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BIOTEC leads Thailand’s leapfrog towards self-sufficiency
20 Jul 2010
Tatum Anderson
Source: TropIKA.net
If all goes well, the first malaria drug developed by Thai researchers could reach human clinical trials at the beginning of next year.
The drug, dubbed P218, is the product of research carried out by a group at BIOTEC
, a research centre created by the Thai government to generate biotechnology innovations.
Although several international partners, including Medicines for Malaria Venture (MMV), Yale University, London School of Hygiene & Tropical Medicine and Monash University in Australia, have been involved along the way, it was BIOTEC that conducted the initial research that has eventually allowed new drug candidates, such as P218, to be developed.
The group at BIOTEC, led by Professor Yongyuth Yuthavong, discovered the structure of an enzyme inside the malaria parasite P. falciparum that is normally targeted by a widely-used class of anti-malaria drugs, called anti-folates. Drugs within that class, including sulfadoxine–pyrimethamine, have gradually become ineffective against the parasite, as it has evolved resistance. Resistance to this class of drugs is now known to be caused by mutations in that enzyme, called dihydrofolate reductase (DHFR) [1], which reduces the binding affinity of anti-folate drugs [2].
Armed with knowledge of different DHFR structures, researchers were able to design and develop new anti-folate drug candidates that bound both the wild type and mutant enzymes. P218, therefore, is one of these candidates that have been optimized with promising oral efficacy and lack of host toxicity.
Breaking new ground
The development has broken new ground for Thailand, explains Yuthavong, who is now project leader for P218. “This is the first time that drug that has been designed by Thai people, has reached this stage. Up to now we have only accepted what other people have made. We are very excited that we can make these drugs ourselves,” he says.
P218 is one of a number of malaria research projects being pursued by BIOTEC. Another researcher at the institute, Dr Bongkoch Tarnchompoo, has won a grant from the Grand Challenges Exploration Program, funded by the Bill and Melinda Gates Foundation, to design more new anti-folates that will eliminate or retard the development of resistance.
BIOTEC runs a Medical Biotechnology Research Unit (MBU) looking at diseases that specifically affect the Thai population. That’s why it has looked at malaria, which continues to be a major problem, especially in the areas bordering Cambodia and Myanmar. Emerging resistance to new artemisinin-based drugs is a worry here and, as a result, is a research problem at BIOTEC too.
The institute has projects focused on the influenza virus and other related respiratory pathogens, following regional outbreaks of SARS, and both H5N1 (“avian”) and H1N1 (“swine”) flu. Tuberculosis (a major cause of death among HIV/AIDS patients in Thailand) is a priority too. With the University of Illinois, BIOTEC has, for instance, looked at the structure of a new TB target called MtFBA using Xray crystallography [3].
And because the largest dengue burden is borne by countries of the Asia Pacific region, there are several projects looking at the molecular biology of the dengue virus as well as new dengue vaccine and diagnostic candidates. The late Professor Nath Bhamarapravati at BIOTEC studied the theory that four dengue serotypes might have to be included within a single dengue vaccine and led preliminary work on a vaccine that was eventually bought by French vaccine maker Sanofi-Pasteur but later abandoned (as reported on TropIKA.net).
And in May, another group of researchers including some from BIOTEC published a paper on a rather puzzling phenomenon, whereby people who have been infected by one of the four dengue fever serotypes are likely to suffer a more severe attack of the disease if they are later infected by one of the others [4].
The BIOTEC labs have now started looking into diseases that don’t particularly affect the Thai population. Work on enzymes in P. vivax, has led to a possible strategy for trypanosomiasis research for instance.
The fact is that BIOTEC has been able to take advantage of the plummeting cost of DNA sequencing in recent years. Lower costs have allowed Thai researchers to sequence small genomes of organisms that could become crucial for local research problems.
Born of frustration
The institute itself was founded in 1983, after Thailand lost out in its bid to become home to a new International Centre for Genetic Engineering and Biotechnology (ICGEB) being created by UNIDO. India and Italy were chosen instead.
“Unfortunately politics [intervened]. We were rather frustrated so our minister, who went with us to Madrid to offer Thailand for the centre, said, ‘Why don’t we do our own centre?’” says Yuthavong. As he had led efforts draft the UNIDO proposal, he was tasked with drafting a plan for a wholly Thai-run operation. “I wrote the proposal on the plane back,” he adds. (Yuthavong would later become director of BIOTEC as well as its umbrella government department, the National Science and Technology Development Agency (NSTDA), and Thailand’s Minister for Science & Technology before returning to research).
