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  • Faculty of Science and Engineering, Department of Physical Sciences
  • Understanding the mechanisms of life at the molecular level
    Unraveling these mysteries leads to the discovery of new physical laws
  • Professor Michio Tomishige
  • Faculty of Science and Engineering, Department of Physical Sciences
  • Understanding the mechanisms of life at the molecular level
    Unraveling these mysteries leads to the discovery of new physical laws
  • Professor Michio Tomishige

Approaching the mysteries of life through physics

Physics began with ancient researchers and has since unraveled many mysteries. On the other hand, the physical approach to biology has not been widely adopted until modern times. It has been treated as an "unknown area," so to speak.

In 1944, the famous physicist Schrödinger wrote a book called What is Life? A Physical View of the Living Cell, in which he attempted to use physics to redefine what living organisms and life are, for example from the perspective of thermodynamics. From that time on, there was a growing movement to use physics to unravel the mysteries of life, and young physicists began to take an interest in molecular biology. I myself enrolled at the University of Tokyo with an interest in physics, and came into contact with this field at the boundary between physics and biology. I was so inspired by this idea that "biology can also be understood through physics," that I decided to embark on research in this field.

As you can see, the history of biophysics is not that long. In Japan, Professor Fumio Osawa, one of the contributors to the establishment of the Biophysical Society, elucidated the mechanism of polymerization of "actin," which is responsible for muscle contraction, by extracting molecules from rabbit muscle and observing them in the 1960s. This led to the idea that by improving the accuracy of observation at the single-molecule level, there may be something that cannot be explained by existing physics. In other words, it was strongly suggested that life is full of possibilities for discovering new physical laws.

For example, the law of increasing entropy in thermodynamics indicates that matter becomes more disordered (entropy increases) over time and eventually breaks down. However, we living organisms never lose order over time. It's as if they defy the law of increasing entropy. In this way, there are many things hidden in life that cannot be explained by conventional physics. Discovering these things through research and establishing new theories will be an endeavor to expand upon conventional theories. People 50 years ago may not have imagined a world in which people all over the world use ICT (information and communication technology) as we do today. However, research into quantum mechanics, which is the basis of such technology, was underway at that time, and the "seeds" of technology had been sown. Now it is an era in which they have blossomed. In the same way, we cannot imagine what society will be like 50 years from now, but I believe that confronting the mysteries of life in modern research, unraveling them, and establishing new physical laws will surely become the "seeds" of future technology. I believe that biophysics is a field of study that holds the key to the future.

Kinesin, the cell's delivery service

Within the field of biophysics, the subject of my research is kinesin, a protein present inside cells.

Within the size of a cell, which is approximately tens of micrometers, different locations play different roles. Some locations within a cell create new proteins, but someone needs to transport the created proteins to the locations where they will work. Kinesin is responsible for this transport. Kinesin is like a delivery company within the cell, carrying cargo along rails called microtubules, but it moves in a special way, moving forward by putting two legs forward alternately, as if walking.

Using the "single molecule measurement method" that visualizes and directly observes each molecule, the way kinesin moves has been elucidated to a great extent. Some Western researchers now think that "everything that can be investigated has been investigated," and that "kinesin research has passed its peak." However, I don't think so. Rather, I think that "this is where the real work begins." We have finally reached the starting point.

We have indeed succeeded in detecting and understanding the way kinesin moves. However, this only means that we are now able to draw a picture of its movement. We have not yet been able to explain what kind of reactions are occurring energetically. Our goal is to elucidate such new physics through the study of living organisms.

For example, the movement of kinesin's "legs" occurs in milliseconds, with one step taking about 20 milliseconds. However, conventional imaging technology for single molecule measurement has a limit of 100 frames per second (10 milliseconds per frame). In other words, one step takes two images. This makes it impossible to understand the fine movement of the legs. We in the Tomishige Laboratory felt that a technology to observe at higher speeds was necessary, so we decided to use gold nanoparticles instead of fluorescent dyes attached to molecules. This significantly improved the accuracy of observation, allowing us to take images at 20,000 frames per second (0.05 milliseconds per frame). This allowed us to observe how kinesin's legs move in greater detail and with greater precision.

"The Fluctuation World" and Ratchet

Kinesin is an extremely small entity, measuring just a few nanometers, so it exists in a world where the physical laws of gravity and inertia that apply to our macroscopic world do not apply. Kinesin moves in a "world of fluctuations" that is greatly affected by collisions with various molecules, such as water molecules flying around at high speed. Therefore, kinesin's legs do not move in a firm manner like animals', but rather, the legs that are raised behind swing loosely, and when triggered, they swing forward and land. It has become clear that this type of movement is repeated.

