 Hello and welcome to the OIST podcast, bringing you the latest in science and tech from the Okinawa Institute of Science and Technology Graduate University. Today we speak with Sir Jim Smith. Sir Jim is head of the Welcome Science Review and group leader at the Francis Crick Institute's Developmental Biology Laboratory. He is also a Fellow of the Royal Society and was knighted in 2017 for services to medical research and science education. He came to OIST to deliver a lecture entitled Making a Human, Lessons from the First 10 Hours in the Life of a Frog. In his talk, Sir Jim brought to life how one fertilized cell manages to turn into, in humans at least, 40 trillion cells, all in the right place, at the right time, and working correctly. It was a fascinating lecture, bringing together some of Sir Jim's well-known research findings. In this talk, we move beyond Sir Jim's research to talk about the future of research in his area, including new stem cell therapies for humans. We also talk about how he decides who gets funding, how to make science more collaborative, and how to bring a diverse community of people together for the best results. It's a fascinating glimpse into the mind of a distinguished scientist and great leader. We hope that you enjoy. Sir Jim Smith, thank you so much for joining us today. It's a great pleasure. You currently have roles at both the Crick and the Welcome. I'd like to ask how you think about what it is that you do. My main work is with the Welcome Trust. Until recently, with the Welcome Trust, I was head of science and responsible for ensuring that we funded the best science. Whether by response-mode funding or through the institutes and centres that we support. More recently, I've put that role to one side, and I've become the head of the Welcome Science Review. The work in the Science Review is really to take a good look at what Welcome funds through science, to make sure that we are funding the right things, to make sure that we're taking advantage of our independence, to make sure that we respond to changes in science as they happen through the world, and to respond to changes in the world. At the moment, one gets worried about climate change, mental health, things like antimicrobial resistance. We're asking how should the Welcome Trust respond to those existential things that are happening to the world. That's my welcome job. At the same time, when I moved into the Welcome Trust, I had previously held a senior position at the Crick, and I was very loath when I moved into the Welcome Trust to leave behind my research, so I agreed when I moved into Welcome that I would run my lab, and so that's what I do. It's tough on the people in my lab because I don't see enough of them. I probably spend about half a day, maybe a whole day a week in the institutes and the rest of the time in Welcome, but mostly I feel guilty all the time. I feel guilty when I'm not in the Welcome Trust because I should be in the Welcome Trust, and I feel guilty when I'm not with my lab because I feel I should be with my lab. And then add the family into the mix as well. I'm sure it's just... Add the family into the mix and it gets even worse. It's a terrible life. But you'll hear in Japan to give a talk, making a human, lessons from the first 10 hours in the life of a frog. So I guess the general direction that people tend to head in in their careers is sort of more into that managerial and away from the thing. It is that once got them into it in the first place. But I do just want to ask you, how did you find yourself in the world of frogs? Well, I'm not going to answer that question immediately because I want to pick up something you just said if I may, which is the one about taking on managerial roles, which I think is quite interesting. And if I don't answer it now, I probably won't. So one of the things that happens to scientists, if they've been successful, which I was, you know, by any objective criterion, you get moved by people, you get asked by people if you want to run stuff. And it's very easy to say yes. And the challenge with that frequently is that, first of all, you're taken away from the thing that you are good at and put into something you may not necessarily be very good at. So I claim that I, you know, the managerial stuff I've managed reasonably well. But I think it's something that we as a scientific community have to bear in mind that just because you happen to be a good scientist, it doesn't mean you're necessarily going to be a good leader. And I think leadership in science is incredibly important. And I think that appropriate training in leadership for people who eventually take on these roles is really important. So I just wanted to say that. Now, how did I get into frogs? I'll give you a longish answer actually, because it's sort of interesting when I was at school. So I'm going back to school. I did math, physics, chemistry. I didn't do any biology at all. Because I went through a fast stream at school. And it went so fast, you didn't have time to do biology, you did math, physics, chemistry. And then when I went to university, I was intending to do math, physics and chemistry. But my tutor, my director of studies said, try doing biology. And I thought he was bonkers actually, because I'd never done it. But he persuaded me to take a course. I took it and I loved it. So there's this sort of road to Damascus moment when I'd been a physical scientist up until my late teens. And then suddenly, there's this wonderful course on cell biology, and it changed my life. So I think that was an interesting thing. How did I become interested in frogs? Well, I had these very interesting lectures as an undergraduate from John Gerdin and Peter Lawrence. And they introduced me to the work of Lewis Walpert, who had come up with a model he called the French flag model, which was effectively how do the right cell types form in the right place in an embryo. And it was a rather intellectual approach, if I can put it that way, to