Stanford Immunologist Calls For More Research On Humans, Not Mice

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Mouse Trap? Stanford Immunologist Calls For More Research On Humans, Not Mice

27 Dec 2008

The fabled laboratory mouse-from which we have learned so much about how the

immune system works-can teach us only so much about how we humans get sick and

what to do about it, says a leading researcher at the Stanford University School

of Medicine.

The time has come for immunologists to start weaning themselves from

experimental rodents and to embark on a bold, industrial-scale assault on the

causes and treatment of specifically human disease, writes immunologist Mark

, PhD, in an essay to be published Dec. 19 in Immunity. , director of

the Stanford Institute for Immunity, Transplantation and Infection, proposes

that the current mouse-centered, small-laboratory approach be supplemented by a

broad, industrial-scale " systems biology " approach akin to the one that

unraveled the human genome.

" 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, " , the

Burton and n Avery Family Professor and professor of microbiology and

immunology, writes in the essay.

Over the past several decades, the little mouse has proven immensely helpful in

generating a fundamental understanding of how the mammalian immune system works,

said in an interview. " The mouse has been incredibly valuable, " he added.

" That's part of the problem. "

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, argues, researchers

look to the mouse to tell them everything. " In humans it often takes years to

find out anything. There are a lot more regulatory, financial and ethical

hurdles, " he said.

But when it comes to adapting therapeutic interventions that seem to cure all

kinds of infectious disease, cancers and autoimmune conditions in mice for use

in human beings, the record is not so good. The vast majority of clinical trials

designed to test these interventions in people end in failure.

" Mice are lousy models for clinical studies, " asserts in his essay.

There are probably some good reasons for this, said . For starters, mice

are rodents, separated from humans by some 65 million years of evolutionary

divergence from our common ancestor.

That's not all. While it takes about 20 years for a person to reach sexual

maturity, a mouse gets there in three months. The roughly 100 years during which

the furry, diminutive animals have been domesticated and bred in labs are,

therefore, the mouse equivalent of 8,000 human years, during which they have

been inbred and kept relatively disease-free. They would never survive in the

wild, said .

Meanwhile, the past 8,000 years have seen humans crowded into cities, he said.

" 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. " They're in such pristine shape, notes drily, that

researchers have to induce facsimiles of human disease in them. These conditions

may or may not accurately mirror ours.

" We can't depend on the mouse for all the answers, because in some cases it's

not giving us the right answers, " said. " 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. "

The Human Genome Project, which has radically accelerated the pace of human

genetics, was conducted as a large industrial operation carried out mainly in a

small number of large centers, including one at Stanford. In a spirited debate

attending that project's initial conception, many academics objected strenuously

on the basis that doing the same thing over and over isn't a good way to train

students and researchers, said . But, he added, " The Human Genome Project

didn't destroy the small lab. It complemented it. "

In his Immunity essay, writes: " 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. "

sees the need for a national or even international infrastructure to

capture information from blood and tissue samples. A local template is

Stanford's Human Immune Monitoring Core, run by ' colleague

Hirschberg. Affiliated investigators send human samples to this facility, where

copious assays of cell types and immune secretions in blood and tissues extract

data about experimental subjects' immune status, in a relatively short time.

" This information goes back to the principal investigators, but it also gets

captured in a database we're developing, " said.

The creation of high-throughput assays that could quickly and cheaply measure

vast numbers of immunologic variables (many of them first elucidated in the

mouse) in a standardized fashion among very large groups of people-some in

excellent health, others suffering from one or another disease-would greatly

advance immunological discovery, said .

" What if we could define the normal range for all these parameters, and then see

how they're changed by any of the over 100 infectious diseases, or 90-odd

autoimmune disorders, or more than 120 inherited immune deficiencies that

afflict us-or, for that matter, by aging or even vaccination? Maybe we could see

something coming early on and start applying remedies to restore the normal

balance and prevent the disease's progression. "

envisions routine clinical tests that, analogous to the serum lipid tests

we take to learn our predisposition to cardiovascular disease, tell us what

shape our immune system is in or what disease we're starting to get.

" The game here is that we don't know quite what we're looking for yet, " he said.

" But some of this information is going to be useful. "

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