Transitions in development – an interview with Aydan Bulut-Karslioglu

Starting at the beginning, when did you first become interested in science?

I was generally interested in science and technology in high school, and I considered all kinds of career options (at some point I even wanted to be a pilot!). There was not an exact moment where I thought, ‘okay, I'm going to be a scientist’; I think it was more of a process. But eventually, having gone through that process, I figured out what I wanted to be and what I was cut out for, and that was being a research scientist and working on the unknown without any restriction. I love curiosity-driven science and the thrill of a discovery. Most of my family works in the banking sector and my brother is a lawyer, so I really went down a different avenue; I don't know what went wrong!

You completed your undergraduate degree at the Middle East Technical University in Ankara, Turkey, in 2006, where your major was chemical engineering. What then led you to do your Master's and PhD degrees focused on molecular genetics?

I initially decided to study chemical engineering because, unfortunately, basic or fundamental sciences were not seen as a lucrative career in Turkey. So, my decision to study chemical engineering was intended to be the best of both worlds; I thought I could continue to study and be embedded in basic science, but at the end of the day I would have a career where I could also make money after I graduate. However, over time I realised that engineering was not for me, because it confines the science too much as it focuses on efficiency and profitability etc. But I really enjoyed the chemistry parts and that is what I was good at. I also thought molecular biology was really interesting too, and so as an undergraduate, I did a minor degree in biology. At the end, molecular biology won and that's what I chose to continue to pursue. The 2000s were a super interesting time for the epigenetics field, with the first epigenetic writers, readers and pathways being discovered. So I decided to focus on epigenetics after graduation. However, the perspectives I gained from engineering taught me a lot about rationalising and problem solving, which I try to carry forward in my research today.

After completing your PhD in 2013 at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg, Germany, you then made the big move to San Francisco for a postdoc in Miguel Ramalho-Santos’ lab – what did your research focus on here?

During my PhD, I focused on epigenetic mechanisms that control the repetitive elements in our genomes, particularly at pericentromeric regions, and also the retrotransposons that make up the bulk of our genomes. During this time, I used mouse embryonic stem cells because they grew quickly and they could produce a lot of material. Thanks to this project, I became really fascinated by stem cells and so this is what I wanted to continue working on in my postdoc. I also wanted to reverse the balance a little bit; I wanted to mainly focus on stem cell biology and development, while continuing to use my epigenetics and chromatin biology background, and that's why I applied to Miguel's lab. There, my research focused on understanding how pluripotent stem cells retain stemness at the chromatin level. You need a flexible open chromatin structure, which is at the same time transiently repressed at certain sites, for pluripotent stem cells to remain uncommitted. There is a very fine balance at the chromatin level and I wanted to understand the regulation of open chromatin in this context and what factors regulate self-renewal versus proliferation. Here, we showed that there is an acute feedback between cellular growth, translational output and chromatin regulation, and that they regulate each other in a circular manner. This finding at the same time gave rise to our discovery that mammalian target of rapamycin (mTOR) is a regulator of developmental timing in the mouse.

Was it a big adjustment conducting research in the USA compared with Turkey or Germany? How did you find the transition?

I didn't actually struggle with the move at all; I deliberately moved to the USA for my postdoc because I wanted to observe and also absorb a different world view. Although it's still a Western country, I wanted to experience the different scientific dynamics to Europe. On a personal level, I did not struggle because I really felt at home from the first day and UCSF is also a great place to do research; you have pretty much everything you need for your research available to you. So at that point, you're only bound by your imagination, your passion and your skills, and I think that's a great privilege.

In 2018, you were awarded the Sofja Kovalevskaja Award to start your own lab at the Max Planck Institute for Molecular Genetics in Berlin, Germany. What have been the most exciting and challenging moments of setting up your own lab?

For me, the most exciting thing is always when you make a discovery, when you witness something that nobody in the world has before; that moment when you're sitting in front of the microscope or screen and super excited by this new science. Although that euphoria doesn't last long, it's why we do science and it's one of the best rewards. Then, from the perspective of a group leader, what I really enjoy is seeing people transform from students to colleagues. People come into the lab in an excited but naïve way, and they gain experience and they're moulded into scientists over time. Knowing that I have contributed to someone's professional journey and personal growth is gratifying.

Regarding challenges, I've had plenty in the last 5 years, but I think one of the learning curves I had is realising that I'm not working with copies of myself in the lab. I'm working with a group of diverse people (who are deliberately hired for that reason), and everybody has a different perspective and does science a little differently. This is of course why we build a team and it is very beneficial to the science, but it means you have to tailor your approaches; it's not one size fits all and you have to find out what inspires each person to do better science. I think this requires a lot of thoughtfulness and energy, and I can imagine it becoming difficult with large labs unless you have people who could step up to this role. Scientifically, the other challenge is establishing an entire research programme with diverse viewpoints and approaches. As a postdoc you have your own projects that you primarily focus on, but as a group leader you have multiple projects to manage and now you need to zoom out and have a much broader overview. It is a lot of work and has taken several years to get fully up and running, but now we are beginning to collect the fruits of our labour.

What are the main questions your lab is trying to address?

