FY2021 Plans of Activities
I. Plans of Major Activities
Because much of RERF’s research involves longitudinal or large scale long-term studies thattake a significant time to plan and conduct, so a number of ongoing plans for such studies
have already been presented under research achievements. Here we provide highlights of new
research plans or selected plans of note.
1. Research Projects Examining A-bomb Survivors Health1) Radiation and Cancer:
 Updated cancer incidence (RPs 1-75, 18-61): Papers on comparison of cancer incidence
and mortality (Brenner A, et al.) and a summary paper (Brenner A, et al.) will be publishedthen this series of papers will be completed.
 Updated LSS mortality report (RP 1-75) on cancer and noncancer diseases: Periodical
publication of mortality risk of cancer and noncancer disease due to atomic bomb radiationis the most essential work of the Dept. of Epidemiology and the LSS Report 15 will be thehighest prioritized project in the next few years. Available data and the framework ofanalyses will be determined and preliminary analyses will begin in collaboration with theDept. of Statistics. Dose-response shape and radiation risk at low dose levels will be
investigated considering potential confounding by geospatial factors and variation inbaseline rates. Those analyses will include lifestyle factors (smoking, alcohol drinking,body mass index), some indicators representing socioeconomic status, and so on. This is acomplex project that will require several years to complete (Sakata R and all members).
 As part of our goal to examine genetic susceptibility and gene-environment interactions,
we are planning a genome analysis study as part of a potential large-scale GWAS (genomewide association study) program for all AHS subjects, consisting of approximately 20,000
A-bomb survivors, using old samples preserved after 1958. We will analyze genetic
polymorphisms that may be involved in radiation-related cancer development in A-bomb
survivors using the Japonica Array developed for analyzing genetic polymorphisms that
may be involved in cancer development in a Japanese population. DNA samples extracted
from old Wright-stained smears must be used to conduct a genome study for all AHS
subjects. For this reason, it is necessary to determine whether an SNP analysis using theJaponica Array is possible by amplifying a whole genome, using a very small amount of
DNA obtained from a blood smear stored for many years. In FY2021, DNA extraction
from preserved, old blood smears of AHS subjects will be carried out to examine a suitablepreparation method for REPLI-g amplified DNA. Then, we will evaluate DNA availability
by analyzing those DNA samples with the Japonica Array. (Hayashi, RP-P1-19, and a newRP).
 Pathogenesis of MDS (RP1-17, Miyazaki Y and Imaizumi M): We will continue to conduct
phylogenetic analyses to clarify clonal dynamics and evaluate genome data with clinicalcourse to find driver mutations and CNAs (copy number alterations), and assess specificalterations in high dose patients compared with low dose patients. We will submit amanuscript for publication in 2022.
 CML study (RP-P2-19, Yoshida N): We will continue current collaboration with
Epidemiology Department and external leading specialists to evaluate the availability of1

