Download Transport Phenomena in Cell Biology - Thermal

Transport Phenomena in Cell Biology
Eric R. Dufresne
Department Mechanical Engineering
Department of Chemical Engineering
Department of Physics
Yale University
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• 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)
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• Transport Phenomena in Live Cells
Molecular Scale - Ion Channels
Nanoscale – Cytoskeletal Dynamics
Ionic specificity
Voltage Gating
Microscale - Chemotaxis
Sensing
Locomotion
Schaefer, Kabir, Forscher JCB 158 139
(2002)
David Rogers 1950s
Sigworth Nature 423 21 (2003)
Actin Polymerization
Molecular Motors
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• 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.
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• Technical Principles II
Simplified Transcriptional Network of E Coli
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
Ben-Schorr et al, Nature Genetics 31564
(2002)
• 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 19 401 (2001)
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• 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.) ?
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• 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?
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• 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
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• 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.
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• References
1. Random Walks in Biology, H.C. Berg, 1993
2. Molecular Driving Forces: Statistical Thermodynamics
in Chemistry & Biology, by K.A. Dill (2002)
3. Mechanics of Motor Proteins and the Cytoskeleton, by J.
Howard, 2001
4. An Introduction to Systems Biology: Design Principles of
Biological Circuits, by U. Alon, 2006
5. “Systems Biology: A Brief Overview,” H. Kitano, Science 295
1662 (2002)
6. Molecular Biology of the Cell, Alberts et al (2002)
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