In a paper published in Science in 1994, Ralf Sommer and Paul Sternberg provided evidence to suggest that the evolution of organ position in organisms involves changes in the induction and competence of cells. At the time, it was already known that vulva formation in Caenorhabditis elegans happens in the central body region, from adjoining precursor cells, and that it is induced by the gonad. Sommer and Sternberg, through a series of experiments, showed that, even in nematodes in which the vulva is located in the posterior body region, the same precursor cells from the central body region migrate posteriorly and give rise to the vulva. Moreover, in two out of three genera they investigated, vulva induction did not involve the gonad but rather depended on intrinsic properties of the precursor cells. Thirty years after the paper was published, I spoke with Ralf Sommer about the making of this study and the paper, the origins of his interest in evo-devo, and the place of the paper in our understanding of evo-devo today.
Date and place of interview: Via Zoom on 12 February 2025; interviewee was in
Tübingen and interviewer in Klosterneuburg.
Hari Sridhar: I’d like to start by asking you about the origins of this paper. From looking at your Google Scholar profile, I understand that this came as part of was done during your postdoc with Paul Sternberg. Maybe you could talk a little bit about how that happened and what was the context for this piece.
Ralf Sommer: Yeah, so I did my PhD, also already in evo-devo on insect segmentation genes. At that time, we were three labs around the world that had started to do this type of research: Corey Goodman‘s lab in Berkeley with Nipam Patel as a graduate student, Michalis Averof studying with Mike Akam in Cambridge, and myself studying with Diethard Tautz in Munich. And the idea of all of this was really to take the knowledge of Drosophila embryogenesis and see how much can we learn about segmentation processes in all different type of insects. That was a very promising inroad with the problem, because in insects, at the time, we could not really do functional assays. We could clone the genes, we could do expression pattern analysis, but that was it. And therefore, for my postdoc, I was looking for a system in which we would potentially have the opportunity to really get at functional methodology and really understand gene function and their evolution. I attended the Woods Hole course in embryology in 1991, during my PhD, where I met Paul Sternberg. After the course, it was clear to me that that is the system for me to go to, to look with the same logic at vulva development in different species, taking the knowledge from C. elegans as a guideline, and then, from there, branching out to see how these processes evolve.
HS: Stepping back a bit, could you tell us how you got interested in evo-devo and chose to do a PhD in that area?
RS: I am a butterfly collector from school days. That is why I went into studying biology. And I was very fortunate that, very early on in my first university, the evolutionary biologist, the ecologist and the zoologist told me: Don’t come to us, because you already know so much about systematics, taxonomy, phylogeny and all of that stuff; go and train with the geneticist and the molecular biologist and really combine these things later on. And that has always been my guideline. So, here in Tübingen, during my master or diploma studies, I joined one of the labs looking into the developmental genetics of fruit flies. And it was clear from the beginning that I would be interested in the evolutionary aspect of it. They also had an interest in recruiting students with such a background, because, normally, the people that went for developmental genetics, only looked at the flies, or C. elegans worms or zebrafish or whatever. It was very rare, at the time, that there were people that were really interested in bridging these disciplines.
HS: For your postdoc, you worked on nematodes, and nematodes was, already, the study system in Paul Sternberg’s lab…
RS: Right, so I was fortunate that Paul Sternberg himself had an interest in evolution. And he had a person – a postdoc – that collected nematodes. That was for me really lucky. When I arrived in the Sternberg lab, everybody was focusing on vulva development in C. elegans, or neurobiology. Nobody was interested in evolution. But they had this wonderful collection of. nematodes. I even was trained on learning the vulva cell lineage, not in C. elegans, but already on another worm. Paul said, I can teach you this with any worm, so let’s immediately do the first experiment. I didn’t have to go out to the wild and isolate nematodes and then very complicatedly determine what they are etc. We had this wonderful collection of species, and I could immediately use this for my investigations. And the collection was surprisingly diverse, and it had a couple of species that I immediately got tremendously interested in.
HS: In an end note in the paper you describe the taxa you worked on, how they were obtained, and the individuals involved. Could you say a little more about that?