DNA and RNA extracted from old formalin-fixed paraffin embedded (FFPE) samples inmolecular analysis. We will confirm whether DNA and RNA from FFPE samples can beanalyzed by droplet digital PCR and high-throughput sequencing. We will complete theseries of current pilot studies in 2021 and prepare a full research project proposal based on
the current results in 2021.
 Biologically-based mechanistic modeling will be one of the approaches to derive
biological hypotheses from our epidemiological data. As a next project, we will analyze the
LSS colon cancer data. We described a possibility of screening effects related tocolonoscopy and different radiation risks among the sites of colorectal cancers in the latest
update of LSS colon cancer incidence (Sugiyama, Misumi, Brenner, International Journalof Cancer, 2020). An application of a mechanistic model to the previous LSS colon cancer
data showed an association between radiation and chromosome instability (CIN) pathway
of colon carcinogenesis, but not between radiation and microsatellite instability pathway(Kaiser et al. PLoS One, 2014). We will investigate these associations between radiationand molecular pathways taking account of the possible screening effects utilizing the latest
data in collaboration with Dr. Kaiser of Helmholz Zentrum Munchen. The result will give
us better understanding of the applicability and possibility of the mechanistic modeling.
With the better understanding, we will consider extending the application of this approachto other cancer sites.
2) Radiation and Non-Cancer Effects:
 Conduct our Clonal Hematopoiesis program project that consists of 4 projects 1) Detectionof clonal hematopoiesis in AHS samples, 2) Evaluation of inflammation markers, 3) Mouse
model of clonal hematopoiesis and 4) Mathematical design. We are now working on 1) and3).
(1) For Project 1, we have developed strategies for assessments of clonal expansion ofhematopoietic stem cells (HSCs)(i.e., clonal hematopoiesis) and inflammatory changes in
the hematopoietic system potentially contributing to the radiation-associated noncancer
diseases, specifically atherosclerosis. Project 1 of this program aims to test the hypothesis
that, in AHS subjects who were exposed to high-dose (>1Gy) radiation several decadesago, clonal hematopoiesis is promoted with recurrent somatic mutations in epigenetic
modifier genes (TET2, DNMT3A, ASXL1, etc.) and/or DNA damage response genes(TP53, PPM1D, etc.). Clonal hematopoiesis with somatic mutations will be evaluated by
performing next-generation sequencing (NGS) using cryopreserved blood cells from about
100 subjects, in collaboration with Nagasaki University and Kyoto University. Plasma
levels of endogenous danger signals (alarmins), which may promote clonal expansion of
HSCs, will also be assessed in relation to the development of clonal hematopoiesis
following radiation exposure. This project has been approved by the Non-cancer Research
Cluster, outside scientific experts, and the RERF Committee on Biosamples, and applied
for the IRB review (Yoshida and Kusunoki, a new RP of the Clonal Hematopoiesis Project1). This study as yet to be fully approved even next year, until RERF develops institutional
policy concerning the use of cryopreserved samples for obtaining NGS data in A-bomb
survivors. With application of an established policy to this study, we will start the study assoon as possible. (Yoshida, a new RP in the Clonal Hematopoiesis Program Project, Project1).
(2) Project 3 involves the use of mouse models. Current mouse CH studies rely on very2

limited preliminary data that can support the feasibility of the study and that enable power
calculations to determine the sample size. Thus, we are analyzing preliminary wholeexome sequencing (WES) data in 12 and 7 mice irradiated with 3 and 0 Gy, respectively,
and are detecting recurrent mutations in bone marrow (BM) cells with their frequencies>0.02. By targeted amplicon sequencing, we will analyze the frequencies of the mutationsin hematopoietic cell populations including myeloid, lymphoid, and stem and progenitor
cells, as well as in non-hematopoietic tissue cells including brain and tail tissue cells,
which will determine whether the mutations are embryonic mosaic or hematopoietic
specific and whether they are the hematopoietic stem or lymphoid (i.e., mature T or B cell)origins. We will also develop experimental protocols that analyze LDL-receptor knockout(LDLR-KO) mice fed a high fat diet following whole-body irradiation, for 1) identificationand phylogenetic tree construction of early embryonic spontaneous somatic mutations(SPMs), 2) CH identification in BM through WES, and 3) SPM-based evaluation of clonalmonocyte accumulation in atherosclerotic plaques. Preliminary experiments using theseexperimental protocols will enable power calculation to adequately determine the sample
size and a detailed design of a full-scale study investigating the frequency of radiationinduced CH and the involvement of CH in atherosclerosis formation. (Kusunoki, Yoshida,Taga, Hamasaki, Satoh, Uchimura, Misumi and Noda, a new RP in the Clonal
Hematopoiesis Program Project, Project 3).
 Cataract study: We will write a manuscript regarding the relationships between several
types of cataracts and radiation among subjects who were <15 years of age at the time ofbombings (excluding in utero exposed subjects). This will be submitted for publication
during FY2021. Analysis of the relationships between radiation and cataracts among inutero exposed subjects will be started in collaboration with the Dept. of Statistics.
 Atherosclerosis study (RP2-11, part 2 of RP7-09, Nakamizo T): We will start analyzing
data on cytokines representing disturbed tissue repair and differentiation potentiallyinvolved in the pathogenesis of radiation-induced atherosclerosis. This analysis will be
conducted jointly with the clonal hematopoiesis program project because thosepathological processes are interrelated to inflammation, a key player involved in thepathogenesis of radiation-induced atherosclerosis.
3) Genetic Effects of Radiation:
 Previous animal model studies identified more small deletions and multisite mutations in
F1 mice of 4 Gy-irradiated spermatogonia and mature oocyte than in those from unexposedparents. However, larger size mutations including structural variants are not fully
understood. Currently, we are developing a new pipeline to detect larger size mutations
using long-read NGS techniques such as PacBio, Oxford nanopore and Bionano Saphyr.
Our new pipeline is meant to give us the ability to uncover spontaneous de novo mutation
rate and characteristics of such variants (especially in transposon mutations) in mice.
(Satoh, RP 2-13 addition).
 For our germline stem (GS) cell studies described in the achievements section, mutationsin irradiated GS cell clones will be characterized by array CGH (comparative genomic
hybridization) and whole-genome sequencing (WGS) analyses, and then the cell clones
will be transplanted into Busulfan-treated testes of adult male mice. We also plan to makeartificial large-scale deletions or inversions that simulate radiation-induced chromosome
alterations in GS cells via newly developed gene editing systems. After the transplantation,
we will examine the offspring derived from the GS cells for heritable genetic changes.

