Cell scientist to watch – Dan Dickinson

Dan Dickinson

What inspired you to become a scientist?

I wanted to be a scientist for as long as I can remember. As a kid, I was constantly digging in the mud to find living things in the little stream behind my house and making baking soda and vinegar volcanoes, and I have vivid memories of trying to convince my parents to turn our extra bedroom into a chemistry lab for me when I was five. The inspiration for my current scientific track came from my seventh-grade science teacher when I was thirteen. During a brief unit on genetics and heredity, I remember being blown away by the idea that traits are heritable via rules that we can understand, and that the things being inherited are actually little tiny machines that do specific things within a cell. That concept still gives me goosebumps sometimes! That was my introduction to biochemistry and I've been chasing that inspiration ever since. I majored in biochemistry as an undergrad, and while my research has moved towards more developmental questions, biochemistry still frames the way I think about scientific questions.

After your undergraduate degree at Iowa State University, you spent a year in Switzerland as a Fulbright scholar. How was your experience doing research abroad?

This was my first opportunity to work in a lab full-time, in a radiation oncology lab at the University Hospital in Zürich. I learned a lot about how to structure my time, how to plan and be efficient. One of the most important things I took away from that experience was recognising how challenging it is to be a scientist in a foreign country. As an American, I realised that I took for granted the fact that I could go to work every day and speak my native language. When I was in Zürich, I tried to speak English as little as possible, partly because it made me feel awkward to have everyone else accommodate me. There are so many international scientists who come to the US or Europe and operate in a foreign language all the time. Experiencing that myself gave me a lot of respect for people who are able to work at a high level scientifically using a second language. As a PI, it has made me try a lot harder to be welcoming towards lab members from other countries.

Your research background spans cell biology and biochemistry. How do you think these two fields complement each other?

It's more that these fields are two parts of a spectrum. I don't think you can understand cell behaviour without understanding what the molecules that create that behaviour are doing. At the same time, I don't think you can really understand biochemical systems, especially signal transduction systems, outside of the context of what they do during development. I credit my graduate co-advisor Dr James Nelson, an epithelial cell biologist, for instilling my fascination with cell behaviour. I joined his group at Stanford University in California, USA, via a collaboration with my other co-advisor, Dr Bill Weis, who was a structural biologist. From a training standpoint, working in both fields was phenomenal because I had to learn how to talk to people from multiple scientific backgrounds. When I was a PhD student, I had to be equally comfortable talking to both crystallographers and live-imaging microscopists, which are completely different technical fields. What made it work in my case was that my two co-advisors were great friends and had been working together for years. When I'd have meetings with the two of them, they would literally finish each other's sentences! They were 100% on the same page about what I and what the project needed. This training environment got me really interested in thinking about molecules in an in vivo context and bridging the gap between cell biology and biochemistry. Coming up with better ways to think about how proteins regulate cell behaviour has been a holy grail for my career ever since.

In 2017, you started your own lab at the University of Texas (UT) at Austin, USA. What was the biggest challenge you faced as a new PI?

Learning how to mentor people was, and still is, the biggest challenge for me. I think that I have taken pretty good care of the people in my group and have given them good training, but I didn't appreciate until I started my own lab the extent to which every lab member needs a different style of coaching and mentoring. Everybody is good at different things and needs help with different things. Getting to know every person as an individual and adapting my training to what they need is a challenge, but it's also rewarding. When you get it right, you can really see people grow as scientists, and that's very satisfying.

My mentoring style is to ensure that people have ownership of what they're doing. I'm not the kind of advisor who will tell somebody what to do every single day; I like to let their interests, ideas and motivation drive the project. I view my role as a coach who can help them figure out how to get where they want to go, rather than forcing them to go where I want them to. I look for lab members who are self-motivated, who want to be in charge of their own projects, and who are willing to take the bull by the horns and think for themselves. But that doesn't mean that I don't help. I meet with everyone regularly and try to give them guidance to make sure that they don't get too off track. I like my students to be in the driver's seat and take the initiative and that means that sometimes I have to let them make their own mistakes, but I think that is the best way to learn.

