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The Cheaper, Bacteria-Derived Future of Drugs

• July 19, 2013 • 6:00 AM

(PHOTO: JOLOEI/SHUTTERSTOCK)

Drugs made from plants are often too expensive for the people who need them. A group of scientists may have found a solution.

The world is in dire need of cheap drugs to combat malaria. Malaria may seem like a disease from the distant past, but world-wide, it still exacts a large toll. Even worse, today’s malaria parasites are often resistant to the standard anti-malarial drugs. Newer and more effective drugs exist, but these drugs are well out of the price range of the patients in the developing world who need them.

Part of the problem is that the newer anti-malarial drugs come from plants. For thousands of years, humans have been getting their drugs from plants. While plants make a wide range of pharmacologically active compounds, they are not very practical: they can be difficult to cultivate in large quantities, their chemical yield can be unreliable, and the product we’re interested in can be expensive to isolate from other chemicals made by the plant. Add all that up and plant-derived drugs are too expensive for the people who need them. But there may be a solution: drugs made from bacteria (and other microbes).

Different versions of the same class of enzyme can carry out a mind-boggling range of chemical reactions.

The current source of newer anti-malarial drugs is Sweet Wormwood, a plant used in traditional Chinese medicine. The Chinese have long cultivated Sweet Wormwood, but the current world acreage of this plant is much less than we need. And even if there were enough Sweet Wormwood available, extracting the active ingredient, artemisinin, is an expensive and inefficient process.

To tackle this problem, the Bill and Melinda Gates Foundation funded a California-based group of industry and academic scientists to build a microbe that can crank out suitably large amounts of artemisinin (or artemisinic acid, a closely related chemical) while fermenting in an industrial-scale vat. The group recently reported success, which they achieved by making a variety of genetic modifications to ordinary baker’s yeast. The result is a yeast that makes artemisinic acid while fermenting sugar.

In the case of artemisinin-producing yeast, the researchers modified a natural yeast metabolic system, one that converts a chemical called Acetyl-CoA into a steroid. Acetyl-CoA is made by every organism on Earth, and is a precursor of many important biological molecules. The scientists made several genetic hacks to this metabolic system, resulting in a yeast strain whose enzyme levels can be fine-tuned by adding cheap chemicals to the yeasts’ nutrient broth. With the enzyme levels set just right, the yeasts’ Acetyl-CoA-to-steroid machinery gets highjacked to make large amounts of a chemical that is just a few enzymatic steps away from artemisinic acid.

The final genetic modification was to build in new enzymes that finish the job of making artemisinic acid. To do this, the researchers took a set of enzyme genes from Sweet Wormwood and transplanted them into the genome of their engineered yeast strain. The result: a yeast that feeds on sugar and pumps out artemisinic acid, at a fraction of the cost of extracting artemisinin from hectares of Sweet Wormwood.

The project involved substantial R&D, but principles can apply broadly. One reason why this kind of Wormwood-to-yeast metabolic engineering is successful is that the Wormwood enzymes involved are not very different from yeast enzymes that have other functions, making it possible for Wormwood enzymes to function in a yeast cell. In nature, there are many variations on a basic enzyme design; different versions of the same class of enzyme can carry out a mind-boggling range of chemical reactions. There is even a strain of bacteria (which evolved naturally in a contaminated military training range) whose enzymes break down explosives for food. The chemical repertoire of the natural world is tremendous. By harnessing that repertoire in microbial factories, we can make drugs, biofuels, and other chemicals in a way that has the potential to be cheaper, safer, and less damaging to the environment.

Michael White
Michael White is a systems biologist at the Department of Genetics and the Center for Genome Sciences and Systems Biology at the Washington University School of Medicine in St. Louis, where he studies how DNA encodes information for gene regulation. He co-founded the online science pub The Finch and Pea. Follow him on Twitter @genologos.

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