I am currently working in the field of biomathematics, or mathematical biology in which mathematical and statistical models are employed to work with experimental or field biologists in order to understand biological phenomena of interest, or quantitatively characterize data. Technological applications are also aimed to realize a concept that is extracted by theories and mathematical analyses. More broad types of approaches are included in biomathematical study, not only interdisciprinary kinds of research between mathematical and biological sciences but also topics deepening understanding of a specific mathematical or computational subdiscipline. My several research topics can be classified by mathematical and computational methodologies, or subdiscipline of biology. Interdisciplinary collaborative works based on my current research topics are summarized in each separated panel. In each research topic, I try to commit to understanding multiscaleness in biological phenomena, emergence of novel functions by simply gathering structured components without atempt to prepare engineering blueprints (bricolage), and mimetics of ecosystems to artificially design robust and environment-friendly engineer material and agricultual crops (ecomimetics). Please get details in each panel.
Differential equations and theories of dynamical systems are employed in some of research topics. More specifically, qualitative analysis of asymptotic behavior of dynamical systems was achieved based on construction of Lyapunov functions, or evaluation of inequalities. Numerical computations and simulations are often applied to investigate dynamical change of a system of interest. Numerical bifurcation analyses are often employed. Since stochasticity is often indispensable to describe biological phenomena, applications of stochastic simulation are my favorite approach in recent years. Collaboration with biologists is often intiated by analysing omics data such as transcriptome and metagenomic data. Bioinformatics pipelines to deal with these types of data have been operated to peform data mining.
The immune system of a host body prevent invasion of foreign antigen such as virus and bacteria. Blocking of PD-L1 which initiates apoptotic signal of killer T cells (CD8 T cells) has shown its effectiveness on cancer elimination to several broad types of cancers. My current major aim is to obtain theoretical implications why breaking brakes of immune responses can be successful while less effective to promote pressing accelerators. My interesting topic in microbial ecology is to investigate associations between reduced diversity of a microbial community, known as dysbiosis, with several inflammatory or immune related disease in the gut. Theoretical characterization of successfull synbiotic intervention such as microbiota transplantation to cure is my current major aim.
In a research program entitled "Modeling ecology of gut microbiota and the immune system", we investigate dynamics interactions among gut microbiota, epithelial cells and the immune system by way of mathematical modeling and multi-omics approach. Recently-developed novel multi-omics approach --an integrative method of omics analyses including genomics, transcriptomics and metabolomics-- enables us to obtain a variety of basic information; constitution and metabolic activities of gut microbiota, inflammatory gene expression profiles of gut epithelial cells, and (in)direct evidences to interactions among microbiota, epithelial cells and the immune system. Several experiments suggest that undigested carbohydrates are metabolized into short-chain fatty acids by syntrophic consortia in gut environments. Moreover, low-chain fatty acids are suggested to promote protective activities of gut epithelial cells against bacterial infection by promoting their survival and proliferation. With the help of multi-omics approach, another key mechanisms for modulation and maintenance of host defense and health can be identified.
Mathematical modeling approach would help to facilitate and extend potential usage of multi-omics approaches to explore gut environments. In fact, dynamic processes of interactions among resident microbiota, epithelial cells and the immune system in a gut environment can be integrated through mathematical modeling. Moreover, extensive numerical simulations become available to draw possible scenarios and outcomes in gut environments in response to various types of stimulations, such as bacterial infection, anti-microbial drugs, low-chain fatty acids and inflammation. We aim to establish mathematical and computational methodologies which could be a basis for future development of personalized and predictive tools to assess effects of pro/pre-biotics on allergic and inflammatory disorders.
It is obvious that the immune system consists of kinetically, functionally and physiologically different cells. Functional and physiological diversity of cells arises from cell maturation and differentiation. Cell maturation and differentiation to a specific lineage involve changes in the internal component of a cell such as gene expression. The theory of physiologically structured populations provides a mathematical framework to formulate intracellular- and intercellular-kinetics which occur at different scales. This integrated framework enables us to describe physiological heterogeneity among cells. I could have an opportunity to join a work with researchers who are the leading people in the theory of physiologically structured populations.
Divese molecular interactions are simultaneously occurring within a cell. At the same time, cellular interactions affect intracellular molecular interactions in the different spatial and temporal scale. It is therefore important to focus on naturally occurring hierarchy of biological systems in time and space. Multiscale mathematical modeling and simulations are dispensable to find importance of inter-hierarchical feedback regulations. A theoretical framework of physiologically structured population models enable us to incorporate individual heterogeneity by introducing dynamics of i-state variables such as age and body-size, and environmental effects as feedback. By utilizing this theoretical framework while extending it to newly incorporate interactions among i-state and environmental variables would expect to provide novel viewpoint and insights to describe multiscale phenomena. I am currently working on considering a way of mathematical formulation to include inter-hierarchical feedback interactions in a physiologically structured population model. A particular biological target is cellular differentiation which commonly occurs during the development of adaptive immunity. I am currently collaborating with people working in virology, and skin biology on this project.
