▼Sports: A powerful gateway into the spirit of perseverance

• President Shimada　
  　Before we begin, I’d like to thank Profs Ōmura and Yamanaka for being with us today. The Nobel Prize is one of the most distinguished achievements in the world, an honor that only four Japanese scholars have ever won—and we’re lucky enough to have two of them here in our presence. The first Japanese Nobel Prize winner was Professor Susumu Tonegawa, who became a Nobel laureate in 1987 for his work abroad on the rearrangement of immunoglobulin genes. Prof. Yamanaka was the second, taking home the honor in 2012 after discovering iPS cells. The third Japanese winner was Prof. Ōmura, whose discovery of avermectin won him his Nobel Prize in 2015. The fourth and most recent triumph came in 2016, when Professor Yoshinori Ōsumi won a Nobel Prize for his work on the basic mechanisms for autophagy. All their achievements are truly remarkable.

  　Winning a Nobel Prize obviously requires tremendous scientific research capabilities, insight, and creativity. Watching and listening to both of you, however, I always get the feeling that you have something more than that—a certain type of all-around humanity that brings your individual skills together into a fuller whole. I hope that today’s dialogue will shine some illuminating light on those unique, profound traits.

  　From what I know about your personal histories, neither of you grew up in what people would call a “scholarly” household. Prof. Ōmura, you came from a farming family in Nirasaki, Yamanashi Prefecture, and spent the bulk of your early years—all the way through high school—honing your skiing skills. To most people, sports and the Nobel Prize probably don’t have much of a connection. What do you think? Did skiing give you something that helped you develop your career?

  Prof. Ōmura　
  　In my experience, there’s a significant connection between sports and the Nobel Prize. I was an athlete all the way up through high school, and I kept it up at the University of Yamanashi. I probably spent more time skiing than studying, honestly. That doesn’t mean I didn’t learn, though. Sports taught me so much. I focused on cross-country skiing, which demands a lot of endurance. To train at a higher level and push myself even further, I had to combine my own regimen with what my coaches told me and take responsibility for getting better. You can say the same thing about research. If I hadn’t driven myself so hard in my long-distance skiing training, I don’t think I would’ve been able to develop the right mindset for research—a refusal to give in, a sense of indefatigability.

  President Shimada　
  　Prof. Ōmura, you trained under Ryūsaku Yokoyama—a skier who represented Japan in international competition—in both Yamanashi Prefecture and Niigata Prefecture. I remember you talking about the time he caught you wiping your nose during a training session. “If you have enough in you to lift your hand to your face,” he said, “you could be going faster.”

  Prof. Ōmura　
  　You can’t overstate the importance of a good coach. I was fortunate enough to train and learn under what you’d call a “real mentor.” From skiing to studying to everything else, I’ve always had real mentors to inspire me. I’ve been so blessed.

  President Shimada　
  　The phrase “one encounter, one chance” is a favorite of yours, Prof. Ōmura, and your story really speaks to that idea. Let’s hear from Prof. Yamanaka next. Did your experience doing judo and playing rugby have an impact on your career too?

  Prof. Yamanaka　
  　First of all, let me say what an honor it is to be here for the opening of the Satoshi Ōmura Museum. Thank you so much for having me. About sports—I spent a lot of my school years doing judo and playing rugby. That experience ended up having a big impact in a way I’d never anticipated. In 2003, I got my first CREST grant—highly competitive research funding that paid between 50 million and 100 million a year for five years. The selection process included an interview, and mine was with Professor Tadamitsu Kishimoto. He was the president of Osaka University at the time, and he was such an illustrious scholar that he could be extremely intimidating. I’ve never been more nervous than I was going into that meeting. He asked me what my strengths were, and I told him that I was physically strong and mentally determined thanks to my judo and rugby experience. “That’s news to me,” he said. I didn’t know what that meant at the time, but it was apparently a pleasant surprise to Prof. Kishimoto. He decided to give me the CREST grant, which enabled me to do my research on iPS cells. Without judo and rugby, who knows what would’ve happened—I might’ve never gotten that funding, and I might’ve had to give up my research. I’m glad I played those sports way back when.

  President Shimada　
  　Sports obviously played a big part in your formative years, then, giving you something very important in common. Later, you both went on to college and came to a point where you had to make a decision about your next step. You shared another common bond in your relationships with your fathers, it seems, who both encouraged you to follow your academic instincts. Your father, Prof. Ōmura, said that if you wanted to go to graduate school, you should. Prof. Yamanaka, your father suggested going to medical school. You both followed their advice, completed your studies, and transitioned into research. Prof. Yamanaka, you incorporated your love for sports into your initial career plan: sports medicine.

