DNA chips bring
personalized medicine to
China By Matt Young
Overcrowded hospitals and underserved
patients are still part of Chinese
healthcare-as-usual, but some researchers and
businesses are introducing some of the most
cutting-edge Western medical technology in an
effort to personalize medicine in China. Known
technically as pharmacogenetics (sometimes called
pharmacogenomics), their research doesn't involve
better bedside manners, but rapidly analyzing
Chinese patients' individual genetic makeup, which
can affect their response to drugs.
"If
you look at the genetics of the Chinese population
and Caucasians, you see a lot of differences,"
says Dr Michael Shi, director of biomarker
development at Novartis Pharmaceuticals
Corp.
But until recently, even in medical school, those
differences were oversimplified. "Oh, those
Westerners, they have big bodies," said Dr Shi,
summarizing one maxim of old-school personalized
medicine, along with the notion that Chinese
generally have less body mass. As a result,
Westerners used to typically get a higher drug
dosage than Chinese, he said. But personalized
treatment today has more to do with genetics than
crude kilograms, and industry insiders are
starting to see China as both a vast laboratory
and potential market for this advanced health care
technology.
The Chinese pharmaceutical
market grew 28% from 2003 to 2004, to US$6.2
billion, according to a report by Accenture Ltd,
which provides consulting services for
multinationals expanding into China. The Chinese
drug market is expected to be the world's
fifth-largest by 2010, with $24 billion in annual
sales, according to another report by Burrill
& Company, which provides strategic
Pharmacogenetics: Using DNA
chips for medical diagnostics
1
Hundreds of different
DNA samples, called probes, are placed on the
wells of a DNA chip, fabricated with the same
methods used in the computer industry. The
probes are selected to give medically
interesting information; for example, one might
be a version of a gene which is known to confer
higher risk for colon cancer. 2
The probes on the chip
are coated with a patient's DNA sample. When the
patient's DNA matches a probe, the spot will
shine when fluorescent light is beamed on it,
due to prior treatment with a fluorescent dye.
This creates a distinctive pattern of spots
which depends on the patient and the patient's
condition.
3
The
treated chip is scanned by a machine, which
converts the spots to data that can be examined
by a physician.
Images courtesy Hoffman-LaRoche,
Ltd. Used by
permission.
analysis
to life science companies interested in expanding
into China. "Big Pharma" may soon help contribute
custom genetic medical care to that marketplace.
"[Pharmacogenetics] is the future of medicine,
there's no two ways about it," said Dr Klaus
Lindpaintner, head of the Roche Center for Medical
Genomics.
Chips ahoy! Dr
Lindpaintner cited Hoffman-LaRoche Ltd's new
AmpliChip CYP450 test as a way to screen certain
genes to determine whether a person would react
favorably or unfavorably to a drug. The chip has
already penetrated into East Asia, hitting the
Singapore market, although Dr Lindpaintner wasn't
sure if it is available yet in China. "Some of the
genetic variants that are being diagnosed with
[AmpliChip] are more of an issue with Asian
populations than they are in Western populations,"
Dr Lindpaintner said.
In the meantime,
other gene chips are being developed in private
biotech firms in the PRC, such as Beijing-based CapitalBio
Corporation and Shenzhen-based Chipscreen
Biosciences Ltd. Gene chips and other products
appear to be fueling substantial growth at
CapitalBio, where during a visit this year,
Novartis' Dr Shi laughed with CapitalBio CEO Jing
Cheng at not having taken a job offer there
earlier. "Oh, it was so impressive," said Dr Shi,
recalling hundreds of employees working on
cutting-edge technology in a handsome business
environment. He also remembered having been told
that a Nobel laureate was working with the
company.
CapitalBio celebrated
its fifth-year anniversary in September with about
400 employees. Sales will likely grow 200% to
300% annually during the next few years, said
David Sun, senior vice president of business
development and marketing for CapitalBio. "As more and
more pharma companies in the US and Europe are
adopting outsourcing, some of these projects will
transfer to China, spurring tremendous growth in the next
few years," Mr. Sun said. "In CapitalBio, we are
actively building our capabilities in
pharmacogenetics to meet this growing demand."
Santa Clara, California-based Affymetrix,
a market leader in DNA chips, partnered with
CapitalBio in April, allowing the Beijing company
to offer its full line of GeneChip products.
