Intellectual Merit: Transport phenomena are relevant to all levels of biological organization and span length and time scales ranging over many orders of magnitude. Examples on one end of this range are molecular processes such as the transport of ions across cellular membranes and on the other end, migrations of birds and animals over inter-continental distances. A common feature of these phenomena is their intrinsically stochastic (random) character and the structurally complex and dynamic environments in which they occur. A single-celled organism moving in search of favorable conditions relies on stochastic molecular-level, receptor-binding events to determine its direction of motion at each moment, which introduces randomness to its overall trajectory. Thus, randomness at the molecular level produces randomness at the cellular level. Furthermore, the complexity of dynamic environments leads to surprising transport behaviors. Such observations suggest the hypothesis that stochastic processes at one level of organization can manifest themselves in stochastic transport phenomena at higher levels of organization, in predictable ways. This project will develop a versatile theoretical framework, based on the physics of diffusion, to investigate these ideas at three distinct levels of biological organization. At the molecular level, this project will explore how stochasticity influences transport by the molecular motor kinesin and also the collective transport behavior of multiple motors pulling the same supra-molecular cargo. At the cellular level, the project will characterize the motor-driven transport of cargo across the cell along cytoskeletal networks which, to first approximation, are considered static or, more realistically, are changing over timescales comparable to the transport process itself. Finally, at the multi-cellular level, this project will develop models to explore the role of cellular communication and spatial complexity in transport-driven pattern formation in multi-cellular communities of cyanobacteria moving toward a light source.
Broader Impacts: A fundamental understanding of the basic physics of transport at the molecular, cellular and multi-cellular levels of organization will have broad significance for biological research and biotechnology, in particular for the optimal design and control of transport processes. In addition, the general theories arising from this research will have implications for such problems as information transfer and routing on dynamic computer networks and the spreading of populations on large-scale, dynamic ecological and human networks. The PI and Co-PI will also engage in a variety of outreach activities within their institutions and in the local region. The PI will continue to develop and teach a successful and innovative calculus-based, freshman-level physics sequence for biological science majors, that uses biological examples to motivate and illustrate physical concepts. The course will be further developed with the addition of new computational labs and a flash-animation based, interactive website that allows the students to explore physical concepts and their biological connections on their computers. The PI will partner with local community colleges to train instructors in the use of these new course materials, which are designed to add an exciting, quantitative focus to the introductory life science curriculum. Additional outreach activities are targeted at local high schools and, in conjunction with the Co-PI, at high schools in the Bay Area, especially for women and students from underprivileged socioeconomic backgrounds.
Intellectual Merit: This award supported research work exploring transport phenomena in biology across many length and time scales, ranging from molecular motors within our cells to communities of collectively moving organisms such as bacterial biofilms. The research specifically focused on the importance of noise (stochastic effects) and the complexity of the environment and how that affected transport. The research specifically addressed (i) transport within cells driven by groups of molecular motors on a single cargo (ii) transport on cellular scales across complex protein filament networks and (iii) the movements (motility) of communities of bacteria. The research team developed a comprehensive computational model to simulate cargo with multiple motors specifically taking the geometry of attachment and interference between motors into account. The model has been able to give quantitative explanations for experimentally observed phenomena and the analysis enabled the prediction of a novel mode in which groups of motors could work to avoid obstacles. For the problem of transport on cytoskeletal protein filament networks, computational models of explicit cytoskeletal networks were built to study the transport time of cargo to reach specific locations in the cell as a function of the motor properties and the network properties (filament length, density, orientation, topology). Extensive simulations were able to show that the network properties can be designed to optimize transit time and minimize the effects of noise. To study community motility in bacteria, the researchers successfully developed computational platforms for modeling motion biased by light gradients (phototactic) focusing on both single-cell behavior and community behaviors. The researchers have shown that communication can be achieved via surface modification without changes in gene expression or direct chemical signaling and that this is sufficient for collective motility. In keeping with the broad nature of the grant, the research team have also examined stochastic transport in other systems, including (a) cargo transport through the nuclear pore complex (NPC), (b) disordered protein translocation through bacterial cell walls, (c) behaviorally heterogeneous swarms and swarms in spatially disordered environments (d) collective foraging and (e) drug delivery.Twelve papers have been published and three more are in various stages of peer review. The work produced has potential significance not only for communities of researchers interested in molecular motors, proteins and bacteria but also for a broader range of disciplines. For instance, the specific physical basis and regulatory mechanisms of achieving collective motility uncovered in phototactic bacterial communities may have relevance for a wide variety of systems, including developing embryos, wound healing cells, and other bacterial communities. The findings on the effects of environmental disorder and behavioral heterogeneity in swarming can have impact on fields ranging from evolution of swarming behavior in birds and fish to the robotics of drones and the results on collective foraging have implications for ecological and environmental systems where hunting and foraging in large groups is important. Broader Impacts: This award has been instrumental in providing training in computational and theoretical biophysics research to a number of students at all levels. In particular, it has helped four postdoctoral scholars develop the skills necessary for being independent researchers and educators. Three have gone on to pursue further postdoctoral research while one has started as a junior faculty at a research university. Three graduate students have made good progress toward their Ph.D's. The project also provided research opportunities for a number of undergraduate students who were involved both in research and outreach activities. Under the auspices of the grant, the PI has continued development of a introductory physics sequence for biology majors and further developed and taught a new course on Biophysics, an interdisciplinary, co-taught graduate and undergraduate, physics and biology course. Students in the course formed interdisciplinary teams and worked on projects throughout the course. Lecture notes, lab worksheets and computational project material from the courses have been made available and disseminated. Both PI and co-PI have served as principal organizers of international workshops at the Aspen Center for Physics. Under the auspices of these workshops, they organized public lectures about biophysics, provided interviews with science writers and journalists and helped organize programs for kids to learn about science. The Co-PI’s group has organized science outreach sessions with elementary schools in the local California Bay area, serving a diverse population, including a large fraction of underrepresented minorities.
