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On the Trail of Cancer-Causing Genes

We have come a long way in understanding cancer. After decades of intensive research, we have learned that cancer is caused by damaged DNA -- genes that normally regulate cell division stop doing so. Smoking causes lung cancer because chemicals in the cigarette smoke mutate (read “blast away”) the genes in lung cells that stop the cells from dividing ceaselessly. Carefully investigating one cancer-causing mutation after another, researchers have compiled a list of a few dozen “cancer causing” genes that, when damaged, increase your chances of cancer.

What is exciting about this list is it provides researchers seeking a cancer cure with a list of potential targets for therapy. Certain leukemias are being treated successfully by counteracting the specific mutation that causes them, for example. What is discouraging about the list is how short it is. There are not many options to explore.

We know very little about the genes involved in metastasis, for example, the change in cancer cells that enables them to migrate to other sites in the body. The same can be said for the genes responsible for individual differences in cancer susceptibility, and in responses to particular cancer therapies. There are a lot of genes out there which would be attractive targets for therapy, if only we knew which ones they were.

The completion of the human genome sequence has set gene prospectors off on a hunt to identify these genes. By systematically screening cancer patients and comparing their DNA profiles, researchers have compiled a list of some 300 candidates out of the human genome’s 35,000 genes, each candidate gene apparantly associated with cancer in some way. The problem is, we don’t have the slightest idea what most of these genes do.

In the last year, all this has changed. A surprising new discovery has provided cancer researchers with a prospecting tool of surpassing power. Using it, researchers are now taking a closer look at these 300 cancer-associated genes.

The discovery doesn’t seem earth-shattering on the face of it. Last year scientists studying RNA molecules within cells (the copies of DNA that are used to direct the manufacture of proteins) learned that their experiments had been overlooking an important component. Easy to ignore in the presence of huge RNA molecules thousands of nucleotide units long, these small RNAs are only 21-28 nucleotides long. When examined carefully, however, the small RNAs have an unexpected property with an important consequence.

The unexpected property is that small RNAs are not random short fragments, but rather represent portions of genes repeated twice. Because their two ends have complementary sequences, the ends of a short RNA molecule can fold back on each other to form a hairpin loop.

The important consequence is that the small RNA molecules inhibit the gene from which their sequence originates. Thus when a gene is read, producing an RNA transcript to direct production of a protein, a small RNA will stick to the transcript, forming a complex that is recognized, attacked, and destroyed by RNA-eating enzymes. In a very real sense, the small RNA has interfered with the expression of the gene from which it originates. For this reason, researchers call the small RNAs “interfering RNA,” or iRNA.

iRNA provides cancer researchers with just the tool they needed to prospect for cancer-causing genes. Using iRNA, researchers at the British charity Cancer Research and the Netherlands Cancer Institute are examining each of the 330 potential cancer-causing genes in turn. The approach could not be more straightforward: just shut off each gene, and see what happens -- like removing the fuses from your home’s fuse box one at a time, and looking to see in which rooms the lights go out.

To “shut off” a candidate cancer gene, the researchers use the information generated by the human genome project to direct the laboratory synthesis of a short 20-nucleotide segment of the gene, then double the segment to create a hairpin iRNA for that gene. They then introduce the iRNA into human cells growing in culture, and watch what happens.

Of course they are going to miss a lot. Some cancer genes act at the tissue or organ level in a way that won’t be seen in cell culture. Still, many of the cancer-associated genes can be expected to produce effects that can be detected and studied in tissue culture.

This potential payoff is of enormous importance, as it can be expected to produce many new targets for cancer therapy.

©2003 Txtwriter Inc.





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