Because these diseases are inherited by some, but not all, family members, the tissue samples could be compared for similarities and differences in genetic materials. For example, researchers would look at samples from a father and daughter with one of these inherited diseases and try to identify regions with similar genetic material. Then, if possible, they would compare the regions with other family members they had tracked down, like cousins, who also had inherited the disease.

The researchers were looking for common inherited genetic material, figuring the genes had to be inherited in the same manner as the disease. This kind of sleuthing eventually identified regions similar in everyone who had inherited the disease. Once a region and the disease were associated in this general way, the researchers could begin testing individual genes for more specific links.

In one instance of cross-referencing, Dr. Vogelstein?s researchers were led to a particular region on the fifth chromosome. Samples from sporadic tumors, cancerous tumors that develop spontaneously, showed certain bits of genetic material were missing along the chromosome. When looking at tumors resulting from inherited diseases, researchers noticed missing materials in the same region of the same chromosome. After testing all the genes in that region, researchers were able to implicate the same gene in tumor development.

They also employed a third method to identify likely suspects. In the same way police departments across the country share information on distinctive methods used by local criminals, gene researchers circulate profiles of suspect genes that have been implicated in other types of diseases.

Using these investigative techniques, Dr. Vogelstein and his research partner, Kenneth Kinzler, PhD, discovered a link between mutated copies of the p53 gene and colon cancer in 1989. After more research, p53 was dubbed a tumor suppressor gene, which can be best described as operating like the brakes on a car. If a cell begins to divide and grow inappropriately, p53 acts to slow things down. Cells are normally equipped with two copies of tumor suppressor genes. To completely disable the tumor suppression function, both copies of the gene have to be knocked out, so cancerous cells often show no p53 genes at all.

The identification of p53 made headlines around the world and was soon found by researchers to be linked to many different types of cancer. Dr. Vogelstein and Dr. Kinzler, along with other geneticists around the world, began using the same techniques to uncover more genes that played a role in colon and other cancers.

One genetic culprit in tumor formation is the oncogene. Oncogenes normally are in charge of controlling cell division and growth, much like the way an accelerator controls the speed of a car. When these genes undergo a mutation or are otherwise damaged, they can start to function too well, causing the cell to grow and divide in an out-of-control fashion. This kind of out-of-control cell replication is the beginning step in tumor formation. By themselves, excessive cell replication and tumor formation don?t always signal the onset of cancer, but too-rapid cell growth initiated by a single mutation can lead to other, more significant gene mutations that are part of the progression to cancer.

Another way to picture how oncogenes operate is to imagine the cell duplication process as a copy machine that won?t turn off, but the big difference is each copy isn?t always the same. The more copies that are made of the complex chain of genetic material that makes up a human cell, the greater the chance that some genetic material may be dropped or copied incorrectly along the way. That slight variation amounts to a mutation. And if that mutated cell keeps endlessly dividing and replicating itself, the mutation spreads. A mutated cell is more likely to mutate again, each time edging closer to the point where it turns cancerous.

Perhaps recognizing the danger, nature has made sure there is another type of gene that operates as a sort of genetic repairman. Its job is to make sure that the cell is copying itself faithfully. When it comes across a bad copy, it can actually repair the damage. However, if these repair genes are themselves missing or damaged, out-of-control oncogenes can continue to operate unchecked.

There are still other genes that have been identified by researchers as acting like hunter-killers, tracking down damaged or mutated cells and inducing them to commit suicide. Researchers believe in some instances an insufficient number of these genes paves the way toward cancer in human cells.

The continuing discovery of these genetic manipulators has electrified cancer researchers. Dr. Vogelstein and other renowned gene hunters have established beyond any doubt that changes in specific genes can transform a healthy cell into a cancerous one.
 
In the case of colon cancer, Dr. Kinzler said there are at least half-a-dozen genes central to the development of cancerous tumors. But there is much more to discover about how each of these genes are linked to each other, what function they perform, and in what order they must malfunction to produce cancer.

Part IV: Leading Scientist Encourages Young Researchers to Go with Gut Instincts