Animals & Research Part 3: Alternatives in medical breakthroughs

When I began doing research, there were only two anti-viral medications available, and both were rarely used. Now there are 14 licensed anti-viral drugs for treatment of human immunodeficiency virus (HIV) infection alone.

One needs only to look at a picture of Magic Johnson -- who has tested positive for the AIDS virus -- during a visit to a central Seattle Starbucks to appreciate what these drugs have done to help people.

In the United States, Acquired Immune Deficiency Syndrome, or AIDS, which is the disease caused by HIV infection, has gone from a rapidly fatal disease to one that can be slowed significantly by drug therapy. Likewise, anti-viral drugs for herpes virus infections have reduced suffering from lesions causes by herpes simplex, and they have markedly reduced death from viral pneumonia in transplant patients and viral-related transplant rejection.

Similarly, we now have a vaccine against cancer. Hepatitis B vaccine prevents hepatitis B and liver cancer, its major complication.

How has this progress been possible, and what role do research animals and alternative forms of research play in this progress? Do we need animals at all?

In many ways the latter half of the 1900s can be described as the time of development and widespread use of animals in research. Mice were the mainstay of this type of research, to help us understand what caused the cancer and how to stop it. The past 20 years have seen a reduction in the number of animals used and the development and use of alternatives, including elegant cell culture models and computer models.

Animals & Research, a five-part series

Part 1: Unlocking the secrets of genetic disease through animal research
Part 2: Improving medical treatments for animals
Part 3: Animals are key to discovering new medicines
Part 4: The ethics of using animals in research
Part 5: How research animals live

There have been some real changes. The cancer-causing potential of drugs is now tested first in bacteria developed for this purpose and only then in mice or rats. And nearly all testing of cosmetics in animals has stopped. But we still do use animals. Why?

The popular press would have us think that medical breakthroughs come from giant "insightful leaps." In fact, dramatic improvements in medical therapy are made in small, incremental steps by large teams of scientists. But this process is not short. Nor is it smooth or predictable. For all the novel therapies I am aware of, experiments of a candidate antiviral or vaccine showed a glimmer of an effect in the test tube, but not enough to move to the next stage.

Those compounds that work in a test tube -- in vitro -- must then pass the test of activity and tolerance -- called toxicity testing -- in a whole animal. More than 90 percent of compounds that have activity in the test tube against infection or tumor cells flunk animal toxicity studies. There are no substitutes for testing in animals to measure the potential harm of new drugs. These experiments help us see how risky a compound is for use in people, and at what dose.

You may recall the recent gene therapy case of Jessie, who died of organ failure when an experimental virus was used, and we later learned that animal tolerance to this virus was low. This tragic case reminds us that when a treatment does cause poisonous effects in animals, extreme caution is warranted. Animal studies are even more crucial for developing medicines for young infants and children because their rapidly growing cells make them more susceptible to some toxic drugs.

What about computers? Biochemists have developed computer models to look at relationships between drugs and their targets in an effort to build better keys to fit the molecular locks. However, predictions based on those models are imperfect at best.

Let's look at a recent example of two drugs I prescribe every day for my patients: acyclovir and ganciclovir. I remember the first time I used the acyclovir medication on an infant with neonatal herpes. The previous infants I had seen had died. This one miraculously started to get better four days into the treatment, something I had never seen before.

Now, acyclovir is the most-used anti-viral drug in the world -- a very effective treatment for genital herpes and neonatal herpes. Hundreds of my patients take it daily.

Ganciclovir was discovered two years after acyclovir and, in the test tube, looked like a better compound. At the molecular level, the compounds were almost identical. Yet in animals the two were very different. Ganciclovir killed bone marrow cells; acyclovir did not. Ganciclovir caused sterility in animals; acyclovir did not. Human results matched the animal tests.

Acyclovir is one of the safest drugs we have in my field; people can take it daily for years. Ganciclovir has a role in treating transplant and HIV-infected people. It is a life-saving and eyesight-saving drug, yet its strong toxicities limit its use to those with severe illnesses. All this was defined by prudent animal testing.

How about the role of animals in vaccine testing? Vaccines protect people from disease by stopping infections before they can wreak their havoc. Vaccines ultimately are tested directly in people, so why not skip animals?

Let's take as an example the development of a vaccine against HIV to prevent AIDS, which is devastating the African and Asian continents with 16,000 new cases a day and continues to spread throughout the world unchecked.

Because vaccines work by stimulating the body's immune system to fight back against the virus, there is no way to test in cells, or on a computer, how the vaccine will work in the whole animal. New vaccines are given to experimental animals, followed by a "challenge" with the infectious agent one wants to prevent. These animal model experiments define whether novel vaccines are safe enough to initiate clinical trials.

More important, they show whether the vaccine is good enough to justify large-scale testing, which may involve tens of thousands of people and cost tens of millions of dollars. Non-human primates, especially macaque monkeys, are critical for the development of an HIV vaccine.

The work to translate results from the monkey models to vaccines that can go into humans involves intense communication between those of us involved in human vaccine development and those laboratory researchers involved in developing candidate vaccines.

The studies do not substitute for vaccine testing in humans. Without the tests, and without this dialogue, many entirely ineffective vaccines might be tested in people without any benefit, wasting money and time. Does it not seem wise, then, to know what a vaccine does in a primate challenge study before we administer it to thousands of people?

We can and do use alternatives at each step in our process of drug and vaccine discovery and testing, to refine our choices before we go into animals and people. The reality of developing novel therapies and vaccines for human disease is that prudent use of animal resources is a necessary part of the process of medical research to improve human and animal health.

Lawrence Corey, M.D., is professor of laboratory medicine and is head of the virology division, University of Washington School of Medicine. He also is head of the infectious diseases program at Fred Hutchinson Cancer Research Center.

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