Research Director: Kunihiko Kaneko
(Professor, Graduate School of Arts and Sciences, The University of Tokyo)
Research Term: 2004-2009

Some of the most important and profound questions in science include: how did life start on Earth, how does it evolve, and how do billions of individual cells cooperate to make a unified whole. It is difficult to find answers because everything is so complicated. Just one cell involves a membrane, huge DNA molecules that contain information to regulate the cell, and many proteins and other molecules. Organisms can be composed of many billions of cells. Still, some scientists are finding hope by thinking in terms of complex systems theory. Complex is quite different from complicated. In complex systems, each element is influenced by the whole, and thus there is mutual relationship between the whole and the elements, with which a different level of hierarchy is interrelated, such as cell versus chemical components, tissue versus cell, society versus individual. From this perspective, the fundamental logic of life is searched for, with the emphasis on very basic concepts, such as fluctuation, diversification, robustness, and irreversibility while giving physicists a chance to reveal universal characteristics about the fundamental nature of biology.

Kunihiko Kaneko has been interested in complex systems since the 1980s, especially those with many interacting chaotic components. Mutual relationships exist between the microscopic components (elements) and the macroscopic average (whole). Kaneko found something very interesting: even if each element is completely identical, through interactions they can differentiate. He then developed dynamical systems theory to elucidate conditions why this effect occurs.

Multicellular organisms have many cells, but identical genes (rules), and the cells can interact with each other. This view fits Kaneko’s model for individual elements and the total system. Different dynamical levels cause mutual influences. The state of a cell can change, and each element can change in accordance with the total behavior, which is the important part of complex systems. Though people tend to think that biological systems are very much tuned through the evolutionary process, there are more universal properties that all life systems must obey. Understanding universal properties is a physics-type approach. To apply this to biology, a strategy called constructive biology is taken where some basic property is constructed, experimentally and theoretically, and one then tries to understand why it occurs.

Outline of Research

The Kaneko Complex Systems Biology project is attempting to obtain an understanding of living systems. Although there are many different themes, the important thing is that in complex systems like life, each level is not completely separated, but very mutually influenced. Lower levels influence higher levels, and vise versa. While developing a theory of this flexible change, the following themes are being explored:

Artificial cells: Efforts are being made to create very primitive artificial cells that can replicate themselves, including the cell membrane, DNA and various chemical species. All of these components must work together synchronously, like in a real cell. A key point is that the number of each molecule is not large, and therefore large fluctuations can be expected to occur. The big question is how with these fluctuations recursive production is possible. As long as some kind of recursive production exists, there should be some kind of universal constraint, basic rules that should also be satisfied in the present cells. Through the construction of artificial cells, universal statistical laws on such fluctuations and regulation mechanisms are searched for both theoretically and experimentally.

Adaptation: Biological systems must adapt to the external world. If the environmental condition, such as nutrients, changes, the internal chemical dynamics is shifted to adapt. An effort is being made to understand the general principles and rules of such adaptation. Study with the present gene regulation network, already fully developed through evolution, would not be relevant to extract some universal mechanisms of adaptation. Instead, spontaneous adaptation is being studied with the use of an artificially embedded genetic network that is not a result of evolution. Together with this experimental study, a general universal mechanism for adaptation that is not related to evolutionary tuning will hopefully be elucidated in relationship with the fluctuation and growth dynamics.

Multicellular organisms: By putting bacteria under crowded conditions, it is being studied how cell differentiation occurs and leads to the formation of distinct types to constitute a prototype of multicellular organisms. On the other hand, the differentiation of special cells for the next generation (spore) is being studied by using slime mold. By measuring the differentiation processes through genetic expressions, universal logic for irreversible differentiation, robust development, and individuality as a multicellular organism is being searched.

Evolution: In evolution, whereas genetic change is usually the main consideration, the basic problem might actually be related to fluctuations. Even with the same gene there can be fluctuation of the phenotype (behavior). For instance the number of proteins in a bacteria can differ significantly even if they have the same genes. The question is how this phenotype fluctuation is related to evolution. Borrowing the idea of statistical physics, it is naively expected that the larger is the fluctuation, the larger is the response to the change in the external environment, implying higher flexibility. If this simple impression is true, then even in a cell or an organism if there is more fluctuation in phenotype, then there is higher adaptability and ability to evolve. This possibility is being checked by both theory and experiments. A theory has been proposed of genotype-phenotype correspondence in terms of fluctuations and dynamics, or phenotype plasticity. The concept of plasticity is formulated by adopting a thermodynamic type approach, which is related to fluctuation and evolution.

Endosymbiosis: Work with ameba and bacteria is being conducted concerning symbiotic relationships among organisms. Usually an amoeba eats bacteria, but under some condition it forms a symbiotic relationship. In this case the properties of the amoeba and those of the bacteria both change. The question is how is this possible. If each were a very pure and highly tuned system, the two combined would not work, just as two independently developed computer programs would be incompatible. But bacteria and amoeba in some way very flexibly change their state to make this symbiotic relationship. So again the problem of plasticity or flexibility exists. An attempt is being made to quantify this in terms of fluctuations and dynamics of gene expression.