BAR HARBOR, Me.-Small glass wafers resembling computer chips are poised to take clinical genetics an order of magnitude closer to workaday medicine.   Called DNA chips, or arrays, they can already reveal genetic defects in tumor cells and spot drug-resistant strains of HIV. The likelihood is that one day they’ll predict risks of heart disease, osteoporosis, and cancer. Indeed, some versions of these chips may soon lead to blood tests for early diagnosis of certain malignancies.   Studded with strips of DNA instead of transistors, the chips work by detecting polymorphisms. They finger the telltale genetic subtleties of a tumor cell or infectious microbe.   “The use of DNA arrays to interrogate biological information represents a paradigm change that will profoundly alter biology and medicine,” the University of Washington’s Dr. Leroy Hood told a meeting at the Jackson Laboratory here.   The key to the chips’ clinical use is knowing what genetic variations mean when they’re found. To that end, researchers are using DNA chips to search among thousands of people for links between specific DNA quirks and disease risk or prognosis or to measure treatment efficacy. Indeed, this effort is fracturing diseases, such as breast cancer, into genetic subclasses needing different therapeutic approaches.   The chips work by DNA hybridization. When two DNA strands hybridize perfectly, knowing the sequence of bases on one strand reveals the sequence on the other.   One type of chip, developed by Affymetrix in Santa Clara, Calif., is programmed with between 65,000 and 400,000 clusters of unique DNA strips, each probe with a specific string of A’s, T’s, C’s, and G’s and a known location. By detecting where on the chip the DNA in question binds most tightly, a computer can reconstruct the exact chemical lettering of the unknown DNA.   Though the same data can be gleaned with the automatic gene sequencers now used in the Human Genome Project, this is impractically slow and expensive for analyzing large amounts of an individual’s DNA. Basically, it amounts to repeating the decade-long genome project for each person.   The advantages of the arrays could be enormous if a physician must scan a large fraction of a patient’s genome for signs of a complex disease like Alzheimer’s or researchers must decode the DNA of thousands of people to find meaning in their genetic variations.   And the chip is already beginning to prove its worth in the more limited task of finding HIV mutations. The HIV test, based on the Affymetrix chip and offered by Laboratory Corporation of America since June, can pick up more than 60 mutations in two critical HIV enzymes-reverse transcriptase and protease. Because some of these mutations have been correlated with resistance to drugs that inhibit either enzyme, this test, with one for viral load, is used to select drugs most likely to work best.   The chip performs the test some 10 times faster than the most high-tech DNA sequences and provides identical results, according to Dr. Tim Alcorn of LabCorp’s Center for Molecular Biology and Pathology in Research Triangle Park, N.C.   A commercial test to detect p53 mutations in cancer patients, also based on the Affymetrix chip, is nearly complete. Developed with OncorMed of Gaithersburg, Md., the test, as a clinical-research tool, rapidly detects more than 1,000 mutations in the p53 tumor-suppressor gene. The gene is thought to be defective in half of all cancers.   Some p53 errors suggest a good response to aggressive treatment using specific chemotherapy drugs plus radiation. But patients without p53 errors may warrant gentler therapy.   “One breast cancer is not the same as another,” says OncorMed’s Dr. Leslie Alexander. Each has distinct genetic features-normal or abnormal p53, the presence or absence of estrogen receptors, high or low levels of HER2/neu-that may warrant different treatments.   Defining these and other disease subclasses requires additional data, which the chip is helping researchers gather. Glaxo Wellcome is using Affymetrix chips to screen the DNA of 1,600 HIV-infected patients-a group that may expand to tens of thousands-to correlate genetic variations in the virus with patients’ responses to different antiviral drugs or drug combinations.   Likewise, researchers will be using the p53 assay in clinical trials for cancer drugs to obtain more data on the link between p53 mutations and various forms of therapy.   Aside from mutations and polymorphisms, DNA arrays can also detect patterns of gene expression at rates thousands of times faster than older technologies.   For example, Stanford’s Dr. Patrick Brown and colleagues are using DNA arrays to determine what genes are turned on in melanocytes when they turn malignant. They’ve found several hundred genes linked to the cancer. Their goal is to characterize gene expression patterns for melanoma and other malignancies that show the presence and stage of a tumor.   To that end, Dr. Hood’s group is developing a gene-expression chip that will, once the critical genes are discovered, spot early signs of prostate cancer from blood cells and reveal whether the cancer is growing fast enough to require immediate surgery.   Ultimately, there may be a set of chips that will let physicians screen for susceptibility to all the major diseases. -Ingrid Wickelgren