good NYTIMES article.
December 21, 1999
Biology Meets High Technology
Biochips Signal a Critical Shift for Research and Medicine
By LAWRENCE M. FISHER
oming soon, to a chip near you, your own genes.
The biotechnology industry, which has long lived in the shadow of Silicon
Valley and envied its many overnight successes, is now tapping into that
same technology in a bid to speed up its own growth significantly.
These biochips look like the integrated circuits
in a personal computer, but instead of containing
tiny semiconductors, they are loaded with bits of
actual DNA that make up genes or fragments of
genes. Inserted in a PC-sized analytical
instrument, the chips allow scientists to perform
thousands of biochemical experiments at a fraction of the cost and time
required for traditional tests.
"This is a basic tool for change in the laboratory," said Michael R.
Knapp, vice president for science and technology at Caliper
Technologies in Mountain View, Calif. "We have been operating with the
test-tube paradigm for basically as long as anybody has been doing
anything."
Biochips, or microarrays, as they are also known, will bring genomics,
the study of all the genes in a living organism, out of the research
laboratory and into the daily practice of medicine. If genomics delivers on
its promise, health care will shift from a focus on detection and treatment
to a process of prediction and prevention. Fortunes will be made.
The initial market for biochips has been in drug discovery, and the major
customers have been the large drug companies. By analyzing the subtle
changes in genes when a cell becomes cancerous or is infiltrated by a
virus, scientists at these companies search for new molecular targets for
drugs. This needle-in-a-haystack process could take many years using
test tubes and petri dishes but is accelerated a thousandfold by biochip
technology.
The market for biochemical research instruments is in the billions, and the
transformational power of biochips has not gone unnoticed by the stock
market. Shares in Affymetrix, the pioneering company in biochips, have
risen more than fivefold the last year, giving the company a market value
of about $3.08 billion. Other public companies in the field have had
similar gains.
But the biochip makers are now chasing a bigger opportunity: personal
genomics. Even as the public and private efforts to spell out the three
billion biochemical letters that make up the human genetic code race to a
conclusion, the biochip companies say they will bring genomics to an
affordable desktop system that could be deployed in clinics and
physicians' offices. Sophisticated genetic analysis could be performed at
the individual level, making possible early prediction or detection of
disease, more accurate diagnosis and customized therapy.
Originally the province of a handful of start-ups backed by venture
capital and operating in a sort of gray area between Silicon Valley and
the biotech world, the biochip market has lately attracted the attention of
major electronics companies like Motorola, Hewlett-Packard, Texas
Instruments and I.B.M., all of which have chips in development.
Motorola's recent advertisements promote the company's "digital DNA,"
while those of Hewlett-Packard proclaim the "DNA of Silicon Valley."
The message may be metaphoric, but the market is very real.
"The biochip space lies at the intersection between high-technology chip
manufacturing, signal processing, software skills and more traditional
molecular biology and genomics," said Nick Naclerio, vice president and
general manager for Motorola's biochip systems division. "So it seemed
right for Motorola to get involved in what we think will ultimately be a big
business."
The biochip companies are one of three new industries that piggybacked
on the human genome project, the multinational decade-old effort to
identify the 100,000 or more genes -- made from the three billion letters
or base pairs of nucleotides -- that inform every aspect of human biology.
That project is expected to be completed within a year or two, either by
the national labs or private companies or, as seems most likely, a
combination of the two.
Genomics companies like Human Genome Sciences, Millennium
Pharmaceuticals, Incyte Pharmaceuticals and the Celera Genomics
Group of the PE Corporation rushed to beat the public effort by finding
and patenting genes of medical utility. Bioinformatics companies, like
DoubleTwist.com and Informax, offer software to interpret genomic
data. The chip companies, led by Affymetrix, based in Santa Clara,
Calif., offer a tool to automate the arduous lab work of biochemical
research -- and maybe to do much more.
"We're going to burn a set of chips with the whole human genome," said
Stephen P. A. Fodor, president and chief executive of Affymetrix. Dr.
Fodor headed a group that pioneered the field of biochips, with a 1991
paper in the journal Science describing how photolithography, the
standard process by which semiconductor companies etch circuits in
silicon, could also be used to synthesize biological materials on a chip.
Companies like Eli Lilly, SmithKline Beecham and American Home
Products have been eagerly buying Affymetrix's GeneChip arrays,
helping to increase the company's revenues in the first nine months of this
year to $65.7 million, from $35.8 million in the comparable period a year
earlier.
Often lost in the excitement about the completion of the genome project
is that the first human genome will be a consensus, culled from the DNA
samples of dozens of anonymous donors. The sequence of each gene will
be arrived at only after billions of taxpayer dollars and a decade of study
in laboratories lined with $300,000 gene-sequencing machines and other
elaborate devices. What the makers of biochips promise is to offer that
same depth of information at the individual level and at low cost.
