Interview with former director Alexander van Oudenaarden

What inspired you to become a scientist?

“I think I was already very interested in science as a kid; I bought my own microscope when I was 10 or 12. I was already very much into studying and exploring things back then and I was very much into biology. Then in high school, it turned out that my best topics were Math and Physics. I wasn’t that good at Biology actually… That’s why I went to engineering school at Delft Technical University. I started studying Material Science, but at some point, I realized that I liked Physics better. Therefore, I got a Bachelor and Master Degree in both Material Science and Physics. I also did my PhD in ‘hardcore’ Physics that had nothing to do with Biology: quantum mechanics and superconductivity.”

I already wondered, because I have never seen a physicist make such a big switch. How did the switch happen?

“That was around the time that I also started to have more academic ambitions. When I was doing my PhD and I felt that things were going pretty well, I thought: ‘Well, perhaps I can be a professional scientist in the future’. Towards the end of my PhD, I started thinking about how to do that. And then this old enthusiasm for biology came back. I thought: ‘If I want to do anything related to Biology, I’ll have to do it now, because once I do a postdoc in Physics and super connectivity, it will become very difficult to change’. So I made a tour through the US to interview people that were interested in Biology. In the end, I got two offers: one at Princeton and one at Stanford. I ended up going to Stanford. Steven Boxter, my postdoctoral supervisor, was actually a chemist, but he did biophysics type of work. I am very happy I ended up there, because he gave me a lot of freedom. At that point, it was already pretty clear that I wanted to continue in academia. I was just hoping that I could study biology or biophysics even though I didn’t have any track record there.”

Would you say that you decided you want to stay in academia during or after your PhD?

“I guess that as a PhD student, I knew that I wanted to study more biological work, but I was not really sure if I wanted to bring that to the professor level. During my postdoc however, I definitely wanted to give that a chance. When I was a postdoc at Stanford, there was an opening at Stanford at the Physics Department, for Biophysics. I applied for the job, but I didn’t get it. At the same time, MIT asked me to apply to their Physics department. I think this was because of my PhD work, because I was very early in my postdoc and had not published papers yet. I had the interview at MIT and got the job. They were very flexible with it, I had the freedom to do what I wanted. So after my postdoc at Stanford, I went to MIT and started my lab to study biophysics.”

Did you have to take extra biology classes in order to make this switch?

“No, I never took any biology classes after high school. I did a lot of reading, textbooks. When I started with biology, I read both Stryer, the biochemistry book, and the Molecular Biology of the Cell. Those are the two books I went through. Not in one weekend but over a long time. I also learned a lot from reading and talking to people.

Because I never got a formal education in biology, there are a couple of topics that I still don’t know anything about. That is a little bit embarrassing, but what I do then is read papers, learn a piece of biology and go very deep. Sometimes my naivety was really useful, because other people, who were educated in this particular topic for a long time, overlooked it. They said: ‘Okay, that is not interesting anymore’. But why? Why does it happen? I don’t know yet. So, the naïve physicist is sometimes useful. But that gets harder now, because the gaps in my knowledge are filled up and the naivety becomes a bit rusty.”

What was the stage in your career that played the most important role in shaping who you are as a scientist and how you do science?

“It is very difficult to find a particular moment. What is clear in my research path, is that it is divided in several blocks. For example, before my postdoc I had a block of Physics. Later, I had a block of more in-vitro biology: trying to get used to biology by working with in-vitro systems. At a certain point, I realized I wanted to work with real cells, not just mixtures or molecules. Therefore, I started working on single-cell organisms, first bacteria and then budding yeast. We worked on this for a period of ten years. Going from in-vitro work to real cells was a big thing, I guess. Then, I got confident enough to go to multicellular systems and started to work on C. elegans. This was actually probably partially inspired by the Hubrecht Institute, because I did a sabbatical of one year here when I was at MIT. That was a moment when the lab went in a really different direction, focusing on more experimental model systems.

Another thing which was important for me, was to realize how important the development of technology is. Before 2008, we did not really develop any technology, we were just using what was already there. We had more conceptual breakthroughs. But then we developed this technology to visualize single RNA molecules, with which you are helping many others. They could use the new technology and do experiments they never did before. After that, we started developing more technologies. It seems to be useful for a large community and it’s relatively easy to transfer the knowledge. I think that is also what I see at the Hubrecht. I came to the Hubrecht in 2012 and I thought: ‘how can I help as a director?’. It seemed that the easiest way to do so was to basically roll out our technologies as broadly as possible. Indeed, it turned out that many groups benefit from this.”

What is the one big overarching question of your career or as a scientist?

“That comes back to the original question that I have: ‘What are the key things that distinguish one cell from another? What are the processes that turn two identical cells into different cells?’. These are very difficult processes to study, because the molecules are all moving through the cell driven by both random and directed forces. Take random interactions with water molecules, for instance. It would be really nice to know how to quantify that process and understand how you can manipulate it. That way, you can also distinguish the processes that are important from the ones that are not.

On the other hand, I am not someone who is really driven by one single question, I am also very exploratory. I have no problem studying something I have never studied before and see what happens. I always try to find interesting things in the dataset, it is mostly hypothesis-independent research.”

What scientific discovery has fascinated you the most?

“In the last ten years or so, I have been very much into single cell sequencing. There was a paper in Nature Methods in 2011, by Azim Surani’s lab, which was the first paper doing single cell sequencing. When I read that paper, I immediately ran to the lab saying: ‘Okay guys, we are going to do this’, but no one wanted to do it at that time. Nobody was interested, because we were successful in doing imaging and single molecule FISH. I couldn’t really convince anybody at MIT. I guess that was because everybody already had a project. However, it was very convenient that we moved to the Hubrecht one year later and basically started a whole new lab here. Nobody had a project yet, so I thought: ‘Okay, everybody will do single cell sequencing’. In 2011 the very first paper about single cell sequencing, from the Surani lab, came out, and our first paper was in 2014. I think those papers made an enormous impact on the lab and on me, especially on how to think about what is possible and what is not.”

Who has been your inspiration or your role model as a scientist?

“Van Leeuwenhoek, Antoni van Leeuwenhoek. I do not compare myself with him, but it’s in a sense a similar situation. Because what he did, is that he found new technologies to look at something, and therefore allowed people to look at things they did not see before. That is something I’m also trying to do: when we have a new technology, you are looking at properties you have never seen before. I also think that my mentors were all very important to me, to help me figure out which directions to go in this very complicated scientific landscape.”

Do you think it is difficult to balance science as a career with personal life and what would be your advice for upcoming generations?

Science is of course very demanding and, if you have kids, you have to balance it. I don’t have any practical advice, besides that you have to be very effective and efficient. I noticed that pre- versus post-kids, I am so much more organized. Otherwise it just doesn’t work. Before, I spent a lot of time in the lab, probably not spending every hour that useful. After the kids, I really became very organized. That helped a lot because you gain a lot of extra time, which you can use very effectively to make sure you are spending enough time both with the family and at work. So, planning is a very useful thing for me. And structure, too. In the end, it’s amazing how much you can squeeze into one week.”

If you have to give one advice to give to young scientists, what would that be?

“The thing I always say, which is kind of obvious I guess, is that you really have to love science. We also often say that in science, the path through the scientific hierarchy is not easy. That makes it very challenging. You really have to love it a lot to make it through, because, in the end, you have to do it for a pretty long time. I am very grateful that I can be a professional scientist. It is the dream job for me.”