Transitions in development – an interview with Nika Shakiba

Let's start at the beginning – when did you first become interested in science?

My days of science interest probably started with insect collecting as a young girl. I was also influenced by Steve Irwin. He was my idol growing up – I used to watch Crocodile Hunter, where he was catching different kinds of wildlife to explain cool things about them. That got me hooked. I wanted to be Steve Irwin when I grew up!

What did you study for your undergraduate degree?

My undergrad is in engineering science. The Engineering Science program at the University of Toronto is fun because you don't really declare a major. You become an engineering scientist, and then you specialize in the third year. I chose biomedical engineering at that point.

You stayed at the University of Toronto to complete your PhD with Peter Zandstra. What were you working on during that time?

I think my undergrad gave me some vision about what a biomedical engineer is, and I learned how to apply traditional engineering tools to develop medical devices. But when I came across Peter's research lab, I was shocked that engineers could be allowed to play in biological sandboxes. Peter trained as a chemical engineer but is addressing fundamental biology questions. That captivated me. Working in the stem cell field was also intriguing to me, because I came to realize that there's a proud history of stem cell research in Canada, so it was fun to contribute to that lineage of stem cell discovery.

When I entered Peter's lab, I had never touched a pipette or worked with cells. So, I started getting trained in cell culture, and by the end of my PhD I was probably 95% experimental. But I still had this computational side to me, which came in handy. My project was looking at how heterogeneity in the starting fibroblast pool could shape the dynamics of that population of cells as they reprogram to become induced pluripotent stem cells. I thought that perhaps we could apply tools like DNA barcoding to track each of these cells as they're progressing through programming and see if we could pull out some underlying dynamics that are not obvious just by looking at the data, but that really required a mathematical model to interpret. One of the outputs of my PhD was identifying that there are competitive interactions between fibroblasts as they're reprogramming; a subset of them are destined to be elite reprogrammers, and that influences what their neighbors do.

Was it quite a mixed lab group in terms of expertise?

Definitely. Peter likes to bring in cohorts of classically trained engineers, physicists and mathematicians, as well as biologists and immunologists. I really loved that about his group. Of course, it has challenges: it means all those people like me need to learn the basics. But it created a nice environment for peer-to-peer learning, and we also had great collaborators. For example, we worked very closely with developmental and molecular biologists, like Derek van der Kooy, Andras Nagy and Jeff Wrana's group. We also worked with Sid Goyal, a biophysicist, doing stochastic mathematical modeling of our cells during the reprogramming process. Of course, his in silico experiments were a lot faster than my in vitro experiments, so he often beat me in races, but it was a lot of fun to compare our results!

You went on to MIT for your postdoc with Ron Weiss and Domitilla Del Vecchio, where you were developing genetic circuits to guide gene expression. What motivated you to take that next step?

My postdoc was kind of serendipitous, because I first came upon the synthetic biology field while watching a PBS special episode on a flight returning from a conference. They were interviewing George Church and Ron Weiss, and talking about this idea of cells as engineerable systems, like computers that you could program. I was very much in that realm of thinking already, as an engineer, but I was also working with reprogramming of cells where I could just perturb four genes and observe huge changes in cell behavior. It got me thinking that maybe we could apply this synthetic biology lens to mammalian stem cells, and think of them as these engineerable substrates that we could reliably, predictably perturb genetically to get a biologically or clinically relevant output. I told Peter that I'd watched this special, and that synthetic biology seemed like a really interesting field. He said that it could be a good fit for me, because they apply engineering design principles to cells. So he suggested that I attend a synthetic biology conference to find out more, and that's where I met Ron Weiss and Domitilla Del Vecchio. I stayed in touch with them, and later I followed up to suggest that we could work together, because I remembered they were interested in applying synthetic biology to reprogramming. It became a nice marriage of expertise; I joined their teams and started learning the basics of synthetic biology. I had a fantastic senior PhD student, Ross Jones, who became my synthetic biology guru, teaching me all the basics in the lab.

We wanted to develop a new way to genetically engineer reprogramming cells, such that we could precisely tune gene expression levels and really think of this as a parameter that you can control. This contrasted with the tinkering approach I was taking before, where we used classical reprogramming systems to throw in an exogenous cassette expressing these genes and hoped for the best. The aim was to find if there's a sweet spot for these reprogramming factors, so we developed a ‘genetic circuit’ to control OCT4 levels, and we identified the level of OCT4 expression that produced the most efficient reprogramming outcomes. This is just a case study; the idea would be to apply this genetic circuit approach to reprogram cell fate in other contexts, deliberately controlling what the cell is doing by perturbing the genes in a predictable way.

You went on to establish your own lab at UBC. How did you form your research niche?