We have two main areas of research, both of which fall under the umbrella of gene-environment interactions. We want to understand how the environment acts not as a passive but an active player to influence the timing of development and the trajectories of cellular differentiation. I believe this is an often neglected area, as the environments cells are grown under in the lab are highly standardised. It doesn't really give us a full picture of biology if you don't play with the parameters and expose cells to a variety of conditions. Firstly, we are interested in the biology of dormancy within the context of embryonic diapause. This is a reproductive strategy that is mostly known in insects, fish and worms, but is also observed in many mammals. Here, we study the mouse embryo to understand the metabolic, genetic and epigenetic mechanisms with which the mammalian embryo reacts to its environment to completely rewire itself and switch to this resting state of dormancy. In some species, diapause is triggered during periods of nutrient scarcity, whereas in others it is obligate and occurs seasonally to adjust the timing of birth. We hope to understand the mechanisms regulating these processes and whether any of the regulatory pathways are conserved among mammals and between mammalian and non-mammalian species. Our second research focus is hypoxia and how the availability of oxygen acts as an important environmental factor that guides embryo development.

In 2022, you were awarded Development's Outstanding Paper Prize for your work focusing on the influence of hypoxia on gastruloids – could you tell us a bit more about this research and your experience of publishing with Development?

Early development takes place without any direct access to oxygenating tissues in the maternal environment; the embryo is not yet implanted and is not yet vascularised. Therefore, the pre-implantation embryo (and also the early post-implantation embryo) develops in a low oxygen environment. We are trying to understand the effects that this hypoxic environment has on early embryonic development. At this stage, embryonic stem cells are very flexible and have not yet committed to a specific cell fate, so we wanted to specifically see whether oxygen availability changes cell type trajectories or commitment events. In this paper (López-Anguita et al., 2022), we showed that hypoxia induces a primitive streak signature and induces elongation of gastruloids and that this is mediated by hypoxia-inducible factor 1α (HIF1α). Formation of the primitive streak is an important early event that triggers symmetry-breaking during gastrulation via epithelial-to-mesenchymal transition (EMT). In in vitro models of embryo gastrulation, this traditionally requires exogenous Wnt activation; however, we showed that hypoxia can induce symmetry breaking and elongation in gastruloids in the absence of Wnt stimulation.

We decided to publish this story in Development because the manuscripts are handled by Academic Editors who are experts in their fields, and I think there is definitely a virtue in scientific decisions taken by expert scientists. The scientific knowledge was evident in the editorial decision making process, which you don't always find in non-community journals. Aside from publishing, I also really like the efforts made by Development in organising topical conferences and supporting small meetings. I think there's a lot more that Development is doing for the community that goes well beyond publishing, and I think this kind of community building is really important for science and scientists.

More recently, you published a preprint demonstrating for the first time that diapause can be induced in human blastoids and pluripotent stem cells. How did you achieve this and what are the implications of these findings?

During my postdoc, I discovered that mTOR, a major nutrient sensor and promoter of growth, is a regulator of developmental timing and embryonic diapause in the mouse. We showed that inhibition of mTOR induces reversible pausing of mouse blastocyst development and allows their prolonged culture ex vivo. In the lab, we work on several specific mechanisms of diapause regulation, but here we simply ask ‘is this response conserved across mammals’? So, we tested whether we could induce diapause in human stem cells and embryo models (blastoids) by mTOR inhibition. However, if you want to claim that you have induced diapause, you need to achieve three things: delayed development, reversibility of this delay and maintaining original cell identities over this period of dormancy. The cells/embryos/models need to preserve morphology and resume development when released from diapause, and this is what we show in our preprint paper (Iyer et al., 2023), which is rather exciting. This finding still needs to be investigated directly on human embryos to see whether blastoids recapitulate human embryo biology also in this context; however, one clear implication for this is the potential to be translated to clinical contexts in the future. We, in the lab, are more interested in this from an evolutionary developmental perspective and want to investigate principles underlying the diapause response by leveraging the commonalities and differences between species.

What elements, inside or outside the lab, have been key to your success so far?

Science is a difficult job; there are a lot of failures, ups and downs and often a lot of pressure. So, I think in order to succeed, in addition to having that inner drive and motivation, you also need to be resilient and maintain a bit of positivity. It's normal to fail in science; at the end of the day, we are trying to innovate, and that has always been difficult. It is also important to be able to take constructive criticism and feedback on board, which will help make your science better and develop yourself as a scientist. I would say maintaining this focus on the ‘bigger picture’ has definitely helped me to advance in my career.

Speaking of success, congratulations on being one of the recipients of the European Research Council's prestigious Starting Grant Awards for 2023. What does receiving this award mean to you, your career and your research?

It is a great milestone and I am extremely grateful for the award. For me, the most important thing is that we have received really encouraging feedback from the reviewers and the panel in terms of the actual science that we're doing. This funding will allow us to go into a new domain and really address the epigenetic and genetic mechanisms of embryonic diapause, which we have started to do a little bit already, but this definitely gives the lab a bigger push in that direction.

Finally, we all need time to relax outside of work – what is your approach to work/life balance and what do you like to get up to outside of the lab?

I'm not sure if I do have a work/life balance! I definitely don't have a lot of free time outside the lab because I have two young kids, so I spend most of my time with them. If there's ever an opportunity on the weekends, I try to get out into nature. I love being outdoors; nothing fancy, even a simple walk in the park goes a long way for relaxing and soothing. Actually, we have a nice urban park just next to the institute here, and a lot of people, including myself, take walks around there at lunchtime. I find this very helpful for reflecting and creating new ideas. And if I've got any time left, then I try to hang out with my friends. Many of them are my colleagues, so we sometimes end up talking about science anyway, but it's much better to discuss science with a drink in hand instead of sitting on office chairs.

Aydan Bulut-Karslioglu was interviewed by Daniel Routledge, Cross-title Reviews Editor at The Company of Biologists. This piece has been edited and condensed with approval from the interviewee.