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(Noda, RP-P3-17).
2. Research Projects on the Health of A-bomb Survivors Children (F 1 ) Continue to conduct health examinations among the cohort members of the FOCS. This
will continue at least until approximately 2050 to evaluate lifetime risk.
 Continue data cleaning to verify development of multifactorial diseases among about
10,000 FOCS participants.
 Establish methods of analysis based on multi-state models to investigate the effects ofparental radiation exposure on hypertension, dyslipidemia, and diabetes in F 1 offspring of
A-bomb survivors in collaboration with Department of Statistics.
 F1 cohort study (RPs 4-75, 18-61): Regular collection of follow-up information will be
continued.
 For WGS studies of the trios comprised of atomic bomb survivors and their offspring, we
will develop a research protocol to conduct these studies. In addition to the scientificproposal, a key element in the initiation of these studies are ELSI and obtaining informed
consent since many of the parents in the trio sets are deceased.
3. Research to Elucidate Individual Radiation Doses and the Effects of A-bombs
 We plan to further dose error work related to biodosimetry. A joint collaborative project
involving the Departments of Statistics and Molecular biosciences, will develop andexecute a new analysis project which seeks to combine all currently available physiologicalinformation about radiation exposure (e.g., electron spin resonance of tooth enamel,
chromosome aberration frequency scored using Giemsa and FISH methods, and thepresence of acute symptoms) using structural equating modeling in order to characterizeand quantify the extent and nature of dose error in the DS02 system.
 The primary focus of our work on dosimetry during FY2021 is preparation for the
implementation of the revised organ dosimetry using updated computational phantoms.
This includes completing the conversion of existing FORTRAN code and the developmentof additional computational modules. While the Department of Statistics will become
prepared to implement the new organ dosimetry, the ultimate decision whether and when to
implement this new dosimetry will be made by the RERF leadership in conjunction withUS Department of Energy (DOE) and the Japanese Ministry of Health Labor and Welfare(MHLW).
4. Project to Release of Research Results and to Collaborate with Other Scientific
Organizations
Continuing collaborations: Long term collaborations are listed below and these are
expected to continue in 2021:
a.
b.
c.
d.
e.
f.

Partnership with the University of Washington
Partnership with Kurume University
Partnership with Osaka University
Collaborations with the US National Cancer InstituteCollaborations with the University of Florida
Collaborations with Outside Investigators:

