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Roger Brent and the alpha project

Ubiquity, Volume 2004 Issue March | BY Ubiquity staff 


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The work of a multidisciplinary genomic research lab in Berkeley may yield big changes in drug therapy and medicine. Roger Brent is President and Research Director of the Molecular Sciences Institute, an independent nonprofit research laboratory in Berkeley, CA, that combines genomic experimentation with computer modeling. The mission of the MSI is to predict the behavior of cells and organisms in response to defined genetic and environmental changes.

UBIQUITY: Tell us about the Alpha Project.

BRENT: The Alpha Project is an attempt to say that for biological understanding to be mature we need to be able to predict the consequences of a determined change to a [biological] system, just as we can in mechanics or electricity. In certain kinds of science, we can equate the ability to predict the consequences of perturbation to a system with understanding it. That is, if we can predict what the system will do whenever we push on it in any defined way, we will understand it.

UBIQUITY: What do you need to accomplish this?

BRENT: We need to develop ways to measure things inside living cells that we're not now able to measure. We need to put those measurements into predictive frameworks that will operate on those measurements. We need to yet again call on people from other disciplines.

UBIQUITY: Explain generally how those other disciplines contribute. Physics, for example.

BRENT: There's a tradition of physicists moving into biology. Historically, a big wave of immigration occurred immediately post World War II. Many physicists were inspired by a book by Erwin Schrodinger called, "What Is Life?" Now fast-forward to 2004 where we're encouraging a mini-wave of immigration. There are a number of things that we need that can sometimes be helped along by physicists.

UBIQUITY: Such as?

BRENT: One general class of needs is called "building gizmos." Say that we want to illuminate part of the inside of a cell very close to a glass slide but not the whole cell. We want to bounce a beam of light through the glass at an angle and then illuminate part of the cell using the so-called "evanescent wave". An experimental physicist can us build that. We also use physicists to try to make sense of the huge amount of numbers coming out of the things we're measuring inside cells. They help us figure out when effects are real, what appropriate statistics would be, and the like.

These theoretical frameworks in which we've put these measurements are not like the spare, elegant equations that might describe the motion of a planet around a larger gravitational mass. Our frameworks are giant sets of differential equations describing the rates at which various molecules react with one another. The framework to solving those is inevitably some giant computer program.

UBIQUITY: You talk of giant computer programs. What about giant computers? How much of your progress corresponds to increased computing capacity?

BRENT: The main way we go about our research does not require supercomputers. However, we are considering another approach to representing the reality of a single cell on a computer where we would need to take into account individual modules of proteins and represent millions of those molecules in space. Now that does require a supercomputer.

UBIQUITY: Does the Institute have access to a supercomputer?

BRENT: I've built the appropriate liaisons with a group at Sandia and with the Pittsburgh Super Computer Center, in case we need it.

UBIQUITY: What are some of the ways in which advanced computing power assists in biological research?

BRENT: For biological research in general, here are some examples: the more power you have the easier it is to determine the structure of proteins, and/or make very accurate guesses about their structure. These guesses become extremely useful if one is trying to find drugs that might inhibit the action of a given protein by testing those in a computer to see the shapes of the molecules that might bind to a protein and inhibit its action. There are many important things in biology for which the more power you have the better. We would be unable to do what we do without humankind's friend, the computer.

UBIQUITY: How would you describe the institute physically?

BRENT: It's a multidisciplinary genomic research lab, 80 percent wet lab, 20 percent physics, computer, et cetera. It has a little bitty machine shop and a closet with some microscopes, gizmos and lasers in it but much of what we do is bashing proteins inside the cells. Mostly, it looks and feels like a standard state-of-the-art 2004 wet biology lab.

UBIQUITY: Interdisciplinary projects can turn into mish-mash if the people can't really talk to each other. How do you make interdisciplinary projects work?

BRENT: We organize our multidisciplinary projects in a way that I call "project pull." We have a common goal to solve an important problem so we go forward attempting to solve the problem. People who can contribute in various ways naturally form up around that, much like small cars getting some pull from the slipstream of a big truck.

UBIQUITY: How do you attract the smaller cars to the big truck of biology?

