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The Search for the Big Picture: UCSF, May 2011

The science of biology is undergoing a historic transformation, from one based on observation to one based on creation, and UCSF is in the forefront of driving that change. The move to a New Biology promises to accelerate an era of astounding discovery and achievement, in which science will not only cure many diseases and offer new therapies, but will also provide new breakthroughs in energy, agriculture, the environment and other fields in which biology plays a role.

New Biology follows in the footsteps of earlier revolutions in its sister sciences of physics in the 16th and 17th centuries and chemistry in the 19th. New telescopes allowed astronomers to move physics from observation to analysis, ultimately enabling Newton to confirm the truth of his universal principles. Similarly, the development of the periodic table of elements in the 1860s helped establish the principles of chemical structure, and the growth of synthetic chemistry that followed helped propel the Industrial Revolution.

Advances in technology and new discovery are now leading to New Biology, both through the mapping of the human genome and in the use of increasingly powerful microscopes and other instruments. Instead of merely describing what exists, New Biology explores what is possible, leading to broader, more systematic applications.

“How we think of the role of biology is changing,” said Wendell Lim, PhD, professor in UCSF’s Department of Cellular and Molecular Pharmacology and investigator with the Howard Hughes Medical Institute. “We’ve got so much data from the genomic and the proteomic revolutions that we can start to see how biological systems work together.”

“New Biology has two main streams,” Lim says. “We are working to understand biology at a deeper, mechanistic level, and to apply biology to solve a broader swath of problems.”

Lim and Keith Yamamoto, PhD, UCSF’s vice chancellor of research and executive vice dean in the UCSF School of Medicine, have been leading the push for New Biology.Yamamoto testified in Congress to gain support for additional funding, and he and Lim co-authored a National Academy of Sciences report as part of the Committee on a New Biology for the 21st Century.

“Biology is at an inflection point, poised on the brink of major advances that could address urgent societal problems,” Yamamoto told Congress. He described four areas of “urgent need — food, energy, the environment and health” — and said biological research could help bring new advances in each. “It no longer makes sense to talk about biomedical research as if it is unrelated to biofuel or agricultural research; advances made in any of these areas are directly applicable in the others, and all rely on the same foundational technologies and sciences.”

UCSF researchers are already applying the principles of New Biology in their work. In one key aspect of New Biology, “we need to be effective at bringing people from different fields together, breaking down barriers and creating a culture of cooperation,” Lim says. “UCSF has always been a place that is historically not dominated by departments. Turf over ideas doesn’t exist here. It’s the perfect environment to be open to thinking about using different approaches to solving different classes of problems.”

The Team Challenge organized by the Cell Propulsion Lab (an NIH sponsored Nanomedicine Development Center at UCSF) in 2009 was a good example of New Biology in action. In that exercise, Dan Fletcher, a bioengineering professor at UC Berkeley, joined with a team of UCSF and UC Berkeley scientists from different disciplines to conceptualize how to create a vesicle that could deliver therapies to cells. “If you had a blank sheet of paper, and the ability to put together any components you wanted, what would you want?” Fletcher asked. That notion was put to bright people with diverse backgrounds, such as cell biology, pharmacology, bioengineering and chemistry, from UCSF, UC Berkeley and Lawrence Berkeley Laboratory.

“It’s an attractive idea to engineer a new process and find the defining rules of a system, like past engineers and physicists have done for other systems,” says Jessica Walter, PhD, a biology/biophysics postdoc who participated in the vesicle challenge. Walter remembers the inspiring nature of the project. “You could see ideas that at first sounded totally insane, but when people took them to their logical limits, they got something that might be feasible,” Walter says. “It’s counter-intuitive, but crazy ideas could become practical.”

For instance, researcher Aynur Tasdemir, a former postdoc in the Lim lab, proposed a “kamikaze cell,” Walter says, and “everybody laughed at the idea.” But they went ahead and brainstormed, and actually figured out a way it might make sense to give the vesicles something toxic, send them somewhere such as a cancer cell, and then have them release their payload. Jason Park, an MD/PhD graduate student in the Cell Propulsion Lab, continues to pursue this approach.

