2011.7.29
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The RIKEN Center for Molecular Imaging Science (CMIS)The CMIS Advisory Council (AC) meeting on May 10-13, 2011-05-11 in Kobe
CMIS-AC 2011: prof Hideo Saji, prof Norihiro Sadato, Dr Noburo Yumoto, Dr JoannaFowler,Dr Mats Bergström, prof Koichi Tanaka and prof Bengt Långström (chairman)
Background: On the 10th of May the CMIS-AC met and was briefed and updated on RIKEN
business by Executive Director Dr Maki Kawai who also covered some of the visionstatements made by President Ryoji Noyori. The AC went through the prepared programand made some minor adjustments and this program was adopted and followed.
The recommendations from president Noyori given to the RAC to discuss were as follows
1. Evaluate RIKEN’s response to the recommendations made by the 7th RAC report
entitled ‚RIKEN, Laying the foundation for creative advancement‛
2. Under the 5 year plan from April 2013-March 2018, RIKEN will continue its mission as acreative scientific research institute contribute to the gathering of knowledge forhumanity’s continued existence. The AC is asked to advise on the governance,
strategies, research system and management policies.
3. Evaluate RIKEN’s cross boundary research among Centres, Institutes both national andinternational as well as with universities, industry etc. and recommend on how tomaximize RIKEN’s collective strength.
President Noyori furthermore directed the following points to the AC to consider• Does CMIS have achievements of major significance and social impact?
• Does CMIS have a PDCA cycle especially mechanisms for reorganizing, improving orclosing down if not efficient?
• Are personal management practices (hiring employment) world class? A special
concern of president Noyori to determine whether the diversity of researchers ismaintained at a high level.
• Evaluate the CMIS collaborative activities within and outside RIKEN and the efforts tocreate international collaborations.
On the 11-13 of May the meeting started with a review of Dr Watanabe where he also
responded to the comments made the previous AC and clarified actions that CMIS had beentaken. Some of the responses were then discussed.
After Dr. Watanabe’s review, the presentations from the PI’s were given. The AC was2011.7.29
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pleased with this and other materials like the white book sent out in advance and thecollected publications produced the last years. The AC was also pleased with thearrangement to meet the younger scientists in smaller group sessions to listen to theirpresentations and discuss with them their future perspective. With this information, the AC
felt sufficiently informed to make comments on the CMIS’s performance over the 2.5 years
since the last AC meeting.

Summary of the CMIS-AC’s internal discussions
We decided to base our responses on a SWOT analysis and then to propose some future
actions
Strengths
CMIS has an impressive set up of instrumentation, experienced PIs with an international
reputation and an experienced and qualified staff.
Access to several non-anesthetized animal models is a great asset for molecular imaging (MI)research and here CMIS has created a facility and organization with international excellence.
The inclusion of both anesthetized and non anesthestized primates and rodents makes it
possible to keep animals for long time thus facilitating longitudinal studies with repetitive
investigations, even at short time intervals, in the same animal subject. This further
reinforces the strength and value for CMIS in their future research program where notably
the inclusion behaviour in relation to brain physiology is an exciting scope.
This will become even more valuable with the anticipated integration of genetics,
proteonomics and other x-omics information.
The central position of synthetic chemistry and radiolabeling is in the process of being
solidified. The establishment of a large number of radiotracers in short time is indeed
impressive. There are some interesting developments of new labelling technologies andtechniques, which might be valuable in the future.
The centre has been involved in a strong line of drug distribution studies based on goodexternal collaborations, good chemistry for labelling drugs and the access to imaging in
preclinical species and followed by an expansion into humans through transfer of chemistry
to external collaborators in hospitals. Preparation for the GMP requirement is wellunderway.

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The Microdosing concept facilitates early clinical trials and that should make CMIS an
attractive partner for pharmaceutical companies promoting biodistribution studies as one
part of drug development also supporting academic drug discovery.
To belong to RIKEN is an important strength for CMIS, because molecular imaging researchis in ‚an interdisciplinary field that melds various branches of research, including syntheticchemistry, radiochemistry, biochemistry, applied physics, molecular biology, cell physiology,
pharmacology, clinical medicine, mechanical engineering, electrical engineering andcomputer engineering‛.
Within RIKEN, collaborations with the advanced science institute like Centre forDevelopmental Biology, Brain Science Institute, SPring-8 Centre, Bio Resource Centre,
Systems and Structural Biology Centre, and Research Centre for Allergy and Immunology isin progress and maybe of significant value.
RIKEN covers the majority of these fields except for clinical medicine. CMIS is, however,placed in a medical cluster in Kobe, enabling close and mutual collaboration with the clinicalmedicine. Collaboration with Institute of Biomedical Research and Innovation (IBRI)
regarding translational research is an example (White paper P61). This link with the medical
cluster in Kobe makes CMIS unique among the research centres of RIKEN.
CMIS has a strong position in the molecular imaging community of Japan and works nicelycollaboratively with the other centres in Japan as exemplified by a large number of guest
researches.
Potential scientific heights
Based on the strengths of CMIS, the energetic and enthusiastic researchers, the AC is
expecting the organization to accomplish high level of scientific achievements on aninternational level. Some projects hold the promise of forming the basis for a high-level
world-wide hub for specific cellular molecular imaging.
CMIS seems to take responsibility to attract future scientists to the field of Molecular imaging
by setting up a PET academia and doing outreach to the community by open house/activities.
Weaknesses
The AC thinks that to end translational research without a stronger connection to phase 0/1
clinical trials in man misses a major component of gathering knowledge for the improvementof the human condition. We hope the opportunity to attach a clinical site directly to CMIS

