Advances in Synthetic Biology: What Does a Malaria Drug Have in Common With Fueling Your Vehicle?

 
Photo of Professor Jay Keasling courtesy of the Lawrence Berkeley Laboratory.

Some might call it luck, some might call it fate. Nevertheless, the day Professor Jay Keasling found out that a plant-based malaria drug called artemisinin was chronically in short supply – that was a very important day.
You see, back in 2000, Dr. Keasling was looking for an organic chemical to be a suitable focus for his research at the University of California-Berkeley into a new field of science known as synthetic biology.
Artemisinin is a fast-acting malaria drug that, when used in a combination therapy to prevent drug resistance, is the current standard treatment for malaria worldwide. Its precursor chemical, amorphadiene synthase, is derived from the sweet wormwood (Artemisia annua), a plant that is not grown in sufficient quantities compared to need. As luck or fate would have it, amorphadiene synthase is in the class of organic chemicals Dr. Keasling believed would be ideal for study. He envisioned synthetic biology techniques creating a high-quality, non-seasonal, economical supply of the target molecule, in this case, an important drug.
Synthetic biology takes genetic engineering to the next level: scientists use parts of DNA to create a new organism or to change what an organism does. In the artemisinin project, Dr. Keasling experimented with introducing the target gene into E. coli bacteria and a type of yeast. Working with the yeast proved to be the better way to go. Dr. Keasling and his team also found a way to alter the metabolic pathway of the yeast. In other words, he made this yeast create the target molecule as the by-product of its fermentation. As it digests the material it is fed (the feedstock), it creates amorphadiene synthase, which can then be converted to artemisinin.
By 2004, Dr. Keasling's lab was showing so much promise in creating amorphadiene synthase on a small scale that the university and a start-up company, Amyris (formed by some of the post-doctoral researchers), were awarded a $42.6 million, five-year grant from the Institute of OneWorld Health (iOWH). The grant, which originated from the Bill and Melinda Gates Foundation , was to perfect the technology for the commercial production of synthetic artemisinin. According to a university spokesman, Dr. Keasling completed his part of the development of the synthetic artemisinin for the university, and the Amyris researchers took over to complete the translation of lab procedures to a process suitable for the larger-scale operations of a drug manufacturer. Amyris completed its assignment in 2010 after partnering with drug maker Sanofi-Aventis in 2008. The iOWH contracted with Sanofi-Aventis to implement the synthetic artemisinin in its commercial production of artemisinin-based combination therapies (ACTs) and provided the company a $10.7 million grant that also originated from the Bill and Melinda Gates Foundation. Sanofi-Aventis is operating on a no profit-no loss basis, and the University of California-Berkeley and Amyris granted a royalty-free license to it for the use of their technology. The projected date for commercial distribution is 2012.
All involved hope that the efforts of these scientists and philanthropists will have a big impact on the deadly toll of malaria in developing countries. This story has many heroes: one is Dr. Victoria Hale, who founded the iOWH to focus on producing drugs and treatments for neglected diseases of the developing world. The iOWH is the first-ever non-profit drug partnering firm in the U.S. that matches neglected diseases with people who can create solutions and people who want to finance the effort. Although Dr. Hale has moved on to her "second generation" non-profit agency focused on women's and children's health problems, the iOWH continues it mission, targeting diarrheal diseases and visceral leishmaniasis in addition to malaria.
A good story should always have a good epilogue. With respect to Amyris, Inc., the company is making progress on adapting a microbially-produced hydrocarbon, Biophene (TM), to a number of uses, including a drop-in replacement for diesel fuel. The company, now headed by John Melo, a former BP executive, has imminent plans for building a facility adjacent to the world's largest sugar cane processor in Brazil. The company, which had attracted significant venture capital, had an IPO last year. According to its CEO, Amyris is generally hopeful regarding cellulose as a future feedstock for the company's fermenting technology platform.
As for Dr. Keasling, he is applying the knowledge and experience gained in developing artemisinin to focus on the metabolic engineering of microorganisms (that is, altering what the microbe produces from what it consumes) to create, for example, a liquid fuel to replace gasoline. His goal is to do this with cheap, resilient, renewable feedstock like tall grass species. Targeting complex sugars found in cellulose (e.g. plant stalks) is much more ambitious than using a simple sugar like corn or sugar cane. To this end, Dr. Keasling was made CEO of the Joint BioEnergy Institute (JBEI, known as "j-bay"), which is one of three bioenergy research centers funded by the U.S. Department of Energy. He is also a faculty scientist with the Lawrence Berkeley National Lab's Physical Biosciences Division and the director of the SyntheticBiologyEngineeringResearchCenter. And while he serves as a professor for Berkeley's bioengineering department and the chemical and biomolecular engineering department, he enjoys the honor of being the Hubbard Howe Jr. Distinguished Professor of Biochemical Engineering.
Considering Dr. Keasling's contribution to synthesizing a potent malaria drug and the progress his lab is making toward synthetic, microbially-generated renewable fuel, one wonders how many of the world's challenges will he take on?