Research continuum

Into the human unknown


What we understand about ourselves constantly expands, but a fundamental question remains: instead of using data gathered from other animals, what if medical science were based purely on knowledge of human biology? A new institute seeks an answer.

At the heart of pharmacology are mountains of data based on animal tests. These are invaluable, having made drug treatments and therapies possible where once existed only despair. But taking these results and then assuming that they also apply to humans requires a leap of faith and even more careful testing, leading in part to the enormous expenses and time required to produce new treatments. And even then these are not lacking in harmful side effects.

The difficulty is that gathering equivalent data directly from humans has been impossible. Kyoto University’s Institute for the Advanced Study of Human Biology — ASHBi — takes this puzzle as its starting point, seeking to redefine the scientific basis of medicine in human terms. We sat in on a recent conversation including the institute director, Mitinori Saitou (center right), chief ethicist, Misao Fujita (center left), veteran KyotoU scholar of ethics, Carl Becker (far right), and guest moderator and ethicist at RIKEN, Douglas Sipp.

Defining ‘human’

Sipp: Because the mission of ASHBi is finding ways to study human biology using new technologies, an important question for researchers, philosophers, or ethicists is: what makes humans unique? What are the traits that represent that line separating humans from all other species?

Saitou: When I started working on germ cells, the cells that create eggs and sperm, I was interested in the mechanism of why only the germ cell lineage can transmit our genetic information and create new organisms. In an extreme sense it was investigating the mechanism of immortality. Then I started thinking about the purpose of medicine itself. In essence it is to make an immortal human being. That is what made me interested in germ cell biology. After we succeeded in making sperm and oocytes — egg cells — from human induced pluripotent stem or iPS cells, clinicians started to get interested in the possibility of making offspring from them. But that is still very challenging and raises many ethical issues. For example, if you were born from a skin cell using this technology, how would this change your perception of your ‘self’?

Becker: We used to imagine that tool making and communication are what made you human. Now we know that other species make tools. So that leaves the communication. Of course, other species do communicate, but not about specific plans, for example, “meet me at the station at 9:00 am.” That’s distinctly human and becomes critical if you forget where the station is, or what time it is.
The other major distinction that prominent KyotoU primatologists Juichi Yamagiwa, Tetsuro Matsuzawa, and others have noted is our ability to simulate the future. We as a species have developed the abilities not only to discuss our problems, but to simulate and anticipate different possible futures depending on what we do today. That’s basically what ethics is about. If you know what future you want to choose, then you know what’s permissible by and large with a lot of grey areas to be negotiated. If you haven’t chosen what future you want yet, you have no way to get there.

“What makes humans unique?”

Douglas Sipp studies regulatory policy and ethics relating to stem cell research and regenerative medicine. Originally from the United States, since 2002 he has worked at RIKEN — Japan’s largest network of research institutes — and also serves as visiting professor at Keio University School of Medicine. He has authored more than 70 peer-reviewed publications and serves on many international committees and working groups.

Public opinion and iPS cell technologies

Sipp: The ethical issues surrounding artificial gametogenesis, the creation of sperm and eggs in the lab — which could potentially be used in novel forms of human reproduction — open up lots of new questions that are being asked here in Japan and around the world. At what stage is the Japanese public right now?

Fujita: I am not sure if they know that we theoretically could create gametes and embryos — and even babies — from iPS cells. When I conducted a questionnaire about gametogenesis, we provided detailed information explaining the technology first, then asked about their attitudes. Most respondents were very surprised about the technology’s applications in reproduction: they mostly thought of iPS cells as tools in basic research and therapy.

Animal models for human medicine

Becker: Western research increasingly acknowledges that mice are not very useful. There are some things they can teach us, but millions of mice are raised and exterminated for things that are not useful, and when we bring the results into human trials we find out later that all of that research was not helpful.

Saitou: Ten or twenty years ago, the key model systems for mammals were mice, the most advanced models we had. However, even at that time I was already realizing the limitations of the animals. A very obvious example is in our field of germ cell specification. The precursors of both sperm and egg are formed very differently in mice compared to other organisms. The moment we started researching the development of human embryonic stem cells is when we started to really investigate the basic mechanisms of human development. People were struggling to figure out why there is such a difference between human and mouse stem cells.

“Training a new generation of bioethicists is the most important thing we can do.”

Misao Fujita is professor of iPS cell ethics at KyotoU’s Center of iPS Cell Research and Application — CiRA — and is now also professor of bioethics at ASHBi. As an undergrad, Fujita majored in clinical psychology at Tsukuba University — where she first met Carl Becker — and began her foray into bioethics. After serving as assistant professor at the University of Tokyo’s Department of Biomedical Ethics, she moved to CiRA to study the ethical issues surrounding iPS cell research. With the increasing possibility of producing germ cells with iPS cells thanks to Saitou’s research, Fujita is keen on exploring the ethics behind this new technology.