CapitalBio isn't just a hanger-on, though; the
company has enough unique capabilities to be a
viable player in the gene industry, Mr Sun said.
"We are the only company that is capable of
providing personalized 4-D information [about a
patient], at gene, protein, cell and tissue level,
with its own products and services," Mr. Sun said.
But Dr Shi was once senior director of
applied genomics for now-defunct Genometrix Inc, a
gene chip company that ran out of capital and
folded in 2001. Dr Shi is too bubbly a personality
to have a chip on his shoulder from the affair,
but his experience has taught him that
CapitalBio's success is not going to be easy.
Meanwhile, Chipscreen has
developed chips that screen for gene mutations
known to be associated with diabetes in Asians,
although the chips are currently undergoing
testing. "We hope we will have the chance to
identify the relationship between those mutations
and the response or even adverse effects [to
various treatments] among the population," said Dr
Xian-Ping Lu, Chipscreen founder and CEO.
"Eventually the conclusion will help to design a
way of so-called personalized medicine as
treatment."
But gene chips are more of a
consequence of Chipscreen's core business: using
chemical genomics to accelerate the discovery of
new medicines. As a result, experiments with the
chips are progressing slowly. "We have to go over
100 patients [to draw significant conclusions],
and so far we haven't reached that number yet," Dr
Lu said. "A major hurdle for this is financial."
Chipscreen, a four-year-old company, doesn't have
any income to spare, as it doesn't plan to log a
profit for the next year or two.
Dr
Hong-Hao Zhou, director of the Pharmacogenetics
Research Institute at Central South University in
China, sees a bright future in his country for
gene screens because they help get the right dose
of the right drug to patients, and because they're
cheap. He has developed gene chips called
"Personalized Pharmacotherapy Chips" to tailor
therapy for hypertensive patients, although he
doesn't expect them to be available in the market
until perhaps next year. He performs gene screens
at his clinic at a cost of $100, which, although
costlier than a blood or urine test, only needs to
be performed once in a patient's lifetime. "It's
not so expensive, and it's exceptional for the
patients," Dr Zhou said.
From
diagnostics to drugs So far, there have
been limited and hard-won victories in developing
customized drugs. Nitromed Inc received clearance
from the US Food and Drug Administration in June
to market BiDil as a treatment for heart failure
in African-American patients. But Dr Lindpaintner
said "it's one in a million" drug discovery that
is "not going to happen that quickly again." He
added that Roche would be uncomfortable with
marketing drugs for specific ethnicities.
"Skin color or self-confessed ethnicity is
nothing but a cheap surrogate for some underlying
genetic variant that is more common in
African-Americans than in Caucasians," Dr
Lindpaintner said. As a result, Roche would likely
never market a drug as Chinese-only unless it were
lifesaving, worked exclusively for that ethnic
group, and an underlying genetic cause could not
be found, he said. However, Roche does
internationally market Herceptin, which is a drug
that has been shown to be effective in women with
metastatic breast cancer who test positive for a
specific version of a gene called HER2.
"[Herceptin] has become a major
blockbuster," Dr Lindpaintner said. "If you have a
medicine that may be applicable only to a smaller
part of population but is uniquely well applicable
ˇ then you tend to actually penetrate that market
segment very completely." Sales of Herceptin
totaled 851 million swiss francs (US$656.2
million) in the first half of 2005, up 24% from
the drug's revenues in the first half of 2004. The
drug also is effective in Chinese women, although
it was not developed specifically for them.
"Bridging" studies, in which drugs are
initially developed for Western populations and
then are shown to be effective for Asian
populations in clinical trials, are already
common. But Dr Shi said some drug studies
performed for Asian populations have had
surprising results. For example, Iressa, a drug
marketed by AstraZeneca PLC for lung cancer, has
been limited in the United States to patients who
are currently benefiting or have benefited from
the drug. The US FDA doesn't consider the drug to
be substantially effective. "But that drug has a
higher clinical benefit in the Asian population
compared with the Western population," said Dr
Shi.
It's not a reach then to imagine that
drugs specifically developed for Asians may not be
far away, although China's lack of patent
protection is still a turn-off for drug
manufacturers. One thing researchers are keeping
in mind, though: Asians aren't a homogeneous
group. There are 56 official ethnic groups in
China alone, which could make for a lot of
bridging studies.
