About CDB

Report of Advisory Council 2016 [ July, 2016 ]

Advisory Council Reports

Report of Advisory Council 2016 [ July, 2016 ]

The CDB Advisory Council (DBAC) held its ninth plenary meeting from July 13 to 16, 2016 to conduct an extensive review of the research programs and administrative organization of the Center. Dr. Janet Rossant, Chair of the DBAC, compiled the results of the Council’s evaluation and its recommendations for the future. The full text of that report is shown below.

Detailed responses to the Terms of Reference from the RIKEN president
Item 1. International stature of the Institute and immediate plans

International stature
CDB has undertaken a major overhaul of its management structure since the 2014 Advisory Council meeting, when it was confronted with the restructuring of the research portfolio, down-sizing of the workforce and allocation of the diminishing resources. The leadership of the Center is commended for working resiliently through this difficult time to maintain the momentum of the research productivity.
To enhance cohesiveness of the research effort, sixteen research teams are currently placed under four research themes: Cellular Environment and Response, Organogenesis, Stem Cells and Organ Regeneration and Developmental Biology and Mathematical Sciences, together with the Research and Development Project consisting the Retinal Regeneration team that engages in the basic science to translational research on cell-based therapy for blinding eye diseases. This suite of research teams covers the broad scope of developmental biology research, encompassing molecular cellular biology, developmental genetics, morphogenesis and organogenesis, to downstream applied research on disease mechanisms, tissue engineering and regenerative medicine.

The breadth and the depth of the basic and translational research in model organism developmental genetics, cellular biology, organ formation and neural development and degenerative diseases, including retinal regeneration, and the active engagement of the CDB with the international development biology community are the most significant strengths of the Center. The performance of the CDB as a whole has been outstanding and the productivity of the research, in the context of high quality publications, conference presentations, development of intellectual property and success in competitive funding, is on a par with the leading research organizations in similar disciplines, such as CiRA (Kyoto University), IMEG (Kumamoto University), Stowers Institute (USA), EMBL and Max Planck Institute for Molecular Cell Biology and Genetics (Germany). Citation metrics collected by the Center illustrate that, per capita, the Center continues to publish the same number of highly cited papers as before the reorganization. This is a testament to the ongoing excellence of the research programs.

CDB has made significant contributions to major areas in developmental biology and regenerative medicine in the immediate past years. Highlights of notable achievement are the elucidation of the cause of age-related errors in chromosome segregation in the gamete that may lead to infertility and genetic disorders, the role of migration of specific type of neuroendocrine cell types for lung cancer development and metastasis, the nutrient-dependent control of body growth, the characterization of early processes of organ formation in organoids and the transplantation of embryonic stem cell-derived retinal tissue for cellular therapy in retinal disease in primate models and humans. The outcome of these works has significant merit for the understanding of the fundamentals of the developmental mechanisms as well as potential translational implications to health and industry. The model of appointing junior team leaders on fixed term contracts and giving them considerable freedom to explore new and exciting areas has ensured a healthy turnover within the institute and kept CDB from stagnating.

Outreach to the community
The Center is very active in outreach to the international scientific community through its annual symposium, which attracts an enthusiastic audience, (including around 25% foreign participants). The Themess of these symposia are broad-ranging and challenging, and include topics such as Time in Development and Growth, Shape and Allometry. As such, they attract a diverse, interdisciplinary audience that exemplifies the Center’s broad reach. The Center also reaches out to University undergraduate students, through a summer internship program held jointly with other RIKEN institutes. It is also actively engaged in high school education through summer school for high school students and a training course for high school teachers. The AC is impressed with the Center’s outreach to society and would encourage additional activities in this area, such as public lectures and internships for clinicians and industry partners. This will broaden their impact locally and across Japan.

The Center is an active participant in the Kobe Innovation Cluster, which includes Institutes, Hospitals and industry. The AC encourages the entire faculty, not just the leadership of the institute, to take advantage of this growing cluster and explore novel interdisciplinary partnerships that can take their science to new levels and make a major impact on society. The newly forming Kobe Eye Institute, in which Dr Takahashi is a major player, is an excellent example of how CDB can act as the seed for major new initiatives.