2011.7.29
4will be fulfilled, but also realize that such undertaking will impose organizational andscientific challenges.
CMIS has still limited experience in imaging in drug development especially as PD marker
for optimization for dosing and scheduling. Furthermore, the tools for supporting patient
selection is still in its infancy and therefore CMIS can, as of today, only play a limited role indrug development. The excellent examples of drug distribution shown by the site, includes
also a weakness in the sense that such studies is only requested to a limited extent bypharma.
CMIS is under-resourced for the "planned missions" (alternatively CMIS needs to focus on
increasing their visibility).
In relation to the scientific excellence, CMIS has comparably a few international
collaborations and few grants from international bodies.
In the interest to label new compounds and old drugs and perform biodistribution
studies,CMIS has sometimes lacked in the depth of validation and exploration of thecomplexity of biological processes underlying this in vivo distribution.
More emphasis needs to be placed on understanding and characterizing of the biologicalprocesses which influence the distribution and kinetics of labelled compounds in vivo.
Careful validation is even more important when a promising labelled compound istranslated to humans, and back-translation into the mechanistic pre-clinical studies arenecessary.
Opportunities
Use the chemistry, the radiochemistry and the animal models strengths of the CMIS for theevaluation of PK/PD relations in order to bring new knowledge to the field of drug
development.
Inclusion of PK/PD modelling already in the pre-clinical animal studies would make a nicetranslational path towards modelling in Phase 0/1 human studies. Association with
Computational Biology is here a great opportunity.
One of the contributions to drug development where CMIS could be of value is to further
speed-up the decision process in the early phase of drug development where PET is uniquein enabling the assessment of specificity and bioavailability.

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5With the right guidance and further collaborations with pharmaceutical companies CMIS
can be expected to make an impact in drug development.
This could be achieved by the combination of the labelling chemistry, animal models andPET imaging systems that have been established within CMIS. The full potential of theseresources will be realized with the future development of the infrastructure for humanstudies.
Access to knowledge and distribution of various molecules through research collaboration
with pharma and the establishment of the clinical network will be valuable.
Collaboration with several national and international research institutes has been establishedand will be important.
RIKEN / CMIS has no formal education responsibility: however CMIS/RIKEN should lead ina future mission of communicating/discussing with regulatory bodies and society institutes
regarding safety/risk benefit analysis and foster a new generation of health service
researchers in the hurdles and benefits of molecular imaging. This is important for the futureof MI and will have a positive societal impact. That mission should also be taken on withregard to an international responsibility.
Bring in people with a deeper understanding to some areas of human physiology and who
can bring in the important questions and knowledge gaps around the clinical needs. This is akey point and closely connected to the need of establishing a first time in man possibility for
new molecular entities.
The combination of labelling chemistry and PET imaging systems especially when applied invarious experimental designs is a powerful scientific tool allowing new ways to explore
physiology and pathophysiology. This is an area where CMIS and it’s collaborators can makesignificant contributions to new knowledge.
To work on eminent research target, which has significant societal impact would beimportant. An example is chronic fatigue syndrome, which has been continuously
investigated by Dr Watanabe et al and might be such a target area since it holds many
challenging elements fitting into the field of molecular imaging.
Use the strengths to get visibility and recognition by high impact publications.
The possibility to collaborate with the new Quantitative Biology centre can also be beneficial.

2011.7.29
6The establishment of a network for promotion of clinical studies may become a very strong
link, which needs to be recognized.
Threats
Working with pharma requires a high degree of structure and compliance to their formalities,
which can be missed by a research oriented organization and which may also be difficult toappropriately integrate in a research structure.
Not being able to clarify the area where CMIS would have a unique niche and where it
should and can contribute to.
Sub-critical resources may drive CMIS to become a service organization.
Missing the opportunity to inform researchers in- and outside CMIS about the directions of
the research conducted because of the interdisciplinary functions of CMIS.
Not continuously keeping a self critical attitude and performing reality checks.
For the sustainability it is necessary to foster the next generation of leaders.

