Valerie Wilson is Professor of Early Embryo Development and a group leader at the Centre for Regenerative Medicine at the University of Edinburgh, UK. Val's lab works on the development of the vertebrate head-to-tail axis, focusing on the differentiation potential of axial progenitors. In 2022, she was awarded the British Society for Developmental Biology's (BSDB) Waddington Medal, which recognises outstanding individuals who have made major contributions to UK developmental biology. After her award lecture, we spoke to Val about her career and heard her thoughts on the past, present and future of the field.
Let's start at the beginning: when did you first become interested in science?
When I was five, I was writing stories and I drew two pictures. The captions of the two pictures were something like, ‘this cat has five legs; it is ill. This cat has four legs; it is well’. I like to pretend that that's the dawn of my interest in development! But I actually didn't know that I was interested in embryo development until much later. I went to University in Glasgow and I chose to do biology because I believed that biology was easy, and I did chemistry because I was interested in chemistry. My first classes showed me that biology is not easy. It's not just describing and learning names but also trying to work things out, so that made me pay more attention. Then, learning genetics, when you could predict something from the information that you had, that really started to get me interested in biology. I had a bit of a formative summer between my second and third year. I spent 2 weeks in my dad's office as a management consultant's assistant. Straight after that, I spent 2 weeks in my uncle's lab, Andrew Wyllie, who first described apoptosis. I was just following people around and watching basic lab techniques but I was just in complete awe. I thought, ‘there's no way I am ever going to work in an office!’ It was so much fun! My uncle was a really inspirational person, but there was also something about the lab environment that I liked.
You studied with Martin Evans in Cambridge for your PhD. What attracted you to working with embryonic stem cells and could you summarise your research projects during that time?
At the time I went to Martin's lab he had just published a Nature paper on genetically modifying embryonic stem (ES) cells (Kuehn et al., 1987), part of the work for which he was eventually awarded a Nobel Prize. They had successfully isolated cells that lacked a gene called Hprt, which is on the Y chromosome so you only needed to mutate one allele. As an undergraduate, I thought that was interesting but I don't think I was quite aware at the time of just how world-changing it was. Joining Martin's lab was also partly the lure of being in Cambridge. I had also been interviewed in Edinburgh but I liked the idea of Cambridge and Martin's lab.
When I joined the lab, Martin said, ‘you have complete freedom – just target a gene!’ So what do you choose? At the time, because people had managed to target one gene, it seemed like we could do literally anything. But there was a very long frustrating period in which everyone was trying to target genes like crazy but it wasn't very efficient. I remember Andrew Furley talking about screening thousands of clones – and not with any robotic help. He was just doing Southern blots on thousands of ES cell clones to try and find one targeted clone. We didn't know at that time that isogenic DNA from the same inbred strain (so there are no basepair changes) was important, so, of course, that made targeting very inefficient. I was trying to target a Hox gene using a nifty little promoter-trap strategy. It had worked with the Hprt gene, but Hrpt was actually expressed in the ES cells – Hox genes were not! Looking back, it was never going to work! However, I learned a lot about how you handle ES cells. We did some replica plating with ES cells that worked, but that was the only publication at the time from my PhD thesis. By the end of my PhD, I didn't feel like I was much of a scientist and I almost didn't think it was worth going on in science. It was actually a postdoc in the lab, Catherine Boulter, who said, ‘I know Rosa Beddington is looking for a postdoc – why don't you try?’ But that's probably your next question.
By the end of my PhD, I didn't feel like I was much of a scientist and I almost didn't think it was worth going on in science
Yes, what attracted you to join Rosa Beddington's lab, initially at the Centre for Genome Research in Edinburgh?
I wouldn't have had the self-belief to go for a postdoc position if it hadn't been for Catherine who encouraged me to apply. I think by that time I knew that I was interested in developmental biology. I hadn't done much development in Martin's lab but whenever we did anything embryo related I knew that this was something fascinating. So, I went to an interview with her. I was ready to say ‘yes’ when she offered the position. During the interview, she just asked some standard questions and then she seemed to run out of things to say to me. She asked if I wanted to do some DNA preps and we sat side-by-side and did DNA preps – not an interview strategy I'd ever experienced before! So when I got offered the place in Rosa's lab, I was happy to go. When I went to join, she was just about to move from Oxford to Edinburgh.
