An interview with Mansi Srivastava Free

Let's start at the beginning. When did you first become interested in science?

I've been interested in science for as long as I can remember. My mother was a middle school and high school biology teacher, so I was always in a science-positive environment, and I loved biology from the get-go.

What did you study for your undergraduate degree?

I grew up in India, but then came to the USA for college, primarily because I felt like I could get opportunities to do research earlier on in my training in the USA than I could back then in India. I went to a small liberal arts college, where I had access to professors who challenged us to think deeply and broadly. I majored in biological sciences, and spent some summer research time in the lab of Nipam Patel, who's now the Director of the Marine Biological Laboratory (MBL) in Woods Hole, USA, trying to study weird, understudied animals.

Did your work with Nipam spark your interest in leveraging unconventional species?

Yes, and it also deepened my interest in regeneration. In my undergraduate studies, I became fascinated by feather duster worms. They're segmented worms that live in tubes, and they have a beautiful plume of feathery tentacles that comes out when they're filter feeding. More than 100 years ago, when developmental biology was basically cut and paste experiments, people studied regeneration in these worms. They didn't know about genes, and they didn't have fancy tools, but they did have razor blades. So, they would cut up embryos and animals and then ask questions about what happened next. What was fascinating about these worms is that, at a particular point in their body, there's a dorsal-ventral inversion in the segments. You can cut the worms at different positions and, every single time the worm regenerates, it knows the place where that inversion must occur. So, that's where my interest in regeneration biology started, through reading the old literature about people spending time at the MBL cutting things up. For my undergraduate summer research, I spent time in Nipam's lab trying to develop new annelid model systems where I could study regeneration. Most things didn't work, but it was fun to come to his lab and play around with lots of different annelid worms!

Where did you do your PhD, and what were you working on during that time?

I went to the University of California at Berkeley for my PhD in the Molecular and Cell Biology programme. I went there because, at that time, they were hiring people to create a hub for evo-devo research, so, folks like Mike Levine, Nicole King, Richard Harland and Nipam Patel had labs located on the same floor. My PhD advisor, Dan Rokhsar, used to be a physicist, but he had also joined the Department of Molecular and Cell Biology because he had become involved in sequencing lots of understudied animal lineages and he was a director at the Joint Genome Institute. My original plan for my PhD had been to study nervous system development in sea anemones, but I realised that joining the lab of a physicist to do experimental developmental biology was probably not the best idea, and so I ended up learning computational biology! I was involved in the work that sequenced the very first sponge genome, the very first cnidarian genome, and the very first placozoan genome. So, my thesis focused on comparative genomics, trying to shed light on key events in early animal evolution by comparing the genomes of sponges, cnidarians and placozoans to the genomes of well-studied animals, such as fruit flies, nematodes and mice.

You moved to the Whitehead Institute for your postdoctoral research. How did you get back to the bench after working on such a computational PhD project?

It was a very deliberate choice. My PhD allowed me to see the power of genomic data, but it also highlighted its limitations. At that time, genomic data were an amazing tool for generating hypotheses, but we had limited tools to actually test and validate these hypotheses. So, I wanted to get back to more functional experimental work, because I felt like I'd had a lot of fun generating hypotheses, but I was more interested in actually testing them out. I also wanted to go back to my original love of regeneration biology. When I wrote to my postdoc advisor, Peter Reddien, whose lab focuses on understanding the mechanisms of regeneration using planarians as a model system, I was explicit in stating my interest in not studying planarians themselves, but in trying to develop other model systems where we could also study regeneration at a mechanistic level, to then ultimately be able to make comparative statements to understand the evolution of regeneration mechanisms.

So, you were working in Peter's lab, but developing these new systems. Is that how you established your research niche for your own group?

Absolutely. Peter's lab was just an amazing environment for me, where he gave me lots of freedom to be bold, to be creative, and to take risks. I spent my first year there testing out lots and lots of different species. I tried working on acorn worms. I tried working on really tiny flat worms from the Concord River, which is close by to us in Cambridge, Massachusetts. And then, after a series of trials and failures, Peter and I went and collected the three-banded panther worm (Hofstenia miamia), which is the species my lab focuses on primarily now, and that system just took off.

