Grant Abstracts 2009   Princeton University William Bialek Princeton, NJ $1,000,000 2009 The three-year program entitled Physical Limits and Biological Function will support the principal investigators as they lead a group of postdoctoral fellows in collaboration with researchers at the Lewis-Sigler Institute and the Center for Theoretical Science, as part of a broader theoretical effort at the interface of physics and biology. The group will be investigating key theoretical questions about the way in which the building blocks of life are organized to solve the problems essential for an organism’s survival, development and reproduction. More specifically, they will explore the idea that life’s solutions to these problems are not merely consistent with the laws of physics, but in many cases have been driven to the limits of what the laws of physics allow. As theorists, their goal is to turn this hypothesis about operation near the physical limits into a predictive theory, in the physics tradition, from which many aspects of the underlying biological mechanisms can be predicted. They will search for common theoretical principles that cut across many levels of biological organization, from the early events of embryonic development in fruit flies to the dynamics of sensorimotor control in primates and from lifestyle choices in bacteria to human perception.   University of California, Berkeley Lydia Sohn Berkeley, CA $1,000,000 2009 Why do embryos form limbs while postnatal humans form scar tissue? This fundamental question remains elusive under existing medical research paradigms. Current knowledge of amphibian limb regeneration cannot explain the lack of functional tissue re-growth in adult mammals. Although limb regeneration via blastema has been observed in neonatal mice, little is known in cellular or molecular terms. Consequently, controlling and enhancing postnatal organogenesis for therapeutic ends appears to be an intractable challenge. Thus, the researchers seek to transform present understanding of the dramatic decline in regenerative capacity after birth by inventing technology capable of probing cellular and molecular determinants of regeneration in single mammalian cells. Their combined efforts will develop: 1) a novel cell-sorting tool to isolate from tiny tissue clusters the single cells that are pivotal to mammalian tissue regeneration; 2) new tools to study molecular mechanisms orchestrating the regenerative behavior at single cell levels; and 3) 3D ex-vivo systems to recreate the regenerative processes biosynthetically, thereby identifying molecular cues driving tissue regeneration. This single-cell approach may surmount prevailing limitations, thus advancing the frontiers of biomedicine and engineering.   University of California, San Diego Ralph J. Greenspan La Jolla, CA $1,000,000 2009 Demonstrating that there is a fundamental, unifying principle for the operation of biological networks, one that cuts across phylogeny and type of network, could revolutionize the natural sciences. This project will use a research strategy based on the concept of relational networks, in which the coordinated interactions among functional sectors of the network are more critical than the specific identities of any of the interacting components. The program combines experimental network perturbation and global monitoring in genetic and neuronal model systems, followed by theory development, going beyond the standard computational modeling to capture the essential, relational nature of the system at a higher level. Should there prove to be fundamental, universal principles underlying the relations and function of biological networks, they will have substantial implications not only for many areas of biology, including the prospects for synthetic cells and therapeutic developments, but also for the design and implementation of artificial networks in applications as diverse as computing, engineered devices and communications.   University of California, San Francisco Joseph DeRisi San Francisco, CA $1,000,000 2009 Among the greatest achievements of modern medicine is the development of vaccines, but for many important diseases, such as HIV, tuberculosis and malaria, the production of safe and effective vaccines has been elusive. This is especially true for malaria, a disease that disproportionally affects children. An important first step in developing a rationally designed synthetic vaccine is the identification of antigens and their epitopes that are the actual determinants of immunological protection. The investigators propose to develop a new platform for the production of programmable proteome-scale peptide arrays on beads using a novel approach, whereby millions of peptides can be made deterministically and inexpensively on spectrally encoded microbeads. They will then conduct immunoassays on these beads to map epitopes across the entire proteome, using rodent malaria as a model system. The overall goal is to correlate mapped epitopes with actual protection from disease to inform the vaccine design process. This proposal embodies several major technological and conceptual innovations, and beyond vaccine design, this approach has the potential for broad impact on many fields of biomedical research, including cancer diagnostics, autoimmunity and allergy.