embryology. And I loved it. So I went and I did a PhD with Lewis working on the chicken limb. And then after I moved to Boston, Massachusetts for two years, where I worked on PDGF, a particular growth factor, I came back to London to work with a guy called Jonathan Slack and he worked on frogs. And I just realized at that point that frogs are an incredibly powerful model organism for understanding early vertebrate development. At the moment, and in my view, they are underused in that area, but they're incredibly powerful. And I've seen some of the videos that you've put together of those initial cell divisions that take place. And it's really quite captivating. It's really quite magical. It's really quite beautiful. For you as a scientist, when you're looking at those processes taking place, what kind of feelings in you does that evoke? Watching an embryo develop is a beautiful thing, actually doesn't have to be a frog, it can be a chicken, it can be a can be a zebrafish or whatever the process of watching cells divide and move to become from the fertilized egg to become a vertebrate embryo is a remarkable thing. And I love it. And I think, you know, you can see things every time you watch a movie like that, you can see things coming along that you may not have spotted before. Perhaps not so much in the early cleavages of the frog egg that I showed you yesterday, but certainly in the more complicated processes, later stages, perhaps in the fish and the mouse. But it is beautiful. And I love watching it. And there's an element of that. If the word is beauty, that I really do like when I watch embryos develop. And I'd love to understand it. Because things happen in the embryo, you know they're happening, you know, they're about to happen, but you don't necessarily know what's happening inside the embryo that makes them happen. And it's that quest, you know, to understand that that really, you know, keeps me up at night and gets me into the lab in the morning. That quest for basic science is a very powerful driver. I suppose that exists in a tension with perhaps what is expected of the scientific community. So part of your talks title was making a human. And we're talking about frogs. I just wonder if you could comment on the feasibility of transferring that information into realistic therapeutics for humans. Well, I think it's it is real. I think that when I began the work that I began, so I began working on frogs in about 1981. And when we were doing that, initially with Jonathan Slack, and then on my own, I think we paid lip service to the idea that the results we got could be important for human embryology and human health. But I don't honestly know how seriously we took it. But then as time went by, and as we began to understand the molecular basis of how frogs develop, fish develop, chicks develop, and we began to realize that perhaps the most powerful message from the early 1990s is that developmental mechanisms are enormously highly conserved. And in particular, the molecules that drive early development, they're the same. And as we began to realize that, we began to realize that surely the same is is exactly the case in human beings as well. And then when along came embryonic stem cells, and induced pluripotent stem cells became clear that those molecules that we identified in early embryos, would surely be able to drive the differentiation of those embryonic stem cells. And that is entirely true. It's not just the molecules that I found other people, of course, worked on other ones. And cocktails of those molecules applied in different concentrations at different times to embryonic stem cells, it proves you can drive those stem cells down particular pathways. Had I anticipated that 20 or 30 years ago, not really. But when I was doing the work, I really care about that. I was just interested in the problem. I wanted to solve the problem. And I think that was the thing that drove me then and probably still drives me now. I'm delighted that what we've done may lead to helping people. But really, what I care about is just, you know, to share, share, comprehend or whatever it was, you know, I just want to understand. I heard you previously spoken about some of the low hanging fruit as it were being hoovered up in developmental biology. I wonder, from this point forward, what you perceive as being the next steps and what we can realistically expect to see coming out from that space in the near future? That's a really good question. So that hoovering up remark was an interview I did in the journal Development, I think. And there was undoubtedly a period in the early to mid 1990s, maybe towards the end of the 90s as well. When I was doing this work, Peter Gruess was doing this work. And it was an amazing time when it seemed that we were uncovering new principles and new molecules in early development all the time. And when I say hoovering up the low hanging fruit, which is a rather awkward mixed metaphor, but nevertheless, you know, like a management consultant, there are experiments that we could do that we did. And we reached a stage, I think, where we began to have to look a bit harder to find what are the right experiments to do because the easy ones have been done. And I think at the moment, we've reached a stage in developmental biology, this might be an unpopular view with some of my colleagues, but we've reached a stage where we have to take stock and redefine some of the questions we're looking at, use the new technologies that are coming along. And in many cases, sort of circle around the problem, looking for the right way in to solve it. So yesterday, I was talking about one of the challenges I think is growth. And I was referring to the fact that one's left arm is the same length as one's right arm, even though they develop completely independently in the embryo. So that growth is really well controlled. And whilst we know, for example, a certain amount about the interactions that define cell type, so in a leg, it might be