Ajikumar Parayil has tinkered with the digestive system of a common gut and sewage bacterium to produce in abundance a chemical compound that promises an inexpensive route to a blockbuster cancer drug.
Parayil, an Indian scientist at the Massachusetts Institute of Technology (MIT), has helped coax E. coli bacteria to make taxadiene, a precursor compound for paclitaxel, a drug widely used to treat breast, lung and ovarian cancers.
Paclitaxel was first isolated in the 1970s from the bark of the Pacific yew tree, but early production methods required cutting down two to four fully grown trees to extract enough of the drug to treat a single patient.
Recent production methods involve harvesting the drug from plant cells grown in the laboratory, but even this process yields small quantities, and the drug is still expensive — about $10,000 per dose in the US.
Now Parayil and his colleagues at MIT and Tufts University in Boston have analysed the complex sequence of steps in the synthesis of paclitaxel and used that knowledge to engineer genes of E. coli to produce taxadiene. They have described their results in the journal Science on 1.10.2010.
“This bacteria produces 1,000 times more of this precursor than any other engineered microbe,” said Parayil, a postdoctoral associate at MIT, who had obtained a PhD from Mahatma Gandhi University, Kottayam.
Parayil first engineered E. coli to eliminate a bottleneck that was interfering with the synthesis of taxadiene, and then gave the bacteria two genes from the Pacific yew tree to get them to produce copious amounts of taxadiene.
“There are several more steps to obtain paclitaxel from taxadiene, but the taxadiene synthesis is the most challenging step,” Parayil told.
Although organic chemists possess the knowhow for chemical synthesis of paclitaxel, their methods involve anywhere from 35 to 50 steps, and in any case yield quantities that are not economically viable.
“If you can make (paclitaxel) a lot cheaper, that is good, but what really gets people excited is the prospect of using our platform to discover therapeutic compounds in an era of declining new pharmaceutical products and rapidly escalating costs for drug development,” said Gregory Stephanopoulos, a professor of chemical engineering at MIT.
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