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Pufferfish, Pigs, and Silkworms

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Speed, fervor, and a search for niches characterize genomics across Asia today. Governments are pledging funds, private investment is growing, and researchers are scrambling to analyze, interpret and mine the genome. There is a catch-up-with-the-West sentiment, but Asian researchers are also trying to seek out and harness the continent’s strengths to address some unique Asian problems.

China is sequencing the pig and Indian researchers are probing the silkworm genome, while Japan and Singapore are vying to set up centers of excellence in the new biology. “Asia can be expected to contribute significantly to the global knowledge pool and generate intellectual property,” says Manju Sharma, secretary in India’s department of biotechnology, who has asked the Indian government to commit at least three billion rupees ($62 million) on genomics research over the next five years. “Asia’s ethnic diversity, its disease burdens, and its biodiversity make it a promising site for post-genome research,” says Sharma.

The zeal is tempered by the recognition that Western researchers and industries are ahead in post-sequence activities. Yet some researchers do not view their countries’ relatively late entry into genomics as a handicap at all. “We’re actually in a position of advantage,” says Hyang-Sook Yoo at the Korea Research Institute of Bioscience and Biotechnology, who is directing Korea’s largest human functional genomics program. “We can now participate in the process to exploit the knowledge that was generated by the human genome sequencing effort,” she says.

Government interest in genomics is reflected in funding patterns: Chinese researchers expect their government to spend 3.2 billion yuan ($400 million) in biotechnology research over the next five years, with a big chunk earmarked for genomics. Japanese public funding for genomics research climbed from 17 billion yen ($140 million) in 1999 to 41 billion yen ($335 million) in 2000. Singapore’s Genome Institute has a seed budget of 69 million Singapore dollars ($38 million) and its National Science and Technology Board has promised a 190-hectare biopolis to accommodate at least 20,000 scientists. And Korea says it will disburse 12 billion won ($10 million) each year for the next 10 years exclusively for human functional genomics.

Private investment is growing, and governments are encouraging more of it. Japan’s Yamanouchi Pharmaceuticals plans to spend 50 billion yen ($400 million) on genomics-based drug discovery over the next five years. Another Japanese pharmaceutical giant, Takeda, is building a $140 million genomics-based drug discovery center. Singapore’s economic development board is flush with a billion Singapore dollars ($545 million), much of which will go into helping the growth of the life sciences industry. And India might finally be witnessing a trend that the country has long awaited: research-driven startups and industry-laboratory tie-ups in the genomics sector. In the past two years, a dozen genomics and bioinformatics companies have sprung up across India, heralding a culture of entrepreneurship among its scientists.

The new companies are seeking contract research for domestic and international clients offering services ranging from genome data analysis and data mining in genomics and proteomics to in silico drug testing.

As the business bug spreads, scientists are abandoning their relaxed academic mindsets to display fresh business acumen. Jongkyeong Chung, professor of biology at the Korea Advanced Institute of Science and Technology, estimates some 40 companies in Korea have ventured into genomics in the past two years, but declines even to name the company that he works with. “I can’t say anything about it at this point,” says Chung, who heads a molecular genomics lab studying cell proliferation. He adds cheerfully: “And I’d prefer you don’t even use information from the lab website.”

Asian policy-makers also believe that their countries could serve as attractive sites for clinical trials of new drugs, particularly against long-neglected diseases rampant across Asia: hepatitis, dengue, malaria, and tuberculosis. In the hope of participating in the drug discovery process, researchers have launched structural genomics and pharmacogenomics programs.

Asian researchers are also forging international partnerships: Johns Hopkins University has established a research center in Singapore; Chinese scientists are collaborating with institutions in Denmark and the US; and Indian and Japanese teams are discussing complementary roles in a joint silkworm genome initiative. “Asia’s biggest advantages are talented people and rich genetic resources,” says Huanming Yang, director of the Beijing Genomics Institute. “The best strategy for Asia — individual researchers as well as countries — will be to sharply focus and pursue something that they are really good at.”

Here is a kaleidoscopic view of genomics activities in Asia:

China

Gastronomic compulsions might have influenced China into selecting the pig for its next big sequencing effort after contributing one percent to the human genome sequence — the so-called Beijing region. But the spin-offs from the pig genome program will transcend concerns of food, promises Huanming Yang, the man who directs China’s pig genome project.

China has a voracious appetite for pork and the pig genome project is expected to lead to more economically efficient pig-breeding. But porcine genomics will also have applications in human medicine, says Yang, director of the Beijing Genomics Institute of the Chinese Academy of Sciences. “The pig genome sequence will help us develop new animal models for human diseases and evaluate the pig as a source of organs for xenotransplantation,” says Yang. In collaboration with the Danish Pig Genome Consortium, the Beijing institute has already sequenced 50,000 cDNA clones and hopes to reach one million and unveil a working draft of the pig genome sequence within the next two years.