Future plans
Moving forward, the Leadership plans to focus on Life Cycle Biology and Regenerative Medicine and will restructure the research activity into three themes: Embryogenesis/Organogenesis, Regenerative Biology and Homeostasis & Aging. The AC considers these themes to represent a strong base on which to build for the future, recruit outstanding scientists and provide an opportunity to develop interdisciplinary interactions, as outlined elsewhere in the report (Item 2 and 3.3).

Nurturing a conductive environment for translational research
Notwithstanding the primary objective of the Center is to achieve excellence in the research on Life Cycle Biology and regenerative biology, much of the outcome of the basic scientific research may have translational potential that would deliver health and economic benefit. While the downstream applied research may go beyond the remit and capability of the investigators at CDB, it would be useful to instill a culture of awareness of translational potential of the scientific knowledge, and the commitment (and action in appropriate cases) of the scientific leadership to invest resources in building the specific technological infrastructure and administrative capability for the capture and development of intellectual properties and exploring partnership with health practice and biotechnology industry. For the clinical translation of the scientific discovery, the involvement of the clinical researchers and practitioners in the research activity of the CDB team would facilitate the sharing of expertise and insights that may promote the progression to translation. A strategic alignment with clinical institutions such as the Hyogo Perfectural Kobe Children’s Hospital, the Kobe Eye Center and the Kobe City Medical Center General Hospital, and the partners of the Kobe Biomedical Innovation Cluster would also engender opportunities for translational research.


Item 2. Areas of focus and interdisciplinary interactions

After in depth discussion, the AC endorses the proposed strategic goal of the Institute to extend its scope from developmental biology to encompass the whole life cycle, from embryogenesis through organogenesis to homeostasis and aging processes. The Center will be reorganized into three themes; embryogenesis & organogenesis, regenerative biology and homeostasis & aging. These areas mesh nicely with the strategic goals of the Japanese Government in promoting regenerative medicine and measures to deal with the aging population. They also act as hubs for recruitment of new team leaders and for outreach and collaborations with other RIKEN institutes and other researchers, clinicians and industry in Japan and worldwide. CDB researchers can contribute important fundamental discoveries in these areas that have immediate translatability into applications in regenerative medicine and addressing the chronic problems of aging. These themes are complementary and cut across the research themes of several other RIKEN institutes, enabling future inter-institute themes to evolve.

Looking to the future, there is a necessity for CDB to develop a stronger pipeline leading from basic to translational science. Indeed there has been a clear mandate given in this regard from the government and the central CDB administration. More importantly, it is the direction and future of modern basic biological science. Our knowledge of biological phenomena has grown dramatically in the last decades, from a surface understanding in broad strokes to deep mechanistic insights that, if exploited, can provide conduits for developing novel therapeutic approaches. Moreover, tools for biological inquiry have become extremely powerful, such that when the potential for translation is identified, subsequent studies to test clinical relevance can move forward with increasing rapidity. The opportunity for society to benefit from basic science has never been higher. The AC, thus, enthusiastically supports the view that the CDB must make increasing its translational impact one of its central goals looking forward.

That said, the AC strongly believes that it would be a grave mistake and a deep loss for biological sciences in Japan to redirect efforts at CDB away from hypothesis driven basic science, for the following reasons. First, CDB is internationally acknowledged as a leading center in basic research, perhaps the leading institute of basic science in all of Japan. The quality and scientific impact are so high that it would be a serious mistake for it to be undermined. Second, strong basic science must be maintained in Japan for it to continue to provide the foundation for translational discovery in the future. Third, and most importantly, it is our unanimous view that directing basic research efforts towards goals driven by preordained translational agendas in a “top down” manner is a far less effective way to reach the goals of translational advance and contribution to human health than to let translational research grow organically from basic research programs. The true breakthroughs in clinical impact and commercial success are built upon basic discovery providing opportunities that are often unanticipated.

