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From the Wall Street journal
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January 24, 2003


 SCIENCE JOURNAL
By SHARON BEGLEY

Can Burgeoning Genetic Science Solve Vexing Toxicity Question?

Where are the bodies?

Ever since scientific concern over industrial chemicals in the environment
escalated in the 1970s, the alarms raised by public-health advocates have
been parried with a simple question by defenders of chemicals: If benzene,
dioxins, vinyl chloride and all the rest are so bad, how come bodies aren't
piling up in the streets? And relatedly: How can minuscule amounts of lead
be neurotoxic when my kid breathed lead his whole life and got into
Princeton?

Regular readers of this column know that I am no cheerleader for genetic
determinism. But understanding genes and genetic variation just might answer
both of the above and more, through the emerging field of environmental
genomics.

The better-known "pharmacogenomics" studies how your unique genetic profile
determines how you metabolize drugs, and so whether a particular medication
will cure you or kill you. Analogously, toxicogenomics studies the
interaction between toxic chemicals and genes. Subtle variations in those
genes, called polymorphisms, affect how well they do their jobs --
metabolizing the compound to make it more toxic or less, for example, or
allowing the compound to bind to DNA (generally a really bad idea) or not.

In 1997, the National Institute of Environmental Health Sciences in Research
Triangle Park, N.C., launched the Environmental Genome Project. The EGP is
essentially a resequencing program, in which genes thought to affect
susceptibility to environmental chemicals -- especially genes that play a
role in DNA repair, cell division, gene expression and metabolism -- are
examined for variations that affect their function.

Typically, says biologist Debbie Nickerson of the University of Washington,
Seattle, project scientists resequence genes from about 90 people
representative of the ethnic diversity of the U.S. population. So far, they
have identified 554 environmental susceptibility genes and more than 9,000
variants of 123 of them.

Why can some people withstand exposure to otherwise neurotoxic
organophosphates (nerve gases like sarin and insecticides like malathion,
parathion and dichlorvos)? About one-quarter of Asians and 10% of Caucasians
have a protective form of the gene for paraoxonase, an enzyme that
detoxifies organophosphates 10 times as fast as the more common enzyme. Odds
are, Tokyo subway riders who survived the 1995 sarin attack by the Aum
Shinrikyo cult were among them.

Why do fewer than one-quarter of smokers get lung cancer? Common variants of
genes for the P450 enzymes determine how you metabolize the carcinogens in
cigarette smoke; with certain polymorphisms, the carcinogens are less
harmful. And polymorphisms in a gene called NAT1 determine how cells
metabolize arylamine (also in cigarette smoke), and so whether a smoker will
get bladder cancer.

How do some petrochemical workers survive years of exposure to benzene, a
known cause of leukemia? People with a polymorphism that dials down activity
of the CYP2E1 enzyme, which converts benzene into byproducts that damage
chromosomes, are at much lower risk. In contrast, a polymorphism in a
related gene, CYP1A1, seems to increase the chance that exposure to the
industrial chemicals PCBs (polychlorinated biphenyls) will cause
postmenopausal breast cancer.

Envirogenomics has also turned up common polymorphisms that affect the
binding of lead, and thus how much harm it does. Another polymorphism
increases the risk that children exposed in utero to tobacco poisons from
their mothers' smoking will get asthma (with a different polymorphism, they
don't). Variations in genes that regulate dopamine levels inside neurons may
increase the likelihood that exposure to heavy metals or pesticides will
cause Parkinson's disease, especially after age 50, says William Langston,
president of the Parkinson's Institute in Sunnyvale, Calif.

If envirogenomics pans out, risk will no longer be couched in oddsmakers'
terms. "It's likely that people will have a sort of a bar code that records
their polymorphisms and therefore their susceptibility to various
environmental agents," says NIEHS Director Kenneth Olden: Your risk from a
particular chemicals would be 100% (if you carry certain susceptibility
genes) or 0% (if you lucked into protective ones).

Despite the progress, partisans of the EGP are frustrated at the slow pace.
"We could find all the variations of interest in two or three years if we
had the money to hire the sequencing centers" that did the Human Genome
Project, says a leading scientist. (The EGP has a 2003 budget of only $7
million.) "The capacity is there; what we lack are the financial resources."

But maybe we need a little breathing room to figure out what to do with the
results of envirogenomics. What will happen when we know who is and who
isn't at risk from a specific environmental chemical? Will society let
farmers nuke their fields with pesticides and factories fill the air with
carcinogens, figuring we can underwrite organic groceries and buy
respirators for the sensitive among us? Maybe we should just send them for
gene therapy to get their resistance up. No one said the ethical issues
raised by genomics would be simple.

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