SciMy Interview: Prof. Philip Crosier (University of Auckland)

Professor Philip Crosier is the Professor of Molecular Medicine in the School of Medical Sciences, at the University of Auckland, New Zealand. His laboratory uses the zebrafish model to investigate aspects of human disease focussing in the areas of innate immunity, hematopoietic stem cell development, cancer and lymphangiogenesis. His laboratory has generated several transgenic zebrafish lines that fluorescently label cellular compartments such as neutrophils and haematopoietic stem cells. His work has been published in high impact journals such as Nature, Cell Metabolism, and Cell Stem Cell [1-3]. At a recent zebrafish workshop in Malaysia, the PR team of the Cancer Research Malaysia had the opportunity to speak to Prof. Crosier about his life and research. 

Q1. What got you interested in developmental biology and who was your source of inspiration?

After my degree in New Zealand, I worked for a professor who was a geneticist in Paris – he inspired me to continue to work in science. As my career developed, I got interested in stem cells/hematopoietic stem cells and how genetics can be used to understand stem cell development. I was working in Boston a number of years back and attended a number of seminars where groups were starting to utilise the zebrafish in biomedical research. After hearing these talks, I realised this is a system that can be utilised to explore the development of stem cells and the hematopoietic system.

Q2. What do you enjoy about your current research?

Within my research group, we have developed a group of talented individuals and what attracts me is the fact that they are the people who are driving the innovation and ideas in our research! Apart from that, I enjoy thinking about how the zebrafish system can be used to investigate areas previously unexplored. A number of years ago, we started using the power of zebrafish as a genetic tool to understand aspects of the immune system. That has been very exciting in terms of all the new opportunities that have been presented to us and has led to new things in our research group. For example, our group’s research on the interface between the immune system and metabolism has contributed to the emergence of the new field called immuno-metabolism. Through this, people have now recognised that different diseases such as cancer, type II diabetes and even obesity have a strong inflammatory component that drives the disease processes. It is truly exciting to bring together two seemingly quite separate scientific disciplines to understand key questions related to human disease.

Q3. What are the main advantages of using the zebrafish as a model system for cancer?

In general, this model system is very cost effective. We have a very large zebrafish facility at the University of Auckland. More types of experiments can be done compared to using rodents/mice, which requires significantly more space and budget. You can make scientific advances without needing tens of millions of dollars. Why use zebrafish in cancer? We know that cancer is a genetic disease, so if you can understand aspects of cancer using a powerful genetic model like the zebrafish, you can begin to pull apart the disease process. Cancer is a complex disease. What I mean by that is that cancer results not only from one gene functioning aberrantly, but it is a collection of genes coordinating in some manner to drive cancer progression. So if you have a highly genetically tractable, manipulatable and transparent model organism, you can then start to visualise cell migration, for example cancer stem cells in the development of zebrafish. So the opportunities to model the aspects of human cancer are very substantial. We have done work in modelling human acute myeloid leukaemia. Others have developed models of paediatric cancer, muscle cancers and neurological cancers. This is a growing opportunity as you can use them as a platform in the drug discovery process. The whole process is scalable, so you can develop biological readouts of these zebrafish systems and start finding small molecules, drugs or even natural product extracts that might work in these targets that you have identified.

Q4. Having worked in different countries (New Zealand, France and USA), are there any differences in the research culture?

Not really. To be successful in science you have to be driven by curiosity.  It doesn’t matter if you are from Malaysia or the United Kingdom, or the States or New Zealand. You have got to have that energy and passion to pursue questions to discover unknown processes. So, in fact, I think there is a certain commonality between countries.

Q5. How was the funding situation like at the beginning when you were exploring a relative new area of science?

When we started this work in New Zealand, it was quite challenging. The conventional wisdom and the people working in biomedical research at that time were not deeply aware of the value of using alternative models like the zebrafish. So initially it was a struggle to get recognition and the funding. As our research became better and more sophisticated, we progressively got recognition especially with some of the top scientific journals and managed to secure meaningful funding to build up our lab. It has been a gradual process over time.

Q6. What has been your most exciting breakthrough?

There is not one in particular. No eureka moments. The science that we work on takes a long time and it is resource-intensive. We are trying to unravel a puzzle and try to understand it as best as possible. Over time, it is an incremental process that leads to these discoveries. I think what we have done at the University has been driven by having very talented staff and students in our group. We have developed a strong international reputation with many of our graduates now working around the world in highly regarded institutes. You know you are training the next generation of researchers who are trying to discover knowledge and hopefully contribute towards the future health of humanity.