  Prof. Yamanaka　
  　I had to deal with some sports injuries when I was in school, so I wanted to go into orthopedics and help people who were battling similar injuries. That was my vision when I was a student.

  President Shimada　
  　But, for better or worse, you weren’t as proficient a surgeon as you thought you’d be.

  Prof. Yamanaka　
  　My dad was an engineer—and extremely good with his hands—but I had so much trouble with surgery. Operating on people made me so nervous, considering that the littlest mistake can be disastrous. I was really good at experimenting on animals, though, so research was perfect for me.

  President Shimada　
  　If you would’ve been great in the operating room, you might’ve gone on to be a star in orthopedics—but you might not have a Nobel Prize to call your own.

  Prof. Yamanaka　
  　I wasn’t that bad (laughs). After I won the Nobel Prize, some reporters interviewed my orthopedics professor—someone I really respect. Do you know what he said? He told them I was awful in the operating room. Not long after, I got a call from him. “Sorry, sorry!” he said. He told me he never wanted to say I was bad, but the reporters wouldn’t leave unless he gave them a juicy line.

▼A desire to learn in new areas paves the way to research

• President Shimada　
  　Prof. Ōmura, you set out to become a high school teacher after completing your undergraduate studies. I’ve heard that you couldn’t find a teaching job in Yamanashi Prefecture, though.

  Prof. Ōmura　
  　Well, teaching jobs were hard to come by in 1958. The recession back then was so bad that Yamanashi Prefecture was only hiring P.E. teachers. I decided to take the licensing exams for junior high school and high school jobs in places like Kanagawa Prefecture and Hokkaido Prefecture, both of which I failed. The only one I managed to pass, however, was the one in Tokyo—supposedly the hardest one around. I couldn’t believe my luck, honestly. I got a job teaching evening classes at a metropolitan high school. I really couldn’t think of myself as much of a teacher at that point, especially considering I’d made skiing my top priority for so long. I tell you—it was a big reality check when I saw my students take their tests. Most of them worked at little factories in the area during the day, and they’d come and sit at their desks and fill out their exam sheets with oil and grime all over their hands, so determined to improve their prospects. Seeing that scene play out in front of me, I knew I had to push myself harder. If they had the willpower to do what they were doing, I should be able to go back and really apply myself.

  　I went to the Tokyo University of Education and spent a year auditing classes in the Faculty of Science. That’s where I met Professor. Kōji Nakanishi, a great instructor in the natural sciences, who wrote me a recommendation for admission to the Tokyo University of Science. When I think about it now, I’m surprised my body held up: I’d spend my days prepping for lab experiments and taking lectures at the Tokyo University of Science, head to the high school to teach classes in the evening, and then zip over to the Tokyo Industrial Laboratory (now the National Institute of Advanced Industrial Science and Technology) to do lab research late into the night.

  　It actually took me three years to finish a two-year Master’s program. The strenuous schedule was part of it, but there was another wrench in the works: I’d done some good research and pretty much written my paper when I found out that a professor at Yokohama National University had actually done the exact same project and published his findings before I could. That quashed my hopes of publishing my paper, so I had to do another year. I’m glad I did, though, because that extra year was when the Tokyo Industrial Laboratory got the first 60 MHz NMR facility—and, even though I was a student, I got to use it late at night. I can’t even begin to explain how valuable that opportunity was in the research I went on to do. I was probably the first person in Japan to use NMR on natural products.

  　After I got my degree, I came back to Yamanashi and met yet another great mentor in Professor Kin’ichirō Sakaguchi. Everywhere I went, Lady Luck was looking after me, bringing me into contact with extraordinary teachers. Prof. Sakaguchi gave me some words of wisdom that’d play a big part in shaping my future: “Microbes,” he said, “have never let me down.” Taking his words to heart, I got into the Kitasato Institute and threw myself into research on both microbes and chemistry.

  President Shimada　
  　If there had been positions open and you’d become a science teacher in Yamanashi, I wonder where your career would’ve taken you.