“We thought 20 years ago, we could attack cancer with a magic bullet, like radiation or chemotherapy,” Walter says. “But determining which cells are bad or good requires more computation than a single marker. It’s the kind of problem where an engineer might come in handy.”

Fletcher says the tools that have developed in the intervening years have made this kind of thinking possible. “Rebuilding parts of cellular processes to harness them as therapeutics is not something that was realistic years ago,” he says. “Now it has become a real opportunity, because we have new technology to control the assembly of new materials, together with increased knowledge of what the molecules do and how they do it.”

Cancer was the target in the spring of 2011, when Wallace Marshall, PhD, an associate professor of biophysics and biochemistry at UCSF, organized a meeting of cancer biologists and physicists. Recognizing the complex ways cancer operates, Wallace considered the notion that many problems that arise in cancer biology are similar to those faced by physicists in understanding the behavior of complex systems. His symposium studied whether the approaches used for understanding physical systems — conceptual, experimental, and computational — might provide useful insights into the behavior of cancer cells and tumors.

“The basic idea is to try to put some more general principles into biology to make it more of an engineering discipline than just a collection of facts,” Marshall says. “I’m an engineer by training so that works for me. I’m trying to figure out how cells solve their own engineering problems. If a cell wants to change its structure, how does it do that?”

One sure sign that science is heading in this direction, Marshall says, is that students arrive at UCSF “wanting to do this.” When he was a student, he had a “weird double major” of electrical engineering and biochemistry, with the goal of finding out, “how do I build things inside of cells?” Now universities are encouraging this sort of cross-fertilization, and he says it’s essential for moving science forward.

Talk to Marshall and others in the field, and a theme emerges — a search for the big picture, for the same sort of principles underlying biology that Newton found when he studied physics 400 years ago. Some examples:

* Zev Gartner, PhD, an assistant professor in pharmaceutical chemistry, is studying the body’s building blocks – from molecules to cells to organs – to better understand biological processes relating to tissue structure and its breakdown during disease. “At its core, we are trying to understand the way different systems and modules fit together in the complex task of maintaining homeostasis,” (the body’s ability to remain stable) Gartner says. “We’re not looking at, ‘How does this one little piece work?’ It’s only recently become possible to think about things in this way.”

* Michael Fischbach, PhD, an assistant professor in bioengineering and therapeutic sciences, also works with the principles of modularity, but his lab’s approach is to build things and then study how they work. “When we build something, we have the potential to create something that we can actually understand in all of its complexity,” Fischbach says. And then, when scientists “perturb,” or disrupt the system, they can see the results of that single action reverberate throughout.

“Think of synthetic ecology,” Fischbach says. “How do we construct a community of bacterial cells that I can put into the gut of a human being and get them to perform functions that are beneficial to the host? How is it that a community of hundreds of thousands of bacteria interacts? How are they structured physically? How do they alter one another’s behavior? And how does that play a role in how microbes interact with the host? That’s a great example of where you can take the lessons from old fashioned ecology, and the new fashioned studies that have revealed a wide range of organisms, and try to construct synthetic communities of bacteria to study.”

* Hana El-Samad, PhD, an assistant professor in biochemistry and biophysics, is like Marshall an engineer by training who is deep into the search for sweeping biological principles. Instead of studying cruise controls and autopilots and other human engineered systems, El-Samad is studying the “homeostatic feedback systems that nature has evolved.” “There are so many similarities between complex biological systems and the technological systems we were so successful at designing.’

“The challenge,” she says, “is that there are also differences between engineering and biological systems. In engineering, people can build a laptop to such precise specifications that millions will roll off an assembly line, and each will perform in exactly the same fashion. Natural systems don’t work that way, instead exhibiting stochastic, or unpredictable, behavior. Cells could all be cloned from each other, and yet each behaves differently. But now scientists have the ability to run 1 million tests on those cells, get a distribution of outcomes, and we can quantify probability. That’s a good first step towards finding the principles that biological systems use to tune their fidelity and precision.”

“We’ve gotten very good at collecting data we can analyze,” El-Samad says. “But we don’t know how to extract principles out of the data. Once we know those laws, the sky’s the limit.”

 

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