Machines in the macroscopic world in which we humans live have trouble moving accurately if there is any irregular fluctuation. However, kinesin, a machine of the molecular world (nanomachine), utilizes these fluctuations to convert them into kinetic energy. This conversion is achieved by a ratchet, a mechanism like a wing or tooth stop that only moves in one direction. When a large force is applied in a certain direction, the force is converted into power, but the mechanism does not allow it to return to its original position in the opposite direction.

It has become clear that kinesin, a soft protein that is not rigid like macroscopic machines, is driven by thermal fluctuations and ratchets. However, to understand the form and conditions under which this kinetic energy is generated, and how it is generated, we need to further improve the precision of our observations. For example, observing the movement of the legs. We are currently continuing various challenges, such as observing the angle of kinesin's legs by adding markers called gold nanorods, which are rod-shaped gold particles, and discovering structural changes in the protein caused by fluctuations.

Even just adding a marker is a delicate task that requires extremely minute precision, and is not an easy task. However, if we stop understanding at the notion that "kinesin walks like humans," we will never arrive at new physical laws. If we do not compromise and continue our pursuit, and we unravel the new mechanisms of nanomachines, this may be applied to new technologies, for example, 50 years from now, leading to the development of society. Our research is the "seed" that will generate various ideas for the future.

New physics and the seeds of the future

Our bodies are made up of a collection of nanomachines such as kinesin. However, it would be a struggle for humans to create nanomachines with their own hands. Just as macroscopic machines have blueprints, nanomachines have blueprints contained in their genetic information, which allows living organisms to create nanomachines accurately and at low cost. This is another big difference between giant machines and the machines of the molecular world. But why does genetic information enable the creation of sophisticated nanomachines at low cost?

The mechanism by which nanomachines extract kinetic energy from fluctuations, or the mechanism by which they create extremely ingenious ratchets - such targets that we must unravel in the future are contained in genetic information. As researchers, how can we formulate the blueprint contained in this genetic information, discover the laws that govern it, and deepen our understanding? We are currently searching for answers, standing between information and physics.

In the world of physics, when an object is left for a certain period of time, it will reach a state where it maintains a certain temperature, volume, etc., and this state is called "equilibrium." Up until now, physical science has accurately explained this mechanism. However, living organisms are constantly taking in and releasing energy, repeating a "non-equilibrium" state, and existing physics has difficulty explaining this.

Furthermore, there is the concept of "nonlinearity." A linear system is the idea that if you divide an object of observation into parts, observe each part, and finally connect them together to understand the whole, but this is not the case with living organisms. For example, when ATP (adenosine triphosphate), an energy source, is attached to a protein, a major change appears in a completely unrelated place. Living organisms are "nonlinear" entities in which simply connecting together observations of each part does not lead to an understanding of the whole, and existing physics is not good at explaining this either.

These "non-equilibrium" and "non-linear" characteristics are the major differences that separate living things from the matter that has been elucidated by physics up until now. However, on the other hand, if we can unravel the mysteries of living things and deepen our understanding of the physics of "non-equilibrium" and "non-linear," there will be a lot of room to build new physics. The new knowledge established in this way has the potential to become the "seed" that will greatly advance the future through new physics, just as quantum mechanics has greatly advanced engineering and IT.

Breakthroughs in the world occur when something that was not yet understood becomes understood through some trigger. When we look at the world of living things through the lens of physics, there are many things that we do not yet understand. I believe that the development of biophysics will greatly contribute to society in both engineering and medicine in the future.

Related articles

  • "In Search of Living Things" by Fumio Osawa (Fujiwara Shoten: 2017)
  • "Biophysics" by Shoichi Toyabe, edited by Takaharu Otsuka, Masaki Sano, and Seiji Miyashita (Nihon Hyoronsha: 2022)
  • “Single Molecule Biology” edited by Yoshie Harada and Shinichi Ishiwata (Kagaku Doujin: 2014)
  • "Non-equilibrium statistical mechanics - from fluctuation thermodynamics to information thermodynamics" by Takahiro Sagawa, edited by Shozo Sudo and Makoto Oka (Kyoritsu Shuppan: 2022)

Study this topic at Aoyama Gakuin University

Faculty of Science and Engineering, Department of Physical Sciences

  • Faculty of Science and Engineering, Department of Physical Sciences
  • Professor Michio Tomishige
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