Genetic Engineering 15


A biochip, also called a gene microarray, is a square of glass smaller than a postage stamp, covered with millions of strands of DNA like blades of grass. Biochips were invented nine years ago by gene scientist Stephen Fodor. In a flash of insight, he saw that photolithography, the process used to etch semiconductor circuits into silicon, could also be used to assemble particular DNA molecules on a chipa biochip.

Think of the chip surface as a field of assembly sites, much as a TV screen is a field of colored dots. Just as a scanning beam moves over each individual TV dot instructing it to be red, green, or blue (the three components of color), so a scanning beam moves over each biochip spot, commanding the addition there of a base to a growing strand of DNA. A computer, by varying the wavelength of the scanning beam, determines which of four possible nucleotides is added to the growing DNA strand anchored to each spot. When the entire chip has been scanned, each DNA strand has been lengthened one nucleotide unit. The computer repeats the process, layer by layer, until each DNA strand is an entire gene or gene fragment. One biochip made in this way contains hundreds of thousands of specific gene sequences.

How could you use such a biochip to delve into a person’s genes? All you would have to do is to obtain a little of the person’s DNA, say from a blood sample or even a bit of hair. Flush fluid containing the DNA over the biochip surface. Every place that the DNA has a gene matching one of the biochip strands, it will stick to it in a way the computer can detect.

Now here is where it gets interesting The mad rush to sequence the human genome is over. The gene research firm Celera has recently announced it has essentially completed the sequence, with over 90% of genes done. Already the researchers are busily comparing their consensus “reference sequence” to the DNA of individual people, and noting any differences they detect. Called single nucleotide polymorphisms, or SNPs (pronounced “snips”), these spot differences in the identity of particular nucleotides record every way in which a particular individual differs from the reference sequence. Some SNPs cause diseases like cystic fibrosis or sickle cell anemia. Others may give you red hair or elevated cholesterol in your blood. As the human genome project charges toward completion, its researchers are excitedly assembling a huge database of SNPs. Research indicates that SNPs can be expected to occur at a frequency of about one per thousand nucleotides, scattered about randomly over the chromosomes. Each of us thus differs from the standard “type sequence” in several thousand nucleotide SNPs. Everything genetic about you that is diferent from a stranger you meet is caused by a few thousand SNPs; otherwise you and that stranger are identical. How Biochips Can Be Used to Screen for

One of the biggest decisions facing an oncologist (cancer doctor) treating a tumor is to select the proper treatment. Most cancer cells look alike, although the tumors may in fact be caused by quite different forms of cancer. If the oncologist could clearly identify the cancer, very targeted therapies might be possible. Unable to tell the difference for sure, however, oncologists take no chances. Tumors are treated with therapy that attacks all cancers, usually with severe side effects.

This year Boston researchers Todd Golub and Eric Lander took a vital step towards treating cancer, using new DNA technology to sniff out the differences between different forms of a deadly cancer of the immune system. Golub and Lander worked with biochips.

The way to tell the difference between two kinds of cancer is to compare the mutations that led to the cancer in the first place. Biologists call such gene changes mutations. The mutations that cause many lung cancers are caused by a tobacco-induced alteration of a single DNA nucleotide in one gene. Such spot differences between the version of a gene one person has and another person has, or a cancer patient has, are examples of SNPs.

Golub and Lander obtained bone marrow cells from patients with two types of leukemia (cancer of white blood cells), and exposed DNA from each to biochips containing all known human genes, 6,817 in all (figure 16). Using high-speed computer programs, Golub and Lander examined each of the 6,817 positions on the chip. The two forms of leukemia each showed gene changes from normal, but, importantly, the changes were different in each case! Each had their own characteristic SNP.

Biochips thus may offer a quick and reliable way to identify any type of cancer. Just look and see what SNP is present.

The Use of Gene Chips Will Soon Be Widespread

Biochip technology is likely to dominate medicine in the coming millennium, a prospect both exciting and scary. Researchers have announced plans to compile a data base of hundreds of thousands of SNPs over the next two years. Screening SNPs and comparing them to known SNP data bases will soon allow doctors to screen each of us for copies of genes leading to genetic diseases. Many genetic diseases are associated with SNPs, including cystic fibrosis and muscular dystrophy.

Biochips Raise Critical Issues of Personal Privacy

The scary part is SNPs on chips. Researchers plan to have identified some 300,000 different SNPs by 2001, all of which could reside on a single biochip. When your DNA

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