What questions did you initially set out to address when you established your own lab?

The big question, which is still a focus of the lab to some extent, was trying to get at whether the many instances of regeneration across the animal tree of life are related somehow, or if they are just independently evolved phenomena. The particular kind of regeneration that we're focused on is called ‘whole-body regeneration’, which is the ability of an animal to replace any missing cell type. Our bodies, and the bodies of traditional model systems, such as zebrafish, nematodes or Drosophila, are not capable of whole-body regeneration. However, most animal phyla have species that can do this. So, is whole-body regeneration some kind of ancestral property that many, many extant species inherited, and then somehow the human lineage was unlucky enough to lose that ability? Or could it be that animals are able to achieve whole-body regeneration again and again in their independent evolutionary histories where, at a high level, the process looks similar, but if we started digging into the mechanism maybe we would find differences?

The original goal in my lab when I started it was to begin reconstructing the mechanisms that underlie regeneration in different species and to compare them to each other. To pursue this goal, I basically had two choices. One was to stick with Hofstenia and go deep into mechanism, because you can't really go deep into mechanism in one lab by studying lots and lots of different species; you'd have to build lots of tools, and that's just not feasible. The alternative option would have been to start working on many more species and to make more, but shallower, comparisons. If you look back at the 10-year history of my lab thus far, the choice I made is very clear, which was to focus on one organism and to go deeper into mechanism in order to build frameworks that, in the long run, can be used by other labs to gain mechanistic insight into their species of interest. Then, working together as a field, we can make comparative statements. To some extent, that's still my dream. I don't think we're anywhere near having full answers, but the idea is to ask whether regeneration might have unifying principles in the same way that development has revealed its unifying principles to us. When people first started studying the embryos of flies, nematodes and mice, we didn't expect there to be much similarity because these animals are so different. Yet there is so much unifying biology underlying all these very different looking animals, so that's the question I find myself thinking a lot about in the context of regeneration.

Do you also think about the question of whether regeneration is a recapitulation of development?

Yes, absolutely. This is a great question, which many people have asked over the last 100 years, and it's one of the factors that has shifted the focus of my lab in a big way. Thomas Hunt Morgan, who is credited for having launched the field of genetics, used to spend his summers at the MBL cutting up flatworms. He published a book in 1901 titled ‘Regeneration’ in which he ponders upon this question of how regeneration and development intersect. What I've realised over time is that being able to make any meaningful statement about the evolution of regeneration requires us to think about development, because, so far, many of the processes that we've revealed as being important for regeneration are also important for development. For example, there was a famous study of planarian regeneration in which the researchers inhibited Wnt pathway components, cut the worm, and allowed it to regenerate. This produced a two-headed planarian, with heads on both the front and the back end of the animal. This experiment tells us that Wnt signalling is required for correct AP axis polarity during regeneration. But we also know that Wnt signalling controls the AP axis during development in virtually every animal studied. So, that raises the question of whether we are studying regeneration itself, or merely the recapitulation of developmental processes in regeneration.

I think it's also important to think about the history of the field. I'm not the first person to think of regeneration in this way – in the early 1980s, folks like Sue Bryant and Ken Muneoka wrote about how, to understand the evolution of regeneration, we really should be focused on how developmental processes are activated in regeneration. A priori, we might expect that animals are not going to invent wholly new ways of making head and tail axes if they already knew how to do that during development, so they'll call upon those developmental processes when they need to regenerate a head and a tail. But how do they call upon those developmental processes? If regeneration is an ancestral process, operating on shared mechanisms across species, those activating mechanisms would also be shared. But, if animals independently came up with ways of calling upon their developmental processes, then those activating mechanisms might be different across species.

