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Spreading Influence

color = "#FFB459"; Spreading Influence As the source of many mosquito-borne diseases, Thailand is becoming a source of new treatment strategies as well. By Pennapa Hongthong Loi Krathong, festival in Chian Mai, Thailand Every year, Juthatip Mongkolsapaya packs up her research from Bangkok’s Mahidol University and heads to London’s Imperial College. “In Thailand we have an excellent repository of specimens and as

Pennapa Hongthong

Spreading Influence

As the source of many mosquito-borne diseases, Thailand is becoming a source of new treatment strategies as well.

Loi Krathong, festival in Chian Mai, Thailand

Every year, Juthatip Mongkolsapaya packs up her research from Bangkok’s Mahidol University and heads to London’s Imperial College. “In Thailand we have an excellent repository of specimens and associated clinical information, but London has better labs,” says the immunology researcher.

Juthatip is one of a new generation of Thai scientists who find themselves globetrotting more and more as the country’s capacity in infectious disease research gains recognition. But Thailand’s contributions toward battling so-called “neglected” diseases such as dengue fever and malaria goes even further, to tackling HIV, tuberculosis, and thalassemia.

Dengue hemorrhagic fever won’t be found outside Juthatip’s London lab, but the tropical disease infects 170 Thais every day, and remains a health threat to 40 percent of the world’s population. Her work...

Loi Krathong, festival in Chian Mai, Thailand

Every year, Juthatip Mongkolsapaya packs up her research from Bangkok’s Mahidol University and heads to London’s Imperial College. “In Thailand we have an excellent repository of specimens and associated clinical information, but London has better labs,” says the immunology researcher.

Juthatip is one of a new generation of Thai scientists who find themselves globetrotting more and more as the country’s capacity in infectious disease research gains recognition. But Thailand’s contributions toward battling so-called “neglected” diseases such as dengue fever and malaria goes even further, to tackling HIV, tuberculosis, and thalassemia.

Dengue hemorrhagic fever won’t be found outside Juthatip’s London lab, but the tropical disease infects 170 Thais every day, and remains a health threat to 40 percent of the world’s population. Her work is just a small part of Thailand’s effort to address such diseases, whether through improved diagnosis, treatment, or vaccine development and production.

Thailand’s commitment to these diseases is driven by a desire to improve the quality of life for its own population, the benefits of which may find their way to other developing countries, and even some wealthier nations.

Many mosquito-borne diseases—including malaria, dengue, and West Nile virus—are endemic to tropical countries, but are increasingly appearing in northern latitudes and reappearing in countries where they were eradicated, the result of growing urban population density, international travel, and global warming, among other factors.

“Malaria is a global threat, especially since we are running out of effective drugs,” says Yongyuth Yuthavong, senior biochemist of the National Center of Genetic Engineering and Biotechnology (BIOTEC), who works on malaria research. “What we’re doing does not only benefit Thais.”

Mosquitoes Maladies

No insect causes greater human suffering than the mosquito. More than one million people die from mosquito-borne diseases annually. Topping the list are dengue fever and malaria. Fifty million people are infected with the dengue virus every year, approximately 20 percent of whom develop dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), which causes internal bleeding and potentially shock. Once shock occurs, dengue patients have a 50 percent chance of survival if left untreated. Another 250 million people are newly afflicted with malaria annually.

Besides having no effective treatments or vaccines, these diseases are also difficult to diagnose. With dengue fever, for instance, physicians are often unable to verify the presence of the disease until severe DHF symptoms emerge.

These issues with diagnosis and treatment are what prompted the Mahidol University’s Medical Biotechnology Unit (MBU), in collaboration with BIOTEC, to launch the Dengue Clinical Database (DCD) project with Imperial College and Oxford University 8 years ago. The MBU is the project leader, and receives laboratory support from the London partners.

“This project is the most powerful weapon to affect real change in the way we address the disease’s diagnosis and treatment,” says Prida Malasit, who leads the DCD project. As part of the project, Juthatip probes the virus’s cellular immunology, while colleagues at Siriraj Hospital collaborate with Chiang Mai University to look at how the complement system interacts with the virus, and use locally produced monoclonal antibodies to develop diagnostic tests. Other researchers are looking into the genetics behind various clinical phenotypes and the protein structure of the dengue virus.

So far, these efforts have helped elucidate the complement system’s role in the pathogenesis of internal bleeding and shock, as well as the molecular mechanisms behind the interactions of the dengue virus and host protein. Now, the researchers have established a method for determining the risk of developing hemorrhagic fever and shock syndrome, by comparing the levels of the dengue virus protein NS1 and the levels, or absence, of the terminal complement complex (SC5b-9).

