Department of Molecular Biosciences
The new Department of Molecular Biosciences (the result of a merger between the former departments of Genetics and Radiobiology/Molecular Epidemiology), which was established at the beginning of 2016, will be responsible for the conduct of RERF’s basic science program involving (1) studies of genetic effects and (2) studies of carcinogenesis mechanisms.
In the studies of genetic effects, the frequency and nature of heritable mutations in members of survivor families (mother, father, and offspring) have been examined with screening of mutations at hyper-variable mini- and micro-satellite loci and at about 1,000–2,500 loci per genome. None of those studies indicated statistically significant genetic effects of parental exposure to radiation. Recently, high-density microarray comparative genomic hybridization (CGH) methods using over one million probes have been introduced to detect relatively large deletion/amplification mutations throughout the genome. This method was first used to estimate the trans-generational effects of radiation in the offspring of model animals and currently in the children of A-bomb survivors. We are also planning whole genome sequencing-based genetic studies using next-generation sequencing technology that will provide the capability to detect the entire spectrum of mutations. We are also developing a green fluorescent protein (GFP) mouse model for quantitative measurement of germ-cell mutations.
In the studies of carcinogenesis mechanisms, we aim to clarify mechanistic relationships between radiation exposure and cancer development. Toward this end, we are analyzing early molecular events in thyroid, colorectal, and lung cancer development in the LSS and are also assessing the carcinogenic potential of altered genes found in these radiation-associated cancers using in vivo and in vitro experiments. We are also examining genetic factors in breast, thyroid, and skin cancers. Cytogenetic damage of in utero-exposed mice is being evaluated for cells in various organs and systems, such as the thyroid and the hematopoietic system, to test the hypothesis that chromosomally aberrant fetal stem cells were negatively selected.
We are also making efforts to identify and evaluate biomarkers linking radiation exposure to diseases among A-bomb survivors. Biomarkers currently being assessed involve immunological endpoints potentially related to radiation-induced attenuation of immune function and to enhanced risks of chronic diseases among A-bomb survivors. We are also examining the genetic basis for inter-individual differences in immune functions and the impact of genetics on susceptibility to radiation-associated diseases. Unrepairable DNA radiation damage, DNA methylation, and transcription are being analyzed to seek epigenetic mechanisms that lead to increased risks of diseases following radiation exposure. The frequency of stable-type chromosome aberrations (translocations) examined using fluorescence in situ hybridization (FISH) indicates a wide scatter of individual translocation frequencies against physical dose but a smaller scatter against another independent biodosimeter̬electron spin resonance (ESR) using tooth enamel. We anticipate that such biodosimetric data will provide information on possible random and systematic dose uncertainties in individual doses calculated by DS02 and prove to be valuable for use in cancer risk estimation.
The Molecular Genetics Laboratory is developing techniques to detect mutations among children of survivors and is conducting preliminary studies. Another major project will prepare the lymphocyte cell lines from 1,000 families to include both parents and their child/children for future study. (At least half of those families will include one parent who is a proximal A-bomb survivor.)
Most researchers believe the process of cancer development involves multiple steps. For a normal cell to become malignant, mutations and alterations of selected genes must accumulate in the cell, often resulting in disfunction of regulatory systems responsible for the tightly controlled cell growth and death. Ionizing radiation is known to damage DNA, e.g., gene mutations and epigenetic changes. Presumably, atomic-bomb radiation damaged some of the important genes involved in cancer development.
Our molecular oncology studies explore the molecular biological mechanisms behind radiation carcinogenesis by identifying the damaged genes and gene systems that have been altered in the post-bombing population. Our researchers use state-of-the-art molecular biological techniques to analyze survivors’ tissue samples.
The immune system protects the body from the intrusion of alien substances, such as bacteria and parasites, and in some cases from the continued proliferation of malignant cells or even from constantly-generating malignant cells (immunosurveillance against cancer). Host immunological response, specifically inflammatory response, is thought to be a key mechanism in development of various lifestyle-associated diseases such as diabetes, coronary heart disease, and several cancers. Through repeated division, a pool of blood stem cells produces cells that, in turn, differentiate into the functionally and phenotypically heterogeneous cell subpopulations that make up the immune system. These subpopulations closely interact with and regulate one another to effectively eliminate intruding substances.
Our immunology studies investigate radiation-induced immunological changes relating to disease development in A-bomb survivors. In addition, we have studied somatic mutations in blood cells using immunological methods.
The human genome, the complete set of genetic information in people’s DNA, differs among individuals, and this is in part responsible for individual differences in biological predispositions such as susceptibility to environmental chemicals, radiation exposure, and development of lifestyle-associated diseases. Our Immunogenome Study investigates genetic polymorphisms responsible for inter-individual differences in susceptibility to radiation effects and also the development of lifestyle-associated diseases such as cancer and diabetes mellitus, aiming at personalized prevention of radiation-associated diseases.
The Cytogenetics Laboratorystudies the lymphocyte chromosomes of A-bomb survivors. We replaced the past Giemsa-staining method with the recently developed fluorescence in situ hybridization (FISH) procedure to find the relationship between the frequency of chromosome aberrations and the estimated individual dose of radiation. The Cytogenetics Laboratory is also involved in developing a biological dosimetry system (the electron spin resonance [ESR] technique applied to the enamel coating on teeth extracted for medical reasons and made available by A-bomb survivors) to complement the physical dosimetry system.
Research scientists and their research interests
Arikuni Uchimura, PhD, Laboratory Chief
Molecular geneticsYasunari Satoh, PhD
Yoichiro Kusunoki, PhD, Laboratory Chief
Reiko Ito, PhD
Radiation molecular pathology
Radiation tumor pathology
Masataka Taga, PhD
Kengo Yoshida, PhD, Laboratory Chief
Asao Noda, PhD, Laboratory Chief
Kanya Hamasaki, PhD