Transitions in development – an interview with Amy Shyer and Alan Rodrigues

Alan Rodrigues (L) and Amy Shyer (R)

Let's start at the beginning – when did you first become interested in science?

AR: I was inspired by my parents, who are healthcare practitioners. I think I saw science as a way to better understand the human body and health.

AS: The origin for me, I think, was being a teenager and wanting to understand what was going on in my brain. Initially, I got interested in psychology and then realised that I wanted to understand the underlying biology, which led me into an undergraduate degree in psychobiology (similar to a neuroscience major).

So, Amy, how did you move from neuroscience into developmental biology?

AS: As an undergrad, I worked in a neuroscience lab, using a Drosophila model to study synaptic transmission. After college, I wanted to spend some time working in a lab full time as a research assistant, and I was looking for positions close to home in the Bay Area in California. I initially applied to Arnold Kriegstein's lab (a neuroscience lab); he'd just hired someone but told me about a new lab setting up next door that was looking for a technician. This was Jeremy Reiter's lab, and I ended up becoming Jeremy's first tech. I hadn't even taken a course in developmental biology as an undergrad but when I started dissecting mouse embryos, I was totally won over by the beauty of the embryo, and so I started exploring options for graduate training in developmental biology.

What about you Alan – how did you come into the developmental biology field?

AR: I came to developmental biology indirectly. I was a chemistry major as an undergraduate, and throughout most of college I was planning to go on to medical training. But I then got interested in systems biology, in thinking about how you could move beyond reductionist approaches to science and medicine. I chose a PhD programme at Harvard and I rotated through lots of different labs, but it dawned on me at some point that development is such an obviously systemic phenomenon and that's how I chose to pursue developmental biology. I have to say that a big part of this realisation was Cliff Tabin – when I read his work, it was clear that he had a big-picture, and therefore systems-thinking-friendly, approach to development. It felt like he was very conceptually driven, and this was a big draw for me.

You were both PhD students in Cliff's lab. Can you tell us a bit about what each of you worked on there?

AS: I came in excited about morphogenesis – I was really interested in shape and pattern, and I really fell in love with Cliff's lab from day one. But to be honest, I also came in swept up in some of the trendy ideas in development at the time. This was around 2008, and non-coding RNAs were really fashionable, so I said to Cliff that I wanted to work on microRNAs. And his response was, ‘sure, you could do that, but we've got this really interesting work on intestinal morphogenesis going on at the moment – why don't you take a look at that?’. The person who mentored me during my rotation, Natasza Kurpios, was such a warm and engaging mentor, and the project was incredibly exciting – they'd opened up the space to consider that there were mechanical processes at the root of the pattern of gut looping in the chick. They already had a collaboration underway with L. Mahadevan (an applied mathematician) and it was such a great opportunity to work with that group, so this was what I ended up working on. After the project on gut looping, I tried to carry the ideas forward to explore the pattern of villi morphogenesis, and then finally I started to consider how shape and geometry might feed back to how the stem cell population is isolated to the crypt later in development.

AR: I joined Cliff's lab a year after Amy, and she was really pioneering this new focus of the lab on mechanics, which – at the time – was still kind of niche. Coming from a chemistry/biochemistry background, and with an interest in systems biology, I was interested in the idea that, in order to understand a system, you would try to reconstitute it. I wanted to explore whether you could do some sort of cellular reconstitution or develop ex vivo or culture systems to allow us to study some of the questions Cliff had been working on for a long time. Things have changed a lot now, but, at the time, there was a lot of scepticism about studying development outside the embryo. It turned out that Cliff had been trying to get someone to develop culture systems for limb progenitors but was struggling to recruit anyone to do this for their entire PhD. It was a great match that changed the course of my life. So, much of my PhD was focused on trying to develop methods to stabilise progenitor cells, which to this day get far less attention than embryonic or adult stem cells, in vitro. Inspired by the reprogramming field, I used similar methodologies to uncover the minimal subset of transcription factors that were crucial for defining limb progenitor identity, and also worked on understanding how Hox gene expression within progenitors responded to exposure from multiple signalling pathways at the same time. I didn't plan for it, but I also gained an intuition for culturing primary progenitor cells that helped enable the ex vivo platforms we use in our lab at Rockefeller.

Did you start collaborating already at that point?

AS: During our PhDs, I'd say that there was at least a length scale between us in terms of our interests – I was very much focused on the tissue scale, whereas Alan was working at the molecular and cellular level. I would do Alan's cryosectioning, and he'd do my qPCR, and when we became partners, we obviously supported each other through our theses, but there wasn't yet an overlap in our work conceptually.

