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Program in Physical Biology

Director: Joshua Zimmerberg, MD, PhD

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Human embryonic development, on which the future child's health depends, is a complex phenomenon within the female starting with egg-spermatozoa fusion. In each individual, a plethora of molecular recognition events mediate the development of an immune system to defend against pathogens, of a musculo-skeletal system to maintain the body, and of flexible networks of molecular expression to manage environmental stress. Traditionally, studies on these processes have been divided among biochemistry, cell biology, virology, toxicology, etc. However Nature does not know these artificial divisions, and new understandings are emerging from the interface between mathematically-minded physical scientists and biomedical researchers. The Program of Physical Biology, led by Joshua Zimmerberg, is a unique scientific body that approaches human development in normal life and pathology as an integral process and that encompass first-class cell biologists, physical chemists, biophysicists, virologists, and immunologists, who not only successfully train post-docs and students within their own fields in work on their own projects but also collaborate widely, building and uniquely promulgating multidisciplinary approaches to the most important biomedical problems in the framework of the NICHD mission.

The Section on Molecular Transport, led by Sergey Bezrukov, advances biophysical methods as tools to understand molecular interactions, notably by studying, in the context of human development, disease, and pharmacological intervention, the interactions of beta-barrel membrane channels with drugs and cytosolic proteins, as regulated by upstream signaling. Using single-molecule functional approaches, one project aims to unveil the physical mechanisms regulating the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane in cell proliferation, reprogrammed cancer metabolism, kinase-regulated cell signaling, cytoprotection, and neurodegeneration. The past year's work on the VDAC focused on the effect of lipid composition on the regulation of the interaction between tubulin and the VDAC. Surprisingly, changing the composition had effects that were measured in orders of magnitude. Work on toxic pores continued with a study on the interactions of high-affinity cationic blockers with the translocation pores of B. anthracisC. botulinum, and C. perfringens binary toxins. The physical theory of facilitated transport was also investigated.

The long-term goal of the Section on Membrane Biology, led by Leonid Chernomordik, is to understand how proteins drive membrane fusion in important cell biology processes. Whereas each kind of protein has its individual personality, membrane lipid bilayers have rather general properties manifested by their resistance to disruption and bending. Analysis of molecular mechanisms underlying important and diverse membrane rearrangements will clarify the generality of emerging mechanistic insights and likely bring about new strategies for treating diseases involving cell invasion by enveloped viruses, intracellular trafficking, and intercellular fusion. In recent studies, the Section focused on the cell-to-cell fusion stage during development and regeneration of muscles and bones.

The general goal of the Section on Intercellular Interactions, led by Leonid Margolis, is to understand the mechanisms of pathogenesis and sexual transmission of human pathogens, including the human immunodeficiency virus (HIV), which requires comprehensive knowledge of its transmission and pathogenesis in human tissues, where the critical events of infection by HIV and other pathogens occur. In their studies, members of the Section use a system of human tissues ex vivo, originally developed in this Section and now used by many investigators, to study viral infections and to test antivirals. During the last year, the Section's work had three aims: (i) to translate in vivo their earlier ex vivo observation on HIV-1 suppression by the common anti-herpetic drug acyclovir; (ii) to develop and to test in ex vivo human tissues new anti-HIV-1 antivirals that are based on the newly synthesized heterodimer of AZT and 3TC, two widely used anti-HIV-1 drugs; (iii) to extend the newly developed flow virometry technology to study antigenic composition of individual extracellular vesicles that are now considered to be important mediators in cell-cell communications in norm and pathology. The Section’s studies during the last year provided new insights into HIV-1 transmission and pathogenesis that may lead to new concepts in anti-HIV-1 strategies.

The Section on Cell Biophysics, led by Ralph Nossal, studies physical and physical-chemical mechanisms underlying cell behavior, for which the Section develops and applies mathematical and computational methodologies and uses biochemical and cell-biological techniques. Projects currently include: (i) elaborating a mathematical model to understand the physical basis of coated vesicle biogenesis during receptor-mediated endocytosis, focusing on how the size dependence of nanoparticle uptake relies on mesoscopic cell mechanics; (ii) developing quantitative measures of eukaryotic cell chemotaxis; (iii) exploring how the physiological behavior of neural tissues and other cell elements are mediated by temperature-linked phase changes in the lipid bilayer of the cell membrane; and (iv) understanding how certain small molecules interact with microtubules to act as antimitotic agents, and how microtubule arrays function in mitosis to produce accurate segregation of chromosomes. We also develop new experimental modalities to characterize these and related phenomena. We have a particular interest in the ways in which cellular activities are coordinated in space and time.

The Section on Macromolecular Recognition and Assembly, headed by Donald Rau, focuses on the nature of forces, structure, and dynamics of biologically important assemblies. The group showed that measured forces differ from those predicted by current theories and interpreted the observed forces to indicate the dominant contribution of water-structuring energetics. To investigate the role of water in binding, the group measures and correlates changes in binding energies and hydration that accompany recognition reactions of biologically important macromolecules, particularly sequence-specific DNA–protein complexes. By investigating differences in water sequestered by complexes of sequence-specific DNA–binding proteins bound to different DNA sequences, members of the Section correlated binding energy and water incorporated with the energy necessary to remove hydrating water from complexes. The emphasis on water permits a different approach to recognition reactions than standard practice. The Section also continued its work on sperm nuclear DNA packing and focused on the effect of temperature on the packing transitions in viruses, which facilitate infection. The Section discovered a novel, temperature-mediated transition in DNA packing for both the bacteriophage lambda and human herpes simplex virus type 1 (HSV-1). Both X-ray scattering and cryoEM reconstruction indicated a transition in DNA packing that occurs at about 30°C and is characterized by a substantial increase in the amount of disordered DNA in the center of the capsid.

The Section on Membrane and Cellular Biophysics, led by Joshua Zimmerberg, studies membranes, viruses, organelles, cells, and tissues in order to understand the molecular organization of cellular membranes, the physico-chemical mechanisms of membrane remodeling, and the molecular anatomy of tissues, which will lead to deeper insights into viral, parasitic, metabolic, developmental, and neoplastic diseases. The Section aims to use the expertise and techniques they perfected over the years to address several biological problems that have in common the underlying regulation or disturbance of protein/lipid interactions. During the past year, the Section (i) defined a new heritable virulence trait for the malaria parasite that correlates with erythrocyte indices and is reduced in thalassemia-trait erythrocytes, (ii) discovered a hemolytic activity of the parasite perforin PPLP2 that is essential for gametocyte egress as a result of permeabilization of the erythrocyte membrane and depletion of the erythrocyte cytoplasm, (iii) collaborated on the shape and energy landscape of a putative cavity within the bilayer membrane that may be relevant to traumatic brain injury, and (iv) discovered that the fruit fly Drosophila is competent to mobilize translocation of sugar transporters to the cell surface in response to insulin and exhibits an analog of insulin resistance.

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