(Long) very interesting (bullish) piece on Affymetrix (from "Technology Review").
(I learned of this article from another SI thread -- Biotech News
Subject 31045
which I highly recommend).
Jon.
*******************************
technologyreview.com
DNA Chips Target Cancer
By Marc Wortman
July/August 2001
Within a few years, DNA microarrays could help diagnose and treat this
killer, perhaps even before tumors form.
In preparation for minor surgery, John
Leventhal needed a routine chest
x-ray. When the New Haven, CT, doctor
joined the radiologist who was
examining the film, he was shocked by
what he saw: an opaque blotch deep in
his lung. "As a physician," says
Leventhal, "you're taught in medical
school that when you see a mass like
that, it means lung cancer." Leventhal's
medical training also taught him that to
confirm the diagnosis, his doctors
would need to crack open his rib cage
to get a piece of the suspect tissue that
would be closely examined by a
pathologist—an extremely painful and
hazardous operation. The weekend
before that surgery, Leventhal went off
on a family ski vacation. He recalls
thinking, "This is the last time I will go
skiing for a long, long time."
That was five years ago. Today the
medical profession's way of dealing
with cancer could be about to change.
Around the same time that Leventhal
underwent surgery, researchers at
Stanford University and Santa Clara,
CA-based startup Affymetrix were
beginning to build the first "DNA
microarrays." More commonly known as
DNA chips, these are DNA-covered
silicon, glass or plastic wafers capable
of analyzing thousands of genes at a
time to, for example, identify the ones
that are active in a sample of cells. Now
these microarrays appear poised to
join the war on cancer. DNA chips,
predicts National Cancer Institute
director Richard Klausner, are "going
to have a huge effect" on the diagnosis and treatment of the disease.
One reason for the excitement is that DNA chips offer a whole
new—and potentially much earlier, easier and more precise—way of
detecting cancerous cells.
Most forms of cancers go unnoticed until lumps, coughs or pains
develop, at which point it is often too late. And even then, once a
pathologist gets a biopsy from a tumor, distinguishing one form of
cancer from another can be difficult or even impossible with existing
techniques, which involve noting distortions in the cells' architecture
under a microscope. Better diagnostic information could be used to
make better treatment decisions, perhaps making the difference
between life and death.
Within the next two years, pathologists
expect to begin using DNA-chip-based
tools to spot genetic differences among
cells; these telltale differences could be
used to help detect cancerous cells
long before symptoms develop and to
distinguish one type of cancer from
another. In short, the chips will provide
a genetic profile of a cancerous cell
that can be read like a criminal's rap
sheet. The physician will know where
the cancerous cell originated, how far it
has progressed, and which therapies
will work best to halt its further growth
and spread.
Leventhal was lucky. His lung biopsy
was negative, and he was back on the
slopes the next winter. But it took him a
month to recover from the biopsy
surgery, and today he has an angry
scar down the middle of his chest to
remind him of the ordeal. By the end of
the decade, it is likely that a patient like
Leventhal will be able to skip invasive
diagnostic procedures altogether. A
DNA-chip-based device might be able
to read a sputum sample right in the
doctor's office, checking for the genetic
changes in the lung cells that are
naturally sloughed off into the viscous
fluid. If the news is bad, the patient
might well have a host of new treatment
options. That's because DNA chips are
also speeding the discovery of new and
better cancer drugs. "We're on the
threshold of a new era," says Klausner.
"Technologies like DNA chips will tell us not only that something may be
amiss, but what it is and what we can do about it."
Gathering Speed
With one out of every two men and
one out of every three women in
the United States likely to get
cancer at some point in their
lives—and about 560,000
Americans expected to die of the
disease this year alone, according
to the American Cancer
Society—advances can't come fast
enough. As many as 500 research
laboratories in academia and
industry are already employing DNA
chips to develop sweeping new
genetic pictures of different
cancers. In 1999, the National
Cancer Institute alone provided
$4.1 million to 24 U.S. academic
cancer institutions to set up or
upgrade microarray centers.
Meanwhile, the pharmaceutical and
biotech industries are drawing on
information gleaned from DNA chips
to develop new and better
diagnostic tests and more effective
anticancer drugs with fewer side
effects (see "Corporate Cross
Section," right). Indeed, all the
major drug companies and at least
a dozen biotech firms are already
using DNA chips to tackle cancer.
At the same time, large
manufacturing companies such as
Agilent Technologies, Corning and
Motorola are seeing the potential of
DNA chips. All three have allied with
academic research centers to come
up with DNA chips that will analyze
genes related to specific cancers.
And while at the moment DNA chips
are far too expensive to compete
with existing diagnostic
technologies, the involvement of
these manufacturers and their
production facilities could drop prices as low as $10 for a chip, once
large-volume production gears up.