AR: But by the end of my PhD, I had come to the feeling that if you want to really understand development, you need to go beyond just how a cell perceives and processes information – you had to come up with a view of things beyond just the cell. But at the time, the focus of the field was still very much on molecular-level mechanisms (e.g. gene regulation and signal transduction) and it wasn't clear to me how Amy's work on tissue scale mechanics was going to come together with this body of literature. The two perspectives sat next to each other without clear conceptual coherence.

Amy, you moved to Richard Harland's lab at Berkeley for your postdoc. Why did you choose this lab, particularly given that you continued to work on the chick, which isn't Richard's main system?

AS: I wanted to continue working on mechanics and morphogenesis, and to explore the extent to which the ideas I'd developed working on the gut were applicable in other organs. While doing dissections, I'd noticed the beautifully ordered follicle pattern on the avian skin, and to me they looked a bit like villi. So, I settled on the idea of exploring skin morphogenesis from a mechanical perspective. I wanted to move back closer to home, in the Bay Area, and there wasn't really a lab there working on the topics I wanted to pursue. But given that I knew what I wanted to work on, I was looking for a mentor who provided their postdocs with a lot of latitude, and who was experienced, sharp and generous. That's Richard, and when I went to visit I fell in love with his group and the lab environment. One of the other clinchers for me in making the decision to move to Berkeley was the opportunity to apply for a Miller Fellowship, which I was lucky enough to get. This is a great programme that covers all the natural sciences – they take about 10-12 fellows a year, and you meet up weekly and so interact with other biologists, but also chemists, mathematicians and physicists. There are also UC Berkeley professors that are Miller professors, and they also host sabbaticals for professors from around the world, so you get access to this wonderful community of scientists. It's something I'd highly recommend for people interested in doing a postdoc at Berkeley. With this, it was an easy choice to go and work with Richard.

Alan, what was your next career step?

AR: As I mentioned, my PhD led me to the feeling that development had to move to thinking beyond the cell. But I had trouble identifying a lab that was wholeheartedly committed to this way of thinking. Also, I had spent so much time in academia, and – up to that point – had never had a job outside it. I felt that, given the degree to which for-profit economics dominates society today, I wanted to have a better understanding of how it worked. When I was offered a job at a premier management consulting firm, I decided to take it. But I could not stop thinking about how to move beyond a cellular/molecular view of development, and Amy uncovered some key thinkers that led to an ‘aha moment’ for me. I'd say that the key person here, who I think is now becoming more appreciated, is Pere Alberch. He passed away in 1998 but I consider him to be my post-doc mentor, of sorts. Together with George Oster, he presented theories on how you could link the tissue scale phenotype to the molecular scale by thinking about collective behaviour (Oster and Alberch,1982). Through his work, I was able to envision a ‘post-molecular’ research path in morphogenesis and development. So, I was working a full-time job, but in all my spare time, I was talking and thinking with Amy about these ideas, and going into the lab with her to start working on these problems. As fate would have it, my ‘detour’ into management consulting enabled me to pursue independent postdoctoral work with full intellectual freedom.

Tell us about your postdoc time Amy – how was it being embedded in a Xenopus lab, and what did you discover during this period?

AS: Richard is of course a pillar of the frog community, so it wasn't an obvious place for me to be doing chicken experiments. But he'd had some people doing a bit of work with chicken embryos, and it's a very portable system – you can buy the incubators from Amazon, and you just need to know where to get the eggs. I actually wrote my fellowship proposal about wound healing and the mechanics of regeneration in frogs, but I ended up not touching Xenopus at all – I just ran with the question of skin morphogenesis in chick. I started out with the assumption that there would be some similar principles at play as what we had learned in the gut – that different tissue layers would be growing at different rates, and that this would lead to buckling, but it became clear early on that this was not quite what was happening. Instead, some kind of collective cell event was going on in the dermal layer. This was where I felt out of my depth in terms of understanding what was going on, which is why I started reaching for this old work from Alberch and Oster and others from the 1970s and 1980s. And this was also where dinner table conversations with Alan became important – his experience was in thinking at the subcellular and cellular level whereas I'd been working at the tissue scale. Between us, we were able to start figuring out what the mechanics were at the collective-cell scale, but also how these served as a trigger for molecular-scale events. We began to appreciate how morphogenesis at the collective cell scale creates information in its own right and can even regulate molecular patterning.

Clearly, you'd been pretty independent during your postdoc Amy – presumably this put you in a good position when you started to look for PI positions. What were the most important considerations for you in your job search?

