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FEATURE STORY 83
One convert to Sinclair s views on the e ects of resveratrol
was Christoph Westphal, then a partner at Polaris Venture
Partners, based in Waltham, MA. Though only 35 years
old, Westphal had already cofounded two publicly traded
companies, Momenta Pharmaceuticals and Alnylam Phar-
maceuticals---both Cambridge, MA, biotech startups devel-
oping novel drugs. Westphal read the paper and e-mailed
Sinclair, who was already working on starting a company.
Sinclair had had someone else in mind as CEO, but he and
Westphal hit it o .
"David was young and controversial," says Westphal.
"Half the people thought he was crazy, and they were
pounding on him. But I saw something in him and believed
in his science." Westphal and Sinclair are now close friends,
with adjacent desks in a small o ce at Sirtris. Sinclair
spends his Saturdays at work, often bringing his two older
children to play with Westphal s two kids. Sinclair says that
he and Westphal exchange 50 e-mails a day.
I accompanied Westphal one day last winter on his
morning walk from his home in Brookline, MA, across
the Charles River to Sirtris s o ces in Cambridge. He
explained that Sirtris s intention is not to produce dr ugs
that extend life span. "That is not an end point recognized
by the FDA," he said. "Our end points will be speci c dis-
eases." The company has developed a supercharged ver-
sion of resveratrol, called SRT501. It has also discovered
novel small molecules that are not related to resveratrol
but, it claims, are a thousand times as potent in activating
the sirtuins. So far, animal tests have shown that the drugs
may help treat neurological disorders and diabetes.
This past spring, the company launched phase I human
trials of SRT501 in patients with diabetes; it also plans
human trials later this year to test the drug as a treatment
for Melas syndrome, a rare disorder that hastens aging and
causes fatal deterioration of the brain and muscles. Sirtris
expects to begin human trials of its non-resveratrol com-
pounds in the rst half of 2008.
From his modern ninth- oor o ce on the Har vard Medical
School Campus in Boston, Sinclair has a view that includes
Fenway Park. "I can see the scores light up at night," he says.
I m there on an oddly war m day in January, when a few
trees are budding and the sky is crystal blue. On a shelf are a
book by the Australian golfer Greg Norman called The Way
of the Shark and a number of textbooks. Behind Sinclair s
desk are pictures of his wife and children.
Sinclair s Har vard lab, now well funded, is working
feverishly to clarify the health bene ts of resveratrol and
other compounds, and to discover exactly how sirtuins work
on aging and the diseases of aging. In experiments involv-
ing thousands of mice, researchers are homing in on dif-
ferent sirtuin pathways and determining how they a ect
di erent diseases. Sinclair smiles and tells me they are get-
ting great results, but he can t say any more on the record.
He does say he is working with Guarente on some experi-
ments. "Lenny and I typically don t work on things that
aren t important," he says.
It has been two years since I last saw him, and in that
time Sinclair has become more seasoned, more con dent
about fending o critics, and more comfortable with his
stance as a scientist-zealot. "I am a science rebel," he says.
"That s who I am. Everything we publish is criticized."
In the conference room where I join his team to watch a
presentation, the table is made of blond wood, and the black
mesh chairs look expensive. Sinclair is dressed conser va-
tively in a dark-red button-down shirt and gray slacks---not
exactly the clothes of a rebel. A postdoc, Juan J. Carmona,
gives a talk about what happens to the SIR system when a
worm is exposed to the stressor of heat; Sinclair asks ques-
tions, pushing hard. Like most leading academic scientists
with labs, he does little bench research himself, leaving
the experiments to his students. His own success is highly
dependent on their work. In the end, Sinclair looks pleased
when Carmona describes how heat activated the sir2 path-
way and increased life span in the worms.
Students in Sinclair s lab say he sometimes seems driven,
and he admits that he is: "I m driven to get to goals as fast as
possible. It fr ustrates people in my lab who have something
they think is cool, but if it doesn t move us forward, I don t
want to do it." He says he views all the experiments being
done at Sirtris, all his work, as part of a master plan. "I see
this laid out in my mind, every step. But it s happening faster
than I imagined---it s taking 10 years instead of 20 years."
"When will it be ready for humans?" I ask.
"This will impact humans within a decade," he says.
"That s why I don t think there is anything more important
than this quest. That s why I take chances, and why the con-
troversy is worth it: because I think we are right."
He is also not averse to discussing the possibility that a
Nobel Prize will someday be awarded to longevity research-
ers---something Lenny Guarente has also mentioned, though
with the "I don t really think much about it" attitude that is
typical of senior scientists talking about the ultimate award.
If such a prize is given, Sinclair says, Guarente and Cynthia
Kenyon are likely to be two of the winners---out of a possible
maximum of three.
"And the third person on the prize, who will that be?"
Sinclair smiles coyly and says nothing.
David Ewing Duncan is a freelance journalist. His last article for
Technology Review was "Brain Boosters," in the July/August issue.
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