  Prof. Ōmura　
  　I might’ve worked my way up to school principal, I suppose. When I think about it now, though, I know that everything I saw as a setback actually put me in a better position in the end. My whole NMR experience is a perfect example. I taught at the high school for five years, went to the University of Yamanashi for two years, did research on fermentation chemistry, and then landed a spot at the Kitasato Institute. I got in without any special leverage, just like a new graduate would—same test and everything. At the time, nobody knew much about the structures of the compounds that Kitasato Institute researchers had discovered. People poured in, devoting themselves to structural research, but nothing much came of their efforts. That’s where my “off year” of NMR investigations came in extremely useful. Others had invested as many as five or six years toward structural research, all to no avail. It only took me a few months to do what they spent more than half a decade trying in vain to pull off. With that, I wasn’t the same as a fresh graduate anymore; my director let me do what I wanted to. If I’d already gotten my Master’s degree without any problem, I doubt things would’ve gone the way they did.

  President Shimada　
  　At the Kitasato Institute, you started out as a technical assistant—not even a full-fledged assistant.

  Prof. Ōmura　
  　Not even much of anything—I was wiping blackboards! That’s why I want young people to understand that repeating a year of education isn’t the end of the world—it can be the perfect chance for a new beginning.

▼Chasing the mysteries of the unexpected

• President Shimada　
  　Prof. Yamanaka, you worked in the Department of Pharmacology at the Osaka City University, where you made new discoveries in the study of blood pressure. Could you tell us a bit more about that experience?

  Prof. Yamanaka　
  　I did a two-year residency, and I quickly learned how a single medical school can be home to two completely different worlds. When you’re a resident, it’s all about doing what you’re told—you’re pretty much at the mercy of your superiors always getting lectured, always absorbing things, and focusing on following orders down to the smallest detail. Graduate school is an entirely different beast: no one teaches you anything hands-on, really. The only thing your professors tell you is to read papers and think about what you want to do on your own. I spent my time with my books and my thoughts all the way through the summer. At one point, I remember, my advisor told me something that really resonated with me: “We researchers might be few in number, but we can compete with the best in the world.” It went against my whole perception of what “medical school” was. I’d never once thought about “competing on the global stage” when I was a resident.

  　The first experiment I did during that summer vacation produced results that went directly against my hypothesis—it was completely the opposite of what I’d been expecting. What surprised me more than the results, though, was my reaction to it. I wasn’t disappointed in the least. I was so curious, so excited. That’s when I knew that research was my calling. There are people who find surprises disheartening, and there are people who see unexpected outcomes as thrilling opportunities. I’m not saying that one type is better than the other; it’s a matter of personality, after all. But I do know that I fall into the latter category. Unforeseen surprises light sparks of curiosity in me. That first experiment I did in graduate school kind of defined my future path.

  President Shimada　
  　You then went on to write several highly esteemed papers and obtain your graduate degree, after which you embarked on a study abroad program.

  Prof. Yamanaka　
  　That’s right. I went to the United States and worked under a professor there, testing out his hypotheses in the lab. As luck would have it, the unexpected results kept on coming. The project was on genetics; my boss was trying to prove that a certain gene could help prevent arteriosclerosis. We had our sights set on a major breakthrough, one that could save millions of lives—like the research in Prof. Ōmura’s body of work. The experiment shot that hypothesis right down, however. Instead of showing disease-curing effects, the gene turned out to be cancer-causing. My boss was shell-shocked, but, true to form, my curiosity got the best of me. I needed to know why the gene, which we’d though would have an impact on arteriosclerosis, triggered intense cancer. That question ended up driving most of my research from that point on, steering it in a new direction that ultimately brought me to ES cells and then iPS cells.

  President Shimada　
  　During your time abroad, your team discovered the APOBEC1 oncogene and NAT1—a gene that APOBEC1 targets.

  Prof. Yamanaka　
  　In examining the mechanisms behind cancer formation, I eventually found that the key to inhibiting cancer was the versatility of ES cells. Ever since, I’ve been obsessed with embryonic stem cells.

  President Shimada　
  　There’s that “something special” again—it’s a facet of your personality, Prof. Yamanaka. The results went completely against your suppositions, and that’s what got you going.

  Prof. Yamanaka　
  　It might’ve just been pure luck that my first experiment went the way it did. It could be about attitude too, though. When I’m teaching students, I like to see how they respond to unexpected outcomes—which happen a lot. Do they get frustrated? Or do they get excited? That reaction can make a big difference.

