Research: Chris Myers

Systems biology

Biological information processing and the functional organization of biomolecular networks

I am broadly interested in information processing in cellular networks, and particularly in understanding the structure and function of gene regulation and signal transduction networks. There are many basic questions underlying this interest. How does information processing emerge from the underlying molecular hardware? How are biomolecular networks organized to be robust and evolvability, and how is interaction specificity arranged in such organizations? How can we describe and compute biological function as it emerges from molecular activity, and how is that function composed through the assembly of different modular units? To what extent is there cross-talk across modules, and how is that managed? I am interested in studying both simple abstractions of information processing networks and detailed descriptions of experimentally-validated biochemical pathways. Questions about tradeoffs between specificity and evolvability in biomolecular networks are connected to similar questions that arise in the field of software design.

A particular application concerns the reliability of communication in cellular regulatory and signaling networks, given the propensity for many interactions to be somewhat fuzzy and promiscuous, rather than highly specific. In a simple model of protein-protein interaction and crosstalk among competitive proteins, I have examined the nature of sequence niches and their disappearance in the face of increasing competition for sequence space. This has connections to phase transitions in NP-complete computational problems, and the organization of error-correcting codes in communication theory.

References

C.R. Myers, "Satisfiability, Sequence Niches, and Molecular Codes in Cellular Signaling" (submitted, 2007).[pdf]

Gene regulation in bacterial pathogens

In collaboration with researchers from the USDA Agricultural Research Service (ARS) and from Cornell, I am investigating gene regulation in the bacterial plant pathogen Pseudomonas syringae. This includes:

inference and modeling of gene regulation networks from experimental data (microarrays, promoter traps, transposon mutagenesis, etc.)
use of bioinformatic techniques to identify promoters and transcription factor binding sites in the P. syringae genome
statistical and comparative analysis of bacterial genomes to detect horizontal transfer

References

A.O. Ferreira, C.R. Myers, J.S. Gordon, G.B. Martin, M. Vencato, A. Collmer, M.D. Wehling, J.R. Alfano, G. Moreno-Hagelsieb, W.F. Lamboy, G. DeClerck, D.J. Schneider, and S.W. Cartinhour, "Whole-genome expression profiling defines the HrpL regulon of Pseudomonas syringae pv. tomato DC3000, allows de novo reconstruction of the Hrp cis element, and identifies novel coregulated genes", Mol. Plant-Microbe Int. 19(11), 1167-1179 (2006). [pdf] [website]

M. Vencato, F. Rian, J.R. Alfano, C.R. Buell, S. Cartinhour, G.A. DeClerck, D.S. Guttman, J. Stavrinides, V. Joardar, M. Lindeberg, P.A. Bronstein, J.W. Mansfield, C.R. Myers, A. Collmer, and D.J. Schneider, "Bioinformatics-enabled identification of the HrpL regulon and type III secretion system effector proteins of Pseudomonas syringae pv. phaseolicola 1448A", Mol. Plant-Microbe Int. 19(11), 1193-1206 (2006). [pdf] [website]

M. Lindeberg, S. Cartinhour, C.R. Myers, L.M. Schecter, D.J. Schneider, and A. Collmer, "Closing the circle on the discovery of genes encoding Hrp regulon members and type III secretion system effectors in the genomes of three model Pseudomonas syringae strains", Mol. Plant-Microbe Int. 19(11), 1151-1158 (2006). [pdf] [website]

Modeling, sloppy and otherwise

Computational modeling of biomolecular networks underlying regulation, signaling and metabolism is useful in helping to understand experimental data and in making predictions regarding future experiments. I have been collaborating with Jim Sethna and his group to develop the theoretical and computational infrastructure needed to model complex biomolecular networks. We find that most such networks are ``sloppy'', in that they are vastly more sensitive to some parameter variations than to others. This has important implications for parameter estimation, model validation, and the generation of falsifiable predictions. The code we have developed to support these network simulations, SloppyCell, is available to the public.

