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Site:
Laboratory of Systems Biology and Medicine (LSBM)
Research Center for Advanced Science and Technology
University of Tokyo
4-6-1 #34 Komaba, Meguro-Ku, Tokyo 153-8904, Japan
Date:
December 13, 2004
WTEC Attendees:
C. Stokes (report author), M. Cassman, A. Arkin, F. Katagiri, F. Doyle, S. Demir, R.
Horning
Host:
Tatsuhiko Kodama, Director
Sigeo Ihara
Hiroyuki Aburatani
Takao Hamakubo
An overview of the laboratory and some of the technology development was given by Dr. Kodama. His
colleagues who also attended, Dr. Sigeo Ihara, Dr. Hiroyuki Aburatani, and Dr. Takao Hamakubo, described
research projects.
BACKGROUND
The Laboratory for Systems Biology and Medicine (LSBM; www.lsbm.org) is part of the Research Center
for Advanced Science and Technology (RCAST) and is focused on both basic and applied systems biology
research. LSBM has a basic research thrust that Dr. Kodama termed reverse systems biology, and an applied
research thrust that he called genome-based antibody diagnostics and therapeutics. The research is focused on
lab and data-driven hypothesis testing, with an emphasis on genomics- and proteomics-based data-generation
and analysis. There is much statistics-based data analysis but little or no mechanistic or dynamic modeling.
There is a significant emphasis on development of antibodies for therapeutics and antibodies, and this as well
as the basic research is supported by number of centralized, shared research facilities and resources that are
utilized by the 11 faculty and associated staff and students.
RESEARCH
LSBM basic research focuses on learning how genes translate into cell behaviors, not just finding out what
genes are involved. They have a strong interest in the mechanisms of cancer and arteriosclerosis, among
other things, and have established a number of cell based model systems for the study of these diseases. They
use genomic measurements and genetic and biochemical perturbations to probe for disease relate genes and
to study how the gene products are function in a disease process in their model cell systems. They emphasize
the measurement and analysis of temporal profiles and spatial localization of proteins as part of this work.
Dr. Kodama noted that their basic science research on for mechanisms of cell function is not as advanced as
their applied antibody research.
LSBM applied research is focused on the development of antibodies for diagnostics and therapeutics. This
development and commercialization is a major metric of success for the laboratory, according to Dr.
Kodama. Specifically, they have a goal of developing 150 new antibodies per year, some of which they will
choose to develop for commercialization. To date they have generated several hundred antibodies, and of
these they are taking forward five antibodies for diagnostics and two for therapeutics. Their goal is to have
generated 1200 antibodies, and be developing 10 of those for therapeutics and 42 for diagnostics, by 2008.
To carry out this work, they have developed several facilities and resources within the laboratory to support
transcriptome analysis, informatics, protein expression, antibody generation, and assays/histology/pathology.
The last in particular utilizes collaborations with medical schools and other universities. They discussed in
more detail their gene expression database, their protein interaction database compiled by text mining and
analysis, and their large-scale generation of antibodies.
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B. Site Reports
Dr. Ihara described the protein interaction database platform that they’ve developed to help understand
mechanisms and select protein targets against which to raise antibodies, in development since 1999. Using
the platform they have built pathway maps by literature mining, analyzing more than 1.6 million abstracts in
PubMed and extracting more than 700,000 protein-protein interactions through noun-verb-noun
combinations. This platform consists of several parts including a dictionary, an index of articles and a way to
query gene names. Pathways are generated from pairwise interactions resulting from such a query. Dr. Ihara
discussed some of the challenges to this work, including that there are “too many” interactions making the
resulting networks very dense and large, and that a large number of errors occur in the database and pathways
in large part because many genes have multiple names. The database is accessible within the institute now,
and a prototype is accessible on the web. They’re patenting some aspects of the work. A paper is submitted
for publication, and Dr. Ihara expects to make some parts of the database available publicly once the paper is
published.
Professor Aburatani presented their work on a gene expression profile database as infrastructure for the
laboratory, and for the public eventually. They’re using array-based high throughput biology of various
types, including typing arrays and tiling arrays using Affymetrix chips. The typing arrays are used to find the
copy number of chromosomes as well as typing information. With the former they can discriminate which
parent is the source of the chromosome as well as copy number. Hence they’re using arrays for analyzing
mechanism, not just identifying genes. They’re integrating a number of genomic approaches including SNP
typing and RNA expression. There is a dynamic aspect of their work, for instance some experiments include
running transcriptome arrays every 15 minutes for eight hours.
Once they have selected a protein against which they want to make a specific antibody, they express
membrane proteins on a baculovirus and inoculate the mouse to raise antibodies against the membrane
proteins. Mice do not immunologically recognize the baculovirus, making it a good vector for this work. The
cleaved N-terminal protein is also useful for serum detection of protein. Generation of antibodies that can be
used for the basic research as well as potential commercialization is a major effort within LSBM.
The LSBM works closely with the university’s computer-human interface group to visualize data in
revealing ways, for instance to visualize the aberrations between patients, and for chromosomal data analysis.
As an application of these resources, cancer is a major focus of the laboratory. They have found a number of
cancer-specific genes from microarray applications since 1999. They’re currently generating antibodies
against certain of these cancer-associated genes. Liver, stomach and lung cancer are their focus because
they’re the most common cancers in the Japanese population. In one project, they have generated an
antibody against heparan sulfate which they’ve shown kills liver cancer. It is now in development as an anticancer drug.
Another application focus is on nuclear hormone receptor genes. They have expressed 45 of 48 known
nuclear hormone receptor genes and raised antibodies against them. They are using the same technologies as
above to probe the function of the nuclear hormone receptors and find associated genes.
On the diagnostics, they would like to be able to diagnose a condition from a single drop of blood. They
don’t expect to find a single marker for a cancer but rather combinations that can form a diagnostic.
Their interest in commercialization of their antibodies as therapeutics and diagnostics requires an emphasis
on developing and protecting intellectual property (IP). LSBM collaborates with at least eleven companies,
necessitating significant effort on how IP is shared as well. LSBM utilizes their status as a public, academic
institution to access resources such as unique reagents that are typically shared among academics, while
handling the knowledge gained through their research use carefully so as not to impair IP protection. For
instance, Dr. Kodama noted that they would forgo publication and/or patenting a finding in order to keep
their commercialization options open. He also noted that they often work without formal agreements in place
in order so that they can proceed with research. One of the faculty specializes in medical economics, and Dr.
Kodama implied that this faculty member was central to handling IP issues for LSBM.
B. Site Reports
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PERSONNEL
There are about 120 personnel of LSBM, including the following professors:

