Pathway to Independence – an interview with James Gahan

Image credit: Melanie Burford (Michael Sars Centre, Bergen, Norway)

Can you take me back to the moment when you first became interested in science?

I don't have a super interesting ‘origin story’ of how I became interested in science. I grew up in the countryside in Ireland and I was always interested in nature, but I only really became interested in science when I went to school. I was good at science and I liked it, so my interest just naturally continued from there and doing science at college was an obvious progression for me. My Bachelor's degree was in Biochemistry at University College Cork and I wanted to do a PhD, but my grades weren't good enough so I stayed to do a Master's degree first. My Master's programme was in Biotechnology, which was tailored towards working in industry but also had a research experience component. I ended up doing some research on stem cells in mice and I liked it.

You received your PhD working with Uri Frank at the University of Galway, Ireland. Can you tell me about what you worked on during that time?

During my Master's I was looking for PhD positions in the general area of stem cells and I saw an advert from Uri Franks’ lab to work on this weird animal called Hydractinia that I had never heard of. Hydractinia is a cnidarian, so is closely related to corals and jellyfish. Hydractinia has the remarkable ability to regenerate any lost body parts and they have a population of stem cells that they keep throughout their life and are technically immortal. Even though I knew nothing about evolution or cnidarians, I thought this sounded like a really cool topic and so I just went for it. My original project, which was to transplant cells from transgenic donor animals into wild-type recipient animals and trace the cells to determine if there were individual pluripotent stem cells, completely failed for several reasons, but mostly because the necessary technologies in the organism just weren't well-enough established at the time. Interestingly, a few months ago, Áine Varley, another PhD student in Uri Franks’ lab, finally published this exact experiment (Varley et al., 2023) and showed they are pluripotent – 8 years later! I ended up switching to investigating Notch signalling in the nervous system and showed its role in neurogenesis has been lost in Hydractinia. It wasn't the most ground-breaking research, but I got a paper that I'm quite proud of and since my PhD was such a struggle I feel I really learned a lot.

Were there any other challenges of working with an unconventional model system?

The bigger cnidarian community is ever growing but the Hydractinia community is still quite small and close-knit. It was a nice community to work in because people help each other, and this is important when things can be so difficult. There are a lot of things that you take for granted in established model systems that we just didn't have. During my PhD we worked on the European species H. echinata, and now the whole field works on the American species H. symbiolongicarpus. H. echinata was difficult to grow in the lab and even doing simple things like getting second-generation animals was a challenge. With H. symbiolongicarpus, researchers have managed to do amazing things that were simply impossible in my time. We also didn't have good transgenics at the time, and this was something that I worked on improving. But those challenges are balanced against the fact that every discovery is new – every small thing you do can often reveal completely novel things.

In 2017, you then moved to the Michael Sars Centre in Bergen, Norway, for your first postdoc. What contributed to your decision to move there?

A primary motivator was that I didn't want to do a postdoc in Ireland. I was interested in still working on stem cells or progenitors, but I wanted to switch to working on chromatin. During my PhD in Galway, we were in the Center for Chromosome Biology (CCB). I learned a lot about chromatin and epigenetic regulation, and I wanted to try to apply this to cnidarian model species because we had no idea of how epigenetics or chromatin was working in these organisms at that time. Having struggled during my PhD with developing models, I wanted to work on something slightly more established. Nematostella was, and is still, by far the most technically advanced cnidarian model. Fabian Rentzsch's group, who were here at the Michael Sars Centre and are now at the University of Bergen, had really pioneered Nematostella as a model to understand differentiation in the nervous system and were absolute experts in transgenesis in this system. Fabian had also just received a grant from the NFR (the Norwegian Research council) and was also excited to understand how chromatin was playing a role in neural differentiation. It was a perfect match!

How was your experience moving from Ireland to Norway?

It's not that big a difference compared to moving from some other countries. Norway is quite rainy, but I lived in Galway, where it's also quite rainy. I think if you come from somewhere like the Mediterranean, then Norway can be a real shock! The Michael Sars Centre is a unique place. It's an international centre where most PhDs, postdocs and group leaders are not Norwegian. It's like a family and a welcoming place for international people; everyone's in the same boat. In that regard, it was quite easy to fit in because you have this pre-existing community that you can just slot yourself into.

What did you work on while in Fabian Rentzsch's lab?

When I was in Fabian's lab, I worked on a couple of different projects to dissect different layers of gene regulation in the nervous system. I worked on Lsd1 and CoREST: two chromatin regulators that Fabian identified in a screen for genes expressed in neural cells. I published a series of papers on the function of those regulators in the nervous system (Gahan et al., 2022a,b). I also had a – still unpublished – project using ATAC-seq to map epigenetic changes between different neural cell types. The final project was on the evolution of the Polycomb system, not just in Nematostella, but in animals in general. We found that certain components of PRC1 (polycomb repressive complex 1), which were thought to be vertebrate specific, had emerged before the evolution of the cnidarian-bilaterian ancestor and are therefore much older than originally thought (Gahan et al., 2020). This work led me a bit away from my original interests and I have now shifted to working on the evolution of Polycomb repression and of chromatin more generally.