I was really lucky, because my PhD supervisor, Peter, and my postdoc co-supervisors, Ron and Domitilla, were all very supportive of my aspirations. I was applying for faculty positions the moment I walked through the door at MIT, which was probably atypical, and I did a rather short, two-year postdoc. So, I was already crafting my research identity, anticipating what synthetic biology could allow me to do and merging that with my stem cell bioengineering background. Ron and Domitilla were quite supportive early on about seeing that intersection and carving out my niche. And my niche really formed around some of the things I had found in my PhD, which was how competitive cell interactions could be impacting what the cell population does. My idea was to apply synthetic biology to reverse engineer these interactions and understand how they work. Then, once we know these rules that influence cell-cell interactions in our stem cell systems, maybe we can forward engineer them or program them.

Can you summarize the research themes of your group at the moment?

We are broadly interested in understanding how cell interactions impact cell fate decision making in developmental systems, and our substrate of choice is pluripotent stem cells. Within that theme, we have some relatively diverse projects. Our more translation-oriented projects focus on developing, for example, robust manufacturing pipelines for growing pluripotent stem cells at scale. These cells are often grown in bioreactors and suspension cultures. We now know that competitive cell interactions in that context are important because they shape which cells overtake that culture system. We are trying to understand those competitive interactions and how we could leverage them to make sure that we're making safe, high-quality pluripotent stem cells for cell therapy development. We also have projects looking more at the differentiation side. Once we've got pluripotent stem cells, can we predict which ones will go on to differentiate into specific cell lineages or cell types? And we have reverse-engineering projects looking at the molecular basis of cell-cell competition. We now know that pluripotent stem cells engage in competitive interactions with each other where there are winners and losers. Winners are often bullying the losers in a contact-dependent way, causing them to be eliminated from culture. We're using omics approaches to understand the basis of that, and then to program cells once we know the rules.

We also pepper in some computational projects. We're doing some game theory modeling with a collaborator (Maria Abou Chakra in Gary Bader's lab) to try to understand the evolutionary basis of competition. Cell competition in embryos has been reported since 1975 in Drosophila, but in the past decade we've realized it happens in mouse embryos too; around one-third of the epiblast cells get purged early in mouse development. That seems rather costly, so why are these kinds of competitive interactions happening? We're also modeling the gene regulatory networks inside pluripotent stem cells and seeing if we can predict their fate.

What were your most important considerations when looking for group leader positions?

I had very practical considerations. I had a kind of existential crisis towards the end of my PhD, where I was wondering what I should do, and whether I would get an academic position as a group leader. It's a risky strategy, since the majority of people don't end up getting group leader positions. So, I started opening all the doors to see which one would be the most suitable. I applied to medical school and to industry positions. Soon after, I applied to my postdoc position with Ron and Domitilla, which I thought was such a good fit. It was also a good option practically, because it was in Boston; at the time, my husband and I were living in Toronto, and he was unable to move. With those options open, I had a lot of input from my mentors, particularly Peter, who encouraged me to talk to people in each of these three professions to find out more about their experiences. I ultimately decided on the postdoc option because I figured, you know what, I'll set myself a timer, I'll give myself 2 years. And if I don't get a position in that time, I won't do this anymore, I'll do something else. So I started applying for faculty positions as soon as I started my postdoc, to maximize the options. My husband and I wanted to live in Canada; Canada's a large country, but really doesn't have that many universities, so I put out a handful of applications and hoped to get a position in the end.

At the time I was making my faculty applications, there was a lot of interest in Canada to bring in more synthetic biology expertise, so I had a unique niche and something that was being sought after. I ended up with a few offers, which was a lucky position to be in. The thing that ultimately drew me to the University of British Columbia was that they were developing a new School of Biomedical Engineering. I really liked the idea of helping to shape a new image of what a biomedical engineer is. I had been encouraged to start thinking about biomedical engineering not just in terms of devices that we engineer around the body, like ultrasounds, or MRIs, or prosthetic devices, but in terms of engineering biology itself, and engineering the molecular interactions inside the cell. I wanted to bring that perspective to the School of Biomedical Engineering. I also loved that there was a strong cohort of stem cell researchers in Vancouver, and that Vancouver is a biotech hub; the largest biotechnology company in Canada, Stem Cell Technologies, is in Vancouver.

What have been the most challenging aspects of transitioning to a group leader role?

I think part of the challenge is that you don't really know what to expect. Every day was a new adventure, and a new thing I needed to learn: how to do financial management and tracking of our ordering, figuring out where to fit all our equipment and the best equipment to choose, figuring out how to hire a team, developing a mentorship framework that would work for each student. I don't think I really appreciated what those different hats would entail, and how much more learning they would require. I also started my lab during the pandemic, in July 2020. It was a bit of a ghost town on campus. Our building was rather empty and there were few people around to share the enthusiasm of starting a lab. There's something so important about having other excited scientists around you as you're setting up a research group. So building up a rapport and team spirit was challenging.

And, on the flipside, what do you most enjoy about running a research group?