Fertile genetic
ground Similar to how the Galapagos Islands
assisted Charles Darwin's discoveries about
evolution with its array of endemic species, rural
China may be able to spur modern-day genetic
research with its unique gene pool, which could
lead to further development of the biomedical
industry.
"Immigration is not
that intensive, in some areas of China", said Dr
Zicai Liang, who currently is moving to Beijing
from Sweden to work on genomics research at a
Beijing University lab. "That means people have
been living there for generations and if you have
many members in the same family that have the same
disease, then one can have a better chance to
precisely position the gene responsible for the
disease." This is the method that was used to, for
example, isolate the Huntington's disease gene to
the end of human chromosome 4 in 1983, by
analyzing a large, extended family in the Lake
Maracaibo region of Venezuela. In China, the
Chinese National Human Genome Center at Shanghai
identified a gene responsible for atrial
fibrillation (AF), the most common chronic
arrhythmia in humans, with the technique.
"Through analysis of a large family with
inherited AF, we now have the first molecular
explanation," said Dr Zhu Chen, the center's
director, in the European Molecular Biology
Organization's EMBO Reports journal. "At the same
time, we identified a gene coding for an ion
channel as a potential drug target. In China, we
have to take advantage of our huge population,
particularly in the western part, where we still
have many isolated populations, representing a
precious genetic resource."
But even rural
Chinese could be worth as much as eventual
customers to drug companies as guinea pigs. "In
situations where patients themselves or their
[families have] to directly pay [for healthcare],
that is a situation where they can benefit from
that [genetic] information to make better
choices," said Howard McLeod, director of the
Pharmacogenetics for Every Nation Initiative
(PGENI), which seeks to assist public health
decision making related to genetics in 20
countries. China will be among the eventual 104
countries that the initiative, funded primarily by
the National Institutes of Health, plans to
assist.
Roche, for one, is not flirting
with the idea of gene research in China. The
company is actively collaborating with prominent
Chinese scientists at genome centers, and has been
doing so for at least five years to see whether
gene variants are associated with the presence or
absence of certain illnesses, Dr Lindpaintner
said. Eventually, such findings could lead to
better diagnostic capabilities or better
medicines, he said.
Specifically, Roche
supported the Chinese National Human Genome Center
in its work on diabetes and schizophrenia,
according to the Burrill & Company report.
Roche also recently established its fifth global
research and development center in Shanghai.
Meanwhile, AstraZeneca participated in a joint
study with Shanghai Jiaotong University to
identify the genes linked to schizophrenia, the
report said.
Aside from psychiatry, the
areas of cancer and autoimmune disease are ripe
for genetic discoveries, Dr McLeod said. Even
traditional Chinese medicine has a role in
pharmacogenetics. Dr Zhou recently discovered that
Yin Zhi Huang, an herbal compound used to treat
jaundice in Asia, does not allow the heartburn
medication Prilosec to be metabolized properly for
people with certain genetic makeups.
But
groundbreaking research doesn't always attract
industry support, as Dr Lindpaintner admits. "We
need to have some sort of inkling as we start a
project that a medicine will come [out] of this,
not just some very fundamental bit of knowledge
that eventually may help bring new medicines on
the market," Dr Lindpaintner said.
Indeed,
The Royal Society, a British independent academy
dedicated to promoting excellence in science,
reported in September that it would be another 15
to 20 years before the use of tailored genetic
medicine is widespread. But Dr Shi doesn't
entirely agree, saying that the practice of
tailored medicine in oncology isn't nearly that
far away. "It's today," he said, referring to the
availability of the drug Herceptin and Novartis'
Glivec, which is indicated for all stages of
Philadelphia chromosome-positive chronic myeloid
leukemia. Sales of Glivec were up 33% in the
second quarter of 2005 to $537 million. "We are at
the start" of pharmacogenetic developments,
PGENI's Dr McLeod said, but "not the very
beginning."
Matt Young is a
Washington, DC-based freelancer and a staff writer
for EyeWorld Magazine and EyeWorld Asia-Pacific
Magazine.
Copyright (c) 2005 Matt
Young. Used by permission.
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