Thomas L. Daniel - US grants

The research revolves around two approaches to understanding the physical determinants of motility. One approach examines the physics of propulsion from an engineering standpoint. Forces generated by appendage movements are used to estimate thrust and body trajectories for a variety of situations, including aerial, aquatic, and terrestrial locomotion. A goal is to determine what motions and body morphologies are feasible for accomplishing certain movements such as flight, swimming, or running and the limitations to movements in terms of design and energetics. A second approach centers upon the physiology of the muscles that generate locomotor movements. A number of important limitations to muscle contractility have been shown with the maxima for force and the inverse relationship between the force and velocity of contraction both etermining overall muscle and appendage motions. While both above approaches have yielded fruitful insight into the limitations to animal motility, no previous study has explicitly linked these two components. Daniel proposes to combine these two areas to determine both physical and physiological limitations to one extreme mode of locomotion: escape from predation. We use a local species of shrimp, Pandalus danae, that exhibits an escape motion involving a rapid flexion of the abdomen that lasts approximately 30 ms. The hydrodynamics of this mode of locomotion has already been worked out. He has shown that both the size and shape of these animals are constrained by the dynamics of accelerational locomotion. He proposes to address basic questions regarding these and related contractile systems: (1) What are the forces generated by such rapidly contracting muscles (2) How do active and inactive antagonistic muscle groups respond to such rapid extensions? and (3) How is this activity regulated and transferred into productive motility.

Muscle contraction is driven by conformational changes associated with portions of myosin molecules when they are attached to actin filaments. This shape change results in a sliding motion between these two muscle proteins and thus, shortening of the entire muscle. Attempts to understand the dymamics of this system have relied on two approaches: (1) experiments that employ rapid mechanical transients applied to activated muscle and (2) mass action models that treat these proteins as independent chemical species. Our research re-examines these two approaches with a combination of theoretical and experimental approaches. From a theoretical standpoint, we will show that rapid mechanical perturbations applied to single muscle cell preparations lead to propagating waves of internal strain and that these waves may account for the behaviors that have been incorrectly attributed to mysosin kinetics. Using recent experimental methods that employ high - speed laser diffractometry, we show such waves occur and we use such data to corroborate our theoretical predictions. We will also develop a new theoretical approach for modelling thedynamics of interacting proteins. In this new approach, we relax the assumption that each myosin molecule acts independently. Instead, we argue that the kinetics of each molecule can be represented as an oscillator whose behavior depends on the kinetics of its neighboring myosins. This system of coupled oscillators can yield kinetics of an ensemble of molecules that is vastly different from the kinetics of each individual. These two approaches challenge the classic views of muscle as a system of slow, independent molecules whose kinetics can be extracted from experiments employing rapid mechanical perturbations.//

This award to a group including 10 faculty in 4 departments (Applied Mathematics, Botany, Statistics, Zoology) provides 6 positions for graduate students enrolled in an interdisciplinary training program in applied mathematics and biology. The students are to be divided among three areas of biological research: cell and developmental biology, physiology and morphology, and ecology and evolution. The progrm will emphasize the role of mathematics in understanding and guiding experimental observations. As part of its training activities, the program will offer a new "super-course" that will bring in distinguished outside faculty to give series of lectures on specialized topics.

Daniel IBN-9511681 Insect flight is a highly efficient mode of locomotion. Interest in studies of insect flight arises partially from the need to develop new design criteria for artificial robotic systems. This research project focuses on the development of computer models for flight and flight control in insects. The goal of this work is to better understand how sensory feedback from the wings and pattern-generating circuits in the central nervous system govern flight performance. The current approaches of studying any single component of insect flight (muscle mechanics, aerodynamics, or neural control) alone cannot be used as predictive models. In this work, mathematical and experimental approaches are incorporated into the models in order to understand the physics of force production by muscles and the physics of aerodynamic lift and thrust generation by wings. Computer models will solve these problems of physics simultaneously to predict flight performance in the moth Manduca sexta, the tobacco hornworm moth. This group of researchers couple these processes in developing a novel biological and engineering approach for a priori predictions of flight dynamics in response to a suite of physiological and physical parameters. By this method we can better understand the physics, physiology and control of flight dynamics.