Can you tell me about your current research?

I'm interested in animal evolution and in particular the role of chromatin and gene-regulatory changes in this process. We know very little about how the first animal evolved and one way to try to understand this is to study some of the most closely related groups to animals, such as choanoflagellates – the sister group to animals. We also know that chromatin-based gene regulation is essential during animal development, but when the mechanisms underlying this regulation evolved is unknown and no-one has looked at gene regulation or chromatin in choanoflagellates. I want to dissect the mechanisms underlying gene regulation in choanoflagellates and compare this to animals.

I have a Sir Henry Wellcome Postdoctoral Fellowship and my supervisor is Professor Rob Klose at the University of Oxford, UK, a ‘hardcore’ chromatin biologist working on embryonic stem cells. David Booth at the University of California San Francisco (UCSF), USA on the other hand has really pioneered genetic tools in the choanoflagellate S. rosetta. I put these two together and wrote a proposal on chromatin and specifically Polycomb-mediated repression in choanoflagellates. I spent 1 year in David Booth's lab at UCSF, and now I'm back here in the Michael Sars Centre as a guest researcher in Pawel Burkhardts's lab, continuing the project.

The topic sounds related to The Company of Biologists' Evo-Chromo workshop that you attended. Was it a useful experience for you?

I think my research is quite timely, in that many people are becoming interested in how chromatin evolved as well as how changes in chromatin have impacted evolution (Drinnenberg et al., 2019). It's an emerging field and so it's a great time to be in that community. The workshop was organised by Fred Berger and Ines Drinnenberg in 2018, and was the first meeting of this new field working on the evolution of chromatin. The workshop was great and I was a co-organiser of the first big meeting of this group, which was an EMBO meeting in Aarhus in Denmark last year. It came about because I was part of the postdoc/PhD organising committee for seminars here at the Michael Sars Centre and invited Ines Drinnenberg to come and visit. I asked if there would be another meeting and mentioned that I'd love to be involved. Luckily, the organisers were generous enough to invite me to be on the committee, even though I was just a postdoc. I think it was a great opportunity: it's great for your visibility, your reputation within the community and your CV, of course. I would encourage more established principal investigators to try to incorporate postdocs into these kinds of organising activities.

How did you hear about Development's Pathway to Independence Programme and what motivated you to apply?

I heard about it on Twitter and it seemed like a great programme. At the time, I was writing my ERC grant and I was just applying for my first faculty position so it seemed like a perfect opportunity because we have very little training and mentoring for this stage of our career.

What do you expect from the programme?

What I hope to get from it is twofold. The first is to get mentoring advice and training when it comes to applying for positions. My mentor is James Briscoe and we've had meetings to discuss career development. He also gave me some useful feedback and advice on my research proposal that I submitted for different positions. The second thing is to build a network of people at the same career stage. That's probably going to be the biggest benefit of the programme in years to come: to have this network of people who are currently going through or have gone through the process of establishing a lab, to help each other.

You were recently awarded an ERC Starting Grant – congratulations! What was this process like and what does that mean for your future?

Everyone has a lot of advice in this regard so I don't know if mine is better than what is already out there! I think the ERC Starting Grant is a hard grant to write. It took me almost a year to write and most of that time was thinking. There's a very specific way that ERC grants are written and structured, so it was very difficult to go from having this wonderful idea to then boiling it down into something that was a real and competitive application.

You've also secured a position at the University of Galway. Why did you decide to go back there to start your own group?

I wanted to go back to Galway, which is, in some ways, my scientific home where I first became interested in chromatin and chromosome biology. It has an amazing group of around 12 principal investigators in the CCB working on different aspects of nuclear organisation, DNA damage, epigenetics, etc. For me, this is going to be a perfect intellectual home to broadly study the evolution of chromatin because, although I have my own ideas, there's a welcoming community of people there who have their own specialist areas that will likely feed into my thinking and experiments. The most important thing is that the environment is right, and I know the CCB to be a wonderfully supportive place to do science. The CCB and the University of Galway were also extremely helpful in preparing my application for the ERC and offered me a permanent Associate Professor position once I got it, so from that point of view it is a really great host that I would recommend to anyone thinking of applying to ERC.

What culture would you like to establish in your lab and who would you encourage to apply?

