Princeton: Center for Quantitative Biology

Peter Andolfatto , Ph.D. (Ecology and Evolutionary Biology) combines both computational and experimental approaches to address a broad range of topics in Evolutionary Genetics/ Genomics using laboratory and wild-caught Drosophila as a model system. Current research is aimed at: (1) Quantifying the mode and strength of selection acting on coding and non-coding DNA in the genome; (2) Quantifying the effects of non-coding DNA divergence on patterns of gene expression; (3) Quantifying recombination rate variation in the Drosophila genome and its effects on patterns of genome variability and evolution; and (4) Determining how changes in population size and and structure influence patterns of genome variability.

Bonnie Bassler , Ph.D. (Molecular Biology) focuses on the molecular mechanisms that bacteria use for intercellular communication through the exchange of chemical signaling molecules. This process, termed quorum sensing, allows bacterial populations to coordinate gene expression. Quorum sensing bacteria produce, release and detect autoinducers that accumulate in the environment as the cell population increases. Recently, her group determined the biosynthetic pathway for such a compound, a furanosyl borate diester with no resemblance to any previously characterized autoinducer.

William Bialek , Ph.D. (Physics) believes developments in statistical mechanics and dynamical systems have prepared the physics community to address theoretical questions posed by more complex systems that need to be addressed in biology. From observing the dynamics of single biological molecules to building theories for the neural networks that make possible our perception of the world, there are myriad challenges for physicists and biologists willing to explore the boundary between their disciplines.

David Botstein , Ph.D. (Molecular Biology) is active in two research areas: (1) genome-wide studies of gene expression through the life cycle and experimental evolution of budding yeast (Saccharomyces cerevisiae) and (2) quantitative analysis and intuitive display of genome-scale biological information.

James Broach , Ph.D. (Molecular Biology) does research directed toward understanding cellular regulation at the molecular level, using the yeast Saccharomyces cerevisiae as a model system. Specifically, he is investigating (l) signal transduction regulating initiation of cell growth, and (2) the mechanism underlying the control of cell type in yeast. His group approaches these problems using a combination of yeast genetics, biochemical analysis, cell biology and genomic techniques.

Curtis Callan , Ph.D. (Physics) is a theoretical physicist broadly interested in problems that raise general conceptual issues, such as the representation and transport of information, the stability of biological systems against the large fluctuations associated with small numbers of critical elements and so on. He is currently working on strategies for improving the precision with which transcription factor binding sites can be identified. Roughly speaking, the intent is to marry general ideas from statistical mechanics and learning theory to the vast amount of specific information made available by modern genomics. He hopes to use results from this study to learn the principles underlying the construction of the networks that control gene transcription in bacteria.

Hilary Coller , Ph.D. (Molecular Biology) is combining experimental analysis, computational analysis and technology development to understand quiescence in human cells. Quiescence is the counterpart to proliferation: a reversible, non-dividing state. The laboratory is creating models of quiescence in human fibroblasts and other cells. By applying microarray gene expression profiling, metabolomics, functional genetic screens, in vivo immunohistochemistry, and candidate gene testing, the laboratory hopes to understand the molecular changes that occur during quiescence in human cells.

Edward Cox , Ph.D. (Molecular Biology) focuses on the origins of spatial patterns in Dictyostelium, with a special emphasis on the use of mutants to define the origins of cAMP oscillators and waves. This work combines mathematical modeling, genetics, and molecular biology with the goal of developing robust models that can be tested genetically.

Lynn W. Enquist , Ph.D. (Molecular Biology) aims to understand the molecular mechanisms of herpesvirus neurotropism and spread in the mammalian nervous system and to understand how the mammalian nervous system responds to neurotropic virus infections. He uses two general approaches: 1) studying the genetics and molecular biology of viral genes that affect virus attachment, entry, movement within neurons, virion assembly, trans-synaptic passage and virulence and 2) using neurotropic viruses as tools to study the mammalian nervous system. In particular, he is using these viruses as tracers of neural connections in the rat brain and in developing chick embryos.