RS: Lynn Carta is the postdoc I just mentioned, who provided the collection. In addition, we obtained strains from Robin Giblin-Davis, a nematologist interested in nematode-insect interactions, and David Fitch. The issue at the time was that much of the classical work on free-living rapid nematodes has been written in German. The ‘pope’ in the field at the time was Walter Sudhaus. He’s still alive. He must be in his 80s, at the Freie University in Berlin, and his PhD thesis from the early 1970s has really been the Bible in the field. And already, when I joined the Sternberg lab, many labs had a strong interest in getting this translated into English, because they simply didn’t have access to much of the primary systematic taxonomic knowledge there was at that time. Walter Sudhaus always refused to write books, but he had many reviews and many revisions of complete genera. But there was another person, István Andrássy from Hungary, who has published a big monograph of nearly 400 pages on free-living nematodes. And luckily for me, he didn’t do this in Hungarian but in German. So, I had, really, primary access to all of the classical works on the systematics, as well as the potential ecological and evolutionary significance and scenarios of these different nematodes. For me, it was a wonderful starting point. I came to Sternberg’s lab, they had a nice collection of species, and I could immediately go to the classical literature and get indications about what type of potential ecological associations these organisms would have,
HS: What was the collection being made for in the lab?
RS: Paul himself had done his PhD with Bob Horvitz, who, later on, was one of the first Nobel Prize winners in C. elegans. Horvitz, together with John Sulston, had done the original cell lineage of post-embryogenesis in C. elegans. And then, when Horvitz started his own lab at MIT, he did big genetic screens, and it was clear that these screens would identify many mutants in which the cell lineage of the worm would be altered. But to interpret these differences, you needed to first understand the lineage. Paul Sternberg was one of the first graduate students with Bob Horvitz, and Bob gave him, as the first part of his PhD project, the cell lineage analysis of another nematode. So, Paul did Panagrellus redivivus in the early 1980s, to teach himself the lineage, so that later on, when they had the genetic screens, Paul could come in and really identify what is wrong in particular cell lineages in certain C. elegans mutants. And actually, this work – these cell lineage papers from 1981 and 82 – were what convinced me to go originally into the worm. That is what I learned when I took this embryology course in Woods Hole, where Paul was a teacher. And it was clear from this work then that we could really homologize cells at the level of individual cells. This was not intuitive at the time, but there was this indication from this one comparative study that this could work. And therefore, Paul always had an interest in different species of nematodes. And then, when this woman came along, Lynn Carta, and asked if she could work with him, he said, yeah, why not make us a collection of different worms? And for me, that was the lucky starting point to really initiate my project.
HS: Where were these collections being made?
RS: This is very simple and straightforward with nematodes. Wherever you are, if you take soil samples, the diversity of nematodes is so huge that you will always get something. The collection at that time was not really comprehensive, in comparison to what we do these days. These were maybe 25 to 30 species. These days, we have hundreds of species in our collections, and we do our surveys in a completely different way. But it was very broad coverage for the time. I had really enough genera to start with different phylogenetic distances to C. elegans. When I started, I had no clue what to expect, but we had to start somewhere. And I got, in the first couple of months, a very good overview what type of alterations are really out there, which aspects are similar to C. elegans, and what is really different.
HS: How did you finally pick the three species for this study?
RS: The majority of the species of nematodes, including C. elegans, have their vulva in the central body region. The most obvious morphological difference in this regard is that there are species that have a posterior vulva. That means they do not form the vulva in the central body region, but in the posterior body region, close to the anus. And because there were also potential cells that could form the vulva there, I thought this is the most obvious question to begin with: How do species with a posterior vulva form their structure? Which cells do they use? That was a very easy and straightforward cell lineage project. And I was lucky that all of the three different genera in the Rhabditidae family that were known to have this phenomenon, were all represented in the collection in the lab.
HS: Could you say a little bit about what it was like to work with Paul Sternberg? What kind of a collaborator was he?
RS: Paul is a great guy. He is still very active. You can really excite him about anything. He always said, I don’t care what you do, but do it right. He was really always pushing everybody in the interest of science. You could go into his office every part of the day and talk science with him. And I must say, I learned that from him, and I do the same thing with my own lab. Paul has really been a big motivator, and has always encouraged us to do our own thinking and go really into diverse directions.
HS: For this piece of work, was his role mainly to provide guidance? Was he involved in doing the experiments too?