Q7. What is your first impression of the Malaysian zebrafish research community?

I am very grateful to be invited to come to talk in this workshop. I really think that the level of energy and enthusiasm amongst the people and the diversity and curiosity in adopting this system here in Malaysia is an excellent formula to be successful. I think this workshop is important for researchers to understand what different groups are doing around Malaysia and to fuel this enthusiasm by bringing in experts from other countries to share their expertise and wisdom. It is wonderful to see these young people, many whom have worked outside of Malaysia and have returned to do something significant. The organisers of this workshop should be very delighted with the simple fact of bringing everyone together, because this will go on to become something more significant and worthwhile. I am very confident of that.

Q8. How do you think you have contributed to the zebrafish scene in Malaysia in this workshop?

Hopefully the participants have picked up my enthusiasm and developed a keen interest in this field. I have also tried to get across the idea that you have to think laterally and outside of the box in terms of how to apply this system to discover new research areas and to understand human disease. I think that is what we have adopted in this workshop in a way. I have emphasised the importance of innovative and inventive and thinking about tackling problems relevant to human disease commonly found in Malaysia. In a way it is about thinking through and asking unique questions that no one else has thought of and then using and developing the tools to answer those questions. More importantly, start thinking about how you can adopt the zebrafish system to understand some of the disease profiles that tend to be more prevalent in Malaysia. That presents itself as an essentially unique opportunity. One has got to capture these opportunities and produce discoveries that will ultimately benefit the people in Malaysia and other countries. There are cancers and other diseases prevalent in Malaysia which could potentially be studied using the genetic tools of the zebrafish system.

Q9. What would you say is the most urgent challenges in your area of research in general?

I think the challenge is in translating the discoveries made in a tropical fish in the lab to understanding how to understand and eventually treat human disease. That is not going to happen by just using the zebrafish system.  One key solution is scientists actively collaborating and using their collective expertise in solving a research question and making progress. This also takes a considerable amount of funding. Funding needs to be kept at a sustainable level over several years. In addition, there is an ongoing need to train new people to continue research programs and bring in new ideas. The challenges also lie in continuing to think how you can use the system – the sky is the limit, the only limit is people’s imagination. And I think it is how to continue to fuel that power of imagination and innovation that will be crucial to our research success.

Q10. What is your advice to Malaysian students considering a career in science?

The science landscape is changing dramatically. It is important to learn the skills of critical evaluation, of recognising innovative research questions, dismissing the not so good ideas and being able to recognise meaningful data. Students should have a strong grounding in what I believe are the core disciplines such as genetics, developmental biology, how proteins and small molecules work. It is important to see how biology interfaces with other subjects such as mathematics, chemistry, physics and engineering. Science is a global business and a vital factor towards success is having strong national and international collaborations. Students have to understand how to talk to individuals working in science outside of one’s own country. How can you develop research networks that you can then work together towards solving problems? Another important skill in science is about communicating your results, and there should be an emphasis on science communication. At the end of the day, it is the government and philanthropies that fund our research. The politicians, the funders and the public need to know and understand what we are doing as researchers.  Often the public has a real curiosity about new discoveries that may impact on their health. Students should be encouraged to communicate what they are doing to their parents, siblings, communities and eventually the politicians too – for them to understand research can make a strong contribution to society.

Q11. What are your interests outside of science?

I do enjoy a lot of outdoor activities. In New Zealand, I do what we call tramping in the wilderness. I enjoy fishing and I like the oceans. I am passionate about cooking and good food, accompanied by excellent wine. I am also very interested in painting.

References

1. Hall, C.J., et al., Immunoresponsive gene 1 augments bactericidal activity of macrophage-lineage cells by regulating beta-oxidation-dependent mitochondrial ROS production. Cell Metab, 2013. 18(2): p. 265-78.
2. Hall, C.J., et al., Infection-responsive expansion of the hematopoietic stem and progenitor cell compartment in zebrafish is dependent upon inducible nitric oxide. Cell Stem Cell, 2012. 10(2): p. 198-209.
3. Oehlers, S.H., et al., Interception of host angiogenic signalling limits mycobacterial growth. Nature, 2015. 517(7536): p. 612-5.