Research Theme: Systems biology approach to atherosclerosis and inflammation

Education and Training

• NIH Mentored Quantitative Research Career Development Award,
  Institute for Systems Biology; Seattle Biomedical Research Institute (2010-present)
• Senior Fellow, University of Washington Genome Center (1998)
• Ph.D. (Physics), University of Maryland, College Park (1997)
• Sc.B. (Mathematical Physics), Brown University (1992)

Research Interests

• Role of macrophages in atherosclerosis
• Macrophage foam cell formation
• Computational network inference in systems biology
• Biocomputational modeling

Contact Information

Email: stephen.ramsey@seattlebiomed.org
 
Seattle Biomedical Research Institute
307 Westlake Ave N, Suite 500
Seattle, WA  98109, USA

Other Websites

ResearchGate user name: Stephen_Ramsey.

Linkedin user name: sramsey.

Research Overview

One of my main areas of research interest is in the role of macrophages in atherosclerosis and sterile inflammation. Within this area, I am presently working on a project to study macrophage-specific transcriptional regulatory mechanisms involved in the pathogenesis of atherosclerosis. My collaborators and I are using systems biology approaches to map the transcriptional regulatory network underlying the formation of macrophage foam cells, which is a key step in atherogenesis. The macrophage foam cell project is supported in part by an NHLBI K25 mentored career development award, on which Alan Aderem (Seattle BioMed) and Ilya Shmulevich (ISB) are co-mentors. [The figures at right show: (top) a micrograph of a tissue section from an atherosclerotic mouse aortic sinus, that has been stained with the lipophilic dye Oil Red O and (bottom) a micrograph of a macrophage foam cell stained with the lipophilic fluorophore, BODIPY 493/503.]

Complementing the macrophage foam cell project are a variety of collaborative projects in the areas of atherosclerosis, vascular biology, macrophage biology, and computational systems biology. For example, I am collaborating with Liz Gold, Irina Podolsky, Mark Sartain, and Alan Aderem on in vivo studies of atherosclerosis and plaque lipids involving mice deficient in a candidate regulator of foam cell formation. I am also collaborating with Ed Fisher (NYU) and Yuliya Vengrenyuk (Fisher Lab, NYU) on a transcriptome profiling study of smooth muscle foam cell formation. Another key collaboration, involving Liz Gold and the Fisher Lab, is a transcriptome profiling study of plaque macrophages in a mouse model of atherosclerosis regression.

In addition to the atherosclerosis-related projects, I have a long-standing interest in computational approaches to infer biological networks and in computational modeling as a tool for understanding biological and biochemical systems. Prior to my work on atherosclerosis, the area where I have mainly applied computational network inference has been the transcriptional network governing macrophage activation through Toll-like receptor stimulation. On the modeling side, past projects include transcriptional networks governing cytokine release in response to TLR stimulation in macrophages, responses to fatty acid and galactose in model organisms, and design of microfluidics-based bioassays. Much of the transcriptional network modeling work has been carried out in collaboration with members of the labs of John Aitchison and Ilya Shmulevich at ISB, and with members of the lab of Hamid Bolouri when he was at ISB. The immunoassay modeling projects have been in collaboration with Elain Fu (University of Washington).

A short biography

As an undergraduate at Brown University, I majored in mathematical physics and carried out my senior thesis research (in cosmology) with Robert Brandenberger. This work provided my first exposure to computational modeling and simulation, and led to graduate study in the physics program at the University of Maryland. Under the supervision of Bei-Lok Hu, I studied the nonequilibrium dynamics of quantum fields in curved spacetime. The computational dynamical modeling work that I did for my Ph.D. research sparked a more general interest in harnessing the power of large-scale computational approaches to solve complex modeling and analysis problems. This interest in scientific computing led me to Maynard Olson's laboratory at the University of Washington Genome Center, where I spent a year developing computational tools for genome mapping, as a part of the consortium to sequence human chromosome 7. This fellowship provided an important foundation in biology and in computational genomics. Motivated by a desire to broaden my computational skills, in 1999 I joined InterNAP, a (then) start-up technology company specializing in performance-based routing of Internet traffic. There, I developed computational software and algorithms for network monitoring and traffic routing optimization. Through this work I gained experience with algorithms to efficiently solve high-dimensional optimization and temporal prediction problems. A key turning point in my career was realizing the potential power of these computational techniques for solving difficult problems in biology.