Ward 9531892 Ammonoid and nautiloid cephalopods are externally shelled molluscs with an extensive and diverse fossil record. The shell is subdivided into a number of chambers; the partitions dividing these chambers (the septa) have shown a remarkable evolutionary pattern of increasing complexity. The intersection of these septa with the lateral walls of the shell form a complex and foliate suture. These sutures, in turn, have long been recognized as one of the most complex and rapidly evolving structures in the fossil record. But their function ("the ammonoid suture problem") remains one of the oldest unresolved questions in paleontology. The prevailing interpretation, the ammonoid septa and their sutures were buttresses to prevent implosion, is now largely unchallenged. In this proposal, however, we provide evidence that strongly challenges this view. This evidence follows from a combination of approaches including finite element analysis of stress distributions in models of septa exposed to pressure loads, data from the fossil record that are inconsistent with the idea of buttressing, and a new modeling effort that suggest septal surface elaboration may be related to the transport of liquid from the chambers. Since this cameral liquid transport is related to both the growth rate of the animals and to short term buoyancy regulation, we suggest that one selective process in the evolution of these complex characters is related to the physics and physiology of cameral liquid transport. The proposed research revolves around two central hypotheses: (1) that septal surface elaboration reduces the stress in the chambered portion of the shell (the phragmocone) and (2) septal surface elaboration augments cameral liquid transport rate. These hypotheses with a combination of computational and mathematical approaches as well as physical modeling and morphometric approaches. Limited set of clades for which there is an ample fossil record that contains well preserved specimens. The fossils will provide morphometric data with which we will examine the above hypotheses. Then use a new mathematical method to quantify the shapes of septa and sutures from digitized data. This method will also used to prescribe shapes for both stress and cameral liquid transport analyses. Currently developed finite element analyses for stress distributions and will apply this method to both real and hypothetical ammonoids to examine the relationship between stress and surface elaboration. Theoretical models that will describe relationships between cameral liquid transport and surface elaboration, we will develop models to test our transport ideas. In sharp contrast to conventional views, our preliminary work suggests that surface elaboration leads to augmented stresses on portions of the phragmocone. Moreover, our initial modeling efforts on cameral liquid transport indicate that septal surface elaboration is manifested as greater rates of chamber liquid flux. Thus, an exciting consequence of this work is that we suggest that this surface elaboration involves two conflicting selective processes: increased cameral liquid transport at a considerable mechanical risk. The consequences of this trade-off, let alone its possible existence, have not been previously proposed.

Professors James Callis, Thomas Daniel, Martin Gouterman and Gamal Khalil of the University of Washington are supported by the Analytical and Surface Chemistry and Fluid Dynamics and Hydraulics Programs to develop the use of pressure sensitive-paint to study the dynamics of insect flight. The goal of this Small Grant for Exploratory Research (SGER) is to map the pressure over an insect's wings in flight. The idea is to utilize a biocompatible, phosphorescent dye painted on the wings of a honeybee to report on the tiny pressure changes that evolve at high speed. A bank of violet LED's is used to excite the dye and a CCD imager captures two sequential images synchronized to the light source modulation. The instrumentation is first being tested in a wind tunnel that shows unstable flow around a square cylinder and, secondly, using a propeller system at low rotational velocity. While computational fluid dynamics calculations by others have predicted surface pressure maps over insect wings during flight, this data would provide some of the first experimental measurements for comparison.

The remote measurement of small pressure variations utilizing this spectroscopic-based method could have applications not only in understanding insect flight, but also for aerodynamic design of rockets, or micro air vehicles, for example. The work has implications for national security as well as space exploration, and many other possible applications.

Project Title: Collaborative Research: Molecular Determinants of Power Inputs and Outputs of Synchronous Flight Muscle In Vivo

Principal Investigators: Irving, Thomas C, and Thomas L. Daniel

NSF Project Numbers: IOS 1022058 and 1022471

All moving animals, from humans to flying insects, operate with muscles that not only cyclically generate force, they do so while generating significant heat. This research project is aimed at understanding the molecular basis and physiological consequences of temperature dependent force generation in muscle. As with many other biological rate processes, the speed and power output of muscle is strongly influenced by temperature. Surprisingly, heat generation by the muscles that power flight in Hawkmoths show a large temperature gradient, with more superficial muscles operating at cooler temperatures than deeper, more insulated, muscles. This temperature gradient has profound functional consequences and is likely a general result for many moving creatures. The researchers will examine the notion that thermal gradients lead to functional gradients. Thus, deeper warmer, muscle subunits may serve as power generators driving locomotion whereas cooler subunits may act as elastic energy storage systems. All of this function operates with protein motors that will be examined from the molecular level to the fully intact muscle in a moving animal. A mix of high-speed x-ray imaging methods and whole muscle force and energy measurement methods will be used to tackle this problem. The combination of heat generation by the volume of muscle in humans and other animals, combined with processes that dissipate heat suggests that temperature gradients may be more common than historically assumed. Thus it is likely a general phenomenon that the temperature dependent function of muscle will vary spatially within a single muscle group.