  President Shimada　
  　The thing that gets me is how you’ve relished that initial shock instead of seeing it as a roadblock—that’s a sign of vision, I think, and you’ve turned that inspiration into exciting new discoveries. Could you talk about your formative research experiences, Prof. Ōmura?

▼The best path isn’t always the easiest one

• Prof. Ōmura　
  　I learned everything about how to use NMR, from the basic principles to measurement techniques, during my Master’s work. Using that knowledge, I managed to determine lots of structures over the course of a few months at the Kitasato Institute—which is where I made another important discovery. The lab next to mine had been researching microbes, trying to work out a new discovery. They’d spent a year searching but they hadn’t been able to find what they were looking for. I took a peek in and watched them keep going and going through the process. I, on the other hand, was next door, sitting and waiting for a discovery to come through the pipeline so that I could determine the structure behind it. I thought to myself—“What am I doing? The people next door are pouring years of work into finding things, and then I just do the structural work in a matter of weeks.” It felt unfair, really. The thought of it all bothered me so much that I made it my mission to help make some of those discoveries myself. It was a great time to set off on a new course. I put NMR behind me and got going on an initiative that I knew could really help people.

  　I managed to make a few new discoveries, one of which was staurosporine. Phosphorylation activates proteins, a phenomenon that can lead to cancer. Staurosporine is a substance that inhibits the activity of phosphorylation-causing enzymes. It’s been a crucial foundation for cancer treatments, establishing the basis for as many as 37 anticancer drugs. I’m sure I would’ve made solid progress if I’d kept on with my structural analysis research, but I was looking for a more rewarding, fulfilling challenge. That’s what exploratory research gave me. Without that experience, which really centered my focus on science’s contributions to society, the idea for an industrial-academic collaboration framework would’ve never hit me when I came back from my studies abroad. It wasn’t an easy road—but it got me to a really inspiring end.

  President Shimada　
  　Staurosporine is a basic drug that inhibits phosphorylation, which can lead to cancer. Given that context, staurosporine drove the development of leukemia treatments like imatinib (and Gleevec). Your work on isolating the compound, has thus had an enormous impact. That’s just one of the many achievements you’ve made over the years—you also developed avermectin and discovered a variety of other fundamental drugs. Let’s go deeper into how you got there. Could you tell us about your studies abroad? Meeting Professor Max Tishler at Wesleyan University must have been a big turning point for you.

  Prof. Ōmura　
  　I went abroad in 1971, right in the middle of Japan’s economic boom. My destination was the United States, and I set off with the aim of developing some of the interesting antibiotics I’d discovered. Shortly after I arrived at Wesleyan University and started working under Max Tishler, he became the president of the American Chemical Society. He was so busy with his new responsibility that he asked me to take care of his students. I had to balance that with my own research, of course, but it all worked out. My structural research on the antibiotics I’d brought over turned up some good results, as did my work on action mechanisms, and I ended up publishing eight papers on my findings. That must’ve impressed Max, because he took me under his wing and let me pursue a lot of my research interests.

  　You’ll probably laugh when you hear the story of how the connection between me and Max came about. I made up my mind to study abroad and decided to send letters to five professors I knew of, asking them to host me. Everyone gave me an OK—but everyone also proposed a different salary. Most of them said they’d give me around $16,000 a year, but one floated a much different number: $7,000 a year. That was Max. I needed to know why he only wanted to give me less than half of what the others were offering. I figured that difference had to mean something. I decided to find out what it was. After I convinced my wife that it was the right choice to make, I agreed to Max’s terms. Choosing the lowest-paying position, it turns out, would be a life-changing decision for me.

  　The facilities at Wesleyan were great, and I had everything I needed to probe my interests. While most doctoral research fellows don’t do much more than assist their bosses, I got to do my own thing and had plenty of students to assist me. About two months after I got settled in at Wesleyan, I had an experience to remember: I got to meet ProfessorKonrad Bloch, who’d won the Nobel Prize for his research on lipid biosynthesis and metabolism. He knew Prof. Tishler and a friend of mine who was a general manager at Pfizer too. My friend rang me up and told me that Prof. Bloch was planning to visit the company, so he invited me to come over and chat with Prof. Bloch about cerulenin. Meeting him was such an incredible honor. He was my gateway into biochemistry, a field I hadn’t studied very thoroughly.

