Herbert Levine - US grants

Research will be conducted on microscopically realistic models of interfacial patterns in non-eqilibrium condensed matter systems. These models should be sufficiently accurate so as to allow for quantitative tests of current theoretical concepts. These concepts include the "solvability" theory for ordered structures, bifurcation theoretic analysis of secondary instabilities in cellular patterns, mean field methods for "ensemble-averaged" Diffusion Limited Aggregation and ideas regarding the emergence of braod-band spectra in non-linear systems via self-organized criticality." These ideas must be combined with specific and detailed models if they are to yield quantitative predictions regarding pattern forming behavior. In the course of this work, studies will be made of the solidification of monolayers, where the reduced dimensionality enables one to perform exact shape calculations and compare to general schemes for bifurcation of cellular states; a new mathematical model will be developed for the recent stream instability experiment which exhibits a transition to broad-band dynamics; solvability theory for free dendritic growth will be extended to the realistic case of non- axisymmetric crystals with cubic surface tension anisotropy so as to be able to directly compare with experiment; and, mean field Diffusion Limited Aggregation calculations will be done on a variety of geometries and dimensions so as to ascertain the generality and usefulness of this new approach. %%% A variety of problems in the exciting new field of nonlinear science which impact condensed matter physics and materials research will be studied. The problems focus on models of the nonlinear dynamics of interfacial patterns which are realistic and can, thus, be compared with experimental results.

9415460 Levine This research project involves analytical and computational studies in non-equilibrium condensed-matter physics aimed at elucidating the interplay between ordered and disordered structures. One aspect of the research involves using continuum field theoretic methods to analyze the recently discovered connection between the disordered (often fractal) structures seen in diffusion-limited growth and ordered patterns in the same systems. Also, it is hoped to develop related methodologies to understand this interplay in a variety of fluid systems (Faraday ripples, rotating convection, etc.) where similar connections have been discovered by recent experiments. In addition, the study of ordered non-equilibrium structure and their breakdown by focusing on non-linear spiral waves in a variety of systems and models will be continued. The eventual goal of this effort taken as a whole is to push forward the ability to go from the microscopic physics of non-equilibrium systems to the observed macroscopic complex behavior. %%% When condensed-matter systems are driven far from equilibrium, they exhibit a variety of complex behaviors in both time and space. The goal of the research in this area is to understand which features of a non-equilibrium system are most crucial for determining the degree of order in the spatial structure and which aspects of the states which are disordered ("chaotic") in space and time are truly universal. To answer these questions, a variety of systems will be studied, ranging from spiral non-linear waves in chemical and fluid systems to fractal patterns in solidification using state of the art techniques.

Statement of Objectives The objective of this research is to develop a computational model for the morphogenesis which occurs in the development of Dictyostelium discoideum. The life cycle of this microbial eukaryote progresses from that of a solitary amoeba to a differentiated multicellular organism, under the control of interlinked genetic and physico-chemical processes. The work will focus on extending successful models of early aggregation (encompassing chemotaxis and nonlinear cAMP waves) to the mound structure and subsequent tip elongation; also, we will incorporate recent data regarding the role of genetic networks in the signal transduction process into a more sophisticated and hence more predictive cAMP wave model. Experiments will be used to motivate modeling choices and subsequently to test predictions, leading after several iterative cycles to a simulation capability currently unavailable for this (or any other) developmental biology system. Methods to be Employed Simulations will be based on the recently introduced hybrid scheme where the individual amoebae are treated as automata which interact with the physical world of chemical signals, stress fields, etc., treated as a continuum. This methodology allows the modeler great flexibility in representing the manner in which a Dictyostelium cell obtains information from the surrounding world, reacts (via moving, emission of chemicals, modification of its internal state variables, etc) to that data. Supporting experiments will be performed by confocal fluorescence microscopy using cells which express green fluorescent protein under a variety of distinct promoters. This setup allows us to measure mound morphology dynamics as well as track individual cells (from specific differentiated cell lines if needed ) in the three dimensional multicellular body. Significance of the Propose d Activity to the Advancement of Knowledge or Education Computational methods are beginning to play an important role in biology. As the experimental data begin to indicate the complexity of genetic interactions and how these exert control over the developmental program, one will increasingly need to rely on computational procedures to get from single cell behavior to multicellular morphogenesis. This research suggests a case study of the? possible role of computation for the development of Dictyostelium. If successful, it will not only speed the rate of progresq in understanding Dictyostelium development, but will also serve as a guide for longer term efforts to bring a predictive simulational capability to the entire field of developmental biology.

9805036 Levine This is a renewal grant which puts forward an ambitious plan for making substantial progress on interface structure and motion in spatially-extended non-equilibrium systems. The primary focus is on the disordered interfacial structure (sometimes with fractal scaling) seen in diffusion-limited growth, unstable viscous fingering and related processes. Interfaces which arise in non-equilibrium chemical reactions and interfaces that arise in simple models of of biological evolution will also be studied. One recurrent theme is that in all of these cases, one has both deterministic effects and stochastic ones; the stochastic effects typically enter as multiplicative noise acting on a set of reaction- diffusion equations describing the "mean" structure. These studies will use both computational techniques and analytical methods; formulations will be investigated in terms of stochastic partial differential equations, or alternatively in terms of coupled correlation functions. The goals include a better understanding of the origin of scaling, a more quantitative approach to the calculation of the overall probability distribution of the growth patterns and a deeper appreciation of exactly which changes at the microscopic level can drastically alter macroscopic structure. If successful, our efforts will provide a firmer basis for applications of interface dynamics to systems ranging from enhanced oil recovery and alloy solidification to diffusion-controlled chemical reactions and microbiological evolution. The lessons learned here will also have a significant impact on the understanding of non- equilibrium spatially-extended dynamical processes, one of the frontiers of modern physics. %%% This theoretical grant will support research on interface structure and motion in spatially-extended non-equilibrium systems. The analysis will include both deterministic and random effects. Results will provide a foundation for applications of interface dynamics to enhanced oil recovery, alloy solidification, diffusion-controlled chemical reactions and microbiological evolution. ***

Abstract

DBI 9970199
Onuchic, Jose
Computational Laboratory for the Development of new Approaches to Complex Biological Phenomena


A computational biology center will extend modeling and computation to real biological processes especially in the area of molecular biophysics, molecular genetics, developmental control and evolution. The three primary research projects concentrate on protein folding and simulation, modeling Dictyostelium development and hybridization and folding of nucleic acids. Current methodologies of MonteCarlo, stochastic automata and dynamic programming will be used. New simulation concepts will lead to a better understanding of the complicated issues involved in making quantitatively valid predictions for biological systems. This broadly based facility will advance the field of computational biology, which is becoming increasingly necessary for biologists to keep track of and make sense of data of ever increasing complexity.

This project details an integrated, multiscale and multidisciplinary approach towards characterizing and understanding the development of Dictyostelium discoideum, from gene expression to morphology and multicellular organization. The basic underlying premise is that the time is ripe for the concerted application of quantitative methods, both experimental and theoretical, to a central problem of modern biology, namely how one can form an integrated picture of an organism that connects genetic information to behavioral response. For a variety of reasons, Dictyostelium is the logical system in which to tackle this challenge.

