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Johns Hopkins Bloomberg School of Public HealthCAAT

Changing the Face of Research

Mike Field
Article reprinted from the "Johns Hopkins University Gazette," September 16, 1996

In the late 1970's a troubling development was noted in many of the nation's farms. Agricultural workers who came in contact with a sub-class of organophosphate pesticides were developing delayed but serious reactions, including the loss of sensation or functions in their hands or feet. Oftentimes, the symptoms would not manifest until one or two weeks after contact with the chemicals.

This condition--known as delayed neuropathy--is difficult to study in the lab. The time lapse between exposure and reaction introduces many variables that can determine the course of each reaction, and the reaction itself is not seen in all animal species. Yet the safety of farm personnel necessitated a closer look at how and why the chemicals affected people the way they did.

"We knew that, in this instance, live animal studies wouldn't enable us to gain the understanding of these chemicals' effects that we were after," recalls Alan M. Goldberg, who began researching the problem about 18 years ago as a professor of toxicology in the Johns Hopkins School of Public Health.

"We needed to look for a more refined system with which to study the problem."

Eventually, Goldberg and his colleagues settled upon a novel approach that would have enormous implications for future research: they would forgo the use of live animals and instead inoculate individual tissue cultures with the chemicals, thus enabling the researchers to more closely monitor variables such as dose, exposure and duration of exposure to the toxins. It was one of the very earliest experiments with the use of in vitro--literally, "in glass" --methodology to determine toxicity.

In doing so, Goldberg's research was to have repercussions far beyond the study of toxic pesticides. Without knowing or intending it, the Hopkins researcher had helped pioneer techniques that were to lead to a quiet but fundamental revolution in the use of live animals for product safety testing.

At about the same time that Goldberg was initiating his work, utilitarian philosopher Peter Singer published Animal Liberation and ignited a growing animal rights movement that remains active to this day. The early movement culminated in part in a full-page advertisement in The New York Times which asked, "How many rabbits has Revlon blinded for beauty's sake?" The cosmetics industry was blinding bunnies--or at least, so it seemed--and consumers were quick to express their concern. Something had to be done.

It was not long before a consortium of cosmetic industry concerns--under considerable public pressure from animal welfare organizations--approached Goldberg and the School of Public Health about creating the nation's first center for the study and development of technologies that could assure product safety without the use of live animals.

September 1996 marks the 15th anniversary of the founding of the Johns Hopkins Center for Alternatives to Animal Testing at the School of Public Health. It was created in 1981 with a record-setting $1million grant from the Cosmetic, Toiletry and Fragrance Association.

CAAT fosters the development of scientifically acceptable in vitro testing methods and other alternatives for use in the development and safety evaluation of commercial and therapeutic products. Equally important, say Goldberg and Zurlo, are the center's efforts to educate the public and the scientific community about the uses, advantages and limitations of alternative testing methods.

Their work has helped lead to a significant reduction in the number of live animals used in product testing. Goldberg notes that animal testing of cosmetic products is only a fraction of what it once was. Several leading cosmetics manufacturers have even eliminated live animal testing entirely. But the effort to change the way scientists and industry think of animal testing has often been an uphill battle.

"I remember the first talk I gave, about a week after the center was founded," says Goldberg, who was appointed founding director and has remained with the center ever since. "I went to a meeting of the Washington area chapter of the Society of Toxicology and spoke about what we hoped to accomplish. It is not enough to indicate the audience did not believe me. To them I was fringe, on the very border of scientific acceptability. And because I had the prestige of Johns Hopkins behind me I was dangerous fringe. If they could have tarred and feathered me, they would have."

Part of the resistance encountered by the center has to do with a misunderstanding of its mission and, in particular, the word alternative, says associate director Joanne Zurlo, who has been with the center for six years.

"When we say alternatives to animal testing, we are actually talking about a range of options known as the three Rs," she says. "There is the refinement alternative, in which the reseracher continues to use the animal subject, but adapts the protocol to produce less pain or distress. There is the reduction alternative which looks at using fewer numbers of animals and relies on a sophisticated use of statistics to project likely outcomes. And finally, there is the replacement alternative, where, when possible, live animals are replaced by other means."

The Three Rs, first suggested by zoologist William Russell and microbiologist Rex Burch in their 1959 book The Principles of Humane Experimental Technique, have become the cornerstone of the modern animal alternatives movement. "We see this movement as the beginning of a proces of turning from the widespread use of animals in product safety testing and scientific research to newer, more sophisticated tests," Goldberg says.

Scientists at the center believe that in many--but not all--research efforts animal testing can be refined, reduced or eliminated entirely by developing other tests that are just as accurate, and often, less costly. In such situations the impetus for change is scientific and economic, not, as many assume, ethical.

"The pregnancy test is the perfect example of this evolution," Goldberg says. "In the previous tests for HCG hormone indicating pregnancy, a woman's urine was injected into a rabbit and then the rabbit was killed and dissected. If its ovaries were bloody, this indicated a positive test for pregnancy. Mind you, the woman needed to be at least six weeks pregnant, and it took 24-48 hours to conduct the test at a cost, today, of around $400."

Advances in basic science have all but eliminated the need for such primitive tests today. "Now you can buy a kit at the pharmacy for $10 to $15 that will tell you in just a few minutes if you're even two or three weeks pregnant," Goldberg says. "By developing a simple biochemical test that need for animal testing was eliminated."

Not all animal tests are so easily and elegantly replaced, he warns. But overall, an increasing number of scientists have come to acknowledge that the movement toward genetic and molecular research heralds an era of more specialized and sophisticated testing.

"When we started, tissue culture was a brand new science, and human cell cultures were not commercially available," Goldberg says. "Now the direction basic science is heading--toward the use of molecular tools--means that many of these replacement alternatives being developed are simply the natural extension of current scientific activity."

Recently, the center has turned attention to helping research scientists meet requirements of animal welfare legislation, much of which is based upon the three R concept. Goldberg and Zurlo stress the concept that the three Rs are a fundamental building block of good science at any level.

"Product testing has a specific endpoint in mind and so is more easily defined," says Zurlo of her efforts to reach out to Animal Care and Use Committees to spread the word. "With pure research you're looking for knowledge in general as opposed to a specific answer. You can't state the endpoint and so it becomes more difficult to design alternative protocols."

"My optimistic self likes to believe that the scientific community will come to view the three Rs not as a threat, but as a challenge," she says. "The purpose of the center is not to impede progress, but rather to augment it through an ongoing effort to improve and refine research techniques. We see ourselves as advocates for both science and animal welfare. We don't believe they are incompatible goals."