  　After about a year at Wesleyan I got a letter from the Kitasato Institute telling me to come back. ProfessorTōju Hata, a distinguished academic who’d discovered mitomycins, was retiring—and I was apparently going to fill the void. It was hard to swallow; I’d just gotten started on all the research I’d been hoping to do, and I knew that going back to Japan would mean going back to lower-quality facilities. If that was how it had to be, my research would stall. Then, I figured out a way to honor my obligation to the Kitasato Institute and still get the funding and resources I’d need. They call it the “Ōmura method” now, I guess: doing joint research with a company to get the necessary backing in exchange for licenses to patents on promising compounds that come out of the research. The joint-research contracts I signed all included that provision.

  　Max was a great ally along the way. Before he became a professor at Wesleyan, he’d worked at Merck—rejuvenated the company, actually—and he was kind enough to give me a referral there before I went back to the Kitasato Institute. At that stage, I’d been to places like Pfizer and Lilly, and most of them said they’d give me 2 to 3 million yen a year for around three years. When I told Max what they were offering, he just kind of smirked. I couldn’t make sense of that reaction until later, when I found out that Max had already called the director of research at Merck and told them to “sign a contract with Satoshi—his research is worth supporting.” Max was gracious enough to take an interest in my research, recognize the potential, and take the initiative to secure sources of support for me.

  　Back then, a normal university professor got around 2 or 3 million yen a year in research funding. Max told Merck to “Give Satoshi $80,000 a year,” which came out to about 20 million yen. What’s more, he recommended a full three years of funding. Imagine that—the professor who’d given me the lowest salary of all at the beginning ended up landing me the largest package of research funding in the end. Merck went on to keep supplying me with the same amount of financial support for 20 years.

  President Shimada　
  　You went overseas as a visiting professor, not a post-graduate researcher. Did that put you on equal research footing withProf. Tishler, essentially?

  Prof. Ōmura　
  　Since I’d published papers detailing my NMR-based structural research on things like macrolide antibiotics, I might’ve been on a level playing field with him in a way. I doubt he’d heard much about my research, but it doesn’t really matter. I’m just happy that I went to Wesleyan.

▼The importance of being earnest: Why tackling challenges is always worth the struggle

• President Shimada　
  　Prof. Yamanaka, your work in Japan gave you enough exposure to land you a fellowship at the Gladstone Institutes. The deciding factor were your publications, correct?

  Prof. Yamanaka　
  　I wrote my publications on the unexpected results of the research that I’d done in graduate school but I don’t think that was necessarily the deciding factor. Genetic engineering was all the rage in the United States back then, and I contacted plenty of places about getting a position where I could explore the topic. What they were looking for, though, were people who could hit the ground running—not a former orthopedic surgeon who was just getting his feet wet in genetic engineering. I decided to bluff. In my letters, I told them that I could do so much in genetic engineering. My white lies didn’t really do the trick, unfortunately. I kept getting passed over until I finally got a call from Prof. Tom Innerarity, a head researcher at the Gladstone Institutes. At the very end of our conversation, he asked me if I’d be all right with working on Saturdays. “Of course,” I told him. “Japanese people are hard workers.” That, I eventually heard, was the deciding factor. I had about six months before I was scheduled to go to the United States, so I went to Osaka City University, studied under a genetic engineering professor, and learned all I could to make sure that my initial bluff would hold water.

  　As soon as I got settled stateside, the orders came fast and furious: my boss would tell me to make this gene by this date and this gene by that date, or else the team wouldn’t be able to inject the genes into the fertilized eggs of their lab mice on the scheduled date. Everything was on a tight deadline, which obviously made for some pretty tough pressure. I figured that Tom was testing me. I didn’t want to come up short, so I pushed myself really hard to meet the requirements.

  President Shimada　
  　You still flourished in the United States, discovering new genes and doing impressive work all-around. When you finished your studies abroad and came back to Japan, you took a position as an Assistant Professor in the Department of Pharmacology at the Osaka City University. You’ve said that, upon making that transition, you developed a case of “PAD”—so-called “Post-America Depression,” a feeling of desolation at not having access to the kind of top-quality environment and research resources that you’d benefited from stateside. Could you take us through that experience?