"As soon as the reference DNA is out there, this will move in a thousand
different directions," Dr. Fodor said.
Nevertheless, most of the chip companies agree that the next big
application will be the interpretation of how genetic diversity affects the
efficacy and side effects of drugs, a field known as pharmacogenetics.
The idea is to use the chips to spot genetic differences known as single
nucleotide polymorphisms, or SNP's (pronounced SNIPS), because they
consist of a misspelling of just one letter of the genetic code.
A typical person has thousands of
SNP's, most of which are
inconsequential, but some can
predispose one to a disease, or to
adverse drug reactions. As
researchers discover new SNP's
every day, "SNP's on Chips" has become a rallying cry for the biochip
industry.
"If this SNP enterprise becomes what people think it might, you can
imagine having an infant tested at birth and given a chip, and a result that
says you are susceptible to diseases A, B and C," said Mark Schena,
who did early research on biochips while studying at Stanford and is now
a visiting scholar at TeleChem International, a biochip company in
Sunnyvale, Calif. "Based on this knowledge you can make appropriate
lifestyle changes to prevent the disease or delay its onset"
Such testing, of course, raises many ethical question. Biochip companies
are working on encryption technology to keep such data private, but
most industry executives believe that legislation will be necessary.
Because the chip companies are all chasing similar markets -- and in part
because Affymetrix's early lead allowed it to lock up patents on many of
the ways to put DNA on chips -- they are distinguishing their offerings by
using different technologies.
Some, like Caliper and Orchid Biocomputer have added microfluidics, a
complex network of tiny valves and capillaries that allow researchers to
move liquids on and off the chip. Nanogen, based in San Diego,
incorporates both microfluidics and electronic circuitry on its chip, to
allow researchers to create their own custom microarrays. And Aclara
Biosciences of Mountain View, Calif., uses plastic cards instead of glass
chips or silicon chips, to keep its devices cheap and disposable.
Orchid, based in Princeton, N.J., has been chosen to perform testing on
genetic markers identified by the SNP Consortium, a group of 10
pharmaceuticals companies and 5 academic centers, which expects to
find and publish 300,000 SNP's the next two years. Next year, Orchid
plans to start GeneShield.com, a Web-based business that will allow
consumers to send their own DNA samples, gathered with a simple
cheek swab, for analysis against chips loaded with reference SNP's
associated with known diseases or drug interactions.
"The number of SNP's being scored now is a horrendous Moore's Law,"
said Dale Pfost, Orchid's president and chief executive, referring to the
observation by the Intel co-founder Gordon Moore that the number of
devices on a chip would double every 18 months. "Genetic diversity is a
whole new industry that people don't know exists," Dr. Pfost said.
"We're enabling that industry."
As biochips move from the research laboratory to the clinic, the
technology must not only achieve something approaching absolute
accuracy but also far higher levels of what the industry calls throughput,
meaning the number of tests that can be conducted rapidly or
simultaneously.
Indeed, evaluating the 300,000 SNP's promised by the consortium in
1,000 people would mean performing 300 million different tests, and any
single mistake might create a serious health risk. "You need an industrial
technology for that," said Hubert Koster, the chief executive of
Sequenom, a San Diego biochip company. "You cannot use a technology
that is 99.9 percent accurate. In the research world that would be O.K.,
but not in the industrial world because it would give you 300,000 errors."
The next step will be even more challenging.
If biochips are also to aid in quick diagnosis of disease, they need the
ability to follow the trail from a gene, which instructs a cell to make a
given protein, to the actual proteins produced within the body.
Unfortunately, proteins are harder to label and measure then the DNA
itself.
"The proteins are the molecular equivalent of a symptom, and your
proteins get altered long before you go to a doctor," said William Rich,
president and chief executive of Ciphergen Biosystems in Palo Alto,
Calif., which has developed a protein chip and associated instruments.
"We think the impact on diagnostics will be huge."
Dr. Schena at TeleChem International agrees. "Biochips started out with
a lot of diagnostics but sort of drifted away from that as reality set in and
the pharmaceuticals industry was so needy," he said. "But it will come
back. If so, the market is probably in excess of $10 billion a year."
Some biochip companies are looking well beyond medical applications:
genetic diversity also accounts for people's different perceptions of taste
and smell. Indeed, Affymetrix already counts a candy manufacturer and a
cosmetics company among its customers.
"If you look at a map of the genome, what you see are markers for
dysfunction," Dr. Fodor said. "It's a real marketing failure. Let's look at
new applications like fragrance or taste. There are going to be a lot of fun
things." |
