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To Build a Genome


Synthetic biology is based on the idea that researchers can engineer the core components of a gene, cell, or other biological system to achieve a particular end. Given how new the field is, however, researchers have yet to discover the best practices, methods, and approaches to making the parts they need — nothing has yet been standardized and codified to allow them to build upon each other's work.

The Synthetic Biology Engineering Research Center, or SynBERC, aims to fill this gap. This collaborative group, classified as a National Science Foundation Engineering Research Center, is made up of some of the best-known synthetic biologists.

"The goal is to really take a systems-level approach to either build a particular system or solve a particular problem," says Jay Keasling, a professor at the University of California, Berkeley. "It was pretty clear back in about 2005 that we had groups of individuals that were starting in the area of synthetic biology, and it would be really great if we could somehow stitch them all together and start thinking about issues around synthetic biology like standardization of components, and how you take individual components and put them together in larger systems that will function and perform as you desire them to."

The group — made up of researchers from UC Berkeley, the University of California, San Francisco, MIT, and Harvard — is funded by an NSF grant for about $4 million a year. Its original grant was awarded in 2005 for five years, but has since been extended another five. Stanford was later added as an institutional collaborator when Drew Endy moved there from MIT in September 2008. The various principal researchers will often collaborate on projects, and they also have their own interests, Keasling says. But where the group's real work lies is in creating an infrastructure for synthetic biology that the participants hope will enable researchers to advance the field.

The approach

SynBERC is essentially made up of two departments, Keasling says: "the thrusts and the testbeds." The thrusts department is in charge of investigating four things: parts, devices, chassis, and best practices for synthetic biology researchers to share their work with the public. The parts section works on making new components, describing what works and what doesn't, and standardizing those parts, Keasling says. This would include things such as DNA sequences that might be binding sites for regulatory proteins, promoters, and ribosome binding sites, among others. The devices section works on finding ways to put those parts together to form a larger device that will actually function. The chassis researchers work on the microbes that the parts and devices will eventually go in to. "We call it a chassis because it's analogous to the computer chassis, which has a power supply that you put all the components into, like the hard drive and the sounds card and so on, and that makes a computer," Keasling says. Finally, the human practices department deals with public perceptions of synthetic biology, the risks and ethical issues surrounding the engineering of biological systems, and the intellectual property aspect of the project — whether certain information should be open-source or patented and licensed.

Whereas the thrusts department employs a bottom-up approach to synthetic biology, the testbeds department takes the opposite approach to find answers to specific problems using all the thrusts, Keasling adds. One testbed project involves creating a tumor-seeking bacterium, he says. The idea is to create bacteria that, when injected into a cancer patient, would hunt down the tumor and release a toxin to kill it, and then kill themselves. "You think about all the circuits that it might have and the particular chassis — you can't cause septic shock — and -everything around that, and that really becomes a driver for how you build all those components," Keasling says. The two other testbeds include the creation of bacteria with precursor pathways that would enable researchers to synthesize a variety of products from renewable resources, including different biofuels, and the construction of a biological system that can be programmed to sense and respond to different conditions during the industrial fermentation process.

The synthetic factory

In addition to the thrusts and test-beds, SynBERC has partnered with the Lawrence Berkeley National Laboratory and the BioBricks Foundation to create the world's first facility for the design and manufacture of broad collections of biological parts. Once the International Open Facility Advancing Biotechnology — or BioFab, created in 2009 — is fully operational, it is expected to produce tens of thousands of standard, engineered biological parts made freely available to any researcher working on synthetic biology. Keasling likens it to a "catalog" of various parts and devices that researchers could essentially look through and order supplies from.


"Basically what we're trying to develop is an operating system for programming cells at the genome scale," says Stanford's Drew Endy, SynBERC's strategic director. "If you wanted to have a collection of regularized genetic functions that you can use to quickly prototype a designed genome that actually has a chance of working, then that's what the BioFab is producing."

What Endy and his colleagues are trying to do is analogous to writing a computer program. If you were to write a computer command telling the computer to produce the word "hello" on the screen, you have a reasonable expectation that the word would, in fact, appear on the screen, Endy says. If you were putting together an equivalent command for a cell, it might have a promoter for transcription, a UTR for initiating translation, and a coding sequence with start and stop codons, with the expectation that the correct protein will be synthesized.

Right now, the probability of the correct protein being synthesized is somewhere between 60 percent and 80 percent, he says — much lower than the certainty of a computer properly executing a command. But BioFab aims to collect data on both failures and successes from attempts to program biological systems in order to raise that level of certainty to somewhere around 90 percent. The goal would be to produce biological parts that researchers can use with confidence, and do synthetic biology research without having to reinvent the wheel — more specifically, the parts — each time. "We may never get there, but it's a driving goal," Endy says.


Berkeley's Keasling says he has a lot of optimism when it comes to what SynBERC can achieve because of the experience and reputation of the researchers involved. "We have what I think are really the best synthetic biologists at these five institutions — a star--studded list of investigators," Keasling says.


The collaborative effort, he adds, "naturally came together" as each investigator fell into the role of heading up the particular thrust or testbed that corresponded to his or her personal work. Harvard's George Church, for example, had already done a lot of work on building chassis, while UCSF's

Wendell Lim and MIT's Christopher Voigt had spent a lot of time building devices, Keasling says. At UCSF, Tanja Kortemme's research focus is on protein design, so she heads up SynBERC's parts section.

But despite the ease with which the collaboration fell into place, working within SynBERC is not without its difficulties. The researchers are far-flung, spanning different time zones, and it's difficult to get people to talk on a regular schedule to keep everyone up to date on various efforts, Keasling says. And because the researchers are so well-known they also have several other demands on their time.

Stanford's Endy says that when the collaborators are able to talk to each other regularly, their projects work very well, but that when the researchers don't spend enough time together, they stop seeing ideas in the same way. SynBERC does have two meetings a year, one in Boston and one in San Francisco, to get everyone together to talk about their progress, which helps keep the group connected.

"It's wonderful, stressful, horrifying," Endy says. "Working together, you can bring very different views together, and if there's cohesion and synchronization for a sustained moment on a topic, you can really -advance." n>The Breakdown

The Breakdown

Participants: University of California, Berkeley; University of California, San Francisco; Harvard University; MIT; Stanford University
Funding: NSF funds the project
for about $4 million a year.
Timeline: The grant began in 2005 and has since been extended though 2015.

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