JSPS Grant-in-Aid for Scientific Research (C) (Grant number 16K05265).
Environmental problems such as global warming are caused by excessive human activities. One of the most important tasks for scientists is to evaluate the burden of human activities on eco-systems in rational ways. Systems understanding of eco-systems is essential to make reasonable decisions to maintain sustainability of our eco-systems.
Emergence of novel biological functions via accidental participation and interactions of agents (molecular, cell, human and et cetera) is an essential event in the evolution and formation of complex socio-ecological systems. Some of biological functions are generated via bricolage: a manner of emergence of unexpected novel biological functions arisen from interactions of accidentally encountered agents. As exemplified by symbiosis, some parts of socio-ecological systems have been shaped by successive inventions of novel functions via bricolage. In other words, elucidation of the concept bricolage is inextricably linked with the understanding of socio-ecological systems.
In this research topic, we undertake an interdisciplinary study to develop a practical systems theory to describe how robust socio-ecological systems are formed and evolved via bricolage. Our project is composed of the following three essential research topics: (i) development of control and dynamical systems theories to describe the evolution of socio-ecological systems via bricolage, (ii) construction of chemical and cellular experimental models to monitor an evolution of socio-ecological systems via bricolage, and (iii) experimental validation of the developed theories. On the basis of sub-projects (i)---(iii), as an interdisciplinary study, we aim to construct an artificial eco-system to simulate policy intervention to reduce CO2 emission.
JSPS Grant-in-Aid for Scientific Research (C) (Grant number 15KT0147).
Microbiome study is an emergent field for investigating microbial ecosystems in various environments including soil, marine, organism's tissue, and extreme environment. Recent extensive use of meta-genomics analysis benefitted from popularization of next generation sequences has revealed ubiquitous existence of enormous uncultured species in various environments. Current aim of microbiome study includes identification of species composition and its network structure, profiling of community function, and integration of transcriptome, proteome and metabolome (omics) data into meta-genomics data.
Although community profiling by utilizing microbiome data is a promising way to understand the composition and structure of the microbial community, systems perspective is required for understanding inherent complexity of natural microbial community. Functional profiling of microbial community reveals inference of associations among species interacting via proteomic and metabolic activities. More generally, integration of omics data is required for precise and detailed functional profiling.
There are more than different types of interactions captured by conventional omics data that form microbial community. Diverse microbial interactions include cell-cell communication as exemplified by quorum sensing. Cell-cell interactions are also essential to biofilm formation. Moreover, emergence of sociality occurs via interactions at the individual (cellular) level. Understanding of species interactions at the population level is critical to infer geographical spread and long-term persistence of microbial ecosystems. Therefore, multi-scaleness in space and time as well as interaction is an essential key concept to adequately integrate knowledge and data to reveal mechanisms and rules governing the maintenance of robust diverse microbial ecosystems.
Efforts in the last three decades in empirical and theoretical community ecology studies shed light on identifying mechanisms underlying maintenance of species diversity. Functional analysis of microbial community is expected to identify community assembly rules governing species coexistence. Mass emergence of a particular species population accompanied with reduced biodiversity is often observed, which is caused by excess human activities. Dysbiosis is a term to represent an imbalanced state of a microbial community in a body. Dysbiosis in the gut is known to be associated with several inflammatory diseases such as inflammatory bowl disease. Alternative stable state theory can be a practical guide to understand sudden change of a state triggered by external environmental stress. Although numerous concepts in community ecology can be useful clues to elucidate microbiological phenomena, lack of validation hampers predictive power of existing theories.
We propose a term “ecomics” to specifically represent a type of research to investigate a given microbial community by integrating omics data on the basis of community ecology theories and methodologies. Ecomics studies play a complementary role to bridge classical community ecology and microbiome studies: it brings understandings of microbiome and related data under the light of community ecology theory as well as validation or challenge to existing theories.
Synthetic or constructive ecology is an emergent research field which utilizes a handful of cultivable species to construct an artificial microbial ecosystem. Constructive approaches are compatible with novel design, theoretical validation and prediction. A term “ecomimetics” is motivated by the existing word “biomimetics”: a type of research to get insights from existing biological architectures such as a wing of the bird to construct a novel technological architecture using artificial materials. Ecomimetics is proposed to represent a type of study to extract the essence of community assembly rules from existing microbial ecosystem to construct a novel artificial microbial community. Ecomimetics study is expected to clarify hidden roles of a majority of uncultivable species in a natural community as a complimentary set of a well-understood in artificially constructed community.
Any research tpics are welcome that potentially contribute to further understanding of the microbial community in various environments. Applications of microbial community functioning in medicine, engineering and agriculture are highly appreciated proposal in ecomimetics study. More detailed descriptions for the proposal read as follows.
Japan Science and Technology Agency (JST) PRESTO (Grant number 12907).