  Prof. Yamanaka　
  　I was in the United States for about three and a half years, and I met a lot of other foreign researchers. One of them, a student from the Netherlands, told me to watch out for “Post-America Depression” after I came home to Japan. At the time, my research in the United States was going great; I was confident that I’d be able to make it as a researcher. PAD hadn’t ever crossed my mind. When I did come back to Japan, however, I started to get the feeling that I’d been overconfident in my abilities. I realized that my research successes were more about my boss’s help and the top-notch facilities I had at my disposal than a result of my own skills and insights. Papers of mine that had passed reviews in the United States ended up getting turned down in Japan. Referees said that they couldn’t understand my English. Sometimes, I’d just get a straight-out “no,” a flat refusal. It was disheartening. It was a crippling case of PAD, just like my Dutch colleague had warned me about. I wanted to go back to the United States as soon as I could—it was the place where I felt like my research was appreciated, but it felt so far away.

  President Shimada　
  　And then you made a bold move: you applied to fill a vacant Associate Professorship at the Nara Institute of Science and Technology (NAIST).

  Prof. Yamanaka　
  　I saw a blurb about an opening at NAIST in a journal I was reading. By some odd stroke of luck, I fitted the bill exactly—I was precisely the researcher they needed. I’d applied to lots of different laboratories but I didn’t have the right connections to get my foot in the door. The opening at NAIST sounded perfect; I couldn’t imagine not getting it. That’s why I made a resolution: I told myself that if I didn’t get it, I’d give up on my research career and go back to clinical practice. It was my way of giving myself an ultimatum, I suppose.

  President Shimada　
  　There was a lot riding on that application, then. I heard you told the NAIST administration that you could do your gene research alone—even though that might not have been completely true.

  Prof. Yamanaka　
  　In the United States, you can get proficient engineers to do the technical work for you. That’s how the system works. The problem is that there isn’t any comparable system in Japan. I knew that when I applied, though. I was familiar enough with the setup.

  　I’ve got a funny story, actually. Back then, I took care of a bunch of mice for research purposes. When the obon holidays rolled around in mid-August and everyone was off work, I was at the university on a regular basis to look after the mice. One day, when I was at the lab, the phone rang. No one was there to pick it up, so I answered—and it was someone from NAIST. The selection committee had picked me as a finalist for the position, and they wanted me to come in for a seminar. I eventually went, attended the seminar, and got hired. That was it. I couldn’t help but wonder about that phone call, though. Why had they rung the lab up during obon break, when things normally shut down? Apparently, it was all part of a plan: the selection committee wanted to make sure that obon wouldn’t stop my research, to make sure that I’d be there during vacation, even. I tell you—taking care of those mice was so tedious that it gave me pangs of PAD, but being there every day was what got me that position at NAIST—which is what let me continue my research. Like Prof. Ōmura was saying, you never know when or how an opportunity is going to come by. “Inscrutable are the ways of heaven,” right?

  President Shimada　
  　You’re fond of that saying, aren’t you? It’s a great one. After you took your position at the Nara Institute of Science and Technology, you had to recruit graduate students to your lab. The odds weren’t in your favor, however: you were an Associate Professor, while everyone else on the recruitment trail was a full-fledged Professor. Tell us how you managed to attract young researchers to your program.

  Prof. Yamanaka　
  　NAIST is a graduate institution without any undergraduate faculties, so the student body is full of college graduates from around the country. It’s a war every year, trying to get those fresh graduates into your lab. The ball’s always in the students’ court, and they have the right to choose their advisors. They always flock to the best Professors, of course, but the cards were stacked against me. I was the youngest one, an Associate Professor with virtually no research funding, no papers, and no recognition whatsoever. I had no idea if I’d get any students to work with. I decided to bluff, again, and tell the students what I was dreaming of accomplishing. I told them about creating iPS cells from adult skin cells. I talked to them for 30 minutes, I’d say. Having spent more than a decade doing the relevant basic research, I knew how difficult it’d be to make that happen—but I never let on that much to my audience. After a half an hour, I had my limit of three students. They were my first graduate charges. I’ll never forget them, how wonderful they were to have in my lab. I’m still collaborating with one of them: Kazutoshi Takahashi.

  President Shimada　
  　You always aim high and push the envelope a bit. That’s definitely one of the keys to all your successes.