Christodoulos A. Floudas , Ph.D. (Chemical Engineering) is interested in the areas of (i) product and process systems engineering, and (ii) bioinformatics and computational genomics, which lie at the interface of chemical engineering, applied mathematics/operations research, computer science, computational chemistry and molecular biology. The unified thrust of his research is to address fundamental problems and application areas through detailed mathematical modeling at the microscopic, mesoscopic and/or macroscopic level, rigorous optimization theory and algorithms, and large-scale computations on high performance clusters.

Zemer Gitai , Ph.D. (Molecular Biology)

Thomas Gregor , Ph.D. (Physics) applies experimental and theoretical approaches at the interface of physics and biology to understand early developmental processes such as signaling and patterning in a variety of model systems. He believes that a quantitative understanding generated by a combination of high precision measurements of the relevant molecular mechanisms and mathematical formulations describing these mechanisms will lead to new unifying underlying principles. Current projects range from self-organization in amoebae populations, to transcriptional regulation and pattern formation in early fruit fly embryos, to in utero imaging of mammalian embryos.

John Hopfield , Ph.D. (Molecular Biology) centers his research on how the nervous system computes. Two systems are particularly studied; early olfactory processing and early auditory processing. The problems being addressed include issues such as how an odor can be recognized independent of odor intensity, and even in the presence of strong background odors; how new odors can be quickly learned; and how an environment containing several different unknown odor objects can be parsed into separate objects. Similar issues are present in the early auditory processing which results in our ability to hear spoken language and break it up into an alphabet of short acoustic symbols.

Leonid Kruglyak , Ph.D. (Ecology and Evolutionary Biology) is interested in the genetic basis of heritable traits, including diseases. The genetic basis of most traits is complex, involving many genes that interact with each other and the environment. The Kruglyak lab conducts experiments in model organisms (principally the yeast Saccharomyces cerevisiae), as well as computational analyses of human and canine populations, aimed at understanding how changes at the level of DNA lead to all the observable differences among individuals within a species.

Simon A. Levin , Ph.D. (Ecology & Evolutionary Biology) is broadly interested in using mathematical and computer modeling as a device for exploring ecological or evolutionary relationships. A primary interest is in disease dynamics, from genomic analysis to epidemiology. More generally, he studies the responses of organisms or populations to heterogeneous environments, problems of pattern formation (such as schooling and swarming, and gap phase dynamics in forest ecosystems), and the evolution of life history characteristics. He is also interested in modeling coevolutionary processes, from the dynamics of tight host-parasite systems to the diffuse evolution of chemical defenses, to the self-organization of ecosystems.

Kai Li , Ph.D. (Computer Science) is interested in computer architecture, operating systems, parallel systems, and networking. Current research projects focus on architecture and system issues in building and using Universal Memex and Scalable Display Wall systems, and Universal Memex. The Universal Memex project investigates how to build and use systems that can extend human memory. Such a system can remember everything a person reads, writes, hears and sees, and can retrieve desired information quickly. The Scalable Display Wall project explores research issues on how to build and use immersive systems to collaborate across space and time. Current research topics include seamless imaging, parallel rendering, ultra-high-resolution videos, tools to create applications for scalable displays, and data visualization for large scientific and genomic datasets.

Manuel Llinas , Ph.D. (Molecular Biology) focuses on the molecular mechanisms of the deadly malaria parasite Plasmodium falciparum. In an effort to identify additional vaccine and drug treatment targets for this disease, the lab uses a combination of computational and whole genome approaches to investigate the regulation of gene expression in P. falciparum. The lab merges state-of-the-art DNA microarray technology and bioinformatics, with classic protein purification and cell culture methods to achieve these goals.

Coleen Murphy , Ph.D. (Molecular Biology) is interested in understanding the molecular mechanisms that govern how we age. She uses the nematode C. elegans, which shows signs of aging in its two-week lifespan, as a model system. By using microarrays to analyze the transcriptional changes that occur during aging and in long-lived mutants, the genes that are important for longevity can be identified. Because C. elegans is highly genetically tractable, these genes' specific roles in longevity can then be functionally tested. Additionally, meta-analysis of the information from gene expression experiments will help elucidate the global transcriptional regulation of aging. By fully understanding how a simple animal ages, the rules that regulate the rate of aging and the genes that are important for longevity in higher organisms should become clear as well.