Much of the basic scientific research at CDB may have translational potential that would deliver health and economic benefit. While the downstream applied research may go beyond the remit and capability of the investigators at CDB, it would be useful to instil a culture of awareness of translational potential of the scientific knowledge, and the commitment (and action in appropriate cases) of the scientific leadership to invest resources in building the specific technological infrastructure and administrative capability for the capture and development of intellectual property and exploring partnership with health practitioners and biotechnology industry. For the clinical translation of the scientific discovery, the involvement of the clinical researchers and practitioners in the research activity of the CDB team would facilitate the sharing of expertise and insights that may promote the progression to translation. A strategic alignment with clinical institutions such as the Hyogo Prefectural Kobe Children’s Hospital, the Kobe Eye Center and the Kobe City Medical Center General Hospital, and the partners of the Kobe Biomedical Innovation Cluster would also engender more opportunities for translational research.


Item 3. Response to the five strategic goals of RIKEN Initiative for Scientific Excellence
3.1 Research management model

Under the direction of RIKEN Central and with the leadership of Dr Hamada, CDB has undertaken a major overhaul of its management structure since the 2014 Advisory Council meeting. The Institute is managed by a Management committee, chaired by Dr Hamada with members from the junior team leaders and external members from other RIKEN Institutes and Universities. This brings a broad spectrum of expertise to the day-to-day and strategic management of the Institute. However, the absence of senior research leaders from CDB in this committee is a limitation, as it places considerable responsibility on junior team leaders and leaves Dr Hamada without internal high-level advice when making management, recruitment and budget decisions. The Center has several operational sub-committees that report to the Management Committee and oversee Personnel, Budgetary issues and Facilities. This structure ensures that there is an open and transparent process around research direction, research infrastructure needs and budgetary allocation. The Director makes the final decisions, but there are strong checks and balances to ensure a careful evaluation of all research programs.

Budgetary allocation is a fair and open process with defined budgets for each group according to their level of position in the Center. The Director also reserves funds to be able to respond to strategic opportunities, such as the need for new technologies and to support interdisciplinary research across RIKEN Centers and with clinical programs.

The Center is not solely dependent on internal funds but investigators are encouraged to apply for external peer-reviewed funding and have been very successful in such competitions, always succeeding at a higher rate than the national average. The AC felt that a more structured internal peer review process to help junior investigators craft excellent grant proposals could improve external funding success even further and ensure that when PIs leave RIKEN for the University environment, they are well-positioned for success.

3.2 World-leading excellence
This is covered in Item 1 and 2.


3.3 Hub for scientific and technology innovation

Interdisciplinary innovation
CDB is already an active partner in several cross-RIKEN initiatives aimed at making RIKEN the leader in innovation interdisciplinary research and its impact on society. These include ‘Epigenome and disease” and ‘Aging”- both of which are natural areas for CDB to take a major role. There is no question that CDB is ready and willing to drive new interinstitute initiatives as defined by the overall goals of RIKEN. CDB reaches out beyond RIKEN and has productive interactions and partnership across Japan. One potential mechanism to promote such interactions is to develop an interdisciplinary postdoctoral fellowship program, in which two labs from different institutes would come together with a research proposal to support a post-doc on a common interdisciplinary goal. This could be a cross-RIKEN initiative under a competitive mechanism. A similar program has been in place at the EMBL with considerable success in opening up new areas of research.

CDB has also played an essential role in Japanese science in building partnerships with Universities and other institutes, and this should be further promoted. Many researchers in universities interact and collaborate actively with CDB. CDB’s skillsets and resources are shared openly and enable researchers across Japan to perform top science. For example, many universities sent their graduate students and/or postdocs to CDB for short periods to learn novel techniques such as imaging and organoid formation. Transferring such novel techniques to universities is beneficial to promote overall science in Japanese universities.

CDB and CiRA at Kyoto University have recently started to hold joint workshops in the area of regenerative medicine and there are active collaborations on production of iPS cell-derived tissues, which will be transplanted to patients. These collaboration will promote clinical application of iPS cells and become another hallmark for CDB. The combined expertise of CiRA and CDB place Japan as one of the world leaders in the clinical application of stem cell biology.

CDB has been also doing a very important service in terms of transgenic mouse experiments for Japanese and overseas researchers, and this service is undoubtedly crucial for promotion of mouse genetics as a tool to understand human disease. It was agreed that the separation of this transgenic mouse facility from CDB by the Riken reformation is very unfortunate not only for CDB but also for Japanese science. Thus, this facility should be returned to CDB as soon as possible.