“This discovery will enable doctors to differentiate between those dengue-infected patients who require hospital care from those who are unlikely to develop complications,” says Prida. All that’s needed now is for the private sector to step in and develop a rapid test kit, he adds.

While Prida’s team has been tackling the detection of dengue, a group of malaria researchers are focusing on treatment. For decades, science has waged a back-and-forth battle with the malaria parasite. All successful treatments eventually wane in effectiveness due to eventual resistance.

In 2002, with financial support from Medicines for Malaria Venture, Wellcome Trust, the European Union, and the World Health Organization, Yongyuth and his team were able to determine the structure of an antimalarial drug target, the enzyme dihydrofolate reductase (DHFR). A number of antimalarials act by inhibiting this enzyme, but eventually mutations caused the parasite to resist the drugs. Knowing the structure of the enzyme—including how it changed through mutations—enabled his group, together with international collaborators, to design and make drug candidates that are effective against the resistant parasites. Yongyuth is now embarking on a new effort to limit the parasite’s ability to mutate and develop further resistance.

Vying for Vaccines

Thailand’s efforts in the battle against dengue fever go even further—to stop the disease altogether. Vaccine research on the disease is yielding promising results, reinforcing Thailand’s growing role in the global vaccine hunt to fight infectious diseases.

Not far from where Prida spends his time searching for dengue diagnostic clues, Sutee Yoksan, director of Mahidol University’s Center for Vaccine Development, is tackling the dengue problem from another angle. By attenuating dengue virus through serial passage in certified primary cell cultures, Sutee’s team has developed live attenuated dengue vaccine that potentially can be manufactured. “Right now we have a candidate vaccine in preclinical trials, and we hope to move to clinical trials within one year,” he says.

Promising dengue vaccine research is also taking place at Chiang Mai University’s Faculty of Medicine, where a team led by Nopporn Sittisombut is developing a vaccine in which he inserts pieces of the dengue virus envelope protein into a flavivirus.

With financial support from the National Science and Technology Development Agency (NSTDA), Nopporn has been able to develop almost 100 vaccine candidates. About 15 have passed early in vitro testing, and are now in animal testing.

Prasit Palittapongarnpim, NSTDA’s vice president, hopes to see at least 200 potential candidates, of which at least one will be a viable candidate to prevent transmission of the dengue virus.

But Nopporn and Sutee have competition. Sanofi-Pasteur, in cooperation with the Thai Public Health Ministry, has recruited 4,000 Thais to participate in clinical trials of a recombinant live attenuated dengue vaccine. Establishing the capacity to host such clinical trials has been one of the building blocks of Thailand’s overall vaccine development program. In September 2009, Thailand made international headlines for hosting the world’s largest HIV/AIDS vaccine trial. Some 16,000 Thais participated in what many feel is among the most promising steps to date in developing a defense against HIV. The trial of RV144 HIV vaccine, which was developed based on HIV strains that commonly circulate in Thailand, demonstrated that it was modestly effective in preventing HIV infection, lowering the rate of HIV infection by 31.2 percent.

Last year, Thailand’s vaccine production achieved another milestone when the Government Pharmaceutical Organization (GPO), a state enterprise under the Ministry of Public Health, in collaboration with NSTDA, produced a local version of the H1N1 vaccine, now undergoing trials.

Minding the gene gaps

The achievement of the Human Genome Project accelerated Thai scientists to step up work in genomic medicine. In 2002, they launched the Thai Single Nucleotide Polymorphism (SNP) Project to isolate and map 30,000 polymorphisms in Thais. The project has helped Thai scientists identify disease-associated genes and work on pharmacogenomics. New research on thalassemia, tuberculosis (TB), acute leukemia, cancer, HIV, and post-traumatic stress disorder have all benefited from the Thai SNP project.

Thalassemia has become a particular concern to Thai health officials, because an estimated one-third of the Thai population carry thalassemia genes. While only three percent of Thai carriers have contracted this inherited blood disease in its severe form, public health experts fear that, with such prevalence in the country’s DNA, the percentage of severely afflicted carriers could skyrocket.

Genomics has been a welcome tool in Suthat Fucharoen’s 20-year effort to diagnose and treat the disease. From his lab at Mahidol University’s Institute of Science and Technology for Research, he has been developing a diagnostic method for detecting fetal abnormality. A novel approach to managing and treating newborn thalassemia patients using anticoagulation drugs, including aspirin, is also being tested and shows promising results.

Given the rate of blood transfusions required for thalassemia patients, the burden on the public health budget is tremendous. As a result, authorities estimate that Suthat’s efforts will help contribute to nearly $1 billion in savings over 5 years under a government program to better diagnose and treat thalassemia patients.

