The people behind the papers – Emily Bulger and Benoit Bruneau

Emily Bulger (left) and Benoit Bruneau (right)

Benoit, can you give us your scientific biography and the questions your lab is trying to answer?

BB: I obtained my PhD in Physiology at the University of Ottawa in Canada with Adolfo de Bold, who had discovered that the heart is an endocrine gland. I then did a postdoc with Jon and Christine Seidman at Harvard Medical School, where I married my love of developmental biology and modelling human disease in mice. My first independent lab was at the Hospital for Sick Children in Toronto, after which I was recruited to the Gladstone Institute of Cardiovascular Disease where I have been for the last 17 years. My lab broadly aims to understand how the genome is wired to control decisions in heart development, and how this wiring goes awry in congenital heart disease.

Emily, how did you come to work in the lab and what drives your research today?

EB: I was really excited by the lab's expertise in understanding how gene dosage regulates development and how this complemented the work I had done in Dr Todd McDevitt's lab using in vitro tools to better understand both basic biology and disease models. I'm interested in finding the first signals that go awry when development doesn't progress how we expect it to, and I think in vitro models have a ton of potential for complementing in vivo work to teach us some of the basic principles of cell behaviour and fate.

Can you tell us about the background of the field that inspired your work?

EB: Brachyury has a rich history in developmental biology as one of the first gene mutations isolated by a radiation mutagenesis screen by Nadezhda (Nadine) Dobrovolskaya-Zavadskaya in 1923. Since then, it has been foundational for understanding mammalian gene regulation and embryonic development. Still, questions remain about how and why gene dosage leads to dramatic differences in phenotypes. We were excited by the prospect of applying relatively recent tools, such as single-nucleus sequencing and in vitro stem cell models, to get at these questions with more precision and detail than has been previously possible. We were also motivated to extrapolate findings generated by the field from model organisms to the behaviour of human cells, which have been historically inaccessible.

Can you give us the key results of the paper in a paragraph?

EB: We found that TBXT dosage directly correlates with the timing of a process known as the epithelial-to-mesenchymal transition, or EMT, a change in the physical properties of the cell that enables cells to become more migratory. Interestingly, this transition seems to occur independently of mesoderm specification, since all our cell populations seem to generate nascent mesoderm regardless of TBXT dosage. We suspect that the precise timing of EMT is crucial for the subsequent development of the mesoderm and cell migration that enables the patterning of the adult organism.

When doing the research, did you have any particular result or eureka moment that has stuck with you?

EB: Doing time-lapse imaging and being able to clearly visualize differences in cell migration across the genotypes was really striking to me. Looking at cell fate using in vitro differentiations is one thing but recapitulating certain aspects of cell behaviour in vitro is another, and it was impressive to me that even without the confines of the embryo or signals from adjacent tissues the cells still showed such clear differences in their shape and movement patterns.

And what about the flipside: any moments of frustration or despair?

EB: As the flip side to the prior question, it took us quite a bit of troubleshooting to figure out the best ways to quantify cell movement in our in vitro system. Cell density can be a big obstacle in confined gastruloids, and ingression-like movements often occur in the z-direction, making imaging tricky. We went through a significant amount of optimization to find a way to differentiate mesoderm cells and visualize differences in cell behaviour, but I'm really proud of the tools and analysis pipelines we were able to add to the lab's arsenal and the biology lessons we were able to gain from them.

What is next for you after this paper?

EB: I am currently wrapping up my PhD dissertation at UCSF. Going forward, I'm excited to leverage the tools I've acquired in developmental and stem cell biology to generate and effectively communicate science in the biotech industry. Details to be determined!

Why did you choose to submit this paper to Development?

BB: For 25 years, Development has been one of my favourite journals to read and publish in. A venerable journal with a rich history and a fair review process.

Benoit: Where will this story take your lab next?

BB: We are keen to model transcription factor haploinsufficiency in human systems, and to mechanistically understand its basis. We have embarked on new experiments to address the question of what happens to the remaining 50% of the transcription factors.

Finally, let's move outside the lab – what do you like to do in your spare time?

BB: I have teenagers who keep me busy, especially on the soccer pitch sidelines, but otherwise I like to catch some bands (last week, two shows: Ministry and Branford Marsalis!) and eat some good food (the spicier the better!).

EB: I really love art and have recently been spending a lot of time drawing and painting. It lets me dig into the creative and meditative sides of my brain, which I like to think leads to better science! I'm also a big fan of the outdoors and love finding new trails near the redwoods in our area.