NYTIMES Article and link July 4, 2000
The Next Chapter in the
Book of Life: Structural
Genomics
By ANDREW POLLACK
AN DIEGO -- Now
that scientists have
effectively determined the
complete sequence of
human DNA, research
teams are gearing up for
a follow-on project that
many say will be every bit
as ambitious and difficult
-- but also full of promise
for medical research.
The new endeavor
focuses on proteins,
which are the substances
made by the body in
response to instructions
provided by the genes. It
is actually the proteins
that form the body and
carry out its functions, so
they are in some sense
of more direct relevance
to medicine than the
genes themselves.
The Human Genome
Project has led to the
discovery of genes
coding for the production
of tens of thousands of
proteins. But in most
cases, the functions of
these genes and their
proteins remains
unknown. One clue,
however, could be
provided by the shape of
a protein, since proteins
interact with other
molecules based on their
three-dimensional
configuration, like keys
fitting into locks.
So the new effort, known
as structural genomics,
aims to determine the
three-dimensional
structures of thousands
upon thousands of
proteins, much as the
genome project
determined gene
sequences en masse.
"It's basically the next
step after the Human
Genome Project," said
Dr. Helen M. Berman, a
professor of chemistry at
Rutgers University and
director of the Protein
Data Bank, a federally
financed database of
protein structures.
"Instead of a list of letters,
we'll understand biology in
a three-dimensional way."
Besides helping to
determine the function of
a protein, knowing its
shape could also make it
easier to design drugs
that bind to the protein,
turning it on or off. AIDS
drugs known as protease
inhibitors were designed
using this so-called
structure-based
approach. But the
technique has not been
widely used until now, in
part because the
structures of many
interesting proteins are
not known.
Much like the quest for the
genome itself, structural
genomics is being
pursued by a big publicly
financed project that will
make its data public and
by private companies that
will sell their data, raising
the prospect of the kind of
public-private rivalry that
marked the genome
effort.
Proponents of structural
genomics say structure
determination is now
where the genome
search was about 15
years ago, when
scientists began to
envision sequencing the
entire genome, without
knowing the functions of
the genes in advance,
rather than working on
one gene at a time. In the
past it took years to
determine the
three-dimensional
structure of a protein by
examining protein crystals
using X-rays. But new
techniques -- particularly
powerful X-ray generators
known as synchrotrons --
have reduced the time to
weeks.
"We're building tools that
will allow us to solve
structures at a historically
unprecedented rate," said
Dr. Nathaniel E. David,
director of business
development at Syrrx, a
new structural genomics
company based here in
San Diego. It has hired
former General Motors engineers to design
robots to automate the process of preparing
and examining protein crystals.
Still, no one believes it will be cheap or easy.
"This is big science," said Dr. Tim Harris,
president of Structural GenomiX Inc., a
year-old company also based here. Dr.
Harris, who likens his company to Celera
Genomics, the private company that raced
the public consortium in the genome effort,
expects to spend $100 million to $500 million
to determine 5,000 protein shapes in five
years. "This is not for the faint-hearted," he
said.
In April, the National Institutes of Health and
Britain's Wellcome Trust sponsored the first
international structural genomics meeting to
discuss plans for the public project.
The two organizations are also the sponsors
of the Human Genome Project.
In the next few months the N.I.H.
will award grants for four to six pilot projects
in its Protein Structure Initiative. Total
financing for the five-year pilot phase could
reach $100 million, said Dr. Marvin
Cassman, director of the National Institute of
General Medical Sciences, the N.I.H. division
coordinating the project. If the pilots work,
financing could grow much beyond that,
though a final figure is not known, he said.
Projects are also getting under way in
Germany, Japan and other countries.
The striking parallels between structural
genomics and genomics raise questions
about whether there will be the competition
and petty sniping that accompanied the
efforts by Celera and the Human Genome
Project until their recent truce. "I think
everybody's aware of it and everybody's
thinking about it," said Dr. Raymond C.
Stevens, a professor of molecular biology at
the Scripps Research Institute.
For now, both academic scientists and
corporate ones say this will not be the case.
Celera and the genome project are pursuing
the same target, the complete human
genetic code. But no structural genomics
company or laboratory will be able to do
more than a small subset of all proteins. And
they will choose their targets differently.
The private companies will pick proteins that
are medically useful. The public project aims
to determine the shapes of a wide variety of
proteins to understand protein structures
better.
"We're choosing our targets on the basis of
trying to cover as much of the protein
landscape as we can," Dr. Cassman said.
"That's not the same thing as choosing your
targets based on medical interest."
Still, some applicants for N.I.H. grants want
to focus on medically useful proteins. And
the potential for conflict is there because the
public project calls for the structures to be
placed in the Protein Data Bank, freely
available to all researchers. But the private
companies say they will offer most of their
data only to subscribers and will patent the
structures and functions they discover.
"We want to lock up as much of that
proteome as we can," said Dr. John Chiplin,
president of GeneFormatics Inc., a start-up
company based here. The term "proteome"
refers to all proteins produced by a species,
much as the genome is the entire set of
genes.
