An interview with Hernan Garcia Free

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

I think it was because my dad had a subscription to the Argentinean equivalent of Popular Mechanics! I also read a lot of science fiction. I really liked Isaac Asimov, which led me to one of his books (Asimov's New Guide to Science) that acts as an introduction to science and walks you through all sorts of scientific fields and scientific thinking. It all felt fun! I also enjoyed the science component of high school, although I don't think they succeeded too much in telling me what the scientific process looks like. Basically, I signed up for a career in research without really knowing what it involved because it just sounded like something I would have fun doing.

And what then attracted you to physics?

I was curious about all things related to space exploration, so physics seemed like a good option for me. My choice was also partly fueled by my obsession with science fiction.

After your undergraduate studies in Argentina, you moved to the USA to carry out your PhD – what spurred this decision?

Well, it was a combination of all sorts of things. First of all, when I was about to graduate, there was a crisis in Argentina that led to having five presidents in one week. So, prospects for science did not look great. Second, I had lived in Germany for a while as an exchange student, and I always liked travelling, so I was excited about the idea of leaving the country for a PhD. Although I had a lot of connections in Europe, the thing I really liked about the US system is the opportunity to rotate and talk to people in different labs before committing to your PhD lab. So, I decided to only apply to US PhD programs.

I moved to Caltech to pursue a PhD in Physics. On the first day, I just showed up – I didn't know that you had to register for classes or that you could take classes outside the physics department! Just by chance, I ended up taking a class by Rob Philips. The class opened my eyes to the power of engaging in a dialogue between theory and experiment to understand biological phenomena. As a result, I started talking to Rob and eventually joined his lab.

What was your PhD focused on?

It was focused on cellular decision-making in bacteria. We asked whether knowing the DNA sequence of regulatory regions – the placement and affinity of binding sites for transcription factors within these regions – was sufficient to predict how gene expression is regulated. Initially, we came up with theoretical models that made very precise experimental predictions. However, we couldn't find anybody willing to do the measurements to test those predictions. Fortunately, at that time, my PhD advisor got a big National Institutes of Health (NIH) grant, so we had the resources to learn how to do experiments and measurements ourselves. It was a fantastic PhD experience because I was working with a mentor that was extremely accomplished on the side of theory, while we were both learning how to be experimentalists together. (reviewed by Philips et al., 2019).

You then moved across the USA – from California to New Jersey – and also switched gears to work on Drosophila for your postdoc research. What was the motivation for this?

When I was taking the Marine Biological Laboratory (MBL) Physiology course back in 2005, Eric Wieschaus gave this amazing talk about how they could watch cellular decision-making in real-time in living fly embryos. From that moment, I became interested in developmental biology. It felt very natural to switch to that for my postdoc and to ask the same types of questions that we answered in bacteria, now in the context of cells within a multicellular organism.

What were your most important considerations when you were then looking for group leader positions and somewhere to start up your own lab?

Well, I mean, beggars can't be choosers! I had no idea how competitive I was; what I do is at the interface between fields, which can be challenging because you don't know in which category you fall. I applied everywhere and very broadly, to biology, bioengineering and physics departments. My feeling was that I was going to end up in a physics department, but the biology department at Berkeley was fantastic and I could arrange it so I could have a connection to the physics department. It sounded like a great opportunity. One thing I liked about this place when I came to interview was that everybody I talked to made me want to drop what I was doing and work on their projects – I have such an inspiring set of colleagues!

What are the main research themes/aims of your group at the moment?

The big question is whether one can predict an organism's development and physiology from just its DNA sequence. To make this possible, we take widespread cartoon models of how regulatory molecules work together to dictate cellular decision-making and turn them into precise mathematical statements. These theoretical models predict, for example, how the number, placement and affinity of transcription factor binding sites dictate gene regulatory input-output functions: the functional relationship between input transcription factor concentration and output transcriptional activity. Much like our experience in bacteria, we found that, despite having precise theoretical predictions, we lacked the technology to test those predictions experimentally. As a result, a big push in the lab over the last few years has been the development of technologies to ‘light up’ the processes of the central dogma in single cells of living embryos as a means to measure these input-output functions and test our models.

