Interns, Zainab and Kalea, had the amazing opportunity to interview Dr. Subramanian, associate professor and lab leader at ISB and an Affiliate Assistant Professor in the Department of Immunology and Department of Global Health at the University of Washington, Seattle. She talks about her journey to her current position, her research interests, and advice for students of all ages:
What was your journey to becoming an associate professor and lab leader at ISB and an Affiliate Assistant Professor in the Department of Immunology and Department of Global Health at UW and what inspired you to pursue these jobs as a career?
My scientific journey started when I was doing my Phd program in graduate school. There, I really got hands-on experience in doing experiments which made me realize how much I enjoyed them. During that time, I was back in India and I studied the innate immune system, which is the most primitive form of immunity that we are all born with. It’s a form of immunity that is conserved from lower invertebrates into mammals essentially, so we share many of our innate immune genes with organisms like food flies and plants for instinct. This really tells you about the architecture of the innate immune system and how it’s conserved. It’s also a form of immunity that preserves the development of what we call adaptive immunity, which is things like T cells and B cells, which is the reason why vaccines work. Essentially, that’s what I studied during my graduate schooling and I was studying it in the context of host pathogens interactions. I was trying to understand how pathogens, especially bacteria, interact with our immune system, and how the host defends itself against those pathogens. It’s like a double edged sword, the host wants to defend itself against pathogens and the pathogens in turn can dupe things to hijack the host immune system to establish itself in the host environment. That’s kind of where my journey started, and going forward from there after I finished my Ph.D., I really wanted to expand my horizons and move beyond studying one bacteria to really try to understand the basic principles underlying the innate immune system and how it works. I learned the way the innate immune system works is through using a series of proteins to sense foreign invaders. You can think of these as guards that are guiding a fortress for instance, so if an intruder comes in, your guard or your innate immune system, is the first thing that jumps into action before everyone else comes to the scene, such as the adaptive immune system. Thus, in my postdoctoral work with NIH and one of the best immunologists alive, it really broadened my horizon into studying the basic mechanisms of innate immunity. It also expanded my thinking into the adaptive immune system, and how innate immunity in turn controls the adaptive immunity, etc. Beyond that was the opportunity to learn a lot of new technologies! Technology development has really become so key these days, and that really facilitated the kind of questions I could ask. We could start getting answers using things such as big data. Through the ability to collect gene expression data, we are able to look at the system as a whole, not just one gene pathway. When you do this, you can really investigate the immunities black box. You’re not only measuring one thing, you’re measuring a lot of things. You start to expose patterns that you actually have never imagined. That introduction to technology and using technology to answer new questions kind of brought me to systems biology. When we think about systems biology, we always talk about emerging properties, which are properties that are born out of many parts of a system, often organisms working together, not things working in isolation. Everything in our body works together, cells interact with each other, molecules within cells communicate with each other, almost every pathway in the cell communicates with every other pathway in the cell, they don’t just work in isolation! Biology back in the day was so reductionist. We always thought of these things as linear, one gene, one pathway, so on and so forth. Systems biology started to uncover all of these nonlinear relationships, which tells you a lot more about how different parts of the system upack each other. From an Immunologist perspective, Immunology, I feel, is the original question that systems biology was born to address because the immune system is many different types of cells working together and communicating with each other leading to an emerging property which could be a particular signaling outcome. A lot of what inspired me was the science, and the fact of our ability to really start opening Pandora’s box with a lot of the new technologies that we have at our disposal these days, which really inspired me to keep going in this area. Also, academia gives you the unique opportunity to keep learning all your lives. You get paid to learn new things, make mistakes, and keep growing and growing your skill set (which not a lot of jobs pay you to do)! It’s really enriching in that regard. The final thing is that you get to train the next generation of scientists! You get to really leave an impact in any small way possible, and you get to see people develop their own careers, flourish into scientists, go into great things, and discover great things. The ability to teach, communicate, and see that you can inspire the next generation of scientists, that in itself is a very satisfying thing!
Could you give some insight on any projects or research you are currently working on, and what motivates you to work on this specific research?
