Liz Patton is a MRC Programme Leader Scientist in the MRC Institute of Genetics and Molecular Medicine and Chair of Chemical Genetics at the University of Edinburgh. After completing her PhD in Molecular Genetics at the LTRI with Mike Tyers, Liz moved to Harvard Medical School to work with Len Zon, where she developed some of the first cancer models in zebrafish. Zebrafish followed her to Edinburgh where she now runs a research group focusing on using zebrafish to study melanocyte development and melanoma.
What is your current research?
We study zebrafish, particularly developing melanoma models. We are trying to understand how melanoma works at the molecular level, and to identify drugs for melanoma therapies.
What did you study during your PhD?
I did my PhD with Mike Tyers at the Lunenfeld-Tanenbaum Research Institute (LTRI) in Mount Sinai. We studied the yeast cell cycle, with particular interest in understanding how budding yeast went through a transition phase called “start”. During the cell cycle there is a growth phase called G0 in which the cell accumulates mass, and then it will go through a phase called “start” which allows it to enter into G1 of the cell cycle. We were interested in that transition step, and at the time we were working with a series of yeast mutants which we later found out form part of a Skp, Cullin, F-box containing (SCF) E3 ubiquitin ligase complex. Our work was among the first to show that this ubiquitin ligase complex allowed for progression through the cell cycle by targeting specific cyclin proteins for degradation. The timing of cyclin degradation is really important because you need these critical thresholds of cyclin-CDK complexes to push through the transitions of the cell cycle, and then to quickly turn them off.
Did you enjoy your time in the Tyers lab?
Yes, I loved it! We started off at the Banting and Best Institute which was more of an old-fashioned lab with wood panelling everywhere, and then we moved over to the LTRI which was very modern. There were some absolutely fantastic people at the LTRI. There was a great student culture, and I think our cohort of students was quite special, and a lot of us have gone on to become PIs from that time. The PIs were also fantastic: Tony Pawson, Alan Bernstein, Janet Rossant, Mike Tyers, Frank Sicheri, Jeff Wrana, and Joe Culotti. It was an amazing group of people that made my time in Mike’s lab really special.
How did you decide on the Tyers lab after rotations?
It was a really hard choice. I had rotated in Joe Culotti’s lab where we were performing a genetic screen in worms looking for unc mutants. I also, of course, rotated with Mike while he was still at the Banting and Best. It was a difficult decision, choosing between the two of them. I loved the Culotti lab, and the genetic approach. Joe had trained with Lee Hartwell, who won a Nobel prize for his contributions to understanding the yeast cell cycle, so he was very understanding when I told him I wanted to keep working on yeast. In the end, I think I just fit into Mike’s lab really well, and the story was moving very quickly so it was an exciting time.
Did your interest in yeast arise from your undergrad research?
Yes, I studied yeast as an undergraduate with Gerry Johnston at Dalhousie University, who also had worked with Lee Hartwell. In the Johnston lab I studied a cold sensitive mutant that was also involved in exit from the G0 phase. So I was already very interested in the field when I started my graduate studies in Toronto. Gerry was heavily involved in the Terry Fox Foundation, so even though it was “just” yeast I also knew it had profound implications in cancer. I think that was fundamentally what I wanted to do, and even though I loved Joe’s lab, I loved the idea of studying cancer pathways even more.
What drew you to Toronto from Dalhousie?
Toronto was and still is the biggest and the best research university in Canada and I wanted to be in the most competitive place. I had other options that looked great, but in the end, when you’re young, you want to be where the action is, naturally.
What was your career path; how did you come about starting your own lab?
After completing my PhD in Mike Tyers’ lab, I went to the United States on a Human Frontiers Program Award to do a post-doctoral fellowship at Harvard Medical School with Len Zon. I went in thinking I would do a screen for cell cycle mutants in zebrafish, just like had been done in yeast, and test their potential to develop cancer. We started that screen and had some great initial success, but during that time, the BRAF kinase was discovered to be heavily mutated in melanoma and so we took the mutant allele of human BRAFV600E and put it into fish. We showed it was sufficient to cause precancerous nevi to form, and then secondary mutations could cause the nevi to become melanoma. That was the first animal model to show that BRAF could really be an important driver in cancer. I was at Harvard for 3 years, after which I came to the UK to set up my own lab.
How did you come about finding that post-doc opportunity?
As I was nearing the end of my PhD, it was an exciting time for yeast and cell cycle research. The yeast genome had been sequenced, and many mutants had been identified from various cell cycle screens, and understanding the roles and molecular mechanisms of the corresponding genes was an area of active research. Yeast research was also beginning to work at the genomic scale. One idea I had was to continue in some of the excellent yeast labs studying the cell cycle. I had also considered moving to a multicellular model system, but I knew I wanted to stay in the cancer arena. As I was mulling things over, Alan Bernstein requested to see me to discuss my post-doc ideas and we had a very good chat. His advice was not to fall in love with the organism, but fall in love with the biological question. His worry was if I became too attached to yeast I wouldn’t develop the breadth to be able to ask good questions outside of yeast. Around that time, Janet Rossant had a small library on the 8th floor and there was an issue of Development that reported on some big genetic screens from zebrafish that had been completed a few years earlier. The compelling cover story showed a bunch of different tail fin mutations that showed pigmentation defects. That was so amazing to me, because now I could see how one could take the power of yeast genetic screens and do it in a vertebrate. Although really exciting, I was not sure how to proceed because I wanted to study cancer more than development. Mike knew I was interested in multicellular organisms; he told me he had met Leonard Zon, who was performing cell cycle screens in zebrafish. I went to Boston, interviewed with him, and was excited to be offered a postdoctoral position.