RS: No, but he taught me all of the basics. I learned the lineage from him and I did my first ablations with him and some senior graduate students. And then, I would just go into his office and discuss the project: which long-term perspectives we should take, and about the everyday work we could really do. Everybody, and in particular the post docs of course, could do whatever they wanted.
HS: What memories do you have of doing these experiments? I’m asking that also in relation to how you might do similar experiments today.
RS: I must say I was, initially, an outsider in the lab, because I was the only one not working with C. elegans. Many postdocs in the lab, of course, came from a medical perspective, because in vulva development, at that time, people, and in particular from our lab, had figured out that many of the important genes have strong similarities to genes involved in human cancer. So, that meant that many people really came with a genetic molecular background and cancer biology as the long vision. That somebody would come there as an evolutionary biologist, being interested in different worms, was a bit obscure to some of my colleagues. But that turned around relatively early on.
I started in January 93, and the biggest finding that resulted in this paper, I’d already made on April 20 – a little bit more than three months – where I had ablated the gonad of this Mesorhabditis – one of the species with a posterior vulva – and found it had a normal vulva. The gonad was gone, which in C. elegans would mean it would get no vulva differentiation whatsoever. And I still remember this moment – it was completely crazy. The gonad was ablated, I put the worm under the microscope, I look at it and say, yeah, the vulva is there, as it should be. And then I thought, no, it should be gone! And then I looked again, just to make sure I had properly ablated the gonad, which I could easily see was the case. And it was such a fascinating moment. These are moments that you have just a couple of times in your life, where you make a fundamental observation and you know it contradicts all predictions and all knowledge that is there. I still remember, I ran to Paul’s office and said, Paul, I did the Z1-Z4 ablation in Mesorhabditis. “Yeah?” And I said, they have a vulva. “Yeah, yeah”. And then he looked amazed and said, “What? I don’t believe this”. And then we ran to the microscope, and then we immediately knew what that meant. It was clear it would take a little while longer to figure out the complete story, but, as you can see, we had published already in mid-1994, so it all went relatively rapid, from the original observations to having the final story in the final manuscript.
HS: Do you have any recollections of the writing of the paper itself, and how long that took?
RS: As a non-native speaker, I had to learn real English American writings. What was very good at that time was that science was done in a different way. I knew many faculty at Cal Tech very well, also from my Woods Hole embryology course, and I could really go to many of the professors for help. First, of course, we wrote many drafts of it, in particular for the first paragraph and the last paragraph, to put all of this in a context, so that the journal would really see what was the significance of this work. And then, I really had the opportunity to get feedback from many of the top developmental biologists at Cal Tech.
HS: Was Paul Sternberg involved in the writing?
RS: Oh yeah, yeah, yeah. We wrote this thing together very intensely. I remember he sent back my drafts of the first paragraph of the paper eight days in a row, because he was never happy with the Introduction! And because of that, when I read it again last week, whenever I came to a certain sentence, I could still remember exactly what the next sentence would be. It took such a long, intense time to really get that message through.
HS: Do you remember how you made the figures for the paper?
RS: You know, these were very early days of computer programs. In comparison, today, with BioRender, everything is very simple. But I must say, we did not have to spend so much time on figure making like we have to today. And I prefer this to a certain extent. The writing was, of course, very important, because you have to convince your audience that this is an important biological, evolution and philosophical aspect. But the figure representation was, in comparison to today, very simple. All just very basic programs and nothing very special.
HS: What has changed significantly in the way such experiments are done today? What are the most striking ways in which you would do this experiment differently, if you did it today?
RS: This type of research is no longer done. At that time, no matter if we were doing evo-devo approaches or trying to understand the underlying regulatory principles, we worked with single mutants, right? There was no way, in nematodes, of doing biochemistry at the time. There was, of course, no way of doing a complete transcriptome. Therefore, we had a completely different methodology from what we are doing today. There is no way of comparing the two. At that time, if you would want to do some basic biochemistry, you had to collect worms in big flasks, given how small the worms were. These days, we can downscale all of these approaches. You know, just before we started this interview, I did an experiment with my technician, which a couple of years ago would have been impossible. You need so little input these days, such that all type of biochemistry is becoming feasible. And all type of ‘-omics’ you can do from a single worm. We can sequence the complete transcriptome from a single worm, something that was completely out of reach at the time. That has, of course, influenced the science so much that we now ask completely different questions from what we did at that time.