I think I'm appreciating now that the part I love most is the people. Often, I think group leaders like me say that the science is the coolest thing. Obviously, it would be amazing if we could achieve the dream of making cells into these programmable units, and I definitely have my eye on that prize, but the thing that brings me day-to-day enjoyment is the individuals that I work with. It's the humans that make the scientific endeavor so fulfilling. I think it's because you have an opportunity for immediate feedback when you're mentoring or working with people. By contrast, you hope that your scientific work will change our understanding of the system or how we can engineer the world around us and make our lives better, but there's no guarantee that will happen. Sometimes it doesn't even happen in the lifetime of the scientist. So, the immediate reward for me is the people: seeing my trainees grow, overcome challenges, mature in their professional and personal identities, and figure out what it is they want to do and how they want to do it.

What has been your approach for hiring new team members?

I think everyone has a different rubric when assessing applicants. I look for whether that person has a genuine scientific passion for what we do in our lab, our ethos of applying an engineering lens to biology, and the kinds of questions that keep us up at night. We select for that passion first, because that's something I can't teach. To me, this is more important than how well someone has done in their courses. I also try to select for someone who's comfortable with being uncomfortable. Perhaps they've switched fields or learned new things. I think that's a really important quality in science: to be gritty, resourceful and willing to learn. I hope that we can provide everything else, such as the technical training and the support to learn, so I'm not really selecting for technical skills. This perspective could change over time, but that's the strategy we've taken so far.

What advice would you give to people starting their own labs?

For me, the most impactful thing so far has been my peer network. My mentors were absolutely influential in shaping my early trajectory, and my pool of mentors has only continued to grow. Now, my peers are also my mentors, not just the more senior supervisors. Usually, the first people I will go to for advice, or to figure out what to do in an unknown situation (which is daily life for me now!), are my peers. So I would say to be very active and conscious in developing this network of people that are at the same career stage as you, and perhaps in a similar environment to you, who can understand some of the same challenges you'll have to face. I also find the mid-career researchers that are a step ahead of me to be really important. They often have the most relevant advice, since they probably just did the thing that I'm trying to do!

I understand that you co-founded Advice to a Scientist, an online resource of professional advice compiled by researchers. What motivated you to establish this platform?

During my undergraduate engineering program, I did not have time for many extracurricular activities, so I used my PhD to do all the things that I missed and that I loved. This included a lot of scientific outreach for high school or elementary students. I got involved with a great national initiative called StemCellTalks, which was running a symposium for high school students about the stem cell research and ethics world. I was also helping with Let's Talk Science, a really great national charitable organization that goes into classrooms, from kindergarten to grade 12, and does science demos. Scientific communication and outreach became part of my scientific brand and, when I went into my postdoc, I kept that desire to engage in those areas. Then, one day, Ron emailed us a link to a Dropbox folder in which he was collecting all these really interesting articles, blog posts, books and podcasts that he thought would be helpful for someone in the scientific career pipeline. I would not have known that these articles exist, or what to Google to find them. And I thought that this was great, but it was hard enough to find things in the folder, let alone the internet as a whole, so I wondered if we could develop some sort of structure around this to make it more accessible for our group, but also for other groups around the world. Ron thought this was a great idea, so we got together and formed the idea of Advice to a Scientist. We ended up founding it together as a website (https://advicetoascientist.com/). It's continuing to evolve, and it's still very much a passion project of mine. We've been lucky to bring other likeminded people on board to help, and I now run it with Dr Jennifer Ma. Jen and I did our PhDs together in Peter's lab, and she now does a lot of science communication, so she became interested in the project. Overall, our goal is to make this a hub where someone can take their first step to find the advice they need on different topics. We're hoping to build this out to a network where people can engage in peer-to-peer mentorship to break geographical boundaries as well, because often these kinds of resources and access to high-quality mentorship are only available in certain regions of the world. And why should that be the case?

Alongside promoting mentorship through Advice to a Scientist, what is your approach to mentorship within your own lab?

I try to adjust what I offer as a mentor to my student, depending on what that individual needs. Obviously, every student's goals are different, so creating a custom roadmap for their mentorship is challenging, but in my experience that is the most effective approach. It might mean that some students need more meetings than others, or that some students may need a lot of hands-on support for designing their experiments compared to others. I try to give the more hands-off approach to students who are more independent; I let them take the lead in their project or develop new side projects. I've had students who pitch side projects to me that they think are cool, and I've thought, ‘I don't think there's any way this is going to work. But you know what, I'll be your investor. I'll sponsor some preliminary work in this and let's see where it goes.’ Sometimes they totally prove me wrong and it becomes one of their main PhD projects. It's fun to be able to step into this role of sponsor and investor in other young minds.

What do you enjoy doing outside the lab?

That's changed over time, depending on my context. During graduate school and my postdoc, I was involved in a lot of science communication activities. Outside of that I'm a foodie, so I always love to explore new restaurants. But now that I'm a West Coaster, I've embraced the region's natural beauty. There are mountains, there's the ocean, and so now hiking has become a regular part of my endeavors. I'm now also a cat Mom. I've got two cats and I spend a lot of my time trying to teach them new tricks!