| Engineering Life
by David Pescovitz
Professor Adam Arkin was named one of Time magazine's "Time 100 Innovators" in the year 2000. (Peg Skorpinski photo)
If you could snap together genes, proteins, and cells like Tinkertoys to build complex systems that don't already exist in nature, what would you build? UC Berkeley researchers have no shortage of ideas. For example, a microbial "factory" that produces an antimalarial drug could cut the cost of pills from dollars to dimes, saving millions of lives every year. How about microrganisms that glow red in the presence of certain environmental contaminants and digest the toxins?
This is the vision of synthetic biology, building living systems from the bottom up to do our bidding. Bioengineering professor Adam Arkin is pioneering the computer modeling tools that will help make that vision a reality. The aim is to develop software for designing new living systems from a library of validated interoperable genetic "parts" with specific functions.
"Most genetic engineering is done by hook-or-by-crook," Arkin says. "It takes a lot of trial-and-error to build simple things into cells, like the ability to produce a lot of a functional protein. Now though, we want to actually program cells as if they're computers so they can do much more complicated tasks."
In some ways, synthetic biology is not as far removed from computer design as one might think. Genetic "circuits," comparable to electronic circuits, consist of specific sections of DNA that interact to produce a predictable result. As the specifications become more exacting, Arkin adds, the complexity of the bioengineering skyrockets.
Arkin's frequent collaborator, chemical engineering professor Jay Keasling, made a major biological circuit breakthrough last year. He engineered E.coli so that the bacteria produces the precursor to artemisinin, a chemical compound used to fight malaria. Currently, artemisinin is extracted from the leaves of the wormwood tree, an expensive process. Keasling transplanted genes from the wormwood tree into E.coli and assembled them into a new metabolic pathway enabling the bacteria to spew out artemisinin. Eventually, the same technique could be used to produce drugs that target cancer or HIV. While Arkin calls the work 'stunning science', he points out that it took several years for the artemisinin factory to step up production.
"Jay didn't have the mathematical models to guide him or the biological parts in the freezer," says Arkin, who is also a faculty scientist at the Berkeley Lab's Physical Biosciences Division. "Our aim is to make the process he used orders of magnitude more efficient. So we're trying to develop a principled approach to creating a store of characterized genetic circuits and parts that we can then use much like the electronics industry uses transistors and capacitors. "
Continuing the metaphor, Arkin is pushing ahead on the development of Berkeley BioSPICE, software that represents and simulates cellular processes such as gene expression and cell division. Think of it as CAD (computer aided design) for genetic circuits. A project of the California Insitute for Quantitative Biomedical Research (QB3), Berkeley BioSPICE analogous to SPICE (Simulation Program Integration Circuitry Evaluation), the industry-standard tool for integrated circuit design invented at UC Berkeley. The project's motto, "open source biology," refers to the fact that the fruits of the research are freely available for anyone to use and improve upon.
The idea is that once accurate computer models of the various cell behaviors and genetic circuits are created, researchers will be able to use BioSPICE to model and test new synthetic biosystems before they are fashioned in the wet lab.
"We can engineer these systems in theory," Arkin says. "And the multidisciplinary connection with Jay enables us to test out our ideas in the experimental world."
For example, Mike Cantor, a PhD student in Arkin's group, is working with Keasling to design a genetic "pulse generator," a device that responds to a biological signal and responds by generating a protein. Such a device could increase our understanding of genetic processes while helping characterize new parts. Meanwhile, former biophysics graduate student Leor Weinberger is leading an effort with Arkin and chemical engineering professor David Schaffer to develop early mathematical models for synthetic viruses that might someday be used to treat HIV.
"One of my mottos is that you don't really understand a system unless you can predict, control, and design in its media," Arkin says. "So right now, we're in the stage where we're determining if we can manufacture biological systems to spec."
Arkin Laboratory for Dynamical Genomics
Synthetic Biology at Berkeley Lab
BioSPICE Community Web Site
"Synthetic Biology Offers New Hope For Malaria Victims" (Science Beat, March 24, 2004)
California Institute for Quantitative Biomedical Research (QB3)
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