Joshua Rabinowitz , MD/Ph.D. (Chemistry) aims for a holistic, quantitative understanding of cellular metabolism. The cellular metabolic network consists of some 700 chemical reactions involving approximately 500 molecules, which convert nutrient inputs into the energy and macromolecule building blocks required for cell function and growth. The Rabinowitz lab develops methods to quantify in a highly parallel manner metabolite concentrations and fluxes using tandem chromatography - mass spectrometry. In addition, it measures how these concentrations and fluxes change in response to the cellular environment, and models computationally the regulatory controls responsible for such changes.

Herschel Rabitz , Ph.D. (Chemistry)

Gertrud M. Schupbach , Ph.D. (Molecular Biology) has focused on a signaling pathway that operates in Drosophila oogenesis. In response to a localized signal from the oocyte, the Drosophila EGF receptor is activated in follicle cells. Her group has isolated a number of mutations that affect either the production of the signal or the response in the follicle cells. They plan to complement the genetic approaches with microarray gene detection techniques that should allow them to identify genes that are transcriptionally up- or down- regulated after activation of the EGF receptor in follicle cells, regardless of their mutant phenotype. They are also collaborating with Stas Shvartsman's group who has developed a mathematical model to describe the genetic feedback loops in the follicle cells.

Joshua W. Shaevitz , Ph.D. (Physics) is interested in the role that cytoskeletal filaments play in the definition of cell shape and motility in bacteria. It was recently discovered that bacteria use homologs of the eukaryotic proteins actin and tubulin to guide cell growth and produce gliding and swimming movements, however physical details of these processes have been lacking due to the miniscule size of most bacterial cells. His lab is developing new experimental techniques that combine mechanical perturbation of cells and molecules with visualization of key protein and macromolecular structures to explore the physical side of these topics. The lab's toolbox includes unique combinations of optical microscopy, fluorescence and deconvolution microscopy, optical trapping, atomic force microscopy, as well as biophysical modeling and simulation.

Thomas Shenk , Ph.D. (Molecular Biology) works on HCMV. Laboratory strains of human cytomegalovirus (HCMV) were originally developed as attenuated vaccine candidates by serial passage of clinical virus isolates in fibroblasts. As a consequence, laboratory strains are genetically and biologically different than clinical isolates of HCMV. For example, the laboratory strains lack a set of ORFs present in clinical isolates. Further, laboratory strains grow efficiently in fibroblasts, but they have lost the ability to replicate in cell types where clinical isolates replicate. In spite of these differences, molecular studies of HCMV have extensively utilized laboratory strains, primarily because they replicate much more efficiently in fibroblasts than do clinical isolates. We are studying the replication of clinical HCMV strains in epithelial cells, endothelial cells and macrophages, which are targeted by the virus within an infected human.

Stanislav Y. Shvartsman , Ph.D. (Chemical Engineering) focuses on the Epidermal Growth Factor Receptor (EGFR) network, an evolutionarily conserved regulator of epithelial tissues. The current challenge is to understand how the EGF network operates in multicellular systems and tissues by integrating information from genetic, biochemical, and cellular studies into predictive quantitative models. His group develops biophysical models of EGFR signaling, analyzes them computationally, and tests the modeling predictions experimentally. Since most of the intercellular signaling mechanisms are conserved across species, model genetic organisms, such as Drosophila melanogaster, can be used to study the general principles of cell communication in tissues. They combine modeling of cell communication networks with the experimental advantages of fruit fly genetics in studying the dynamics of tissue development and regulation.

Mona Singh , Ph.D. (Computer Science) does research in bioinformatics. Within this area, her group focuses on developing computational methods for deciphering genomic data at the level of proteins. In particular, she develops algorithms for genome-level analysis of protein structure, function and interactions.

John Storey , Ph.D. (Molecular Biology) develops and applies quantitative methods in genomics. He is particularly focused on functional genomics problems involving high-dimensional data sets, such as that obtained from large-scale genotyping, gene expression monitoring, and mass spectrometry based proteomics. Because his research deals with large amounts of noisy data, a key thrust of his research is to develop theory and methods for statistics and machine learning.

