Biochemistry

By Jian Cui
Genius
Pehr Harbury’s
Innovation and
Uncovered Daring Awarded
“Research means going out into the unknown with the hope of finding something new to bring
home. If you know in advance what you are going to do or even find there, then it’s not research
at all; then it is only a kind of honorable occupation.”
- Albert von Szent-Györgyi, Nobel Laureate in Physiology or Medicine (1937)

O A
ver a span of nine days in September, Stanford Associate Profes- fter completing his B.S. and obtaining a Ph.D. from Harvard Univer-
sor of Biochemistry Pehr Harbury was awarded two grants guar- sity followed by a post-doctoral fellowship at the University of Cali-
anteeing him no less than $3 million in research money for the fornia, Berkeley, Pehr Harbury joined Stanford’s Biochemistry department
next five years. At only forty years of age, he has garnered the attention in 1997 as a bright young researcher with ambitious ideas. His research
that comes with two of the most prestigious prizes that can be awarded has focused on three major areas: 1) designing proteins with computer
to an American biochemist aside from the Nobel Prize: the MacArthur programs, 2) measuring protein changes in physiological environments,
Fellowship and the National Institutes of Health (NIH) Director’s Pioneer and 3) developing a technique called ‘DNA display.’ As an extension of
Award. his PhD work, Harbury’s first focus of research is the use of computers to
The MacArthur Fellows Program award, more widely known as the design proteins that bind specific small molecules. This will enable sci-
MacArthur “genius” grant, is seen not only as a prestigious award by the entists to engineer biocatalysts—biological molecules such as enzymes
scientific community, but by the general public as well. The award of- that catalyze reactions in the cell. The second focus of Harbury’s research
fers $500,000 to a person over the span of five years, with no restrictions intends to improve methods for
on how this money is spent. The hope is that the recipient can continue predicting protein structure by http://mednews.stanford.edu/harbury.html
to push the boundaries of human understanding and creativity without measuring the conformational
financial restraints. fluctuations that proteins undergo
In many ways similar to the MacArthur grant, the NIH Director’s Pio- in their native environments in the
neer Award is one of the most important grants given by the National In- cell.
stitutes of Health, the primary government organization providing funding The third—and arguably most
for medical research. It is awarded to scientists working on innovative exciting area of his research—is
scientific approaches that may potentially yield high impact results. The the development of a technique
award consists of $500,000 per year in direct costs over five years. called ‘DNA Display’ for which
In a world where competition for funding dominates the science are- he received the Pioneer Award.
na, scientists often find their attentions The DNA Display technique uses
“In the fields drawn away from their laboratories and DNA as a blueprint for guiding
of observation, whiteboards to fund-raising missions. a large collection of small mol-
chance favors While the Nobel Prize acknowledges past ecules to “evolve” into molecules
only the achievements, the MacArthur Fellowship that can perform specific desired
prepared mind.” and the Pioneer Award provide resources properties. “The primary thing I
-Louis Pasteur to promising scientists who may lack the intend to do,” Harbury says, “is
means to conduct the research traditional to turn the DNA Display project,
funding agencies see as overly ambitious and risky. this project of evolving small ^ Dr. Pehr Harbury is a Stanford
Most of the money used for scientific research is in the form of grants, molecules in a test tube, into a Associate Professor of Biochemistry
many of which are from government agencies such as the NIH. The tra- very practical tool for drug dis-
ditional grant offered by the NIH is the Research Project, or R01, grant. covery.” He predicts that within a year, the technique will be sophisticated
The competition is intense, but it can consist of hundreds of thousands of enough to routinely generate and identify small molecules that will bind
dollars for periods of up to five years before renewal. While only approxi- to particular targets. He will then study the effectiveness of the technique
mately 20% of the submitted proposals receive funding, Harbury faced by analyzing the activity of the created molecules in four mouse models
much more difficulty receiving funding than many of his peers. of human disease.

Layouts designed by Jian Cui Volume IV 17

Biochemistry Genius Uncovered

D espite the great potential of his research, obtaining funding for this
research had been “exceedingly difficult” and “extremely stressful”
before September. The Harbury lab had operated on a “shoe-string bud-
get” and lab members were unable to purchase even the basic building
blocks needed to create the large chemical libraries required for the DNA
Display. “We couldn’t buy the tools that we needed to actually develop the
technology to be extremely practical,” Harbury remembers. Fortunately,
the funding from the MacArthur Fellowship and the Pioneer Award pro-
vide a “huge relief,” at least for the next five years.
“[Harbury] was somebody who has had a relatively difficult time get-
ting funded through the traditional RO1 mechanism,” says Dr. Jeremy
Berg, Director of the National Institute of General Medical Sciences. “He
submitted a large number of applications that haven’t been funded and

