Today, Rodents With Psoriasis; Tomorrow, Super-Brainy Mice!
The HLA-B27 is one sorry rat. Bred--or built--by the DNA designers at GenPharm International, the recombinant rodent is genetically altered to suffer the afflictions of arthritis, psoriasis and inflammatory bowel disease. You can take him home for $285.
If your taste runs to precancerous mice, consider GenPharm’s best-selling TSG-p53 “knockout” mouse for $155--a creature with its p53 gene (the one implicated in many cancers) effectively “knocked out” of its genome.
Not good enough? “We do ‘custom-tailor’ mice,” notes GenPharm corporate development director Howard B. Rosen. “We view them as the canvas upon which we do these genetic transplantations.”
In fact, these genomic canvases are fast becoming the new mass medium for biomedical innovation. Much as sculptors carve stone and cinematographers light film, molecular biologists now struggle to genetically manipulate their mammals into research masterpieces. Where Gregor Mendel had his pea patch, Caltech’s Thomas Hunt Morgan bred drosophilae (fruit flies) and an entire era of budding molecular biologists was raised twiddling E. coli bacteria, it’s clear that the next generation of experimental media is now scurrying in.
From Caltech to the Pasteur Institute to the National Institutes of Health, these four-legged “biomedia” will ultimately determine which human diseases get cured and when. The better-engineered the mammal, the better--and, possibly, more cost-effective--the medical options for humans.
Consequently, this transition will have as big an impact on the future of biology as the shift from printing presses to video technology has had on pop culture. A mouse-based world looks and feels different from one viewed through microorganisms.
“Right now, if one wants to understand human disease processes, a knock-out mouse will probably give you more bang for the buck than E. coli ,” says Dr. Michael Lenardo, a senior investigator at the NIH’s National Institute for Allergies and Infectious Diseases. “There’s no question that an enormous amount of money and effort is going to be spent on them--to some extent at the expense of E. coli “--the species of bacteria in humans and all vertebrates that is widely used in biological research.
“There’s certainly been an explosion in transgenic mouse models of disease,” says Caltech science historian Daniel Kevles, who recently co-authored a book on gene mapping. “Research funding patterns may be such that it’s encouraging people to move into it--but that doesn’t mean E. coli or drosophila is a dead field.”
But cancers occur in living animals, not single-cell organisms. So while just three years ago knockout mice were involved in only 5% of the experiments in Lenardo’s lab, more than a quarter of his research efforts now involve mice. Within three years, he expects that genetically-tailored mice will used in the majority of his lab research.
Indeed, in terms of pure usefulness, mapping the mouse genome now rivals mapping the human genome in terms of importance. Just as E. coli became the gateway to genetic engineering, the mammals will become our models for understanding gene therapies. For all intents and purposes, mice are becoming the E. coli and drosophila of the 1990s.
“In general, if you look at the history of biomedical research, certain media have become prominent,” says NIH’s Lenardo. “I think one of the most interesting and important things about American science is its diversity of media. For example, (Nobel laureate) Barbara McClintock did her work out of the genetics mainstream using maize as her research organism.”
While standards aren’t inevitable, Lenardo and other researchers acknowledge that certain organisms come to dominate a field. The properties--and constraints--of these media explicitly shape the kind of science that gets done.
For example, most neurophysiologists avoid using mice as research media because mouse brains are inconveniently small. But suppose that knockout mice and transgenic mice end up with their brains redesigned in unexpected ways? You can be sure that mice would quickly become essential to the new genetics of neurophysiology.
“I think what we will see is a proliferation of models,” says Caltech’s Kevles. Indeed, knockout pigs are growing in popularity. Maybe we will see knockout/transgenic baboons bred for similar purposes. Now that the ban on fetal tissue transplant research has been lifted, we can expect researchers to start excising and modifying bits of the human genome as a research tool.
“In the early days,” says NIH’s Lenardo, “we researched how molecules relate to each other; now we can study how molecules make cells relate to each other.”
Even with television, camcorders and computers, we still read and write with paper. Similarly, traditional biomedical media won’t go away just because the mammals are coming. But the fact that we are mammals makes that new reality that much more compelling.
