An interview with Purushothama Rao Tata Free

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

I have always been fascinated by nature: evolution, species diversity and patterns in biological systems. I grew up in rural India and I'm a first-generation student – I didn't know a single person in my family who finished high school, but, growing up, my brothers and I motivated each other. As an undergrad, I double-majored in botany and biotechnology, and as part of my biotechnology course I did one experiment that was kind of a magic moment in my scientific life. This was a plant tissue culture experiment, where I could take a small piece of plant tissue and make an entire plant grow from that. What I found amazing about this was that, irrespective of which part of the plant I took, it formed an intermediate tissue called callus, and this could turn into any part of the plant – or a whole new plant – depending on the supplements we provided. I remember asking the course director how this happened, and whether there was the equivalent of a callus in humans. So, I guess this was how my interest in regeneration started.

How did you then come to move to Germany for your PhD, and what did you study during this time?

After my undergrad, I went on to do a Masters in India, and I chose to go into animal sciences. It was during this time that I got to learn about embryonic development, and I was particularly fascinated by the Spemann Mangold experiments, and how a mass of cells could self-organise to generate a body axis. I applied to various PhD programmes and got into schools in both the US and Germany, but I chose to go to Germany because I would be able to finish my PhD in a shorter timeline.

Moving to Germany was an exciting time because I had never actually travelled to any foreign country. It was a big transition in many ways. The day I left India it was +35°C, and I landed in Germany at −20°C – that was a moment to remember! I joined the lab of Michael Kühl in Ulm – he was one of the early pioneers identifying the Wnt-calcium pathway. One of the important things for me about the lab was that we had five model systems – fly, frog, fish, mouse and embryonic stem cells. Obviously, I didn't work on them all, but it was an incredible experience learning about comparative developmental biology, and it was a stepping stone for me to get to know about model systems. My project focused on understanding the role of non-canonical Wnt signalling in cardiac tube formation, using both frog and mouse. During this time, I also started to work with stem cells on side projects focusing on transcriptional and post-transcriptional regulation.

You then moved to Jay Rajagopal's lab at Massachusetts General Hospital in Boston for your postdoc – why did you choose Jay's lab?

I spent a lot of time in the last six months or so of grad school thinking about what I wanted to do, and decided to study adult stem cell biology. Independently, I had become interested in the lung through working with frogs – I was fascinated by metamorphosis, and how this phenomenon is aligned with the evolutionary transition from aquatic to terrestrial life, which was effectively the birth of lungs as an organ. I didn't know much about it, but I thought it would be interesting to study lung stem cell biology. I wanted to move to the US for my postdoctoral studies, and – like many I guess – I was attracted to Harvard. So, I started looking and I found Jay's lab. Jay had only set up his lab about a year earlier, but I wanted to work with a junior PI, so this was appealing. During my PhD, I had a great time working at the bench with my direct supervisor, Ioan Sirbu, and I liked the idea of joining a lab where the PI spent a bit of time in the lab. It didn't quite turn out this way as Jay wasn't in the lab that much at the time, but that gave me the freedom to explore what I wanted to do, so, it worked out well.

As a postdoc, you discovered that fully differentiated airway epithelial cells can de-differentiate upon injury and contribute to regeneration. How did that discovery come about?

It wasn't something I'd ever really thought about and, as far as I know, neither had Jay. The discovery was purely serendipitous. Our initial hypothesis was that, when we ablated stem cells in the lung, the tissue would undergo atrophy and this might induce fibrosis. But in fact, we didn't see this – even after ablating 80-90% of the stem cells, the tissue could regenerate. Initially, we thought that the residual stem cells were replicating and replacing the lost cells, but we found that a neighbouring differentiated cell population also started to replicate. So then we went on to do the obvious experiments – coupling cell ablation with lineage tracing of the differentiated cells, and we found that indeed there was de-differentiation of committed cells. At that time, the concept of this kind of plasticity was quite new (though now there are many examples). We knew one could reprogramme cells, but generally this was achieved through forced expression of reprogramming factors. In our case, reprogramming was happening purely naturally – tissues know how to maintain the appropriate number of cells and in the appropriate ratios. These experiments really taught me a lot about the self-organising properties of tissues.

You have been working on lung stem cells and regeneration ever since, having set up your own lab in 2016. How did you choose Duke as a place to start your independent career, and what were the most important considerations for you when looking for group leader positions?

When I was looking for independent positions, I mainly focused on positions with strong stem cell and developmental biology programmes. I was fortunate enough to get multiple offers, but one important consideration for me was my wife and kids. I wanted a place that was safe, and where we could grow as a family. North Carolina was great from this perspective – it is very affordable, and we are close to the mountains and the beaches. Scientifically, Duke was very appealing. Brigid Hogan, who also works on the lung, was Chair of the department at the time, and Ken Poss was leading the initiative to set up the Duke Regeneration Center, so I saw the potential there to grow as a stem cell and regenerative biologist.

What's your lab working on at the moment?

We are fascinated by cell-cell communication and how that controls the self-organising principles of the lung. Two of the questions that drive us at the moment are: how does the tissue know how to maintain the appropriate numbers of cells, and how do the cells know where they are? Lung architecture is quite remarkable – the surface area has been estimated to occupy half of a tennis court, and it is fascinating to consider how that can be packed into our chest cavity and how it can regrow and reform this complex structure after injury. Understanding the links between cell communication, tissue organization and tissue function are the key problems we are really focusing on.