The research project has three components: First, DNA microarray techniques combined with the knowledge of hundreds of well-characterized mutants will be used to acquire a large body of gene expression data relevant to Dictyostelium development. Second, a new generation of experiments, focusing on the cell response to external signals that coordinate multicellular development, will be devised and carried out. Finally, computational simulations will be used to tie together the different pieces, e.g., genetic networks with protein networks, protein networks with cellular response, and cellular response with multi-cellular morphogenesis. To accomplish these tasks, a high quality, interdisciplinary team of scientists has been assembled at the interface of biology, physics, and computation.

0101793
Levine
This award supports theoretical and computational research on pattern formation with applications to physical, chemical, and biological problems. The focus of the research includes pattern nucleation, self-organized flocking states, and stochasticity in interface dynamics.
The PI aims to apply a combined numerical and analytical approach to the problem of pattern nucleation. Pattern nucleation refers to the creation of patterns by fluctuation effects in systems exhibiting multistability. The research effort will include applications. Of immediate interest is the spontaneous creation of intracellular calcium waves by stochastic channel openings.
Flocking behavior occurs in interacting multiparticle systems away from any simple equilibrium state. Self-organized structures arising from flocking have been found in a wide range of diverse systems from microorganism colonies to human pedestrian traffic. Continuum equations will be devised for these processes with an aim to better understand allowed parameter ranges and instability mechanisms. Results from model calculations will be compared to real-world data obtained in part through collaboration with leading experts in the fields of animal flocking, traffic patterns, and amoeba aggregation.
The PI will also continue his studies of how stochasticity influences interface dynamics. Efforts will focus on extending two possibilities, pulse backfiring in excitable systems and noise-induced diffusive instabilities. The PI aims to find an analytic approach and to find necessary and sufficient conditions for the occurrence of these anomalous noise effects. A new effort is planned on an application to noise effects during infection spreading.
This award also supports education through research results that are incorporated into a course on pattern formation and through the preparation of a textbook on pattern formation.
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This award supports theoretical and computational research on the physics of non-equilibrium processes, especially in the emergence of spatial patterns in extended systems. The research will in part, capitalize on tremendous advances in the field over the past decade to make critical and nontrivial predictions regarding the behavior of a wide variety of complex systems. The work will focus on how fluctuations influence the formation of patterns in systems with coexisting dynamical states, on understanding the self-organizing properties of interacting self-propelled particles, and on better characterizing the conditions under which noise-sensitive interfaces occur.
Results of this work will provide a foundation for a wide range of specific applications to physical, chemical, and biological systems. The PI will focus on the spontaneous creation of intracellular calcium waves by stochastic channel openings, animal flocking, traffic patterns, amoeba aggregation, and infection spreading. This award also supports education through research results that are incorporated into a course on pattern formation and through the preparation of a textbook on pattern formation.
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A Center for Computational Biological Physics is established at the University of California, San Diego as part of the Information Technology Research Initiative (ITR). This ITR Center, located in La Jolla, CA and operating as a partnership between UC San Diego, the San Diego Supercomputer Center, the Scripps Research Institute and the Salk Institute for Biological Studies, will pioneer new computational paradigms in support of this overall goal. This is critical as biology evolves into a data-rich predictive science and increasingly turns to complex systems physics for help in in developing the necessary conceptual underpinnings and the concomitant calculational strategies.

Specifically, the Center will focus on two major projects, one each at the supra-molecular and sub-cellular scales. The first involves combining molecular dynamics with powerful electrostatic solvers so as to enable the study of large-scale biological machines. The system to be used as a testbed is the ribosome, where the recently determined structure allows for the application of these ideas. The second involves extending the MCell concept, originally developed for synapse simulations, into a broadly useful tool for studying sub-cellular-cellular scale signal transduction processes. Here the target applications concern calcium dynamics in cardiac cells and its control by hormonal action. In addition to these research goals, the Center will be actively involved in training a new class of computational scientist, one who can directly communicate with experimentalists and focus the computation so as to answer meaningful questions for these systems. Finally, the ITR Center is directly coupled to a complementary effort, the Physics Frontiers Center for Theoretical Biological Physics, which is focused on the conceptual advances that will eventually serve as a source of new demand for novel computational strategies.

The ITR award is jointly funded by the Physics, Materials Research and Chemistry Divisions of the NSF.

This award provides partial support for the participation of graduate students and postdocs in the upcoming topical conference, "Opportunities in Biology for Physicists, II", sponsored by the American Physical Society in San Diego from January 30 to February 1, 2004. The conference is aimed predominantly at graduate students and postdocs in physics who are considering applying the methods of physics to biological topics. Physicists and biologists who are leaders in their fields will be asked to give broad overviews of five broad areas at the interface between physics and biology. In addition, there will be a panel of young researchers who will discuss their careers and in particular how they moved their research field from physics to the biology/physics interface. Funds for the support are provided by the Divisions of Physics and Materials Research in the Mathematical and Physical Sciences Directorate and by the Division of Molecular and Cellular Biosciences in the Biosciences Directorate.

The events studied in Projects 1 and 2 are essential prerequisites for the actual movement of cells towards the source of cAMP. Translocation of the cells allows them to aggregate into groups of up to 105 cells and proceed through multicellular development. Cell movement is an essential process in many multicellular organisms. In vertebrates it plays essential roles in embryogenesis, organogenesis, wound healing and, when aberrant, can lead to birth defects and cancer metastasis (Baggiolini, 1998; Behar et al., 1994; Clark, 1996; Condeelis et al., 2005; Dormann and Weijer, 2003; Muller et al., 2001). Dictyostelium cells are highly motile even while growing as they search for food. The rate of cell movement increases to a peak during the aggregation stage when they signal each other with periodic pulses of cAMP. We have recently shown that a molecular circuit involving the cAMP receptor, adenylyl cyclase, cAMP phosphodiesterase, MAP kinase and PKA generates spontaneous oscillations in cAMP synthesis (Laub and Loomis, 1998). We also have evidence that many of these components are essential for chemotaxis in a natural wave (Maeda et al., 2004; Stepanovic et al., 2005; Wessels et al., 2004; Zhang et al., 2003). Our working hypothesis is that the circuit is coupled to cell movement such that signaling and response are always in phase (Loomis, 2007). Dictyostelium cells provide an excellent test system to further understand the basic biology of cell motility, which appears to have been conserved during evolution leading to vertebrates. In Project 3, we will focus on several aspects of the chemotactic response to temporal and spatial aspects of cAMP waves that leads to aggregation. We will be able to benefit from the expertise we have developed in controlling the cAMP environment within microfluidic devises and the computer assisted quantification of instantaneous velocity of a large number of cells. Three specific aims will be addressed in Project 3.