In the early days of evo-devo, with the very molecular and mechanistic background from Drosophila segmentation and embryogenesis in mind, the idea and hope was that one could pinpoint certain morphological transitions to particular genes or gene activities. With the development of these new technologies, questions have been revised and a genome-wide perspective became possible. This is something that was simply not out there in the late 80s and early 90s. Like in other areas of modern biology, the single gene and mechanistic questions have been replaced by genome-wide, more systemic, approaches. This has resulted in different questions being asked and being addressed over the years.
HS: I want to go over the people whom you acknowledge in the paper, just to get a sense of who these people were, and what they contributed to this paper.
RS: Lynn Carta was the nematologist. David Fitch was an early colleague at NYU – New York University – who had a long standing interest in nematodes and evo-devo questions. He had joined Scott Emmons’s lab in New York as a postdoc earlier and had just gotten his first faculty position. David worked on male tail development. Nematodes occur in two sexes – either females and males, or hermaphrodites and males – and males have to mate. Morphologically speaking, male tails are the most diverse structures, which the male uses to sense the female or the hermaphrodite, or grab it to initiate matings. The problem was – and this is why I didn’t choose to study them at that time – our understanding of the molecular processes was not comprehensive enough. In Drosophila segmentation, or C. elegans vulva, we know the gene regulatory networks quite well. From there, we can start to figure out what has really changed during the course of evolution. You first want to see a deviating morphological pattern -e.g. a different way of making the vulva at the cellular level – but at the end of the day, you want to connect this to the underlying genetic and molecular principles. This has always guided my choice of research topics. That is why I picked the vulva. But David was interested in other aspects, and therefore he picked ray formation in the male tail.
HS: You thank him for strains.
RS: Yes, he also had a strain collection. We have obtained strains over the years to have a more comprehensive collection. And we have always exchanged strains, in all directions, to make sure that all of our collections are as comprehensive as possible.
HS: The next name is E. Davidson.
RS: Eric Davidson, Scott Fraser and Elliot Meyerowitz were professors at Cal Tech. Eric Davidson was the director of the embryology course in Woods Hole that I had taken. So, I had, since the early 90s, detailed interactions with him. Scott Fraser is a microscopist, and was also a teacher there, and I have always discussed my project with them. That was really something that was very fortunate at Cal Tech, namely, that you could really step into other professors’ offices and really talk with them about your project. Elliot Meyerowitz is a plant developmental geneticist. He was a floor down, and with him too I had detailed interactions.
HS: L. Zimmer
RS: We met her at conferences early on. She has seen early drafts and then was interested in really looking into early drafts of our manuscript before we finally submitted it to the journal. Yeah.
HS: In the last line of the acknowledgements, you say you were supported by an EMBO long-term fellowship. Can you say a little bit about this what this fellowship was for?
RS: EMBO is the European Molecular Biology Organization. In the long-term fellowships, they basically provide you with funding for two years to go abroad. That is, still today, but already at that time, the most prestigious fellowship here in Europe for going abroad. You submit very short applications, and then, if you’re shortlisted, they invite you to an interview. So, I had to go to Cambridge (UK) to meet Jonathan Hodgkin, who was a very respected senior C. elegans geneticist, who also had some interest in evolution. I still remember that interview. It was at the LMB in the hospital outside of Cambridge. The interview was in the coffee room for whatever reason – I think they expected that nobody would come for an evo-devo talk – and then we had, I think, 60 or 70 people in that coffee room. People were sitting on the floor! I had to present my PhD work with Diethard Tautz on the evolution of segmentation genes. And that was really a fascinating thing. My major paper from my PhD was at that time under revision at Nature, and my suspicion was that somebody from Cambridge was the reviewer that was really in charge. And that was Mike Akam, who even came from downtown Cambridge to my seminar. So, I gave my talk, followed by the discussions, and then later on had my interview with Jonathan Hodgkin. Jonathan said, I will promote you as much as possible; I don’t know if it will work with the fellowship, but we will see. But before I bring you back to the train station, Mike Akam wants to talk to you. So, he brought me to Mike, I sat down in his office, and Mike said, Okay, I believe the story now. It will be accepted! And then, I actually had my Nature paper accepted and my EMBO fellowship selection within 24 hours. On Thursday, I got my Embo fellowship, and on Friday, I got the paper.
