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.
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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