We developed criteria for the selection of our Driving Biological Projects (DBPs). Our portfolio of DBPs should individually, or in aggregate, satisfy these criteria.The criteria below drove our choice of our initial DBPs, and will drive our choice of problems throughout the life of the Center.
- Canonical The problem should be an archetype of the problems that occur in an entire field of inquiry, so that results are guaranteed to have broad applicability.
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Cover a range of scales To exercise our capabilities and identify our shortcomings in multi-scale modeling, it is critical that each DBP have some range of scales at which questions can be posed.
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Physics-based The DBP should present a problem that can be addressed by representing and analyzing the geometry and physics of the biological system.
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Be data rich Biology is dominated by experimental data. These data provide the real-world constraints that drive and validate models and simulations.
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World-class, engaged experimentalists Although the RFA allows distributed groups, we feel that a key strength of our Center is the initial density and proximity of computational and experimental investigators. This allows for close integration and deep interactions among the participants. As the Center matures, we will seek partners at other institutions.
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Collectively cover a broad area of biophysical modeling Because the goal of the NIH is to create a handful of centers that, together, cover most of NIH-supported science, we have endeavored, even in our initial DBPs, to show that we will create an environment relevant to molecular biologists, cell biologists, neurologists, neuroscientists, and surgeons. There are holes in our current menu of DBPs, as they are limited to four. We are aware of these gaps and will fill them as we recruit new DBPs from around the country.
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Have important implications for disease We will ensure that our DBPs are related to disease processes or treatments, to ensure that they contribute to the overall advancement of human health. In our initial set, RNA structure has implications for rheumatologic diseases, myosin dynamics is important for understanding myopathies and the generation of motive force throughout all organ systems, neuromuscular dynamics must be understood to better treat movement disorders such as cerebral palsy, stroke and ParkinsonÕs disease, and cardiovascular dynamics has important implications for coronary artery and peripheral vascular disease.
Our four initial DBPs satisfy these criteria and are briefly reviewed here:
RNA FOLDING
This project represents a macromolecule-scale study of the process of folding. It is ultimately relevant to RNA, DNA and protein, but focuses on RNA as an intriguing experimental system. The folding of RNA is a function of the physical forces that act on it. Dr. Herschlag has assembled a world-class team from the Stanford Departments of Biochemistry, Genetics, Physics, and Applied Physics. Three external scientists (Drs. Pollack, Brenowitz, and Chance) are also participating. The importance of RNA function has recently been magnified with the discovery of RNA inhibition and a large number of microRNA genes. RNA, even more than DNA, seems to implement its functions using complex structural strategies. Although the primary scale of the RNA work is at the atomic level, certain computations are too expensive to perform atomistically; thus, the project requires coarse-grain representations in which, for example, a single base is represented as a ball, or a segment of A-form double helix is represented as a cylinder.
MYOSIN DYNAMICS
This project represents a scale that is one order of magnitude larger than RNA. Myosin is a large protein, and, in a muscle cell, organizes itself into fibers. Myosin represents the fundamental source of motive force in many living systems, and so its biological importance is high. It is fundamentally a physical problem: how does the cell turn the chemical energy of ATP into movement? Experience with myosin will no doubt improve our ability to address other molecular machines. Dr. Spudich has a distinguished history as a leader in the field of myosin biology. The relevant scales for myosin range from Angstroms to nanometers, as the molecules assemble into larger aggregates. Dr. Spudich's project uses a range of experimental biochemical, molecular biological, biophysical and genetic experimental techniques to approach this problem, so there is ample data, and (like the RNA project) a very real opportunity to collect additional data if it should be required by the modeling and simulation effort. Although this is an extremely challenging system to simulate, we have already begun preliminary work on this project through an internal seed grant.
NEUROMUSCULAR DYNAMICS
The range of scales relevant to this problem is impressive: the precise physical properties of a muscle cells at the micron scale, all the way to the macroscopic forces generated by muscles on the scale of centimeters. Although this DBP focuses on walking, the findings will be generalizable to other motor control systems. The modeling of human motion is a biomechanical and physical problem, and Dr. Delp is a pioneer in the development of methods for modeling motor systems. The functional implications of this work are paramount: a primary application of this work is in the planning of interventions to assist patients with abnormal movement dynamics, including children with cerebral palsy, and adults with stoke and Parkinson's disease. Advances in imaging and instrumentation provide rich data sets for building and evaluating neuromuscular models.
CARDIOVASCULAR DYNAMICS
This project represents scale from millimeters to meters, and focuses on the dynamics of fluid flow through the branching system of blood vessels in the human cardiovascular system. While focusing particularly on aortic structure and strain, the findings are generalizable to other flow systems. This DBP is important because the physics of fluid flow are markedly different than the physics of multi-body dynamics used at the molecular and neuromuscular level. This DBP is therefore will stress our systems for representation and organization more than others, and guarantee generality. Drs. Zarins and Taylor are leaders in patient-specific modeling of vascular flow, and its use in surgical bypass planning. Thus, the clinical significance is high.
These four initial DBPs provide a challenging set of diverse object types and underlying relevant physics. The research challenges outlined in the following Core descriptions are drawn directly from an analysis of the modeling and simulation challenges equired to unify biophysical modeling and simulation. The multiscale nature of each of these four DBPs is important. Artificial disciplinary boundaries separating different modeling and simulation communities (e.g., structural biology and mechanical engineering) have limited the creation and application of multiscale simulation techniques in biomedicine. The recognition that these boundaries limit our ability to perform useful simulations makes their removal critical for long-term success. We believe that multiscale capabilities are not a set of features that can simply be added to existing disciplinary packages for simulation. These packages are predicated on fundamental assumptions that make them effective within a certain dynamic range, and ineffective outside. Instead, multiscale capabilities must be built as part of the founding concept of a simulation environment. This conviction forms the basis of our proposal to build an environment that can, from the start, approach all four of these.