You said in your award lecture that you didn't want to do any more gene targeting, so how did you decide on a project in Rosa's lab?
Rosa just set me off on a project that was to look at the brachyury (T) mutation, which she had recently got interested in and were actively making ES cell chimeras. But, actually, the very first thing that I did was to look at primordial germ cells (PGCs) in brachyury mutant embryos just by staining them with alkaline phosphatase. We were looking at PGCs because the place that they form, the allantois, is very strange in brachyury mutants. The question was: were the PGCs there? I saw that there are fewer PGCs in brachyury mutant embryos, but this was just one of these pieces of work that never really found a home in a paper. Until 2021 that is, when Carolina Guibentif, Bertie Göttgens and John Marioni (Guibentif et al., 2021) asked for some help in interpreting their data on single-cell RNA-sequencing of brachyury mutant embryos. My contribution – apart from commenting on stuff – was to add that first postdoc data. Going back to my postdoc work in Rosa's lab, there was also a need to make chimaeras between brachyury mutant ES cells and wild-type embryos, and because I could do blastocyst injection, at least I could do that.
You did in fact end up at the NIMR after Rosa moved her group from Edinburgh to Mill Hill in London. How was the experience of moving between labs and institutes?
I love Edinburgh but at the time the NIMR was also really special. There were many postdocs, a very intense scientific environment and it was just huge fun. Maybe it's always been like that, but I went into an environment that felt very much above the level of where I was. In Rosa's lab itself, there were a bunch of other postdocs and students who really stretched my knowledge and understanding. I spent months just absorbing everything before I felt like I could really contribute. It was very exciting – very stressful – but very exciting. I think it was a very special place.
You then moved back to Edinburgh to establish your own group. What influenced your decision to go back to Scotland?
When Rosa left Edinburgh, Bill Skarnes, one of the mind-stretching postdocs I mentioned earlier, stayed and set up his own lab there. During my time in Mill Hill, I went back to Edinburgh for a brief period to make some gene-trap mutant ES cell lines. My idea was that I would pick out the axis development mutants and work on those. During that time in Edinburgh, I thought ‘I would like to be here’. Something about the fact that there's a high enough concentration of people that are interested in developmental biology: people are interested in mouse, stem cells, regeneration, that sort of area – and I just love Edinburgh.
Would you advise early-career researchers to consider the research environment when choosing positions?
When I first went to Edinburgh, I worked in a place called the Molecular Medicine Centre, which was just across from the Human Genetics Unit. The Human Genetics Unit was headed by Nick Hastie and had a lot of people that I liked very much, which attracted me there. But in the Molecular Medicine Centre, I was in a lab called ‘the hotel space’, which was for career development researchers who weren't attached to a lab. It was very tough to sit there on my own without a bunch of people around, looking at my computer and thinking that if I don't do something, nothing will happen. I had a career development fellowship from the MRC, so there was money, but I had to set up everything and that was hard. That sort of environment might suit some very focused people but that was not an atmosphere that was great for me. There was one other career development fellow who worked on cystic fibrosis; other than the fact that we were both early-career researchers, we didn't have much that we could chat about. It was quite isolating. I think it makes a big difference to be in an environment where there's plenty of interaction.
Can you summarise the main research themes of your group at the moment?
We are still trying to work out what makes neuromesodermal progenitors (NMPs) move from one state to the next. If we know what makes them do it, we can stop them at one place and make cells of a defined phenotype. We also have a project I'm also quite interested in. Sitting right beside the NMPs are a set of lateral mesoderm progenitors that the NMPs interact with but have completely different dynamics. We are trying to understand these lateral mesoderm progenitors and what makes them tick. We're also trying to understand the origins of endothelia, which I think may be a little different from what's been published. I'm hoping that we'll be able to say something new.
I got the impression from your lecture that you enjoy the technical aspects of research, such as grafting and blastocyst injection. Why is that so appealing to you?
I just really like looking at embryos. I feel that it's something that I can do and I like to be able to contribute. I love looking at data, but it's quite nice to be able to have some practical input too.
I just really like looking at embryos. I feel that it's something that I can do and I like to be able to contribute
You've incorporated both in vitro and in vivo techniques and approaches in your research. How important do you think it is to have complementary model systems?
