Tsutsui Ken-Ichiro is Project Manager (PM) of the JST Moonshot Program Goal 9 project Development of “Jizai Hon-yaku-ki (At-will Translator)” connecting various minds based on brain and body functions, while Yanagisawa Masashi is the PM of the Japan Agency for Medical Research and Development (AMED) Moonshot Program Goal 7 project “Deciphering and Engineering Sleep and Hibernation -- The Future of Medical Care“ and a leading researcher in sleep, one of the greatest mysteries of neuroscience. Here, these two scientists have a stimulating discussion that looks set to generate a new cooperative relationship.

What is the “Jizai Hon-yaku-ki”?

Tsutsui： The theme of this Moonshot project is the development of a “Jizai Hon-yaku-ki,” or “At-will Translator.” I heard that because of the slightly strange name, some people associate it with Doraemon, the robot cat that always retrieves rather improbable gadgets [laughs]. In fact, it is a support device to bring about free, non-verbal communication.

To be a bit more specific, by holding "Jizai Hon-yaku-ki (At-will Translator)" up to the person you are communicating with, consensually of course, you can get some valuable hints about his/her thoughts and feelings. Also, it will be able to display in a user-friendly way how the other person sees you. It is the development of this software we are working on. It may perhaps prove useful for people working in collaboration in the metaverse.

To achieve this, we will make use of the latest technologies in brain/neuroscience and molecular biology. Implementation in society is far broader than implementation in the medical field, and we need to keep the general public in mind. We have experts in virtual reality, robotics, and artificial intelligence taking part in the project.

Yanagisawa: To make this a reality, you will need to be able to read various signals from the other person. What sort of read-outs are you thinking of?

Tsutsui: We have narrowed the target down to two signals. The first is brain waves, and I think this will link in with your research into sleep. The second signal is exosomes *, which have recently been attracting huge interest in various different fields.

I have always been fascinated by the mind, and of course the mind is not just the brain, it is related to the body as well. You often hear about the relationship between the brain and the bowels, but the brain is also believed to be related to various other organs as well, such as the liver, the heart, and the lungs. The autonomic nervous system and the endocrine system both play major roles in messaging between the brain and other organs, but I am sure exosomes do as well, and I am focused on exosomes as a clue to reading a person’s state of mind.

Yanagisawa: That is interesting. Have you managed to obtain any findings to show that the state of the brain or the autonomic nervous system is reflected in exosomes?

Tsutsui: Comparing the exosomes of people with autism spectrum disorder (ASD) and people with typical development, we have found many differences. There are also data showing that when the quality of life of people with ASD is improved by making improvements to their lifestyle, the features of their exosomes become closer to those of the exosomes of a person with typical development. There are research teams around the world that have begun to focus on analysis of exosomes within the brain, but I think Hoshino Ayuko from our research team was the first to carry out research from the perspective of interactions between the brain and other organs throughout the body.

Yanagisawa: The “Jizai Hon-yaku-ki” would certainly be enormously helpful for people with ASD or others who have difficulty reading interpersonal situations; on the other hand, I wonder if it could pose a problem for people who don’t normally have trouble communicating. After all, there is nothing more private than what goes on in your mind.

Tsutsui: Yes, there are things you wouldn’t want other people to know about, and it is very important to be able to turn the switch off at times like that. We are working on the ethical issues of how this development can be used once it is successful by thorough discussion with experts within the team.
Another application that can be envisaged is using the development for improving communication skills. If you can get readily comprehensible feedback on the state of your own mind and on how others see you, this would be very beneficial for improving communication skills.
First of all, our goal is to be able to read pleasure and displeasure in real time with a high degree of accuracy.

We are currently working on the development of a computational method to estimate activity deep in the brain from surface brain waves. This involves experiments with monkeys and mice in which electrodes are simultaneously placed deep in the brain and on the surface of the head. We are still some way　from the technology to estimate brain activity in humans, but we aim to improve the algorithm through animal experiments and establish basic principles that can be applied equally to mice, monkeys, and humans. We hope to create practical applications for use by humans as soon as possible.

Another major objective is that we hope to be able to read a person’s dreams while they are asleep, and then use the information to change negative states of mind such as stress or post-traumatic stress disorder (PTSD) into positive states. If someone has a bad dream, we could intervene in some way or other to ensure it doesn’t stay in the memory.
A member of our project, Sasaki Takuya, recently published the results of a study using mice that showed there is a greater tendency toward depression in individuals that write unpleasant memories into the hippocampus during sleep.

Yanagisawa: So you will try to record activity deep in the brain from the surface of the head. It sounds like you have set the bar quite high. In our laboratory, we have used machine learning to read high-density, multichannel brain waves during REM sleep, and we have gotten as far as being able to read a few different emotions during dreams. We have subjects go to sleep and then wake them when they are in REM sleep to find out what dreams and emotions they were having.

Tsutsui: Moonshot is a program to promote challenging research and development based on bolder, original thinking for 2050, so we intend to work slowly and carefully.