Kodama – Director; cholesterol, atherosclerosis

Ihara – previously director of research at Life Science Division at Hitachi

Aburatani – Genomics

Shibasaki – Membrane traffic and visualization

Nomura – Previously in a pharmaceutical company, cloned G-CSF

Sakai – Previously in Dallas, metabolism and diabetes

Reid – Membrane microdomains

Noguchi – Chemistry

Minami – Formerly at Harvard, vascular biology

Sakihama – Formerly at Brigham and Womens Hospital in Boston

Moriguchi - Medical economics

Hamakubo – Expression methods for membrane proteins
There are about 20-30 graduate students and about 20 postdocs. The rest of the 120 or so personnel are
technicians. They don’t have undergraduates. While they do wet biology, a number of the researchers have
backgrounds in math and physics, which Dr. Kodama noted influences their thinking about research
approaches. Dr. Kodama noted that a number of people from companies also work at the institute as part of
various collaborations.
TRAINING
The graduate students are educated within the institute and in other departments, including training in
informatics, biology and analytical tools. There are no continuing education courses for outside researchers,
although there are many lectures and seminars and people are very interactive within disciplines. A
significant aspect of student training is through interaction with people from various disciplines, facilitated
by everyone being housed in one building or very nearby. To foster interaction they have a weekly lab
meeting with all the graduate students, as well as a 2-day annual retreat. After graduation, about a third of
their graduate students go to work in industry, a third stay at universities in Japan as postdocs and a third go
to the US (presumably as postdocs).
FUNDING
The LSBM budget is about $10M/year, with the government accounting for about 40% of their funding right
now. They get funded through multiple mechanisms:

Licensing for their patented inventions

RCAST has a venture fund (ASTEC) that has funded ($10M to date) a spin-off company, Perseus
Proteomics. Some of these funds come back to LSBM for collaborative research.

Company collaborations. Kowa is a collaborator, providing $4M to the department from the
commercialization of one of their antibodies.

Funding from the government as part of the “Millennium Project”

Various government ministries