HS: Do the EMBO fellowship selections still happen in the same way?
RS: Now we do it by zoom. I’m an EMBO member. About two months ago, I had a Zoom interview with a candidate, which is not that nice. You save money, obviously. It is no longer that complicated. In my case, it was all done on very short notice, and so I had to book a very expensive flight to London at the time. But it had, of course, this personal aspect, which is fundamentally different these days.
HS: Was Science the first place you submitted this paper to?
RS: It was the first choice. And in retrospect, it went in extremely easy.
HS: So, the peer review was smooth?
RS: It was very straightforward. But I must say, that was, of course, different times. The C. elegans community was much smaller. So, I had presented this work already in June 1993, six months after I joined Sternberg’s lab, at the International C. elegans meeting, which at that time was in Madison, Wisconsin. Completely different from these days. We had 700 people! At that time, really, more or less everybody would attend the meeting. We had three poster sessions where you would always be in front of your poster. And, actually, every C. elegans PI had seen this work before it was submitted. And we had, at that time the Worm Breeder’s Gazette, where you would publish a one-page abstract of your work before you would submit it to a journal. I still don’t know who the reviewers of this paper were, but it is super likely that this person already knew about the work, because they had seen me at my poster, and they had read the Worm Breeder’s Gazette abstract. That, of course, makes a difference, right? And, for me, I was not in competition with anybody. People were happy that finally somebody was doing evolution in nematodes. They said, that would not be my thing, but it’s great that Paul does it! And therefore, this was an ideal starting situation.
HS: Say a little more about the Worm Breeder’s Gazette.
RS: At that time, C. elegans research was always a community effort. It started small, and at the time the people would really try to share their reagents. Or, if you find a certain allele of a gene or a certain phenotype, and if you were not necessarily interested in this yourself, you would write a very short abstract about this in the Worm Breeder’s Gazette. And then somebody would write you a letter, or later on an email, and say, Can you please send me that strain? It was really a community effort, because there was so much to be done in the early days.
HS: Has it changed now? Does the Worm Breeder’s Gazette still exist?
RS: No, it doesn’t exist. The competition is higher. The projects are more comprehensive and bigger, and it is, of course, now, a completely different way of doing science, than it was in the in the old days. There are so many labs. We have more labs than cells in C. elegans, so therefore, by definition, the competition is higher.
HS: When the paper was published, do you remember if it received any reactions? Did people reach out to you?
RS: For me, the response was really overwhelming. I was already, at that time, on the job market. I, of course, wanted to return to Germany, sooner or later, and I knew that for this type of work I could only go to the Max Planck Society. At the university, all of this would have been complicated. Nematode research is very cheap once you have the starting microscopes and big equipment that you need to begin with. That would have been very complicated to get at a university, so therefore I aimed at the Max Planck Institute. And the only Institute where I could see a future topic-wise was the institute where I am right now. They had two group leader positions, and unfortunately, they were vacant at the same time. So, the advertisement was in November 1993. I went to Paul, and I said, What should I do? I don’t have a paper. I only have a Worm Breeder’s Gazette abstract. He said, Yeah, apply. I was 11 months into my postdoc when I applied for the job. I had no paper. I sent them the manuscript that we had submitted to Science. And, surprise, surprise, they invited me for an interview. They had two open positions, one was fixed for Drosophila, and I was one of three other candidates. And, actually, what had happened with my Nature paper and the EMBO interview happened there again. I got the job on a Thursday, and, on the Friday, I got this paper accepted in Science. So, these were the most spectacular weeks in my life! No, the recognition was there immediately, because it was something novel. Evo-devo was going uphill anyway – it was still a young field – but this was the first time that this was done outside of insects, but in a system where deep molecular knowledge was available. And then, the fact that we could really show you can homologize cells between multiple species over large phylogenetic distances was something really revolutionary. Here, in Tübingen University, one of the chairs in zoology, Wolfgang Maier, who was a mammalian anatomist, at his birthday party when he turned 80, just a couple of years ago, told me again, When you arrived here and told us that you can homologize single cells, I thought this is impossible. He came from the vertebrate skull and worked on anatomical structures, and there comes somebody who says, Oh, no, you can homologize a cell over hundreds of millions of years. I think, the impact of this people saw immediately.
