2010/03/16
RIKEN Harima InstituteResearch Promotion Division

Report on SR System Biology Research Group Midterm Review
Laboratory Leader: Group Director, Seiki Kuramitsu (D. Sci.)
Date: Saturday, November 7th, 2009
Venue: RIKEN Harima Institute (SPring-8)
Reviewers: Prof. Masayoshi Nakasako (Faculty of Science and Technology, Keio University)
Prof. Mitsuaki Yoshida (Graduate School of Frontier Sciences, The University of Tokyo)
Dr. Midori Kamimura (Pharmaceutical Discovery Research Laboratories, Teijin Pharma Limited)
Prof. Soo Hyun Eom (Department of Life Science, Gwangju Institute of Science and Technology)

Abstract of the reports:
REVIEWER 1
1. Consistency of the SR System Biology Research Group’s mission and the RSC’s mission
The main mission of this research group is construction of the research field of “Whole-cell systems
biology at an atomic level”. Only if this group’s mission is successfully completed fits this group’s mission
with that of RSC’s of “Exploring, Promoting and leading the research utilizing advanced SR facilities atSPring-8”, since the trial of the systems biology research with connection of structural biology research isthe novel and top notch research area.
2. Research Object
The final goal of SR System Biology Research Group is the understanding of all fundamental biologicalphenomena in a cell based on three-dimensional structure and function of all molecules using a modelorganism of extremely thermophilic bacterium, Thermus thermophilus HB8. As a continuation of the“Structurome project (1999~2005), this group has three research objects.
i) Functomics Integration Research Team- Structural genomics for whole-cell imaging- Developing new platforms for functional genomics- Bioimagingii) Functomics Biology I Research Team- Structural and functional analysis of transcription factors- Functional identification of functionally unknown proteinsiii) Functomics Biology II Research Team- Structural and functional analysis of protein involved in DNA repair systems- Functional discovery of functionally-unknown proteins involved in DNA repair systems- In vitro reconstruction of DNA repair systems- Construction of systems for the single-molecule imaging by using DNA repairing proteins- Analysis of cell-wall construction system for cell imaging
Addition of structural information and the functional identification of proteome is significant contribution in
the structural biology research filed. This traditional structural biology approach, however, is continuationof the structurome project. To have a novelty, this research group has to focus and elaborate more insystems biological research objects.
3. Research Results
This research group solved 111 structures in this term (2006~2009), succeed in the classification of the~140 functionally unknown proteins, and published about 80 original papers. These research outputs are
scientifically significance especially on the field of structural biology. In addition, this research groupsupported research communities by supplying resources (plasmids) and information (protein production,crystallization, structure, and functomics) obtained during the half-term of this research project. Thesepublic services obviously have high social impact to structural biology community.
4. Management of the Research Group
This group composed of three research team: Functomics Integration Research Team (FI), Functomics
Biology I Research Team (B1) and Functomics Biology II Research Team (B2). Each research team iswell equipped and has proper man power for the structural and functional research, but the connection
or interaction between three research teams is somewhat weak point. Three research teams havegenerated a large amount of phenomics, transcriptomics, proteomics, and metabolomics data by genedisruption experiment in addition to the structural information. The effort for the integration of the alreadyobtained massive data, however, seems to be insufficient. To complete the “Whole cell Systems Biology
at atomic level” successfully, FI team with the strong connection of B1 and B2 research team should
focuses more on the integration of the phenomics, transcriptomics, proteomics, and metabolomics data
and the network analysis.
5. Future research plans
This research team proposed to develop the analytical methods for functomics and construct functomics
resources in addition to the structural genomics data production including membrane proteins andmulti-subunit proteins. In addition, this research team proposed to construct the database andcollaboration with other researchers at RIKEN.
For the successful systems biology research, however, the reviewer suggests to build a core system not
only for the functional database construction and management but also for the integration of all thefunctomics data and network analysis within the research group as a core research team. Since theintegration and the network analysis is the most important part of this project, out-sourcing for this coreresearch area would not be recommended.
Although the original goal of the research group is the “whole-cell systems biology”, this research group
may focus on the transcription and translation systems biology for the next half-period, because thisresearch group has strong research background and output on this area. Otherwise, the given research
period and fund may not be sufficient to complete the whole-cell systems biology research.

REVIEWER 2

From industrial side, new technology is essential in this field. Especially I’m interesting in two different
technologies of this group.
One is in vivo expression of membrane proteins.

This group gave the data that twelve transmembraneproteins were tested for overproduction by the Mistic system and eight of them were successfullyexpressed. They said almost 70% success rate is enough for the future membrane-protein project forstructural and functional analysis.

Of course the expression rate is high but we want to know how many

protein is obtained for the crystallization.

In this point of view, this technology should be developed as a

general method that can be available for mammalian proteins with some original ideas.

