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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.
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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
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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/).