One of the reasons we're really getting into comparing regeneration and development now is that we have an awesome model system for these questions. When I first picked Hofstenia out of a marine pond, we didn't know if it was capable of whole-body regeneration. We got lucky, because it regenerates really well. The other big stroke of luck was that the worms started producing embryos in the lab, which means this is a special case where we can study both embryonic development and regeneration in the same species. Today, I would say that there are almost more studies of development going on in my lab than of regeneration itself.

You are a Guest Editor for Development's Special Issue – Lifelong Development: the Maintenance, Regeneration and Plasticity of Tissues. Why is it important to consider development across the lifespan of an organism, and not just during embryogenesis?

I think about development as the process of going from a zygote to the adult form of the animal or plant, where you go from a single-celled entity to a multicellular entity that has shape and size and pattern. In some species, you go directly from embryonic development to the adult form. In other species, you go through intermediate larval forms. Furthermore, the shaping of the organism does not stop at the point that embryonic development ends. For example, in mammals, lots of change occurs after birth. There are also processes such as ageing that cause tissues to change long after the animal has reached sexual maturity. So, it feels like a false boundary to say that development stops at the end of what we would call ‘embryonic development’.

I think that scientists used to have a much more integrated perspective on this, because the same people who were sitting at the MBL chopping up embryos were also chopping up animals. Then, at some point, we became a bit narrower in how we think about development. But new tools are opening up our ability to study things further in developmental time, so maybe now we can get back to those questions in a way we hadn't been able to before.

What do you think are the biggest challenges for researchers who are working in the field of lifelong development?

Let's take regeneration as an example of a lifelong developmental process. We were just talking about how, during regeneration, there's redeployment of genes that also have roles in development. So, if you mess up one of these genes, you could end up with a dead embryo. In some ways, it's easier to study earlier processes, because you perturb the gene, you get a phenotype, and then you don't care if the animal dies later. But to study lifelong development, you need to have tools that allow you to make more specific perturbations at the later time point that you're interested in studying. So, I think some of the challenges are technical.

What do you think are the most exciting questions in your field today?

In the regeneration field, I think it's this question of how regeneration can redeploy developmental processes. Biologists formulated this question years ago, and we still don't have full answers to that. Most animal genomes have about 20,000 genes, and a huge number of them get deployed during development, so you can imagine what a huge battery of them must be operating during post-embryonic processes. Figuring out how genes are tightly controlled to play a role in one process versus another is going to be exciting to study. For example, if a gene plays a role in development, but then also in regeneration, how do you get it to turn on at different points in different contexts, and get it to do maybe slightly different things?

Why did you accept the invitation to become a Guest Editor?

I think that Development is just such an important journal for our field. Yes, the title is ‘Development’, but the journal takes a broad view of what developmental processes encompass. These processes can be embryonic, post-embryonic, larval, and so on. I think that by launching this special issue, the journal is making it more explicit to the community that we should collectively have a broader definition of development. So, it was very exciting for me to be part of that process of sending out a reminder to the field that development is a lot of things, and we benefit by taking a broader view. Another thing that's really close to my heart is the idea that we should not limit our studies to a handful of model organisms, but that we learn more general things about biology by broadening the organisms we study. To have an opportunity to promote research in more diverse developmental processes and in more diverse organisms was really exciting to me.

What have you enjoyed most so far about curating the special issue?

It's really fun to engage in the consultative process with folks at Development when considering each paper or presubmission inquiry. I've seen just how much effort goes into thinking deeply about every single paper and every single question that comes through to us. It's been really rewarding to engage deeply about science beyond my own in a collaborative way.

Finally, what do you enjoy doing outside the lab?

I would say that I am not a specialist – I'm more of a generalist in what I do, because I don't have one specific hobby, and I'll do just about anything once. Many commonplace activities bring me joy, like cooking for my friends and family or enjoying a walk in the sun after months and months of winter.

Mansi Srivastava was interviewed by Laura Hankins, Reviews Editor at Development. This piece has been edited and condensed with approval from the interviewee.