Cell scientist to watch – Rebecca Voorhees

Rebecca Voorhees

What inspired you to become a scientist?

Both my parents are scientists, so I grew up immersed in science. My mother loved to do ‘kitchen science’ with us, like boiling red cabbage to make a pH-sensing solution. But I didn't always know that I wanted to do science; during my ‘teenage rebellion’ stage, I was interested in writing. As an undergraduate, my plan was to go to medical school. I had the funding to do a Master's degree, and I thought it would be interesting to go abroad, so I went to the University of Cambridge in the UK with the plan to do research for 1 year and apply for medical school during that time. But after a few months at Cambridge, my supervisor, Prof. Venki Ramakrishnan, convinced me that I should do a PhD. At the time, Venki's lab was pushing the boundaries of structural biology to resolve structures of ribosomes in complex with elongation factors and other translation machinery. The idea of staying and doing research in this amazing lab was so fantastic that I cancelled all my medical school applications!

What drew you to the field of structural biology and protein translation?

As an undergraduate at Yale, I worked on the biochemistry of ribosomes in Scott Strobel's lab and I really enjoyed the idea of understanding how cells make proteins. At that time, it was becoming clear that if you wanted to understand the chemistry and the molecular basis for protein synthesis, looking at structures of the ribosome during this process was a very powerful approach. That's why I became interested in structural biology – I always found the chemistry behind biology interesting, and I was intrigued by the idea of actually seeing how that chemistry happens.

My PhD was purely X-ray crystallography – I think I was the last student to do crystallography in Venki's lab! It was really only as I was finishing up my PhD that getting high-resolution structures became possible with cryo-electron microscopy (cryoEM). But there's something magical about looking at an X-ray diffraction map for the first time and knowing that you're the first person to see how certain molecules work and fit together. The puzzle of interpreting the data is such a satisfying process that it makes up for all the stress that comes with it: trying to generate protein crystals, iteratively screening dozens of conditions, and the randomness of success or failure. We used to joke that it seemed like magic whether you got crystals or not! I think I have a love–hate relationship with structural biology: it's incredibly powerful when it works, but it can be a frustrating field.

Your PhD advisor, Prof. Venki Ramakrishnan, was one of the recipients of the 2009 Nobel Prize in Chemistry. What was it like to work in a Nobel Prize-winning lab as a PhD student?

Venki hadn't won many of the ‘pre-Nobel’ prizes that suggest the recipient might be on the list for the Nobel, so I think he had written off the possibility of being included if they awarded a prize for work on the ribosome that year. The day of the announcement, he came in late because he had a flat tyre on his bike, he had to walk to work in the rain and he was in a horrible mood. We heard him take a phone call in his office and get progressively more irritated with the caller, saying “This isn't a very funny joke. I don't know why you think this is amusing. You have a very good Swedish accent.” He genuinely thought it was a prank call. Finally, he said, “If this is real, then put Måns Ehrenberg on the phone.” Måns Ehrenberg is an eminent Swedish biochemist in the ribosome field who was on the Nobel committee and whom Venki knew personally. Måns got on the phone, and everything went quiet. Then it was suddenly pandemonium!

Venki didn't let the Nobel Prize change him or his science very much. Something I appreciated about Venki as a mentor is that at the end of the day he was just a humble scientist who was there because he loved research. It's been his life's work to understand the molecular basis of translation; he loves the ribosome and was always excited about understanding how it works. The lab environment largely stayed the same as well. Venki's lab was very collaborative, and that kind of environment was a function of doing crystallography – it was so hard that you had to have multiple people working on a project. Back then, we still had to physically spend hours and hours at the X-ray synchrotron. One person can't stay up alone for 48 h to collect data! You needed people to help each other, so we had a team mindset. I've tried to implement that mindset in my lab too.

For your postdoctoral work, you joined Manu Hegde's lab, where you employed structural approaches to understand the cell biology of protein secretion. What inspired you to move into cell biology?

