Prof. HORIE Takeo’s report (part 4 of 4) Always smile 2022.10.26

My only rule is: "enjoy your research"

I love science

The only rule in my lab is "enjoy your research." I don’t force anyone to produce research results. I say that I want people to come to my lab by 10 o’clock, but I’m not strict with rules, including how long you stay in the lab. Michael Levine emphasized getting lab members devoted to their projects. After I returned to Japan, I went to see him give a talk at the kick-off symposium between Princeton University and the National Institute for Basic Biology where he spoke about how much you have to love science, an attitude I emulate. I think the reason I am where I am now is that I truly love science. Love research. Even though I faced many setbacks, loving what I do has never changed.

Also, there is another rule I impose upon myself: always smile. If professors are on edge, students will be as well. If the students see me smiling and enjoying my research, they might think that being a researcher looks fun or choose to pursue a career in research—and that would be great! Researchers I respect, such as Dr. Michael Levine and Dr. FUKADA Yoshitaka, say they get good ideas when they’re upbeat rather than when they’re anxious or brooding. Sometimes I get burned out in the midst of busy days, but I strive to not show that to my students. When I was a post-doc, Prof. SASAKURA often said to quit using the word "busy." So instead, I say, "Ah, today’s pretty rough."

Understanding the human brain through ascidians

Comparing the brains of animals

Now, we are using the simple central nervous system of ascidians to reveal how the brain is made and how it works at the single-cell level. As I’ve learned how to do single-cell transcriptome myself, I’m now able to do the brain research I’ve always wanted to. When I was in the US, I had the opportunity to do joint research with someone from China, and we compared nematodes and ascidians. I had no experience studying other creatures, but when I looked at the nervous system of the nematode, I was amazed at how similar they were to ascidians.

I started a project to study mechanisms common to different kinds of creatures by broadening the scope of my research to include species such as Drosophila and African clawed frogs, and current transformative research has allowed me to develop that research even further. That includes research to elucidate the universality and diversity of the development of the central nervous system by studying animals such as nematodes, Drosophila, ascidians, killifish (Japanese medaka), marmosets, mice, and even organoids^*.

The brain is rich in variety, but I want to focus on clarifying the fundamental mechanisms that have always been present in it and try to reveal those same mechanisms in higher vertebrates using single-cell transcriptome. Until now, it has been difficult to directly compare ascidians and human brains because they are so completely different. But with single-cell transcriptome, we can compare cell types, so we can examine whether the cell types in ascidians are present in the brains of humans and/or mice. As I mentioned, my research focuses on comparing the brains of animals, even humans. This is the kind of research promoted by the Grant-in-Aid we received for Transformative Research Areas (A)^** from the Ministry of Education, Sports, Science and Technology (MEXT).

• *A mass of cells produced from iPS or other cells in a Petri dish with a structure and function similar to a living organ.
• **Grant-in-Aid for Transformative Research Areas (A): "Cell type census of adaptive neuronal circuits: biological mechanisms of structural and functional organization," Adaptive Circuit Census, ACC (https://ac-census.org)

Our research is to study the simplest brain functions in ascidians. But our current goal is not to understand the ascidian brain. Ultimately, we want to do research that goes beyond ascidians and leads to a greater understanding of the human brain. To do so, I believe it is important to understand a simple brain model, e.g., ascidian brains, not try to find a novel way to study the human brain.

Research across 3 fields

Just as some people study Drosophila and others study nematodes, it is not necessary for everyone to study the same animal.

It is important to use the most appropriate animal for the phenomenon you are interested in. I use ascidians as a means to know the construction, mechanisms, and functions of brain/central nervous systems at the single-cell level. I believe this research may lead to, for example, circuit-selective deep brain stimulation (DBS). Even when expressing viral vectors, we can find specific promoters through single-cell transcriptome to efficiently stimulate deep into the brain. This may lead to the development of methods to stimulate neural circuits to compensate for immobility caused by, for example, a stroke.

It may also lead to advancements in regenerative medicine to repair neural circuits, such as through the induction of neuronal differentiation using iPS cells and organoids, a process already being actively studied. We are striving to artificially create different types of neurons in ascidians and have already succeeded in creating dopaminergic neurons and neurons that produce GABA, a neurotransmitter. Using a similar method, we would like to apply what we have discovered in ascidians to research involving iPS cells and mice to develop a method to artificially create iPS cells and ultimately, treat patients.

I’m also researching machine learning algorithms that learn from living organisms and have also recently teamed up with an engineering professor to build a robot that mimics the movements of an ascidian. We are also working on simulations of the relationship between electrical and neural circuits, as well as other research in the field of engineering.

I think conducting research that integrates different fields is very important for our graduate school. When working at the Shimoda Marine Research Center, I engaged only in ascidian research that focused on the field of science, but now, at Osaka University, I would like to challenge myself over the next 20 years to do research that spans three fields: science, medicine, and engineering.

What makes me happy

A graduate school full of potential

The Graduate School of Frontier Biosciences is a place full of potential where I can fully realize the ideas I have been sitting on. I am truly grateful to be here and have never been happier. Every day has been fulfilling. Students often tell me I’m an idea man, but it’s just that I enjoy thinking and using my imagination.

Along with myself, students, and technicians, there were about 6-7 of us at Shimoda. Now we have 14 lab members, including the secretary. Next year, we plan to add another 10 or so. I think we will soon grow to about 30 or 40 people.

I really appreciate everything here. Until six months ago, my lab had only one or two students, and even then, we had to borrow other labs for research because mine was too small to fit them, but now we have so many students coming in. So one of the happiest things for me is to be able to let out all the ideas I have been sitting on for so long.

These are pictures of me gathering ascidians when I was a student. Back then, we used to hang flowerpots on ropes at fishing ports to harvest^* ascidians. Now, we are provided with ascidians by the National BioResource Project.

• *Ascidian larvae prefer dark places. They stick to the inside of flowerpots, metamorphose, and remain there as they grow into adults. Ascidians attached to these flowerpots are then collected.

This is a group photo of the Tsuda Lab members taken at the 21st Century COE Program Research Report Meeting. Prof. TSUDA is in the center, with Prof. KUSAKABE to his right, and me next to him. At that time, Prof. KUSAKABE was an associate professor and is now a professor at Konan University. When I became a professor, the other lab members sent me a message saying that they were proud to be classmates of mine and congratulated me on my success. This, of course, made me very happy.

My academic career was a series of setbacks full of ups and downs and wasn’t always smooth sailing. But I think my choices to research the ascidian and begin my studies at the Himeji Institute of Technology were good ones. I have a mission to show those after me that they can also do well as a researcher. I hear that many students in the Graduate School of Frontier Biosciences come from the University of Hyogo (formerly the Himeji Institute of Technology). I hope they would come and visit my lab. I also hope that students can see that someone from humble beginnings, who was clumsy and had setback after setback after setback can still make it as a professor in the end, and I hope my story will give them confidence so that they, too, may achieve great things.