BRENT: We use the metaphor of immigration. Biology needs you. Send us your poor, your tired, your hungry, the wretched refuse of your teaming shores, and become biologists. We will teach you the lingua franca. By your coming you will enrich our culture and we will all do better even though there will be continual mutual, cultural clashes and breaking of stereotypes. It's like New York City on a good day in 1910. It's an interesting place to live. On a good day there are no riots but the pot is simmering away.

UBIQUITY: What is the lingua franca that you mention?

BRENT: The lingua franca is English. You can't work in this space if you're hazy on the distinction between [mRNA] transcription and [protein] translation. There is a tremendous premium on precise communication. Then there's a tremendous premium on honesty, to one's self and to others. That is, if a biologist reports a research finding to me, I can ask clarificatory questions. I can cross-examine to the point where I'm satisfied about whether a certain point is nailed down or whether it's a little squishy. But if a physicist reports something new, I can't do that with anywhere near the intuition-guided perception that I have in biology. I must trust him or her. So there's a tremendous premium on striving for mutual intelligibility and the somewhat unexpected but wonderful necessity for people to represent honestly what they can and can't do, what they do and don't know. Otherwise we would be talking past each other and nothing would happen.

UBIQUITY: How often does everybody see each other and talk with each other?

BRENT: Daily. We're all in one 8,800 square foot built-up space. We built it out of a retail space in downtown Berkeley. It's a wonderful place for labs. We're over an optometrist and a coffee store and a candy store. � The biologists are on one side of the lab, with giant centrifuges and heavy freezers and stuff. Then somewhat separated physically but visible across an atrium is a quieter area for people whose normal work is with computer and computer display monitor and keyboard.

UBIQUITY: Denise Caruso and Tom Kalil are on the MSI board of directors. Both have been interviewed by Ubiquity. What do they think of the Institute? Do they try to tug you in any particular way?

BRENT: The board is small and everyone on it is important. Denise is simply a tremendous person with a tremendous conscience, a tremendous heart. We do expensive stuff. The total funding for the Alpha Project during its life will exceed $20 million. The National Institute of Health's Genome Research Institute gave us one of their coveted Center of Excellence grants in order to support this research direction. Those sums of money mean that people at MSI are members of the establishment. We have access to various levels of the American government. The technology development arm of the Defense Department, DARPA, funds some of the Alpha Project's computational work. Denise is the fierce voice of integrity, keeping everybody honest, worrying that we may slip over to some dark side. She's just terrific. Tom Kalil is our policy person, our connector to the world of science technology policy in the government.

UBIQUITY: Who are the other board members?

BRENT: Kevin Sweeney is a gifted corporate lawyer who helps the Molecular Sciences Institute. His metier, the place where he likes to work, is at the rites of passage for companies and organizations — births, deaths, marriages, divorces. He's guided us from start-up mode to gangly adolescence over the past now almost six years. The fourth board member, Charlie Canter, is a biologist whose strengths lie in being able to devise new ways to do things. Charles and I go back a long way. He and I, on occasion, advise the US government on matters related to defense against biological attack. We know each other quite well. In what is a tiny organization of say maybe 25 people, one main well of the board here is to keep me on track and to provide complementary skills and abilities that I lack or the tiny number of people who have a more executive function at MSI lack.

UBIQUITY: You talked about the relationship that you have with government. What is your relationship with industry?

BRENT: At the moment we get no money from industry. In general our work toward predictive biology cannot quickly be used by biotech or pharmaceutical companies, which have much shorter time horizons. Other work is, however, quite suitable for corporate support and patronage. I expect as it goes forward that those patrons might be computer companies or other technology companies who wish to contribute to biology, as well as pharmaceutical companies.

UBIQUITY: What would you like to get from industry?

BRENT: Money. Money and to a certain extent equipment. Most of the things we need to build are little ensembles of protein inside living cells.

UBIQUITY: Is there something that you can offer industry right now?

BRENT: The Alpha Project has already produced methods that could have impact on detecting pathogens in the environment and diagnosing diseases in people. I've requested $16 million from the NIH in order to build up the capability to produce it on demand here at MSI. We're not precluding commercial development of it.

UBIQUITY: How would the Institute's research help analyze the suitability of particular drugs for particular people?