After my PhD, I wanted to work in mammalian systems because I had always been interested in studying processes with relevance to human disease. Manu had just moved down the hall from Venki's lab to the Laboratory of Molecular Biology (LMB), and I was inspired by the way he talked about his science. He is a fantastic communicator, and his work seemed like it was on the next frontier of what was possible in the translation and protein quality control field. Part of this move was also serendipity; my husband was also a PhD student in Cambridge, and he hadn't quite finished at that time, so we were trying to find a way to both stay in the same place. Manu's lab was a good fit for the direction I wanted my career to take, so I got lucky with this opportunity to join an exciting lab that allowed me to stay in the same location with my husband.

My initial plan was to bring my crystallography expertise to the lab. I actually spent the first 2 years trying to resolve a crystal structure of a membrane protein complex involved in membrane protein biogenesis and insertion. However, other labs at the LMB were starting to take cryoEM seriously because it was opening up many new possibilities. I still remember the day I threw out 1000 empty crystal trays at the end of 2 years of unsuccessful work. I went into Manu's office and I said, “I'm done. No more crystallography, I'm going to learn cryoEM.” I came back the next day and completely switched projects! Manu suggested that we think about SEC61, which is a translocon complex involved in protein secretion found in the endoplasmic reticulum (ER) membrane that binds ribosomes and inserts proteins into either the ER membrane or lumen. I was able to learn cryoEM from other people at the LMB, who were kind and generous with their time to teach me.

In 2017, you started your own lab at Caltech. What did you feel was the biggest challenge to overcome as a new PI?

The hardest part was and still is managing, supporting and mentoring people. A new PI needs to figure out how to do that for each individual with their unique background, personality and goals, and make this work both on the individual level but also for the whole lab. I'm still learning, and it remains the most challenging but also the most rewarding part of the job when you get it right. One of the most important things a PI does is train people who will go on and do fantastic things in their careers. The truth is that our science is rarely going to be life-changing for many people, but training people who go on to train other people who go on to train other people creates a ‘domino effect’ that I think can have a legitimate long-term impact on a field in a way that no single discovery that you personally make really can. The ability to mentor people so that they can achieve their own goals and continue to pay it forward is one of the greatest privileges of working in science.

How are the challenges that you face now different?

In a sense, I'm tackling the same problems I had as a new PI in a slightly different way. In the last 6 months, the first wave of people who joined my lab very early on have graduated and moved on to academic or industry positions. My favourite part of being a PI is seeing students come into their own: watching the transformation of a student who starts from scratch in terms of lab experience, not very confident in their abilities, into someone capable of amazing ideas who isn't afraid to give feedback in lab meetings and present their scientific story is a huge privilege. Of course, I go to pieces at thesis defenses – I cry every time! Their success is probably the thing I'm most proud of, but your team members' success also inherently means that people will leave your lab, and refilling those roles is always going to be challenging. An integral part of your team and how the lab functions is now gone and doing their own thing. It's important to plan for this and make sure that you have continuity of your institutional knowledge. Even with proper handover of data, knowledge and skills, finding the right new people to maintain the lab environment and positive team rapport is really hard. I feel like I'm almost rebuilding the lab again. It's scary, but also exciting to hire new people who will carry on the legacy that my first students created.

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

We want to understand the molecular logic of how cells make, target and degrade proteins in order to maintain homeostasis or to enact particular cellular process, such as differentiation or apoptosis. How does the production and transport of different proteins at the molecular level cumulatively lead to a decision at the cellular level? Currently, we mostly focus on integral membrane proteins. Membrane proteins create ‘bottlenecks’ in cellular decision making, because they often are the mediators of communication either between neighbouring cells or between cells and their environment. If you want to control what a cell does, the activity of a membrane protein, its localisation, expression level, stability or degradation are major parameters you could target. We're interested in these questions from a fundamental biology angle, but also because if we can understand how membrane proteins function and how they are regulated, then we might be able to intervene in diseases in which these processes go wrong.