If we're going to make any headway with human systems, for example, we need to use in vitro techniques; but also I think there are things you can do with cultured pluripotent cells that you cannot do in vivo. For example, you can grow loads of cells and easily film individual cells; you can look at things in 2D that you can't easily see in the 3D embryo. But I think if you only go for in vitro and you don't have the embryo in mind, you might be looking at something that cells can do; but what relevance does it have to what cells actually do in embryos?
Anterioposterior axis elongation has been a common thread throughout your career. If you hadn't followed this path, what do you think you might have studied instead?
For quite a long time, until well after I was a group leader, I thought that I was doing what I thought was fun in preparation for finding my mission in life. I was planning on doing this work on the anterior-posterior axis thinking, ‘I love this, but it's not useful’. I wanted to be of some use in society and that was often in my mind. If I was to start again, I might try to do something a bit more relevant to the world. That's not to say this research isn't relevant – I'm much more reconciled to the fact that it has helped our understanding of biology fundamentally. I thought if I wanted to be useful and be a scientist, then I would be an epidemiologist and go into public health. Interestingly, one of my fantastic grafters, Noemí Cambray, took that complete career change and went into global health. Maybe, if I had the courage, I might be an epidemiologist. I think that if you wanted to improve health you can't do it at the level of CRISPRing everybody that has anything wrong with them, you need to change behaviours, and I think epidemiology might have the biggest impact.
What is it about the axis that has held your interest throughout your career?
I like the axis. I like the fact that the vertebrate axis is so diverse yet so conserved; there's huge conservation and yet the ability to play with it. Out of this basic vertebral pattern, you can make a tiny axis (an adult frog has about six vertebrae) or you can make hundreds of vertebrae in a snake. It's amazing that there's so much plasticity. Not just in the number of vertebrae, but in the identities and the size of the vertebrae too.
What are the ‘big questions’ and what research excites you most in the field?
It's interesting that NMPs now seem to be something that people talk about. I thought I was just working away in a niche by myself quite happily but now there actually seems to be a field and I'm quite excited by that! I love the fact that people are looking in such detail in imaging to see how cells interact. I think it's really exciting that people are applying this knowledge to various systems, including gastruloids, and it seems to have helped understand what's happening in an embryo, in a gastruloid and various other organisms. I think there's a lot of interesting research at the moment looking at the timescale of developmental events, and also at the sub-cellular level, such as forces in cells and cellular organelles. I'm also excited by work on deconstructing and reconstructing cells, tissues and embryos. I think our lab will move into using organoids and micropatterns to understand a bit more about self-organisation.
I thought I was just working away in a niche by myself quite happily but now there actually seems to be a field and I'm quite excited by that!
Who have been the significant mentors that have influenced you and your career?
Rosa was probably my first mentor in embryo development. She was fierce and I was quite scared of her – as many people were – she was very fond of making pronouncements about what people should or shouldn't do. But she was also completely inspirational. She loved embryos so much and it was good to find somebody who had that passion for their work. She gathered around her people that were similarly interested in embryos and she was just able to make that passion blossom. She could also be very encouraging – at times(!). She said that I'd done something good when I did my first graft and that really encouraged me to keep going.
The other person I would like to mention as a mentor is Austin Smith. He was just a fantastic boss. After 2 years in Edinburgh at the Molecular Medicine Centre, I got a lectureship and went to the Institute for Stem Cell Research (ISCR). Austin was head of the Institute there and he was just amazing at pointing out ways to go in new directions. He was so thoughtful on other people's behalf – he just couldn't have been better.
This year, you have been awarded the BSDB 2022 Waddington Medal for outstanding contributions to Developmental Biology in the UK. What does this award represent to you?
I wasn't expecting to be nominated and I certainly wasn't expecting to win it! It's just an amazing honour.
What do you consider to be your greatest contribution to the field?
I feel very proud of the paper that showed that single progenitors make neuroectoderm and mesoderm (Tzouanacou et al., 2009). I should say that Elena Tzouanacou was just incredible at putting the thinking together for that paper. I feel like I helped but I think the combination of the three of us (myself, Jean-François Nicolas, who contributed a lot of the theory, and Elena, who was so meticulous in her descriptions and her razor-sharp logic) worked very well. Elena said I taught her to really look at the embryos – turn them around and look at them properly.
Finally, is there anything Development readers would be surprised to learn about you?
I did my own personal developmental biology project a bit late in life, at age 48, when I developed a daughter.