Inside Salk - October 2009 - page 6

Inside SalkOctober 2009
But themachinery isn’t fool proof. For reasons not yet com-
pletely known, cells with DNA damage sometimes go unrepaired
and continue to divide asmutant copies of their original self.
Thesemutant cells are prime candidates for cancer develop-
ment in cases where the affected genes are normally designed to
regulate cell growth (oncogenes) or cell death (tumor suppressor
genes, such as p53). In the unfortunate event a second or third
mutation occurs tomultiple genes, cancer will always develop.
The process is expedited if an oncogene ismutated in combina-
tionwith damage to p53 in the same cell, Shaw says.
“P53’smain function is to serve as a sensor for cells tomake
sure it is safe for them to reproduce their genetic dowry, or to
prevent them from attempting to do so when conditions are sub-
optimal,” saysWahl. “If p53 function is lost because of damage
to its gene, then the cell has no ability to sense impending
dangers, which enables the cell to divide and leads to production
and perpetuation of mutations. This creates opportunities for
additional mutation to form, and that’s when things really start
going haywire. The problem just compounds itself.”
Geoff Wahl will never forget the day in 1989
when he got a crazy idea for a new experiment. He had already
been at home for some time when it hit him just before 9 p.m.
He rushed back to his lab at Salk that night hoping somebody
would be there. He was in luck. He found his postdoc,
Yuxin Yin
“This is what’s great about science. I told him, ‘I’ve got this
crazy idea, but it’s a good crazy idea because it suggests an
experiment,’ ”Wahl says.
For more than a decade, Wahl’s lab had beenworking to un-
derstand themechanisms behind genetic instability
and its link to cancer, and by this point they
suspected the p53 gene, which is now
known to bemutated in half of all human
cancers, played a key role.
Wahl’s crazy idea came at a time
when his labwas studying an anti-pro-
liferating compound. When administered
to cancer cells, most would die off, with the
exception of a few resistant ones that continued
to divide. But what if the drug was applied to noncancerous
cells with normal p53 genes?
AsWahl predicted, the cells stopped dividing completely,
which led him to test one final idea: replace themutant p53
gene of a cancerous cell with one from a normal cell. To his
team’s relief, the cancer cells stopped dividing.
Published in 1992, the series of experiments was among
the first to demonstrate p53’s role inmaintaining genomic
stability – leading many in the field to regard p53 as the
Guardian of the Genome.
It is in fact at the genetic level where cancer begins. To be
precise, it is themutation of specific types of genes that leads to
the development of the disease, which theNational Cancer In-
stitute (NCI) estimates will claimmore than 562,000 lives this
year (1,540 per day) in theUnited States. It also estimates that
nearly 1.5millionmore will be diagnosedwith cancer in 2009.
Mutations in our genes take place every day of our lives. The
simplest examples are DNA damage to skin cells caused by the
sun’s ultraviolet rays, or in the lining of our gut from toxins in
food that we ingest, or in the lung as a consequence of smoking
cigarettes. Despite the common frequency of these biological
events, many of usmay never develop cancer.
Why? Cells are equipped withmechanisms -- p53 chief
among them – that detect and either repair DNA damage or
signal the cell to self-destruct if the damage is too great.
“These genes are part of the normal growth process for hu-
man beings. This is howwe have evolved,” says
Reuben Shaw
Hearst Endowment assistant professor in theMolecular and Cell
Biology Laboratory, who, likeWahl, is one of 30 facultymembers
in the Salk Institute’s NCI-designated Cancer Center. “Every
species has evolved amechanism to get rid of the cells that are
chronically exposed to something that could be bad for them.”
Scientists were first clued into cancer’s genetic nature after
Salk’s Distinguished Professor andNobel Laureate
collaborated on a study that explained how oncogene-
carrying tumor viruses interact with host cell chromosomes
to replicate themselves and induce cancer. The work led to
Dulbecco’s Nobel Prize in 1975 and revolutionized the way
scientists think of the disease.
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