References

R.N. Gutenkunst, J.J. Waterfall, F.P. Casey, K.S. Brown, C.R. Myers, and J.P. Sethna, "Universally Sloppy Parameter Sensitivities in Systems Biology", PLoS Computational Biology 3(10), e189 (2007). [pdf] [website]

F.P. Casey, D. Baird, Q. Feng, R.N. Gutenkunst, J.J. Waterfall, C.R. Myers, K.S. Brown, R.A. Cerione, and J.P. Sethna, "Optimal experimental design in an EGFR signalling and down-regulation model", IET Systems Biology 1(3), 190-202 (2007). [pdf]

R.N. Gutenkunst, F.P. Casey, J.J. Waterfall, C.R. Myers, and J.P. Sethna, "Extracting falsifiable predictions from sloppy models", Ann. N.Y. Acad. Sci. 1115: 203-211 (2007), in "Reverse Engineering Biological Networks: Opportunities and Challenges in Computational Methods for Pathway Inference". [pdf] [website]

C.R. Myers, R.N. Gutenkunst and J.P. Sethna, "Python unleashed on systems biology", Computing in Science and Engineering, 9(3), 34-37 (2007). [pdf] [preprint]

J.J. Waterfall, F.P. Casey, R.N. Gutenkunst, K.S. Brown, C.R. Myers, P.W. Brouwer, V. Elser and J.P. Sethna, "The sloppy model universality class and the Vandermonde matrix", Phys. Rev. Lett. 97, 150601 (2006) [arxiv] [pdf]

F.P. Casey, J.J. Waterfall, R.N. Gutenkunst, C.R. Myers & J.P. Sethna, "Variational method for estimating the rate of convergence of Markov Chain Monte Carlo algorithms", arxiv.org/abs/physics/0609001 (2006), submitted. [preprint]

K.S. Brown, C.C. Hill, G.A. Calero, C.R. Myers, K.H. Lee, J.P. Sethna and R.A. Cerione, "The statistical mechanics of complex signaling networks: nerve growth factor signaling", Physical Biology 1, 184-195 (2004). [pdf]

Software systems, engineered and evolved

Structure, function, and evolution of software networks

Software systems emerge from mere keystrokes to form intricate functional networks connecting many collaborating modules, objects, classes, methods, and subroutines. I have examined the underlying network architecture of several open-source software systems, to understand how features in the network topology (broad degree distributions and non-random clustering) are related to underlying software design principles and methodologies. I have also developed a simple model of software system evolution - based on refactoring processes - which captures some of the salient features of the observed systems. This work has interesting implications for studies of network robustness, evolvability, and degeneracy, and suggests insights into biochemical processes - such as regulated recruitment - which are used to organize regulatory and signaling networks.

References

C. R. Myers, "Software systems as complex networks: structure, function, and evolvability of software collaboration graphs", Phys. Rev. E 68, 046116 (2003). [pdf] Also republished in the November 1, 2003 issue of The Virtual Journal of Biological Physics Research.

Data for software graphs studied

The emergence of design patterns

Software design patterns arose in part from the notion of architectural design patterns (as developed by Alexander), the role of which is to resolve tensions that arise in systems. While software design patterns are generally not discussed in such terms, they are - in fact - not unlike localized coherent structures that arise in nonequilibrium spatiotemporal systems: design patterns (in the functional realm) and coherent structures (in the spatiotemporal realm) both serve to localize large deformations. In physical systems, one naturally finds a menagerie of patterns - vortices, dislocations, boundary layers, grain boundaries, fronts, pulses, crack - which serve to localize strain. Similarly, software design has catalogued its own flora and fauna - adapters, proxies, factories, visitors - which act to localize design tensions and those aspects of code which are highly variable. I am interested in studying nonequilibrium models of software systems to ascertain whether functional patterns of this sort can naturally emerge.

Design and development of software systems for scientific computing

References

C.R. Myers and J.P. Sethna, "Python for education: computational methods for nonlinear systems", Computing in Science and Engineering, 9(3), 75-79 (2007). [pdf] [preprint]

C.R. Myers, R.N. Gutenkunst and J.P. Sethna, "Python unleashed on systems biology", Computing in Science and Engineering, 9(3), 34-37 (2007). [pdf] [preprint]

C. R. Myers, T. Cretegny, N.P. Bailey, C.-S. Chen, A.J. Dolgert, L.O. Eastgate, E. Iesulauro, A. R. Ingraffea, M. Rauscher, and J.P. Sethna, "Software methodologies for multiscale descriptions of defects, deformation and fracture", Proceedings of the 10th International Conference on Fracture (2001). [pdf]

C.R. Myers, S.R. Arwade, E. Iesulauro, P.A. Wawrzynek, M. Grigoriu, A.R. Ingraffea, P.R. Dawson, M.P. Miller, and J.P. Sethna, "Digital Material: a framework for multiscale modeling of defects in solids", Mat. Res. Soc. Symp. Proc., Vol. 538, 509 (1999). [pdf]

C.-C. Chang, G.J. Czajkowski, X. Liu, V.S. Menon, C.R. Myers, A.E. Trefethen, L.N. Trefethen, "The Cornell MultiMATLAB Project", Proceedings of The 1996 Parallel Object-Oriented Methods and Applications Conference, Santa Fe, NM, Feb. 1996.