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44 Japanese Institutions
9 North American Institutions
8 European Institutions
1 Asian, Oceanian Institution
5. Training Programs for Domestic and Overseas Specialists
RERF will hold a training course for non-epidemiologist radiation researchers to learn thebasics of epidemiological research and increase understanding of radiation health risks. In
addition, RERF will train persons capable of working in the fields of radiation protection,
radiation emergency medical care, and radiobiological research. Furthermore, decisions onwhether these activities could be held and how they would be held will be madeconsidering the rate of COVID-19.
Activity plans for FY2021:
i) RERF will hold an online epidemiological training course for radiation biologists inJapan to enhance understanding of results from epidemiology research on A-bomb
survivors.
ii) RERF will accept overseas research trainees to support the activities of suchorganizations like the International Council for Health Care of the Radiation-exposed(HICARE), the Nagasaki Association for Hibakusha’s Medical Care (NASHIM), andthe Japan International Cooperation Agency (JICA).
iii) If there are any invitations for the MHLW-sponsored FY2021 International Exchange
and Research Program, RERF will consider accepting trainees from overseas.
iv) The Department of Statistics will apply to the FY2021 International Fellowships for
Research-in-Japan program, sponsored by the Japan Society for the Promotion of
Science (JSPS), and provide research opportunities to young post-doctoral researchers
from various countries.
6. Public Information Programs
From the days of its establishment until the present, RERF has investigated the medical
effects of radiation, in atomic bomb survivors and their children (the second-generation).
In terms of RERF’s public information programs of utmost importance are our efforts tocommunicate in simple fashion our research results to atomic bomb survivors and thechildren of A-bomb survivors, both of whom have long understood and cooperated in
RERF’s research, as well as members of the public. To succeed at communicating withsuch audiences, good relations with national and international media, starting withmembers of the media in Hiroshima and Nagasaki, are crucial to reaching a wide audience
with our messaging. In FY2021, RERF will work on the public information programs,
outlined below, to ensure that such target audiences can gain further understanding about
RERF.
i) RERF public lecture series
RERF’s new public lecture series, initiated in 2019, targets peace volunteer guides
among other such individuals, in partnership with external organizations such as theHiroshima Peace Memorial Museum. This series was temporarily shelved due to thecoronavirus pandemic but will be reinitiated once the coronavirus is contained. Basedon such efforts, RERF will be able to provide an opportunity to enhance understanding5

of the foundation’s research and learn more about radiation’s health effects to evengreater numbers of atomic bomb survivors, second-generation survivors, and the public.
ii) RERF Open House event
RERF will hold its 26th and 24th Open House events at the Hiroshima and Nagasaki
RERF Laboratories, respectively. In FY2021, RERF has decided to take a different
stance and hold the Open House event in a virtual format, out of consideration of theeffects of the continued spread of the coronavirus.
iii) Strengthening of social media-related activities
Given the limited contact with the public due to the COVID-19 pandemic, social media
such as Facebook and Twitter has become the most effective method of communicatingwith the outside world. In FY2021, because the most important task facing RERF is
obtaining understanding from atomic bomb survivors, the second-generation, local
communities, and the media, social media will be used effectively to achieve that goal.
Through a particular focus on visual information on Facebook and Twitter, a series ofvideos will be created to give outside people access to our facilities, research,
explanations of research policies, and so on, through a virtual format. RERF will also
continue refining our messaging on the platforms, with the aim of both increasing ourfollower numbers and expanding our reach and engagement through increased sharingof our posts by our followers.
iv) Promotion of public relations activities targeting media
RERF will respond to the extent possible to media requests for coverage of RERF
related to various issues surrounding our research and policies this year, with the aim ofallowing the media to accurately understand ABCC–RERF’s research achievements andto report based on that clear understanding. In FY2021, RERF’s PR staff plans to holdlectures and study sessions for the media, in continuation from similar efforts made lastyear.
v) Enhancement of RERF website
In FY2021, RERF will continue aiming at enhancing the homepage. Particular focus
will be placed on conveying readily understandable research-related and otherinformation to the public, through the utilization of more video and other methods.
vi) Enhancement of online news-delivery system
RERF’s email magazine system, E-News, which replaced the printed Update newsletter,
will be enhanced in terms of content and used to not only distribute the latest research
results and information about RERF events and activities but also to attract readers to
RERF as “members,” by offering a sense of “buy-in” with respect to RERF as anorganization.
vii) School Visit ProgramThis program was first established in FY2016 to convey to elementary, junior-high, andhigh-school students the reality of radiation health effects. Based on the program’s
popularity, each year, numbers of requests for such classes increase and a now stablegroup of available teachers has provided RERF the opportunity to teach an increased
number of classes. In FY2021, RERF will work to expand its public relations activities
by, in addition to conventional on-site lessons, conveying to students how to teach thebasics of radiation to their peers in a student-led education drive.