David Tank , Ph.D. (Molecular Biology and Physics) focuses on persistent neural activity, a form of neural circuit dynamics that is associated with short-term memory. His group studies the mechanisms of persistent neural activity in experimental preparations that allow advanced electrophysiological, imaging, and genetic techniques to be applied. One neural system they study is the oculomotor neural integrator. Experimental results are compared with mathematical models and numerical simulations of biophysically realistic neural network models of the goldfish integrator. A second system they study in which genetic dissection of persistent neural activity may be possible is the head direction cell circuit in the mouse. This system is critically important in navigation and the current view is that it represents one component of the "sense of direction." Professor Tank's laboratory is also involved in the general development of methodologies and instrumentation that can provide measurements of chemical and electrical dynamics of neurons in vivo. Considerable progress has been made in the adaptation of two-photon laser scanning microscopy for the study of calcium concentration dynamics in dendrites and nerve terminals in intact neural circuits, including the mammalian neocortex.

Saeed Tavazoie , Ph.D. (Molecular Biology) is interested in understanding the structure and dynamics of biological networks, mainly transcriptional regulatory networks. He is studying the global architecture of transcriptional regulatory circuits, connected by interactions between such DNA-sequence motifs and the proteins that recognize and bind them. A major focus of the lab is the development of experimental and computational approaches for discerning the combinatorial logic of regulation mediated by multiple such DNA-sequences. They approach the problem of understanding cellular systems in an inter-disciplinary manner, making extensive use of genomic, computational, statistical, and analytic methods to identify network elements, discern their interactions, and model their dynamics.

Olga Troyanskaya , Ph.D. (Computer Science) combines computational methods with an experimental component in a unified effort to develop comprehensive descriptions of genetic systems of cellular controls, such as those that regulate development or whose failure may result in cancer. To achieve that goal, she is designing systematic and accurate computational and statistical algorithms for biological signal detection in high-throughput data sets. Specifically, she is interested in developing methods for better gene expression data processing and algorithms for integrated analysis of biological data from multiple genomic data sets and different types of data sources (e.g. genomic sequences, gene expression, and proteomics data). The experimental component in the lab focuses on S. cerevisiae.

Sam Wang , Ph.D. (Molecular Biology) studies dynamics and learning in neural circuits. The laboratory uses conventional and novel (chemical) two-photon methods in conjunction with traditional electrophysiological techniques to probe network activity in functioning neural tissue. Two-photon fluorescence microscopy allows the observation of activity at a single-synapse level, either in brain slices or in the whole animal. The laboratory is also developing tools to allow the manipulation of single synapses with light. Using multiphoton approaches, his laboratory has found that in the cerebellum, a brain region associated with sensory learning and planning of movements, learning rules may help explain how synaptic change translates into learning by the behaving animal.

Eric Wieschaus , Ph.D. (Molecular Biology) is interested in the patterning that occurs in the early Drosophila embryo. Most of the gene products used by the embryo at these stages are already present in the unfertilized egg and were produced by maternal transcription during oogenesis. A small number of gene products, however, are supplied by transcription in the embryo itself. His group has focused on these "zygotically" active genes because they believe the temporal and spatial pattern of their transcription may provide the triggers controlling the normal sequence of embryonic development.

Ned Wingreen , Ph.D. (Molecular Biology) focuses on the architecture of intracellular networks in bacteria. Even in a single bacterium such as E. coli, there are hundreds of coexisting networks. Probes of the internal dynamics of the network such as fluorescence resonance energy transfer (FRET) or direct imaging of dynamic spatial structure, will be critical in developing and testing quantitative models. A preliminary list of networks to be studied includes (i) quorum sensing, in which the cell slowly integrates signals from its neighbors to commit to a developmental decision such as invasion of a host, (ii) chemotaxis, which requires adaptation and rapid response to changing chemical concentrations, (iii) cell-division networks, where accuracy and checkpoints are essential, and (iv) metabolic networks which tie together diverse inputs to maintain homeostasis.