Of course, for DNA chips to help win the war on cancer, it will take
considerable effort—and years of further development. For one thing,
DNA chips generate tons of data, and researchers will need to beef up
their computing capabilities and nail down data standards in order to
make sense of it all (see "Gene Babel," TR April 2001). And any new
drugs or diagnostic devices will have to prove themselves in clinical
trials. But the initial fruits of the efforts to apply DNA chips to
cancer—new diagnostic tools—could begin saving lives as early as the
end of next year. The first anticancer drugs developed using DNA chips
will enter human trials around the same time, with dozens more to
follow. With all those new tools available, currently untreatable forms of
cancer may, one day, no longer mean death sentences.
Profiles in Cancer
The first step toward that grand
vision is generating a profile of the
genes that are activated or shut
down when a normal cell becomes
cancerous. While most genes are
quiet in any given cell at any given
time, the ones that are active, or
"expressed," tell a lot about that
cell's health. And though many of
us tend to think of diseases as
being caused by particular
genes—say the gene for
Huntington's disease or cystic
fibrosis—most diseases actually
involve complicated interactions
among a large set of different
genes. However, just as a person's
fingerprints can be distinguished
from virtually all others by just a
small number of differences, a sort
of genetic fingerprint, perhaps involving a hundred active genes or
even fewer, could distinguish cells showing even the very earliest signs
of cancer.
The beauty of using a technology like DNA chips to find those
fingerprints, says Klausner, is that "we're not limited by preconceived
knowledge or notions." In other words, cancer investigators no longer
have to bias their experiments by looking individually at the genes they
suspect might be involved with a particular cancer. "Instead of focusing
on one gene," explains National Cancer Institute researcher Louis
Staudt, "with microarrays we get to look at the entire genome and let
the cancer cell tell us what the important genes are."
The flagship in the National Cancer Institute's efforts to demonstrate the
validity of the DNA-chip approach is the so-called Lymphoma/Leukemia
Molecular Profiling Project, which is directed by Staudt. The study is
looking at diffuse large B-cell lymphoma, a relatively common cancer of
the white blood cells that affects more than 15,000 people in the United
States each year. When oncologists give those patients standard
chemotherapy treatments, about 40 percent respond rapidly. Their
cancer melts away, and the majority are still alive five years after
diagnosis. But of that other 60 percent, most are not so lucky. The
cancer may go into remission briefly, but when it returns, it comes back
with a vengeance. A few patients benefit at that point from radiation
treatments and bone marrow transplants, but for most it is already too
late to halt the spread of the disease. Clearly there is something
different about the two groups, but under a pathologist's microscope
their cancer cells look identical.
The surprising answer is that these patients respond differently to
treatment because, in fact, they are suffering from completely different
types of lymphoma. Using what they dubbed a "Lymphochip," a
customized Affymetrix DNA chip, Staudt and a group at Stanford led by
geneticist David Botstein discovered distinctive genetic differences
between the cancers in the patients with large B-cell lymphoma who
died and those who survived. "I was blown away by what we found,"
says Botstein. Effectively, they were looking at two different illnesses.
"It's remarkable," says Staudt. "We found something in this disease that
was missed for all the years pathologists were looking at it."
Similar projects are now under way to profile various forms of cancer,
from different types of melanoma to colon cancer. Most other cancers
present pictures similar to that of lymphoma: some patients get better
and some do not, but predicting who will respond to therapies is
impossible. If there were some way to identify the patients who won't
respond to standard chemotherapy, doctors could turn immediately to
alternative treatments—and save lives. Indeed, says Pat Brown, a
Stanford University School of Medicine geneticist who helped invent one
of the two main types of DNA chips, "The same story is coming out for a
bunch of cancers we look at—cancers with different clinical outcomes
have different molecular subtypes." And knowing the precise subtype of
cancer afflicting a patient could help doctors pick the right treatments,
right from the start.
Perfecting Detection
Once researchers know the fingerprints of different cancers, they'll be
able to craft customized DNA chips that doctors can use to diagnose
patients with previously unheard-of accuracy. Says Staudt, "The
textbooks on cancer diagnostics are going to be rewritten over the next
three to four years....[DNA-chip-based diagnostics] will very soon
become routine technology."
But the ability to read subtle genetic changes could allow doctors to do
more than pinpoint the exact identity of a cancer; it could also help them
read early warning signs that normal cells are about to turn
cancerous—long before such changes are evident to a pathologist.
That's what University of South Florida cancer geneticist Melvyn
Tockman is hoping, anyway. He and his colleagues are working on an
early-detection method for lung cancer—a method that could make
John Leventhal's scar a relic of the medical dark ages.
The researchers take sputum samples from ex-smokers and use DNA
chips to analyze which genes are active in the lung cells. By comparing
the genetic profile of these damaged cells to profiles from both healthy
and cancerous lung cells, Tockman hopes to find the fingerprint that
indicates a cancer is just about to form. In the future a patient at risk for
lung cancer might take a simple DNA-chip-based test for this genetic
fingerprint each time he went for his regular checkup.
That's a few years in the future, but the initial payoff of DNA chips in
detecting cancer may come even sooner. Researchers are already
using the chips to identify telltale proteins that can be detected by
conventional cancer-screening tools. "If a cancer has one hundred
uniquely expressed genes," explains Mohan Iyer, the vice president of
business development at Santa Clara, CA-based diaDexus, "the home
run hit is to find one [of the proteins those genes code for] that can be
used in a simple blood test to screen individuals for cancer." If a protein
were found to be unique to a certain cancer, says Iyer, standard
hospital equipment could easily detect it in a blood sample.
