Xinhui Li and Kevin Sitek
Kicking off the 2023 Keynote Lecture Series
Xinhui Li (XL): Your PhD focused on studying the molecular mechanism of the circadian clock in fruit flies, and then you investigated the molecular and genetic mechanisms underlying hippocampus dependent plasticity and learning as a postdoc. Could you tell us what motivated you to work on these projects? What triggered your interest in neuroscience?
Hongkui Zeng (HZ): My undergraduate degree was in biochemistry, so my background is more on the molecular and biochemical aspects of biology. When I went to Brandeis University for my PhD, there was a very strong neuroscience program, and I became more interested in how the brain works. I started with the circadian rhythm research because it's a great combination of my molecular background and my interest in neuroscience. Then I became fascinated by the brain. I like to think about questions at a systems level, so I would like to move beyond just studying the brain from the molecular genetic point, but also to link it with physiology and behavior. That's why—for my postdoc—I investigated the role of genes in driving neuroplasticity as well as regulating behavior. I am really fascinated by the brain, its complexity, and how these brain cells work together in a circuit to control behavior.
XL: After your postdoc, you joined the Allen Institute in 2006. Could you please share what your research career trajectory has been like at the Allen Institute?
HZ: I have been at the Allen Institute for more than 16 years. I started with my own group hiring the first two scientists on the genetic tool project. My team then grew from 2 people to 10—and eventually to a group of 25 people. The projects that we did also expanded from creating transgenic mouse lines to using adeno-associated virus (AAV) vectors to map connections in the brain. We then began to explore new technologies to characterize cell types and single cells in different parts of the brain.
I personally experienced the dramatic transformations of the Allen Institute itself, starting from a single large-scale project, the Allen Brain Atlas, to a variety of different gene expression atlases, and then to connectivity atlas, which was spearheaded by me and my team. In 2016, I was promoted to be the executive director of the Structured Science division. I moved from running a lab of my individual research team with about 25 people into running an entire division with about 130 people. In 2020, I was promoted again into the Executive Vice President and Director of the entire institute. That was another jump for me from managing 130 people to managing the institute of 250 people. I felt really fortunate to have this extraordinary opportunity to do open science and team science and to address important biological questions in a systematic manner.
XL: Amazing! You are currently leading multiple projects at the Allen Institute including the Transgenic Technology program, the Human Cortex Gene Survey project, the Allen Mouse Brain Connectivity Atlas project, and the Mouse Cell Types and Connectivity program. Do you find it challenging to coordinate so many large scale projects? How do you manage to solve these challenges?
HZ: Yeah, it is very challenging, especially at the beginning. Fortunately, I didn't just jump into large-scale projects right away, everything was built from the initial pilot studies. It went from small to big, just like the Chinese saying: "A journey of a thousand miles begins with a single step (千里之行始于足下)."
I realized there are three key points. First, you need to see the big picture, why we do this, what the most critical key issues are, and what it takes to get this done. Second, you need to prioritize. Understand the prerequisites, break up the challenging task into multiple components, and understand the mutual dependencies of different components. Third, it's very important to simplify the process. A large-scale project involves many different teams and many different components. Sometimes we show a diagram of a pipeline with many steps and linkages. But you need to identify the key points and simplify the process as much as possible and convey that simplified version to people so that people don't get confused by the complexity. It's really a learning process.
XL: Could you tell us the exciting projects that you are currently working on at the Allen Institute?
HZ: The central question that we are focusing on now is understanding the diversity of the different types of cells in the brain. Now we have a series of questions we would like to address; for example, what is a cell type? How many types of cells are there in the brain? Where do the cell types come from? What are the key factors during development that define the cell type identity?
We are also interested in understanding if cell types are conserved between species, especially between mouse and human. Does the human brain have the same set of cell types compared to the mouse brain? What are the similarities and differences? We know that cell types are the basic functional units of the brain and any other parts of the body. So the uniqueness of the human brain itself must come from the cell types or their interactions in networks. We want to do a cross-species comparison.
Finally, we want to know what cell types do, how they work together to generate function and how they contribute to the different kinds of behaviors that the brain controls.
XL: Your team at the Allen Institute recently published a preprint titled “A high-resolution transcriptomic and spatial atlas of cell types in the whole mouse brain”. Could you please comment on the potential impact of this work? How will this mouse cell type atlas help us to develop a better understanding of mammalian brains?
HZ: Yeah, we are very excited about this project. Our team truly believes that this is a landmark study in creating a high resolution, cell type atlas for the entire mammalian brain for the first time. It's a very comprehensive catalog of cell types. It's based on high quality datasets that we generated—single cell RNA-Seq as well as spatial transcriptomics data. It provides a reference atlas for the entire neuroscience community, so that people can relate their work on specific circuits and cell types within that circuit into our reference atlas. They can use our reference atlas to look at genes expressed in specific cell types and infer the potential functions of the cell types. People can use our reference atlas as a baseline to look for gene expression changes that may be happening under different behavior conditions, and especially under different disease conditions. People can also use this as a reference atlas to begin to compare with other species. We are building an online platform to present this entire dataset to allow the research community to easily use our data.