Eager to apply these computational methods in biology, in 2003 I joined the Institute for Systems Biology as a senior research scientist. In the laboratory of Hamid Bolouri, I worked on computational modeling projects in the areas of cell signaling and transcriptional regulation. As a part of this work, I developed a software program, Dizzy, for simulating the stochastic dynamics of biochemical reaction networks, based on Monte Carlo solution of the chemical master equation. Dizzy has been used by researchers in over a hundred institutions around the world. In 2005, I joined Ilya Shmulevich's lab at ISB, where I worked on various computational inference and modeling projects studying transcriptional regulatory networks in the areas of innate immunity (in collaboration with Alan Aderem) and metabolism and organelle biogenesis (in collaboration with John Aitchison). Through the innate immunity projects, I became interested in how macrophage sensing of pathogens is linked to alterations in cellular lipid metabolism. This interest led to an ongoing collaboration with Liz Gold to study the role of macrophages in atherosclerosis, with an emphasis on lipid metabolism and foam cells.

In 2010, I started work on an NIH K25-supported project to study foam cell formation using a systems biology approach involving transcriptional profiling. In April, 2011, I moved to Seattle BioMed and joined the laboratory of my K25 co-mentor, Alan Aderem. At Seattle BioMed, I am continuing my investigation of the role of macrophages in atherosclerosis, as well as continuing various other collaborations in immunology, vascular biology, lipoprotein metabolism, and systems biology.

Peer-Reviewed Publications:

* indicates that these authors contributed equally.