Legal questions and fresh blood for bioethics

Sipp: Since ASHBi will be looking very closely at the generation of gametes — egg and sperm — how is the Japanese government handling this? They appear to be treating this as a strictly research activity.

Fujita: Yes. The problem is that there are many ethical guidelines for basic research in creating gametes and dealing with human embryos. In clinical settings, though, there are no laws or regulations. And that is a concern to many in government. Recently, the health ministry released a notice about needing to create new laws regarding the editing of human embryos.

Sipp: What might be a way that Japan could address this new set of technologies that are appearing one after another?

Fujita: Training a new generation of bioethicists is the most important thing we can do. There are very few young researchers in this field. Whenever I go to a conference, the participants are mostly the same familiar faces.

Sipp: How are you attracting younger people to your research group in ASHBi?

Fujita: We are recruiting graduate students first, along with postdocs. Another concern is English. Most social scientists in Japan do not read or speak English. We have difficulty keeping up with global developments, because everything moves so quickly. I also need to improve my own language skills together with a new crop of bioethicists.

Sipp: One thing that is interesting about the ethics community is how diverse the backgrounds are. You find some people who are essentially clinicians or medical doctors or sometimes research scientists. You also get philosophers, legal scholars, social scientists: they all come together, bringing different perspectives.

Fujita: Yes, my research team is quite diverse. We now have someone who specializes in research analysis, philosophers who specialize in policies, and even nurses and administrators. We are also working with other universities constantly.

Becker: Your team is quite multi-disciplinary. It’s a good example of something which is often very hard to do in Japan.

Saitou: That is very important and a really fortunate aspect for ASHBi, especially in the context of science in Japan. Japanese are not really good at communicating frankly among different disciplines. I think this may be a cultural thing. Japan is very isolated and is mostly composed of similar kinds of people. Nonetheless, we are in a period where traditional bioscience academics really need to fuse with different disciplines, because we have so much information and data to share.

Sipp: How do you think you can break that bottleneck and bridge the different disciplines and thoughts?

Saitou: While it’s difficult to organize and bring people together, I think what is necessary is for people to work together in a close environment, like this building we are in now. It stimulates conversation. For example, for over a year now we have been holding periodic meetings with our mathematical group. Every two weeks or so, pure mathematicians and pure biologists come together and discuss common topics we can work on. This allows us to gradually understand the language of our respective topics. I’m already thinking of biological questions as mathematical ones, and visa-versa from my mathematics collogues.

Becker: You also collaborate with Cambridge University and other foreign institutes and teams: a good incentive to broaden your perspective.

Saitou: Yes, we have overseas PIs based at McGill in Canada, EMBL in Germany, and also Cambridge, with many other collaborative projects underway.

Fujita: How is the training of younger researchers at ASHBi going so far? We’ve had a few seminars and workshops that feature their work.

Saitou: One of the current problems in Japanese science is that there are very few places where early career researchers can freely concentrate and work on their science. So, one of the reasons why I wanted to be involved in the WPI initiative is to create such opportunities for young researchers. There are many talented new researchers looking for positions, but not in Japan. I welcome them to ASHBi.

“There are many talented new researchers looking for positions. I welcome them to ASHBi.”

Mitinori Saitou has spent decades extensively investigating the genetic and epigenetic mechanisms that determine the development of germ cells, the cells fundamental to all life. Using iPS cells, he has recently succeeded in generating human primordial germ cell-like cells, or PGCLCs, which are responsible for producing sperm and oocytes. He is the recipient of numerous prestigious awards including the Takeda Prize for Medical Science and The International Society for Stem Cell Research Momentum Award.

As director of the newly formed institute ASHBi, Saitou is committed to leading an international and interdisciplinary effort to define a human basis for the future of medicine. ASHBi was selected in 2018 to be part of the Japanese government-sponsored World Premier International Research Center Initiative, or WPI program, joining an extensive network of ground-breaking institutes across the country, including the University’s first WPI institute iCeMS — the Institute for Integrated Cell-Material Sciences — which was founded in 2007.

The search for a philosophy of human biology

Sipp: So, we’ve looked at the scientific, ethical, legal, and policy sides of ASHBi’s research effort. What other big challenges or questions are there for the institute?

Saitou: One thing that has become evident is the necessity of having better understanding of bioethics, especially when we start investigating the core concept of ASHBi: What is it to be human as a biological entity? This question is being dealt with globally, and to progress in human biology, we really need to take special care in how we move forward.

Becker: ASHBi is a good way for a younger generation of researchers become knowledgeable in bioethics.

Saitou: Yes. A friend who is a gynecologist — and pushes me to pursue applications of my research— tells me that what is important is the philosophical reasoning to justify the birth of humans from non-reproductive, somatic cells. Moreover, the reasoning should be written or referenced within Kitarô Nishida’s Kyoto School of philosophical thinking. I have little knowledge of philosophy let alone Nishida’s work; his writings are very difficult for me to understand. Yet Nishida is strongly rooted in the university and in the city of Kyoto, and had unique thoughts on life. I feel that understanding his work is going to be vital for us.

