Dr. Jay D. Keasling speaking at PopTech Energy Salon 2011 in New York City
|Institutions||University of California, Berkeley, University of Nebraska-Lincoln, University of Michigan|
|Alma mater||University of Nebraska-Lincoln
University of Michigan
|Thesis||Dynamics and control of bacterial plasmid replication (1991)|
|Doctoral advisor||Bernhard Palsson|
|Known for||metabolic engineering|
|Notable awards||Bill & Melinda Gates Foundation grant, 2012 Heinz Award|
Jay D. Keasling is a Professor of Chemical engineering and Bioengineering at the University of California, Berkeley. He is also Associate Laboratory Director for Biosciences at the Lawrence Berkeley National Laboratory, the Founding Head of the Synthetic Biology Department in the Physical Biosciences Division at Lawrence Berkeley National Laboratory, and chief executive officer of the Joint BioEnergy Institute. He is considered one of the foremost authorities in synthetic biology, especially in the field of metabolic engineering.
Keasling received his Bachelor's Degree at the University of Nebraska-Lincoln where he was a member of Delta Tau Delta International Fraternity. He went on to complete his Doctor of Philosophy degree at the University of Michigan in 1991 under the supervision of Bernhard Palsson. Keasling performed post-doctoral research with Arthur Kornberg at Stanford University in 1991-1992.
Keasling's current research involves the metabolic engineering of the Escherichia coli bacterium to produce biofuels and of the Saccharomyces cerevisiae yeast to produce the anti-malarial drug artemisinin. Although it is an effective, proven treatment for malaria, current methods of producing artemisinin (found naturally in the plant Artemisia annua) are considered too expensive to cost-effectively eliminate malaria from developing countries. By producing the drug from a microbe, rather than harvesting it from a plantation, the Keasling Lab intends to lower the cost of artemisinin production from $2.40 per dose to $0.25 per dose.
Malaria is a global health problem that threatens 300-500 million people and kills more than one million people annually. The chloroquine-based drugs that were used widely in the past have lost effectiveness because the Plasmodium parasite that causes malaria has become resistant to them. Artemisinin, a sesquiterpene lactone endoperoxide, extracted from Artemisia annua L is highly effective against Plasmodium spp. resistant to other anti-malarial drugs. However, there are several problems with current production methods for artemisinin. First, artemisinin combination therapies (ACTs) are too expensive for people in the Developing World to afford. Second, artemisinin is extracted from A. annua, and its yield and consistency depend on climate and the extraction process. While there is a method for chemical synthesis of artemisinin, it is too low yielding and therefore too expensive for use in producing low-cost drugs. Third, although the World Health Organization has recommended that artemisinin be formulated with other active pharmaceutical ingrediates in ACTs, many manufacturers are still producing mono-therapies of artemisinin, which increase the chance that Plasmodium spp. will develop resistance to artemisinin.
Jay Keasling’s laboratory at the University of California, Berkeley has engineered both Escherichia coli and Saccharomyces cerevisiae to produce of artemisinic acid, a precursor to artemisinin that can be derivatized using established, simple, inexpensive chemistry to form artemisinin or any artemisinin derivative currently used to treat malaria. The microorganisms were engineered with a ten-enzyme biosynthetic pathway using genes from Artemisia annua, Saccharomyces cerevisiae, and Escherichia coli (twelve genes in all) to transform a simple and renewable sugar, like glucose, into the complicated chemical structure of the anti-malarial drug artemisinin. The engineered microorganism is capable of secreting the final product from the cell, thereby purifying it from all other intracellular chemicals and reducing the purification costs and therefore the cost of the final drug. Given the existence of known, relatively high-yielding chemistry for the conversion of artemisinic acid to artemisinin or any other artemisinin derivative, microbially-produced artemisinic acid is a viable, renewable, and scalable source of this potent family of anti-malarial drugs.
A critical element of Keasling’s work was the development of genetic tools to aid in the manipulation of microbial metabolism, particularly for low-value products that require high yields from sugar. His laboratory developed single-copy plasmids for the expression of complex metabolic pathways, promoter systems that allow regulated control of transcription consistently in all cells of a culture, mRNA stabilization technologies to regulate the stability of mRNA segments (Carothers et al. 2011 Science 334:1716), and a protein engineering approach to attach several enzymes of a metabolic pathway onto a synthetic protein scaffold to increase pathway flux (Dueber et al. 2009 Nat. Biotechnol. 27:753). These and other gene expression tools now enable precise control of the expression of the genes that encode novel metabolic pathways to maximize chemical production, to minimize losses to side products, and minimize the accumulation of toxic intermediates that may poison the microbial host, all of which are important for economical production of this important drug.
Another critical aspect of Keasling’s work was discovering the chemistry and enzymes in Artemisia annua responsible for synthesis of artemisinin (Martin et al. 2003 Nat. Biotechnol. 21:796; Ro et al. 2006 Nature 440:940). These enzymes included the cytochrome P450 that oxidizes amorphadiene to artemisinic acid and the redox partners that transfer reducing equivalents from the enzyme to cofactors. The discovery of these enzymes and their functional expression in both yeast and E. coli, along with the other nine enzymes in the metabolic pathway, allowed production of artemisinic acid by these two microorganisms (Ro et al. 2006 Nature 440:940; Chang et al. 2007 Nat. Chem. Biol. 3:274). S. cerevisiae was chosen for the large-scale production process and was further engineered to improve artemisinic acid production (Paddon et al. 2013 Nature 496:528; Paddon and Keasling. 2014. Nat. Rev. Microbiol. 12:355).