AS: First, I want to acknowledge that Richard was very generous in letting me work in his lab, on a project that was outside his main area of interest and expertise. I had a long leash, but he was always there for critical counsel and support when we needed him, and he was also very welcoming to Alan. But there was no question that we would be able to take the project with us to start up our own lab. In terms of what we were looking for, it was important to us to find somewhere that we'd be allowed to keep doing this work, and we'd have the latitude to pursue our interests, even though they were a bit outside the box.

AR: We needed to find a home where conceptual (rather than technological) innovation was at the forefront. Of course, you need technology, but we wanted to be in a place where the concepts guide the technologies you build and use. Our discussions with Rockefeller gave us the impression that this would be possible there.

AS: Another positive about Rockefeller is that there is an atmosphere that encourages you to go after a big question. We went several years without publishing, and the system at Rockefeller meant that this was OK. And they were willing to allow for the sort of lab structure that we were hoping for – with both of us leading it together.

AR: I think our situation is pretty rare – where the two of us are developing one research programme. Often, when PIs collaborate, they have separate but overlapping projects, but in our case we really wanted it to be one programme based on the synergy that emerges from us working together. In a sense, we wanted to extend and mature the working relationship we established during our post-doctoral work.

How was the experience of transitioning to independence? What were the biggest challenges and what have been the best moments?

AR: One challenge stemmed from trying to develop a lab that's aiming for conceptual innovation. We were starting our lab when single-cell sequencing was taking off, and, although we do a little bit of this, we didn't really have fancy new technologies to sell to potential students. It's the era of CRISPR, and we were starting a lab working with chickens and not doing any genetics. We still haven't knocked out a gene; we still haven't purchased a PCR machine! My PhD work gave me a lot of respect for molecular approaches and we plan to incorporate them over time, but we've had to work hard to maintain the lab's focus on pioneering approaches at the collective cell length scale.

AS: The other thing we really had to work on, and this was probably amplified by global events, was our emotional resilience. I feel like starting a lab is a bit like becoming a parent. You're suddenly responsible for other people, and you don't really get any training for this. There was a real learning curve for us, and we had to put in the internal work to be resilient with regard to our own emotions and reactions so that we could lead a lab effectively and best support our team members.

AR: Suddenly you're not thinking just about yourself anymore: there's a scary feeling when you realise that you're on the hook for generating the enthusiasm and interest in your lab, and you're also responsible for the people who choose to commit their time to the lab. Each of them is their own person – you have to work with them to figure out what they want to be and achieve; it's not about trying to create multiple clones of yourself. We've now got to a point where we can really see the benefits of having people in the lab who are very different from us and from each other, and we're embracing the diversity of skill sets, talents and motivations. But in the beginning, it's hard to do this because you're still trying to develop a coherent vision of what you want for the lab as a whole.

AS: But there have been a lot of good moments. I remember recently being in a lab meeting where one of our postdocs was presenting, and everyone else in the group (me included) was enthralled and excited about the work and had so many good questions. And at the end, another postdoc turned to the woman who was presenting and said, ‘you're a rock star’. It was just amazing to see the community that had developed under our watch – how these people had come together to make something that was greater than the sum of our parts.

AR: Yeah, I'd echo that. It's wonderful that we've had the chance to develop a culture based on a set of scientific values that are important to us, and that they now exist beyond just the two of us. It's also very gratifying that we've managed to lead people in the lab to their own realisations of how a conceptual focus on the supracellular scale is a valuable approach.

Tell us a bit about what you're working on right now.

AR: Broadly, we're exploring the idea that morphogenesis is not just an outcome of mechanisms that can be ascribed to molecular or individual cell scale features. We have developed methods that are beginning to reveal that regulation also occurs through collective cellular behaviour. Primarily, we're interested in how this happens during development, but we're also starting to explore morphogenetic regulation in the context of disease – in cancer for instance.

AS: We move back and forth between the chicken embryo and ex vivo culture, taking advantage of both these approaches to gain insights into morphogenesis. Many of the systems that have really been powering the field of mechanics in development are epithelial, and we know a lot by now about the mechanics of morphogenesis in epithelia. But we're more interested in the mesenchymal tissue, where a lot less is known, and where the extracellular matrix plays a crucial role. The other theme that cuts across our work both in development and disease is how you generate robust structure from the interaction between epithelial and mesenchymal tissue, and how these structures are then disordered in cancer.

AR: We have been influenced by work from soft matter physics to help us conceptualise supracellular properties (e.g. emergent properties that relate to the continuum created by a collective of cells). I'd say we're trying to return to what I'd describe as the materiality of development. In addition, we are very interested in integrating our work with key molecular regulators; for example, we've just wrapped up a story looking at how a full understanding of the role of morphogens requires consideration of supracellular material properties and mechanics.