C.R. Myers, "Abstractions, applications and accommodations: Thoughts on developing object-oriented software using someone else's class library", Proceedings of The 1996 Parallel Object-Oriented Methods and Applications Conference, Santa Fe, NM, Feb. 1996. [html]

From the archives...

Multiscale modeling of defects in solids

L. O. Eastgate, J. P. Sethna, M. Rauscher, T. Cretegny, C.-S. Chen, and C. R. Myers, "Fracture in Mode I using a Conserved Phase-Field Model", Phys. Rev. E 65 036117 (2002). [pdf]

E. Iesulauro, K. Dodhia, T. Cretegny, C.-S. Chen, C. Myers, and A. R. Ingraffea, "Continuum-atomistic modeling for crack initiation and propagation in polycrystals", Proceedings of the 10th International Conference on Fracture (2001). [pdf]

T. Vegge, J.P. Sethna, S.-A. Cheong, K.W. Jacobsen, C.R. Myers and D.C. Ralph, ``Calculation of quantum tunneling for a spatially extended defect: the dislocation kink in copper has a low effective mass'', Phys. Rev. Lett. 86, 1546 (2001). [pdf]

N. Bailey, J.P. Sethna, C.R. Myers, "Dislocation mobility in two-dimensional Lennard-Jones material", Mat. Res. Soc. Symp. Proc., 578, 249 (2000); later version Materials Science and Engineering A 309-310 152-155 (2001). [pdf] [preprint]

B. Carter, C. S. Chen, L. P. Chew, N. Chrisochoides, G. R. Gao, G. Heber, A. R. Ingraffea, R. Krause, C. Myers, D. Nave, K. Pingali, P. Stodghill, S. Vavasis, P. A. Wawrzynek, "Parallel FEM Simulation of Crack Propagation - Challenges, Status, and Perspectives", Lecture Notes in Computer Science, Vol. 1800, pp. 443-449, Springer Verlag, 2000. [pdf]

C.R. Myers, "The dynamics of localized coherent structures and the role of adaptive software in multiscale modeling", Structured Adaptive Mesh Refinement (SAMR) Grid Methods, The IMA Volumes in Mathematics and Its Applications (Springer-Verlag), Vol. 117, p. 111, 1999. [pdf]

Fracture and slip complexity on earthquake faults

C.R. Myers, B. Shaw and J.S. Langer, "Slip complexity in a crustal-plane model of an earthquake fault", Phys. Rev. Lett. 77, 972 (1996). [pdf]

J.S. Langer, J.M. Carlson, C.R. Myers and B.E. Shaw, "Slip complexity in dynamic models of earthquake faults", Proceedings of the National Academy of Sciences Colloquium on "Earthquake Prediction: The Scientific Challenge", Irvine, CA, Feb. 1995. [pdf]

C.R. Myers and J.S. Langer, "Rupture propagation, dynamical front selection, and the role of small length scales in a model of an earthquake fault", Phys. Rev. E 47, 3048 (1993). [pdf]

Patterns and criticality in nonequilibrium systems

J.P. Sethna, K.A. Dahmen, and C.R. Myers, "Crackling noise", Nature 410, 242 (2001). [pdf] [preprint]. Excerpted as "Crackling noise", Drunken Boat (Online Journal of the Arts) 3 (2001).

C.R. Myers and J.P. Sethna, "Collective dynamics of sliding charge density waves: II. Finite-size effects", Phys. Rev. B 47, 11194 (1993). [pdf]

C.R. Myers and J.P. Sethna, "Collective dynamics of sliding charge density waves: I. Critical phenomena", Phys. Rev. B 47, 11171 (1993). [pdf]

Singularities in electronic structure

C.R. Myers, C.J. Umrigar, J.P. Sethna and J.D. Morgan III, "Fock's expansion, Kato's cusp conditions, and the exponential ansatz", Phys. Rev. A 44, 5537 (1991). [pdf]

Chaos and nonlinear dynamics

R.V. Jensen and C.R. Myers, "Images of the critical points of nonlinear maps", Phys. Rev. A 32, 1222 (1985). [pdf]

Last modified: Thu Jan 17 16:04:13 EST 2008