HS: In your next job did you continue the work in some way or did you switch to doing something different?
RS: No, I did not continue with the species. In the paper, we argued that, most likely, Mesorhabditis is a hermaphrodite, but it turned out that it is parthenogenetic. It was then clear that one could not really address this question at the molecular level. So, the open questions in the last paragraph of the paper we have still not addressed until today, because there is simply no model system that one could develop, in a nematode with a posterior vulva development, so that we would get at the underlying molecular principles. But, in parallel, already when I was working on this paper, a second nematode turned out to be even more promising. That is what we do today. This species, Pristionchus pacificus, belongs to a different family. It’s even more distantly related than the others. It is a hermaphrodite. It shares many of the technical features with C. elegans. So, my group has really developed this as a second nematode satellite model organism, where we have, by now, all, or nearly all, the methodology as good as in C. elegans. Vulva formation, again, was fundamentally different, but with different types of changes. We studied that in great detail during my time as a group leader. And then, when I became director here at the institute, we continued this for the next 10 years. These days, we study something fundamentally different. We work on developmental plasticity because, this nematode, Pristionchus pacificus, although it is a hermaphrodite and the animals are genetically identical, has two different mouth forms. They have to decide, during post-embryogenesis, if they want to be a bacterial feeder or potential predator of other nematodes. And we are now studying the underlying genetics and the ecological and evolutionary significance of developmental plasticity for evolutionary novelty.
HS: Did you discover this species when you were doing your postdoc?
RS: No, this species was in the Sternberg lab collection. It had been isolated by high school students. Associated with Cal Tech, is the NASA Jet Propulsion Laboratory (JPL), and they had a program for worms in space. The person who was running this program at the time was interested in isolating nematodes. With high school students, they had taken soil samples from downtown Pasadena, and one of the soil samples contained the species that we are now working with. It was isolated in 1988. Nobody had looked at it. And when I joined the lab, in the first week, I thought, from all of these nematodes, this here is the best growing. And it was clear it was a hermaphrodite. I did the cell lineage early on, and it had completely different vulva differences to the other species. And then Paul said, do they form males? And I said, yeah, there are males on the plates. And then he said, Do they mate? I did a cross and said, yeah, they mate. And then after a year – before this paper was out – he said, do a mutagenesis. Let’s see if you can really generate mutants. And I did a mutagenesis and everything worked. From day one. And it was very soon clear that this species would be much, much better. And now we are still working on this. We have a huge community. I first – this I have to say – had to describe this species, because it was new. So, I have the description paper for Pristionchus pacificus. I’m very proud of this. The journal in which it was published no longer exists, but that doesn’t matter! And now, we are a community of around 30 labs worldwide, all studying Pristionchus pacificus and its different ecological associations. Two years ago, we had our first in person international Pristionchus meeting here in Tübingen, and we had around 30 PIs. I have always followed the idea that my postdocs should take their own project with them, like I did it with Paul. So, my postdocs have worked on different aspects of predation, sensing of other nematodes, and all type of behavioural aspects, and now we are a big community which studies the various different aspects of this system. We have, by now, a couple of C. elegans PIs that have joined the Pristionchus efforts. This, for me, was always a bit frustrating, because I would have loved that this had happened earlier and faster. But now, we are really a good community, with methods developments and international Pristionchus meetings.
HS: I read somewhere that you now have a field station.
RS: Yes, we have a field station. That was another reason for picking Pristionchus as a model. The ecological association was given in the classical books as beetle-associated. You can isolate them from soil samples, but very often they are associated with scarab beetles. And then, when I became director here at the institute, I hired an entomologist, Matthias Herrmann, to look at this in more detail. And we have now done worldwide samplings and understand things in great detail about the phylogeny of that genus and beyond. We have an island in the Indian Ocean where we have very, very high infestation rates, and that allows us really to look at the ecology of this mouth form plasticity, and we tie this up with modelling. I just came back two weeks ago from our last field trip, where we have collected 800 beetles, brought them back alive to Tübingen, and then here in the lab, we kill them, and look at the very early steps of the decomposition process.
HS: What do you see as the place of this paper in the literature on the topic? Why should someone read this paper today?