This award provides a second five-year term of funding for the Center for Theoretical Biological Physics (CTBP) located at the University of California, San Diego (UCSD). This second period builds on the extensive research, education, and outreach successes achieved during the initial five years to both expand the reach and accelerate the rate of scientific progress on critical issues in biological physics and extend the scope of training and outreach activities. Crucially, it continues the strategy of both developing and using concepts and techniques from physics and applied mathematics to tackle otherwise intractable problems in the science of living matter and conversely to use biological problems to motivate new concepts of broad applicability throughout physics.

The research program includes three projects that utilize the depth and breadth of the collective expertise of the center participants to target specific biological areas for rapid advances. These are: Cellular Tectonics- the dynamic mesoscale structure of the intracellular milieu; Computational Approaches to Intracellular and Intercellular Communication - chemical-based reaction-diffusion governed communication across complex spaces; and Gene Regulatory Networks - genetic/signaling networks exhibit specificity and robustness in the face of intrinsic stochasticity, and yet retain evolvability. Each of these areas has reached the stage where approaches based on developing and using fundamental physical principles can be effectively implemented. A separate part of the research plan will be organized around smaller seed projects and around junior investigators. This part will ensure flexibility in keeping abreast of newly emerging directions and allow for re-orienting the principal projects as needed. This overall strategy is enabled by the success the center has demonstrated to date in creating an environment which fosters multi-investigator collaborations, interdisciplinary thinking and a sense of excitement at the possibility of helping build what is, in some ways, a new branch of physics.

A main challenge at the biological physics frontier has been the training of physical scientists to become leaders in this inherently multi-disciplinary subject. A significant number of students and postdocs trained in the center have secured leading national and international positions in both physical and biological sciences. This cadre of talented individuals is contributing to the notion that deep physics-based conceptual approaches can now encompass living-system complexity. Educational approaches that have proven successful, including training workshops, a visiting scientist program, a biological physics curriculum and the seminar/reading courses/journal club activities are being continued. The process whereby students learn biological physics will be formalized to a great extent by integrating the courses into a comprehensive syllabus and by creating individualized plans for meeting biology background shortfalls. New ideas for disseminating center practices to the broader community are under development.

The outreach program focuses on bringing under-represented groups into the research pipeline at the undergraduate level by working with partner institutions in Southern California. An earlier effort with Cal State University San Marcos is making progress, and this will be enhanced and expanded to other institutions. The overall excitement engendered by research into living systems will be exploited as a vehicle to interact with the K-12 educational sector.

This award is jointly funded by the Directorate for Mathematical and Physical Sciences (MPS) and the Directorate for Biological Sciences (BIO) as part of a partnership to foster research and education at the mathematical and physical sciences - life sciences interface. Funds are provided by the Physics Frontiers Centers program and the Condensed Matter and Materials Theory program in MPS and the Biomolecular Systems cluster in BIO.

This proposal request funds to support the annual International Conference on Chaos and Nonlinear Dynamics: Dynamics Days 2009, to be held at the DoubleTree Hotel, San Diego, California on January 8-11, 2009, and hosted by the University of California,San Diego. The principal co-organizers are Professors Michael Todd (mdt@ucsd.edu) and Herbert Levine (hlevine@ucsd.edu), of UCSD?s Engineering and Physical Science Divisions, respectively. Dynamics Days is an annual conference organized with the specific purpose of providing an interface for researchers from diverse scientific disciplines but with common interests in nonlinear dynamics, chaos, and complex systems. This meeting has become internationally known as a very effective mechanism for researchers to share their most recent results in understanding, modeling, and controlling nonlinear dynamical systems.

The Physics of Cancer Metastasis Meeting to be held in Arlington, VA on Nov. 1-2, 2010 will discuss the prospects for defining a set of short term (3-5 year) projects, which could be successful in leading the way to deeper understanding of the fundamentals of the metastatic process and possibly to radical new treatment ideas. The discussion will be held between leading cancer researchers and leading physicists working at the interface of biology and physics. The physics community working at the physics-biology interface is excited by the possibility of contributing to the fundamental understanding of cancer, which is a failure of multi-cellularity, but is also an essential byproduct of evolution. The meeting is sponsored by the Physics Division at NSF.

This collaborative award will support formation of a Physics of Living Systems Graduate Student Research Network, a trans-institutional community-based network of graduate students and graduate student educators all working on the physics of living systems. The initial participating institutions are the University of California, San Diego (which will coordinate the program), the University of Illinois, Urbana-Champaign, Princeton University, Yale University, Cambridge University, and University College, London. The network structure will allow students at participating institutions (and a select number of other students) to meet their peers (both in-person and in-silico) and collectively help define the research agenda for this field. It will also allow for the creation of visiting internships, which will serve both as a way of broadening students perspectives on possible approaches to difficult research topics and as a way of creating collaborative ties between groups at the various sites. This structure will also enable the exploration of various means of educating these students in biology, while also ensuring that they develop and maintain a firm grounding in physics. This award is supported by the Physics of Livings Systems Program in the Physics Division in the Directorate for Mathematical and Physical Sciences, as well as Molecular and Cellular Biosciences in the Directorate for Biological Sciences, and the Office of International Science and Engineering.

There has been significant progress over the last few years in understanding many of the detailed dynamical mechanisms underlying mammalian cell motility. These include the role of focal adhesions, the spatio-temporal organization of actin flow, the response of the leading-edge membrane to actin polymerization and conversely the role of myosin minifilaments in creating contractile stress at the rear. It is now an opportune time to combine this knowledge into a mathematical model which can treat the morphodynamics of the whole cell, and correlate motion with both mechanical data (such as traction-force measurements) and sub-cellular signaling information (such as localization data for specific molecular players.) This proposal aims at constructing and validating such a model for endothelial cells. From the mathematics side, the novel element includes embedding all of the aforementioned processes into a moving cell geometry, enabled by the phase-field approach; the latter has shown its relevance in many moving boundary problems in fields ranging from solidification to multiphase fluid flow. Experimental data will be obtained by utilizing state-of-the-art microfluidic devices so as to provide controlled cell environments and will include the measurement of spatial patterns of signaling molecules (location and activation) as well as forces. Model predictions will be tested in a number of different cell lines and in cells subject to a variety of pharamacological treatments.

Obtaining a quantitative understanding of cell motility is of importance for many critical biomedical systems, ranging from cancer metastases to inflammatory response to pathogens. Biophysical tools have reached the point where one can obtain high-quality data about various parts of the motility mechanism; for example, we can measure the forces exerted by the cell on the substrate on which it moves. At the same time, advances in computational modeling have shown how to tackle complex problems involving fluid flow and chemical reactions taking place inside a moving domain. Our proposal aims at combining these two capabilities, experimental biophysics and computational modeling to create a quantitative approach to the motion of a specific type of mammalian cell. Once successful, our methodology could be extended to other cell types and to cells moving in more complicated spaces. The eventual payoff would be both an increased fundamental understanding and an increased capability of affecting cell motility, perhaps to prevent cells from a primary tumor from establishing secondary colonies in target tissues.

The proposal was submitted in response to the Joint DMS/NIGMS Initiative to Support Research at the Interface of the Biological and Mathematical Sciences. The grant is funded by the Program of Mathematical Biology of the Division of Mathematical Sciences and co-funded by the Program Physics of Living Systems in the Physics Division of NSF.