▼Never pass up an opportunity to connect with other fields

• Prof. Yamanaka　
  　The students at NAIST were great, of course, but another plus was that I got to do research in the same building as scholars in fields as diverse as plant and genome research. I’d get to bounce ideas around with some of the best minds around. When I told a plant researcher about how I was having trouble making iPS cells, he sympathized—but he also told me that plants were loaded with ES-like cells. “If you use a plant cutting, you get things with ES-like properties and even leaves.” I was floored, to be honest. Up to that point, I’d made misgiven assumptions about what was possible. Hearing what he had to say, though, I thought I might have a great new avenue to explore. I don’t know what I would’ve done if I hadn’t had the chance to reach across academic boundaries so easily. The environment at the University of Yamanashi offers the same kind of opportunities, I think.
•  
• President Shimada　
• 　You just talked a bit about a Dr. Takahashi. He was the one who discovered so called “Yamanaka four factors”, correct?

• Prof. Yamanaka　
  　That’s right. He originally graduated from the Doshisha University Faculty of Science and Engineering, but he’d never studied any biology in school. His grades weren’t anything special, either, and he failed spectacularly when I had him do an experiment. I feel bad just saying it, but that’s how it was at the beginning. After a year or so, though, he’d made unbelievable progress. He kept on taking up challenge after challenge, even when I’d ask him to do things that might not have even been realistically feasible. I didn’t know much about genetic engineering, after all. In those types of situations, students with good grades tend to say, “Sorry, but I don’t think that’s possible.” Not Takahashi. Back then, you were lucky if you could introduce two genes into a single cell. Takahashi asked me if he could put 24 in—conventional wisdom would’ve written him off as crazy right then and there. Not to pat myself on the back or anything, but I told him to give it a shot—and I found all 24 genes, actually (laughs).

  President Shimada　
  　That’s amazing. Going up against what people assumed to be impossible was what led you to the discovery of iPS cells. Prof. Ōmura, you set up your own lab when you came back to Japan. You had your own “Takahashi-san,” too.

  Prof. Ōmura　
  　The Kitasato Institute assigned a handful of students to work in my lab when I got back. Two were high school graduates enrolled in night classes at a technical school. Takahashi-san was one of them. Then there was one student with a Bachelor’s degree and two more with Master’s degrees. That was what I had to work with, all together. I was still pretty young at the time, figuring I still had another 27 years or so to go as a Professor, so I didn’t think time was much of an issue. I made a plan: I’d help these five assistants of mine get their degrees, first of all, and develop them as specialists with the capabilities to do the things I couldn’t do. I didn’t want to clone myself—that would’ve been pointless. The goal was to see them through to becoming specialists in fields like organic synthesis, microbes, and biochemistry, which would give me the right blend of people for a collaborative research framework. Since that point, what started out as a fledgling, understaffed little lab has turned out more than 100 doctorates and 32 professors. Balancing my research with those types of educational efforts has been really satisfying.

  　One of our research topics centered on finding animal drugs, which wasn’t a very popular field of study at the time. That’s why I felt the urge to do it. From where I am now, I think my main job is to put the right people together in effective teams. There’s only so much I can do by myself. They say that “a true gentleman is well-rounded,” and I’ve learned how true that adage is. What goes into good research leadership? The right specialization is key, of course, but what’s even more important is the ability to see the big picture and assign researchers to roles where they can make the most of their unique skillsets. I think I managed to do that.

  President Shimada　
  　Prof. Yamanaka, you set up “CiRA,” the Center for iPS Cell Research and Application, at Kyoto University. I love the name because it broadens the focus from research alone to “application.” You’ve always had a strong interest in the clinical applications of your studies, and that focus is expanding the scope of your successes.

  Prof. Yamanaka　
  　The team that discovered iPS cells was really small. After we found them, though, the job shifted to how we’d usher our findings into real-world medical applications. That’s a completely different task. Seeking out and realizing those medical applications went beyond what I could do on my own, so success hinged on how well I could form a solid team. CiRA helps us do that. The moment that iPS cells come into being is kind of a dividing line: the work you do before that point and after that point is completely different—and equally crucial. It’s the same researchers doing everything, but the core objective shifts as soon as you have the iPS cells you’re looking for. The initial basic research is like going from 0 to 1; the application part, however, is like going from 1 to 10 to 100. It’s worlds different. We know that, and that awareness shapes what we do.

▼Choose the road less traveled

• President Shimada　
  　People are talking about how Japan’s scientific and technological capabilities are on the decline. National universities are grappling with major cuts in research funding, putting educational research in peril. What are your views on the situation?