In 2003, Surakameth Mahasirimongkol, medical researcher with Thailand’s Public Health Ministry’s Medical Sciences Department, assembled a team to study Thai genetic susceptibility to TB. The project became the first in Asia to study genome-wide, SNP-based linkage analysis of TB patients.

Only 10 percent of all TB carriers become symptomatic. Researchers have speculated that immune system differences play a crucial role in TB susceptibility. Surakameth’s research confirms this suspicion—genotyping of 195 TB patients from 93 families revealed that a region on chromosome 5q is associated with developing symptoms of TB.

However, it is too early to identify specific genes associated with protective immunity, he cautions. “We’re still working toward that goal so we can provide a method to differentiate individuals who are genetically predisposed to succumbing to TB to aid in the disease’s prevention and treatment,” he says.

Going Generic

In 2002, Thailand made a major contribution to HIV patients in the developing world when the GPO released GPO-Vir, a single tablet that contained the three antiretroviral (ARV) drugs—nevirapine, lamivudine, and stavudine. Costing 10 percent of the market price of the three drugs individually, GPO-Vir was a major breakthrough in generic drug manufacturing, causing new facilities to emerge in Africa and Asia.

“While our capacity to develop new drugs may be limited, we take pride in our ability to push the boundaries of generics and giving the world its first generic AIDS cocktail,” says Achara Eksaengsri, director of GPO’s Research and Development Institute.

GPO-Vir has given hundreds of thousands of AIDS patients in developing countries access to treatment that they otherwise would have gone without, says Achara. It’s a critical first-line defense; but unfortunately, GPO-Vir is not effective for all patients, she says, and the longer patients stay on it, the greater the likelihood that resistance will develop.

In response to this resistance, the GPO is manufacturing the generic version of two second-tier HIV treatments—efavirenz, and lopinavir combined with ritonavir. But the GPO’s decision has sparked intense international controversy, as both these drugs are under patent. The Thai government asserts that it is within its right to grant what’s known as Compulsory Licensing (CL) for generic manufacturing of these drugs, since HIV has been defined as a “health emergency” in Thailand, in accordance with policies from the World Trade Organization.

Pharmaceutical companies and many Western countries disagree with Thailand’s claim, however, and argue that as a lower-middle-income country, Thailand should be able to afford to pay a “reasonable price” for these drugs, and not exercise the emergency condition to produce them generically.

However, Somsak Chunharas, secretary of NSTDA’s Medical and Public Health Cluster, looks at CL as an appropriate tool for countries like Thailand to exercise.

“It would be regrettable if business models impede scientists’ discoveries from benefiting the public,” says Somsak. Intellectual property protection is a cornerstone of the drug industry, he concedes, but not when it makes valuable drugs inaccessible because of their high prices.

Somsak’s views are not universal within Thailand’s scientific community, but as CL is established government policy, local scientists are reluctant to express their sentiments publicly. “There’s a balance somewhere that can ensure appropriate profits are made, and equitable treatments are delivered; we just need to find it,” expresses one senior researcher, who asked not to be named.

The Missing Link

While there may be disagreements on the CL, there is one area where Thai scientists see eye to eye: the need to address the lack of public and private investment funds to support products generated by local researchers.

The efforts of Mahidol University’s Medical Biotechnology Unit to detect the severity of dengue infections is a case in point. “We may have the patent, but as a state institution we have no capital to invest. And so far, no one from the private sector is stepping forward since there is no guaranteed market,” says Prida.

Arpornpun Pochanukul, Managing Director of Bio-Genomed Co Ltd., adds that she would like to expand her laboratory equipment company to include such test kits, but the lack of any signal from the government that the kits would be utilized in the public health systems gives her pause.

If the government took steps to guarantee investors that there would be a market for such devices, it would send a strong signal to investors that there is money to be made in Thailand. “Attaining worldwide recognition in emerging disease research is not yet enough to stimulate the level of investment that is clearly warranted if Thailand is serious about integrating medical science into economic development,” says Arpornpun.

As tough as it may be, the government needs to assert greater leadership in the development of biomedical products, and the “Made in Thailand” brand. Until such time as Thailand has established credibility in this marketplace, Arpornpun argues, customers in developed countries in particular will remain off limits.

There are several different investment methods governments are using, says Somsak, including serving as a guaranteed customer, or “picking the winner” of research breakthroughs.

“I don’t know which model is the most suitable for our country, but all sectors have to talk and get something underway. The only thing of which I am quite certain is we urgently need stronger partnerships between research and development and manufacturing if we’re going to fully realize the benefits of our home-grown medical science,” he says.

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