REVIEWER 3
3-1 On the consistency of the Group’s mission and the RSC’s mission
The RSC has missions on the scientific researches for both material and biological science based on
cutting-edge measurement techniques utilizing X-rays provided from the SPring-8 and the X-ray Free
Electron Laser (XFEL). The Research Group utilized SPring-8 in their structure analyses of proteins, andshows their ideas or plans in utilizing XFEL in the future. However, they are still users. Although thegroup reader emphasized that they could be a powerful developer and heavy user of XFEL, it must bevery difficult for the researchers, who had little experience in beam line design and construction. Thus, atthe present stage, the Group’s missions do not match with those of the RSC. In other word, the Grouprequires technical supports from the RSC and the SPring-8, but the researches carried out by the Groupare not necessary in the missions of the RSC. It will be better to reorganize one of two teams to carry
more SR and/or XFEL oriented science research, if the project still continues in the next phase at theHarima Campus.
3-2 On the research objectives
At the present stage, the Research Group seems to contribute little to the system biology and whole-cellimaging of the bacteria. The major part of the research is simple structural analyses of soluble proteins
crystallized easily by the commercially available crystallization buffers. The research project contributelittle on the methodologies and techniques in utilizing synchrotron X-rays from the SPring-8. If this groupwill continue in the next phase, the scientific objectives must be more discussed and clearly shown. Theresearch group should have their own tactics and strategies for the system biological approach, because
the research group seems to work as an outstation of the RIKEN Yokohama at the present time.
3-3 On the research results
The group has published 68 peer-reviewed research papers in collaboration with the research groups inuniversities or the RIKEN Yokohama institute. The level of each research is at a standard level. Throughthe last 10 years including the Structurome project, the Group obtained a set of large data on thestructures and functions of proteins from the thermophilic bacteria. The results are well organized in adatabase through the efforts of young scientists. However, the Group seems to have little idea to use
effectively the database. The data may be better handled by bioinformatics groups in Tsukuba and/orYokohama campus. This may be clever choice to utilize effectively the research results.
3-4 Management of the Research group

Group member composition
In the last four years, 87 researchers from the fields of structural biology and molecular biology,
including the visiting researchers and trainees, joined to this research project. On the other hand, little
physicochemists, theoretical biologists and biophysicists joined to the research group. Thus, thecomposition of the researches seems to be inappropriate for the missions targeting the system
biology.
Researchers’ interaction
Young scientists seem to interact with each other or the team leaders within the Campus. The
opportunities to interact with scientists outside the RIKEN may be limited in the meetings of JapaneseProtein Society and the group meeting in every summer at the Campus.
Facilities and equipments
Although the set of equipments is suitable to carry out crystal structure analyses of proteins, from 2007,
the number of group members is insufficient for the set. At that time, the leader should decide toreduce the size of the research group or to get external budget to maintain the activity.
3-5. Future research plans
The future research plans of the Group are presented both in the report and the talks in the review
session. In my impression, the project leader showed little about future research plan. He still stands
within the protein science field. If the Research Project will be continued, a project leader, who is more
professionals in the system biology field, may be better choice for RIKEN. In addition, the group is
expected to show their scientific activities independent from the RIKEN Yokohama institute.
3-6. Possibility of cooperation with related fields
Dr. Mochiduki, a young PI and a theoretical biologist of the WAKO main campus of the RIKEN, may help
researches the molecular interactions in small cell systems.
3-7. RIKEN’s management
Why does the RIKEN approve closely similar or redundant research projects in Yokohama and Harima?
The RIKEN spent about 721 million yen for this basic science research project at the Harima Campus.
About this point, the group reader spoke that their researches are complementary with those at
Yokohama institute. However, the research results seem to be redundant or simple collaborations
between them. The RIKEN must explain clearly the necessity to the government and the tax payers. This
mid-term evaluation may provide a good chance to merge the research group or to terminate one of thetwo.

REVIEWER 4・ Mission: The SR System Biology Research Group aims at understanding the whole-cell phenomenain the cell at an atomic-resolution. This sounds logically, but certainly requires very long period to beachieved and could be almost end-less. The initial phase of the project has started from structuraland functional analysis of all protein components of thermo-stable bacterium. This trial fits in a scopeof RIKEN SPring-8 Center’s mission, which contributes to life science providing a powerful tool for
protein structural analysis. Targeting the thermo-stable bacterium for whole-cell system biology

sounds reasonable in view of its genome size and stable properties of the components. However,such logical target selection has a weakness in other hand in less availability of biologicalinformation and collaboration due to extremely small research community when compared withothers such as E. coli.
・ Objectives: The objective of the program overlaps with an ultimate goal of the life science in generalin full understanding the whole-cell biology as a system. It is too high to challenge even for a huge
research group, therefore should be arranged into stepwise composition. In fact, the group has
proposed a long term strategy in stepwise propulsion such as structural genomics, functionalgenomics, and interpretation of global biological phenomena; however, each goal, even at initial step,
is obscure in its scale and timing. For example, the term “all proteins” in structural analysis of allproteins in thermophilus should be practically defined. It would not be clear probably even to thegroup, therefore, it would be hard for any one to make decision or assess the program.
・ Research results: The group has determined crystal structure of over 300 proteins of thermophilus
and published the results. The results were all original and contributed to understanding function ofeach protein at atomic levels, and also contributed to the National Project so called “Protein 3,000”
through depository of the results into the Protein Data Base. So far in the world, about 400 proteinsof thermophilus were structurally analyzed and the group contributed to 75%of those, thus theircontribution is predominant. On the other hand, proteins so far success fully analyzed stays at thelevel of 20% of whole proteins of thermophilus. Driving further the structural analysis would require
new technologies, thus require more efforts than to date, since proteins which are technically difficult
to be analyzed have been postponed.
・ Management of the research group and future: Despite of their efforts on structural analysis, theselection of target proteins was random-based. As result, most of their own data are left as alone
without integration into any significant arrangement or system. Unfortunately, the efforts indeveloping system biology were very limited. Development of system biology in conjunction with thisproject might provide any better strategy for the project. The group’s skill is so focused on structural
analysis and may not retain any capacity to challenge bioinformatics, therefore, close collaboration
with other groups focusing on the system biology is strongly suggested.
・ The basic and long term programs are critically important for RIKEN in a point of view different fromthe university, however, the goal should be set clearly for understanding the progress and also formaking decision at any stages.