For different types of environmental conditions, the logarithmic changes in each concentration Xj, denoted by δXj(E), are proportional for almost all components, over a wide range of perturbations, where the proportionality coefficient is given by the ratio of change in cell growth rate δμ(E). Then consider the evolution after applied environmental changes. Let the change in log concentration be δXj(G) and the change in growth rate be δμ(G). The theory suggests that δX_j(G)/ δX_j(E)= δμ(G)/ δμ(E), as confirmed experimentally. With evolution, the right hand term gradually moves toward 0, accordingly the change in concentrations does. This is a process similar to the Le Chatelier principle of thermodynamics. The relationships described above arise because phenotypic changes due to environmental perturbations, noise, and genetic changes are constrained to a common low-dimensional manifold as a result of evolution. This is because the adapted state after evolution should be stable against a variety of perturbations, while phenotypes retain plasticity to change, in order to have evolvability. To achieve this dimensional reduction, there is a separation of a few slow modes in the dynamics for phenotypes. The variance of phenotypes due to noise and mutation is proportional over all phenotypes, leading to the possibility of predicting phenotypic evolution.

The other facet of adaptation, immutability or homeostasis, is discussed. Dynamical system models that buffer external changes in a few variables to suppress changes in other variables are presented. In this case, some variable makes a transient change depending on the environmental change before returning to the original state. This transient response is shown to obey fold-change detection (or Weber–Fechner law), in which the response rate by environmental changes depends only on how many times the environmental change is to the original value. As for the multicomponent cell model, a critical state in which the abundances of each component are inversely proportional to its rank is maintained as a homeostatic state even when the environmental condition is changed. In biological circadian clocks, the period of oscillation remains almost unchanged against changes in temperature (temperature compensation) or other environmental conditions. When several reactions involved in the cyclic change use a common enzyme, enzyme-limited competition results. This competition among substrates explains the temperature compensation mentioned above. In this case, the reciprocity between the period and the plasticity of biological clocks results.

After a brief review of dynamical systems theory, which is a key to understanding the dynamic process of biological states, we present the methodology adopted in this volume. It consists of (A) macroscopic phenomenological theory based on biological robustness, (B) universal statistical laws at the microscopic level, (C) general laws derived as a consequence of macro-micro consistency, (D) hierarchies with different time scales, and (E) experimental approaches to uncover universal properties and laws, as well as (F) consequences of a possible breakdown of consistency. To illustrate the consistency between cellular growth and molecular replication, we present examples of general statistical laws in gene expressions and the correlated change of expression levels across genes in response to environmental changes, together with their experimental confirmation. Later chapters explain the application of the methodology (A–F) to reveal fundamental properties in life.

Cells are capable of maintaining a long-term memory in addition to genetic information, which is generally referred to as epigenetics. In the study of memory, digital memory has been often assumed, which is understood as multistability, whereas in the cell there is another form of memory – continuous (analog), kinetic memory. Referring to the kinetic constraints of the glass theory, it is shown that a kinetic memory with slow relaxation emerges as an alternative to the conventional memories of multiple stable states. It is characterized by a slow logarithmic change with several plateaus that can be occupied during the relaxation process. If the same enzyme catalyzes a stepwise reaction, as long as the amount of such enzyme is not sufficient, the reaction process can be hindered by enzyme-limited competition, resulting in kinetic memory. A combination of catalytic reactions can create a negative correlation between the amount of substrate and enzyme in it, thereby allowing a slow relaxation process with many plateaus, where multiple states can be maintained over a long period of time.

This chapter summarizes the concept and methodology of the present volume by emphasizing the relevance of macro-micro consistency. It also discusses current research topics on the origin of life, the relationship between developmental and evolutionary processes, the resilience of the ecosystem that maintains diversity, and dynamic memory in the brain, as well as possible future directions for establishing a theory of universal biology. All in all, fresh views of biology are presented with a physicist's perspective to reveal universality.

