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DNA Arrays

Biologists are using technology from the microprocessor industry to take genetics research to a new level of effectiveness. Until recently, genetic research and analysis depended largely on the isolation of particular genes and gene sequences in order to determine genetic effects. Researchers have discovered, however, that the effects of genes frequently depend on the presence and activation of a baffling mix of multiple genes within chromosomes. Identifying systemic genetic effects using tools based on gene isolation looked to be a major roadblock. But DNA arrays will provide the means to conduct systems analysis on genetic effects.

A DNA array consists of a glass, silicon, or filter-paper substrate divided into hundreds or thousands of small areas, each containing a sample (containing up to a million copies) of a known DNA segment. The unique DNA segment can be long or short, consisting of only several nucleotides or a million depending on the length of the DNA segment the scientists are targeting for identification. Each area, with its multiple copies of a distinct DNA segment, is a probe. Affymetrix, a company in Santa Clara, California, uses photolithography to construct microchips containing as many as a million individual probes, though 200,000 to 300,000 probes is a more typical size for the chips they hope to commercialize. Companies such as Affymetrix will be able to mass-produce these DNA chips in the same way that computer companies mass-produce microprocessors.

Picture of a microscope.When scientists want to identify genetic characteristics of a tissue sample, they label it with a fluorescent marker and apply it to the chip or array. The sample washes over every probe on the array but attaches DNA fragments only to the probes containing nucleotide sequences matching DNA segments in the sample. Examination under a microscope reveals certain coordinates that glow because they have latched onto (through nucleotide matches) significant amounts of the sample's DNA. Because the researchers know which DNA sequences lie in each of the chip's coordinates, they can identify the sequence of the sample.

DNA arrays have the potential to alter the health care business on several fronts. First, they will aid in the diagnosis of diseases. Because the arrays can contain so many probes, they allow researchers to analyze thousands of genes at once. Some of the most dangerous and common diseases, such as colon cancer, involve a variety of possible malfunctions in an as-yet-unknown number of genes. The DNA array technique appears to be ideal not only for characterizing the genetic components of the disease but also for providing an inexpensive and relatively rapid means of diagnosis.

Second, DNA arrays enable customization of diagnosis and treatment. Affymetrix and OncorMed of Gaithersburg, Maryland, are developing a chip to detect irregularities in a particular gene (p53) that researchers have isolated as being frequently involved in cancer metastasis cancer patients with the irregularity may want to pursue a more rigorous treatment than other cancer patients. The experimental chip combines probes necessary to characterize the complete normal sequence of the p53 gene with probes for several hundred known mutations of the gene.

In general research, treatment regimens are currently abandoned if they don't result in the desired effects across a majority of the entire treatment population. DNA arrays provide a possible means to understand why certain regimens are effective in only 20% (for example) of a test population. If this hypothesis works out, arrays would also be able to prescreen patients to determine if they are part of the segment of the population for which a particular treatment is safe and effective. Ultimately, medical professionals might even be able to create drugs tailored to individual patients.

Third, DNA arrays may provide a mechanism by which doctors can identify proclivities for certain conditions and prescribe drugs in a preventive regimen. DNA arrays may help health care evolve into a proactive process instead of the predominantly reactive process it currently is.

DNA arrays will also greatly enhance research. The systems approach that the arrays enable will provide a much more accurate characterization of just how extensively genetic factors contribute to particular diseases or character traits. Enhanced understanding will probably lead to completely new, more accurate taxonomies for diseases. DNA arrays will also provide an effective tool in combating the emergence of drug-resistant bacterial and viral diseases. The rapid and inexpensive nature of the microchip array process will enable researchers to track more accurately the nature of rapid genetic changes characteristic of diseases such as cancer. Quick and inexpensive assays will also provide an unprecedented look at gene expression, the process by which only certain genes are active, depending on the cell's location in the organism.

Several companies, each of which has developed variations on the array process, are active in the DNA array field. Affymetrix is the only company that has gone public. Nanogen of San Diego, California, will develop diagnostic tests for infectious diseases, including diagnosis of whether the particular infection has developed resistance to various antibiotics. Nanogen has developed a proprietary electronic hybridization technique to speed analysis and is funding its efforts through private offerings. Hyseq, of Sunnyvale California, uses filter paper as a substrate for its arrays and plans an initial public offering soon. Synteni and Genometrix of The Woodlands, Texas, are two other privately funded participants in the industry.

Rapid progress in DNA array technology will accelerate the need on the part of society to address the ethical and legal issues already under discussion regarding genetics. If past practice in the ethical and legal arenas is any indication, social, political, legal, and cultural constraints are likely to be more important considerations in predicting the progress of genetic research than are the technological constraints on DNA arrays. Privacy and health care cost issues will become increasingly important as researchers successfully quantify the genetic components of health and behavioral traits.

For more information
Science News , 8 March 1997, page 144
Fortune , 31 March 1997, page 56
Nature Genetics , December 1996, page 441

 


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