The CMIS-AC has also responded to Director Watanabe’s suggested topics:• Recommendations on CMIS’s future research policies and the management structure topromote research, such as organization of teams, etc. for RIKEN’s next Mid-term Plan
(third 5-year plan from April 2013 to March 2018)• Evaluation of Principal Investigators (excluding head of Drug Discovery Chemistry
Platform Unit and Drug Discovery Imaging Platform Unit.)
AC acknowledges the CMIS roadmap, the new organizational plan and its underlying
strategic emphasis on health science with focus on fatigue and pain. Rearrangement of theroadmaps according to the future plan would clarify the research strategy.
A plan has been submitted for funding for the development and construction of a
Collaborative Research Centre for Molecular Imaging for first-in-man evaluation ofpotential new radiotracers. The AC strongly supports this initiative for evaluating promising
new tracers in humans including the development of kinetic modelling strategies for thequantification of molecular targets directly in humans. This initiative will result in new
knowledge, which is anticipated to have broad public impact.

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7To facilitate the development of a human imaging program, the AC recommends therecruitment of a physician scientist to work across groups in the CMIS to build up this partof the program and to integrate across projects. Along this line the AC recommends adding
another box called Human Studiesto cover First-in man studies (radiotracer quantification,
dosimetry and radiation protection, protocol development, institutional approval, subject
care and safety, documentation and medical records etc) to the diagram (below) as describedin Dr Watanabe’s future vision.

The AC has been pleased with meeting the younger scientists in smaller groups in order tocarry out discussions. These meetings were very stimulating and confirmed that the CMIS
has created a stimulating scientific environment. The AC found this very encouraging.
However a comment is that there is still a need of improvements in speaking andunderstanding the English language, even if it continuously is improving. The AC would ask
if CMIS could arrange that there is a possibility to obtain professional internal language
training and to foster an internal climate of use of English.
As a comment with regard to the language the chairman of AC acknowledge, that for thefirst time he had been attending a Takeda symposium organised by RIKEN collaborators andthe whole meeting was performed in English.

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8Another issue which was briefly has been discussed before within the AC was the genderaspects of CMIS and the results is presented below is not indicating any change. However,
Dr Doi mentioned that in radio-chemist group, there is now equal male female ratio (50: 50).
2008.10.01

MaleFemale

Total

Lab Head

6100%

00%

6Research Scientist

1983%

417%

23

Research Associate & Technical Staff

939%

1461%

23

Visiting Fellow

7082%

1518%

85

Graduate Student

1594%

16%

16

Support Sraff & Assistant

533%

1067%

15124

74%

4426%

168

Total
2011.3.31

MaleFemale

Total

Lab Head

8100%

00%

8

Research Scientist

3088%

412%

34

Research Associate & Technical Staff

1129%

2771%

38

Visiting Fellow

10387%

1613%

119

Graduate Student

3581%

819%

43

Support Sraff & Assistant

835%

1565%

23195

74%

7026%

265

Total

GREIThe achievement of novel imaging instrument (Gamma-ray Emission Imaging devices) isexcellent at the scientific level. Development of multi-molecular simultaneous imaging
technology is an important issue to be solved in this field, but the contribution of this groupto the activity of CMIS is limited at this moment. For example, regarding the research
direction, it is not clear what is the merit for the PI to combine the development of GREI
cameras and tracer development. Divided labour might be better. The cost for developmentof GREI system is another concern. The scientific /clinical merit of multi-tracer imaging, andtarget biological question to which the multi-tracer technology will be fruitfully applied,should be clarified, in relation to the development cost.
In the future development within CMIS the use of the excellent research animal models willplay an important role in the translation of biological knowledge into applications in man. A
common denominator in human biology and physiology is the endogenous compounds andthe radio-labelling and assessment of such agent’s distribution in vivo is hitherto

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9undervalued.
To further extend the chemistry competence there is a need to reserve cyclotron time andhotlab space in order to perform basic radiochemical research and have time for thenecessary (appropriate) technology development. These points may be very important if
CMIS is going to be a leader in forming a promotion committee for the clinical consortium.
The Clinical consortium with its promotion committee will be important in many aspects oftranslational molecular imaging as well as a resource for obtaining extramural funding.

Proposal to actions / recommendations:● To increase budget by seeking International funding of joint programs● To stimulate collaborations and other relationships with university & external partners.
One of the remote research goals of CMIS is to obtain Proof of Concept (POC) of thepathophysiology of diseases such as dementia and refractory cancer, in the frame-work ofneuro-immuno-endocrino interaction to open the field of ‘live-science’.
CMIS has strong background of synthetic chemistry and radio-labelling, with access toseveral non-anesthetized animal models with solid imaging capability. These competences
are critical to achieve the goals. However, the number of PIs in the medical field or young
researchers with medical backgrounds, who are indispensable, is still small.
To pursue the goal, therefore, AC expects CMIS
(1) to recruit PIs of MD/PhD in the field of medical research with imaging capability andinterest in pathophysiology of diseases, and(2) to accept MD/PhD students from medical schools using consigned PhD student system.