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Osaka University Distinguished Professor - "The Best Part of Research is Challenging What We Don't Know"

"If you do it for a year, one day is bound to go well"

“The research I do is nothing specially, really…” he said with a tone of humility, but there is a reputation to in-depth research. “As part of the multi-faceted personnel affairs and evaluations at Osaka University, including basic research, I’m so thankful to have been chosen as an Osaka University Distinguished Professor,” he said with a smile. Professor Hamada’s field of study had been full of mysteries until just a few years ago, and there were many things that he didn’t understand. The more he performed his research, the more unexpected results came about. There were times when he was completely baffled, but even in this, he says, one can find meaning. “If you do it for a year, one day is bound to go well. The joy of research is continuing to build on it until that day comes.”

A Meeting at OU, and a New Development

In an animal’s body, there are 3 axes: front to back (head to tail), back and belly, and left and right. Of these, the difference between left and right are decided at the end of the growth process, but the true identity of this was a mystery until the mid-1990s. The core of Professor Hamada’s research is “The Decision Mechanism of Left-Right Asymmetry.”

Before taking his position at OU, while investigating the genes that control morphosis in mouse embryos with Professor MENO Chikara, a graduate student at the time (later Assistant, Assistant Professor, and currently Professor at Kyushu University) and SAIJOH Yukio, an Assistant at the time (currently Assistant Professor at The University of Utah), he happened to discover the factor (protein) involved in the differentiation of cells, called “Lefty,” which is only expressed on the left side of the embryo. In order to investigate this mechanism, a knock-out mouse, which is missing a particular gene, was needed. “As luck would have it, when I took my position at OU, I had an encounter with Professor KONDOH Hisato, who had the technology to create knock-out mice from ES cells, a technology which was scarce in the world at the time. This would advance my research by leaps and bounds,” said Professor Hamada.

 As he went on investigating Lefty, he discovered some peculiar things. If Lefty were inactive, it seemed that the left side would not form, which would create two right sides. However, what resulted was the complete opposite: the body creates two left sides. What solved this paradox was the discovery of Nodal, which is expressed in nearly the same location as Lefty. Nodal formed the structure of the left side, while Lefty adjusted this function by restraining Nodal and preventing runaway formation. In the research that followed, the mechanism of the emergence of left-right asymmetry was elucidated from the gene expression control mechanism of the mutual functions of Lefty-1, -2, and Nodal.

The Physical Phenomenon of Flowing Water Disturbs Left-Right Symmetry

Why do Lefty and Nodal only appear on the left side? This answer was also in an unexpected place. In 1998, Professor HIROKAWA Nobutaka of the University of Tokyo discovered that in the node, a small dent, near the center of the abdominal region of the mouse embryo, amniotic fluid was flowing from right to left. From this discovery, NONAKA Shigenori, at the time a researcher in Professor Hamada’s laboratory (currently Associate Professor at the National Institute for Basic Biology) applied a reverse flow on the embryo from left to right using a pump. This caused the formation of right and left to reverse. In other words, it was clarified that the point of departure for the differentiation of left and right in the body was the physical phenomena of flowing water.

So why does this flow occur? The cilia rotate clockwise at a rate of 600 rotations per minute, which should cause a vortex. So why, then, does this flow occur from left to right? Professor Hamada asked professors at the School of Engineering and found that this flow was a hydrodynamic phenomenon due to the tilt of the rotational axes of the cilia. Due to viscosity occurring in liquids, the flow of water on the semicircle with cilia close to the cell’s surface is inferior to that which occurs on the semicircle separate from the surface. These results show that nodal flow occurs from right to left.

Genetic Disorders Which Reverse the Right and Left of Organs

 The genetic disorder that causes heterotaxia, which reverses the construction of left and right in the body, has been known for quite some time. It was also known that this disorder was accompanied by various disabilities due to cilia not moving in the trachea. All of these were confirmed to stem from the absence of factors that drive the cilia.

The inquisition goes even further. Why does the tilt of the cilia line up? The cilia are located on top of the basal body of the cell.

Each cilium protrudes from a basal body. The position of the basal body changes during development  and shifts toward the posterior side (in the direction the tail will form). It is thought that the basal body shifts using the already determined positional information.

 

Further research on the cause of this mechanism is currently being carried out.

The Secret of Non-Moving Cilia

Then, how does the flow of the node transmit information about left and right? Is it flushing some kind of matter? A surprising conclusion was gained from this as well. It seems that the mechanical stimulus of the flow of water itself held some meaning. Two to three hundred cells are lined up in the node. Most of these make the cilia rotate, but there are some cilia on the outside that do not. These cilia get pushed by the flow of water, and the calcium ion Ca2+ is brought in. Put simply, it is thought that the cilia that do not rotate act as sensors for the flow of water, and discern the left side. In order to clarify this, testing is being carried out to apply physical energy to these non-moving cilia and investigate the results.

All of these things indicate new medical and physiological knowledge. There are many cells in the body that have cilia. However, there are those that do not move or cannot move due to being buried amidst cellular structures. These cilia are “traces” thought to be useless. But now it has been found that these non-moving cilia act as antennae to receive signals. For example, there are “non-moving cilia” in kidney tubules, which may be detecting the flow of the urine produced there.

Never Forget to Be Curious in Research

There is still a load of research yet to be done. The reason why cilia rotate in a clockwise fashion is thought to be due to their formation, but it’s an interesting problem. “The best part of research in challenging the things that we don’t know,” said Professor Hamada. “If taking the things you enjoy as the subject and performing research you enjoy becomes satisfying work for you while also contributing to society, then that’s fine.” Students who have gone off from this laboratory have made use of this method and way of thinking to thrive in various fields. Professor Hamada’s message is simply, “Never Forget to Be Curious in Research.”

About Hiroshi HAMADA

Born in Kagawa Prefecture in 1950, Professor Hiroshi HAMADA graduated from the Medical School at Okayama University, and completed the graduate school program there in 1979. He served as an assistant professor at Memorial University in Canada as well as Tokyo University before entering the Tokyo Metropolitan Institute of Medical Science. In 1995, he became a professor at the Institute for Molecular and Cellular Biology (IMCB), Osaka University. Due to reorganization, he became a professor at the Graduate School of Frontier Biosciences at Osaka University in 2002. Professor Hamada is involved with molecular biology and developmental biology education and research, and in 2014, he became an Osaka University Distinguished Professor. Awards received by Professor Hamada include the Osaka Science Prize in 2000, the Naito Foundation Merit Award for Advancement of Science in 2011, and the Medal of Honor with Purple Ribbon in 2014.

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