MITMay/June '98 Technology Review, Stephen Hall writes:
"SCIENCE WRITERS HAVE EXPENDED A GREAT MANY words on "gene chips," which are being touted as biological crystal balls that will diagnose future genetic susceptibility to disease. Having contributed my share of adjectives to this futuristic vision, I know how tempting it is to describe.
But technologies often travel the low road to widespread use, and while prognostic gene chips may well be a routine feature of annual physical checkups in the future, a related chip application has already entered the clinic through the back door. "Molecular profiling" is one name this technology goes by, and these highly precise genetic tests do not exactly predict the future. Rather, these chips assess the molecular stage of a patient's disease, and may ultimately suggest which drugs the patient might respond to...
...Given its importance, clinicians would like to know the p53 status of every tumor they're trying to treat. About two years ago, biochip-maker Affymetrix joined forces with Oncormed, a cancer diagnostics company based in Gaithersburg, Md., to make p53 testing one of the prototypes of chip technology. Their target: the coding region of the human p53 gene, which possesses 1,262 base pairs of DNA-the chemical subunits of the double helix that tell a cell how to make the p53 protein.
Affymetrix, based in Santa Clara, Calif., has created a p53 chip that measures slightly less than 13 millimeters square~bigger than a thumbtack, but smaller than the standard issue 32-cent stamp. Engineers at Afymetrix have subdivided this real estate into a checkerboard of 20,000 "probe cells;' each bristling with a uniform carpet of millions of identical DNA probes measuring 18 base pairs long. Using fluorescently labeled reagents, prepared DNA from a tumor can be washed over the chip, and extremely sensitive scanners are programmed to detect minuscule variations in intensity in the checkerboard pattern-which arise from slight genetic changes in p53. Once the DNA has been prepared, the test can be done in four hours.
Although p53 is only one of numerous genes implicated in the evolution of a tumor, it has already been thrust into a prominent role in experimental cancer treatments. In April of 1996, for example, Oncormed began using the Affymetrix chip to perform "molecular staging"-that is, assessing the status of a tumor-in patients with head and neck cancers prior to clinical testing of an experimental form ofgene therapy developed by Onyx Pharmaceuticals. The therapy is in Phase II testing, and some patients have responded favorably in preliminary results.
The ability to do molecular profiling, according to Leslie Alexandre, a vice president at Oncormed, allows oncologists to determine both the virulence of a tumor and the extent of its metastatic spread. "If there is a p53 mutation in the tumor," she says, "then you would look at the lymph nodes and look for the fingerprint to see how far the tumor has spread." Oncormed has reached agreements with RhonePoulenc Rorer and Schering-Plough to do p53 testing associated with gene therapy trials.
The potential significance of such testing goes well beyond staging individual tumors. Drug companies are intensely interested in ways of predicting which patients are likely to respond to chemotherapy, and there is some evidence that p53-and molecular profiling like it-may help identify patients likelier to respond. Not only will this allow drug companies to achieve higher response rates in drugs being tested, but it may, Alexandre says, provide a way to "resurrect" drugs that fail in Phase III trials by identifying a small group for whom the drug is very effective..."
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