Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
1 Site: Symbiotic Systems Project Keio University, Shinanomachi Research Park 35 Shininomachi, Shinjuku-ku Tokyo, 160-8582 Japan Date: December 13, 2004 WTEC Attendees: A. Arkin (report author), M. Cassman, F. Doyle, F. Katagiri, C. Stokes, S. Demir, R. Horning Hosts: Hiroaki Kitano, Director Douglas Murray Hisao Moriya Noriko Hiroi Akihira Funiyashi OVERVIEW The Symbiotic Systems Project (SSP) is led by Hiroaki Kitano, who is also the director of Sony Computer Science Laboratories, Inc (SCSL) and a professor at Keio University. The basic goal of the project is to develop and apply new technology and computational tools to understand dynamical phenomenon in cellular systems. The primary location for the program is partly housed in a well-designed space in the Shinanomachi district of Tokyo. There is also wet lab space 13 minutes away by foot at Keio Medical School. Research areas of interest to the institute include new approaches to understanding biological robustness, and how software and computational tools can help in addressing such issues. They have a central interest in mechanisms that make cancer difficult to treat and in the control of the cell cycle. The meeting was held at the computational facility in Shinonamachi. The space is well-designed office and computational space. Design is another of Dr. Kitano’s talents. For example, illuminated walls of glass that allow researchers to project slides or write on the walls during a discussion define some rooms. His designs of the workspace and in the robots he helped produce for SONY have been featured at the New York Museum of Modern Art. He is also an expert on high-performance computing and consulted with such innovative computer architecture companies such as Thinking Machines. HISTORY Dr. Kitano has been working in systems biology since 1993 even while he was first starting at Sony. His current program was founded in 1998 by a grant from the Japanese government (Japanese Science and Technology Corporation, JST) as part of their ambitious ERATO (Exploratory research for Advanced Technology) program. In 2000, the ERATO project officially became part of the newly created Systems Biology Institute. The Systems Biology Institute was founded in 2000 to provide an entity that could accept funding from other sources so that the research seeded by ERATO could be stably funded. This institute garnered follow-on funding from the ministry of agriculture and NEDO, a subbranch of METI (the Ministry of Economics, Trade and Industry). In 2003 the ERATO project finished, but with this extra funding and additional support from the Solution Oriented Research and Technology Program (SORST) in the Ministry of Education, the projects have expanded and continued. The first round of ERATO funding targeted research on fundamental modeling and model standards technology such as the Systems Biology Workbench and the Systems Biology Markup Language, as well as new theory of the robustness of cellular networks and their application to yeast signaling. The current funding continues to support the work on standards and has expanded the research focus. 2 B. Site Reports The project operates at approximately $2M/year total cost down from $3M/year when the project started. However, that initial funding included research on humanoid robots that spun out into a company and is not part of the current research program. This funding covers approximately six researchers including 2 full time and 1 part-time researcher, 1-2 part time graduate students, and 1 technician. RESEARCH FOCUS In addition to the broad areas above, Kitano outlined a number of other areas of research in the institute including signal transduction in yeast and mammals (collaborating with the Alpha Project and the Alliance for Cellular Signaling), respiratory oscillations in yeast and calcium oscillations in mammalian cells (including collaborations with the Karolinska Institute), and advanced hardware platforms for simulations. Institute personnel discussed a few of these areas in detail. Douglas Murray, a relatively new researcher at the Institute and late of the Dynamics Group, Department of Biology, Beckman Research Institute of the City of Hope Medical Center, presented his research on the respiratory and reductive phase oscillation in the budding yeast, Saccharomyces cerevisiae. He has developed a highly controlled continuous culture system in yeast. The cycle he is studying was discovered in 1973 by Mochen and Pye and evolves after glucose repression followed by diauxic shift to become a respiratory oscillation with an approximately 40 minute period. In subsequent work, these oscillations have been shown to be linked to pathways as diverse as apoptosis, transcription and cell cycle and to be correlated with morphological changes in the cell. Other redox intermediates show oscillations in or out of phase with the aerobic respiratory response: NADH oscillates in phase with O2 usage and glutathione oscillates out of phase. Thus, a complex redox cycle is set up. Murray has related the oscillations shown here to the chronobiological processes of circadian rhythms. Like the circadian rhythm, this cycle seems to be temperature and partial pH