RS: That’s a very good question. My students, with our switch in interests will, of course, no longer read these type of papers, because we are not doing things in the developmental cell lineage context. But I think it is a historical paper, because it really opened the door to fundamental evo-devo cell lineage based research in different nematodes. When I proposed this, it was not clear that that would work, right? When I did my EMBO interview with Jonathan Hodgkin, we both had to say, we don’t know if this will work. We don’t know if it will work, and if it works, we don’t know what I will find. And we can only formulate the questions once we know what type of changes are out there. So, that EMBO fellowship proposal, when I read it today, I see that we got everything wrong. Our anticipation of what type of pattern changes we would find was completely off. We found something completely different. So, what is in this paper – that we have difference in vulva induction and the different competence of cells – we would have thought is impossible. We had completely different ideas on how evolution would take place. Actually, one should write a commentary on about this, because our ideas at the time were fundamentally different. So, when I wrote my proposal, I had something completely different in mind. One other reason why I went into nematodes is that people in C. elegans had established DNA-mediated transformation. You could stick a needle into the gonad and you get transgenic animals. And that was, for me, another reason to go to nematodes, because I thought, oh, that will work in every species, right? Once you have the protocol, that is very straightforward; if you don’t kill the nematode, that will work. At the same time, I was sure forward genetic screens will never work. And it was completely the opposite. It took my lab 10 years to develop a DNA-mediated transformation in Pristionchus, while forward genetics was a piece of cake, and very very straightforward. Which tells you – and I follow this today when I evaluate proposals – one has to trust researchers more. If you see that a proposal is sophisticated, and that it’s really an important philosophical question, then one should give people the benefit of doubt and say, Yeah, let’s try it, work it out. If you find a host lab to do this, go there and do it, work hard, and then you will see where you go. And then always think back, and that is what I have done every month during my postdoc – I have revised my proposal depending on what I was finding. I wrote something in that EMBO proposal, but it was clear after six months, the project is going into a completely different direction based on what I had already found.
HS: You’ve published hundreds of papers. Is this paper one of your favourites?
RS: I think, with Paul I had 10 papers. In retrospect, the description paper is, of course, very important, but we couldn’t know what would come out of Pristionchus, at the time. For me, I would say it was my Number Two paper with Paul. Number One would be the one, later on, on Pristionchus, where we already, in the first paper, showed that we could isolate mutants. We could not only show the cell lineage difference for vulva development between Caenorhabditis and Pristionchus, but we could show that we could isolate mutants that would tell us what the differences were. We also sent that to Science, but they didn’t take it. They said, If you show the mutants, you have to clone the genes. That was, of course, impossible at the time, and it took us a couple of years more to get there. So, I would put that paper on top, because it would have been, when I started my postdoc, unthinkable that, within 15 months, you can show differences with regard to morphological structures at a cellular level, and you can already isolate mutants, which might pave the way on understanding what the underlying regulatory differences are. The shortcomings of this Science paper, unfortunately, is that, given the mode of reproduction, until today, not us and nobody else was able to really follow this up, to really see the underlying molecular logic. But for a long time, I must say, when we were doing our nematode hunting, I always said, if one day we will find a Mesorhabditis that is a hermaphrodite, I would be willing to go back and really try to figure out how that works, by doing appropriate genetic screens. But, unfortunately, that has been impossible. Still, for me, this Science paper is one of my top five to top 10. It’s always hard to say – I’m close to 300 or so – but it is, for sure, one of the top papers, in particular for my career.
HS: Since you said that the Pristionchus description paper is one of your favourites, can you say a little more about it. This must have been completely different from all the work you’d done till that point. How challenging was it to write such a paper?
RS: Fortunately, we had Lynn Carta, the nematologist, who did the description part. Description papers in nematodes are very, very strange. You take measurements, you make drawings. The sentence structure for morphology is not even full sentences. It’s a different type of language, which is, however, very precise in its nomenclature. And, Paul and I, we couldn’t even judge this. The paper has three parts. It has the molecular part, it has the morphological description – we show that we can isolate morphological mutants – and we have some basics on the biology – six chromosomes, we have DAPI stainings of the chromosomes in there, we say roughly how big the genome is. And I still remember that the journal sent this paper out to three different reviewers, who were all experts, either in taxonomy or in genetics or in molecular biology, and they all came back with their reviews and said, I can only judge one-third of this paper.
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