research forefronts at the interface of the physical and

Research Forefronts at the Interface of Research Forefronts at the Interface of the Physical and Life Sciencesthe Physical and Life Sciences

Fall Meeting of the Board on Physics and Astronomy05 November 2006

J. Onuchic

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ContextContext

• Research activity at the interface of the physical and life sciences is not new, but opportunities (and needs) have expanded tremendously

• Within the NRC, Board on Physics and Astronomy and Board on Life Sciences began discussing barriers to research collaboration in 2003

• Further attention stimulated by Congressional report language leading to several NSF/NIH conferences (most recent, Nov 2004)

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NRC workshopNRC workshop

• In Dec 2004, NRC hosted a weekend workshop at SLAC in Stanford, CA

• NRC Boards involved– Board on Physics and Astronomy– Board on Life Sciences– Board on Chemical Sciences and Technology– Board on Mathematical Sciences and their Applications

• Purposes– To evaluate the need for an NRC study of the opportunities

for and barriers to research at the interface of physical and life sciences

– To advise on how such a study could most usefully be structured

4Center for Theoretical Biological PhysicsQuickTime™ and a

TIFF (Uncompressed) decompressorare needed to see this picture.

Physics can provide conceptual guidance for the quantitative understanding of living systems

Living systems can help us learn new physics by focusing our attention on complexity

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Key issues discussedKey issues discussed• Distinctions between interdisciplinary and multidisciplinary research

• Need for bidirectionality in any initiative– Physical science for life science AND vice versa– New and yet-unimagined opportunities/synergies are the real payoff!

• How broadly should “physical sciences” be interpreted? Need to maintain focus but avoid arbitrary boundaries

• Cultural differences between the disciplines

• Need for a paradigm shift in mechanisms for research, training, and support

• Identifying grand challenges: Emphasis on scientific opportunities? Societal priority and impact? Or both?

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Study proposalStudy proposal

• With full support of Dec 2004 planning meeting, BPA and BLA undertook preparation of a proposal for an NRC study of the “research forefronts at the intersection of the physical and lifesciences”

• Goal is to provide framework for organizing research at this interface– Transcend the current paradigm!– NOT What can physics do for biology and vice versa?– INSTEAD What can physics & life sciences do for the country by

working together?

• Jointly filed with many different program offices– NSF (BIO, ENG, MPS/CHE, MPS/DMR, MPS/PHY)– DOE/BER, DOE/BES– NIH/NIBIB, NIH/NIGMS, NIH/OD– ARO, AFOSR, ONR

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Charge to the committeeCharge to the committee

• Develop a conceptual framework for the scientific forefronts at the interface between the physical and life sciences and conduct an assessment of this work.

• Identify and prioritize the most promising research opportunities at this interface, articulate the potential benefits to society, and recommend strategies for realizing them.

• Explore ways to enable and enhance effective interdisciplinary collaboration, such as education, training, instrumentation, andcyberinfrastructure, which bring together the life and physical sciences to address the most compelling opportunities.

• The committee will explore areas such as biomolecular machines; gene regulation and signal transduction; mechanics and spatial structure of the cell; and the origin of self-replicating systems. The committee will also identify other key research areas in which the interaction of physical and life scientists is needed for scientific advancement.

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Moving forwardMoving forward

• NSF and NIH have committed their shares of funding; DOE has promised an FY2007 commitment– Patience has paid off – Now time to discuss committee membership, give final

guidance on work plan…and get going!

• BPA & BLS may seek small contribution from private foundations to enlarge the “workshop” or glossy up the final report

• Committee is slated to meet four times over 12 months, including a large public workshop adjacent to one meeting

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Membership considerationsMembership considerations

• In contract negotiations, all agencies expressed anxiety about the makeup of the committee– Initial thinking has been for co-chairs (one “physicist,” one

“biologist”)

• Committee needs to have credibility in the eyes of many separate, elite audiences– NIH, NSF, DOE– Congress, OSTP– Physical and life science disciplinary communities

• Suggestions welcome!



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How does the macromolecule accomplish the functional task?



Large-scale conformational changes in biological systems

Protein synthesis: ribosome

Not accessible from standard molecular dynamics simulation

Combination of new analytical theories and simulational approaches will be needed!

From Folding to Function

Transcription - Replication

Related to function

Observed by:

X-ray

electron microscopy …..

Frank J. et al. 2000, 318, Nature

RNApolymerase



Molecular basis of transcriptional control

• Possibly, complex protein-protein interaction

• Alternative: regulated recruitment (Ptashne & Gann ’97)– simple, glue-like interaction between TFs/RNAP– arrange DNA binding sites/strengths to accomplish

desired control functions

Genetic Switches/Networks



Biological Dynamics

We study how signaling systems in space and time allow cells (and higher order multi-cellular structures) to function

Cardiac Cell - Ca++

•Voltage-gated Ca entry•Signal Amplification•Modulation by adrenaline•Cell contraction•Restoring pumps



Calcium dynamics in myocytesA nonlinear stochastic spatiotemporal process

Developing approaches to these problems and understandingthe role of the molecules in making the system function robustly is at the forefront of complex-systems physics

research forefronts at the interface of the physical and

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