As artemisinin is a hydrocarbon similar in composition to the hydrocarbons found in diesel and jet fuels, the same organisms that were engineered to produce artemisinin could be modified to produce biofuels to replaced petroleum-based fuels. Keasling and his colleagues have engineered both E. coli and S. cerevisiae to produce diesel, jet fuel, and gasoline replacements (Steen et al. 2010 Nature 463:559; Keasling 2010 Science 330:1355; Peralta-Yahya et al. 2011 Nat. Commun. 2:483; Bokinsky et al. 2011 Proc. Natl. Acad. Sci. USA 108:19949; Goh et al. 2012 Appl. Environ. Microbiol. 78:70; Chou et al. 2012 Appl. Environ. Microbiol. 78:7829; Peralta-Yahya et al. 2012 Nature 488:320). The production of these advanced biofuels from sugar using engineered microorganisms will substantially reduce the production of greenhouse gases.
Keasling’s microbial production process has a number of advantages over extraction from plants. First, microbial synthesis will reduce the cost of artemisinin, the most expensive component of artemisinin-based combination therapies—by as much as ten fold—and therefore make artemisinin-derived anti-malarial drugs more affordable to people in the Developing World. Second, weather conditions or political climates that might otherwise affect the yield or cost of the plant-derived version of the drug will not affect the microbial source for the drug. Third, microbial production of artemisinin in large tanks will allow for more careful distribution of artemisinin to legitimate drug manufacturers that formulate artemisinin combination therapies, rather than monotherapies. This will, in turn, hasten the development of resistance to this drug. Fourth, severe shortages of plant-derived artemisinin are projected for 2011 and beyond, which will increase the cost of artemisinin combination therapies. Finally, microbially-derived artemisinic acid will enable production of new derivatives of artemisinin that Plasmodium may not be resistant to, thereby extending the time over which artemisinin may be used.
To ensure that the process he developed would benefit people in the Developing World, Dr. Keasling assembled a unique team consisting of his laboratory at the University of California, Berkeley; Amyris Biotechnologies, a company founded on this technology; and the Institute for OneWorld Health, a non-profit pharmaceutical company located in San Francisco, CA. In addition to assembling the team, Dr. Keasling developed an intellectual property model to ensure that microbially-sourced artemisinin could be offered as inexpensively as possible to people in the Developing World: patents granted from his work at UCB are licensed royalty free to Amyris Biotechnologies and the Institute for OneWorld Health for use in producing artemisinin so long as they do not make a profit on artemisinin sold in the Developing World. The team was funded in December 2004 by the Bill & Melinda Gates Foundation to develop the microbial production process. The science was completed in Dec. 2007. In 2008, Sanofi-Aventis licensed the technology and worked with Amyris to develop the production process. Sanofi-Aventis has produced 35 tons of artemisinin using Keasling’s microbial production process, which is enough for 70 million treatments. Distribution of artemisinin combination therapies containing the microbially-sourced artemisinin began in August of 2014 with 1.7 million treatments shipped to Africa. It is anticipated that 100-150 million treatments will be produced using this technology and shipped annually to Africa, Asia, and South America.
In 2009, Keasling was awarded the first annual Biotech Humanitarian Award by BIO, the Biotechnology Industry Organization. In 2004, the Bill and Melinda Gates Foundation awarded a $42.5 million grant to the Institute for OneWorld Health to develop and distribute the low-cost malaria treatment based on Keasling's technology. In 2006 Discover magazine awarded its first ever Scientist of the Year Award to Jay Keasling. Keasling is a member of the National Academy of Engineering.
- Palsson laboratory alumni. Gcrg.ucsd.edu. Retrieved on 2012-05-22.
- Palsson, B. O.; Keasling, J. D.; Emerson, S. G. (1990). "The regulatory mechanisms of human immunodeficiency virus replication predict multiple expression rates". Proceedings of the National Academy of Sciences of the United States of America 87 (2): 772–776. doi:10.1073/pnas.87.2.772. PMC 53348. PMID 2405389.
- Jay D. Keasling Faculty Page at UC Berkeley. Cheme.berkeley.edu. Retrieved on 2012-05-22.
- The Keasling Lab Web Site
- About JBEI. jbei.org
- Keasling, Jay D. (1981). Dynamics and control of bacterial plasmid replication (PhD thesis). University of Michigan.
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- Ro, D. K.; Paradise, E. M.; Ouellet, M.; Fisher, K. J.; Newman, K. L.; Ndungu, J. M.; Ho, K. A.; Eachus, R. A.; Ham, T. S.; Kirby, J.; Chang, M. C. Y.; Withers, S. T.; Shiba, Y.; Sarpong, R.; Keasling, J. D. (2006). "Production of the antimalarial drug precursor artemisinic acid in engineered yeast". Nature 440 (7086): 940–943. doi:10.1038/nature04640. PMID 16612385.
- Martin, V. J. J.; Pitera, D. J.; Withers, S. T.; Newman, J. D.; Keasling, J. D. (2003). "Engineering a mevalonate pathway in Escherichia coli for production of terpenoids". Nature Biotechnology 21 (7): 796–802. doi:10.1038/nbt833. PMID 12778056.
- Specter, Michael (2009). Denialsim How Irrational Thinking Hinders Scientific Progress, Harms the Planet, and Threatens Our Lives. Penguin Group. p. 229. ISBN 978-1-59420-230-8.
- An Age-Old Microbe May Hold the Key to Curing an Age-Old Affliction. Science@Berkeley. May 30, 2006
- Jay Keasling Receives Inaugural Biotech Humanitarian Award, bio.org. May 20, 2009
- Carl Zimmer Scientist of the Year: Jay Keasling. Discover Magazine. November 22, 2006
- Shukla, Shipra. (2009-03-02) LGBT Scientists Hear About Coming Out on the Job. Ucsf.edu. Retrieved on 2012-05-22.
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- Jay Keasling talk given at PopTech conference