Dr. Zhigang He shares his memories from starting as a medical student in China to his graduate studies in Jim Ingles’ lab to finally, becoming a Professor of Neurology at Harvard Medical School. Zhigang discusses his inspiration and work in inducing axon regeneration in the central nervous system in order to develop better neural repair strategies. He also provides advice to students, such as the importance of keeping an open mind and being receptive to the many opportunities around them.
Can you describe your current research for us?
My lab is in the Kirby Program in Neuroscience of Boston Children Hospital, which is part of Harvard Medical School. Neural damage and degeneration are major medical issues but currently there is no effective functional restoration treatment for these diseases. The main goal of our research is to understand why axons in the central nervous system cannot regenerate, in a hope to develop novel neural repair strategies.
People in our field have been trying to understand this question for more than a century. Actually, a few people related to UofT have made important contributions to this field, such as Alberto Aguayo and Charles Tator. For example, Aguayo and his colleagues showed that some injured axons in the CNS could grow into grafted permissive tissues. However, most injured axons cannot regrow. To find out why, we have been taking molecular genetics approaches and identified several key molecules in the pathway of this process. As a result, when we manipulate these molecules, we can see induced axon regeneration. Therefore, these results told us that it is feasible to achieve axon regeneration. Now, our research focuses on following up to see if the regenerated axons are functional and what functional outcomes can be achieved.
When did you first realize that you wanted to become a scientist?
When I was a child, I never thought I was going to be a scientist. Accidentially, I went to medical school in China. When I was an intern, I found that, for many diseases, we didn’t have any treatment. For some disease, we didn’t even know what the disease mechanism and what the fundamental problem was. That made me realize the importance of basic research for the discovery of cures for these untreatable diseases. That might be the main reason I decided to pursue my graduate studies at UofT.
Can you share some of your favourite memories from graduate school?
There are a lot of nice memories from those days at UofT. I particularly enjoyed my interaction with my advisor, Jim Ingles. He was a wonderful advisor. He was very critical yet his lab was very small, which allowed for a lot of daily communications with him. In addition to that, our lab had very close collaborations with others in the Banting and Best Institute, such as Jack Greenblatt’s lab, which was also extremely inspiring.
What was the most important thing that you learned in graduate school?
I learned a lot in graduate school, but perhaps the most important was the critical thinking. When you first start in graduate school, you read a lot of papers and it is all quite confusing. It seems like every single molecule is connected to everything else. It was quite difficult to discover something unique. But throughout graduate school, through different avenues, such as reading papers, discussion with your advisors and attending seminars, you start to develop a critical mind that allows you to develop a hypothesis. Of course, many hypotheses may turn out to be wrong or do not work out. But if some of those times your hypothesis is correct, it becomes very good for your interest and confidence, which is very important for your scientific career.
What scientific discovery are you most proud of?
As I mentioned above, for a long time, there were a lot of efforts in our field trying to find a way to promote axon regeneration, but with limited success. Back in 2008, we tested a hypothesis. The question was: why can axons grow during development, but not in the adult CNS? We thought that this phenomenon is not limited to just neurons. In fact, every type of cell has a size control process. During development, cells in the body will increase in size and/or number, through the regulation of growth factors. But at a certain point towards adulthood, most will stop growing. Why don’t cells continue to grow? Studies in cell biology and cancer biology told us that it is due to the effects of different tumour suppressors, which prevents individual cells from dividing and growing. Thus, we hypothesized that these tumor suppressors might limit regenerative ability of mature neurons. To test this, we did a small-scale screening to see if knocking out any of the known tumour suppressors could lead to axon regeneration in adult mice. As a result, we found that deletion of PTEN indeed promoted robust axon regeneration in mouse optic nerve. This suggested that it is possible to induce axon regeneration by molecular manipulations.
Of course, because PTEN is a tumour suppressor gene, it is not a good target for clinical intervention. But this inspired us to look for alternative approaches that can mimic the effects of PTEN inhibition. In fact, our recent studies identified a molecular strategy that is able to promote axon regeneration but bypassing PTEN inhibition. Importantly, we also showed that regenerated axons induced by such manipulations can form functional connections and could mediate some degrees of functional recovery. I would think that this is an important step towards our goal of developing neural repair strategies.
What advice would you give younger students on choosing a mentor?
Different labs all have their own unique aspects. It is important to find the lab that is the right fit for you. In some departments, some labs are very popular and often attract a lot of graduate students. But they might not be the best fit for everyone. Some people may want to be very independent, so they would like to handle everything themselves, so perhaps a big lab will be fine. But if you enjoy more daily communications with the advisor or other lab members, smaller labs may be better. So don’t just follow to the popular choice in the department. Find the time to meet with different professors and talk with them or a lab member. I think it is a very important practice to select the right person for you.
What was the most difficult aspect of transitioning from a post-doc position to starting your own lab as the principle investigator?
I would have to say lab management. As a post-doc, you can pretty much concentrate on your project. If there is an issue, you can always ask your advisor(s) and other lab members. But as a PI, particularly these days, it is very difficult to conduct bench work yourself. That means a lot of the experiments are conducted by the lab members. It is really important to find a way to communicate your ideas to your lab members and develop effective strategies to monitor them. You need to spend time to train people and build trust between yourself and your lab members.
What do you think are the key elements of running a successful lab and research program?
I would say at least three elements. First, find a scientific direction that can keep you interested for a long time. For that, personal judgment is an important component. There are totally different lab styles. Some labs focus on addressing a question whereas other labs like to develop new technologies, which can both be very successful. What I think is perhaps not wise is to follow the fashionable thing. It is better to find an important question that deserves long-term investment.
Second, an interactive and collaborative environment. Sometime it is difficult to think about everything clearly. Communicating with others, either your colleagues or friends, could be very helpful. On the other hand, many times, to address a question, you may need very specific expertise. However, it is very difficult for one lab to be experts in everything, so a collaborative environment would be extremely valuable.
Third, it is extremely important to recruit good people. This is extremely important, and is a challenge for all PIs.
What do you think is the biggest challenge facing scientists today?
Perhaps the most striking one is the way we are running labs these days is more like running a small business. In addition to coming up with scientific ideas, at least in the US and Canada, the PI needs to spend a lot of time on writing grants. Although this could help organize the research ideas, the review processes are rather less predictable (because of the highly level of competition). As a result, some important scientific projects might not be sustained. Moreover, PIs might be afraid of thinking of new and risky ideas. That, I think, could a big problem and makes the job less enjoyable. You have less time to exercise intellectual freedom.
What was the best career advice you received when you were preparing to graduate?
I would like to tell you my personal experience. I had the opportunity to take a professorship position in Singapore towards the end of my graduate school. However, my supervisor (Jim) advised me to open myself up to all the possibilities to see what was the best fit for me. That turned out to be very important advice.
What advice would you give to students and post-docs hoping to pursue a career in academia?
Despite some issues, being a scientist and making new discoveries is very exciting. No other profession can enjoy this kind of excitement. Remember that everyone has strengthens and weaknesses. I would think that one of the goals of the training process is to find out what strengths and weaknesses you have, which could be an important consideration for choosing a career path. For post-docs, I would recommend finding questions that fit with your interests and are important, and will keep you focused and satisfied. For graduate students, my advice would be similar to what was given to me, which is to talk to many people. I think in some cases, people think “I’m working on this transcription factor, so for my post-doc, I want to continue to work on that”. That may be okay, but perhaps you may miss opportunities to see the other sides of the world. So, I think it’s important to be open-minded.