Q: What kind of research are you doing?
A: I am studying the mechanisms of axonal transport. In neuronal cells, membrane vesicles are transported by motor proteins (such as kinesin) to their destinations along a highway of microtubules. The aim of my research is to elucidate the mechanisms of this movement.
The most obvious feature of living things is that they move. When you observe the movement of motor proteins directly under the microscope, you'll see those tiny molecules move smoothly along the linear track formed by the microtubules, just like a movement of trains running along a railroad track. It may give us the impression that motor proteins are living organisms. At the same time, we cannot help admiring that how nature can build such a sophisticated machine in such a tiny molecule. Being inspired in various ways, I never get bored with observing their movements.
Q: What is the mechanism of that movement?
A: Motor proteins travel along microtubule tracks using the energy released from adenosine triphosphate (ATP) hydrolysis. According to the common model, motor proteins are believed alternately move its legs along the microtubule so that it appears to "walk" like a human being walks on the ground. In this model, the microtubule is stationary. However, motor proteins in reality do not appear to move independently.
Nine years ago, as a researcher at the then Japan Science and Technology Corporation, I encountered a phenomenon that suggested something was also happening on the "ground," or rather the microtubule. I had coated a glass slide was covered with kinesin and placed microtubule on it. The force generated was measured as the microtubule moved along the kinesin. When the microtubule initially contacted the kinesin on the slide, no interaction occurred. However, movement suddenly started and once it had been initiated, it occurred instantaneously when the microtubule was placed on kinesin at any location on the slide. It was as if the microtubule had been initially OFF but was suddenly "switched" ON. After observing this phenomenon, I spent two years developing an experimental system to quantify the ON and OFF states of the microtubule. Eventually I was able to demonstrate that a microtubule's state changes dynamically in tandem with motor movement.
Q: How were your experiments received?
A: At the time my ideas were vigorously rejected by my own laboratory colleagues and at academic meetings, must to my surprise. The consensus argued that "this must be the result caused by a certain artifact" and that "a microtubule can never be dynamic". My conclusion that the "ground" also change dynamically encountered unexpected resistance partially because it overturned conventional wisdom about the mechanism of motor protein transport.
Q: How did your subsequent research develop?
A: After that, presentations I made at an academic meeting produced strong, split reactions from supporters and skeptics. My submitted papers were repeatedly rejected, misunderstood or severely criticized by reviewers. However, I continued to enjoy investigating the dynamics of the microtubule. I was excited by the wonder and beauty of the phenomenon every time I observed it, and was not discouraged.
As my experimental work move forward, more serious interest in the subject gradually emerged among my colleagues. Several academic societies have even held symposia focusing on that "dynamic ground." And I finally published a paper this spring, at the start of my fourth year in RIKEN.
Q: How do you feel when you look back over these past events?
A: When I started this project, I did not imagine that I would be involved in such controversy. The last nine years seem like a drama that interfered with the course of my life. Looking back to when I was at graduate school, I was strongly interested in two issues: the physical properties of protein polymers and the mechanisms of motility in living things. In the work I am doing now, my vague desires to "engage in work aimed at an understanding of the mechanisms of living things, based on their physical properties" had been realized.
Q: How did you come to BSI?
A: I was interested in the work of the late Dr. Gen Matsumoto, who investigated the relationships between the dynamics of the microtubule and membrane excitation in giant axons. My research began with the motor protein and recently led to microtubule dynamics. However, it was more than twenty years ago that Dr. Matsumoto and his staff had conducted a series of revolutionary experiments that suggested the importance of the microtubule in the mechanism of membrane excitation. Unfortunately, the significance of the phenomena they observed was not fully appreciated at the time, because with the technology of those days, it was difficult to reach an understanding of the mechanisms at the molecular level.
Whether it is the motion of motor proteins or the mechanisms of membrane excitation, the essential features of the phenomenon will only become clear after a means to quantify the underlying microtubule dynamics is developed. It is a difficult mission, but I believe that brain science must continue to expand its scope beyond the "molecular" level. In the future, we should also deal with, or at least challenge ourselves to understand, the "dynamics" of the systems involved.