With DNA-chip tools now helping to identify the proteins associated with
breast, lung, colon and ovarian cancer, to name a few, Incyte
Genomics, Corning and a handful of other companies are developing
new protein-based screening methods for diagnosis of the diseases.
These new tests should begin to reach diagnostic laboratories in the
next two years or so.
Remedies, Rapidly
But better diagnostics will begin to make a real difference only when
they're coupled with more effective treatments, treatments that are
fine-tuned to combat particular types of cancer. Even "if you can
distinguish 50 different lymphomas," says Yale University School of
Medicine pathologist Michael Kashgarian, "what does it matter whether
it's type A or type Z if the therapy is the same?"
In this area of cancer drug discovery, DNA chips are also playing a key
role. Just as the rapid analysis of a large number of genes is helping to
profile cancer for better diagnostics, it is also providing valuable clues
to how to attack cancer cells.
Researchers have long believed that developing new therapies would
begin with finding cancer-associated genes, but the past two decades
have been filled with disappointment. Stephen Friend, once an
oncology researcher at the Whitehead Institute for Biomedical
Research in Cambridge, MA, and now chief executive officer of Rosetta
Inpharmatics in Seattle, blames what he calls the "my-favorite-gene
approach." Biomedical researchers would spend years tracking down
one gene associated with a particular cancer, then proceed on the
assumption that that gene, or the protein it coded for, would make a
great target for new drugs. But, Friend says, "the chances were in 999
out of 1,000 cases that you'd be wrong." Very few genes work alone
and in such simple and direct relationships with the body to cause
disease. "God, were we stupid!" he says.
Friend is now convinced that technologies such as DNA chips that allow
researchers to find all the genes involved in a disease are the way to
go. (Rosetta plays a role in such research by selling software and other
services for reading microarrays.) Not only can DNA chips help identify
all the potential drug targets for a given type of tumor, they can also
help rule out the genes that are active in healthy tissues. That way,
drugmakers can develop precisely targeted treatments that kill cancer
cells without damaging other parts of the body. "Drugs," says Friend,
"are going to be developed at a tenth the cost and in a third of the time
by improving targeting and making sure compounds don't pick up
unwanted side effects."
Eos Biotechnology, a South San Francisco company that is developing
new cancer therapies using DNA chips from its partner Affymetrix, is
betting he's right. In the company's labs, vice president of genomics
research David Mack holds up one of those chips, which contains
virtually the entire set of human genes. "The ability to generate the
human genome on a chip today is incredible," he says. Eos uses the
chips as a platform on which to compare genetic activity in normal
human cells and, say, a breast-cancer cell. Computers can then sort
out the genes that are active only in the diseased cell. Moreover, they
can select just those genes that present the best targets for drugs.
Under the traditional drug-development paradigm, once researchers
identify a set of potential targets, they begin to stumble ahead into
animal and human trials, with educated guesses about which potential
drugs might be effective against a given target, and which of those drug
candidates might have toxic side effects. Very often, it's only much later
in the process that a candidate's problems become apparent—at a
huge cost in time and money.
By contrast, Eos continues to use microarrays and other high-volume
genomic techniques to test the drugs, better predicting which will be the
most effective and the least toxic before more costly testing even
begins. According to Mack, "We're seeing data-driven science now,
which hasn't been the previous paradigm." Thanks in part to the use of
DNA chips, the company plans in the coming year to begin clinical
testing of its first drug—which attacks a tumor's ability to generate its
own life-sustaining blood supply—with more than a dozen other
anticancer drugs expected to follow rapidly. "The promise of these
technologies to impact patients is here—finally," he says.
While DNA chips have only been around for five years or so, they have
already helped to get a number of new drugs into
pharmaceutical-company pipelines, and to identify many potential new
drug targets and sources of earlier diagnosis. With these advances, it is
likely that cancer therapy will become both more complex and more
effective over the next decade. Eventually, each patient's cancer
fingerprint will be met with just the right drug "cocktail," or combination
of therapies. Doctors will have new tools to diagnose and treat cancers
much earlier—when the chances of cure are far better—and to monitor
a patient's progress, ensuring that tumors don't develop resistance to
the treatment.
It may take more than a decade before such practices become the
norm, but if and when they do, they will change everything for people
like John Leventhal. His (mis)diagnosis of lung cancer came when he
was the age at which his own father got news of the cancer that
eventually killed him—a fact that ratcheted up Leventhal's terror when
he learned he might have cancer. But should his children ever find
themselves in the same shoes, perhaps they won't have nearly as much
to fear.
Freelance writer Marc Wortman is a contributing editor to Yale
Medicine magazine, and creator of the Yale Children's Health
Newsletter. He lives in New Haven, where he writes about
health and medicine, outdoor life and other subjects.
Copyright (c) 2001 Technology Review, Inc. All rights reserved. |