Clinical partnerships
The AC noted that there are only a few PIs and trainees with a medical training within CDB and that yet the opportunities for basic-clinical partnerships between programs at CDB and appropriate clinical partners (eg Nephrology for kidney organoids, Reproductive Medicine for oocyte chromosome anomalies, and Neurology, Dermatology and Respiratory Medicine for neural stem cells, skin and lung diseases respectively)

The AC believes that CDB can catalyze a dramatic increase in translational efforts, while maintaining its primary mission as a basic science research institute. The AC does not consider these to be incompatible or mutually exclusive objectives. However, to accomplish both, it is our opinion that at least two things need to change. First, the concept of translational research should become deeply ingrained into the culture of CDB. Currently there are exceptional translational scientists at CDB, but for many team leaders there is insufficient awareness or thought given to the ways their work might provide a starting point for making inroads into clinical problems. Such an awareness is critical for developing new translational efforts and for elucidating the translational implications to the outside world.

Second, mechanisms need to be put into place at CDB to allow basic researchers with no clinical training of background to seize such opportunities when they arise, and exploit them (in their own labs or though collaborations). The CDB needs to build an infrastructure to actively facilitate translational exploitation of basic advances.

One initiative that could have a significant impact in these regards would be to forge closer associations with clinicians in the adjacent Hyogo Prefecture Kobe Children’s Hospital, and perhaps also the Kobe City Medical Center General Hospital. We envision that this could take place at several levels. First, we suggest an exciting possibility of a joint Translational Research Institute between CDB and the Children’s Hospital where there would be basic scientists and clinicians working along side each other to drive implementation of basic discovery in the clinical setting.

The clinicians in the Translational Research Institute, as associate members of CDB, would participate in meetings, retreats and other events at CDB, providing interactions and insights into potential implications of research from a clinical perspective. As valuable as this would be, it would also be beneficial for researchers at CDB to have interactions on a daily basis with colleagues having a human biological perspective. To that end, we propose establishing a formal program at CDB providing 1-2 Year Fellowships to MDs to work in CDB laboratories. While such MD Fellows would bring a translational perspective, they would benefit from rigorous scientific training in the basic science laboratories. Conversely, by virtue of their clinical background, they would bring a human disease orientation to the environment in which they work, helping to recognize new areas of relevance for potential translation. In addition such Fellows would provide a cadre of bright, hard working trainees for the laboratories, partially addressing the deficiency of available graduate students (an issue addressed elsewhere in this report).

Industry partnerships

CDB already has active partnerships with a number of different biotech and pharma companies, but clearly this could be raised to a higher level through more outreach to companies to visit CDB and learn about the research there. Opportunities for CDB trainees to intern for 6 months to a year in industry and industry scientist to intern at CDB in return should also be pursued. These kinds of direct interactions between scientists in academia and industry can be very productive in developing meaningful partnerships that can translate into spin-off companies, new products and licenses and new job opportunities for RIKEN trainees.

3.4 Global brain circulation and research environment

CDB is clearly one of the most successful international research centers in Japan, based on the quality of its research, its use of English as the working language, its attraction of foreign speakers in seminars and the annual symposia, and the number of overseas PIs and trainees. However, the overall number of non-Japanese employees (85) and foreign PIs (2/17) is not high. Recruiting non-Japanese scientists is challenging and this is not unique to CDB. CDB has made considerable efforts to support non-Japanese personnel, including a help desk and other support to assist with adjusting to Japanese society. The AC believes that CDB’s international reputation and the resources available to PIs through RIKEN should place it in a good position to recruit internationally. More direct approaches to foreign candidates at the CDB symposia and at international meetings would be helpful. In addition, holding more courses and workshops at CDB for senior post-docs as they approach the job market would allow them to have more familiarity with the CDB asa potential place of employment.

There is also need to improve the percentage of female PIs in the Center. Overall 44% of employees are female, but there are only 3 female PIs, including the new recruit, Dr Phng. At 16% (3/19, including Dr Phng), this is below international standards (greater than 30%). Again this is not unique to CDB and the management is very aware of the need to pay special attention to recruiting female PIs. RIKEN as a whole has a strong gender equality program which certainly needs to be promoted. In addition, the AC recommends that all recruitment searches must include qualified women in the final short list. If suitable female candidates cannot be recognized in that particular search, then the search must be reopened. This is an aggressive measure, but it incentivizes the faculty to be proactive in seeking qualified women.