What are the main questions your lab is currently trying to answer?

We work on cell polarity, which is a problem that's fascinated me for a long time. Polarity is understudied compared to processes like cell migration or division, yet it's a cell behaviour that is totally fundamental to the way that our tissues are built and the way they operate. Polarity is characterised by two opposite sides of a cell acquiring different properties. At the biochemical level, how do you build a protein system that can generate an asymmetric pattern that organises a polarised tissue, and how can that system be controlled? Furthermore, how are those signalling systems adapted to function effectively in different contexts? For example, in a healthy epithelium, it's not enough that every cell has its own apicobasal axis: they all need to be aligned and oriented correctly. For this to happen, there has to be coordination between cells, across a tissue and within development. It's not enough to just have a symmetry-breaking system – the mechanism has to be responsive to the cellular environment in the specific developmental context. Understanding these phenomena are the main questions we're interested in.

What do you find most fascinating about the phenomenon of cell polarity?

To this day, I'm still amazed by the fact that protein molecules can generate large-scale patterns within cells and tissues. Molecules that are just a few nanometers across can assemble spatial patterns 10,000 times their own size. Humans can't even do that, and we're ostensibly smarter than molecules! One aspect of polarity I think is particularly cool is the fact that many different cell types in our bodies that superficially look nothing alike use some of the same protein machinery to break symmetry and generate polarity. A priori, you would never think that a neuron, an epithelial cell and an asymmetrically dividing stem cell all use the same machinery to polarise, and yet they do. How can that be? I think there's a tremendous opportunity to understand how molecules can generate different cell behaviours and how these systems are responsive to external signals.

What are some interesting new methods you have adapted to study polarised protein networks?

For the last 12 years, I've been working on an approach for measuring protein interactions in single cells. I'm a child of in vitro biochemistry, which is a powerful approach, but at the end of the day, it's not physiological. Particularly for the signalling pathways we study, everything is driven by post-translational modifications. Reproducing the modification cascades that drive cell polarity in a test tube with purified proteins is infeasible. In contrast, in cell biology, imaging and phenotyping of mutants can give you a lot of information about causality and help put signalling pathways in order, but it's not truly telling you what the molecules are doing. My goal for a long time has been to fill in the space in between these approaches in order to have access to the kind of information you can get from in vitro biochemistry but using in vivo samples.

We've approached this by miniaturising and improving the quantitative power of co-immunoprecipitation (co-IP). We take single cells, confine them in a microfluidic channel and explode them with a pulsed laser to make a tiny single cell lysate. Then we capture and count protein complexes, using antibodies against fluorescent protein tags that we've inserted into endogenous genes. Each single-cell experiment takes about 5 minutes, so we can readily analyse 20 or 30 cells a day. Using single-molecule imaging and computational tools, we can count and measure every complex we observe. This gives us access to a huge amount of quantitative information about hundreds of thousands of individual protein complexes, and it allows us to observe things like precise changes in signalling pathways over developmental time, which is hard using bulk approaches. We can also take measurements of the kinetics within a complex using native proteins in their endogenous context. One of my long-term dreams has been to build enzyme assays into this platform, so that we can simultaneously measure not just what a protein is interacting with, but what its signalling activity is. This system is finally starting to be as effective as I'd always dreamed it could be, and we're learning a ton of cool new things about how the polarity system is organised in C. elegans, how polarity complexes change as cells polarise, and how development regulates biochemistry.

Many cell types in many organisms are polarised at various stages of development – how do you chose which model system is best suited to study the biochemical dynamics of polarity?

C. elegans is a wonderful model to study polarity because a healthy adult worm produces a new embryo approximately every 30 minutes. The embryos all polarise in exactly the same way, following the same steps, with the same timing, which is awesome from a cell biology standpoint. We can also very quickly generate different mutations and modifications to test our hypotheses. Overall, it's a really appealing system for answering mechanistic questions efficiently in an in vivo context. That being said, we don't only work on C. elegans zygotes – we're actively trying to translate what we've learned in worms into other systems. I think it is very important to show whether the principles and mechanisms established in C. elegans hold up in a mammalian system as well. To address the question of how signalling pathways get adapted to different contexts, we're going to have to work on multiple different cell types. I don't think we'll ever stop working on C. elegans, but my goal has always been to have a lab that works on whatever system is most appropriate for a particular question.