Becker: Nishida is great, not because his philosophy is eternal, but because he tried to reach what German philosophers and psychologists in the early 20th century were doing, except from a Japanese perspective. This is the reason why Dr Fujita can be great. Not because she will create an eternal philosophy, but because she will know what is happening in science both in Japan and in other parts of the world. She can be a bridge between different ways of looking at things. Nishida is great but you don’t need to read him.

Saitou (laughing): Yes, I bought one book and I couldn’t understand what he was trying to say.

Becker: Nishida was trying to make Western science understandable in a Japanese philosophic framework. He didn’t succeed in some ways. But the effort to make and use new technologies, whether it’s gene editing or humans from somatic cells, needs to be translated in a way that the Japanese people, and people of the world, can understand.

Saitou: Yes, that’s what I’m also learning. Philosophy itself has a very deep background originally from European countries, and Nishida was one of the first people who interpreted what they said into Japanese culture. Nonetheless, very few scientists understand the history of German philosophy. People at KyotoU might know who Nishida is or at least have heard of him. But if we are to have a research group dedicated to ethics and philosophy we are obligated to have frequent discussions like we do with the mathematicians.

Becker: The goal of Nishida was not to create a unique philosophy. It was to make the cutting-edge science of the early 20th century acceptable to a Japanese world. Therefore, there’s a similar goal for ethics and philosophy here in ASHBi, to make the cutting-edge science of the 21st century understandable and acceptable to today’s Japanese.

Saitou: Can I ask a question? What was the general theme of European philosophy in the 19th and early 20th centuries? Were they competing with pure scientists?

Becker: I don’t think so. Especially if we look at Kant, Hegel, Marx and then psychologists like Wundt, Alzheimer, and Kraepelin — who Nishida was looking at — they were trying to understand how history, society, and humans moved. They used and studied cutting-edge technology, in those days it was looking at light, or biology, like Mendel’s genetics. They were looking at what they knew about genetics and science to try and model history and society. What we know today is much more advanced, and we must develop a new understanding of human society and history.

Saitou: Is that your understanding of the role of philosophy in the current climate?

Becker: That was its role in 19th century Germany. But Nishida did not follow Hegel and Marx; he did not try to interpret history. He looked at Zen no Kenkyû and Basho no Ronri, and for Nishida the big problems were not society and history. He didn’t need to discuss society because Chinese philosophy already did that. Nishida felt that German logic and German truth or ‘goodness’ are very different from Japanese logic and Japanese truth. So, he asked how can I as Nishida understand German truth and German logic as a Japanese?

Saitou: Would it lead to the creation of unique identity or values on a new style of life? Like humans made from somatic cells?

Becker: Well in Nishida’s case, his arguments about Zen no Kenkyû or Basho no Ronri are an antithesis to German thinking. He says that’s not the only way to understand good; we in Japan have a different way to understand good. There is a Basho no Ronri which is different for us. Similarly, even if the Germans or the Europeans all say, “this is our stand on animal experimentation,” you can say, “we as Japanese take a different stance.”

Sipp: The important thing is to be able to articulate that, so that other people can understand that it is a rational argument.

Becker: Exactly.

Saitou: It is important to make a series of general international rules. But if everything is similar it is neither interesting nor appropriate to individual cultures.

Becker: You can’t take American-style informed consent or IVF practices, and use them in a Japanese hospital. You can’t expect these to be immediately accepted by everybody in Japan.

Fujita: With the example of informed consent, I do agree that what works for one country may not work for another, because of cultural differences. But I don’t think many people refuse the concept of informed consent itself. We would agree to the concept of respect for autonomy. I think there is some variance among cultural values, but at the same time we should follow and remember that we also have the same shared values in an international setting.

Becker: So, the challenge then, both for Nishida and for Saitou is figuring out how to adapt those universal values to be suitable to the Japanese culture today.

Saitou: And somehow at the same time to create something original from our viewpoint and then influence the rest of the world.

Sipp: Looks like you’re off to a great start both on the scientific side and the ethics side.

Saitou: It is a great challenge.

Sipp: Thank you. It was interesting hearing about the philosophy of science and looking back at a transformative time in biology and physics. Now we’re seeing very similar transformations in fundamental concepts in science, like the idea of the genome. What we used to think were clear boundaries between human and nonhuman are starting to get fuzzier. These are areas that your labs are now looking at from different angles, both scientifically and ethically.

“Nishida was trying to make Western science understandable in a Japanese philosophic framework.”

Carl Becker is specially-appointed professor of policy science at the University’s Medical School. His research focuses on medical ethics at the end of life, psycho-social support for terminal patients, and burnout of medical staff. Arriving in Japan 45 years ago, Becker was originally impressed with the way that Japanese dealt with end-of-life issues in Hawaii, and wanted to see it firsthand in Kyoto. He began his study on the ethical issues of death and dying at KyotoU’s Faculty of Letters, and moved to the School of Human and Environmental Studies in 1992 to study bioethics.