The research environment and infrastructure at CDB is very strong and Dr Hamada has taken a leadership role in ensuring that state-of-the-art equipment and core facilities are available to the researchers. The cooperative working environment at CDB is also extremely helpful for researchers who wish to apply new technologies to their research- they can learn from each other and from neighbouring institutes. The infrastructure is of international standards.

Given the high international stature of the Center, a formal International Visiting Investigatorship program (with travel and accommodation support from RIKEN) would also be an excellent way of promoting international interactions and achieving global brain circulation.

3.5 Developing world class research leaders

CDB has been playing a major role in promoting the education and research training in developmental biology and regenerative medicine in Japan. CDB has graduate school affiliation with six universities including Kyoto, Osaka and Kobe Universities. CDB organizes lecture programs for these graduate school affiliates, and nearly 200 students/postdocs participate in this program each year. This is a great opportunity for students/postdocs to be exposed to forefront research, and this should be continued. However, the total number of graduate students who study in CDB is relatively small (only 25 in 2016, which means on average 1 or 2 students per lab). Junior CDB team leaders found that it was difficult to recruit graduate students, despite the availability of student stipends from RIKEN. There was concern that these stipends were available only to PhD program trainees and not MSc entry level graduate students. This lack of support for MSc students may disadvantage CDB PIs in their ability to attract students who often stay in the same institute after the Master’s study to pursue further postgraduate training.

However, the AC believes that graduate students are key to training the next generation of scientists and recommend continued efforts and incentives to attract students to CDB. These can include encouraging TLs to teach lectures at several universities to be exposed to potential trainees. CDB regularly organizes international meetings and symposia, which give great opportunities for Japanese researchers to learn the world-leading science: these occasions should include specific outreach sessions for undergraduates to learn more about CDB so that they can apply for graduate study at CDB. Summer internships, special courses and other activities aimed at senior undergraduates can be helpful.

The AC continues to believe that there are real opportunities for CDB, along with other related life science centers in RIKEN, to develop a stand-alone international graduate student program, similar to those in place at EMBL and IMP Vienna. This would serve the goals of attracting foreign scientists and sending them out into the world, as well as providing a great source of motivated trainees to support the research programs of CDB.

As outlined elsewhere in this report, the AC finds that CDB already provides a number of outreach activities, resources and training opportunities for scientists across academia, the hospitals and industry. We support expansion of these activities to demonstrate the value of CDB RIKEN to the broader community.


Item 4. Impact of Center on overall activities of RIKEN

The AC recognizes that CDB remains (and will continue to be) an essential part of the life science sector of RIKEN, promoting RIKEN to the world. Their high reputation as one of the world-leading institutions is not only due to past achievements in the field of developmental biology. Rather, after experiencing radical reorganization, the science ongoing in CDB remains highly competitive against the world standards.

It is truly a strong point of RIKEN to have CDB, QBiC, and CLST as relevant and independent centers in Kobe and the nearby area. These three centers can and will further strengthen their connection with each other to develop interdisciplinary research. The AC believes that uniqueness of each of the three centers is essential for maintaining diversity of approaches within RIKEN.

RIKEN HQ is understandably under strong pressure from the government and other stakeholders to demonstrate the value and societal impact of the research that is undertaken by RIKEN. The pressure to move towards a focus on short-term deliverables rather than long-term innovation driven by fundamental scientific discovery is felt by research funding agencies worldwide. CDB scientists can help RIKEN explain its mission by

  • Continuing to undertake high-quality world class research
  • Communicating with RIKEN leadership, with enthusiasm, on their research and the importance of basic science for understanding the fundamental principles of life.
  • Informing RIKEN leadership with examples of independent international recognition of CDB’s research
  • Highlighting examples of the impact of CDB’s research on societal outcomes, e.g, the retinal transplant program in health care for age-related blinding diseases
  • Ensuring that the CDB members understand the RIKEN mission and work towards its strategic goals