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生物・医学研究
Sarcopenia Project also conducts
bioscience research and basic medical research
Research Overview
Despite the fact that proteins are only about 5 nm in size, they perform a variety of outstanding functions. Our laboratory is interested in the exceptional functions of protein molecules and cells, and we are trying to understand the dynamic mechanisms underlying these functions. The easiest way to understand the dynamic mechanisms of protein function is to perform experiments with purified proteins. However, proteins carry out their functions in cells, so it is important to carry out experiments in cultured cells (cells grown on glass), which are complex and subject to experimental constraints. Furthermore, the ultimate function of the cell is in the individual (e.g. mouse), so although complex and experimentally constrained, it is not possible to say that we understand the true function of the protein unless we challenge ourselves to study its function in detail in the individual. The laboratory uses purified molecules, cultured cells and mice to elucidate several outstanding mechanisms of proteins and cells. Targeted functions include cell motility, muscle contraction, cell division, nervous system formation, immune cell attack and cell death. Theories are developed to provide a unified explanation of the results obtained, and calculations and simulations are used to understand the physical significance of the results obtained and the functions of the molecules.
１．Research involving molecular atoms
Unified mechanisms of proteins involved in the movement and structure building of organisms
The macromolecules (proteins, DNA and RNA) that regulate life are ‘high-performance nanomachines’ with outstanding functionality, but are only a few nanometres in size. These nanomachines replicate DNA, form proteins and perform sophisticated functions such as cell motility and cell division (Fig.) The energy source for the activities of biological nanomachines is the hydrolysis energy of ATP (adenosine triphosphate). Hydrolysis energy is only 13 times greater than thermal fluctuation energy, so thermal fluctuations cannot be ignored for biological nanomachines.
In our laboratory, we are investigating the motor mechanisms of motor proteins responsible for intracellular transport, muscle contraction and cell division, and analysing the physicochemical dynamics of actin and microtubules, the dynamic backbone of the cell. The actin and myosin molecules involved in muscle contraction are involved in the movement of all cells, not just skeletal and cardiac muscle, so once the muscle contraction mechanism is understood, the movement of cells other than muscle can also be understood. Furthermore, other molecules that cause cell division and vesicular transport, such as kinesin and dynein molecules, have multiple functions, including different directions of movement, microtubule depolymerisation and anchoring functions. We want to understand the underlying principles of myosin, kinesin and dynein motility. To achieve this, we are simultaneously developing genetic, single-molecule measurement (Fig.) and imaging techniques to study recombinant proteins with ultra-high precision.
Some interesting results have already emerged. We have found that kinesins perform movement by a mechanism similar to the thermal ratchet mechanism, and that this basic mechanism is common to the movement of various other motor molecules (Fig.) Using this mechanism as a starting point, we hypothesised that by adding some properties, different functions would emerge and are currently conducting validation studies.
２．Cellular research
Exercise, intracellular signaling and cell-based studies of cancer control
Neutrophils, macrophages, and immune cells, the white blood cell cells that eat bacteria in our bodies, perform amoeboid-like movements. This movement is not only interesting in itself, but it is also interesting in both medical and scientific aspects because these cells are targets of drugs. We are investigating the cause of the movement of neutrophils purified from mice and humans in terms of the mode of movement of intracellular vesicles. For example, the tip of the cell movement is less viscous and the rear is more viscous, suggesting that the movement is caused by the dynamic formation and disassembly of proteins at the tip.
Intracellular activity is also active. Membrane proteins are transported from the Golgi to the plasma membrane, and external solutions are transported into the cell, where they are distributed and transported to replenish proteins. Transport is most active during cell division, when chromosomes, mitochondria, intracellular organelles, and proteins are transported to daughter cells. Thus, just as human society is supported by walking, cars, trains, and boats, so transportation supports cellular life in the cell. Because of the presence of obstructing structures and regulatory proteins in these transports, they do not move in a straight line, but frequently turn and stop (Figure). We are currently elucidating the basic principles of intracellular locomotion by examining the intricate movements of these vesicles (cargo) in detail and with high precision. By understanding this principle, we can understand what information the cell obtains and how efficiently it gets to its destination. This is just like the familiar phenomenon of a truck going through different roads, taking breaks, and how much time and gasoline it consumes before arriving at its destination. Since cells are exactly like small human societies, the Higuchi Lab is involved not only in transportation, but also in research on information transfer to cells and methods of diagnosing cancer cells that have disrupted cellular societies.
３．Basic medical research using mice
Observe immune cells and cancer cells in mice and understand their molecular functions
Individuals such as mice not only have many cells interacting with each other in a three-dimensional manner, but also have blood vessels and lymphatic flow, and immune cells are active everywhere. On the other hand, the environment of cultured cells used in cell experiments is very different from that in mice, because a limited number of cells (mainly cancer cells) are grown on plastic. Therefore, we have been developing methods to observe cells and molecules in living mice in order to explore the true nature and function of life. In 2007, we were the first in the world to develop a method to observe a single molecule in mice (Figure), and have clarified the drug delivery process of anticancer drugs in mice. We have made an unexpected discovery that the delivery process is not a general diffusion process, but a repetitive cessation and movement process. Currently, we are investigating the behavior of cancer cells, leukocyte cells, muscle motility, and membrane proteins. These studies have paved the way for serious studies of cells and molecules in the mouse, a field that is expected to develop into molecular biology and basic medicine in the future.
４．Research on the universality of living organisms - Universal physical model of motor function
Our research has shown that vesicles transported by motor molecules through the cell are in seemingly random motions with little directionality for short periods of time. However, after a prolonged period of time, vesicles achieve directional transport, such as gathering around the nucleus, which is a bit strange. The process of vesicle motion must be governed by various types of fluctuations. Therefore, we are constructing a physical model by modeling and formulating how the contributions of “directionality” and “randomness” change with time and space. Based on these models, we are attempting to theorize the relationship between the motion and shape of cells and the motion of protein molecules. This is an ideal research project for students who love mathematics.
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