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http://www.slate.com/id/2142814/#ContinueArticle
Of Mice or Men
The problems with animal testing
By Arthur Allen
June 1, 2006
Every year, in the name of medical progress,
scientists breed and nurture hundreds of millions of
mice, rats, and other subordinate mammals. Then they
expose the critters to substances that could become
the next Zocors, Prozacs, and Avastins. Since the
alternative is to experiment on people, most everyone
other than hardcore animal lovers accepts animal
testing. Periodically, however, a spectacular failure
raises new questions about the enterprise—not for
ethical reasons, but scientific ones.
In March, London clinicians injected six volunteers
with tiny doses of TGN1412, an experimental therapy
for rheumatoid arthritis and multiple sclerosis that
had previously been given, with no obvious ill
effects, to mice, rats, rabbits, and monkeys. Within
minutes, the human test subjects were writhing on the
floor in agony. The compound was designed to dampen
the immune response but it had supercharged theirs,
unleashing a cascade of chemicals that sent all six to
the hospital. Several of the men suffered permanent
organ damage, and one man's head swelled up so
horribly that British tabloids refer to the case as
the "elephant man trial."
Animal rights activists in Britain pounced, declaring
the uselessness of animal experimentation in the
development of human drugs. A group called Uncaged
declared that it was immoral "to subject animals to
painful, distressing and lethal experiments when the
results are not applicable to humans." This is
fundamentally dishonest, of course—there would be no
medical advance without animal experimentation.
Examples range from Frederick Banting and Charles
Best's diabetic dogs, which proved the existence of
insulin in the 1920s, to the mice who confirmed the
value of anti-angiogenesis drugs, which block the
growth of blood vessels that feed tumors. Still, it is
true that animal tests, even on multiple species, do
not always predict the toxicity of pharmaceuticals or
industrial chemicals in humans. This doesn't make
animal testing any less crucial to the development and
testing of drugs. But in an era in which drug
development is growing increasingly sophisticated, it
may point to the need for new designs in animal
testing.
Over the years, toxicologists have developed rules of
thumb for which animals will best model the toxic
symptoms they expect in man. An early example was the
canary in the coal mine. As the Bureau of Mines'
George A. Burrell noted in 1912, in the presence of
excess carbon monoxide, "a bird sways noticeably on
its perch before falling, and its fall is a better
indication of danger than is the squatting, extended
posture that some poisoned mice assume." Dogs, it
turns out—usually beagles, in particular—are man's
best test animal, in that the same compounds
frequently sicken dogs and their masters (though dogs
tend to vomit more than we do).
But just how often do animal tests predict side
effects in humans? Surprisingly, although it is
central to the legitimacy of animal testing, only a
dozen or so scholars over the past 30 years have
explored this question. The results, such as they are,
have been somewhat discouraging. One of the
scientists, Ralph Heywood, stated in 1989 that "there
is no reliable way of predicting what type of toxicity
will develop in different species to the same
compound." The concordance between man and animal
toxicity tests, he said, assessing three decades of
studies on the subject, was somewhere below 25
percent. "Toxicology," concluded Heywood, "is a
science without a scientific underpinning."
In 1999, the Health and Environmental Science
Institute, a Washington, D.C.,-based group that brings
together business, academic, and government experts to
assess risks in public health, began a thorough
examination. Working with confidential data provided
by 12 pharmaceutical companies on 150 compounds that
had produced a variety of toxic effects in people, an
institute-hosted workshop found that only 43 percent
of the drugs produced similar problems in rodents, and
63 percent did so in nonrodents. These are not
reassuring numbers. (Though they would look better if
the institute's review had included the 90 percent of
drug candidates that are screened out by animal
toxicity, and thus never even tested on humans.)
Industry, academic, and government scientists agree
that science is in need of better animal models for
testing drug safety. "Put simply, the inability to
predict the human toxicity of drugs is what's breaking
the promise of genomics to drug development," says
Paul Watkins, a North Carolina physician who is
advising the institute. The high-tech biology era has
seen the discovery of thousands of new targets for
pharmaceuticals, but the number of drug failures
remains as high as ever. It's painful for the drug
industry when $500 million goes toward developing a
drug that then must be scrapped because of side
effects that only surface in human trials. And it's
bad for the public as well when a product like
Rezulin, Warner-Lambert's diabetes drug, is withdrawn
from the market for causing liver disease and deaths
after 800,000 patients have taken it.
An equal source of human suffering may be the dozens
of promising drugs that get shelved when they cause
problems in animals that may not be relevant for
humans. Studies of the comparative biology of humans
and animals have established that some problems in
animals aren't worrisome for humans. For example,
during preclinical, high-dosage tests of Viagra, the
drug constipated mice, swelled rat livers, and gave
beagle dogs "beagle pain syndrome," which included
arching of the back and stiffness—in the neck.
Pfizer's scientists determined, correctly, that these
side effects had no relevance to humans.
Since drugs often fail by causing side effects in
small groups of vulnerable people who take them (think
Vioxx), scientists try to breed and use rodents with
special problems—the "hypertensive rat"—to eliminate
drugs that will hurt special medical populations. But
such methods don't stop government regulators from
insisting on tried-and-true animal-testing schemes,
because doing the same experiment on each new drug
means the result can be measured against a historical
record. Drug companies have grown restive under
certain requirements, such as the two-year rat test
for carcinogenicity, which, it is generally agreed,
isn't reliable. Edward Calabrese, a University of
Massachusetts toxicologist, once wrote that "it seems
almost incredible that the rat is the model so heavily
relied upon when predicting human responses to toxic
carcinogenic agents" given the "profound differences
between the values of the human and the rat" in many
bodily processes.
The hope has been that thousands of new lines of
transgenic mice—with genes knocked out, inserted, or
imported from the human genome—will prove the perfect
test animals. But that's not likely. Tinkering with a
few genes doesn't make them perfect stand-ins for
people. In 2003, for example, Elan Pharmaceuticals had
to stop trials of an Alzheimer's vaccine that had
cured the disease in "Alzheimer's mice," after the
substance caused brain inflammation in human test
subjects.
And then there's the monoclonal antibody TGN1412, an
artificial antibody designed to bind to certain T-cell
receptors, thereby cutting off autoimmune attacks.
Instead of dousing the immune response, TGN1412 seems
to have bound to cells in a way that unleashed a
chemical chain reaction. Animal tests are particularly
tricky for monoclonal antibodies—a hot area of
development for cancer and autoimmune disease—because
these drugs target very complex, specific human
proteins. According to a recent FDA-authored review
article, only chimpanzees and humans provide realistic
models for testing many monoclonal antibodies. And
even our fellow primates have divergent immune
systems. They can be infected with HIV-like viruses,
for example, without getting sick. Plus, the
endangered chimps are not the ideal test animals.
Different as they are, they seem too much like us to
be guinea pigs.
Related in Slate
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In 1999, People for the Ethical Treatment of Animals
placed an ad in Slate reproaching Al Gore for his
support of animal testing, and Timothy Noah offered a
rebuttal. In 2001, Richard A. Posner and Peter Singer
discussed animal rights. Chris Suellentrop explained
the rules for human testing, while Carl Elliott and
Trudo Lemmens showed how pharmaceutical companies get
away with testing new drugs on illegal immigrants. In
2005, Jeanne Lenzer exposed the human cost of
unsuccessful clinical trials.
Arthur Allen's book Vaccine is being published in
January 2007. He can be reached at
artnews@earthlink.net.
Photograph of test mouse by Peter Parks/AFP/Getty
Images. Photograph of rabbit on the Slate home page by
Charles E. Rotkin/Corbis.
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