In addition, the flight muscle of Manduca sexta will provide a new model system for understanding muscle function in animals in general. A result of this project will be development and refinement of x-ray diffraction methods to probing muscle function in vivo.

Over the last decade, the field of neural engineering has demonstrated to the world that a computer cursor, a wheelchair, or a simple prosthetic limb can be controlled using direct brain-machine and brain-computer neural signals. However, technologies that allow such accomplishments do not yet enable versatile and highly complex interactions with sophisticated environments. Today's intelligent systems and robots can neither sense nor move like biological systems, and devices implanted in or interfaced with neural systems cannot process neural data robustly, safely, and in a functionally meaningful way. Doing so requires a critical missing ingredient: a novel, neural-inspired approach based on a deep understanding of how biological systems acquire and process information. This is the focus of this proposal.

The NSF ERC for Sensorimotor Neural Engineering (ERC/SNE or "Center") will become a global hub for delivering neural-inspired sensorimotor devices. Using devices that mine the rich data in neural signals available from implantable, wearable, and interactive interfaces, the ERC/SNE will build end-to-end integrated systems. Examples include: implantable neurochips that can activate paralyzed limbs by electrically stimulating muscles or nerve roots; stationary robots that extract neural signals from a user's touch to provide home-based, post-stroke therapy; neural-controlled adaptive prosthetic limbs that provide sophisticated sensory feedback, and wearable caps that control external exploration devices. Unlike traditional approaches that stress accommodation to the needs of people with neurological disabilities, the ERC/SNE will focus on proactive technologies that provide seamless and adaptive person-machine interaction. It will accomplish this mission with three core engineering thrusts: (1) communication and interface design for devices and data management, (2) reverse and forward engineering of neural systems and neural-inspired devices, and (3) control and adaptation technologies that express sensorimotor functions for individual needs.

The ERC/SNE will nurture future global multidisciplinary leaders. It will develop middle and high school project-based curricula that introduce neural engineering principles to students underrepresented in engineering. It will create multi-institution, undergraduate and graduate Neural Engineering courses with new degree structures and develop vertical research mentoring chains to build a strong research culture from faculty to K-12. It will build long-lasting and deep relationships through faculty and student exchange programs across all disciplines and partnering institutions, with a goal of removing barriers in communication across different fields, countries, and diverse backgrounds. The neural engineering field creates new pathways from the less quantitatively-based biological sciences to the more quantitatively-based engineering fields as well as pathways for people with disabilities to work in an engineering field that addresses their own experience and needs. The women and underrepresented minorities who currently account for over 40% of the Center's leadership team will serve as role models for students and starting faculty. Further, the ERC/SNE will extend its impact by identifying key technologies according to market significance and technical risk. The Center's portfolio will be constructed to deliver a steady stream of innovations over the near and long term. Its industry partnership structure includes not only small and large firms that will help shape Center IPs, but also hospitals and investment firms that will ground research activities to technologies that will truly assist people in need and steer future neural engineering market directions.

The ERC/NSE will strive to enhance the human experience both for persons with neurological disabilities and for the coming generation of global and diverse engineering innovators. The Center's seasoned, multi-disciplinary team will transform healthcare, manufacturing, and the educational infrastructure to guarantee neural engineering global leadership.

This REU Site award to the University of Washington, located in Seattle, WA, will support the training of 10 students for 10 weeks during the summers of 2015-2017. The REU program is open to all undergraduate students who are citizens, nationals or permanent residents of the United States. Students who participate in the program gain skills in lab research, develop their critical thinking and problem-solving skills, understand the process of science, and communicate their research results to their peers and the general public. Students will have an opportunity to present their results in a national conference. The REU program provides students an experience that is typically not available to them in their academic curriculum. Students from schools with limited opportunities for research and from underrepresented groups are encouraged to apply.

The goal of this REU Site is to provide a carefully mentored research experience for talented undergraduate students at the Center for Sensorimotor Neural Engineering (CSNE). Each undergraduate student will enter a collaborative team with a graduate student or postdoctoral fellow mentor and a faculty member as they undertake a research project. The team will focus on a CSNE project that has been carefully selected as a good example of interdisciplinary biosciences and engineering research and one that has ties to industry interests. The students will also participate in a weekly communications course and journal club that deals with both oral presentation and writing skills. Each student will be required to write a journal style report of their research for publication and deliver an oral and poster presentation of their summer research in a mini-symposium session. Emphasis will be placed on recruiting students from under-represented groups. The common assessment tool provided by the NSF BIO program will be used to assess the REU program.