It's even scarier to think about hiring now I actually have to do it! I'm going to be looking to hire both PhDs and postdocs. I want to have a small group at the start because we will have a very specific focus on what we want to understand. From that point of view, I want to have a group of people who are collaborative. Although people will have their own individual projects and I want to set up an environment where postdocs can explore their own ideas that they can then take with them when they leave, I also want to have a sense of ‘we're in this together’ within the group, such that everyone has a feeling that we're working towards a common goal.

At the same time, I also want to have a group that does robust science. I think this is going to be the most important thing for me going forward. There are some principal investigators within every field that have this reputation that their science is solid, regardless of whether it is published in the ‘glam’ journals or not. That is the kind of group that I want to have. On top of this, of course, I want to create an environment where people feel supported and where science can be fun and exciting.

How important do you think mentorship is in navigating an academic career?

I have been so lucky and fortunate with my mentors. Uri Frank has been an amazing mentor and continues to be now that I've decided to go back to Galway. Here in Bergen, Fabian Rentzsch was a fantastic supervisor who gave me the freedom and space to do what I wanted. During my Wellcome Trust postdoc, Rob Klose has been hugely supportive of me, even though I've never actually physically been in his lab. Then David Booth allowed me to go to his lab to do my own thing in San Francisco and Pawel Burkhardt is now being generous enough to allow me to be in his lab. As well as mentors that are your direct supervisors, when you have small communities, it's super nice when more established principal investigators give postdocs the opportunity to do things, like organising an EMBO meeting. So I've been lucky and always had these amazingly generous people around me who have helped me in the best way they can; I hope I can do the same for others in the future both in my own group but also the field in general.

What excites you most about becoming an independent researcher?

Although I've been well supported, as a postdoc, you can do what you want to some degree but someone else controls the budget and you are only one pair of hands so can only do so much. I'm looking forward to having the freedom to be totally creative on my own, which is also a bit scary because the buck stops with me. I'm excited that I can start to do the science that most interests me and then also have young people in my lab doing those experiments. Some of the most exciting times for me in the lab have been when my colleagues or even my own undergrad or Master's students have made interesting discoveries. I love to see that sense of discovery and wonder. As I said earlier, when you work on non-model systems or on questions where nobody knows anything, everything is a discovery and that's exciting. I'm also excited to see where other people's ideas bring me, to have people in the lab who move things in directions I didn't expect and cannot predict.

And on the other hand, what will be the most challenging aspect of being a PI?

I think the most challenging thing is hiring. I will try to keep the group small at the beginning, which means hiring a small number of people, but those people will then be key; having a good first postdoc and student will determine the output and the direction of my lab. That also means that I will be super-invested in those people; their success is absolutely my success. As a PhD student and postdoc, your success is largely on your own shoulders and moving to a situation where you can advise and mentor, but where the success of your projects is underpinned by someone else, is a bit terrifying.

Do you think there's any way for you to prepare?

I have good mentors who gave me good advice and I'm going to try to emulate some of their mentoring practices. Hopefully, I can lean on them for advice when it comes to hiring. We are also going to be doing a training workshop on how to hire people and manage a group as part of the Pathway to Independence Programme, and I also hope James Briscoe will continue to mentor me in the early stages of setting up a lab. Then, hopefully, the other Fellows all get positions, and we can all be in it together and somehow help each other. I think having a peer network of people will be key.

What will be the research focus in your own group?

The research focus, at least in the very first few years, will be to understand in detail how chromatin-based gene regulation operates in choanoflagellates and how this compares to what we see in animals. The lab will primarily work on S. rosetta, which has cell differentiation and therefore different cell types; however, unlike in animals differentiation is not a one-way street and cells are much more plastic. I hope that by comparing the mechanisms underlying this type of cell differentiation to the mechanisms used during animal development, we can understand some aspects of the early evolution of animal cell differentiation. We already know that there are large gene expression differences between some of these cell types and I also have quite nice preliminary data, which show that some mechanisms used to regulate these genes are similar to those used in animal development. The group will build on this to understand these mechanisms using different perspectives. First, we will use Omics technologies, e.g. ChIP-seq, ATACseq and 3D genome mapping, to thoroughly describe changes in gene expression and chromatin in different cell types. On top of this, functional tools (transgenics and CRISPR-Cas9) have been developed in the past few years in S. rosetta and we will use these to functionally dissect these gene regulatory processes.

Finally, what do you like to do outside of the lab?

I live in Bergen, which is one of the most beautiful places in the world for hiking. When I first moved here, I had never hiked and for the first 2 or 3 years I completely neglected hiking, but now I've become a hiking addict! Whenever it's not raining in Bergen, I'm usually hiking and will be hiking 15 days in August to sweat off the summer's excesses.

James Gahan was interviewed by Alex Eve, Reviews Editor at Development. This piece has been edited and condensed with approval from the interviewee.