As part of a Chinese Biological Resource Genome project, researchers also plan to study selected Chinese medicinal plants, applying genomics research to ancient plant-based medicinal science. “The idea is to use human genome data and screen plant compounds to unravel the biochemical pathways underlying their medicinal activity,” says Yang.

In a bid to maintain its position as the world’s leading rice producer, China is also sequencing templates of superhybrid rice, developed by Yuan Longping at China’s Center for Hybrid Rice Development in Hunan province. With yields exceeding 15,000 kg per hectare, superhybrid rice has 50 percent higher productivity than the best hybrid. “Through genomics, we want to understand what makes this hybrid so productive,” says Zhu Lihuang at the Institute of Genetics of the Chinese Academy of Sciences.

The sequencing effort is focusing on Indica templates of superhybrid rice. “This will complement the international rice genome consortium sequence,” says Zhu. Comparative genomics will be used to look for single nucleotide polymorphisms and map agronomic traits,” says Zhu.

India

Whether he’s delivering a talk to fellow researchers, industry delegates, or greenhorn postdocs, Samir Brahmachari never forgets to fish out two slides. One emphasizes that India’s large population, unique community, and family structures are a gold mine for functional genomics research. The other exhorts Indian scientists and industry to work toward generating intellectual property and not remain content providing brains and genetic resources to research and industry collaborators in the West.

“We have to be knowledge partners, not mere service providers and a source of genetic material,” says Brahmachari, director of the Centre for Biochemical Technology, New Delhi, the public-funded institution that has claimed the largest chunk of genomics research funding in the country to date. The CBT has received more than $1.5 million from India’s biotechnology department and signed a $2 million pact with Indian pharmaceutical giant Nicholas Piramal for joint genomics research to work toward novel drugs against diseases ranging from asthma to diabetes.

India’s billion-plus population is made up of more than 3,000 communities and 28,000 endogamous groups resulting from centuries of tradition and socio-cultural practices in which individuals marry within their own communities. Large, extended families make it relatively easy to track down mutations and facilitate functional polymorphism scanning. The target diseases for genomics research are schizophrenia and other neurological behavioral disorders, tuberculosis, and congenital blood disorders.

Funding from all public sources for genomics, bioinformatics, and proteomics in India could exceed $125 million over the next five years. Projects will include the analysis of malaria parasite, hepatitis virus, and Tuberculosis bacillus genomes to identify novel drug targets. India’s National Brain Research Institute says it will also initiate a program on “neuroinformatics.”

And it’s not against human diseases alone that Indian researchers are applying genomics.

At the Center for DNA Fingerprinting and Diagnostics, Hyderabad, biologist Javaregowda Nagaraju has launched a silkworm genomics initiative. India is the world’s second largest producer of silk and the silkworm project is aimed at boosting silk yield and quality. “The goal is to pinpoint economically important genes on the silkworm,” says Nagaraju. “It’s a long-term project, but we’re betting that human fascination for silk will last a long time to come.”

Japan

Takara Shuzo, Japan’s leading manufacturer of distilled spirits, first turned into the country’s number-one enzyme maker. Now, thanks to the vision of Ikunoshin Kato, president of its biomedical division, Takara also runs Asia’s largest private genome sequencing center.

It opened for operations last April, calls itself Dragon Genomics, and is armed with 180 researchers, 45 sequencers, and a cluster of high-performance computers. Its mandate: devote 80 percent of its efforts pursuing contract research services for pharmaceutical and biotechnology companies, and 20 percent on internal projects.

The company will work with parent Takara’s biomedical group to provide low-cost, high-quality genome analysis services ranging from genome sequence analysis to functional analyses such as expression and proteome analyses, says Kato.

Dragon’s in-house projects range from the creation of a genome database for the Mongolian population to the sequencing of marine organisms and mushrooms. Last October, Dragon successfully completed the genome sequence of the first symbiotic microorganism, Symbiobacterium toebii. Among the 3,500 genes sequenced, half do not show homology with genes in any other bacterium. Dragon scientists expect to use these genes to discover novel enzymes for industry.

Japanese agricultural and medical industries might also benefit by building relationships with the Institute of Physical and Chemical Research (RIKEN) Genomic Sciences Center, which is pursuing a broad and ambitious research program to investigate genomes and determine the 3D structures of proteins. The target organisms for protein structure determination are the mouse, Thermus thermophilus, a bacteria that thrives in high temperatures, and Arabidopsis thaliana.

RIKEN researchers are also trying to predict transcriptional units on the human genome by mapping the mouse cDNA sequences and digging into human chromosome 21 to determine the structure and function of all genes and regulatory sequences on this chromosome, known as the site for genes associated with Alzheimer’s disease, leukemia, Down’s syndrome, and some autoimmune disorders.

