Dynamic Living Systems Architecture Lab

We envision arbitrary modification/manipulation of complex organizations inside living cells as a promising future of pharmacology.

Dynamic Living Systems Architecture Lab (DLSA Lab) is developing novel tools that manipulate the dynamics of biomolecules inside living cells. Using chemical and optical stimuli, we design protein-based molecular tools that can arbitrarily modify intracellular organizations, including classical and non-membrane-bound organelles, mainly through dynamic assembly/disassembly of the component biomolecules. These technologies that allow unprecedented manipulation of intracellular designs should eventually reveal complex relationship between cellular organizations and functions. 

Diverse body plans found in eukaryotes suggest close relationships between intracellular organizations and cellular functions/interactions.

All living organisms on Earth are made of cells, and even a single cell can live as an independent organism. In this sense, the cell is the fundamental unit of life.

One of the major transitions in cellular evolution was the emergence of eukaryotic cells. Compared with the relatively uniform interior of prokaryotic cells, eukaryotic cells contain a wide variety of internal structures. They are also generally much larger: while prokaryotic cells are typically 1–10 μm in size, eukaryotic cells range from about 5 to 100 μm. The emergence of eukaryotes therefore involved a dramatic increase in both cell size and the complexity of intracellular organization.

This transition had profound consequences for the evolution of life. All known multicellular organisms are eukaryotes, and multicellularity appears to have evolved independently multiple times within eukaryotic lineages. The emergence of the eukaryotic cell may therefore have been a critical prerequisite for multicellular life, ultimately enabling the extraordinary diversity of organismal size, form, and ecology that we see today.

From this perspective, the acquisition of larger cell size and increasingly complex intracellular architecture may have been a major evolutionary turning point. By expanding the possibilities for cellular function and cell–cell communication, it may have paved the way for multicellularity and, eventually, today’s biological diversity.

Yet the history of life has unfolded only once, and the clues available for reconstructing it are necessarily limited. How, then, can we uncover the principles that connected increasingly complex cellular organization with the diversification of biological function?

We believe that one powerful approach is to experimentally recreate aspects of this evolutionary process in the laboratory. By precisely altering the internal organization of living cells and quantitatively examining how those changes affect cellular functions and interactions, we can explore not only how evolution may actually have proceeded, but also what alternative evolutionary trajectories might have been possible.

To do this, we first need technologies that allow us to freely redesign the interior of living cells. Developing such technologies is exactly what our laboratory is working toward.

Cell as a microscopic "society" 

- dynamic interactions between intracellular organizations enable cellular life -

Proteins, the major players in cellular biochemistry, are only a few nanometers in size. Yet the interior of a cell is crowded with micrometer-scale structures, ranging from membrane-bound organelles such as the nucleus and mitochondria to flexible, droplet-like condensates. These structures are highly dynamic, continuously changing their shape, position, and molecular composition.

Each of these intracellular structures performs essential functions, and cellular life emerges from their dynamic interactions and exchange of materials. In this sense, a cell resembles a small society. Organelles and other cellular structures are like hospitals, stations, power plants, and factories, while molecules move among them like people and goods. These infrastructures are continually maintained, remodeled, assembled, and dismantled as circumstances change.

Thus, each cell can be viewed as a miniature society. Modern molecular biology has revealed enormous amounts of information about its individual components—the sequences, structures, and functions of countless proteins. But does understanding the molecules necessarily mean understanding the cell?

Knowing individual people is not the same as understanding how a society works. Likewise, cells built from similar molecular components can behave very differently depending on how those components are spatially organized. Molecular knowledge is indispensable, but it is only the starting point.

One of the major challenges for biology is therefore to build on our knowledge of biomolecules to understand how the cell functions as an integrated system. We believe that technologies for freely redesigning intracellular organization will provide a powerful way to uncover the principles that govern the architecture of this cellular “society.”

Establish "micro-architecture" of the cellular "society" both for basic biology and for future therapeutics

When the society we live in begins to malfunction, how do we try to solve the problem? There are many possible approaches, but in many cases, we carry out some form of “construction work” to build, remove, or renovate infrastructure. A typical example would be constructing a new railway line and stations to connect a rapidly growing suburban area with the city center when the existing transportation network can no longer handle the increased population. In this way, “construction” allows us to “build” new infrastructure as needed, “demolish” what is no longer useful, and “redesign” existing systems. These are among the principal ways in which we maintain the functions of our society.

By contrast, we currently have very little ability to freely perform such “construction work” on the infrastructure of the cellular “society”—that is, on the diverse structures inside living cells. For example, we cannot simply dismantle a poorly functioning nucleus and replace it with a new one, nor can we redesign mitochondria to give them an entirely different function. The architecture of this tiny society—what we might call “micro-architecture”—has hardly been established as a field of technology.

Our efforts to develop technologies that allow us to freely redesign the interior of living cells are, in essence, aimed at building the technological foundation for this “micro-architecture” of the cellular society.

Arbitrary modificaiton of intracellular organizations should reveal the complex relationships between intracellular designs and cellular functions/interactions.

Dysfunction of the cellular “society” directly leads to disease. Many disorders arise when particular cells malfunction or are lost. If so, a “micro-architecture” that allows us to freely reconstruct the interior of living cells could also become a new way to treat disease by rebuilding the cellular “society” itself.

Many medicines used in modern medicine and pharmacy are molecularly targeted drugs. They act by binding to specific proteins and altering their activity, often by inhibiting proteins that become excessively active in disease. This strategy has been enabled by advances in molecular biology, which have revealed the functions of numerous proteins and their roles in pathological states. By correcting abnormal molecular activity, targeted drugs aim to restore cells toward a healthier condition.

In the cell-as-society analogy, molecules correspond to people and materials. Treating disease with a molecularly targeted drug is therefore analogous to resolving a social problem by changing the behavior of a particular group of people. This is fundamentally different from solving the problem through “construction” of the infrastructure itself.

Molecularly targeted drugs have achieved tremendous success, but they cannot treat every disease. We therefore envision a complementary strategy: repairing cellular dysfunction by directly reconstructing the architecture of the cell. Because this approach operates on a fundamentally different principle, it could open new therapeutic possibilities beyond conventional molecular targeting.

Our goal is to establish an “architecture” for freely designing the ever-changing interior of the cell—the smallest unit of life—and ultimately to develop a new form of pharmacy in which disease can be treated by “rebuilding” this tiny society. This vision is embodied in the name of our field: Dynamic Living Systems Architechture.