Two basic characteristics of adaptation, plasticity and robustness, are discussed. The former concerns itself with changeability – how a system changes its internal state in response to environmental changes, and the latter concerns itself with robustness – how most internal states are unaltered by environmental changes. Although such changes which occur as part of the adaptation process have been explained as an evolved signal transduction system, a generic adaptation mechanism without it is strongly requested, considering the genericity of adaptation. Here, it is shown that adaptation, that is, the selection of an attractor with a higher growth rate, can occur without specific signaling circuits, by considering the dilution of each component by cell growth, the homeostatic process in which components are synthesized to compensate for this dilution, in the presence of noise in the reaction process. Constructive experiments and simulations demonstrating such attractor selection are presented. This attractor selection can occur even when the adaptive attractor is not prepared in advance. Although direct experimental verification of attractor selection has not yet been achieved, it is a strong candidate to explain observed spontaneous adaptation. Besides the abovementioned adaptation with significant state change, the experimental evidence for a passive adaptation mechanism by fluctuation is also presented.

During development, cells sequentially lose their ability to differentiate into other cell types and become committed to different cellular states. This process can be described as a landscape in which the valleys are canalized one by one. This process of canalization is understood in terms of dynamical systems of interacting cells. In fact, as cells with oscillating gene expression proliferate and interact with each other, they differentiate into other expression states. Cells with oscillatory gene expression have pluripotency, either to replicate the same state or to differentiate into other cellular states, whereas cells that differentiate and lose their oscillations of expression simply replicate themselves, that is, they are committed. The proportion of each cell type is robust to changes in initial conditions and noise perturbations. Differentiation by protein expression dynamics is further stabilized by a feedback process of epigenetic modifications, such as DNA modification. The irreversibly differentiated cell state can be initialized to a pluripotent state by restoring an oscillatory state by forcing the expression of multiple genes from the outside, known experimentally as reprogramming.

This chapter presents an overview of the goals of universal biology. It is noted that biological systems are generally hierarchical as molecules-cells-organisms, where the components of each level are quite diverse. How such diversity arises and is maintained is discussed. We then discuss the possibility of understanding such biological systems with diverse components, and explore the possibility of macroscopic theory to reveal and formulate universal properties in living states, noting that robustness, plasticity, and activity are essential to life. Recalling the spirit (not the formulation) of thermodynamics, we explore the possibility of formulating a theory for characterizing universal properties in life, emphasizing macroscopic robustness at each level of the hierarchy and the importance of macro-micro consistency.

Cells reproduce under nonequilibrium conditions. By noting that a cell contains enzymes that drastically increase the equilibration process, it is shown that a cell is an apparatus that reveals the nonequilibrium property of the environment and accelerates equilibration. As a consequence, the entropy generation rate per cell growth is minimized at a finite growth rate, not in the adiabatic limit as in the Carnot cycle. General statistical properties of cells are then presented, including the power law in abundances and the lognormal distribution of cell-to-cell variation. The transition from exponential growth to the dormant state (where cell growth is arrested) is shown to be a general consequence of the accumulation of waste (non-autocatalytic) components, which leads to a jamming of the reaction. Related experiments using single-cell measurements elucidate the distribution of cell-to-cell variation in protein concentrations and growth rates. How cell reproduction and molecular replication achieve consistency is also a fundamental question for constructing protocells and understanding the origin of life. The relationship between minority molecules and genetic information, the synchronization of minority molecular replication and cell division, the separation of genetic information and catalytic function, and the acquisition of evolutionary potential are discussed as universal properties that must be satisfied for all cell reproduction systems.

Consider the evolutionary process under fixed environmental conditions, where genetic change leads to phenotypic change, and fitness is given as a function of phenotype. In this case, the variance Vip of the fluctuation of the phenotype due to noise is proportional to the rate of evolution of the phenotype, termed as evolutionary fluctuation–response relationship. It then implies that Vip is proportional to Vg, the variance due to genetic variation, as derived theoretically under the assumption of evolutionary robustness: the acquisition of phenotypic robustness to noise through evolution also leads to robustness to genetic variation. Here, as the mutation rate increases (or the noise level in the dynamics decreases), a phenotypic error catastrophe occurs, where it is no longer possible to maintain the fit phenotype. While phenotypic variance and evolvability decrease under fixed environmental and fitness conditions, they rise and fall repeatedly as environmental conditions are varied over generations. Phenotypic plasticity and evolvability are maintained under environmental variation. Strong selection under fixed evolutionary conditions can lead to the appearance of mutants with increased phenotypic variance. This may be due to over-optimization to obtain the fit phenotype, which may break consistency with other processes and reduce robustness.