Genomics at RIKEN is also aimed at finding answers to some long-standing questions in biology — call it philosophy, if you will. Yoshiyuki Sakaki, director of human genome research at the Genomic Sciences Center, leads a team studying the chimpanzee genome. Comparative genomics spanning human and chimpanzee genomes, Sakaki and his colleagues believe, might provide insights into “the molecular basis for understanding the human mind.”

Korea

Hyang-Sook Yoo is still getting used to the change in her job profile. Not too long ago, she would sometimes spend 10 or more hours in the lab each day, hunting for novel cDNA that show differential expression in various human T cells. Now she is directing Korea’s largest human functional genomics research program at the Korea Research Institute of Bioscience and Biotechnology, Taejon. “The program focus now is to build a cDNA library from liver and stomach cancer tissues,” says Yoo.

The choice of these diseases was dictated by the unusually high incidence rates of liver cancer and stomach cancer across Korea. The project is part of Korea’s 21st century frontier research program that has pledged an annual 12 billion won ($10 million) each for human genomics, plant genomics, and microbial genomics for the next 10 years. The total public-sector funding for genomics activities in Korea is about 57 billion won ($45 million) per year, says Yoo. “The first applications might be early detection and prognosis tests for liver and stomach cancer,” says Yoo.

Korea’s pioneering research program also supports structural genomics. Among its beneficiaries is protein chemist Se Won Suh at the Seoul National University, who received $250,000 last year to initiate work to unravel the structures of proteins of Helicobacter pylori, the bacteria associated with chronic gastritis and gastric ulcers. Korea has a shockingly high 90 percent infection rate of H. pylori, against a global incidence of 50 percent. Suh is also a member of the global tuberculosis structural genomics consortium with participants from 13 institutions in six countries.

Suh has penciled a plan to unravel structures of 400 proteins of H. pylori and 10 proteins of the tuberculosis organism over the next 10 years. He says Korea’s promise for structural genomics lies in its demonstrated experience in protein structure determination — last year SNU alone deposited 13 structures into the Protein Databank. But Korea will need to worry about the current limited supply of crystallographers and the existing weaknesses in bioinformatics and molecular design, says Suh.

Singapore

The chance of working in a pristine, unfettered environment and building a program from scratch prompted Edison Liu to quit his job at the National Institutes of Health in the US and take over as executive director at the Genome Institute of Singapore last year. Now, in a bid to attract the best talent from around the world, he’s trying to coax other scientists to make the move to Singapore too.

“Genomics research is global,” says Liu, known for his pioneering work on the expression of the HER2 gene in breast cancer. “The venue is relevant only in terms of what resources are available.” Singapore’s ethnic diversity and well-maintained clinical databases make an attractive resource for human genomics research, he says. He hopes to use these resources to create a database of Asian genomic information that will allow scientists to study diseases relevant to Asia and tailor therapies for Asian populations.

Besides the architecture of Asian populations, Liu cites transcript mapping and “the intersection of genomics and medicine” as research goals at the Genome Institute of Singapore. “We’re less than a year old, but we’re resourced appropriately and the focus is to recruit worldwide.”

But while research programs are just about to take off at the GIS, Singapore’s Institute of Molecular and Cell Biology is preparing to celebrate completion of Singapore’s flagship genome project — the sequencing of the Japanese pufferfish, the fugu. Singapore has contributed to more than half of the fugu sequencing effort that involved a consortium of other participating institutions, including the US Department of Energy’s Joint Genome Institute.

A decade ago, at a time when the spotlight was turned on the human genome, Singapore quietly sent fish biologist Byrappa Venkatesh to Cambridge in the UK to begin studying the fugu. “It emerged a powerful tool to validate hypothetical predicted genes and to pinpoint novel genes in the human genome missed by other gene prediction techniques,” says Venkatesh, now the principal investigator of the fugu project in Singapore.

Although the fugu contains essentially the same genes and regulatory elements as the human genome, it carries the sequences in 365 million bases compared to the 3 billion bases in the human genome. With far less junk DNA, finding genes and controlling elements is expected to be a lot easier.

The fugu and humans share similar mechanisms of gene regulation in the nervous system, the immune system, as well as some tumor suppressor genes. The fugu intergenic regions are compact, contain no repetitive junk and thus make it easy to identify the regulatory elements.

“Since the fugu’s intergenic regions are short and its gene density high, we can use a fugu cosmid with six to seven genes of BACs containing 10 to 15 genes to characterize gene regulatory elements as well as locus control regions either in mammalian cell lines or transgenic rodents,” says Venkatesh. “You can’t do this with mouse or human genes because 10 to 15 genes will be spread across a few megabases and thus are not easy to manipulate in transgenic studies.”

Through the fugu, Singapore is contributing to the interpretation of the human genome.

 

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