Students are required to be tracked after the program and must respond to an automatic email sent via the NSF reporting system. More information is available by visiting http://www.csne-erc.org , or by contacting the PI (Dr. Eric H. Chudler at chudler@u.washington.edu) or the co-PI (Dr. Thomas Daniel at danielt@uw.edu).

? DESCRIPTION (provided by applicant): The University of Washington conducts world-class research in the development of big data analytics, as well as in many areas of biomedical research. However, most predoctoral students in biomedical science do not receive cutting-edge training in statistical and computational methods for big data. Furthermore, most predoctoral students in statistics and computing do not receive in-depth training in biomedical science. In short, the university currently lacks an integrated training program that spans computation, statistics, and biomedical science. Given the growing importance of big data across many areas of biomedical research, such an integrated program is critically needed. In order to train a new generation of researchers with expertise in statistics, computing, and biomedical science, we propose the University of Washington PhD Training in Big Data from Genomics and Neuroscience (BDGN). This program will focus on two areas of biomedical science, both of which are characterized by huge amounts of data as well as extensive expertise at the University of Washington: genomics and neuroscience. The program will draw six predoctoral students per year from the following seven PhD programs: Applied Mathematics, Biology, Biostatistics, Computer Science & Engineering, Genome Sciences, Neuroscience, and Statistics. Trainees will be appointed to the training grant during their ?rst or second year of hD studies and will continue on the training grant for two years. They will take a rigorous curriculum that involves three courses in statistics, machine learning, and data science, and three courses in either genomics or neuroscience. Each trainee will be paired with two world-class faculty mentors: one specializing in either genomics or neuroscience, and a second specializing in the development of either computational or statistical methods for big data. Other key features of the training program include three one-quarter rotations, with at least one focusing on genomics or neuroscience and one focusing on statistical or computational methods, a summer internship program, opportunities to attend world-class summer courses run through UW programs, peer mentoring, seminars, journal clubs, and courses on reproducible research and on responsible conduct of research. All predoctoral trainees will leave the BDGN Training Program with a core set of skills and a common language required for generating, interpreting, and developing statistical and computational methods for big data from genomics or neuroscience.

ABSTRACT ? Core D Core D will provide computational modeling and statistical analysis tools and services to investigators in the CTMR. By combining approaches from biology, engineering and computing, the challenge is to transform the field of muscle and movement sciences by focusing on a new understanding of multi-scale muscle biophysics ? from molecules to movement. In doing so, the unifying theory explaining how muscle develops, functions and has dysfunction with disease and impacts other physiological systems will be developed. The core will provide invaluable mulit-scale computational tools and visualization software to be used in multi-scale research on metabolism (energy supply) and mechanical (energy demand/use), how these changes in developing muscle and how they are altered in skeletal muscle disease. In doing so, the core will develop models that are informative and provide predictive power that can guide experimental design and suggest targets for development of novel therapeutic approaches to treat disease. The models and analytical tools developed in this core will accelerate the pace of translational muscle research.

ABSTRACT - Overall The University of Washington (UW) is internationally known for its excellence in all aspects of skeletal muscle biology, especially in mechanistic and translational research of diseases. However, there is currently no centralizing resource that brings together all the muscle investigators from multiple departments for the benefit of facilitating and accelerating their efforts. Therefore we propose the UW Resource Center for Translational Muscle Research (CTMR) to provide a unifying resource and state of the art approaches to enhance skeletal muscle research at the UW. The proposed Center will offer tools, facilities and expertise in a combination available only at the UW to facilitate novel insights to muscle pathologies and move new therapeutics towards the clinic and the marketplace. This new Center will offer 4 cores (one administrative and three research resource) to provide tools and expertise in several areas of interest to current principal investigators. The Administrative Core (A) will provide program management and enrichment by providing a pilot project program, workshops, a seminar series, training and educational opportunities for new investigators and more experienced investigators moving into muscle research. The Mechanics and Devices Core (B) will provide state of the art measurements of muscle biomechanics at multiple levels of integration, and develop new assays for maturation and assessment of early stage muscle. The Metabolism and Energetics Core (C) will provide tools for in depth measures and analysis of metabolomics, energetics, cell respiration and mitochondrial function. The Computational and Quantitative Analysis Core (D) will provide computational and statistical tools for understanding disease, suggesting new therapeutic targets and understanding mechanisms. The CTMR will offer an environment to facilitate using integrative analysis, from single molecule dynamics through muscle structure-function relationships, with interdisciplinary approaches to advance skeletal muscle disease research and therapeutics development.