October 2001

Speeding Drug Discovery

Continued from page 2

By Gary Taubes

A Lexicon for Biology

Before Lexicon came along, researchers had developed two techniques for creating knock-out mice, but both had severe limitations, explains Oliver Smithies, a pioneer of gene-targeting technology at the University of North Carolina at Chapel Hill. On one hand, researchers could target and disable a specific gene whose sequence was already known, but that process, as Smithies says, is "quite laborious, because you can only do one gene at a time." On the other hand, genes could be mutated at random, which can be done quickly and with relative ease; but then the researchers wouldn't know which gene had been mutated until they grew the animals to maturity-and perhaps not even then, if the absence of the gene was particularly subtle in its effect.

Lexicon's advance is a technique that mutates genes at random but does so by using a virus to insert a known sequence of DNA into the genes. That sequence not only disables the mutated gene, creating the knock-out, but remains behind as a signpost to identify precisely which gene has been put out of action. With this technology, says Sands, Lexicon has managed to knock out 40 percent of the genes in the mouse genome, considerably more than all the other mouse researchers in the world have achieved in the last decade. Pharmaceutical and biotech companies, and even academic researchers, can sign on with Lexicon to access this extensive mouse library, which Millennium Pharmaceuticals, Bristol-Myers Squibb, Johnson and Johnson and a half-dozen others have already done.

Because the knock-out mice are meaningless without diagnostic technology to pinpoint the effects of the absent genes, Lexicon's mouse facility in the Woodlands will house, not just 300,000 genetically compromised mice, but what Sands calls a "Mayo Clinic for mice" as well. This new center-where, of course, mice will be experimental subjects, not patients-will include a comprehensive radiology department, complete with MRI machines and CAT scanners designed to image the bones, organs and tissues of mice. It will have an immunology group to dissect rodent immune systems, and a neuroscience group, complete with a battery of behavioral tests, to study how the missing genes might affect brain development and behavior. It will have a developmental-biology group that will study how the absence of genes affects the development of the mice in utero, and a cardiology group, to look at how the absence of genes affects cholesterol, blood pressure, and heart and artery function. "Every medical department at Lexicon," says Sands, "will be geared to study the function of genes in live animals and find those that are the most valuable for drug discovery."