The people behind the papers – Sarah Soliman and Zara Weinberg Free

Zara Weinberg (left) and Sarah Soliman (right)

Zara, can you give us your scientific biography and the questions you are trying to answer?

ZW: My fundamental scientific interest is in how cells specifically respond to practically infinite environmental stimuli using limited signalling machinery. I started my scientific career studying this question from a behavioural neuroscience perspective, exploring the mechanisms of action of drugs of abuse in animal behaviour. During my PhD, this work shifted more toward a focus on G protein-coupled receptor (GPCR) signalling and trafficking. In my postdoc, as I expanded my research to signalling systems beyond GPCRs, I became fascinated by synthetic biology and cell engineering, fields that allow us to repurpose our understanding of cell signalling to drive potentially therapeutic cellular behaviours. Although I don't have an independent lab yet, I hope that future research I direct will uncover fundamental truths about the mechanisms behind important open questions in cell signalling, and that we can use the knowledge gained this way to programme the next generation of cell therapies.

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

SS: I came to the lab with a scientific background in developmental and stem cell biology. I started my scientific career studying the role of intestinal stem cells in regulating tissue dynamics in vivo in the fruit fly (Drosophila melanogaster) midgut in response to fluctuating environmental cues. Later on, I used stem cells to create in vitro models (cerebral organoids) to study neurodevelopment. Drawn by the complex patterning and self-organising properties that emerge in these models, I was further interested in gaining a deeper understanding of the underlying quantitative principles that drove particular developmental processes, such as tissue organisation. This led me to the lab of Dr Hana El-Samad, which uses systems and synthetic biology approaches to study principles of biological organisation. The timing coincided perfectly with Dr Zara Weinberg's presence in the lab, whose research broadly entailed studying cell engineering and synthetic biology approaches for controlling cell behaviour. Our interests perfectly coalesced at a subset of this research, which encompassed engineering stem cells with synthetic biology tools with the greater goal of studying tissue organisation.

What is the background of the field that inspired your work?

SS: I have been quite mesmerised by the elegant and pioneering work in the synthetic developmental biology field from Dr Wendell Lim, Dr Jared Toettcher, Dr Miki Ebisuya, Dr Leonardo Morsut, Dr Sally Lowell and Dr Satoshi Toda. It's the type of science that, when learning about it, I would think, ‘I want to do something like that!’. This work spans the development of a repertoire of sophisticated tools for controlling cellular behaviour that enable customised responses to arbitrary stimuli, including synthetic receptors that enable orthogonal signalling channels, as well as optogenetic systems that enable precise spatial and temporal control of cell function. By implementing these tools in an in vitro or in vivo context, multicellular developmental paradigms, such as differentiation, patterning and cooperative cellular behaviours, are recreated and interrogated with high precision, shedding light on the quantitative requirements for developmental processes. Given the complexity of development, the field would benefit from additional tools that can enable multi-dimensional control over multiple scales necessary to understand and build more-complex developmental systems. From observing the rapid advancement of immunology research as a result of cell engineering and synthetic biology tools, I thought it would be immensely useful to bring similar approaches and tools into developmental biology research.

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

SS: In this work, we characterise three small molecule and two cell contact-inducible systems for gene expression in and differentiation of mouse embryonic stem cells (mESCs). We show that small molecule and cell contact-inducible systems work reliably and efficiently for controlling expression of arbitrary genetic payloads. We identify how these systems function differently across model differentiations. Furthermore, we show that these systems can drive direct differentiation of mESCs into neurons by overexpression of the pro-neural transcription factor neurogenin 2 to varying degrees. Each of these systems can be used on their own or in combination, opening many possibilities for studying developmental principles with high precision.

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

SS: Absolutely – too many to note actually! I would say that throughout the entirety of this work I've been in a steady state of eureka moments. Every element of it has truly been a joy and thrill. My favourite example was while I was imaging the UAS-Ngn2 SNIPR co-cultures and came across a frame with each of the labelled ‘sender’ and ‘receiver’ cells. Receiver cells were differentiating into tublin3⁺ cells only when adjacent to the sender cell! I caught myself blinking and taking a second look to confirm that what I was seeing was true and felt an instantaneous jolt of excitement. Nothing hits quite the same as actually seeing the product of the culmination of the work that took so much rigor to achieve and builds upon the work that I was so inspired by to do the same.

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

SS: Looking back, I would say the moments where I would find myself frustrated always came down to the external limitation of time and needing to part ways from pursuing other really exciting ideas and interesting avenues that would emerge in the process. However, the flipside to even that is that it allowed me to focus on packaging this work into a toolkit that would be useful for the developmental and stem cell biology community, which is something that I am pretty excited about.

Why did you choose to submit this paper to Development?

ZW: I'm a firm believer that publication on bioRxiv followed by post-publication open review is the future of scientific publishing. But until there are more curation services for preprints, journals are still the best way to make work visible to folks with a particular expertise. Because Development offers Gold Open Access, The Company of Biologists is non-profit and the audience of Development is exactly the folks we think will most benefit from our tools, we selected Development as our target journal from the outset of writing our manuscript.

SS: Development has always been an attractive resource with a rich breadth of work for the developmental and stem cell biology community, and I was eager for our tools to reach this community.

Sarah, what is next for you after this paper?

SS: I am absolutely thrilled that, starting this Fall, I will be pursuing my PhD studies in the Developmental and Stem Cell Biology program at the University of California, San Francisco. I am super-excited to further expand upon my research and contribute to deepening our understanding of the quantitative principles that underlie developmental processes.

Zara, where will this story take your research next?

ZW: I'm so excited about the tools Sarah has built to better enable engineering of stem cells. I hope that we can use these tools to ask fundamental questions in developmental neuroscience, such as how networks of synaptically coupled neurons arise and what network topologies enable specific types of signal processing.

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

SS: Outside the lab, I love spending time with my family and chatting about science with my mom who is also a scientist. I love exploring, retreating and immersing myself in nature, whether it be by the coast or amongst the trees. The San Francisco Bay Area and California overall is an incredibly beautiful place in this regard, given its rich natural history. I also really enjoy baking and sculpting pottery/ceramics.

ZW: I love hiking, biking and exploring with my wife and friends. I'm an avid collector of music, and usually feel at my best right after I've gotten to join a mosh pit at a concert. I'm lucky to be a part of a wonderful caring community outside of work, and I love spending time fostering that and supporting my loved ones. And beyond all that, I like to spend as much time with my cats as possible because they are perfect and deserve all the best things.