At that stage called the National Center for Genetic Engineering and Biotechnology (NCGEB), BIOTEC was created to take advantage of the fledgling genetic technology field in the early eighties and being embraced, even then, by Thai scientists working on orchids. A biomedical department at Thailand’s Mahidol University was very interested in looking at genetics too. “We thought this would be a great way to get into genetic science, rather than conventional classical biochemistry,” says Yuthavong.
Since then, BIOTEC has grown and today has over 30 laboratories with 150 principal scientists conducting basic and applied research on agricultural, biomedical and environmental science. It is both an in-house research agency and a research funder; it has provided $3.5 million funding for the rice functional genomics project for instance. It works with satellite laboratories too. MBU consists of three affiliated laboratories including Siriraj Hospital, which is within Mahidol University, and the Department of Microbiology at Chiang Mai University.
It is able to make use of a number of genomic techniques, such as DNA micro-arrays [5], to develop knowledge of human genomic variation. For example, the Thai SNP Discovery Project, which brings together several groups of researchers including some from BIOTEC, has embarked upon a reference database of genetic information of members of the Thai population. The database might be used to study disease associations, such as the genetic susceptibility to clinical malaria or understanding the development of dengue haemorrhagic fever. Other Thai projects are looking at studying the genetic basis for the adverse reactions to certain drugs that affect only particular people.
Béatrice Séguin of McLaughlin–Rotman Centre for Global Health at the University of Toronto has studied national genotyping strategies and says many emerging markets from Thailand to South Africa and India are now looking at such studies. “The initial premise of any country wanting to embark on large-scale genomic studies is that they cannot rely on the data of predominantly western European, predominantly Caucasian-based cohort studies.” (Séguin was a contributor to a 2008 supplement in Nature Reviews Genetics, entitled “Genomic medicine in developing countries”, in which one article [6] looked specifically at the situation in Thailand.)
Local human genomic variation might reap economic as well as health benefits too, if harnessed by the local domestic private sector. “These countries want to be self-sufficient, and do not want to be technology followers; they are now going to leapfrog because they are investing in cutting edge technologies including genomics,” she says.
Certainly in Thailand there has been a heavy emphasis on boosting agriculture, which employs 40% of the country’s workforce and generates $20 billion in export earnings. It has looked at genetically modified versions of local crops, including papaya, rice and cassava, and worked on viruses that affect Thailand’s lucrative shrimp farming exports. (Indeed, BIOTEC is seen to be much stronger in agricultural and aquatic genetic research.)
And a national strategy for biotechnology for Thailand, which was created by a committee chaired by the ousted president Thaksin Shinawatra, crystallized the strategy that biotechnology – with the help of institutions such as BIOTEC – should be used to boost Thailand’s economy and social status.
The plan set out six key goals and some rather ambitious targets – including one to have 5000 people working in professional biotechnology research in public and private sectors, and 10,000 students at bachelor, masters and doctoral level in fields related to biotechnology. Another target was to prevent the economic loss of 32 billion Baht ($1bn) per year due to the major diseases that severely affect Thai people.
What has been achieved?
In some respects the strategy has been successful. BIOTEC has built up a strong laboratory-based genetic engineering.
In addition, BIOTEC and three other state-owned technology agencies are sited at the Thailand Science Park just north of Bangkok, which was set up specifically to support research and development needs for emerging biotechnology businesses and academia [7].
That park has begun to bear fruit with around 60 private companies leasing space. Bioinformatics-related business foreign businesses are setting up with the promise of eight-year tax-breaks.
It is clear, however, that there is still a long way to go.
Genetically-modified food projects, such transgenic papayas, are confined to the laboratory because of public opposition to genetically-modified foods.
And despite almost three decades of promoting biotechnology in Thailand experts industry is yet to match the enthusiasm of the scientific community, say Thai policy makers. Although overall investment in R&D from the private sector has increased gradually, health industries are still in their infancies in Thailand compared to other developing economies.
Somsak Chunharas, chairman of the Medical and Health Cluster of NSTDA said in a recent paper: “Currently, the private sector appears reluctant to take risks, and scientists are not willing or able to take further steps towards research translation. Existing research incentives for the private sector have not been effective enough to bridge this gap”.
One reason suggested is that Thai companies do not focus on innovation. The country has a healthy glut of pharmaceutical companies; 171 modern medicinal manufacturers and 132 factories received Good Manufacturing Practices (GMP). The problem is most are focused solely on dosage formulation and repackaging imported pharmaceuticals.
