“Mice are lousy models,” says leading scientist

From ANIMAL PEOPLE, January/February 2009:

STANFORD–Many people have asserted that
mouse studies are poor models for human disease
research. But few have had the stature within
the biomedical research field of Stanford
Institute for Immunity, Trans-plantation and
Infection director Mark M. Davis, Ph.D., and
few have said so in a leading medical journal.
“We seem to be in a state of denial,
where there is so much invested in the mouse
model that it seems almost unthinkable to look
elsewhere,” Davis wrote in the December 19,
2008 edition of Immunity, in an essay deemed
noteworthy enough that both Immunity and the
Stanford University Medical Center issued press
releases to publicize his statements.

“The mouse has been incredibly valuable,”
Davis acknowledged. “That’s part of the
problemŠIn humans it often takes years to find
out anything. There are a lot more regulatory,
financial and ethical hurdles,” but “Mice are
lousy models for clinical studies,” Davis
bluntly concluded.
Summarized Stanford University Medical
Center publicist Bruce Goldman, “Experimental
manipulations that are commonplace with lab mice,
such as genetically engineering them to express a
foreign protein or to be deficient in the
expression of one of their own, would be
unthinkable in a human. Because experimental
mice can be used to get quick answers, Davis
argues, researchers look to the mouse to tell
them everything.”
Wrote Davis, “We can’t depend on the
mouse for all the answers, because in some cases
it’s not giving us the right answers. But think
about what we can do with people. People come to
hospitals, get vaccinations, give blood and
tissue samples for routine lab tests and clinical
trials. We’re not learning nearly as much as we
could from these samples. As with the recent
history of human genetics, we could be much
bolder.”
Davis pointed out that mice and humans
last had a common ancestor at least 65 million
years ago, but the divergence is wider than that
where immunology is involved. The numbers of
mouse generations raised in laboratories during
the past 100 years are approximately equal to the
numbers of human generations who have lived since
the dawn of civilization. The mice have been
inbred for specific traits and isolated from
exposure to diseases other than those that
scientists deliberately give them.
By contrast, Davis wrote, “We’ve been
selected by urbanization, with plagues such as
the bubonic plague and smallpox that routinely
killed huge numbers of people, and modern
scourges like HIV and malaria that still infect
and kill millions each year. Most humans are
infected with six different herpes viruses, and
who knows what else. And while we’re suffering
away, getting colds and flu, the mice are living
in the lap of luxury in miniature condominiums,
with special filters on the cage tops to keep bad
things out.”
In effect, Davis argued, lab mice have
been reverse-engineered to respond less and less
like humans who have been exposed to disease in
real-world environments, where early or
low-level exposure to some illnesses may confer
immunity to others.
The Stanford Institute for Immunity,
Transplantation and Infection is among the users
of an ultra-secure animal research complex opened
in 1985, at cost of $11 million and years of
controversy. As many as 50,000 mice and rats
were used in experiments there in 1986 alone.
Activists opposed to building the complex alleged
that the planners had used the hypothetical
possibility of break-ins by would-be animal
rescuers to rationalize security precautions that
would actually be used to conduct dangerous
experiments involving recombinant DNA and deadly
diseases.
Considered state-of-the-art then, the
complex represents the emphasis on mouse study
that Davis termed obsolete.
Davis recommended an approach to
immunology research based on “high-throughput”
studies of clinical data, similar to the studies
that decoded the human genome.
Explained Goldman, “The Human Genome
Project, which has radically accelerated the
pace of human genetic research, was conducted as
a large industrial operation carried out mainly
in a small number of large centers, including
one at Stanford.”
Said Davis, “Although the small academic
labs as we know and love them are great for
innovation and out-of-the-box thinking, some
problems in biology, particularly those that
involve a great deal of repetitive assays and
data collection, are much better suited to a
larger-scale organization and execution. The
data are both more uniform and considerably
cheaper.”
Davis’ recommendations paralleled those
issued in the February 15, 2008 edition of the
journal Science by National Human Genome Research
Institute director Francis S. Collins, EPA
research and development director George M. Gray,
and National Toxicology Program associate
director John R. Bucher. Collins, Gray, and
Bucher announced in their paper that the
Environmental Protection Agency, the National
Toxicology Program, and the National Institutes
of Health had signed a memorandum of
understanding to promote developing non-animal
alternatives to the animal tests now required to
meet U.S. federal regulatory standards.
“Historically toxicity has always been
determined by injecting chemicals into laboratory
animals, watching to see if the animals get
sick, and then looking at their tissues under
the microscope,” Collins explained to reporters
at the 2008 annual meeting of the American
Association for the Advancement of Science in
Boston. “Although that approach has given us
valuable information, it is clearly quite
expensive, it is time-consuming, it uses
animals in large numbers, and it doesn’t always
predict which chemicals will be harmful to
humans.”
Besides, Collins added, “We are not
rats and we are not even other primates.”
Collins, Gray, and Bucher revealed
their memo of understanding nine days after the
National Toxicology Program Interagency Center
for the Evaluation of Alternative Toxicological
Methods (NICETAM) and the Interagency
Coordinating Committee on the Validation of
Alternative Methods (ICCVAM) published a
five-year plan for helping U.S. government
agencies to phase out animal testing.
The March 2008 ANIMAL PEOPLE cover
feature “U.S. to phase out animal testing”
detailed the NICETAM and ICCVAM strategies.