watching a cage full of frogs hopping around after crickets. "I like frogs," he explains. "I have pet frogs at home, and I like to keep them healthy." "We scientists have chosen to work with animals, to conduct biomedical research for the good of humans," adds Richard Traystman, head of the anesthesiology and critical care labs at Johns Hopkins University. "Since that's our choice, it's incumbent on us as rational, emotional, ethical, and moral human beings to treat other species in the most humane fashion that they can be treated." The attitudes of scientists like Traystman and Hudspeth go hand in hand with a recent major overhaul of regulations governing laboratory animal use. Revisions to the Animal Welfare Act, passed by Congress in 1985, are the most public aspect of a recodification that has been occurring at every level of science. NIH rules have been revised and guidelines from professional societies strengthened. In fact, animal handling rules at many institutions surpass the national requirements. Stanford, Johns Hopkins, UC-San Francisco, and several others have long required advance approval and institutional supervision for every mouse, hamster, rabbit, or sheep used - not just those falling under NIH rules. Some of these changes can be attributed to animal rights activists. The University of California at Berkeley, for example, dragged its feet about upgrading animal care until the state legislature threatened to hold up $44 million in funding for a new biological sciences building. "I think it is fair to say there have been many advances as a result of animal welfare groups, in terms of taking better care of the animals," says Traystman. But according to researchers contacted by The Scientist, many of the new rules reflect changes in science itself - and in the attitudes of scientists. Most believe that the activists' claims are exaggerated. But they also say that it is not acceptable for scientists to act as portrayed by the activists - as callous or neglectful about research animals. Individual institutions expressing this ethic began more than a decade ago to develop the protocol approval system now mandated by NIH. One result is universities' animal care committees, which "are analogous to the human research subjects committees established ten years earlier," says David Ramsay, vice chancellor at UCSF and founder of one of the earliest animal care committees. Many investigators are learning their animal-care techniques the same way one learns how to splice a gene: from colleagues and through the scientific literature. In Traystman's lab at Johns Hopkins, improvements in painkillers and other handling methods typically come from the research investigators themselves, working with lab veterinarians - or from ideas brought up by the Johns Hopkins animal care committee, which Traystman has chaired for 10 years. "My feeling is now, if they want to have all these rules and regulations, that's fine," he says. "I've been doing it all along." As primatologist Douglas Bowden, associate director of the University of Washington Primate Center said in a speech last year, "Most investigators have always cared [about their animals]. In the past five years we have seen a comprehensive institutionalization of that attitude." For individual scientists, the most visible form of that institutionalization is the animal care and use committee (ACUC) at each university. These are now mandated for all NIH-funded projects. The committees' review process focuses the investigator's attention on the purpose and conduct of animal use at the planning stage of a research project. Members ask for specifics with each protocol: how pain will be prevented, how animals will be cared for after surgery - in effect, exactly what the investigator proposes to do about humane treatment. Many scientists gripe about the time and cost involved in preparing and reviewing animal care protocols. But they admit that the system is an important tool for enlightening researchers who have not adopted the new attitude towards animals. One university committee rejected a protocol three times before the investigator understood that committee members were serious about pain control. As Traystman says, "When every scientist has to sit down and write a protocol before they get Animal One, they think about what they're doing." Even without the ACUCs, however, scientists have a powerful incentive to provide the best care for their animals. It has long been recognized that good science requires healthy research subjects; in some fields of study it is now becoming clear that the animals must be "happy" as well. Concern about research animals' psychological well-being is new, says Tom Wolfle, director of NIH's Institute for Laboratory Animal Research. Scientists thought it was enough to ensure that the animals were not in obvious pain or living in poor conditions. "We use animals as models for human diseases, but when we model backwards, from humans to animals, we typically have called that `anthropomorphic,'" Wolfle says. But more recently, people have realized that "anthropomorphism has gotten a bad rap." Contented monkeys, for example, are essential for the work of University