BRENT: Long-term consequences of the success on this Alpha Project could completely change the current conceptual framework under which drugs are developed and prescribed as therapeutics. If one had quantitative predictive models of mammalian cells and systems, one could identify points at which you could inhibit the action of two or more proteins in a process, even just a little bit. That might give you smaller, less intrusive chemical molecules to use as drugs. The result would be smaller amounts of drugs and fewer side effects.

UBIQUITY: Would this lead to personalized drug therapy based on a person's unique genetic make-up?

BRENT: It would help lead to a model for drug therapy and medicine 20 years from now in which the physicians — or the people who are directing the action of the physicians — would use highly personal information about what has gone wrong genetically or what is different genetically in each person. We would fit into that but we wouldn't be directly responsible for personalized drug therapy. Early spin-offs directly from Alpha will include better ways to detect and diagnose things.

UBIQUITY: What are your peer institutions? Is MSI unique or similar in certain ways to other places that generally do this kind of research?

BRENT: It's pretty unique. What MSI does is sometimes referred to as systems biology, although I don't like that term. Systems biology, as understood by most biologists, has to do with learning about how an entire system, defined as a whole cell or organism, works by putting together information flowing from various so-called high throughput methods that are available to biology now to gather knowledge. I try to distinguish between our own, I hope, much more thoughtful program of research and what I view as the fuzzier, let's look at all the possible information kind. Some models for this type of independent research institute that is psychically next door to academia but sits somewhat outside of it are Cold Spring Harbor Labs on Long Island and The Salk Institute in La Jolla.

UBIQUITY: What about the politics in the broadest sense of the word? Berkeley has a reputation for activism. Do you find it a congenial environment?

BRENT: It's a terrific environment because smart people like to come here. Many of the major intellectual ties are with the University. Some of the best computer scientists in the world are here. In the city we're known to be doing something for the good of humankind and we're not Lawrence Berkeley National Labs, which is sometimes viewed as the devil.

UBIQUITY: People don't think you're busy modifying foods in some horrible way?

BRENT: No. We're a basic research institute. The Downtown Berkeley Business Association gave us honorable mention last year for Sydney Brenner, the fonder of MSI, winning the Nobel Prize. That's a tough crowd, to only give MSI honorable mention.

UBIQUITY: Has the field in the last 10 years been marching along pretty much predictably the way you would have expected it or are there any major changes or surprises?

BRENT: Some aspects of business-as-usual in the middle 1990s needed to change. One of them is the pursuit of this particular research agenda by things like the Alpha Project and the corollary to that is the creation of a more multidisciplinary research environment. Another change, that I did not predict, that has been an important influence on the MSI is the rise of the strong desire to build biological systems, or "synthetic biology." There's a new breed of young engineer whose ambition is to design and build biological systems with the alacrity that a software engineer can write code. They want to write the code that they can put into a plant that will make it produce, say, a plastic, or grow a bridge or a house, or a computer. On a personal note, ten years ago I was a professor in the Genetics Department of Harvard Medical School and I could not have conceived that I would be attempting to run a sprawling, multi-disciplinary research institute with co-workers and coalition partners of such depth and seniority.

UBIQUITY: What are your thoughts on synthetic biology?

BRENT: By the middle of this century, biology may be the main driver for the industrial economy. I've written that the ability to manipulate DNA will be as important to the economy of the 21st century as the ability to manipulate electrons and bits was to the economy of the 20th. But that is easy sloganeering. It turns out that to hang flesh on those organic bones takes the emergence of a disciplined self-conscious, self-confident cadre of would-be engineers of biological systems. One example is Drew Endy of MIT who is one of the leaders of the MIT group attempting to develop this. The "Synthetic Biology" agenda is an example of something outside the canon of what I'll call successful American biomedical research. They did not arise from the gifted experimental biologist well-funded by the NIH or the Howard Hughes Medical Institute, rising to the top of a hill and seeing beyond it to the next hill and then going to that next hill. These are clear offshoots of what would have been the predictable growth of the field.

UBIQUITY: You sound optimistic.

BRENT: An acquaintance of mine, the science-fiction author, David Brin, coined the terms "delusions of adequacy." I believe that those of us in positions where our work impacts on human affairs have an obligation to behave as if we believe that if we try to configure things properly today then the working out of what comes after, the consequences, will be better than if we had made other, worse, choices. There's another quote along those lines from the British author Alasdair Grey that may become an official MSI motto: "Work as if you lived in the early days of a better nation."


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