Transport Phenomena in Cell Biology

Transcription

1 Transport Phenomena in Cell Biology Eric R. Dufresne Department Mechanical Engineering Department of Chemical Engineering Department of Physics Yale University 1

2 Background and Societal Impact Cells are the basic organizing unit of life A cell is a membrane-bound soup of water, proteins, lipids and nucleic acids that grows, reproduces and interacts with its environment Cell biology plays essential roles in human disease, e.g. bacterial infections, cancer Engineers have long exploited cells to process materials e.g. food (bread and beer), medicine and energy (cellulosic ethanol) 2

3 Transport Phenomena in Live Cells Molecular Scale - Ion Channels Nanoscale Cytoskeletal Dynamics Ionic specificity Voltage Gating Actin Polymerization Molecular Motors Sigworth Nature (2003) Schaefer, Kabir, Forscher JCB (2002) Microscale - Chemotaxis Sensing Locomotion David Rogers 1950s 3

4 Technical Principles I Fast Momentum Transport: Re << 1 Dynamics are overdamped Cytoplasm is non-newtonian (viscoelastic) Fast Heat Transport: Fo >> 1 Cells are in thermal equilibrium Mass transport is rate-limiting Bacteria are nearly well-mixed by diffusion Larger (eukaryotic) cells are heterogeneous. Diffusion dominates at short length scales, while active processes drive flow over larger length scales. 4

5 Technical Principles II Mass Transport = Information Transport Wet computers - Networks of molecular interactions store and process information Transcription networks regulate the production of proteins at longer timescales Signaling networks process information from the environment at shorter timescales Simplified Transcriptional Network of E Coli Ben-Schorr et al, Nature Genetics (2002)

6 Technical Principles III Mass Transport = Information Transport Existing models treat cells as well-mixed, but cell heterogeneity or polarity is essential for many important phenomena The role of mass transport in information processing is just beginning to be explored Reaction-diffusion dynamics are currently being explored in theory and in silico More realistic models incorporating non-newtonian mechanics, heterogeneities, time-dependence and stochastic fluctuations are needed Analytical theories are also needed to interpret these complex data Loew and Schaff, TRENDS in Biotechnology (2001) 6

7 Key Questions I How do systems of molecules regulate cellular behavior? How do cells process information? How to move beyond well-mixed models? Generalization and application of control theory? What are the connections between molecules and mechanics? How do cells measure forces? How do cells generate forces, move, etc? How do cells control their structure and mechanical properties (stiffness, etc.)? 7

8 Key Questions II Can cells be programmed to process materials and information? Can tissue scaffolds stimulate cellular processes? What can Nature s design of cellular systems teach us about the design of engineered nano- and micro-systems? e.g. can biochemical control systems be implemented into engineered materials? 8

9 Recommendations I 1. Support research that impacts our understanding of cell-level systems biology. A Development of new technologies that 1. enable quantitative measurements of the spatiotemporal dynamics of biomolecular processes. 2. elucidate the interplay of biochemistry and mechanics in live cells. B Development of simulation tools and collaborative databases that enable in silico hypothesis testing C Development of simple theories that synthesize essential pieces of biochemistry, mechanics and control D Encourage collaborations between traditional engineering disciplines, biology and medicine 9

10 Recommendations II 2. Update curricula to emphasize nano- and micro-scale transport phenomena (low Re fluids, Brownian Motion) and classical statistical mechanics. Encourage coursework in cellular and molecular biology. 10

11 References 1. Random Walks in Biology, H.C. Berg, Molecular Driving Forces: Statistical Thermodynamics in Chemistry & Biology, by K.A. Dill (2002) 3. Mechanics of Motor Proteins and the Cytoskeleton, by J. Howard, An Introduction to Systems Biology: Design Principles of Biological Circuits, by U. Alon, Systems Biology: A Brief Overview, H. Kitano, Science (2002) 6. Molecular Biology of the Cell, Alberts et al (2002) 11