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
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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 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 ?¦ 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."
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Pharmacogenetics: Using DNA chips for medical diagnostics
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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.
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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.
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The treated chip is scanned by a machine, which converts the spots to data that can be examined by a physician. |