The two day Workshop: "Developing Physical Theories on the Emergence of Drug and Immune Resistance in Cancer" will be a two-day highly-focused meeting bringing together oncologists and physicists with interests in both the theory of resistance and in novel measurement technology that would be used to guide any proposed conceptual framework. The goal of the meeting would be to define the scope of the problem, to present to the physicists the data that is available in the oncology community and to formulate an approach to move forward. The panel of physical scientists and oncological clinicians will develop a road map for probing new avenues towards the exploration of cancer etiology, especially drug-resistant cancers. At the very least, this meeting will serve to catalyze discussions between research scientists who traditionally very seldom communicate, and much less with the same language and/or temporal/spatial scale. The intention is that the meeting will result in; a) new research partnerships between theorists and medical experimentalists, and/or a general consensus that drives more basic oncological research with embedded theoretical modeling and simulation. The later will hasten a more detailed understanding of cancer etiology and perhaps treatment regimes.

The final phase of the chemotactic process results in the actual movement of the cell. This movement involves a complex set of cellular processes and includes the generation of protrusive, retractive, and adhesive forces. The mechanisms underlying these forces are poorly understood, partially due to the lack of quantitative data. For example, it is unclear how Dlctyostellum cells adhere to the substrate, and how the substrate adhesiveness and rigidity affect cell motility. New experimental techniques, however, open up the possibility of examining the forces involved in cell migration and can provide quantitative data necessary for a deeper understanding of cell motility. Our goal in this project is two-fold: the first goal is to determine the forces at the substrate-cell interface and their role in cell motility using novel microfluidics techniques in combination with innovative substrates that allow for simultaneous fraction microscopy and Total Internal Reflection Fluorescence (TIRF) microscopy. The second goal is to use this experimental data to build a comprehensive computational model for cell motility that includes force generation, cell-substrate interactions, membrane properties and cell deformations. As in project 1 and 2, the experimental-computational interaction will be critical to achieving our goals. Specifically, we propose:

The International Conference on Stochastic Processes in Systems Biology, Genetics and Evolution, to be held at Rice University on August 21-25, 2012, will focus on emerging trends within the field of systems biology with a focus on the statistical methodologies and probability models that are most valued within the field. Special attention will be given to emerging challenges in systems biology, such as exploring the role of cancer stem cells in tumor development and progression, characterizing the systems pathways in inflammation which trigger sepsis, models of antibiotic resistance, and many other challenges in genetics and evolution. Symposia Topics: Systems Biology, Genetics and Evolution: New Challenges for Stochastic Dynamics Stochastic Processes for New Biology, Stochasticity of Cell Differentiation and Cell Fates, Stochastic Models of Cancer, Stochastic Gene Expression and Intracellular Signaling Pathways, Self-Organization, Epigenetics & Evolution, Branching Processs in Population Biology and Genetics, Stochastic Theory for Biochemical Systems. Junior researchers, students and under-represented groups are offered travel and subsistence assistance.

Recent years witnessed an explosion of biological data, which allow accurate insight into functioning of living beings at the levels ranging from genetic code to biomolecules, cells, tissues and organisms. Due to these new data, it became possible to understand how different levels of organization (scales) of living beings interact. This new science is called systems biology. From the very outset, systems biology has been more mathematically inclined than traditional disciplines of biology. In particular, it is attempting to understand the role randomness (or stochasticity) plays in functioning of living beings. For example, how is it possible that individual biological cells respond in very different ways to environmental stimuli, whereas the organism as a whole is capable of mounting a coherent response? Answers to this and other related questions are the subject of the conference.

This CREATIV award is partially funded by the Biomolecular Dynamics, Structure and Function and the Networks and Regulation Clusters in the Division of Molecular and Cellular Biosciences in the Directorate for Biological Sciences; the Physics of Living Systems Program in the Division of Physics, the Condensed Matter and Materials Theory Program in the Division of Materials Research, and the Chemistry of Life Processes Program in the Division of Chemistry in the Directorate of Mathematical and Physical Sciences.

The objective of this CREATIV project is to investigate the fundamental question of how intricate protein-based molecular machines can determine cellular-level dynamics for living systems. Specifically, the goal is to create a framework for quantitatively predicting functional consequences of designed changes in protein systems. This project will focus on the decision-making circuitry in Bacillus subtilis as a test case for the thesis that, although biology starts from the molecular scale, it is only at the cellular and multicellular scales that one sees life in action, as a distinct form of matter having goal oriented behavior. This is the level at which evolutionary selective pressures operate. It therefore must be the case that the dynamics at these higher-scales are directly determined by their molecular underpinnings. Exactly how this works has not yet been understood even for simple forms of life such as bacteria. Instead, quantitative systems-biology approaches today remain impoverished of molecular detail and one cannot hope for an understanding of either why things work the way they do, or, often more importantly, how we can intervene at the molecular scale to engineer the system performance. The PIs and their collaborators will apply an integrative approach that combines computational and experimental techniques to bridge this huge gap in our understanding and predictive capability of the quantitative functionality of biological systems. Recent progress on the Bacillus system has for the first time enabled this type of trans-scale approach. At the molecular level, advances in modeling and new ideas utilizing sequence-based data can effectively treat protein-protein interactions and conformational changes associated with chemical function. Cellular-level circuits that govern sporulation and competence have been the subject of much recent interest and there is in place an initial set of ideas regarding the logic implemented therein. Finally, the coupling between each cell's decision-making in overall colony structure is being vigorously studied. This research project is inherently multidisciplinary, combining protein chemistry with signal transduction, combining molecular biology and biophysics with complex pattern-formation physics, and combining non-equilibrium statistical mechanics with synthetic biology. This work is high risk and potentially high pay off. Molecular modelers have stayed away from making predictions as to how specific changes will be manifested at the scale of life, as this was considered to be too hard as compared to explaining in vitro biochemistry data. The results from this project would be transformative, changing how we approach the quantitative analysis of integrated biological systems. It is therefore highly appropriate for the NSF CREATIV program.

The basic knowledge generated from this CREATIV project will be crucial for revolutionizing our ability to control biofilms by molecular manipulation. Biofilm control is crucial for bacteria-based environmental remediation and for modern desalination. This project will provide a fertile ground to expose junior scientists to the challenge of cross-disciplinary research, both theoretical and experimental, which explicitly aims to break down the barriers between different subfields. This will lead to a future workforce better able to face the challenges of modern quantitative biology. Finally, bacterial colony structures and their cellular and molecular underpinnings are a fascinating area with which one can draw the public into contact with the ideas of modern science.