of Texas neuroendocrinologist Ernst Knobil. He uses the primates - the only model with a menstrual cycle similar to humans - to study the cascade of brain impulses and hormones that govern fertility and pregnancy. Currently he is investigating the neuron "pulse generator" that triggers the release of gonadotropin releasing hormone. If a female monkey is under stress, this cycle stops, the monkey no longer menstruates - and Knobil's research comes to a grinding halt. "Our system depends on normalcy," says postdoc Cindy Williams. To promote the monkeys' comfort, Knobil was among the first scientists to use a flexible stainless steel tether that protects indwelling probes or catheters from a monkey's prying hands. The tether allows the animal to move about freely in its cage; it is now used nationwide in preference to a chair for long-term monitoring of primates. Lately, Knobil's lab has developed a radiotelemetry device that measures pulses from a neuron without tethering or even handling the animal in question. The result is a reduction in stress, as measured by cortisol levels. In addition, when the monkeys must be handled, researchers work with them slowly to lessen their fears, providing food rewards and - for at least one primate - a calming massage. "Not all of the monkeys like to be handled," says postdoc Williams, "but this one feels comforted if you rub her back." But there is an unpleasant rub for scientists in all this extra care: It costs money. A number of the researchers interviewed by The Scientist believe that the added costs are worth it. But others, such as physiologist Arthur Guyton of the University of Mississippi, worry that these expenses will seriously hamper the progress of science. Guyton's university has already spent $220,000 to meet new USDA regulations regarding facilities used for animal surgery, and he anticipates further costs as more rules are promulgated under the revised Animal Welfare Act. The cost and time of paperwork to obtain committee review adds up; so does the cost of research animals. Dogs, used by Mississippi physiologists for studies of congestive heart failure and renal disease, used to cost $6 each from the pound in the 1960s; now each is purchased from a dealer for $150. One result is a significant reduction in the number of dogs used each year (see chart, page 2). Guyton sees an impact on programs where there is no substitute for a large animal - to train young surgeons, for example. And he says that for smaller research programs, the accumulation of costs may be too much; he has heard one estimate that as few as 300 institutions will be able to afford to continue large-animal research. Certainly, the added costs - and the relentless pressure from animal rights groups - have already reduced the proportion of research done with animals in the U.S. National figures on patterns of animal use are incomplete, but a recent report on the 13 top research institutions in California gives some indication of the trend. The numbers of animals used remained the same for the years 1983-1987, but the dollars spent on biomedical research increased. At UC-San Diego, animal use remained stable from 1981 to 1987, while research grants nearly doubled, from less than $30 million to $55 million. "All I can say to those people [who are concerned about the cost] is that you have be reasonable." says Traystman. "It might be that costs can be cut in order to do certain things. But the bottom line is that you have to be able to take care of those animals appropriately." While the added expense of the new animal research ethic could seriously harm some research institutions, Traystman and other scientist worry that the costs of not improving animal care could be considerably higher. Unless the public perceives that scientists are discharging their moral obligations to animals, explains Minnesota's Arthur Caplan far more intrusive controls could be imposed. "The race is on," he says. "There is some danger that the changes in the scientific community won't keep up with the ethical views of the public at large." Animal rights extremists will never be convinced, but Caplan believes that science can gain the trust of the general public and of lawmakers. The means, he says, lies with the in-house animal care and use committees. Because the ACUCs must contain lay members from outside the institution, they have in effect opened the laboratory door. No one can now say animal research is conducted in secret. "The ACUCs have a tremendous burden and challenge," Caplan says. "They must be perceived as fair, as equitable, as doing their job in terms of animal welfare. If they don't do their job, I think (the current political climate) will lead to severe restrictions, burdensome economic restraints, and very onerous interference with basic research." Adds Traystman, "If we don't speak out about the benefits of animal research, about how we do things, and if we don't take care of our animals, I think the end is in sight. There will be no animals used for biomedical research, period." Janet Basu is a freelance writer in San Francisco

Improving The Lot Of The Laboratory Animal

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