  Prof. Ōmura　
  　I was reading a book the other day and came across a passage that read, “The factors behind the downfall of civilization lie in the factors behind prosperity.” Looking back on everything, Japan has done so much to foster advances in science and technology. With budget resources dwindling, though, I just hope that the prosperity we’ve enjoyed doesn’t end up fomenting a collapse. There’s an old play by Yūzō Yamamoto called Kome hyappyō, which basically foregrounds the idea that the tougher the times are, the more important it is to do right by your educational practices. We have to come face to face with the fact that university research funding, especially at regional universities, is disappearing; we have to know how serious the issue is and do whatever we can to avoid the things that could spell our downfall. If we can’t inject new life into our regional communities, there’s no way we can enliven the country as a whole. In that sense, shrinking research budgets could mean grave consequences for our future.

  President Shimada　
  　Of all the developed countries in the world, Japan is the only one publishing fewer and fewer papers in high-quality journals with impact factors. To me, a lot of that has to do with the growing lack of research funding at Japanese universities. Given the conditions, it’s getting harder to find young scholars who want to pursue the research track or venture abroad for further study. For Japan, that’s a crisis. Do you see the same kinds of trends playing out at your lab, Prof. Yamanaka?

  Prof. Yamanaka　
  　My team is lucky to be at Kyoto University; the research environment there is incredible. Things were much different at Osaka City University, where I spent the majority of my career as a researcher. When I was in graduate school, I only had about 1 million yen a year in funding. I had to figure out how to get 400 uses out of experiment kits that I was only supposed to use 100 times. Everyone was in the same boat, though, so I didn’t really see it as that much of a hindrance. Having seen both sides—research environments with next to nothing and research environments with just about everything—I have to say that the need for change falls on both the national government and university administrations. Japan’s drooping financial standing, along with the shrinking population, makes reforms especially vital. I doubt that we’ll see much fluctuation in total research funding amounts, but the breakdown shows that grants for management expenses are going down while competitive funding is going up. Without more management grants, it’ll be harder and harder to dive into high-risk research and attract the kind of high-caliber human resources we need. The University of Tokyo and Kyoto University have to uphold their positions on the leading edge of Japan’s academic community (not to toot my own horn), but there’s no point in every university trying to emulate the big players and be a “mini University of Tokyo” or “mini Kyoto University.” In my view, universities have to focus on what makes them special as they propel their research initiatives forward. On my visit to the University of Yamanashi today, I paid a visit to ProfessorTeruhiko Wakayama’s lab—and I felt so reassured, so moved at what I saw. The University of Yamanashi is embracing its individuality, conveying the idea that researchers will be able to do unique things if they come here. That’s a model that I think all Japanese universities need to follow.

  President Shimada　
  　Do you have any words of advice for young people?

  Prof. Ōmura　
  　The chancellor at the University of St Andrews in Scotland told me that “Young people these days take the easy road.” I think that statement applies to countries across the globe. When everyone’s opting for the path of least resistance, golden opportunities abound. If you take a risk and push yourself hard in that kind of context, your chances of success can skyrocket. I hope today’s youth can muster up the courage to take their chances and opt for the road less traveled—the challenges will pay off.

  Prof. Yamanaka　
  　I couldn’t agree with you more about the importance of taking up challenges, Prof. Ōmura. The one thing I’d add is how important it is to absorb teaching with a sense of humility. When I was abroad, my teachers and colleagues guided me through the best approaches to giving lectures. I used to put my slides up on a screen and circle key words and phrases with my laser pointer. “Stop,” the others would say. “It’s distracting.” I took that advice to heart and started putting a lot of thought into fixing my pointer on the right words. I was giving a presentation during the screening process at NAIST, and one of the committee members in the audience was a plant science professor. When I finished up, he came to me and said, “Prof. Yamanaka, I study plants. I don’t really understand what you’re researching. But you fixed your pointer on the key points. I could tell right then that you’d really learned the ropes in science.” I guess I fixed the “pointer” in my head right on iPS cells, too, and that ended up paying off. When you stay humble and listen to people’s advice, chances are you’ll go far.

  Prof. Ōmura　
  　 I’d also encourage young people to make friends they can really trust. It doesn’t matter if they’re from other specialties. Treasure those relationships, because your friends are the people who’ll enrich your lives—through both the good and the bad.

  President Shimada　
  　 It’s just as you always say, Prof. Ōmura: “one encounter, one chance.” There’s almost nothing more important than our connections with others. Today’s dialogue, I think, was one of those priceless encounters for a lot of us here. Thank you so much for being with us today, Professor Ōmura and Professor Yamanaka.