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Second Annual Scialog: Molecules Come to Life

Ken Dill, a keynote speaker at the Second Annual Scialog: Molecules Come to Life conference told his 68 assembled colleagues, including 51 Scialog Fellows, 10 distinguished facilitators and representatives from multiple funding agencies, that for the past twenty years he has been interested in the question, raised by Louis Wolpert in Current Biology, “Are there principles in biology of the same type as there are principles in physics?”

Scialog: MCL, co-sponsored by RCSA and the Gordon and Betty Moore Foundation, brought together biologists, physicists and chemists, March 31 – April 3 in Tucson, AZ, to address the challenge posed by Dill. The meeting focused on breakout discussions, connecting early career Scialog Fellows across disciplines, and culminated in an on-the-spot proposal competition to seed new teams of researchers. Of the 51 Fellows at the meeting, 35 organized to form 18 unique teams of 2-4 researchers (some on two teams) and pitch proposals for the second round of Scialog funding.

Following the first Scialog: MCL meeting in 2015, RCSA and the Gordon and Betty Moore Foundation awarded five grants to five teams of investigators. These grants, totaling $731,000, enabled awardees to pursue ambitious, high-potential discovery research on untested ideas in physical cell biology. Each project was interdisciplinary and included both theory and experimental components.

Teams reported to the general session on their impressive progress during the second conference. Topics included:

Building an Artificial Motile Tissue through Self-Organized Rhythmic Contractility; Immersive DNA Force Sensors and Predictive Mechanical Modeling for Tissue Morphogenesis; Rebooting the Gut Microbial Ecosystem using Bacterial Dueling; Uncovering Essential Gene Functions by Exploiting Differentiation within a Biofilm; Rethinking the Idea of Cell Type.

In his address Dill noted a major physics-like principle in biology is whether nature can achieve purposeful-like, goal-seeking behavior through purely stochastic processes. Dill suggested that a biologist might think of this issue in terms of evolution, while a computer scientist might address it when dealing with Monte Carlo dynamics, and a physicist could discuss it in the context of Boltzmann’s entropy formula in thermodynamics.

Dill, the director of the Louis and Beatrice Laufer Center for Physical and Quantitative Biology, Stony Brook University, went on to discuss broadly various aspects of stochastic optimization to make the point that “the past 40 years of molecular, structural, cellular, computational and ‘-omics’ biology have given us vast knowledge of atom-by-atom and molecule-by-molecule detail. The great opportunity for the future is now to understand what it all means.”

He noted that these burgeoning data stores have created an opportunity for leadership from physicists and mathematicians, and for much deeper penetration of model-based thinking into biology.

Dill pointed out, “We have 100,000 protein structures in a data bank, each one at atomic resolution; I can tell you where every atom is to every Angstrom … so each one has huge amounts of information. That’s big data. But the point somebody made is, if big data were the answer to our problems, we wouldn’t have a stock market crash.”

Dill also touched on the subject of the dramatic decline in the funding of basic research – down by half, in terms of overall percentages – since the 1960s. He noted that “we tend to under explore and over exploit, and we need more exploration.”

The conference’s other keynote address was delivered by Jennifer Lippincott-Schwartz, group leader at Janelia Research Campus. A biologist, Lippincott-Schwartz’s research uses live cell imaging to analyze the spatio-temporal behavior and dynamic interactions of molecules in cells. She discussed the increasingly important role that emerging visualization technologies are playing in the study of cell biology, noting that these technologies are now capable of capturing cell physiology at the level of whole organisms down to single molecules.

“We now have spectral detectors associated with confocal microscopes that allow for multispectral unmixing,” she said. “For any particular problem the confocal system will allow light from the system to be passed through spectral grating, so that in a specimen that is expressing six different fluorophores, you can determine which specific fluorophore is contributing to the image – this is called linear unmixing. You can determine six different fluorophores even tied to one pixel. After linear unmixing you can mine this data, track organelles, perform single-frame analysis, and you can use these tools to look at triple and quadruple contacts among organelles. In this way we can being to understand how these contacts among organelles contribute to changes within the cell.”

Lippincott-Schwartz displayed spectacular video and still images from Janelia labs detailing the internal cellular environment captured by Total Internal Reflection Microscopy with structured illumination microscopy (TIRF-sim). She noted that TIRF allows very fast imaging, achieving 84nm resolution at sub-second speeds over hundreds of time points. Imaging individual tubular elements of a cell’s endoplasmic reticulum at a 25 millisecond time frame revealed that these elements were oscillating with an AV amplitude of 260 nanometers and a period of 270 milliseconds.

“Wherever you slice into the tubes you can see they’re underdoing this oscillation,” she said. “Poisons can stop the oscillations. We think this is the result of active fluctuations within the cytoplasm to optimize various activities and is potentially a read-out for these processes. But it has never been seen before.”

Lippincott-Schwartz and Dill set the stage for the intensive scientific dialog that followed in small breakout groups. RCSA Scialog Program Director Richard Wiener said the groups were optimized based on a pre-conference survey to mix Fellows with little or no previous knowledge of each other’s research and then rapidly catalyze new collaborations based on novel blue sky ideas. He said winners of this year’s competition will be announced in a few weeks.

In written remarks addressed to the Scialog: MCL participants, Harvey V. Fineberg, president of Gordon and Betty Moore Foundation, told participating scientists that the hope is “to generate productive and enduring collaborations that will unite theory and experiment, and entice you to explore creative and exciting new research directions at the interface of biology and physical science.” In his welcoming talk, Moore Foundation Chief Program Officer Bob Kirshner echoed these sentiments and emphasized the importance of uniting communities of early career researchers across disciplines.

RCSA President Robert N. Shelton told the Scialog fellows that RCSA personnel have been delighted to work with their Moore Foundation counterparts, including Moore Program Officer Gary Greenburg. He said RCSA looks forward to more cooperative Scialog endeavors with the Moore Foundation as well as other private philanthropies and government funders. 

 

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