Home' Technology Review : January February 2009 Contents FEATURE STORY 51
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THE PERSONAL GENOME
At a recent conference at the venerable Cold Spring Harbor Labo-
ratory on Long Island, James Watson, codiscoverer of the structure
of DNA, sat slouched in the front row of the auditorium beneath
a large portrait of himself. Watson, who for a time headed the
Human Genome Project, had his genome sequenced in 2007. His
was only the second individual genome to be completely mapped.
(Craig Venter, who led the private e ort to sequence the genome,
used his own DNA as the sample.)
Watson isn't known for sitting through successive conference
presentations. But a good portion of this conference was about
him. He attended talk after talk, as scientists presented their analy-
ses of what has become a ectionately known as "Project Jim."
Watson is a seemingly healthy 80-year-old man, and the results
of scrutinizing his genome have so far been fairly mundane. He
has extra copies of genetic variations shown in previous studies
to protect against heart disease and macular degeneration, for
example. An initially worrying mutation in the BRCA1 gene, which
is linked to breast cancer, turned out to be harmless. But the vast
majority of Watson's genome remains uninterpretable. Scientists
have yet to find a genetic component to his intelligence or his
curiosity or his tendency toward politically incorrect outbursts.
Perhaps most important to Watson, it's not yet clear whether he
harbors a genetic vulnerability to schizophrenia that he passed
along to his son, who has the disease.
The Human Genome Project's reference sequence, which is a
composite of genetic information from more than 20 individu-
als, gave scientists a basic blueprint of the genome. But a single
genome has its limits. It's only by comparing multiple genomes
that scientists can begin to get a handle on the genetic variability
that underlies the vulnerability to disease or madness, the ten-
dency to athletic prowess or mathematical genius, the drive toward
altruism or aggression.
Even Watson, who has spent his career trying to understand
DNA, seems less than impressed to see the details of his genome
presented. "We'll see if any of it adds five minutes to my life span,"
he remarked at the conference. Indeed, the meaning of most of
his genetic quirks will remain a mystery until many more people
join him in having their genomes sequenced.
Harvard Medical School geneticist George Church, who has
been working on sequencing technology since his PhD research
at Harvard in the early 1980s, aims to speed that process along.
Three years ago Church launched the Personal Genome Proj-
ect (PGP), which aims to collect genetic and medical data from
thousands of people over the next five years. The project indi-
cates not just the technical and scientific challenges that might
be posed by large-scale sequencing of human genomes, but the
ethical issues as well.
In the pilot phase, the project will focus on 10 volunteers, includ-
ing Church, Harvard psychologist Steven Pinker, and entrepre-
neur Esther Dyson. To start, it will sequence the coding regions
of their genomes---the 1 percent of DNA that directs the produc-
tion of proteins. That information, along with the participants'
medical histories (including prescription regimens) and infor-
mation about their height, weight, handedness, and other traits,
will be deposited in a public database. Church's team hopes that
this database will serve as a resource for scientists, or even mem-
bers of the public, who want to search for links between specific
genetic variations and diseases or other traits.
The first set of data---released to participants in October---hints
at both the promise of sequencing and the current limitations of
genetic analysis. John Halamka, CIO of Harvard Medical School
and another one of the 10 original volunteers, learned that he car-
ries a mutation for Charcot Marie-Tooth disease, an inherited
neurological disorder. This rare variation would not have been
found with existing SNP arrays. But since Halamka survived
childhood unscathed, and only three other people in the world
have been shown to carry that particular mutation, it's hard to
know what impact, if any, it has had on his health. Perhaps many
people carry the variation with no ill e ect, and the link between
the disease and the mutation has been overstated. Or perhaps the
gene has a broader impact than expected, raising the risk of other
neurological diseases. (Or, as George Church notes, the finding
may simply be an error.)
The greater the number of entries in the database, the easier it
will be to understand a finding like Halamka's. And in April 2008,
Church's team received approval from Harvard to expand the
project from 10 to 100,000 participants. (Church plans to scale up
slowly, multiplying the number of subjects by 10 each year.) This
next phase will seriously test both the technology used to sequence
the genomes and the strategies used to interpret the resulting data.
As of November, about a year into the project, PGP scientists had
gotten only about a fifth of the way through sequencing the cod-
ing regions of the original volunteers' genomes. (Church plans to
The latest data suggest that
even the most common
heritable illnesses are
caused by many di erent
variants, each of them
relatively rare. If that's true,
then practicing personalized
medicine could become
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