Researchers learned early that the task ahead of them was enormous. When it came to genes, there were many, many suspects. Some have likened the task to finding a single misspelled word in a 20-volume set of encyclopedias. The genetic content of a normal human cell is approximately nine billion characters, or bits, of genetic information.

Of that nine billion, maybe 150,000 bits perform significant functions. These functional bits are genes. Imagine them as tools, performing some kind of important job in the cell nucleus. The hypothesis was somewhere in this large universe of functional genes, one or more might be misbehaving. But nobody knew how many misbehaving genes were necessary to spark cancer, and nobody knew which were the important genes, or even where to start looking.

Deciding which cancer to study

To begin making the task more manageable, Dr. Vogelstein took a couple of important steps, including deciding what kind of cancer to study. After much consideration, he chose colon cancer, one of the most common types of the disease. Colon cancer was considered easier to study than some other types because the disease follows a steady progression, from small benign polyps in the colon to larger tumors that eventually become malignant. The polyps and tumors are relatively easy to spot and remove by surgery.

Because most hospitals keep tissue samples taken from these polyps and tumors, there was potentially a wide variety of samples available to study. This was considered hugely important for two reasons.

First, Dr. Vogelstein was determined to study cancerous human tissues. Some researchers preferred to study cancer in animals or cancers grown in lab environments because it was thought by many that human tumors were too complex to reveal anything useful. But Dr. Vogelstein believed it imperative to study human cancers affecting real people if the objective was to identify genetic changes.

Second, there were samples of human tissues that spanned the progression from harmless polyp to cancerous tumor and all the points in between. That would make comparison easier and hopefully help isolate the differences between harmless cells and cancerous ones.

Establishing a network of doctors, hospitals

So, Dr. Vogelstein and his lab team worked to establish a network of doctors and hospitals with access to the highest quality tissue samples. Once the samples started arriving, they began examining the genetic content of the cancerous cells. Unsure of what to look for, they at first just looked for anything that appeared out of the ordinary in the genetic information located in 22 regions, or neighborhoods, called chromosomes.

A normal human cell is equipped with two copies of each gene, one inherited from the mother and one from the father. But after looking at dozens of human tumors, Dr. Vogelstein and his researchers began to notice something curious. In many of the cancerous cells, there appeared to be only one copy of some genes.

He began to wonder if what was missing had something to do with the progression from harmless polyp to cancerous tumor.  Still, the possibilities seemed endless. A single region can still contain thousands of bits of genetic information. Which ones were important to the development of cancer and which ones were harmless?

Like a crime in which everyone is a suspect

Imagine a crime in which everyone in the US was a suspect. It could take months, or even years, just to narrow the suspect pool to the population of, say, Maryland. After more time, you might be able to eliminate everybody outside Baltimore.  After still more painstaking effort, you might begin to focus only on a certain city block.

"But you have no idea who lives there," said Dr. Vogelstein. "You have to go on a house-to-house search and find out everyone who lives in the neighborhood. That takes an enormous amount of time and work." Only after determining who lives in the neighborhood can you begin the process of checking alibis and actually eliminating suspect genes.

The painstaking and time-consuming work done in Dr. Vogelstein?s lab produced a map of the genes in each small region of the chromosome the researchers studied, a map that would make the job much easier for anyone coming along after them.  But, as researchers found, it could just as easily turn out that a particular neighborhood was a dead end, and despite all the mapping and testing, no gene in a particular region could be identified as a culprit.

Dr. Vogelstein and his team were faced with making constant decisions about which neighborhood to investigate. Making the right choices was critically important, given the limitations of time and resources.

Next in the series: Exploring the Genetic Origins of Colon Cancer