We're currently building a 3D organoid system with mouse embryonic stem cells (mESCs). When you let mESCs exit naïve pluripotency in 3D culture, they will self-organise into a beautiful polarised epithelium within a spherical cyst that resembles the famous Madin–Darby canine kidney cell model. The great thing about mESCs, though, is that they're karyotypically normal and that the transition to a polarised epithelium actually mimics what those cells do in a mouse during development. It's a system that's accessible for biochemistry and imaging, but still has in vivo relevance. In the long run we hope to be able to push those cells down different differentiation pathways for comparative studies. How does the same signalling pathway work in different kinds of cells? Once we've engineered a particular cell line to answer a specific question, we can analyse the dynamics of signalling along different routes of differentiation.

You recently received a National Science Foundation CAREER award, which recognises outstanding early-career researchers who prioritise integration of research and education. What do you enjoy most about being a science educator?

It means a lot to me to get that kind of acknowledgement. As an educator, I always think back on the mentors and the teachers who inspired me, because I wouldn't be where I am without their efforts. Paying that forward and trying to be that person for somebody else is really meaningful for me. In terms of what I specifically want to accomplish as an educator, I think there are so many people who, even as biology or science majors, have never been exposed to what scientific inquiry really is. Sadly, the impression that a lot of students have is that science only lives in textbooks, and that cell biology just means memorising cartoons. In the classroom and through undergraduate research efforts, I strive to bring students the excitement of learning something new and give them a flavour of what scientific inquiry looks like in modern cell biology. What kinds of questions do we ask? How do we answer those questions? What are the key experimental tools that that we have? I recently finished teaching the fall semester of an undergraduate cell biology course. The motto for this course was ‘How do we know what we think we know?’, which I credit to one of my teaching mentors at Stanford, Joe Lipsick. Especially in our modern era, where facts are not as solid as they once were, asking ‘how do we know’ is more crucial than ever, and it's the most fun part of doing science.

How do you use the research environment to inspire your students?

One of the things that I love about being at UT Austin is the huge and tremendously talented undergraduate population. The College of Natural Science at UT Austin has a programme called the Freshman Research Initiative (FRI), which aims to get as many students as possible engaged in research during their freshman year. I sponsor a stream within the FRI, which provides dedicated space and materials for a group of 36 students per year to do experiments and be trained by a PhD-level staff member on a day-to-day basis. Our students are learning how to do genome editing in worms. They get to look at a gene that's never been studied before or has only been studied in a very limited sense. I have them knock it out, tell me the phenotype, tag the gene and tell me where the protein localises. The worm lines that they generate get sent to the Caenorhabditis Genetics Center at the University of Minnesota, which is the strain repository for the C. elegans community, so they can be requested by anybody. Once the students have spent a year in the FRI, those who are really excited about research can then be brought into faculty members' labs. I have a couple of undergrad researchers in my group who joined through that route, and I think it's been a really good experience for them.

Finally, could you tell us an interesting fact about yourself that people wouldn't know by looking at your CV?

I used to be a fairly serious jazz drummer. I began taking music lessons when I was six; I started on piano and then switched to percussion when I was nine. My undergraduate degree was actually a double major in in biochemistry and music performance. When I was 18, I didn't know whether I wanted to be a musician or a scientist, but I woke up one morning and realised that it would be much easier to be a professional scientist and an amateur musician than the other way around! I've always thought if science didn't work out for me, I would just go get a gig in a nightclub. But as a new PI, staying up late to play in a jazz club and getting up early the next morning to teach classes was a rough combination. In 2018, I helped put together an impromptu jazz band for the Society of Developmental Biology meeting in Portland and played at the closing reception. That was really fun! These days, I play more classical percussion, like timpani.

Dan Dickinson was interviewed by Amelia Glazier, Features & Reviews Editor for Journal of Cell Science. This piece has been edited and condensed with approval from the interviewee.