Bibliographic information	Title	Author(s)	Link
J Exp Med. (in press, 2012)	ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol-induced lipid body formation	Gold ES*, Ramsey SA*, Sartain MJ, Selinummi J, Podolsky I, Rodriguez DJ, Moritz RL, Aderem A	(in press)
Mol Syst Biol. (in press, 2012)	Asymmetric positive feedback loops reliably control biological responses	Ratushny AV, Saleem RA, Sitko K, Ramsey SA, Aitchison JD	(in press)
J Biol Chem. 286:22665-22677 (2011)	Mechanisms of urokinase plasminogen activator (uPA)-mediated atherosclerosis: Role of the uPA receptor and S100A8/A9 proteins	Farris SD, Hu JH, Krishnan R, Emery I, Chu T, Du L, Kremen M, Dichek HL, Gold E, Ramsey SA, Dichek DA	[DOI]
Methods Mol Biol. 781:415-33 (2011)	Mathematical modeling of biomolecular network dynamics	Ratushny AV, Ramsey SA, Aitchison JD	[DOI]
Microfluid Nanofluid. 10(1):29-35 (2011)	Transport in two-dimensional paper networks	Fu E, Ramsey SA, Kauffman P, Lutz B, Yager P	[DOI]
Analyt. Chem. 83(20):7941-7946 (2011)	Enhanced sensitivity of lateral flow tests using a two-dimensional paper network format	Fu E, Liang T, Houghtaling J, Ramachandran S, Ramsey SA, Lutz B, Yager P	[DOI]
J Cell Sci. 123(Pt 20):3558-65 (2010)	ATF3, an adaptive-response gene, enhances TGFβ signaling and cancer-initiating cell features in breast cancer cells	Yin X, Wolford CC, Chang YS, McConoughey SJ, Ramsey SA, Aderem A, Hai T	[DOI]
Bioinformatics. 26(17):2071-5 (2010)	Genome-wide histone acetylation data improve prediction of mammalian transcription factor binding sites	Ramsey SA, Knijnenburg TA, Kennedy KA, Zak DE, Gilchrist M, Gold ES, Johnson CD, Lampano AE, Litvak V, Navarro G, Stolyar T, Aderem A, Shmulevich I	[DOI] Corrected supplement. doc.
BMC Bioinform. 11:377 (2010)	SeqAdapt: an adaptable system for the tracking, storage, and analysis of high-throughput sequencing experiments	Burdick DB, Cavnor CC, Handcock J, Killcoyne S, Lin J, Marzolf B, Ramsey SA, Rovira H, Bressler R, Shmulevich I, Boyle J	[DOI]
EMBO Mol Med. 2(3):79-89 (2010)	A systems biology approach to understanding atherosclerosis	Ramsey SA, Gold ES, Aderem A	[DOI]
Analyt Chem. 81(9):3407-13 (2009)	Modeling of a competitive microfluidic heterogeneous immunoassay: sensitivity of the assay response to varying system parameters	Fu E, Nelson KE, Ramsey SA, Foley JO, Helton K, Yager P	[DOI]
Nature Immunol. 10(4):437-43 (2009)	Function of C/EBPδ in a regulatory circuit that discriminates between transient and persistent TLR4-induced signals	Litvak V, Ramsey SA, Rust AG, Zak DE, Kennedy KA, Lampano AE, Nykter M, Shmulevich I, Aderem A	[DOI]
Proc Natl Acad Sci U S A. 106(10):3758-63 (2009)	Dynamic analysis of MAPK signaling using a high-throughput microfluidic single-cell imaging platform	Taylor RJ, Falconnet D, Niemistö A, Ramsey SA, Prinz S, Shmulevich I, Galitski T, Hansen CL	[DOI]
Biophys J. 95(8):3715-23 (2008)	Control of transcriptional variability by overlapping feed-forward regulatory motifs	Ratushny AV*, Ramsey SA*, Roda O, Wan Y, Smith JJ, Aitchison JD	[DOI]
PLoS Comp Biol. 4(3):e1000021 (2008)	Uncovering a macrophage transcriptional program by integrating evidence from motif scanning and expression dynamics	Ramsey SA, Klemm SL, Zak DE, Kennedy KA, Thorsson V, Li B, Gilchrist M, Gold ES, Johnson CD, Litvak V, Navarro G, Roach JC, Rosenberger CM, Rust AG, Yudkovsky N, Aderem A, Shmulevich I	[DOI] Corrected Table S17.
Proc Natl Acad Sci U S A. 105(6):1897-1900 (2008)	Gene expression dynamics in the macrophage exhibit criticality	Nykter M, Price ND, Aldana M, Ramsey SA, Kauffman SA, Hood L, Yli-Harja O, Shmulevich I	[DOI]
Analyt Chim Acta. 599(1):118-23 (2007)	Dependence of the signal amplification potential of colloidal gold nanoparticles on resonance wavelength in surface plasmon resonance-based detection	Fu ES, Ramsey SA, Yager P	[DOI]
Mol Syst Biol. 3:115 (2007)	Transcriptional responses to fatty acid are coordinated by combinatorial control	Smith JJ, Ramsey SA, Marelli M, Marzolf B, Hwang D, Saleem RA, Rachubinski RA, Aitchison JD	[DOI]
PLoS One. 2:e249 (2007)	Control of signaling in a MAP-kinase pathway by an RNA-binding protein	Prinz S, Aldridge C, Ramsey SA, Taylor RJ, Galitski T	[DOI]