In terms of approach, our lab has moved towards integrating structural biology into cell and molecular biology. We mostly work with human cells, but we also use in vitro reconstitution systems and have even generated some C. elegans models. I don't think I'll ever give up structural biology – it's still so exciting to be able to see molecular machines and understand how they work – but these days I find it a lot more satisfying to do that in the context of a bigger question. If you can understand the molecular biology behind the quality control of a particular protein, then you might be able to influence a disease state or ageing process associated with that protein. This variety of approaches allows us to get at the cell and molecular biology behind these processes.

How do you think that recent advances in structural biology techniques are changing the field of cell biology?

Watching the structural biology field rapidly evolve has been amazing, and I think we're only at the beginning. It reminds me of back when George Palade was first using EM on cells in the 1950s, which allowed huge advances in our understanding of cellular organisation. In the past decade, cryoEM has gone from a niche technique to now the major approach people are using to image complex proteins. With the introduction of cryo-electron tomography (cryoET), I can only imagine what will happen in the next 10 years! The dream for anyone in cell or structural biology is to be able to study protein complexes in situ in the context of their native environment. Advances in cryoET are ultimately going to allow that at a resolution high enough for us to understand the molecular basis of disease processes. Hopefully, we will soon be able to use cryoET to study protein complexes within membranes without taking them out of the lipid bilayer and answer questions about conformational changes, interactions and processes that we can't replicate in reconstituted or purified systems. I think that in the future, structural biology and cell biology will reconverge and be one and the same.

What is your approach to mentoring and establishing a good lab culture?

I think that the way we do science and the people who do the science are just as or more important as the science we do. My goal is for my lab to be a place that people are excited to come to every day. I think the only way to make that possible is to make the lab a positive, supportive and collaborative environment where people enjoy interacting with their colleagues. One strategy that I've taken is to have people work together on projects, with shared reagents and communal resources, which requires a lot of communication. I find that the more communication we have, the more transparency we have between people in the lab, and the better the lab feels, because our success is shared and everyone is working towards our common goal together.

What advice would you give to other scientists aiming to start their own labs?

I hope that my generation of scientists is thinking about how we can collectively improve inclusivity efforts across the scientific collective. For groups that are less represented in the sciences, including women, people from different racial and ethnic backgrounds, LGBTQ+ individuals, and people with disabilities, it's important for them to be able to see themselves in leadership roles in science. When I was a trainee, it wasn't very common to see women with families running research labs, although there are more and more women doing this now. I myself have two young children; the first was born while I was a postdoc and the second after I became a junior faculty member at Caltech. Managing a lab while raising a family is not easy, but it's definitely possible. If you really want an independent academic research career, don't give up! I hate to see women leave science because of the idea that it's not possible to do both things. Academic science has a bad reputation for requiring long hours and being an all-encompassing part of your life, and that can sometimes be true, but it's also one of the most flexible jobs that you can imagine. For the most part, you can set your own schedule, and this flexibility allows you to balance work and family in a way that isn't always possible in other careers or industries.

Are you involved in any outreach activities aimed at improving equity, diversity and inclusion (EDI) in science?

Yeah! I take graduate students into the local public school system in Pasadena, California and do presentations and fun hands-on demonstrations. I was able to get some funding to purchase a whole suite of light microscopes to bring into classrooms. Seeing the pure excitement on a child's face when they first look into a microscope is so special. We tend to forget about this during the daily grind, but for many of us, these types of experiences are why we got into science. I also hope that by sharing science and microscopy with children who might otherwise never have those opportunities at economically disadvantaged schools, we open up the possibility for them to think about science as a potential career option and help increase the pool of people going into science. Having graduate students, especially women and underrepresented minorities, interacting with students at those early ages provides them with role models in science with backgrounds like theirs.

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

I like to decorate cakes and cookies. For my kids' birthdays, I love to make elaborate, multi-tiered cakes that look like Barbie dolls. I eventually want to start making science-themed cakes for my PhD students' graduations, but I haven't had enough time yet. I sometimes wonder if I could take a sabbatical at a pastry school. If science doesn't work out, I'll open a bakery!

Rebecca Voorhees 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.