Frontier Research Institute for Interdisciplinary Sciences
Tohoku University

FRIS Interviews #15

FRIS Interviews#15

  • 千葉 杏子Kyoko Chiba

    Assistant Professor

    Life and Environments

    Research Fields


    Main Research Topics

    Regulation of Intracellular Transport

    Activation Mechanisms of Motor Proteins

    Intracellular Transport in Neurodegeneration


I will continue my research to produce results that are “clear at a glance”

“I’d like to make a big discovery at least once in my career.”
It’s a desire I still cherish.

I've heard that you studied Alzheimer's disease in graduate school.


I wanted to do some research that could help people. So, I entered graduate school of pharmaceutical science, hoping to find a way to treat Alzheimer’s disease patients with new drugs. But as time went on, my interests shifted. Now, I'm doing more basic research which is not directly related to making new drugs.

What made a big impression on you with your Alzheimer's disease research?


I tried to find out the function of the precursor protein of the amyloid which is linked to Alzheimer's disease. I attached a fluorescent protein to the amyloid precursor protein for visualization and expressed it in cells. What I saw was pretty interesting - the precursor protein was moving around in a busy way. Even though this phenomenon was already known in the research world, it was still fascinating to see that the amyloid precursor protein was actually moving within the cell. Seeing it with my own eyes was quite intriguing. I wondered how it moved. This experience actually shifted the focus of my research. I was curious how things move within cells. I became more interested in the proteins that act like little vehicles powering these movements and how the whole system works. So I decided to study abroad and dig deeper into this area. By the way, when the amyloid precursor protein is cleaved by two different enzymes, it produces amyloid-beta which can aggregate in the brain and trigger Alzheimer's disease. It's important to note that the amyloid precursor protein itself isn’t harmful.

What originally motivated you to become a researcher?


During my graduate school years, I didn't have those classic “Eureka!” moments with my research results. I guess it really depends on the project, or maybe I just couldn’t come up with any good ideas to push my project forward. Meanwhile, people in my graduate school said, “During my time in graduate school, I had those moments where I thought ‘Wow, this is amazing!’” during experiments. But for me, those moments never quite happened. So, I kind of felt a bit unsatisfied during my student years. As I mentioned earlier, the movement of the amyloid precursor protein was interesting, but it was different from the thrill of discovering something. That’s what kept me going in my research. I wanted to have that discovery experience myself. And that's how I got to where I am today.

So, after finishing your doctoral program, you became a postdoc in Richard McKenney's lab at the University of California, Davis.


That’s right. I joined his lab in 2017 and stayed there until 2021. When I look back, I can see it took a bit of time to settle into the new environment. But as time goes on, I was able to focus more on my research and had a more fulfilling time. Towards the end of my time in the US, I came up with some experimental ideas to pursue on my own, and returned to Japan with those ideas in hand.

Did you have a set plan for how long you'd stay in the U.S.?


Not really. There were times when I considered returning after two years, and other times when I thought about extending my stay. During my time abroad, I made a “to-do list” of things I wanted to try. It wasn't a list with deep thoughts, but it kept expanding over time. While it's easy to start new project, I felt I should rather focus on my original project first and complete the work. So, I put the “to-do list” on the side.

That “to-do list” is all about those incredible motor proteins – they are like the cellular vehicles, shuttling stuff around inside the cell. The amyloid precursor protein I mentioned earlier is also transported by motor proteins. They've got a bunch of roles, like going from the inside to the outside of the cell, coming back in, and even helping with muscle contractions. When it comes to the ones moving outward, there are roughly 50 different types of them. Plus, there's a lot of diversity in the part that connects to the cargo. Therefore, there are a wide variety of “vehicles.” That's why I'm always intrigued by what happens when I combine this engine with that cargo piece, for example.

One of the characteristics of these motor proteins is that they can cause human diseases. Just a single amino acid change within a motor protein can trigger a disease. Some mutations are relatively new, so we still don't know what those mutations do for motor proteins. For example, if there is a mutation in the “leg” part of a motor protein, you can expect that it loses the mobility, causing issues with the transport. But what if the mutation occurs in the body of the motor protein? You might think it wouldn't matter much. Yet, there are cases where patients develop diseases due to mutations in that area. Predicting the disease mechanism solely based on the symptoms is challenging because sometimes both “leg” and “body” part mutations can result in the same observable symptoms. But by preparing mutants proteins and compare them with the normal, wild-type protein, we can unravel the molecular mechanisms of the disease.