Conference: Cell Decision Making Workshop, Arlington VA, June 10-11, 2013.
Cells from across the biological kingdoms are continuously engaged in the process of decision making, by which is meant that cells take information from their surroundings (including neighboring cells), process this data through complex signal transduction and genetic circuits, and modulate their cellular phenotypes in response. Decision making implies that choices are made from competing options and that once made, these choices have some degree of persistence even as conditions change. This workshop will bring together theoretical and experimental scientists to discuss major issues in cell decision-making processes and the new approaches that may be employed to study these issues. This workshop will serve to catalyze discussions between research scientists with shared interests, but working on very different cell systems (eukaryotic vs. prokaryotic). Broader impacts. The workshop will point the direction to new research partnerships between theorists and experimentalists, and help develop a consensus for this field of research driven by the similarities in the biology of diverse cellular systems. The workshop organizers will write a report summarizing the status of the field, including the limits to current understanding; identification of the key questions for future research efforts; and the barriers to be overcome as the field moves forwards. The workshop supports the goal of broadening participation by the inclusion of women and members of groups under-represented in science.
This award is supported by all clusters in the Division of Molecular and Cellular Biosciences and by the Physics of Living Systems Program in the Division of Physics.

The Workshop: "Physical and Mathematical Principles of Brain Structure and Function" will take place between May 5 and May 7, 2013 in Arlington, VA. Understanding how the human brain works has emerged as a major international focus of research in the coming decade, identified as such in President Obama's State of the Union Address in February 2013 and further developed in President Obama's BRAIN initiative announced on April 2, 2013. This workshop will bring together more than one hundred scientists to discuss how to enable major progress in understanding the brain, an important intellectual challenge of the 21st century. This conference of leading neuroscientists, mathematicians, physicists, materials scientists etc. will identify the specific intellectual challenges that can be met in the coming decades with focused effort. Panels of neuroscientists with expertise in different experimental approaches and model systems will identify important long-term goals that would transform their respective fields and drive progress across neuroscience. In addition, many important questions in neuroscience cannot be pursued with current tools. Bringing together neuroscientists and technologists will catalyze discussions that spur us towards transformative new scientific insights. Advances in systems neuroscience made by integrating existing technologies and devising new methods will provide an intellectual foundation. The workshop will also include many young scientists along with the established leaders in the field.

This project is being jointly supported by the Physics of Living Systems program in the Division of Physics in the Mathematical and Physical Sciences Directorate and by the Division of Integrative Organismal Systems in the Directorate for Biological Sciences.

Imaging plays a critical role in the diagnosis, staging, and in the assessment of therapeutic response in cancer. Imaging is of course a broad discipline encompassing a variety of rather different modalities (X-ray, MRI, PET) and analysis techniques. Principles from the fields of physics and mathematics can be applied to the analysis and interpretation of current imaging techniques as well to development of novel imaging techniques. A key issue for the field is the extent to which different methods can be used synergistically to gain additional information. Another key issue is improving the usefulness of specialized contrast agents to get around existing limitations in signal to noise and/or spatial resolution. To address the aforementioned challenges, the organizers will convene a two-day focused workshop to be held in the Boston area. The two-day highly focused meeting will have a full agenda of topics at the intersection of physics and mathematics and cancer imaging. The meeting will be oriented around a high level of interactions between participants, focusing on problems where fundamental physical and mathematical principles and advanced imaging can be leveraged to make progress towards cancer diagnosis and treatment. Most of each session will be devoted to active discussion within a small group of invitees, who span both the physics and engineering of advanced imaging and biologists and clinicians at the forefront of cancer biology and treatment. This will be the first informal workshop that tries to create an integrated picture of what can be accomplished via noninvasive methods in human patients. It is expected that the white paper generated as part of the meeting follow-up will have a very large impact on the direction of scientific research in this essential area. Bringing together experts from different parts of this field can be expected to lead to new directions and ultimately better imaging "products" for the practicing oncologist. At a more basic science level, it is expected that the ideas generated may be useful for other applications of imaging in biology and biomedicine. To facilitate the spread of ideas generated by this meeting to the rest of the community, synopses of various talks as well as an overall summary will be posted at http://www.martinos.org/martinos/poahi/ and linked to the community Physics of Cancer website: http://physicsandcancer.org/

It has been discovered that cancerous tumors are capable of enrolling support from "normal" cells of the host organism. Some of these cells are then reverting to normally suppressed behaviors such as mobility and invasion as well as resistance to cell death. In the process, cells also lose ability to organize themselves into sheets and other structures common in normal tissue. This process is known as the epithelial-mesenchymal transformation (EMT). Motivated by this example, the investigators developed an experimental model of one type of EMT and, along with biological experiments, are now able to reproduce some features of EMT in computers, i.e., to model the EMT mathematically. In the current project, the investigators pursue research based on these preliminary results. These experiments and computer models give rise to a better understanding of signaling processes and, in some cases, leads to better predictions of the effect of treatments on behavior of cancer cells, thus helping advance the fight against cancer.

In more technical terms, the objective of the proposed research is multidisciplinary and multiscale analysis of the Epithelial Mesenchymal Transformation (EMT). EMT is the process by which epithelial cells reversibly lose baso-apical polarity and cell-cell junctions, acquiring plasticity, mobility, invasivity, stem-cell characteristics, and resistance to apoptosis. This mechanism is important in embryogenesis, as well as in wound healing and in cancer metastasis. The investigators are particularly interested in the role of NF-kB and p53 and their crosstalk in cancer-related (type III) EMT. The goal is to build a mathematical model that will relate signal transduction pathways to changes in cell behavior, focusing on observing and modeling cell motility. An experimental system is developed to measure motility and proliferation using the new Cell Tracker software and Lineage Tracker for quantitation. Gene expression and flow cytometry measurements will be included. Preliminary data show activation of the NFkB pathway increases motility. Results of the project can be used to reduce cellular invasion in epithelial malignancies, or sensitize cancer cells to chemotherapeutic agents. Although the current study has a basic nature, the resulting insights will inform biomedically oriented applications.

Loss of functionality is ubiquitous across Nature, from aging in organisms to the decay of human engineered systems. With time, plants and animals lose functionality and die, mountains erode, buildings and devices structurally fail and decay. In many nonliving systems general principles have been articulated that govern this loss of functionality and these may be applicable to aging. In biological systems, however, a multitude of scenarios and myriads of mechanisms have been proposed to explain the deterioration of the architecture and function of organisms. Looking at mammalian aging from a systems level viewpoint is a critical component in the search for general principles and "levers" that control the system, including the paths to alter the processes leading to aging. A vast amount of experimental data has been accumulated and, with the development of better experimental techniques during the past 20 years, quantitative data is being collected that can be used to design further experiments and develop quantitative theories of aging. The experience in physics is that when one integrates the details of sub-system dynamics into a more holistic systems level approach and search for underlying principles that govern physical processes we gain deeper insight into developing falsifiable theoretical understandings of Nature. This methodology could provide new and important insights into understanding biological aging.

The Workshop: "Connecting the Biology and Physical Principles of Mammalian Aging" will bring together approximately 25 scientists. Approximately half of them will be biologists and half physicists. The meeting will focus on model systems relevant to mammalian aging. The workshop will have discussion of the current understanding of aging, the relevant data, and future directions. Topics of interest to the discussion, but not limited only to these, are centenarian aging, premature aging, cancer and aging, etc. Other questions that could be of interest are the aging of species as a whole. It seems that the human gametes have not aged for millions of years, that Life as a whole on Earth has not aged, and that perhaps the principles of information copying, death of the individual carriers of information, and evolutionary processes together defy the aging of Life. Young scientists who are open to presenting and discussing new, possibly speculative, ideas that will lead to a new perspective on aging will participate at the workshop. The mixed composition of the participants will stimulate new research ideas. The talks and discussions at the workshop will be recorded and made available to the public.

