The Race to Read Genomes on a Shoestring, Relatively Speaking
David Prentice
By ANDREW POLLACK NYTimes February 9, 2008
http://www.nytimes.com/2008/02/09/business/09genome.html
A person wanting to know his or her complete genetic blueprint can
already have it done - for $350,000.
But whether a personal genome readout becomes affordable to the rest of
us could depend on efforts like the one taking place secretly in a
nondescript Silicon Valley industrial park. There, Pacific Biosciences
has been developing a DNA sequencing machine that within a few years
might be able to unravel an individual*s entire genome in minutes, for
less than $1,000. The company plans to make its first public
presentation about the technology on Saturday.
Pacific Biosciences, or PacBio, is just one entrant in a heated race
for the *$1,000 genome* - a gold rush of activity whose various
contestants threaten to shake up the current $1-billion-a-year market
for machines that sequence, or read, genomes. But the company has
attracted some influential investors. And some outside experts say that
if the technology works - still a big if - it would represent a
significant advance.
*They*re the technology that*s going to really rip things apart
in being that much better than anyone else,* predicted Elaine R.
Mardis, the co-director of the genome center at Washington University in
St. Louis.
If the cost of sequencing a human genome can drop to $1,000 or below,
experts say it would start to become feasible to document people*s DNA
makeup to tell what diseases they might be at risk for, or what
medicines would work best for them. A DNA genome sequence might become
part of each newborn*s medical work-up, while sequencing of cancer
patients* tumors might help doctors look for ways to attack them.
To spur such advances, the federal government has awarded about 35
grants totaling $56 million to companies and universities for
development of technology that could put the $1,000 genome sequence
within reach. PacBio has received $6.6 million from that program.
The nonprofit X Prize Foundation, meanwhile, is offering $10 million to
the first group that can sequence 100 human genomes in 10 days, for
$10,000 or less per genome. Six companies or academic groups - although
not PacBio - have signed up for the competition so far.
Computerized sequencing machines use various techniques to determine
the order of the chemical units in DNA, which are usually represented by
the letters A, C, G and T. Humans have three billion such units, or six
billion if one counts the second copy of each chromosome pair.
The industry has long been dominated by Applied Biosystems, which sold
hundreds of its $300,000 sequencers to the publicly financed Human
Genome Project and to Celera Genomics for their sequencing of the first
two human genomes, which were announced in 2000. But two newcomers -
Solexa and 454 Life Sciences - have already started to cut into Applied
Biosystems* sales with machines that are faster and less costly per
unit of DNA sequenced. Solexa is now owned by Illumina and 454 Life
Sciences by Roche.
Applied Biosystems, which is a unit of Applera, recently started
selling its own new type of sequencer, which it obtained by buying
Agencourt Personal Genomics for $120 million in 2006. Helicos
BioSciences, a newly public company, announced its first order on
Friday. It has said its machine might be able to sequence a human genome
for $72,000, with further improvements to come.
*We can look somebody in the eye and say, *This instrument is going
to get you to the $1,000 genome,* * said Steve Lombardi, the
president of Helicos, which is based in Cambridge, Mass.
Intelligent Bio-Systems, a privately held company in Waltham, Mass.,
says it will introduce a machine by the end of the year that might
reduce the cost of a genome to $10,000. Other contenders include the
privately held companies NABsys of Providence, R.I., VisiGen
Biotechnologies of Houston and Complete Genomics of Mountain View,
Calif.
Some contestants say that they might try for the X Prize as early as
next year and that the $1,000 genome is as little as three years away.
But other experts are more conservative.
Jeffery A. Schloss, a director of the $1,000 genome federal grant
program at the National Human Genome Research Institute, said he would
be surprised if it could be done much before 2014.
Richard A. Gibbs, director of the human genome sequencing center at
Baylor College of Medicine, said: *There*s a technical leap
required. Once you talk technical leaps, timetables go out the
window.*
Pacific BioSciences, which was founded in 2004, says it can make the
leap. *If we ever make this work, there would be no other technology
applicable in the sequencing field,* said Hugh C. Martin, the chief
executive.