Could you tell us a little more details about your ongoing project?


Sure. One of my ongoing projects is about Amyotrophic Lateral Sclerosis (ALS). The majority of ALS cases don’t have known genetic factors, but about 5% of cases are due to genetic factors. Multiple genes associated with ALS, and recent studies have revealed that mutations in a motor protein gene are also linked to ALS. Since the disease mutations are found in the “hand” part of the motor protein, scientists assumed that these mutations might result in motors losing the ability to transport cargos. However, in my experiments, cargo binding was not affected in those mutant motors. So, what was really going on? It turns out that the “hand” components were more likely to stick together, forming clusters. These aggregates appear to be the cause cell death.

So, if the hands were disconnected from each other, would that result in a cure?


I think so. ALS is known to have various genetic factors as causative genes, aside from kinesin, but in many cases, aggregates form within cells. It would be great if we could unravel this, but there are no such drugs available yet. However, as we continue to gain a deeper understanding of the process of aggregate formation, drug development is certainly progressing. I conduct experiments with the goal of one day seeing the birth of a treatment for ALS.

Kinesin normally puts the brakes on itself. Think of it like your hands grabbing your own feet. But when some cargo show up, instead of your feet your hands grab that cargo, and the feet get to move freely. It's a fantastic system, isn't it? However, when ALS mutations occur, as I mentioned earlier, those hand regions end up sticking to each other. This means the brakes on the feet don’t work anymore, and kinesin goes into overdrive. Under a microscope, you’d see a mass of kinesin clusters running around crazy.

Meanwhile, with ALS cases without known genetic factors, have we learned anything new?


Unfortunately, we don't have the answers yet. It's still a long road to figuring out whether kinesin holds any key roles. If kinesin aggregates are found in the cells of patients without kinesin mutations, it suggests that kinesin aggregation is related to the disease independently of mutations. And, of course, I don't think kinesin is the sole cause of the disease. Many proteins are on the verge of forming aggregates, just one misstep away. They have this tendency as part of their inherent nature, even without mutations. I believe that under certain triggers, such proteins could rapidly form aggregates. For example, you might have heard of the term 'oxidative stress' somewhere. The accumulation of such stress in cells can make various things more prone to aggregate, possibly becoming a trigger for diseases.

In experiments, it's normal to experience failure."
It's enjoyable when they exceed your expectations in a positive way.

How is research appealing to you?


Experiments mostly end in failure, but occasionally, things go well. Even when I started today thinking it wouldn't work, it suddenly goes smoothly. The moment when that happens is unpredictable, of course. We prepare in every possible way to make it work each time, but being pleasantly surprised in that sense is fascinating. The unexpected is what makes it enjoyable. And at the top of this pleasant surprise is the experience I mentioned earlier, the 'Wow, this is amazing!' moment. However, maybe it's because my expectations are high, but I haven't had an experience where I truly felt, “Eureka!” I really want to taste that at least once.

As I listen to you speak, I notice that you value experiments with easily understandable outcomes


I do enjoy things that are visibly clear. During my graduate studies, I used experimental systems where the results weren't always apparent, and it could be frustrating not being able to state the conclusions definitively. That's why I wanted to find a research lab where I could say, 'This is how it is,' clearly and decisively, and that's how I chose a lab for my postdoc training. Clarity is wonderful. It's easy to understand. I aim to provide simple answers to simple questions. I believe that many people have a perception that research is difficult. But I think there's no need to go too deep from the start. What will happen next is something no one knows until they try.

My experiments are very simple and easy. It can be done by anyone. However, in reality, I might be the only one in the world performing these experiments. There are still many proteins that haven't been observed. So, there's value in doing what I do. It's straightforward, but by repeating such experiments, you gradually uncover new things. I don't dwell on overly complex matters. However, when I occasionally take a step back and look, I realize that there aren't many people doing the same things as I am.

FRIS is an institute that offers young researchers a moratorium.

How did you learn about FRIS?


When I was a graduate student, I had visited Tohoku University and learned about an organization called FRIS. I also found out that many researchers who had returned from studying abroad were part of FRIS. So, even when I was in the United States, I had a vague thought that when I return to Japan, I might consider joining FRIS. When I actually looked into it upon returning to Japan, I found that the conditions of FRIS matched exactly what I was looking for. I thought, “This is really great!” and decided to apply.