Theoretical physics has become increasingly important in understanding complex living systems and is positioned to play a key role in addressing phenomena and behavior on the cellular and multicellular level. Investigations on this scale can also lead to new fundamental theoretical physics principles and advances. This Physics Frontiers Centers (PFC) award to the Center for Theoretical Biological Physics - Houston (CTBP-H) will continue work begun during the past PFC awards at the interface of theoretical physics and biology. The CTBP-H will use information from biomolecules, self-organization in living and non-living material, and non-equilibrium statistical physics in order to create a theoretical biological physics framework for cells and multicellular units. Through interactions with local medical institutions the work can impact biomedicine. Investigations of the self-organization of small-scale matter can impact nanoscale technology and material design. The CTBP-H will continue to provide unique training and fostering of young scientists in biological physics. It will support postdoctoral, graduate, and summer undergraduate research, and also reach underrepresented groups at the University of Houston. In addition, the CTBP-H will act as a focal point of scientific community activities, hosting a visiting scholars program, running workshops, and coordinating student networks.

The CTBP-H will be working to find new fundamental principles and paradigms to understand the complex behavior of cells, as well as the coordination of cells into multicellular functional units. The major research activities include: advancing the understanding of gene-based information storage and utilization, developing theoretical frameworks for the mechanical aspects of eukaryotic cells, and combining these insights to study the self-organization of cells into multicellular biofilms and tissues. In collaboration with local medical centers they will apply their newfound insights from biological physics in biomedical contexts.

This Physics Frontiers Centers award is co-funded by the Physics Frontiers Centers Program in the Division of Physics, the Chemical Theory, Models and Computational Methods Program in the Division of Chemistry, and the Condensed Matter and Materials Theory Program in the Division of Materials Research within the Directorate of Mathematical and Physical Sciences, and by the Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences within the Directorate for Biological Sciences.

From Friday, January 9, 2015 Sunday to January 11, 2015 the Conference: "Dynamics Days" will be hosted by the Center for Theoretical Biological Physics (CTBP), an NSF Physics Frontier Center. Located in Houston with participation from Rice University, the Baylor College of Medicine and the University of Houston, the CTBP mission is to foster the convergence of physics and biology to make sense of complex living systems. At the same time, results from this research will feed back into physics in general, and help develop new ways of thinking about all complex system phenomena. The conference will be attended by 100-200 people, with the core of the audience consisting from physicists and mathematicians, but including a substantial number of people from other fields such as engineering, biology, and chemistry. The conference format consists of a single plenary session. Topics covered in the conference will include dynamics on and of complex networks, nonlinear dynamics of biological systems, synchronization and self-organization of nonlinear systems, geophysical fluid dynamics, and pattern formation. This conference is essential for maintaining coherence among all the disparate researchers involved in using physics and mathematics to make sense of complex systems. Thus, researchers focusing on the Physics of Living Systems (PoLS) will be able to interact directly with researchers who may be pioneering new methods, in other contexts. Conversely, scientists who have never been exposed to the enormous challenges encountered in the biological realm will get to hear talks by leading PoLS researchers and may have much to offer. Even as the PoLS field reaches out to the biology community, maintaining ties with physics remain a high priority. Dynamics Days will help make sure that this occurs. This meeting will bring together scientists actively engaged in Dynamics research. Most of the participants in Dynamics Days will be students and postdocs coming from a broad spectrum of the community. They will all be expected to present posters on their own research work. The most immediate broad impact will be on broadening the educational experience for the junior participants. In addition, local undergraduates, both from Rice and from the CTBP's existing network of collaborating minority- and Hispanic- serving institutions will be invited.

Olfaction is an evolutionarily primitive sense critical for survival across the animal kingdom - finding food, searching for mates, or avoiding predation all depend on detecting, identifying, and discriminating odors. Although early steps in olfactory processing are relatively well understood, significant gaps remain in our understanding of higher-order odor representations and processing during on-going behavior. Deciphering the operating principles of olfaction requires the development of innovative and integrative approaches that combine novel theoretical frameworks, improved mathematical models, and novel behavioral paradigms across the phylogenetic spectrum, experimental methodologies, and engineering principles. The objectives of this 5-day workshop, a so-called "Ideas Lab", is to address this challenge by bringing together researchers from diverse scientific backgrounds to engender fresh thinking and innovative approaches that will transform understanding of olfactory processing in behavioral contexts while spawning new opportunities to elucidate the general nature of sensory representations in the brain. The participants will work collaboratively to develop and hone novel ideas about and approaches to investigate olfactory processing, and then use these ideas and approaches to develop multidisciplinary research projects that contain genuinely innovative and potentially transformative investigations on olfactory coding.

The organizers will make a strong effort to invite women, members of underrepresented groups, and investigators at all academic levels as workshop participants. Participants will include 10-15 quantitative researchers and 15-20 neuroscientists. An integral aspect of the workshop is extensive cross-disciplinary interaction, which will be facilitated by five leading scientists from key disciplines who have agreed to serve as mentors and will guide the project development process. Importantly, this workshop is part of a concerted effort to coordinate and align interagency priorities to accomplish the goals of the BRAIN Initiative. The workshop is anticipated to result in the development of highly innovative research proposals that integrate theoretical and computational approaches with neuroscience toward the goal of elucidating the nature of olfactory processing and sensory representations in the brain in general.

Biological aging is characterized by loss of structural integrity and functional decline with time. It is generally believed that these changes occur gradually with age, leading to the eventual death of the organism. Engineered physical systems also change as time passes, again losing structural integrity and eventually failing to perform their designed function. This workshop will explore the extent to which general ideas regarding these processes can be applied to both living and nonliving systems. There have been many proposals regarding the underlying mechanisms of biological aging, most of which focus on a single molecular process. For example, much work has gone into the issue of telomere shortening as a very specific driver of cellular senescence. However, much of this work begs the central question of whether aging is an inevitable consequence of the physical and chemical processes that take place during life or alternatively whether it is a modifiable consequence of a genetic and/or epigenetic program that is being executed by the cells. Most engineered systems fail not because of prior programmed deterioration of its parts, but because of the natural physical processes that take place when complex systems interact with each other. Are living systems similar? These are the questions that the workshop will address. There are several types of aging processes that take place in physical systems. Erosion, corrosion, and structural defect formation are some of the mechanisms contributing to diminished structural integrity, decrease in fidelity and eventual failure of physical devices. Different systems are subject to different mixes of some of these fundamental mechanisms. In living systems, different parts of an organism age differently. For example, the immune system, the skin, and other organs subject to continuous cell renewal, are believed to age due to diminishing cell proliferative capacity. The intracellular mechanisms responsible for the reduction of the proliferative potential of the cells comprising the tissue are not well understood, although many "theories" exist of how such reduction could be brought by the physical and chemical processes taking place in a cell. On the other hand the knee of an animal ages in a different manner. In this case the friction brought by continuous use leads to wear of the cartilage, and it gradually becomes harder and harder to use as a joint. In the first example of aging the organs become more susceptible with time to various diseases and eventually lead to disease related death. In the second case the animal cannot compete with its predators and gets consumed by them. As their parts fail, biological and mechanical systems can and often are repaired. However, the repair process is also by its nature prone to errors, and cannot keep up indefinitely. How many cars from the 1950's are still operational? This seems to be true both at the individual level and at the species level. But, if we consider life as a whole, evolution seems to have defied this fundamental limitation and life on Earth has been flourishing for most of the history of the planet. Is this just a question of our limited experience with life or will evolution always find a viable strategy.