You've clearly had a very interdisciplinary way of thinking about things from the beginning of your careers. How does this influence the way you've approached hiring people for your lab?

AS: Alan alluded to this earlier, but we've really seen how powerful it is to bring in people with diverse perspectives. We have people in the lab that are hardcore developmental biologists, but also experimental biophysicists, and we're really interested in bringing in people with a background in theory. We always look for people to bring something new to the group, so, for example, our most recent postdoc has a background in cell metabolism, and this is something we're now incorporating into our work.

There's nothing more important to us than getting the best people, but it feels like they come to us – there's not much we can do beyond keep doing the work that interests us and, through that, we attract the sort of ‘poetic rebels' that are drawn to the work. I still feel that I have a lot to learn in terms of skills around hiring and interviewing people, but we've been very fortunate that the people who find us tend to be a good fit.

AR: As Amy says, I'm not sure we can take the credit for the people we've managed to recruit, other than by being very honest about what we believe in and what we think is important. We don't play to fashion, and I think we have what I'd describe as a poetic way of doing this – maybe this comes across in the writing of our papers and how we design our figures – and perhaps there's something in this that appeals to some people.

How important has mentorship been to you in navigating your career, and what's your approach to mentoring your lab members?

AS: I have only positive things to say about our mentors – both Cliff and Richard have been hugely supportive of us and I feel very fortunate to have trained with them both. At the same time, it was clear that we weren't really going to be able to model their approach because they both led very established labs, whereas we were having to start from scratch. As Alan said earlier, our approach has really been to understand and work with each person in our group as an individual.

AR: There's a tension in that we want to maintain a coherent vision, while giving people enough breathing room to express and follow their interests. Mediating this tension requires continual work, open-mindedness and humanity.

What advice might you give to people starting their own labs? What do you wish you'd been told when you were getting started?

AR: I guess what we did, which worked for us, is to focus on what makes you uniquely valuable, and then have the trust that you can develop that. The other thing that we've really benefited from was reading the historical literature – taking a long view on the field can help you better calibrate where you need to go and how your interests can fit in. I think this is as, if not more, important than keeping up to date with all the new stuff that's coming out.

AS: The other advice I'd give comes back to your earlier question about the challenges. It's the same advice I'd give someone about preparing to have their first child, which is to work on yourself. You need to go into starting a lab with as much personal resilience as you can.

As well as working together, you're also married with children. How do you handle the work–life balance?

AS: I'd say we're very good at leaving home at home, but are still working on leaving work at work! As our children get older, they do comment that they wish we could stop talking about the lab. So that's definitely something we're working on, but on the other hand we both enjoy doing what we do enough that talking about it over dinner doesn't really feel like a downside.

AR: I'd also say that it's hard to maintain a family balance when both partners have independent demanding careers. One of the benefits of working together is that it has allowed us to have more family time. There's always someone covering for you – so I can go to a school performance one day and Amy will still be there in the lab, or vice versa.

AS: It's also been very valuable to have someone working with you who can be completely honest with you about your work. It's absolutely helped me evolve professionally to have someone who will tell me the truth about what I'm doing well and what I could be doing better.

AR: Yes, absolutely. I don't think this is necessarily dependent on being married, but co-running a lab does mean that if we encounter a difficult situation with a project or colleague or trainee, we can give each other feedback on how we handled it. So, it helps us learn.

Finally, how do you switch off from science? Is there anything Development readers would be surprised to find out about you?

AS: I guess the obvious answer is our kids. I find the switch from the work day to school pickup is a challenge – moving my mind to the other end of the spectrum so quickly – but I welcome it. The kids demand our attention, and so we switch into family mode.

AR: We sing together as a family, and that's been a really nice way to bring us together. I also do a meditative form of painting, which I find helpful because it's a way to engage with thinking in a very different way.

In terms of things that might be surprising, I studied philosophy at the University of Cambridge after college and wrote a short dissertation on Nietzsche and his philosophy of art. The humanities and arts have shaped how I approach science, especially in sensitising me to the ways in which scientific paradigms evolve as scientific history progresses. I'm a big advocate of the liberal arts and getting a very broad education as preparation for creative scientific practice.

AS: We definitely complement each other from that perspective. Having been a tech for 3 years before coming into grad school, I think I had a tinkering and engineering mindset, whereas Alan brought in a more philosophical background, alongside his chemistry and computational training. And even though we've merged together, we're still quite distinct thinkers; I think that's part of what makes our partnership work. We remain sceptical until we find some promising activity that both of our minds see as true.

Amy Shyer and Alan Rodrigues were interviewed by Katherine Brown, Executive Editor of Development. This piece has been edited and condensed with approval from the interviewees.