You work a lot with human stem cell systems. Do we know the extent to which the human lung can regenerate?

This is a question I often get, and actually we have now got quite a bit of evidence that the lung has more regenerative capacity than we previously thought. COVID-19 has given us a lot of data on this – we have high-resolution CT scans from people with COVID-19, and we can see the damage caused by the infection, but then the remarkable recovery of structure over the following months. There is also evidence coming from longitudinal studies of people with lung cancer, where part of the lung has been removed. If you follow these people over several years, you can see some growth in the remaining lung. We don't know if this is hyperplasia or hypertrophy, or to what extent the new tissue is functional, but it does seem that there is an expansion to meet oxygen demand.

We've now started to develop ferrets as a model system to look at lung regeneration in vivo in a species larger than the mouse. This was primarily driven by the fact that recent work from our lab and others revealed cell types in the human lung that don't exist in mouse. But we found them in ferret, so we've been starting to do some comparative anatomy and cellular characterization of the ferret lung, as well as developing lineage tracing tools so that we can look at these new cell types.

You have just mentioned COVID-19, and you have been directly involved in a few papers exploring the effects of SARS-CoV-2 in the lung. How did you get this work off the ground and is this a research direction you are continuing to explore?

During the early stages of the pandemic, the only labs that could continue to run were those working on COVID-19, and this was a way of keeping the lab running and contributing something useful. We started collaborating with Ralph Baric, a world-renowned expert in coronavirus biology based at UNC Chapel Hill. We had developed a human lung organoid model, so we could infect these with SARS-CoV-2 and we saw some really fascinating things that actually recapitulated human pathophysiology.

What has been rewarding is that we developed the human organoid model for totally different reasons, but hadn't published them, and this work gave us an opportunity to show that our models can be valuable for more applied work. Until then, labs like the Baric lab had been using cancer cell lines to model viral infections, but now we have systems that more closely recapitulate a human lung, which hopefully can give us a better handle on what's happening in diseases.

Last year, you were awarded the inaugural ‘Rising Star’ award from the newly formed International Society for Regenerative Biology (ISRB). What does this award mean to you?

I feel extremely honoured to have received this award. I'm thankful to my peers and colleagues who have nominated me, and also the committee members who selected me. Regenerative biology is at the core of our lab's interests and being recognized by the ISRB feels like a real accomplishment at this point. It also inspires me to think about the next questions we need to ask and get connected with the broader community.

How important do you think mentorship is in navigating an academic career? Can you tell us about your mentors and how they've helped you?

My mentors have played a key role in shaping who I am today. Thinking back to my undergrad studies, only a few students got to do hands-on practical training, and the course director – who was my mentor – gave me that opportunity. If I hadn't done that experiment with the plant callus, I don't know if I'd be here today. Both during my undergrad and graduate studies, my mentors saw the potential in me and spent the time and effort to train me, and teach me about how to do good, rigorous science. And then Jay was a key mentor – he helped me in thinking conceptually – it's not just about doing an experiment, but about seeing the bigger picture, putting it into the broader context. This was very important for me. I also have to mention Brigid Hogan, my current mentor. Even though she has closed her lab, she is still around and helps me in many ways. I admire her very much – she still has such drive, and I always wonder how she is able to maintain that energy. Having a mentor with whom you can not only discuss the science, but who inspires you all the time – that's really important.

How has this carried into your mentorship style for your lab?

Everyone is unique, there is no single formula – it's key to tailor a training plan to each individual. You need to spend time working out what each person wants and what their interests are – do they want an academic career, to go into industry or something else, or have they not figured it out yet? Knowing this means I can help support each person in the way they need. Our lab is relatively young, but so far we have had three postdocs who have gone on to start their own labs, and I'm fortunate that they have all continued working on the lung. I'm very much dedicated to helping build the next generation of scientists in lung and regenerative biology.

Another thing I wanted to mention is that it's important to know how to reboot yourself. I think that grad students and postdocs often think that the harder they work, the more they'll achieve, and that's not necessarily the case. It's important to know how and when to switch off – for me, it's my wife and kids. It's something I watch for with the people in my lab – are they starting to get burned out? If I see that they're getting to that stage, I tell them they need to take some time off. It's a really important message to get out there – it's OK to take a break and switch off for a while.

Do you have any advice that you would give to people starting their own labs now?

One thing about an academic career is that we're not trained to do the things that we will end up doing. You have multiple roles – you're not just a scientist or a mentor, but also a manager and an administrator and so on. I didn't have any training in this, and it was challenging. But what I found was that if I asked for help, I got it. There are many excellent mentors out there who are genuinely interested in helping early-stage investigators like me. I found it was easy to come up with bold ideas of what to do, but harder to frame them in terms of the feasibility, the timeline, the resources available, and this is where my mentors were invaluable. What's also important is to integrate your ideas with your environment – to use interdisciplinary approaches that might be available where you are.

Finally, is there anything Development readers would be surprised to learn about you?

I've been fascinated with sci-fi movies all my life. When I was in college, whenever I watched a movie, I'd go home and write a script for a sequel. These days, my Zen time is watching sci-fi movies – it takes me out of this earth and lets me think about unknown and fascinating things. I'd love to get the chance to direct a movie at some point!

Purushothama Rao Tata was interviewed by Katherine Brown, Executive Editor of Development. This piece has been edited and condensed with approval from the interviewee.