The Race to Read Genomes on a Shoestring, Relatively Speaking

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The Race to Read Genomes on a Shoestring, Relatively Speaking

By Pollack

http://www.nytimes.com/2008/02/09/business/09genome.html?

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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.

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. , the chief

executive.

Mr. , 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. 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 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. said. Among the company's backers are Kleiner

Perkins Caufield & Byers, the powerhouse venture capital firm.

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. "