In this workshop that will take place May 7 - 8, 2015 at Tysons Corner in Virginia. Approximately 25 scientists representing Physics, Materials Science, and Biology will discuss the physical principles and processes underlying aging in living and nonliving system, the similarities and differences between living and nonliving systems and their repair and failure. The workshop participants will discuss what is the relation between non-equilibrium thermodynamics and aging, is there a role for information theory in describing the aging process and how is this information preserved in life as a whole, and finally are there lessons for robust technology development that we can learn from living systems. The workshop especially seeks to have representation at the workshop of young scientists, who will bring their perspective on aging and learn from more experienced colleagues.

Title: Workshop: Systems and Synthetic Biology for Designing Rational Cancer Immunotherapies

Advancing fundamental understanding of cancer biology necessary to formulate a comprehensive strategy for break-through cancer treatments requires that the field embrace an interdisciplinary course of action. This workshop will provide a platform that would allow participants from various scientific, engineering, and medical fields to discuss the most pressing needs and potential solutions for the rational design of personalized cancer therapies using recently developed tools from the field of synthetic biology. By bringing together basic researchers in physics, synthetic biology, and systems biology and oncologists at the forefront of their respective fields, this workshop will catalyze new collaborations that will speed the pace of discovery and translation in cancer treatment. The workshop organizers have made a particular effort in including younger scientist known for their creative and unbiased perspective. Balance in demographics and gender are addressed as well. This is a laudable effort to bring new insights and perspectives to cancer biology and treatment

This award will fund a two-day workshop to discuss the use of synthetic biology to cancer immunotherapy. Leading systems and synthetic biologists, physicists, mathematicians and cancer immunologists will come together to brainstorm on how to develop novel approaches to reprogramming the immune system to fight cancer. The workshop will be held at the Hyatt Hotel at Tysons Corner in Virginia where 25-30 participants will meet on October 6-8, 2016. The attendees include a diverse group of scientists, engineers and physicians from the US and international institutions.

This award is supported by the Physics of Living Systems Program in the Division of Physics, and the Systems and Synthetic Biology Program and Molecular Biophysics Program in the Division of Molecular and Cellular Biosciences.

Cancer becomes deadly when tumor cells become motile and begin to spread throughout the patient's body. To become motile, cells must undergo radical changes in their composition and behavior, the so-called epithelial-mesenchymal transformation (EMT). These radical changes arise as the network of genes controlling the state of the cell transitions from one type of stable fate to another. This project details a joint theory-experiment physics-biology effort to study how EMT is coordinated in space and time by chemical signals passed among the tumor cells. The specific focus here is on the Notch signaling pathway. This pathway has been studied extensively for its role in developmental biology and has been implicated indirectly in cancer, but has never been studied systematically in this context. The hypothesis to be investigated is that this pathway can allow the formation of small clusters of cells that have undergone EMT together, and which thereafter travel as a collective en route to the establishment of a secondary tumor. If proven to be true, these ideas will shed light on the fundamental origins of metastasis and might in the future offer new strategies for both prognosis and treatment.

Cell-cell interactions, both between tumor cells proper and between tumor and stromal cells, are known to be a key component of many solid tumors. The investigators will focus on how one of these interactions, that mediated by the Notch pathway, can coordinate cell phenotypes and can thereby control tumor progression. To accomplish this will require the use and extension of sophisticated theory techniques from the field of non-equilibrium pattern formation coupled to an experimental plan focused on pancreatic cancer cell lines to be studied in both 2d and 3d in vitro conditions, both without and with supporting cancer-associated fibroblasts. Of particular importance will be measuring spatial correlations of EMT state (and other known correlates) and comparing these to expectations based on different signaling assumptions. Iterating these experiments with increasingly realistic model-building and model-solving will allow for the creation of a quantitatively reliable picture for the collective behavior of the tumor, going well-beyond current individual cell approaches.

This project is cofunded by the Physics of Living Systems Program in the Physics Division and the Molecular and Cellular Biosciences Division at NSF.

The success of the BRAIN initiative will depend on widespread access to the technological advancements, computational tools, and data sets created by the initiative. However, there are no existing mechanisms for providing national access to the increasingly technologically and computationally oriented investigations of the brain. The barriers to entry are both financial and structural: not only is technologically intensive neuroscience costly, it requires an investment in physics, engineering and computer science beyond the scope of individual laboratories. This prevents the community's efficient utilization of current technological capabilities and limits the questions and hypotheses that will drive the next generation of innovation. Thus there is a need to counteract the widening gap between the small fraction of laboratories developing and utilizing the most recent technology and the remaining majority of neuroscientists. The successful removal of the gap will require a sophisticated national clearing house to ensure that the correct physics, engineering, and computer science tools are vetted and freely accessible for measurements of brain structure and functions. Successful accomplishment of these goals will require an iterative process whereby specific needs of the neuroscience community will be identified and either paired with the appropriate scientific, technological and computational resources or pipelined for potential future innovation. The model for the operation of this project will be a user facility, housed at Argonne National Laboratory (ANL), and leveraging the existing resources of their science facilities. This award provides funding for seed grants for infrastructure development, conferences, education, and outreach.

The team will enlist the Physics of Living Systems community, most specifically the young scientists therein, to join the neuroscience research effort by connecting to the graduate research network led by the NSF Physics Frontier Center for Theoretical Biological Physics. In order to engage and train a broad community, several annual conferences will be held that will cover a broad range of topics in imaging and quantitative neuroscience. The team will augment the program run by the UC Neuroscience Institute to teach Neuroscience to local 7th/4th graders. Almost all of the students in the target schools are African American and live in the local South Side community. ANL will partner with this endeavor by support through its own educational programs, but for the first time broaching the technology of neuroscience.

This RAISE project is jointly funded by the Chemistry of Life Processes Program in the Division of Chemistry, the Physics of Living Systems Program in the Division of Physics, the Cellular Dynamics and Function and the Molecular Biophysics Clusters in the Division of Molecular and Cellular Biosciences, the Neural Systems Cluster in the Division of Integrative Organismal Systems, the Division of Emerging Frontiers, the RAISE Program and the Office of Integrative Activities.