For me, it really did take about 6 to 8 months of thinking to figure out what my goals were. I strongly recommend going to visit people, because your perspective can really change when you interact in person. I had also visited some labs that had identified mutations in cancers, but realized that many were different sequencing projects and that was not an approach I found as interesting as genetics. I wouldn’t have known that unless I visited in person. I would recommend that you tell people your ideas and get feedback, especially from people that you trust as I did from Alan Bernstein. It is important to listen to them.
How did your time in the Tyers lab shape your approach to mentorship as a PI?
Mike is very driven with a very strong work ethic. I really liked that because I always felt that if I worked hard, it would be appreciated. We produced a lot of great work together. He was very supportive, and created a really positive work environment. He also taught me how to write scientifically, which has been crucial to my success. Mike has a lot of integrity as a scientist, which is something I try to emulate every day. I make sure things are not done slap-dash, but rather carefully and thoroughly. He is incredibly generous, and he always made time to go through data carefully with his students. We were treated as scientists when we walked through the door, and not simply as students, so you quickly felt you needed to work at a high level. Those are some of the qualities I learned from Mike that I really try to channel now in my own lab.
What was the most difficult aspect of transitioning from a post-doc position to starting your own lab as the principal investigator?
One of the difficult things to learn is how to manage people, and it is always harder than it feels it should be. It is not simply about being nice and fair. I think age helps and experience is essential, because as you get older the age gap is bigger and you have more experience to know what issues are big and what are small. You learn what things people will sort out for themselves and the situations where you have to become more involved. Right now I have a strong group in my lab, so it makes my job of managing them a pleasure. I have two children, so it can be hard to balance work and home lives. I was fortunate to have some strong students when I first started my lab so it also made that transition a bit easier.
What do you think are the key elements of running a successful lab and research program?
It’s good to have diversity in the group, both a diversity of skills but also diversity of experiences. It’s nice for me to have a mix of older and younger members in the lab because sometimes the older people have more perspective and insight and they can help mentor some younger trainees in the lab. I have a very heterogeneous group currently and they work extremely well together. I do wish I had more time for the lab. When I was a student, Mike would take us out for lunch as a lab or other social things as a group, which was always a great time. I wish I had more time to do those things with my lab but that's just because I have to balance my family life with my work life and you can’t do everything.
You also have to be very organized, and be trusting of your trainees. You need to be able to trust people to do their work, and it doesn’t help for you to be there in lab all the time. My lab is at a stage now where sometimes the best thing for me to do is to go home and let people do their own thing. Knowing when to step back and when people need support is important. At the beginning I was very hands-on with my trainees, but now the people in my lab are very accomplished and capable. Now they need me at a bit of a higher level: thinking about direction for the project, looking over data and aiding in interpretation, helping them with grants. Figuring out your niche is also challenging. Coming out of my post-doc I had so many ideas that can almost weigh you down, because you can’t possibly address all those questions well.
Finally, it is important to remember that science is a social endeavour, and your interactions with people are key. The way that you review a paper or handle yourself at a conference will be remembered. You have to be able to make friends and interact with people, despite a conflict of ideas.
How do you prune ideas to focus your research questions?
I think that technological advances guide the type of work that can be done and allow us to answer new, different questions. The advent of CRISPR and improved imaging techniques helped because suddenly we could do things we couldn’t do before. A lot of ideas come to me during grant-writing, and writing is really important to help crystallize and flush out those ideas. That’s a big part of my own intellectual development - when writing a grant you can see your aims and what are you going to do to achieve those aims clearly before blindly jumping in. It helps you form a plan and articulate that vision to other people. Of course that vision will change and evolve every 5 years or so as you reassess the direction of the work. It is important to keep it fresh and stay relevant within the field. Finally, I think it is very important for one to be able to define oneself with a tagline, which keeps your research focus defined. For example, mine right now would be “zebrafish, melanoma, and chemical genetics”.
What is your most important/impactful discovery?
I have two big ones that come to mind. In my PhD, our most impactful finding was discovering how E3 ubiquitin ligases target selective substrates for degradation. In my post-doc, my most important contribution was demonstrating that BRAF mutations promote nevi and melanoma in an animal model. That was really a game changer because it was foundational in that field.
What are your favourite memories from grad school?
One of my favourite moments from grad school involves a key observation I made for a story we published back in 1998. There was an emerging idea at the time that SCF-E3 ubiquitin ligases determined substrate specificity through F-box motifs. The substrate of the F-box protein Met30 wasn’t known, but what I showed was that one of these substrates was involved in methionine biosynthesis. I specifically recall doing a Northern blot, and I remember standing in the dark room while the blot came through the developer, and instantly understanding the significance of the result. I remember almost running to Mike’s office to tell him. It was just such a great memory, a real game changer moment for me.
On a lighter note, other great memories involve socializing with our lab. Often we would go up to Bloor at night (we all worked quite late) to get ice cream in the summer. It was special from me having come from Halifax where it would be too cold to enjoy ice cream most days. We would also go to Baldwin Street; there was a Chinese restaurant on the corner where we used to eat quite a lot. Those times were also really fun.
(Contributed by Jonathan Palozzi)