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viii) Internship (work experience) project
RERF has been accepting interns, mostly those with scientific backgrounds, for sometime, but RERF plans to invite trainees such as students to learn about how to perform
RERF’s facility tours and other public relations work.
ix) Other public relations activities• RERF will actively promote the foundation’s important scientific papers to thedomestic and overseas media via press releases and press conferences.
• With the aim of improving public understanding of our research, RERF initiated in
FY2018 a new series of paper synopses that explain research with simpler prose andsmaller word counts than used previously in our “summary explanation” series for
specialists. Through continuation of this series in FY2021, the aim is to improveunderstanding by the public of RERF’s research results.
• A persistent goal again in FY2021 will be the training of more RERF personnel tohandle facility tours in English for overseas visitors, in preparation for when the tours
are restarted in the future after the coronavirus pandemic is contained.
• By increasing our effort at communicating RERF’s research with the aim of improved
transparency related to RERF research and establishment of good communication withthe public, in particular A-bomb survivors, their children, and the media, the PublicAwareness Campaign working group was formed in January 2019. In FY2021, thePAC working group will meet and discuss about how to provide information to the
public on important topics such as the human genome, genetics studies, and other such
topics.
• When it is possible again after the coronavirus pandemic is contained, RERF willcontinue to target small public groups of A-bomb survivors and their children, whowill be invited to come to RERF and speak with directors and staff about
ABCC/RERF history and research results, with the aim of achieving greater
understanding about RERF.
II. Operation and Management of RERF
1. Research Resource Center
The highest priority activity in 2021 is the formalization of the Research Resource Center(RRC) by the RERF ad hoc committees in charge of establishing the RRC. Decisions
regarding physical location within the institute, internal structure (Sections), leadership,reporting lines, personnel and budget are all needed. After those decisions are made,obtaining personnel and initiating the Office of Collaborative Research would provide
immediate benefits to the institute.
The RRC Technical Team needs to decide if Gen3 is a suitable Data Commons for
RERF’s needs. If yes, then a full-scale installation and support structure needs to be put inplace. If Gen3 is abandoned, then a pilot project using different software will need to be
initiated.
The Content Management System (CMS) should see significant progress in 2021 with arecently hired external consultant expert in CMS development. The CMS will store andcategorize scans of paper documents and digital publications. It will allow full search, afeature that is currently not available at RERF.

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RERF’s multifunction copiers will be programmed so that scanning can be performed
locally and deposited directly into the CMS.
A digital presence (web site) with rudimentary functions (data search/assembly,
manuscript/RP search, streamlined procedures to initiate data sharing, etc.) will be put inplace.
2. Review on the relocation of the Hiroshima Laboratory
We will proceed with deliberations on the proposals for candidate relocation sites forachieving RERF’s strategic plans, revolving around the Hiroshima Comprehensive HealthCenter and Hiroshima University’s Kasumi Campus.
3. Transition to a full Audit
To supplement the Auditors’ audit, RERF aims to receive a full audit (financial audit) froman external corporation. From now, RERF will prepare to transition to a full audit fromFY2022 because there are good prospects that the conditions for the transition will be met,
recording the retirement allowance liability and evidence of US subsidy income.
Furthermore, RERF plans to select a contractor for the financial audit, in keeping with theopinions of the Auditors and internal regulations, by the regular BOC meeting in June
2022 and sign an audit contract by August of that year when administrative procedures forthe financial audit are set to begin.
4. Introduction of an attendance and work management system
Following the enforcement of the work-style reform law enacted in June 2018, RERF will
introduce an attendance and work management system with the primary goal of monitoring
employee work hours objectively. RERF will analyze the cause of past unsuccessful
procurements, remove the causes of the failed bids from the specifications, and attempt to
procure a system with these specifications. RERF plans to launch the system fully during
FY2021.
5. Revision of the rules and regulations
We are revising current regulations and establishing new regulations to resolve thefindings of the Auditors’ management letter and Deloitte Touche Tohmatsu’s internal audit.
Along with continuing to resolve these findings quickly and suitably in FY2021, required
revisions will be made to keep this institution’s management operations appropriate. Doingso will provide regulations befitting of a public interest incorporated foundation funded by
Japanese and U.S. government subsidies.

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