compensated. Murray used Affymetrix-based gene expression analysis to follow cells synchronized via either an acetaldehyde pulse or H2S off-gassing. Interestingly, those cells synchronized using the acetaldehyde pulse showed both type 1 and 3 phase response curves whereas H2S perturbations results only in a type 1 curve. These are diagnostic of the structure of the oscillatory cycle as well as the role of these two substrates in the cycle. Using both imaging and microarrays, Murray demonstrated that the redox cycle not only gates the cell cycle but also regulates, in a coordinated manner, nearly all of gene expression (~9/10 of genes are expressed in reductive phase and ~1/10 (mostly RNA synthetases) in respiratory phase). The entire transcriptome, therefore, changes in roughly 8 minutes. Using a Fourier focusing analysis, Murray discovered that appearance for the transcript for a process occurs about 20 minutes earlier than appearance of the phenotype. He then used Cytoscape to display his transcriptional results in coherent networks. Dr. Hisao Moriya had just finished a post-doc in Mark Johnston’s laboratory at Washington University when he joined the institute in April 2004. His research concerns glucose sensing and conserved network structure in yeast as well as the yeast cell cycle. As he has just started and his research involves both experimental and computational components the results are preliminary. He used Kitano’s Cell Designer, a graphical pathway design tool that explicitly represents molecular state and output pathways, to create a model of the hexose transporters induced by glucose exposure. In making the model he uncovered a number of feedback loops that seem to control when and which transporters are brought online. A particular configuration of positive and negative feedback loops found in this system also seems extant in control of both galactose and methionine systems, although there are currently no unifying theories as to the general purpose of this mechanism. Moriya is also exploring robustness in Tyson’s cell cycle model. Noriko Hiroi and Akira Funahashi are working on models to test alternative hypotheses about the way restriction enzymes move on DNA. This is an interesting system in which to study dimension-restricted motion and reaction, as there is a clear endpoint and geometry. Their target of study is EcoRV, a much studied E. coli restriction enzyme. They compare and contrast different mechanisms by which the enzyme discovers and cleaves its DNA target including uncorrelated jumping, and more correlated hopping and sliding processes. They wanted a model (and data) of sufficient resolution to distinguish the hopping from the sliding process. They also wanted to contrast a stochastic process representation to a simpler stochastic model by Coppey et al. They built two separate models to represent different amounts of hopping and sliding B. Site Reports 3 of the restriction enzyme (based on kinetic parameters from A. Pingoud) and simulated the dynamics of cleavage that they could compare to existing data on cleavage rates measured by Stephen Halford. They were able to demonstrate that a correlated motion model was necessary to explain the data and to estimate the relative contributions of sliding and hopping. However, there is more validation to be done. Akira Funahashi then described Cell Designer more fully (this is NOT an open-source tool yet) and a hardware accelerated simulation system based on Field Programmable Gate Arrays (FPGAs). They have built a set of algorithmic design tools called, RecSiP (Reconfigurable cellular simulation platform), which reprogram this software configurable chip for ODE or stochastic simulation. Though all recognized that much speed could be obtained just by algorithm design, the supposition is that whatever the algorithm it could be programmed onto this chip which would then run in much faster than a compiled language would on a more general purpose processor. Funahashi demonstrated that the system obtained an 18-19-fold increase for ODE based simulations and over a 100 fold speed-up for stochastic algorithms such as Dennis Bray’s Stochsim. Following these talks Kitano then summarized a number of other projects he is driving or collaborating in including an pheromone pathway modeling project with Mel Simon and Tau-Mu Yi in which they have tagged with GFP over 30 proteins in the pathway and obtained time-course and localization data under different knockout conditions. With this and other data they are trying to reverse engineer unknown parts of the pathway. Another, interesting project is the tracking of cells and nuclei during development of C. elegans from the fertilized egg through the 32-cell state. They have built automated image analysis systems and a type of 3D Nomarski imaging to localize the nuclei during cell division and track their motion during division. They can then correlate the motion of different nuclei and compare tracks of a given nuclei from multiple eggs to see how controlled and precise the process is. When queried about educational programs, Kitano mentioned that Keio University has a relatively new department of biosciences and informatics with about 30-40 undergraduates. (http://www.st.keio.ac.jp/ english/facu_bio/).