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He’s Got High Hopes

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The Molecular Sciences Institute can’t claim to be bigger, better funded, or more equipped with high-end technology than other systems biology institutes. But if you ask its director, Roger Brent, the institute has its place, knows what it does, and does it well. And as far as he’s concerned, that’s a pretty sure path to success.

The institute was started in early 1998 with some unrestricted money that Sydney Brenner had left over from a Philip Morris grant. Brenner brought the funding, and Brent provided the idea: “I had come up with a fairly coherent research vision where I thought biology should go,” Brent says. “Sydney pointed out that it would not be possible to do that inside Harvard or any [other] university.” Departmental divisions in academia were a hurdle, he thought, that couldn’t be adequately overcome for the kind of research environment he had in mind.

The vision that was so out of place in the late ’90s has become much less foreign today. Brent’s plan to bring together people from a host of different scientific and mathematical backgrounds to help turn biology into a quantitative science now has a familiar ring to it. Still, he contends that even today the university setting doesn’t have the advantages that he got from starting up a standalone research institute. “The world has shifted in the subsequent 10 years, but it would still be very, very difficult to get people of the intellectual quality and the kind of depth of some of the people” who are working at MSI right now, Brent says.

The meat of the Berkeley, Calif.-based institute’s research has always been the Alpha Project, which in 2002 was awarded a Center of Excellence in Genomic Science grant from NHGRI and renamed the Center for Quantitative Genome Function. The goal of the project was to understand, in great detail, a very specific pathway -- and understand it well enough to correctly predict its response to particular perturbations. The pathway itself wasn’t as important as what it would enable: a new method for doing stringently quantitative biology, as well as the development of tools and techniques along the way. Brent chose yeast because it has been so well characterized over the years: “We can control its genetics down to the base pair,” he says. The team selected a signaling pathway that controls the yeast response to a mating pheromone as its proving grounds for the project.

So far, so good. “We’ve learned a great deal about how the thing works,” Brent says. For example, “we can follow the signal as it moves slowly into the nucleus, and the information-carrying capacity of the signal.”

Lingua Biologica

One of the challenges for any institute -- especially one as small as MSI, which has a staff of about 20 -- is making sure people can talk to each other. With Brent’s plan to pick people out of a variety of disciplines, this was a clear challenge from the beginning. They needed a lingua franca, he says.

“It emerged fairly quickly that the language would not be the universal language that is mathematics, but rather the scientific language of 2007 that is English,” Brent says. “English heavily flavored with biology.”

MSI researcher Kirsten Benjamin has experienced her share of this quest for better communication. While her own background is in biochemistry, cell biology, and genetics, she works most closely with mathematical modelers in her efforts to build better simulators for yeast. Her research focuses on understanding which numbers and measurements are most meaningful, and then trying to convert those into building accurate predictive models for the pathway of interest. The math side had a big impact on the biological experiments, she says. “Knowing those numbers really changes how we think about the operation of the pathway. It changes the questions we ask; it changes how we interpret published data.”

Speaking the same language internally doesn’t directly translate to easy communication with the community, and that’s one of Brent’s ongoing efforts. The MSI scientists are committed to making their techniques and tools openly accessible to all researchers in order to encourage their dissemination. “Part of our mission here is to serve the public good in a larger sense,” Brent says, noting that the technical advances made at MSI -- recent examples include better methods for immunoblotting and highly sensitive microscopic cytometry -- should translate to other projects and organisms. “We bring this back for [NHGRI] by giving people tools and lists of genes and polymorphisms … that account for some of the genetic basis of human disease,” he adds.

Beyond providing techniques, Brent says he’s busy considering how to build up an international effort as a follow-on to the work already going on at MSI. That kind of virtual institute could mean applying MSI tools to eukaryotes as one possible growth avenue, he adds.

Keeping It Real

Brent knows a thing or two about setting goals. At MSI, the focus is to do big things -- but in manageable pieces and with fairly limited resources. The institute hasn’t invested in fancy core labs or a lot of high-end instrumentation. Instead, MSI researchers get access to the tools they need through collaborations and figure that when they have a handle on the kind of data they’ll need and what to do with it, they can think about investing in technology of their own.

The institute’s partnership with Dick Smith’s lab at the Pacific Northwest National Laboratory is one example of this. Orna Resnekov, a scientist at MSI, remembers wanting to incorporate a research path into identifying post-translational protein modifications when the team was planning its CEGS grant application. She and her colleagues looked around for collaborators and came up with Smith’s group, which has seemingly limitless mass spec capabilities. “We have no ability to do this at the institute,” Resnekov says. “The idea was that we would do a complete census of sites of phosphorylation and once we had that information, it would be easier to do work in house.”

“By us doing the genetics and biochemistry and them doing the mass spectrometry,” Brent says, “we have gone more deeply into [the yeast] phosphoproteome than anyone’s ever gone before.” By using time course and other data, the team has demonstrated hundreds of new phosphorylation events, he adds.

Other affiliate members of the institute, who remain at their home institution but collaborate in this way, include synthetic biologist Drew Endy at MIT and Shuki Bruck at Caltech.

Beyond managing technology, Brent also works to keep projects well delineated and short enough that people can work freely on them while always remembering the ultimate goal. Having that kind of project means that the institute holds an allure for external researchers who are interested in teaming up with MSI for a very specific period of time or research program, he says.

“Ambitious people, great people, have and will continue to come through here who want to spend some time in this kind of environment and then move on.” He draws a comparison with the UK’s MRC, known for training some of the best scientific minds in the ’60s, ’70s, and early ’80s. “Wouldn’t that be a wonderful thing to have done an analogous thing in this generation?” Brent says. “That kind of entity would be a valuable addition to our scientific ecosystem.”

 

Name: Molecular Sciences Institute

Director: Roger Brent

Staff: About 20, most of whom are junior faculty level or higher. The center also has affiliate members through collaborations; these include Drew Endy at MIT; Shuki Bruck at Caltech; and Dick Smith’s group at the Pacific Northwest National Laboratory.

Funding: Started with part of a grant from Philip Morris, the bulk of the Molecular Sciences Institute’s current funding comes from an NHGRI grant. As a designated Center of Excellence for Genomic Science, MSI was awarded $3 million annually in 2002. Other funding comes from philanthropists and industrial partnerships.

Research focus: MSI aims to gain a thorough, quantitatively-based understanding of a particular signal transduction pathway in yeast, for starters. That project is expected to eventually give rise to related studies in other pathways and other organisms, Brent says.

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