One of the drawbacks of our approach is that we can only apply this dialogue between theory and experiment to the small percentage of enhancers – probably less than 5% – for which transcription factor binding sites have been mapped. Historically, binding sites have been found by mutating enhancers within reporter constructs and analyzing the resulting gene expression patterns in transgenic animals that contain those reporters. Because of the time and effort necessary to create and maintain transgenic animals, these dissections typically do not exceed 50 mutants. However, to systematically map a 100 or 200 base-pair enhancer in an unbiased way thousands (or tens of thousands) of mutants are necessary! One of the next challenges I am excited about is leveraging DNA sequencing technologies to, in high-throughput, not only find transcription factor binding sites, but also engage in the theory-experiment dialogue in the context of the vast majority of uncharted regulatory regions in animals.

You have had your own group for more than seven years. What would you say are the most important things that you have learned about being a group leader since you started?

When I started at Berkeley, my teeth began hurting. So, I went to the dentist who said, ‘you're clenching your teeth a lot because you are stressed out!’ Then I realized that I was stressed because there is so much stuff that needs to happen that you don't imagine when you start; for example, nobody told me I would need to take care of tasks as seemingly mundane as buying chairs for the lab! I learned, first, to just relax. Second, I try to outsource as much as I can. This translates into the lab as a whole. For example, nobody does molecular biology in the lab anymore, we all just pay a company to synthesize DNA. It is not more expensive and now my lab members have more time to think. Finally, I tend to be very open to talking about and sharing our science. This open approach towards science made a difference in creating a great lab environment and in enabling all sorts of interesting collaborations.

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

Try not to stress out too much about tenure – just do your thing. Having said that, when I asked my students whether I was stressed out during my tenure process, they all laughed at me! It is also important to remember that, no matter what you do, the first paper always takes about three years to get out.

What has been your approach to hiring people in the lab?

I have been extremely lucky with the students and postdocs that have joined me at Berkeley. Hiring has been based on who shows up and is interested in engaging with biology from a slightly different angle than in most labs in the department. Most of the people joining the lab have come from maths or physics, and they learn the biology. One thing I have been amazed by is how much our research program has been shaped by the people in the lab. You might have plans, but it depends on your lab members’ skills and interests. Many directions have been opened by people trying to explore their own interests.

I understand that you are also involved in teaching physics to biology students; for example, at various ‘bootcamps’. Can you tell us more about this?

These are intense short courses focused on the theoretical modelling of biological phenomena. They are specifically designed for people that have no maths, physics or computational experience because we want to go at a pace that everybody can follow. We started teaching them at Caltech and then had the great opportunity to teach in the Physiology course at MBL. That effort transitioned into the Physical Biology of the Cell course also at MBL, which we taught for three weeks every summer until COVID. This year, we started a bootcamp here at Berkeley for both the incoming Molecular and Cell Biology and Biophysics students. The bar for success we set for ourselves in these educational endeavors is whether, when these students join their respective labs, they integrate the quantitative approaches they learned into their own thesis projects.

You were recently awarded the SDB Elizabeth D. Hay New Investigator Award – what does this award mean to you?

It says something about how open the community is and how much it is embracing a physical and theoretical approach to developmental biology. It is a huge honor. We all complain about the challenges of the job, but it is important not to lose sight of the pleasures and privileges we have. For example, a lot of my conversations with colleagues end up becoming about funding, but it is important for us to steer the conversation away from that and focus on the science and the pleasure of figuring things out. I am excited to be given this privilege to do science and extremely grateful for all the mentorship I have received over the years that made it possible for me to get here.

I see that you have also been using preprints to share some of your research – how has this experience been for you?

It is useful for everybody because the publication process takes so long! Similarly, when we do faculty searches here at Berkeley, we look at bioRxiv papers. I don't see any negatives. In fact, it has been great for getting feedback, which we have incorporated into the ultimate manuscript.

Finally, is there anything Development readers would be surprised to learn about you?

I guess some people might be surprised that I have never taken a course in biology, let alone developmental biology!