muscle, cartilage, bone, tendon, skin and so on. We don't know what defines in the embryo the amount they grow. And I think, to my mind, that's one of the things that I would really like to understand. And at the moment, it's hard to define the question, let alone come up with the right answers. So I see myself certainly, you know, circling around the problem, looking for a way in, finding that it's the wrong way in, perhaps, and then coming out again, looking for another way in. It's an exciting time of biology, but it's a harder one, because there are frequently more failures than success. But those failures shouldn't necessarily be viewed as rank failures. It's part of the process in trying to understand. And I think people need to understand that that's the way science works. It's not simply a question of, and I've heard somebody say this before, not just a question of having a jigsaw puzzle and filling in the pieces. You don't have the photograph on the front of the jigsaw puzzle that you put on the table and put the pieces in. You don't have a picture. You might have the lower half of the picture, but you don't know what the upper half is. And that's the challenging and exciting part. But it will take time. And those people who support science need to understand that it will take time. And the landscape moving a bit more broadly now, at least at the moment, seems to be more competitive than collaborative. And I know you've also spoken about the need for transparency between different lab groups and fostering more collaborations between institutions in the pursuit of knowledge, as opposed to the current incentive structure that seems to almost pit different people against one another. I wonder if you could comment on how the landscape may help or hinder that quest for knowledge? That's a good question. I mean, I've been very fortunate, I'll just say at the outset, when so my career, there was a period where I was trying to purify a factor that was involved in making particular cells in the embryo become mesoderm. And when you do something interesting, and you know, I claim important at that time, there'll be other people working on it as well. And I was unbelievably fortunate that the community of scientists around us then, the international community, were fantastic. So there was someone called Mark Kirschner, who is supportive and friendly. And it was a wonderful environment. We would tell each other what we're doing, support each other. There was a guy called Igor David as well. It was exactly the same. And it was a very supportive environment. And I just loved it. We would go to meetings and we'd tell each other about our progress. These days, so of course, I sound like an old man, as soon as I use the word these days, there is a great deal of anxiety these days about reproducibility, about the competitive nature of science, about the struggles to get your papers into the high impact journals. And I think there are problems along those lines. I do think we need to address those issues. I don't think it's quite what it was. But I do think the concerns are somewhat overstated, actually. And I think that it behoves people like me to lead from the front to say, in fact, as I think I said in that interview that you've just cited, I think that what people need to understand is that if you're supportive, if you share data, if you share reagents, if you tell people what you're doing, there might be a risk of being scooped or whatever. But actually, that risk of being scooped is far smaller than the positive aspects that will emerge from it, which will be the feeling of community, the feeling of working together to solve a problem. And furthermore, as I think I also said, you will make friends. And I think one of the pleasures I've had in my scientific career is that I've made a whole load of friends through science. And you don't make friends by competing with each other and stabbing each other in the back. You make friends by working with each other. So whenever I have the opportunity, this is the message that I will try and send out. And this is the message I will send to my PhD students and postdocs, that, you know, you may be worried about being scooped, but don't be. Because in the end, the truth will out. And that's the important thing. How do you go about funding the best science? So the welcome trust, we are very keen that we do fund the best science done by the best people. And I think there are two elements to it, in fact. One is that we know that the best people will do the best science. So for those scientists who have been around, who have achieved things in the past, who we know have produced good results, we can be confident that they will probably do so in the future. So when we look at those individuals, we fund predominantly the person rather than the project. So this is an expression you will have heard before, probably. It's one that Howard Hughes Medical Institute use quite frequently. And I think it's right. So for those people, we're not going to be concerned about whether they're using the right restriction enzyme in their experiments or whatever. We just need to know, what are they going to do? Because we know from history that they have done well. And I'm generally speaking, as long as they're putting forward sensible proposals, then I would be comfortable supporting those people based on their history. It's harder for younger people, because younger people, of course, first of all, it's very important to support them. And secondly, they don't have the history that I've just referred to for the more senior ones. So for the younger people, we have to be more careful. And I think the processes that we go through, as well as looking at their applications, interviewing them and finding out whether they have good ideas, whether they can respond to changes in circumstances, think on their feet. But most importantly, ask the big questions. So don't just fill in gaps. You need to have a vision, a recognition that you're