This award is funding Professors Peter Wolynes, Margaret Cheung, Michael Diehl and Herbert Levine at Rice University and M. Neal Waxham at University of Texas (UT) Health-Houston to investigate the molecular mechanisms of learning and memory. The initiation of learning begins with changes at neuronal synapses that can strengthen (or weaken) the response of the synapse. This process is termed synaptic plasticity. Stimuli that produce learning lead to structural changes of the post-synaptic dendritic spine. The initial events of memory and learning include a temporary rise in calcium concentrations and activation of a protein called calmodulin. The next step is activation of calmodulin-dependent enzyme, kinase II (CaMKII). At the same time, structural rearrangements occur in the actin cytoskeleton leading to an enlargement of the spine compartment. How these initial events lead to remodeling of the actin cytoskeleton is largely unknown. This project focuses on the events that lead to the changes in actin cytoskeleton. The research also addresses the question of how these structural changes in the actin cytoskeleton are used to maintain memory. State-of-the-art computational modeling is used to answer these questions. Modeling is applied at molecular and supra-molecular scales. The models examine molecular changes that bridge the time scales between the initial steps and start of synaptic plasticity. The computational modeling goes hand in hand with state-of-the-art structural and functional imaging and biochemical pathway analyses. The research allows graduate students and postdoctoral fellows to acquire specialized training in computer simulations and mathematical modeling of a subcellular system. The students and fellows acquire an understanding of the brain starting from a molecular level. The team of theoreticians and experimentalists working cooperatively on this problem strengthens the training process. This project is integrated into an outreach program to introduce undergraduate students from underrepresented groups to science by participating in the research.

This research project quantitatively characterizes the relevant molecular processes involved in the dynamical "tectonic" reorganization inside a dendritic spine involved in forming memories. It focuses on the actin cytoskeleton using computer simulations and experimental analyses at both molecular and supra-molecular scales. This study therefore contributes directly to understanding the role of mechanics and structure in synaptic plasticity and learning and memory. Explicitly, the hypothesis is that the transient effects from calcium influx create, in a CaMKII-dependent manner, changes in the spatial patterning of the actin structure. Such changes may be be stabilized by feedback loops with prion-like proteins. These stabilized structures may be a type of "structural engram" which then serves as long-term reservoir for maintaining enhanced synaptic strength in the postsynaptic neuron. Testing, modifying, and verifying this hypothesis may help point the way towards a more quantitatively-sophisticated approach to the first stages of learning and memory in the brain.

The physicist Richard Feynman is often credited with the remark 'What I cannot create, I do not understand'. The recent history of cell biology is one in which cells have been studied at increasingly simpler and fundamental levels through 'reductionist' experimental approaches. The purpose of this workshop is to utilize that knowledge to address the Feynman dictum and begin the process of building synthetic cells to more fully understand the functions of their natural counterparts. This has the exciting possibility of not only advancing our understanding of biology and regenerative medicine, but also impacting significantly our food security and biomanufacturing industry.

This project will bring together leading scientists from disparate fields of research including cellular and synthetic biology, chemistry, physics, mathematics and bioengineering to plan the construction of synthetic cells. They will address many different questions including 'what is the minimum set of genes, proteins, organelles, small molecules necessary for a cell to function?' and 'what is the minimum set of activities that would define 'function'' among others? By the end of the meeting, the participants should have identified key barriers to success as well as opportunities where concentrated effort could significantly advance the field. They results of the workshop will be a video record of the proceedings, a written report highlighting obstacles and opportunities and the state of the field, and a plan for future collaboration to leverage the work started at the workshop.

The workshop is jointly funded by the Cellular Dynamics and Function Program in the Division of Molecular and Cellular Biosciences and the Physics of Living Systems Program in the Division of Physics.

Olfaction is an evolutionarily primitive sense critical for survival across the animal kingdom - finding food, searching for mates, or avoiding predation all depend on detecting, identifying, and discriminating odors. Although early steps in olfactory processing are relatively well understood, significant gaps remain in our understanding of higher-order odor representations and processing during on-going behavior. Deciphering the operating principles of olfaction requires the development of innovative and integrative approaches that combine novel theoretical frameworks, improved mathematical models, and novel behavioral paradigms across the phylogenetic spectrum, experimental methodologies, and engineering principles. As part of the BRAIN Initiative, a 5-day focused Ideas Lab workshop was organized in Summer 2015 to bring together researchers from diverse scientific backgrounds to engender fresh thinking and innovative approaches that will transform understanding of olfactory processing in behavioral contexts while spawning new opportunities to elucidate the general nature of sensory representations in the brain. The workshop resulted in three awards to a total of 17 researchers in three project teams. This current workshop brings together the awardees, trainees and experts in Physics, Engineering and Neuroscience to share the exciting developments and findings from the projects.

The workshop features investigators at all academic levels with a mix of quantitative researchers and neuroscientists. An integral aspect of the workshop is extensive cross-disciplinary interaction. Importantly, this workshop is part of a concerted effort to coordinate and align interagency priorities to accomplish the goals of the BRAIN Initiative. The workshop is anticipated to result in sharing of knowledge and development of integrative team approaches to tackle the nature of olfactory processing and sensory representations in the brain in general.

The research will discover the rules for building ecosystems that cycle carbon. Life on Earth is sustained by a global carbon cycle. Understanding how and why this cycling is maintained is a critically important question given the growing impact of human activity on carbon dioxide levels in the atmosphere. Carbon cycling happens through two processes: photosynthesis which creates sugars and biomass from carbon dioxide, and respiration which converts sugars and biomass back to carbon dioxide. Remarkably, roughly half of all of the photosynthesis on the planet is performed by microbes such as algae. Algae provide carbon in the form of sugars and other compounds to bacteria. The resulting growth of bacteria is not only essential for the health and function of nearly all ecosystems on the planet but key to the global carbon cycle. Despite the critical nature of this interaction, the principles that govern how carbon flows from algae to bacteria and back are not known. The project will uncover these principles using closed microbial biospheres: hermetically sealed microbial communities that sustain a carbon cycle between algae and bacteria when provided with only light. Uncovering these rules will open the door to predicting, designing, and controlling carbon flow through microbial communities with applications from modeling global carbon cycling to biofuels. The research is accompanied by a new curriculum that is directed at bringing cutting-edge experimental and data science methods to students of Ecology and Evolution as well as accessible demonstrations of scientific ideas to middle school age students.

The research objective of this proposal is to discover the design principles governing carbon exchange between algae and bacteria and to apply these principles to build synthetic communities with predefined carbon cycling capabilities. A key roadblock to unlocking the power of microbial communities is that we do not know how genomic structure determines metabolic function. The project combines carbon-cycling closed microbial communities, high-throughput measurements, and machine-learning to discover the key genomic features (pathways and taxa) that enable carbon exchange between algae and bacteria. The outcomes of the project will be to: (1) Combine machine learning and high-throughput measurements of carbon cycling to predict carbon exchange between algae and bacteria using taxonomic and metagenomic information and to test these predictions in synthetic consortia; (2) Dissect the interactions that sustain carbon exchange in algae-bacteria communities by exploiting a massively parallel droplet microfluidic platform to measure thousands of interactions; and (3) Leverage these insights to construct a consumer-resource model of carbon exchange and predict the impact of algal mutations on carbon recycling.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.