Certainly, the Thai science park, which was created to enable academic researchers and private companies to cross-fertilize ideas and innovations, has not resulted in the kind of mixing between academics and the private sector that was originally envisaged.
A major increase in human resources has not been achieved yet either. Despite more education in bioinformatics, for example, one paper stated that in 2008 there were just 40 Thai researchers in the field of bioinformatics and computational biology (and most received their doctoral degrees abroad, with scholarship support from the Thai government) [8].
Some even worry that many other dynamic countries of the Association of Southeast Asian Nations (ASEAN) region that are investing in biotech research, particularly Thailand’s neighbour Vietnam, might overtake Thailand.
A coup, and several changes of government since the national biotechnology policy framework was launched, has not helped. But many improvements could be made.
There could be a rethink in the way science parks work, so that there is more trust and contact between private and public researchers. Providing more incentives or setting up dedicated areas where different factions could interact, such as canteens and other areas, may help says BIOTEC’s Yuthavong. (The government has plans to develop and extend the park in the coming year.)
Likewise, Chunharas has suggested that semi-governmental agencies be created to move promising scientific products forward. Thailand’s state-owned pharmaceutical company, the Government Pharmaceutical Organization (GPO) is an existing example.
And more money must be made available for research if Thailand wants to boost its economy too. The country spends just a quarter of a percent of its GDP on science and technology says Yuthavong, who tried unsuccessfully to raise the proportion to 1% when he became Thailand’s Minister of Science and Technology.
The human resources piece needs a boost too. People do return to Thailand from studying abroad with PhDs, but often that’s the last time they ever carry out any research. Yuthavong says: “We have to find some good career paths for research in Thailand, examples of people who stay on in research all their working lives”.
Boosting human resources undoubtedly makes a difference and Thailand has plenty of proof of this. Most promising medical graduates become clinical doctors rather than going into research (clinical work is much better paid) and that has produced an interesting effect – Thailand now hosts one of the world’s largest markets in medical tourism. Further expansion of this market is one of the Thai government’s key goals.
References
1. Yuvaniyama J, Chitnumsub P, Kamchonwongpaisan S, Vanichtanankul J, Sirawaraporn W, Taylor P, Walkinshaw MD, Yuthavong Y (2003). Insights into antifolate resistance from malarial DHFR-TS structures. Nat Struct Biol; 10(5):357-65. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12704428
2. Kamchonwongpaisan S, Quarrell R, Charoensetakul N, Ponsinet R, Vilaivan T, Vanichtanankul J, Tarnchompoo B, Sirawaraporn W, Lowe G, Yuthavong Y (2004). Inhibitors of multiple mutants of Plasmodium falciparum dihydrofolate reductase and their antimalarial activities. J Med Chem; 47(3):673-680. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14736247
3. Pegan SD, Rukseree K, Franzblau SG, Mesecar AD (2009). Structural basis for catalysis of a tetrameric class IIa fructose 1,6-bisphosphate aldolase from Mycobacterium tuberculosis. J Mol Biol; 386(4):1038-1053. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19167403
4. Dejnirattisai W, Jumnainsong A, Onsirisakul N, Fitton P, Vasanawathana S, Limpitikul W, Puttikhunt C, Edwards C, Duangchinda T, Supasa S, Chawansuntati K, Malasit P, Mongkolsapaya J, Screaton G (2010). Cross-reacting antibodies enhance dengue virus infection in humans. Science; 328(5979):745-748. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20448183
5. Ganesan K, Ponmee N, Jiang L, Fowble JW, White J, et al. (2008). A Genetically Hard-Wired Metabolic Transcriptome in Plasmodium falciparum Fails to Mount Protective Responses to Lethal Antifolates. PLoS Pathog; 4(11): e1000214. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19023412
6. Séguin B, Hardy BJ, Singer PA, Daar AS (2010). Universal health care, genomic medicine and Thailand: investing in today and tomorrow. Nat Rev Genet; 9 Suppl 1:S14-19. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18802416
7. Nataporn Chanvarasuth and Ramjitti Indaraprasirt (2009). Thailand biotech business: Product of the national policy. Journal of Commercial Biotechnology; 15:66-72. Available from: http://www.palgrave-journals.com/jcb/journal/v15/n1/full/jcb200834a.html
8. Tongsima W, Tongsima S, Palittapongarnpim P (2008). Outlook on Thailand’s genomics and computational biology research and development. PLoS Comput Biol; 4(7):e1000115. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18654621
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