The Gene Factory
An exclusive peek inside the data machine built to
beat the Human Genome Project.
By Karin Jegalian
March/April 1999
On a day of vivid hues last
fall, an anxious group of
architects, contractors,
engineers and scientists
gathered in the basement
of a building in Rockville,
Md. The structure was
supposed to be converted
by year's end into the greatest DNA sequencing
factory in the world, but the planning meeting
confirmed that problems were piling up. Delivery of a
crucial steam generator had fallen behind. And it
wasn't even clear that the walls of the
113,000-square-foot office building, which had been
occupied by a defense contractor but now stood
gutted, would accommodate all the pipes and wires
needed to run the new laboratories.
The contractors were uneasy, but if the scientists
present in the room weren't overflowing with
sympathy, it was because they had set themselves an
even bigger task with an even more dramatic timeline.
The researchers work for Celera Genomics Corp., a
company formed last May with plans to decode by
2001 all the 3.5 billion chemical letters of DNA that
make up human heredity. Celera intends not only to
beat by four years the target date originally set by the
publicly funded Human Genome Project (which began
in 1990), but also to finish the job for a tenth of the
government project's $3 billion price tag.
If these claims were coming from another company,
they might be dismissed as outrageous. But Celera is
the child of Perkin-Elmer, the instrument company that
monopolizes the market for automated DNA
sequencing machines, and J. Craig Venter, the most
controversial and productive genome researcher in the
world. The partners agreed to give TR a preview of
the substance behind their ambitious plan, and allowed
a reporter to follow along as Celera's facility came into
being.
Much of the scientific expertise that powers Celera
comes from The Institute for Genomic Research
(TIGR), an independent lab Venter founded in 1992.
At TIGR, also in Rockville, Venter's staff has
employed a rapid-fire method known as the “random
shotgun” approach to decode the genomes of nearly a
dozen bacteria. No other lab has produced more DNA
sequence—“readings” of the long strings of chemical
letters designated A, C, G and T that make up the
DNA molecule. Then again, Venter's approach has
never been tried on anything as large as the human
genome, which contains about 1,000 times as much
DNA as your average microbe. “It's hard...to grasp
the entire scale of this,” says Venter, now Celera's
president. “I can deal with millions, at least, because I
spend them all the time now.”
The money behind Celera comes from Perkin-Elmer,
an instrument giant for which the project is a dramatic
shift toward controlling data rather than just making
and selling equipment. The decision by officials at
Perkin-Elmer's Norwalk, Conn., headquarters to put a
powerful new type of DNA sequencer to work for
themselves has stunned the biotechnology industry and
drawn comparisons to Microsoft's move into online
publishing. The partners pre-empted fears that they
might hijack the genome by promising to hand over the
data for free (but with a few caveats) to the public
sector. Between Venter's shotgun method and
Perkin-Elmer's deep pockets and new machines,
Celera looks as if it could well live up to its name: a
play on the word celerity, for rapidity of action.
Factory Tour
Today, four months and many late nights after the
anxiety-riven planning meeting, the gene factory is
complete. The only sign that the glass building contains
what is arguably the world's most prolific molecular
biology lab are two massive air conditioning units
crouching in the grass. The chillers, too heavy to sit on
top of the building, cool 1,600 cubic meters of air per
minute and pipe it into the heart of the facility, where
257 new sequencing machines hum in orderly rows.
The gray, waist-high 3700-model machines were
developed over two years in near-secrecy by
Perkin-Elmer's West Coast subsidiary, Applied
Biosystems. Just one of those machines, says Venter,
has more sequencing capacity than many big academic
labs, most of which rely on an earlier model called the
377. Altogether, Venter calculates, Celera can decode
nearly as much DNA in one day as all the major labs
funded by the Human Genome Project produced last
year.
It's what's inside these new machines that makes
them so fast. Each contains 104 glass capillaries:
hollow, hair-thin tubes that the machine can
automatically fill with a syrupy polymer and later clean
out with a dilute solution of nitric acid. The
sequencer's job is to sort DNA fragments by size.
Pulled along by an electric field, small fragments move
through the tubes faster than large ones. The
capillaries replace cumbersome cafeteria-tray-sized
slabs of toxic gel used in previous models, which had to
be changed by a skilled technician every few hours.
