The first annual NIH Director's Pioneer Award Symposium in Masur Auditorium on Sept. 29 featured talks by all nine of last year's recipients. A key component of the NIH Roadmap for Medical Research, the Pioneer Awards go to individual scientists with innovative ideas rather than to particular research projects. As NIH director Dr. Elias Zerhouni explained in his introductory remarks, the peer review process tends to keep one eye toward managing risk, thus favoring more conservative proposals. The Pioneer Awards are a "pilot experiment," as he put it, to try to unleash more creative potential.

After only the first year of their 5-year awards, last year's recipients took diverse approaches to their presentations, with some emphasizing the conceptual problems they were addressing and others offering several slides of data. One thing was consistent, however: a picture of researchers ambitiously pursuing innovative approaches to major biological questions. As Zerhouni observed, "There was no shortage of bold ideas." Here's a brief survey of the presentations:

• Larry Abbott, a mathematical physicist at Columbia University, began the talks by speaking about the mathematical modeling of neural systems. He sees a great divide within neuroscience between the sensory and the motor systems. What lies between them is thinking: choices and decision-making. Abbott explained his ambition to build a mathematical network with some of the properties of the brain. Mathematicians can now build quite good networks of complex activity, he said, but sensitivity to the outside world is still lacking. His goal is to get these networks to pay attention to the outside world and to be able to formulate a response.



• George Daley of the Harvard Stem Cell Institute explained how he aims to discover the principles underlying the epigenetic code — that is, what determines how genetic information is used. Stem cells promise to reveal the interplay of genes during development in ways scientists haven't yet been able to address. Daley's strategy is to alter cell culture conditions to reproduce critical cell fate transitions in vitro. His lab has already been able to reproduce several of these transitions.

At a Sept. 29 press briefing to discuss progress in the NIH Roadmap for Medical Research and introduce the 2005 NIIH Director's Pioneer Award recipients, awardee Derek Smith of the University of Cambridge (at head of table) discusses how his mathematical approach to understanding and controlling the evolution of pathogens could be applied to prevent a flu outbreak.

• Homme Hellinga of Duke University Medical Center is designing proteins with desired functions, a process he calls synthetic biology. He showed how a receptor can be used as a biosensor for a variety of compounds by redesigning its binding site. The process, which involves complex computational design in 3-D space, can already reengineer proteins to bind metabolites, drugs, explosives and pollutants. Eventually, Hellinga hopes to be able to design complete biological pathways, such as signal transduction circuits that can survey the cell's chemical environment and respond to changing conditions.



• Mike McCune of the University of California at San Francisco explained how Macaque monkeys infected with SIV, the simian equivalent of HIV, develop a rampant inflammatory response after infection and subsequently die of immunodeficiency. African green monkeys, in contrast, have a high viral load but don't develop an inflammatory response and don't develop immunodeficiency. There is a balance, Mc-Cune said, between antiviral immunity, which attempts to clear the virus from the system, and proviral inflammation. While much of the research community's focus has been on antiviral immunity, McCune's hope is to improve survival by reducing humans' inflammatory response to HIV. He pointed out that a better understanding of the human immune system is emerging from the study of HIV pathogenesis that will affect our thinking about many other diseases that cause chronic inflammation.

NIH director Dr. Elias Zerhouni responds to a reporter's question at the press briefing.

• Steve McKnight of the University of Texas Southwestern Medical Center is studying yeast as they cycle between oxidative and glycolytic metabolism. McKnight's hypothesis is that circadian rhythms evolved from a "metabolic cycle" like that seen in cultures of baker's yeast, and he hopes his studies will shed light on circadian rhythm. Using a microarray analysis of gene expression during metabolic cycling of a dense yeast culture, his lab has already identified many periodic genes that "cycle spectacularly."



• Chad Mirkin of Northwestern University described several projects in his attempt to build a suite of nanoengineering tools. One is "dip-pen nanolithography." Adapted from atomic- force microscopy, the technique uses an array of "pens" to deliver reagents to a surface in particular patterns. Chemical manipulations at the tips can also control molecular orientations. Nanoarrays built with different patterns and combinations of molecules can help researchers explore cooperation and interaction between molecular structures. Mirkin's lab has already built nanoarrays of virus particles to explore how their structures interact with cell surfaces in culture.

At the first annual NIH Director's Pioneer Award Symposium in Masur Auditorium, the 2004 Pioneer Award recipients participate in a panel discussion on innovative research.

• Rob Phillips of the California Institute of Technology hopes to use mathematics and physics to transform an empirical understanding of biological events into a quantitative understanding — in other words, to recast biological models in mathematical terms. As an example, he explained how the forces resulting from the looping and bending of DNA molecules have biological consequences. His lab is trying to predict gene expression in the lac operon by computing the statistical weights of different states of its DNA loop. They are also studying the mechanical forces involved in packing long chains of DNA into virus capsids. By varying osmotic pressure and DNA length and then measuring how the DNA ejection rate changes, they hope to gain a quantitative understanding of how these viruses inject their DNA into bacteria. Phillips is applying his new thinking about the interface between physics and biology to write a textbook about the physical biology of the cell.



• Stephen Quake of Stanford University is developing a technology called microfluidics. He designs microchips that use tiny volumes of fluid and contain a maze of channels, valves and collection wells. He can design these chips for ultra sensitive gene expression analysis, for cell culture experiments with single cells and to grow protein crystals for protein structure studies. These small volumes not only consume tiny amounts of precious supplies, but also the fluid physics in such small volumes actually favor certain types of experiments, like protein crystal formation.



• Sunney Xie of Harvard University aims to develop the technology to view single molecules inside live cells. The research community has until recently been looking exclusively at data capturing large numbers of molecules at once. To understand how molecular machines actually work, however, we need to see single molecules working in real time inside live cells. Xie's group has recently been able to observe the production and degradation of single proteins in live E. coli cells for the first time. They hope to advance and apply the techniques they have developed to examine many fundamental processes in biology.

This year's 13 Pioneer Award recipients, who were named at the symposium, are pursuing a similarly expansive range of projects, from Giulio Tononi's exploration of why we sleep to Nathan Wolfe's collaboration with subsistence hunters in regions of high biodiversity to monitor the entry of novel viruses into the human species.

In introducing the new recipients, Zerhouni said, "The Pioneer Award to me is like the scientific freedom award. We want to give them the freedom to explore."

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