Science has long ceased to be simply the

insights and observations of the clever Courtesy of Harbury Lab

and curious. It is now deeply intertwined
with economics, politics, and society.
a lot of times in the review process,” Berg says, “people have been con-
cerned that what he’s trying to do is too ambitious and too risky.”
Science has long ceased to be simply the insights and observations of
the clever and curious. In recent years, as both Berg and Harbury attest,
the government’s budget for biomedical research has tightened. The com-
petition for funding is more intense than it has been in the past, and review
groups have become increasingly conservative. “Study sections reviewing
grants tend to rank proposals that could potentially produce very exciting
results but have unproven components somewhat lower than solid, less
risky, but potentially less high impact projects,” Dr. Berg explains.
L ouis Pasteur, widely hailed as the “Father of Medicine” once famous-
^ According to Harbury, the genetic blueprint directs the assembly
of molecules that can be quickly screened to find the ‘needle in the
haystack’ – the molecule performing a specific cellular function. The
function of the desired molecule can be its use as a ‘drug’ to bind
to a specific target protein, altering the cellular process to achieve a
desired outcome. For example, a defective protein cannot perform
its normal function of inhibiting over-expression of the gene that
it regulates, leading to cancer. To combat this, a specific molecule
can be quickly engineered to interact with this defective protein and
restore its proper function, thus controlling the over-expression of its
regulated gene, and reversing the cancerous state.
ly said, “In the fields of observation, chance favors only the prepared

T his trend has serious consequences. It can discourage and even pre-
vent scientists, especially young scientists, from attempting to study
exceptionally difficult topics. Additionally, the NIH has been criticized for
focusing too much on the specific details of projects and for not acknowl-
edging the individuals working on them. In response, the High Risk Re-
search Implementation Group was created and given the responsibility of
distributing the Director’s Pioneer Award to reward individuals who have
shown extraordinary promise as researchers. The High Risk Research
Implementation Group, says Dr. Berg, who is also co-chair of the Group,
developed the idea of “innovation density” to describe researchers. The
reviewers of the nominations for the Pioneer Award were encouraged,
Berg explains, to look not for “the total amount of innovative research [the
scientist has] done over the course of [his or her] career, but the amount
of innovative work that [the scientist has] done divided by the number of
years that [he or she has] been doing it.”
Berg, who has known of Harbury since he was a graduate student in
Dr. Peter Kim’s lab, says Harbury has always had a reputation as an un-
usually talented and creative researcher who worked on difficult and am-
bitious projects. Harbury’s graduate work in Dr. Kim’s lab, Berg says, “re-
ally took things to a different level than they had been before...” “No one
who knows him or has known his work would be surprised,” says Berg,
“in either the Pioneer Award or the MacArthur. He’s not a total unknown
who all of a sudden burst onto the scene.” Berg concludes, “He was a very
good fit to what we were trying to accomplish with the Pioneer Award…
somebody who has really had the tremendous reputation for being unusu-
ally creative and innovative with a real sense for important problems, but
had not thrived under the traditional funding decision-making process.”
mind.” Breakthroughs occur serendipitously; they are only breakthroughs
because they are unexpected. A certain type of person is needed who
will seek, notice, and understand any chance occurrences that may arise.
Grants such as the MacArthur and the Pioneer Award exist in order to
give these special individuals, these few whose ambition, creativity, and
enthusiasm give them the most prepared minds, the best and most favor-
able chances. In fact, the face of science as we know it may depend on the
ability of these prepared individuals, like Dr. Pehr Harbury, to utilize these
opportunities obtained by unconventional means.
Not every scientist awarded the MacArthur grant or the Pioneer Award
will go on to win Nobel prizes and receive never-ending fame and for-
tune, but nevertheless, the high expectations placed on them are very real.
“I think people are going to be watching him, both within NIH and the
whole scientific community,” says Dr. Jeremy Berg of Harbury. The Pio-
neer Award winners, he says, “don’t really have any excuses at this point.
They have a large amount of relatively unrestricted money to go work on
what they want to work on… The hope is that they will do something that
everybody will be pretty blown away by.”
“I’d rather have money and high expectations than no money and no ex-
pectations,” Harbury laughed. “I want to deliver. I feel good about it.” S
Jian Cui is a sophomore majoring in chemistry and he would like to
thank Dr. Pehr Harbury and Dr. Jeremy Berg for making this article
possible. He likes to sit in his room in A121 discussing the meaning
of life with his drawmates. He would also like to add that this state-
ment is false.

18 Stanford Scientific