Blame Faulty Genes
Cancer is one of the leading killers of adults in the United States, second only to heart disease. Understanding of the disease has evolved, but treatments have not kept pace with knowledge. "Cancer is not a single disease," says Treichel. "Cancer as we know it consists of more than 100 diseases. Each has a distinct modus operandi and unique therapy requirements."

Nonetheless, be it of lung or skin, cancers do share some commonalities. In their early lives, she explains, tumor cells exist as normal cells. But either by genetic misfortune or an environmental assault such as smoking, the normal cells acquire mutations. Such genetic changes render the cells less likely to control themselves, especially when it comes to cell division.

"Suppose you cut your skin," she explains, pointing to the outside of her left palm. "The cells at that site are damaged and will die." In this case, normal cells adjacent to the wound will divide because the body, sensing the loss, sends out biochemical signals. These biochemicals act like "on" signals to prompt the growth of new skin cells. Normal cells, unlike cancer cells, restrict their division to times of healing or to that finite period during our first days as a tiny ball of growing embryonic cells. In other words, normal cells know how to shut themselves down. Cancer cells don't.

Understanding the molecular reasons for that discrepancy has occupied the probing mind of Sandy Morse for more than two decades. The Oberlin alumnus graduated with degrees in zoology and chemistry and, five years later, became the fifth summa cum laude graduate of Harvard Medical School. He settled in at the prestigious National Institutes of Health (NIH) in Bethesda, Maryland, where, on the government's research payroll, he traded the risks of Vietnam War service for the headaches of researching the basics of rheumatology and later, cancer.

"I've always been very peripatetic," says Morse, who bounced from researching animals in college to humans in medical school and then back to animals at the NIH. Indeed, the immunopathologist wanted to create animals with diseases that could mimic those in humans. He became hooked on cancer in part by the work of former National Cancer Institute (NCI) laboratory chief Lloyd Law, who in the 1940s helped pioneer a strain of mice that suffered a form of blood cancer much like a type of leukemia that develops in children. Law, now a poker buddy of Morse's, went on to test potential anti-cancer agents in such strains of cancer-susceptible mice, and the winning drugs advanced to human trials. The approach worked well, at least for some types of blood cancers.

But researchers at the NCI and NIH learned quickly that not all patients with the same diagnosis respond to cancer drugs in the same way. Some patients relapse after several years of treatment, and others never respond at all. Why did some subsets of people fare poorly, while others walked away apparently cured?

"Cancer is a genetic disease, but it is not a disease of a single gene," Morse says. Thus, different genes may be at fault, even in cases where patients outwardly share the same kind of cancer, such as leukemia. A much more sophisticated tactic--a genetic approach--would be needed to separate one blood cancer from another. Morse, who became an expert at mouse genetics, was just the man for the job.

Anti-Cancer Cocktails

About the time that Morse set foot on NIH soil, genetic engineering was in full bloom. Researchers learned what a gene did simply by mutating it in embryonic mouse cells and observing how the animals grew up. If a gene that is defective in people caused a cancer to develop, imprinting that same defect in mice would make the animals susceptible to those same specific "people" cancers. The genetically altered animals would then make ideal test models for successful anti-cancer drugs.

The first step is finding the right genes. Morse, now chief of the laboratory of immunopathology at the National Institute of Allergy and Infectious Diseases at the NIH, is borrowing a technique perfected by the Human Genome Project in which researchers sequenced the entire code of human life. The technique Morse uses is called microarray analysis. It allows a researcher to compare genes that function in tumor cells versus genes that work in normal cells--22,000 genes at a time.

Morse either biopsies mice or receives cancer tissue samples from clinicians. He then extracts the tumor cells and, with the help of fluorescent dyes, flags the genes in the tumor cells that are active. These genes tend to make proteins or enzymes that ultimately advance the cancer. The result is a colored snapshot of the messages being sent out at any given moment by a cell's nucleus.

Morse does the same thing to cells from normal tissue, but using a different color dye. High-tech computer algorithms then compare the two patterns. In the end, tumor cells have patterns of genetic output that look like fingerprints. They differ not only from the gene output patterns of normal cells but also from the "fingerprints" of tumor cells from person to person. "We are trying to identify molecular fingerprints for each type of cancer in each individual," he says.

The ultimate hope is that such fingerprints could better diagnose subsets of cancers or predict who would or wouldn't benefit from a particular anti-cancer therapy. Imagine going into a doctor's office and receiving a personal fingerprint for your kind of cancer. If a doctor knows more precisely what you have, a specific cocktail of drugs--those tested in genetically engineered animals with the exact same disease--could be tailored specifically for your disease.

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