Stocked with chemicals and more than 1,000 DNA
samples, the automated 3700 can run for nearly two
days without human intervention, says Mark Adams,
the young scientist who supervises Celera's
sequencing operation. At full capacity, Celera expects
to read 100 million letters of DNA sequence each day.
More than half of Celera's personnel—backed by
eight 6-foot, 64-bit computer servers located in an
adjacent building—will be devoted to unscrambling the
avalanche of data streaming from the sequencing
facilities. Leading the analysis is Gene Myers, an
expert on pattern analysis on leave from the University
of Arizona's computer science department.
The challenge Myers' staff will face is something like
reassembling a complete Bible from 10 copies that
have been torn into tiny pieces. Since the sequencing
machines can read only short stretches of DNA, the
genome must first be broken into smaller pieces.
Celera scientists began by taking DNA from a number
of human cells and chemically shredding it into millions
of random, overlapping fragments a few thousand
letters long. To keep a library of these fragments, the
scientists grafted them into colonies of E. coli bacteria.
Following the shotgun strategy, Celera will then
sequence 500 letters from each end of a
fragment—repeating the process across the entire
library yields 70 million separate sequences.
Myers' task is to develop algorithms that can assemble
these elements once their code has been read.
Although it sounds like a straightforward job—just line
up overlapping letters and start pasting—it is anything
but. Take the ripped-up Bible. Common phrases such
as “Thou shalt not...” or “Blessed are they...” would
make reassembling the good book much harder
because some fragments appear to overlap when, in
fact, they don't. The genome is similarly crammed with
repeated sequences, some short, some long, some
present in a million copies, others repeated only twice.
For that reason, scientists working on the publicly
funded Human Genome Project have laboriously
mapped out the genome before starting to sequence.
Roughly like figuring out where the Bible's chapters go
before tearing up the pages, it means they will then
have to reassemble many small piles, rather than one
huge one. Elbert Branscomb, director of the
Department of Energy's Joint Genome Institute, thinks
Celera's 70-million-piece puzzle may be unsolvable.
“How much of a problem this will be no one even has
a moderately good guess,” says Branscomb.
Myers contends that the key to the solution is that
Celera's puzzle pieces come in pairs lifted from the
ends of a single fragment, the total length of which
they know. The pairs, he believes, will constrain the
problem enough to arrive at a unique solution. Outside
scientists say Celera's strategy would be impossible
without the sequences already developed at publicly
funded labs, but Myers maintains the puzzle could be
solved anyway. “Outside information is just an
expedient,” he says. “If we were going to do a genome
that we have no data about, say Bermuda grass, we
could do a self-contained operation.”
Whether or not Celera's operation represents
top-notch science is still a matter of some debate in the
genome community. Without a doubt, Celera's version
of the genome will have many, many small gaps. A
photocopy, if you will, that gives the big picture and
most of the detail but may fall short of the high-fidelity
standard envisioned by the Human Genome Project.
After the Genome
The data, however, will be good enough to take to
market. Venter has said he will give away the raw
sequence for free by downloading it into the online
public repository known as GenBank. So what's left to
sell? Quite a lot. Celera's profits may come largely
from licensing to pharmaceutical companies a database
that packages the sequence into a more accessible
form. Drug companies will mine the data for genes
with medical applications, although Venter says Celera
will first find and patent several hundred genes for
itself. Celera will also hold onto information about
single DNA letters that vary between people called
“single nucleotide polymorphisms.” These differences
may predict a person's susceptibility to disease or to
toxic drug reactions. And beyond the human genome
lie others. Monsanto, the large agricultural concern,
has already suggested that Celera take on the rice
genome.
As Venter likes to point out, finishing the human
sequence is simply the beginning of a new era in which
the data can be put to use to improve human health. If
Celera's plans work out, this “post-genomic” epoch
will be upon us sooner than anticipated. In fact, Celera
advanced the timeline for reading the genome before a
single wall had been knocked down for the factory's
renovation. Reacting to the unexpected competition,
directors of the publicly funded Human Genome
Project have announced that they now plan to knock
off the entire project by 2003, two years earlier than
the original schedule called for. And by 2001, when
Celera has promised to unveil its data, public-sector
scientists have vowed to come through with a
“working draft” to match it. Public genome or private,
celerity is definitely the order of the day.
Karin Jegalian holds a PhD in biology and is a
recent graduate of the science writing program at
the University of California, Santa Cruz.
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