Sleep, the greatest mystery of neuroscience, and applications for hibernation

Yanagisawa: We are working on our project with the aim of helping people to live to their 100s and stay healthy right to the end, which we are approaching from better sleep. My own laboratory is mainly using mice in our research. The essential point that I want to uncover is what sleepiness is. If you stay awake for a long time, the pressure to sleep gradually builds up and you start to feel sleepy. We still don’t know what this pressure—in other words, the desire to sleep—really is. This is one of the big unknowns that still remain in neuroscience, and we are carrying out basic research to try to solve this mystery.

Tsutsui: It may be basic research, but the potential applications seem limitless.

Yanagisawa: Sleep is a state in which the brain goes offline. It is a state in which there is little consciousness, either subjective or objective, and the person becomes extremely unresponsive to external stimuli. Why do we have to enter this state? This is also a great puzzle.
The field has been studying sleep in mice and in Drosophila fruit flies—insects and, in fact, even nematodes sleep. Sleep time greatly differs among species; in mammals, it ranges from 2–3 hours to almost 20 hours a day. Also, sleep patterns vary, so even though the total amount of sleep may be the same, some animals go through repeated cycles of sleeping and waking, while others take all their sleep at one time. A recent paper showed that some penguins sleep for just a few seconds several thousand times a day, making up a total daily sleep of around 10 hours.

At the other extreme are us humans. Even among the primates, humans have particularly deep, continuous sleep. The deepest non-REM (slow-wave) sleep can last nearly 1 hour in young people. Maybe this is because only humans have acquired the ability to shape a safe environment for themselves in which they can sleep deeply and continuously. The brain is essentially a biological computer, but why does it need to have this maintenance period of unconsciousness, which can be extremely risky for the organism, in order to function properly?

Tsutsui: That’s true, we spend a very long time asleep, about a third of every day.

Yanagisawa: Exactly. If the purpose of not moving was to stay safe and avoid detection by predators, you would think a better strategy would be to stay awake and not move.
We are also looking at hibernation, and this also shows great variation among species. Hibernation and sleep are two completely different phenomena.
Sakurai Takeshi and his team at our institute have discovered that if you stimulate a very small group of neurons in the hypothalamus of mice, called Q neurons, the mice enter a state similar to hibernation. We want to see if it is possible to do the same thing with monkeys, and we would be very happy if your team could help us with this. Monkeys also have Q neurons, and we know that they are present in humans too.

Tsutsui: I would certainly like to see what happens if we manipulate the activity of Q neurons in primates.
 
Yanagisawa: In mice that have entered artificial hibernation, the body temperature drops to somewhere around 20–25 ºC. Butter hardens at about 25 ºC, so you would expect, if unprepared, the saturated fats in the body of a homeothermic (warm-blooded) animal to solidify at this temperature, but once they are roused from the hibernation-like state their metabolism returns, and they soon become lively. It looks like there is some sort of safety device that keeps the body functioning normally, even during hibernation.
One of Dr. Sakurai’s collaborators at RIKEN, Sunagawa Genshiro, has found that, in cases of serious acute disease, if the body enters the state of Q neuron-induced hibernation, the disease does not progress during this time. This is a very significant finding. If we could manipulate the state of the human body in the same way, it would revolutionize emergency and critical care medicine.

Tsutsui: Hypothermia therapy (therapy in which the body is kept at low temperature) is used in some cases to protect the brain, but I understand it is very difficult to manage. This is different from hibernation, in which the organism has integral control of all its functions.
If you could achieve a practical application of artificial hibernation, it would allow the body to make use of its natural functions in a safe way. This would indeed be revolutionary. In terms of the method, would this involve using drugs to stimulate the neurons?

Yanagisawa: If we can find a specific drug target for Q neurons for example, that would open up a route for drug-induced hibernation. Also, I am sure various other ways of stimulating the depths of the brain will be found.

Tsutsui: Magnetism or ultrasonic waves might be possibilities.

Linking research into the mind with sleep research

Yanagisawa: How did you become a researcher, Dr. Tsutsui?

Tsutsui: I originally had a vague interest in the mind. When I entered university around 1990, the fields that were generally known for studying the mind were psychology and psychiatry. I wanted to be a researcher, so I chose psychology.

After I entered the psychology department, I visited a laboratory where they were using monkeys for research into the brain. It was classic research in which electrodes were placed in the brains of monkeys and the activity of each neuron was carefully recorded during the monkey’s behavior. This was an eye-opener for me, as I realized that this was a scientific study of the mind.

My research has mainly been into the structure of neural circuits and electrical phenomena, but these themes do not really link with social implementation. I have been wondering if it would be possible to link my research to society a bit more, and at the same time science and technology have steadily advanced, giving us a better understanding of structures and functions, as well as the genes that underpin them. I think linking this to research into electrical phenomena would offer the opportunity to broaden the field.