Mr. Martin, who previously ran ONI Systems, a telecommunications
equipment company, is nothing if not self-assured. *When we*re
ready,* he said, *we*re just going to win the X Prize.*
PacBio is based in Menlo Park, Calif. Until now it has remained largely
quiet about its work. And even as the company grew past 100 employees,
Mr. Martin refused to get new space - shrinking the cubicles instead -
until PacBio proved to itself that its technology could work.
But having achieved that last November, PacBio is expanding. It will
also give its first public presentation Saturday at the Advances in
Genome Biology and Technology conference in Marco Island, Fla.
Some outside experts already privy to the technology say it is
promising.
*If it works, it*s the first thing I*ve seen that would have a
chance of winning the X Prize,* said J. Craig Venter, who founded
Celera Genomics and now runs a nonprofit genomics institute.
But PacBio says it will not start selling its first machines until
early 2010, and a second-generation machine that might be capable of a
$1,000 sequence might not be available until around 2013. So the company
could be late to a crowded market. PacBio*s long silence has also
spawned skepticism.
*If you look at how long they*ve been running, they have to get to
the point where they have to show something soon,* said George M.
Church, a professor of genetics at Harvard. Dr. Church was the
co-founder of Knome, the company currently offering the $350,000 genome
blueprints.
PacBio has raised $78 million so far, but probably needs another $80
million, Mr. Martin said. Among the company*s backers are Kleiner
Perkins Caufield & Byers, the powerhouse venture capital firm. Michael
W. Hunkapiller, a co-inventor of automated DNA sequencing and the former
head of Applied Biosystems, is a director and his firm, Alloy Ventures,
has also invested.
PacBio says a big advantage of its machines should be the ability to
read 1,000 or more bases - the chemical units that make up DNA - in one
stretch.
No sequencer can yet read an entire genome at once. So multiple copies
of a genome are broken into fragments, each fragment is then sequenced,
and computers try to assemble the pieces in the correct order.
It is akin to shredding several copies of a book and then trying to
reconstruct the text. The smaller the pieces, the harder it is to solve
the puzzle, particularly in places where there are repetitive
sequences.
The type of sequencer used for the Human Genome Project can now read
more than 800 bases at once. The newer Illumina and 454 Life Sciences
sequencers can go much faster than the older type. But the reading
length of the Illumina machine is only about 30 to 50 bases, while that
of the 454 Life Sciences sequence is 200 to 450.
But these companies say that their sequencers can be used for new
medical applications. The 454 Life Sciences machine was used to identify
a virus that killed three recipients of transplanted organs, after the
usual diagnostic methods had failed, according to a paper published
online Wednesday by The New England Journal of Medicine.
Moreover, these companies say that new sequencing techniques are
allowing genomes to be put together even from the shorter fragments. The
Human Genome Project has already provided a reference genome that can be
used as a template to help figure out where the pieces go.
Illumina, which has already sold about 200 machines, announced
Wednesday that it had sequenced the genome of an anonymous African man
in weeks.
Some experts say genomes made by relying on the reference might not be
quite as accurate as ones done completely from scratch. But some
executives say that using the reference will be the common method in the
future.
Indeed, there is considerable debate on just how much information is
needed to be useful.
Recently companies like DeCode Genetics, 23andMe and Navigenics have
started selling services - for $1,000 to $2,500 - that examine a
person*s genome at up to one million particular points where DNA is
known to differ among people. Studies using DNA from thousands of people
have found that some of these variations correlate with higher or lower
risk of certain diseases.
And yet, new studies suggest that in human genomes whole sections of
DNA might be duplicated, deleted or reversed. A survey of only the
variations at selected points would probably miss those much
larger-scale differences.
Scientists do not know what those bigger differences might mean in
terms of disease risk, because they have not yet had thousands of human
genomes to study. So right now, a personal genome readout would provide
little useful information beyond what could be obtained by the less
expensive scans. And some experts even question how useful those scans
are.
Indeed, said Dr. Schloss, the government scientist, one of the first
paybacks of less costly genome sequencing would be to enable the broad
studies to be done *to find out what we really need to know for
individuals.*