The 2015 Nobel Prize in Physiology or Medicine was awarded earlier this month. In a shared award, William C. Campbell and Satoshi Omura won for the discovery of avermectin and Tu Youyou won for the discovery of artemisinin: drugs used to treat parasitic infections caused by roundworm and the malarial parasite, respectively. Remarkably, both drugs are derived from natural substances.
Omura is a scholar in bioorganic chemistry and an avid golfer. His scientific philosophy has been to study microorganisms and use them to seek cures for common diseases. Five years ago, Omura wrote an article for the Tetrahedron Prize in Biochemistry entitled “Microbial Metabolites: 45 years of wandering, wondering and discovering”. Four decades ago, Omura picked up a soil sample with a promising microorganism near his golf course and sent it to the Merck, Sharpe and Dohme Laboratories to be tested for potency against animal parasites. In particular, the hydrogenated product of avermectin is used in veterinary medicine and in the control of onchocerciasis (river blindness in Africa), lymphatic filariasis (in combination with Albendazole), strongyloidiasis and scabies. Campbell collaborated with Omura but also worked independently on avermectin as head of the Merck Institute for Therapeutic Research. Campbell was instrumental in arranging to distribute ivermectin for free in Africa to cure river blindness. Some have likened the importance and impact of ivermectin to the discovery and impact of penicillin.
If you think Omura’s wandering golfer story is unusual, Tu’s is even more strange. At the height of the Cultural Revolution in China, Mao Tse Tung received a request to help the North Vietnamese soldiers who were dying (in greater number than by bullets) because the local malaria had become resistant to known drugs. Because most scientists had been sent to the villages, Mao ordered a group of scientists from the army to seek a cure. The teams were organized into two streams. One sought the cure in 40,000 known chemicals. The other, lead by Tu, began to look for it in traditional Chinese medicine (TCM) including by asking herbal healers for their secret fever cures. A Chinese herb called qinghao, identified today as sweet wormwood, was written about nearly 2,000 years ago as a fever cure. The herb qinghao generates the active ingredient artemisinin that proved to be nearly 100% effective against malaria in mice. The human body eliminates artemisinin very fast and so it had to be combined with other drugs to retain its impact. Novartis developed this combination by putting together artemether, a derivative, with lumefantrine, another Chinese drug: the company also filed Western patents. In 2001, Novartis agreed to provide this drug at cost to developing countries.
As India goes about tackling big public health problems such as dengue and chikungunya, these case studies can provide valuable lessons. Both stories have an east/west angle, a serendipity angle, a natural source angle and a collaboration angle. The scientific method to develop cures has relied on two techniques: 1) infected cell assays and 2) knowledge-based methods. The assay method tests millions of compounds against infected cells using high throughput screening techniques. It is essentially a trial-and-error procedure akin to what was followed for the Nobel Prizes. The knowledge-based test uses previously identified knowledge and directly targets the molecular or atomic level.
One (controversial) way to limit the spread of dengue is to introduce genetically modified (GM) male Aedes aegyptimosquitoes (engineered by a company called Oxitec) into the environment. These self-limiting transgenic males produce offspring with dengue-carrying females that have a very limited lifespan. In pilot tests in the Cayman Islands, Malaysia and Brazil, Aedes aegypti populations have shrunk by 80% or more, resulting in a dramatic reduction in the probability of dengue transmission. In the meantime, several different approaches to a vaccine are being attempted. Sanofi Pasteur is furthest ahead with a vaccine in Phase III human trials: four others are in various stages of development. The first vaccine may be available as early as 2016.
India’s scientific presence in vector-borne disease prevention and cure is muted. While India is a member of the dengue vaccine initiative, it has not signed up to be an early adopter country. The National Centre for Disease Control and the National Vector-Borne Disease Control Programme appear to be asleep at the switch with their plan to tackle dengue and chikungunya dating back to more than five years ago. Serendipity, natural source/semi-synthetic cures and collaboration take hard work and perseverance. Tu might recommend mission mode and Omura might suggest wandering, but persistence is a basic requirement to both. Chest-thumping by politicians when infected children are denied hospital admission is an alarmingly inept response.
Millions of people attempting to dodge billions of (disease-carrying) mosquitoes does not make for a statistically winnable proposition. This year’s Nobel Prize suggests a more active and persistent attempt.
P.S. “I wonder if I deserve this prize. I have learnt so much from microorganisms, I would much rather give the prize to them”, said Satoshi Omura.
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