working on a really important problem. So an example I would give, so earlier on, I was speaking about, for example, the importance of growth in the early embryo. Another one, again, in my own field, would be the question of something like limber generation. So if I took one of your arms and took an ax to it, you know, chopped it off at the elbow, you wouldn't have an arm anymore. But if I did it in a newt, then that limb would regrow. So it's an interesting question to know why does it work in a newt and not in a human being? And I think that, you know, somebody asking the big sorts of question like that, I would be keen on supporting them. But in the end, you have to take a punt. It's always, you know, taking a risk. You never know what's going to happen. And that's the thing with basic science. You never know. And in addition to never knowing, it can take a long time until you find out. If I award you a grant for, say, seven years, and we think it's important to fund people for a long time, then the papers that derive from that grant won't all be published for, say, nine or ten years. And their impact on the world at large won't be known for, you know, a dozen years. So if I were to award you a grant today, I wouldn't know the outcome for 12 years. I think we just have to live with that, actually. I don't think we have much choice. There are other parties involved, however, who may be driven by more shorter term arrangements. So 12 years in the pursuit of a big question may not entirely align with, say, the industry funder who is involved in that work. So when it comes to the academy, industry and government, how do you set up a healthy relationship between those different groups with different priorities? Yeah. So the first thing is, let me say that I'm speaking now on behalf of the Welcome Trust. Thing about the Welcome Trust is that we're a completely independent foundation. And we're not answerable to the government in any way. We're not answerable to people who shake cans in the road for supporting money for cancer, for example. So we're completely independent. And that independence gives us great freedom, but with great freedom comes great responsibility. And one responsibility I think we have as the Welcome Trust is to do things that other funders are not in a position to do. Other funders, I'm talking about funders whose agenda is driven by the government. Those whose agenda might be driven by those raising money for diseases. They may well have shorter term objectives that will lead to specific outcomes more quickly. From the point of view of Welcome Trust, one thing we can think about is we aren't subject in any way to those sorts of restrictions. So we can take that long view. And I personally regard that long view as being very important. Selfishly coming back to my own research again, I began that work to identify the molecules that pass between cells in an embryo. That work began in 1987, 88, I think. And it's really only now, I mean, not quite now, but you know, it's really taken quite a long time until it's come to fruition. And I think there needs to be a funder that has the ability to take that long view. So that's the first thing. As the Welcome Trust, though, we do have other other responsibilities. We can say to ourselves, are there any other areas that are important that other funders are not funding? And in particular, are there any areas of the major health challenges that are important that we think are not being supported properly? And you can think of things like climate change, for example, something that worries me as a parent should worry all human beings. So at the moment, not very many people are funding research into climate change, or doing the policy work properly. And that's somewhere where we can really make a difference so we can invest there. Science is ultimately a human endeavor. It's a process performed by people. Building on what you were just talking about with respect to the people asking the big questions and attracting the best people. How do you ensure that you get a good mix of people? I think first thing to say is that a good mix of people is really important. The evidence for this in science is lacking, but evidence from other areas has shown clearly that a diverse workforce will lead to better outcomes than a narrowly based workforce. And I'm inclined to think that the same is true for science, that we'll get better outcomes from a more diverse workforce. Secondly, I think it's really important for humankind that everybody has access to both a career in science and is able to be able to benefit from the work that is done in science. So what are we doing about it? So I've been involved in the establishment of an organization called Edis, which stands for equality, diversity and inclusion in science and health. And we began this a couple of years ago, really, it started when I was just wearing both a Crick hat and the welcome hat. And so it began with my Crick hat and the welcome hat. And what we had there was a research institute and the research funder. And we very quickly got GSK involved, pharmaceutical company. And I want to pay tribute to Patrick Valance from GSK who was involved early on in that. And there's now the UK's chief science advisor. So it was initially those three organizations. And I was pleased that we had a funder, an institute and a pharma company. And we built on that as quickly as we could. And we've got a terrific person with us called Lillian Hunt working on this who's been terrific. And what Lily has been able to do is to get other funders and other scientific organizations of various sorts on board with us. I think we've got about 16 organizations now. We've got universities, we've got funders, we've got charities and so on. So it's really, really working quite well. And what we're trying to do with Edis is those things that I just outlined. So make sure that a career in science is open to everybody and that everybody will be able to benefit from a career