How did you feel when you were hired?


I felt relieved. A postdoc position has a lot of uncertainty. However, in FRIS, I can settle into the role of an assistant professor for a defined period of five years, focus on my research. This is exactly what I wanted. I think this system is quite unique not only in Japan but worldwide. In the United States, if you are a postdoc, you can focus on your research, but once you become a professor, your time becomes quite limited due to responsibilities such as hosting guests, teaching, and supervising students. In FRIS, I hold the position of an assistant professor, but I have very few non-research responsibilities. Some people might find this environment lacking, but for me, it's comfortable. These five years at FRIS feel like an extension of the postdoc period, almost like a moratorium. After working as a postdoc for 4 or 5 years, your skills become quite advanced, and you really hit your stride. At this point, you have the energy and mastery to focus on your research before taking on more significant responsibilities. That's the position at FRIS. So, I believe I'm currently making the best use of my time. Researchers, once they obtain their degrees, typically have to take on the roles of “researcher” or “faculty” at some point. As they become busier with experiments and research, and their teaching and mentoring responsibilities increase, they often find it challenging to allocate time for their own learning. FRIS not only offers a stable research environment for young researchers but also provides a chance to refine oneself once more. While five years might seem long, it's actually quite short, and I aim to make the most of this time while working alongside other FRIS members.

What kind of interactions are you currently having with people at FRIS?


Due to the pandemic, I’ve not been able to interact with other people as much as I expected, but I think I am in a relatively good environment than other FRIS members. I say that because my main workplace is in FRIS building, the main division of FRIS. This means that I can meet with other members who come to FRIS building, and that makes it easy to talk with them. For example, I can get advice on research grant applications, handling of an equipment, or learn about academic societies that I’ve never been. There are usually about 10 people in the building, and if there are 10, there will be someone who knows something. Being able to enjoy such immediate access to information is a big thing for me. They say that two heads are better than one, so if you have 10 heads, then, well…! (LOL) FRIS hires new young researchers each year, and this keeps things lively. There are around 50 young researchers in total, and this is the first time I’ve interacted with so many researchers in my age group. Even just hearing about each of their research backgrounds is really stimulating for me. After coming here, I realized that the level of people at FRIS is extremely high in terms of research, expertise, and technology.

You can spend your time free of stress.


I truly feel comfortable here. There comes a time, however, when you have to start thinking about what’s going to happen after your term ends.

When do you think you’ll start thinking about what you’re going to do after the end of your term?


I decided that for the first three years, I’m going to put future plans to the side and concentrate on my research. I’m wondering what kind of path will emerge for me in my fourth and fifth years. There’s nothing I can do to hurry this along, so my idea is to just move forward with the research at hand.

Are there any internal collaborations you’re hoping to have at FRIS?


The thing I’m most interested in is artificially connecting motor proteins with things other than proteins. FRIS has researchers who have that kind of technology, so I’d like to collaborate with them.

Also, while I'm not working with living organisms just yet, there are many researchers at FRIS who do, and so I have thought that I’d like to see how motor proteins function in living organisms. I’m interested in contrasting observing functions within actual cells with the movement of motor proteins that I can view with my eyes. Working together with a researcher active in this area, I expect I’d be able to get a clear picture of these functions. It would be wonderful if I could make connections with actual functions, such as an important role that motor proteins play in cell division or their role in synaptic transmission, for example. I’m currently interested in nematodes, which are worms that live in the soil. The basic functions of nematodes are similar to those of humans, so I am planning to collaborate with a researcher who works with nematodes. So far, I’ve also had thoughts about working with mammal cells, nematodes, and flies.

With flies, I have Drosophila in mind. I feel they would be very effective in the ALS research I mentioned earlier. These files have a head and legs. ALS damages motor neurons. Drosophila can help us see what kind of damage occurs on legs when there’s a mutation in kinesin gene.

You’ve shared a lot of your ideas and desires with us. Based on your experience at FRIS, what kind of researcher do you want to be in the future?


There are huge number of motor proteins to analyze, so I'll work on them one by one. When I've worked through all of them, I might consider quitting research, or if I come across more intriguing research topics, I might shift my focus away from motor proteins. If I stay in science, I want to be a researcher who can properly mentor young people. I aspire to be able to support and uplift others in their research endeavors.

(Interview conducted in May 2022)