Stephen Nutt studied biology at Sydney University and spent four years as a research associate with a Canadian biotech company. In 1994, he joined Meinrad Busslinger’s lab at the IMP via the international PhD Programme. After obtaining his doctorate in 1997, he stayed for one more year as a postdoc. During this time, he identified the key role played by Pax5 in B cell lineage commitment.
In 2001, following post-doctoral training at the University of Cambridge, Stephen established his own lab at the Walter and Eliza Hall Institute (WEHI) in Melbourne, Australia. In 2011, he was appointed head of the newly created Division of Molecular Immunology at the WEHI. Stephen is a Fellow of the Australian Academy of Science and has received prestigious awards such as the Eureka Prize for Scientific Research and NHMRC Research Excellence Award.
Stephen’s research focuses on understanding how transcription factors control lineage commitment and cell differentiation decisions in the immune system. Recent work by the laboratory has established the important functions of PU.1, Irf4, Blimp1 and Myb in the differentiation and function of B and T lymphocytes, natural killer cells and dendritic cells and in suppressing leukaemia.
Stephen, the years you spent at the IMP were extremely productive. You published four first-author papers during this period. What would you attribute this success to?
Before I came here, I had spent four years as a researcher at a biotech company, so I already had a lot of lab experience. My project here was to look at why PAX5 is important in B cells – a pretty open question. The success came from a combination of my being experienced – so, technically, the experiments worked really well – Meinrad being a guru in that subject and the collaboration we had established with Ton Rolink at the Basel Institute for Immunology. He was a world expert in early B cell development and my second supervisor. The two, Meinrad and Ton, had very synergistic skills, and that helped my project to proceed well, both on the molecular and the immunological level. And a bit of luck also helps.
Meinrad likes to recount the story of your serendipitous discovery of the role of Pax5. Can you tell our readers?
I was doing experiments in which I tried to work out the frequency with which PAX5 knock-out B cell progenitors would grow in culture. Essentially, an assay where we made little clones of the cells in 96 well plates. I did this experiment before Christmas and I would circle all the wells that were positive, but the experiment wasn’t optimal. The cells hadn’t grown as much as I had wanted, so I just stuck them in the incubator and went back to Australia for Christmas. When I returned after two or three weeks, I remembered the cells and thought I’d check them again.
If you were to do this experiment with normal B cell progenitors, they would have all died and that’s what happened to the controls. But when I looked at the PAX 5 knockout cells, they hadn’t died, but instead started to regrow even more rigorously. And I could see in the microscope that they weren’t B cells any more, but that they looked more like macrophages.
So it was like a light going off in my head when I realised my cells had transdifferentiated. It’s a big phenomenon that’s rarely ever seen and I got all excited about it. When I showed it to Meinrad, he found it interesting but thought that it might be an artefact. So when we repeated the experiment in a more controlled way, this time during one of my visits to the Basel Institute in Switzerland, we knew it was real. That was amazing and we were able to generate the data for two Nature papers within six months. I guess that’s a good example for when you have to have the luck but then be able to interpret it.
How did you come across the IMP in the first place?
I had been working in Canada when my wife and I decided to come to Europe to do a PhD. I came across the ad for the IMP’s PhD programme in Nature and it looked interesting, so I applied. When I came for interviews, I was immediately impressed by the IMP’s facilities and the scientific vibrancy of the place. It was the second year of the programme, and back then EMBL was the only other place that offered a similar PhD programme. I applied to multiple universities in Europe, but as a non-European it was always a bit problematic, whereas at the IMP once you got in, things were all sorted out for you. When we arrived, we were able to stay at one of the guest apartments, and that was very nice.
What did those years at the IMP teach you, and how did they shape you as a researcher?
In Meinrad’s lab, I was on a floor with Kim Nasmyth and Thomas Jenuwein and a lot of people whose projects were very successful. I got to experience how students next door had their papers published in the best journals and realised they were not superhumans, but they were smart people who worked hard. That sort of environment is a bit infectious and you realise what is required to be as successful as possible. Meinrad is very much a “scientist’s scientist” and very thorough, and he led me through a rigorous training.
The papers I published back then really set my career up. I was offered a lab head position only after about one year as a postdoc!
You have achieved so much and your career has developed beautifully. What are your plans and goals for the future?
As a scientist, you never really completely understand your problem; you just peel away layers. I have spent my career working on factors that control gene expression in the immune system. In the last few years, methods have finally been invented to drug these factors therapeutically, so the proteins that we have been working on have now become drug targets. It’s great to see that some of the work has now moved into the translational phase, although we never set out to achieve that. And with technologies like CRISPR, we can now do experiments in human cells that previously weren’t feasible. I’m very excited to see this progress in our area, in terms of therapies. But we are still ultimately interested in how things work, and you never really get to the bottom of this.
What should ambitious young students look for when they choose a place to do their PhD?
A good thing is to look for a strong academic environment where people ask interesting questions and are successful in discovering things – such as you have here. And in that context, the student then finds their passion. You need these resources, you need the infrastructure around you to succeed in modern research. It’s very resource-intensive. And once you’ve got that, it’s really the passion that counts. And to be open to new ideas!
Interview by Heidi Hurtl, 2019.
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