The patenting of protein structures could be
as disputed as the patenting of genes. The
federal Patent and Trademark Office has
begun granting patents on the
three-dimensional coordinates of a protein in
a computer readable form. But new Patent
Office guidelines make it unlikely that patents
will be granted on protein structures unless
the protein's function is known.
Complicating the public-private issue is that
many of the scientists seeking the N.I.H.
grants are also the founders of companies.
Dr. Stevens at Scripps is a co-founder of
Syrrx, which is being spun out of a Novartis
research center here. Structural GenomiX
was founded by Dr. Wayne A. Hendrickson
and Dr. Barry Honig, both of Columbia
University. Another company, Structure
Function Genomics in Princeton, N.J., is
being started by Gaetano T. Montelione and
Stephen Anderson, both professors at
Rutgers.
Right now, there is
more conflict within
the academic
community than
between the public
and private
sectors.
Some scientists
oppose the public
project, saying that
blindly determining
structures, rather
than working on
proteins of known
interest, is neither
useful nor
intellectually
challenging.
"It's really hack
money," said Dr.
Michael G.
Rossmann,
professor of
biological sciences
at Purdue
University. "The
concepts are to do
things very quickly
without thinking,
and I don't think
that creates good
science."
Proponents of
structural
genomics point out
that similar
objections were
raised at first to
the Human
Genome Project.
But now, they say,
most scientists
agree that having
the entire gene
sequence is
extremely
valuable.
Structural
genomics is just
one endeavor
spawned by
completion of the
genome project.
Another related
one is proteomics,
which involves
determining which
proteins are in
different cells and
how the proteins
work together.
The genome project is expected to lead to
the discovery of tens of thousands of genes,
providing the input for structural genomics
and also the need for it. The challenge now is
to figure out what the genes do. Looking at
the shape of the protein produced by a gene
is one way to do that. "Form and function are
tightly coupled," said Sung-Hou Kim, a
professor of chemistry at the University of
California at Berkeley.
For instance, scientists knew that a protein
dubbed Tubby was connected with obesity
but did not know how it worked. So Dr.
Lawrence Shapiro and colleagues at the
Mount Sinai School of Medicine determined
the structure of the Tubby protein. Its shape
and positively charged face led them to
deduce that the protein binds to DNA, turning
a gene on. With that clue, scientists can now
begin searching for the gene regulated by
Tubby.
Still, critics challenge how valuable structural
genomics will be. The shape can provide
clues only about the type of molecule a
protein is, for instance, that it binds to DNA,
but not what metabolic pathway or disease it
is associated with.
Dr. Thomas A. Steitz, a professor of
molecular biophysics and biochemistry at
Yale University, said that in many cases
scientists cannot tell anything about function
from the shape. He also said that many
proteins are interlaced with others in the
body, so the shape they have when isolated
is not the same as they are in the body.
Moreover, structural genomics will tackle
only a tiny subset of all protein structures,
making it far less comprehensive than the
Human Genome Project.
That is partly because there are more
proteins than genes, since a single gene can
make more than one protein variant and
because proteins can change shape as they
act. Some experts think there are several
hundred thousand human proteins even
though there are only about 100,000 genes.
Including plants, animals and
micro-organisms, there are millions of
proteins.
And it is almost impossible to determine the
shapes of some proteins because they
cannot be made into crystals needed for the
X-ray crystallography. Proteins embedded in
cell membranes -- estimated to be about a
third of all proteins -- are almost impossible
to crystallize. And many of these are the
very proteins to which drugs bind.
Also, even with the more efficient techniques,
it can still take weeks and cost tens of
thousands of dollars to determine a single
structure. Structural GenomiX's slogan is
"5,000 proteins in 5 years." The N.I.H. effort
aims at about 10,000 to 20,000 proteins over
10 years.
Some question how valuable such limited
samples would be. "With a population of six
million sequences, 5,000 structures in five
years doesn't cut the mustard," said Dr.
Chiplin of GeneFormatics.
Instead of X-ray analysis, GeneFormatics
plans to use computers to predict the shape
and the function of proteins, at the rate of
thousands of proteins a day. But computer
analysis has its own shortcomings.
Proteins are made of building blocks known
as amino acids that are arranged like beads
on a string. But the string then folds into a
complex shape. A three-letter genetic
sequence codes for each amino acid, so it is
straightforward to predict the amino acid
sequence from the gene. But no one has yet
been able to predict how this string of amino
acids will fold.
The International Business Machines
Corporation is building a computer 500 times
faster than any available today to predict
how a protein will fold by calculating the
atomic forces acting on the amino acid chain.
Even with that computer, it is expected to
take an entire year of number crunching to
simulate the folding of a single protein, a job
the body does almost instantaneously.
However, if a protein shares more than 30
percent of its amino acid sequence with a
protein with a known shape, computers can
estimate the unknown protein's shape
reasonably well. Indeed, the N.I.H. project is
based on the assumption that there are only
several thousand different classes of protein
folds. Determining the structure of several
examples of each class would provide the
data necessary for computers to model
virtually any other protein.
For now, though, structures estimated by
computers are not likely to be precise
enough to use in drug design. So there will be
need for physical structure determination.
So both the public and private projects are
going forward and hoping to avoid the conflict
that has marked genomics. "One would hope
there might be some lessons learned," said
Dr. Berman of Rutgers. "One would hope.
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