Sens Act B Chem. 123(10):606-13 (2007)	Resonance wavelength-dependent signal of absorptive particles in surface plasmon resonance-based detection	Fu E, Ramsey SA, Chen J, Chinowsky TM, Wiley B, Xia Y, Yager P	[DOI]
Rev Sci Inst. 77:076106 (2006)	One-dimensional surface plasmon resonance imaging system using wavelength interrogation	Fu E, Ramsey SA, Thariani R, Yager P	[DOI]
Nature Genetics. 38(9):1082-7 (2006)	Dual feedback loops in the GAL regulon suppress cellular heterogeneity in yeast	Ramsey SA, Smith JJ, Orrell D, Marelli M, Petersen TW, de Atauri P, Bolouri H, Aitchison JD	[DOI] Corrected supplementary note.
Physica D. 217(1):64-76 (2006)	Feedback control of stochastic noise in the yeast galactose utilization pathway	Orrell D, Ramsey S, Marelli M, Smith JJ, Petersen TW, de Atauri P, Aitchison JD, Bolouri H	[DOI]
Philos Trans R Soc Lond B Biol Sci. 361(1467):495-506 (2006)	Transcriptional noise and cellular heterogeneity in mammalian macrophages	Ramsey S, Ozinsky A, Clark A, Smith KD, de Atauri P, Thorsson V, Orrell D, Bolouri H	[DOI]
Proc Natl Acad Sci U S A. 102(48):17296-17301 (2005)	A data integration methodology for systems biology	Hwang D, Rust AG, Ramsey S, Smith JJ, Leslie DM, Weston AD, de Atauri P, Aitchison JD, Hood L, Siegel AF, Bolouri H	[DOI]
Proc Natl Acad Sci U S A. 102(48):17302-17307 (2005)	A data integration methodology for systems biology: experimental validation	Hwang D, Smith JJ, Leslie DM, Weston AD, Rust AG, Ramsey S, de Atauri P, Siegel AF, Bolouri H, Aitchison JD, Hood L	[DOI]
J Bioinform Comp Biol. 3(2):415-436 (2005)	Dizzy: Stochastic simulations of large-scale genetic regulatory networks	Ramsey S, Orrell D, Bolouri H	[DOI] (Supplement: [DOI])
Bioinformatics. 21(2):208-217 (2005)	A method for estimating stochastic noise in large genetic regulatory networks	Orrell D, Ramsey S, de Atauri P, Bolouri H	[DOI]
Biochem J. 387:77-84 (2005)	Is the regulation of galactose-1-phosphate tuned against gene expression noise?	de Atauri P, Orrell D, Ramsey S, Bolouri H	[DOI]
Syst Biol (Stevenage). 1(1):28-40 (2004)	Evolution of "design" principles in biochemical networks	de Atauri P, Orrell D, Ramsey S, Bolouri H	[DOI]
Int J Theo Phys. 40(12):2231-58 (2001)	Interacting field theories in Robertson-Walker spacetimes: analytic approximations	Molina-Paris C, Anderson PR, Ramsey SA	[DOI]
Phys Rev D. 61:127501 (2000)	One-loop λφ4theory in Robertson-Walker spacetimes: adiabatic regularization and analytic approximation	Molina-Paris C, Anderson PR, Ramsey SA	[DOI]
Phys Rev D. 61:125013 (2000)	Hydrodynamic transport functions from quantum kinetic theory	Calzetta EA, Hu BL, Ramsey SA	[DOI]
Phys Rev D. 59:045009 (1999)	Defect formation and Critical Dynamics in the Early Universe	Stephens GJ, Calzetta EA, Hu BL, Ramsey SA	[DOI]
Int J Theo Phys. 38(4):1299-1314 (1999).	Nonequilibrium dynamics of quantum fields in inflationary cosmology	Ramsey SA	[DOI]
Phys Rev D. 57:6003-6021 (1998)	Nonequilibrium inflaton dynamics and reheating. II. Fermion production, noise, and stochasticity	Ramsey SA, Hu BL, Stylianopoulos AM	[DOI]
Phys Rev D. 56:678-705 (1997); Erratum-ibid 57:3798 (1998)	Nonequilibrium inflaton dynamics and reheating: Back reaction of parametric particle creation and curved spacetime effects	Ramsey SA, Hu BL	[DOI]
Phys Rev D. 56:661-677 (1997)	O(N) Quantum fields in curved spacetime	Ramsey SA, Hu BL	[DOI]

Other Publications or Works:

Bibliographic information	Title	Author(s)	Hyperlink
U.S. Patent no. 7555542 (2009)	Method and system for directing requests for content to a content server based on network performance.	Ayers M, Black BJ, Brown C, Carlson J, Cohn D, Laird S, Miller J, Ronen O, Schachter P, Stiffelman O, Ramsey S
U.S. Patent no. 6981055 (2005)	Method and system for optimizing routing through multiple available Internet route providers.	Ahuja A, Ayers M, Black B, Brown C, Cohn DT, Ramsey S, Ronen O, Schachter PJ, Stiffelman OB, Wheeler CD
Doctoral Dissertation, University of Maryland (1997)	Nonequilibrium dynamics of quantum fields in inflationary cosmology	Ramsey SA (Ph.D. advisor: Bei-Lok Hu)	[ArXiv]
Brown University Physics Report BROWN-HET-922 (1993)	Some statistics for measuring large-scale structure	Brandenberger RH, Kaplan DM, Ramsey SA	[ArXiv]