Kevin Sitek (KS): You mentioned how you can relate it eventually to the human brain. What are the challenges there? Obviously, a lot of this work has been done in mice, and there are a ton of tools available for investigating mouse brains. Eventually, we would like to see some of this done in the human brain. So what are the big challenges you'll see there?
HZ: The first challenge, of course, is the scale. We need to further scale up the work in the human brain. The human brain is 2000 times larger than the mouse brain. So there are a lot more cells, and we have to scale up the profiling and the omics approaches to be able to have sufficient sampling of the entire human brain.
The second challenge is to perform meaningful cross-species comparisons to identify homologous sets of cell types. We already know that there are substantial gene expression variations across species, which makes the search for homology challenging. The way to tackle it is to organize the cell types in a hierarchical manner. For cross-species comparison, it's really important to compare all these different hierarchical levels at a crude, but a major class level, and then go down to the fine-grained type or subtype level, and you see where the conservations are and where the divergences are.
The third challenge would be the individual variations in the human population. In mouse, we study an inbred strain, and genetically identical inbred strain does not have so much across-animal variation. But when we go to the human population, there's tremendous genetic variation at structural and functional levels. How to reconcile that is going to be a major challenge as well. That's also the interesting and important part about the human brain.
We plan to finish the human brain atlas in five years. Maybe it will take a few more years to complete the data analysis to truly understand the human brain. But we have a pretty ambitious plan because the technology is advancing very fast.
XL: Yeah it's really exciting. As a PhD student, I gradually realized that it's very important to develop insights of what questions are important and what research directions we need to pursue. How to explore and identify what questions are important fundamental in neuroscience? Do you have any suggestions to junior researchers on how to develop such insights?
HZ: Yeah, that's a very important question. My PhD and postdoc mentors emphasized to me to focus on asking the right question. They said it takes the same amount of time and effort to work on an important question versus working on an unimportant question. It's not like if you work on something trivial, then it will be easier. You will spend the same amount of effort to do that. So it's really important to identify the right question to work on.
How to do that? I feel that you really need to have a deep understanding of the field. Read a lot of great papers, discuss with others, and go to conferences to absorb a lot of information and knowledge. It will help you tremendously in identifying the right question to ask.
XL: I'm also curious, how did you identify the current questions that you are trying to answer at the Allen Institute?
HZ: At the Allen Institute, we now have a good model of collective decision making process. We convene multiple ideation sessions and workshops, and discuss with both internal and external experts. Many different discussions are about “what questions are important to the neuroscience field—that we could address using our unique capabilities—that will generate the greatest impact?”. For example, when I took on the director position in 2020, we had multiple ideation sessions with our internal scientists and we came up with a ranked order priority list about what questions we should address. After that, we had multiple workshops focusing on each of those specific areas, invited experts in those areas and had further discussions about how to do it. The first set of meetings was to address the questions of what and why. Then the second set of meetings would be addressing questions on how to do it.
KS: At the 2023 annual meeting, you will be opening up the OHBM annual meeting, presenting the Talairach lecture. Can you give us a preview of what you think you'll be talking about at that lecture?
HZ: The main focus is our most recent publication that Xinhui mentioned. I'm going to talk about the cell type organization across the entire mouse brain. I will also introduce our previous work, to give a systematic overview of what we have done over the last five years to begin addressing the cell type questions using different approaches, and then focus on the whole mouse brain cell type atlas that we have generated. If time permits, I may zoom into a particular example about further analysis that we have done for a particular brain region or circuit. The last part would be the ongoing work to understand the brain cell type diversity, and maybe even how it relates to behavior and function.
XL: I'm really looking forward to your keynote. As a major female figure in neuroscience, have you noticed any changes in attitudes towards women in neuroscience during your career from junior scientists to senior PI? Do you have any suggestions to create a more open and inclusive research environment?
HZ: I think there have been a lot of positive changes. When I started, it was indeed a very much white male dominated field. I was not the person who was vocal about it. As a young student coming from China, I just tried to fit in. I feel very fortunate that my mentors and my colleagues at the Allen Institute were very supportive. But when I went to conferences and gave presentations, I had the feeling that I had to prove myself that I'm capable, whereas one of my peers could be just assumed to be talented and capable. People would turn to that person, respecting and listening to that person more rather than me. I had to work hard in order to catch up, in order to move up. So I did have that kind of feeling.
I think the issue was that there was no open conversation about this. Things are getting better now because we began to talk about it. I really admire those women scientists who stepped up to point out this issue and made other people more aware of it. By talking about it more, by making these issues more open, people will modify their behavior and attitudes, and try to reduce their implicit bias as much as possible.
For younger generation scientists like you, Xinhui, it's very important for you to see role models and make you believe that this is the place that you belong. If there's no such person showing that you can make it, you just feel like “this is really not a career path for me.” Having role models is very important. That's also one of the reasons I agreed to take on this position. I know it's going to be a lot of challenge, it's going to be a lot of work, it's going to be a lot of burden, but it's time for me to step up to become this role model.
XL: I have been looking up to you, and your experience really inspired me to grow up as a scientist like you. Thank you for being a role model for everyone.
Thank you so much for your time. We look forward to your keynote at OHBM!