Yanagisawa: You have stuck to research themes that study the science of the mind. It really does look as if your work could tie into a brain-machine interface. Human research using invasive techniques has advanced a very long way in Europe and particularly in the USA, but in Japan, we are more limited in what we can do. This means that Japan’s strength lies in non-invasive research.

Tsutsui: Non-invasive methods are needed to treat a variety of diseases, not just diseases for which there are no other treatment options, and also for wider social applications, and I very much hope we can show our strength in this area. There are not many translational primate research projects in Japan, so I am very keen to produce results that will make us a good model for future research. How about you, Dr. Yanagisawa, what led you to become a researcher?

Yanagisawa: I went to medical school because I wanted to do research. Clinical research looked attractive, but when I graduated I chose basic research. At that time, my motto was to “help patients in the day after tomorrow.”
As a graduate student, I managed to discover endothelin, a substance that constricts blood vessels. As a result of that, I was recruited in the USA, and at the age of 31, I set up my own laboratory. I ended up staying in the USA for 24 years.

Tsutsui: Was it the discovery of orexin that changed your path to sleep research?
 
Yanagisawa: Yes, it was. This was in the late 1990s, before the completion of the genome project but when the mRNA sequence database was becoming available. Looking at the database, there were plenty of new genes for G protein-coupled receptors, but the corresponding signaling molecules for many of these receptors were unknown. I was sure that if I could discover the unknown ligands, it would open up a whole new field of study, and I started my research project in 1996.

The first such substance we found was orexin—this really was a piece of beginner’s luck. It was when I was working with my long-term research associate Dr. Sakurai, who had come to Texas as a post-doctoral researcher. Orexin is a neuropeptide manufactured in the hypothalamus, and at first we were unable to understand its function. It is produced in large quantities during fasting, and it causes appetite when injected into the brain.
Tsutsui: And this is produced in the lateral hypothalamus?
 
Yanagisawa: At that time, this part of the brain was also known as the feeding center. Yet when we created mice that were unable to produce orexin, they did not eat less or lose weight. This was not what we expected. We decided to observe their behavior at night simply because the mice are nocturnal species. Mice sleep mostly during the day and are active at night, but these mice would suddenly fall asleep at night. These mice were suffering from narcolepsy, a then-mysterious disorder of extreme sleepiness. It was later discovered that narcolepsy in humans is also a result of deficient orexin, and it became clear that orexin is an essential substance for properly maintaining wakefulness. This led us to switch the direction of our laboratory toward sleep research.

Tsutsui: That was quite a drastic change of direction!
 
Yanagisawa: My style is to go for exploratory research. Endothelin was the result of searching for a contractile substance derived from vascular endothelium, and I discovered orexin when I was trying to find the signal molecule for an orphan receptor with an unknown partner. With the discovery of narcolepsy as well, I didn’t have any particular hypothesis—mice are nocturnal, so I simply carried out exploratory observations by watching them at night, and this led to the discovery.

With the Moonshot project at the moment, I am carrying out exploratory research into the genes responsible for sleep by causing random DNA mutations in mice and looking for individuals whose sleep patterns are upset. It is working reasonably well, and I am hoping to uncover the underlying principles of sleep.

Tsutsui: There are many unknowns in biology, and it is indeed very important to search widely and not overlook any significant phenomena, along with the research style of first building a hypothesis with a theoretical basis.
 
Yanagisawa:  I also established the venture company S’UIMIN in 2017 to develop and commercialize an easy-to-use, in-home electroencephalograph, which is an essential tool for accurately visualizing sleep in humans. With this, anyone can easily measure brain waves during sleep at home, and this device is already being used at some 220 medical institutions around the country. You can apply to try out the device through the company’s website.

Tsutsui: If there is anything from our research that may be useful, please use it to give additional functionality to your tool.
 
Yanagisawa: Thank you. Our electroencephalograph currently has four channels, but it would certainly be good to add extra functions.

Tsutsui: You have put together a large organization, and with that as your base you have built a whole new field of sleep studies. The present Moonshot project will be the first time for me to implement research results in society, so it is a completely new challenge. Since you have already made use of research results to launch a venture company, I will certainly be looking to you as a role model in the future while I work as hard as I can on my project.

Written by Furukori Etsuko
Photos by Mori Takahiro

Related information

■Moonshot Research and Development Program

■Moonshot Goal 9
Realization of a mentally healthy and dynamic society by increasing peace of mind and vitality by 2050.

■Goal 9 R&D Projects
Development of “Jizai Hon-yaku-ki (At-will Translator)” connecting various minds based on brain and body functions
(Project Manager: Tsutsui Ken-ichiro)

■Moonshot Goal 7
Realization of sustainable care systems to overcome major diseases by 2040, for enjoying one’s life with relief and release from health concerns until 100 years old

■Goal 7 R&D Projects
Development of new-generation medical care systems through customizing sleep and hibernation
(Project Manager: Yanagisawa Masashi)