in science. We've had one symposium and another one coming up that is about making sure that research is as inclusive as we can make it. So many experiments are done with just mail mice, for example. Many experiments are done with mail cell lines. Many cohorts are just middle-aged old white males like me. And it's very important that the research we do is as broad as we can get it. So these are the sorts of things that Edis is trying to promote. I think we're doing a good job. I also think if I can make an advertisement, we need more people to work with us on this. I think it's the first group that has taken across, and I hate the word sector, but I'm going to use it across sector approach because different organisations can learn from each other. And I think that's really important. It's a bit like what I was saying earlier about the way scientists should be working together. I think in something that is as important as this, we need to work together. And for people that are perhaps in more junior positions in their career, people who tend to come from those groups, they're quite well represented in science. Someone like myself, what can we do? I think you have to bang the drama along with the rest of us. In the end, I think everybody has to take part. So you're young, you're white. I imagine you're fairly middle class. I don't know. Sounds like it. Yeah. It's a very good looking guy. So I think you just have to join us. You know, I think the leadership in this is really important, but leadership isn't only the older people. It's not just all grey people like me. It's, you know, joining us and banging the drum. I think I think actually that one of the important things is that I think if I've been able to do anything, it's that I've been able to say the things I say and support the things I believe in and to do so from the perspective of being old, white, male, heterosexual and Cambridge educated and all those other things that I am. For me to do that, I think carry is a certain amount of weight because I don't have an obvious vested interest. In fact, on the contrary. So I think to do it from my perspective and for you to do it from your perspective, I think that's the important thing. So it really involves those people who at the moment are in a privileged position in a way saying, look, I know I'm privileged, but there's loads of people out there who aren't. So we need to make sure that they can be helped as well. So we're here on a beautiful island somewhere in the middle of the Pacific Ocean in this. Institute called the Okinawa Institute of Science and Technology. What do you make of OIST? I think OIST is a really interesting and fun place. I think that the thing that I really appreciated on that, you know, the 24 hours that I've been here speaking to people is the breadth of the research and the willingness to engage in multidisciplinary research to have no departments and to make it possible for somebody working on microfluidics to engage with somebody working on imaging to work with somebody working on cells and cellular behavior. And I think that by placing those people next to each other to encourage interactions between them, that is where OIST has a unique selling point, if you like. And I think it needs to make the most of that. I think it's challenging because scientists sometimes can disappear into their own fields and you have to work hard to make scientists broad enough to appreciate things outside their areas. So, you know, it's working well now, I think, but I think if I were to advise Peter Gruess, you know, hardly for me to do. But I think, you know, you have to keep working at it. You can't just throw things together and expect it to work. You have to keep working at it. But I know Peter can do it because I know Peter. So I love it. I think it's really exciting. And since you're giving advice to President Peter Gruess, I'm sure you can provide some advice to this other group I'm going to ask you about now. If you had a single piece of advice for young scientists today, what would that be? It's hard to come up with a single piece of advice because there are so many things that I think are important. But I would say two things. One is what I've already said, actually. And that is that by collaborating, by being open about what you're doing, by sharing data early, that will do you good. Do you good because your experiments will benefit? It will do you good because you'll make friends. And in the end, you know, the thing that I've enjoyed in my scientific career is making friends. So that's the first thing. The second thing is to take your career into your own hands. So. I'm sure that there's great support and mentorship at OIST. And, you know, they're really ought to be. But in the end, it's your career and you have to look after yourself. So don't wait for stuff to happen. Take your career into your own hands. And then putting on my science communication hat. What would your advice be for people communicating about science in a professional capacity? Be honest. Don't try and oversell your data. Tell people why you're doing the work. I'm a huge believer in knowledge for knowledge's sake. I think it's one of the things that makes us human is the fact that we get pleasure from understanding things. And I don't think that's anything to be ashamed of. You know, I know that stuff that we do today that's aimed at understanding life may not have an immediate outcome for humankind. Except that we understand. And I think accumulation of knowledge and understanding, whether it's through science, literature or art is what makes us human. So, Jim, thank you so much for your time today. Thank you very much. Thank you for listening to the OIST podcast. If you enjoyed this episode, please remember to subscribe, leave a review and share it with others who you think will enjoy it. You can also get in touch with us on Facebook and Twitter or by sending an email to media at OIST.jp. Thanks again for listening. We'll see you next time.