Right now, we are working on the role of innate immunity in defending our bodies against pathogens and how pathogens can hijack the innate immune system in turn. We are especially working on a set of cells called macrophages, which are the first defenders against pathogens. The innate immune system is like a set of security guards that come into play when you see an invader, so macrophages are one of the first cells that shoot into action upon seeing pathogens. Currently, we’re looking at the ability of the immune system to defend the body against pathogens, but the immune system is really a double edged sword as I said earlier. It’s very important to defend your body against pathogens, but it also has to be kept in check. If you get too much of an immune response, such as too much of an inflammatory response for instance, you start getting problems or diseases because of it. As a result, you can get things like autoimmunity, cancer, and other inflammatory diseases. The immune system has to be really tightly regulated and kept in check, so that you are able to mount an immune response that corresponds to the threat and pathogen. Our lab is really at that junction, we study both the host pathogens interactions aspects of it, and also think about what happens when you have too much of a response from the innate immune system to where it starts tipping into diseases. The project we’re working on right now, just in very broad terms, is looking at a complex called the inflammasome. It’s a complex that is involved with innate immune signaling, and we’re looking at how it defends the body against bacterial infection, like Somalia and mycobacterium tuberculosis. We’re really trying to characterize what these innate immune proteins, or inflammasomes, do when they see pathogens. On the flip side, we’re also looking at what these pathogens do to the innate immune system in return, how they actually adapt themselves into cells like macrophages, and how they survive in these host cell environments. For example, macrophage’s environment is a really hostile environment as they are really good at killing things, so intracellular pathogens that have adapted to survive within these cells and salmonella and mycobacterial are two such pathogens. Essentially, we’re looking at how these intracellular pathogens are able to hijack the host to survive within these cells. We are also looking at how too much of a response or dysregulation of inflammasomes lead to diseases like autoimmunity. One of the diseases we are starting to focus on is type 1 diabetes. We are trying to figure out how dysregulation of some other innate immune proteins and how a very low amount of persistence signaling through these proteins, can actually lead to tipping of cells into a cancerous state. We’re trying to figure out how that is regulated within the cells, so that we can hopefully develop strategies to interfere and block such things from happening.
Throughout your career, you have released many publications, what is your favorite research work you’ve done so far and why?
This is a difficult one! You’re asking me to choose between my mentors and my students, which is very tricky. I would say there were lots of them. It’s really difficult to pinpoint one, but if I had to, I would say two things. One, was work I did when I was a postdoctoral fellow before I started my lab. We found this mechanism by which mitochondria is involved in innate immune signaling, specifically inflammasome signaling (inflammasomes are innate immune complexes that are important for signaling against pathogens). We really didn’t quite understand how these proteins come together and signal within the cell. What I found back in the day is that they actually use mitochondria as platforms to assemble within the cell! The mitochondria actually amplifies signaling through a particular innate protein called NLRP3, and that was a really basic finding that changed the prevailing model of inflammasome signaling. We learned that in response to different stimuli and different triggers, you can start engaging other proteins within the cell. Basically, you can start engaging mitochondria as an amplification mechanism. It really opened up the field in terms of groups exploring the role of mitochondria and inflammasome activation. We recorded the role of one protein on the mitochondria, but many other groups followed up on the roles of many other mitochondrial proteins that were involved. It also exposed this whole nonlinear behavior in the innate immune system where it became quite clear that in response to different triggers different sets of proteins are engaged. It’s not just two or three proteins involved in a pathway, but many more! That was essentially my postdoctoral work. However, the coolest thing I’ve done in my own lab is finding that very small changes in gene expression over time can lead to tipping off of cells into cancerous states. Cancer is a complex disease, we always think of it as a disease that is controlled both by the environment and by genetics, and many different genes can be involved in the progression of a cell to characterize cancerous behavior. If you look at a lot of literature out there, there is a lot of data showing that a lot of these proteins that are the executioners of signaling in cancerous cells, does not change the gene expression that much! The gene expression only changes 1.5-3,4 range. Our work was the first to show a very small change in gene expression, if persistent over time, can cause cells to dip into a cancerous state. It really opens up our minds to start thinking about how diseases, like autoimmunity and cancer, can develop in humans as they age; how these age related diseases develop, and how that can actually link to small changes in gene expression accumulating over time. The fact that small changes that are persistent over time can cause these big effects is very intriguing, and I hope that we open up a lot more investigations.
What advice would you give to high schoolers or anyone else who may be hoping to pursue a career in healthcare or the STEM field based on your own journey and teaching of college students?
Dr. Subramanian (top) with interns Zainab (middle) and Kalea (bottom).
The biggest advice I could give to anybody is that whatever you do, do it with your whole heart! Don’t cut corners. I think that there are things that hold us back, such as we do this much, but we don’t do enough. But if you do it, do it at the leading edge, do it the whole way, do it with your whole heart, you will definitely succeed. Have perseverance, especially for high school students who want to do research since research is an accumulation of failures. You fail a number of times and you figure out all the things that don’t happen before you figure out what happens. Which can actually be very rewarding because a lot of things that don’t work usually leads you to the right thing. Don’t get discouraged if something doesn’t work, have perseverance, and keep at it. That’s really the key! You have to work hard, stay focused, and go outside of your comfort zone. Research means that you’re learning potentially for the rest of your life. You have to be open to learning new technologies, using them in your research, and not being afraid to go outside of your comfort zone to do new things. Don’t get caught up in a mood where you keep doing the same things again and again because that’s the easiest way. For high school students, go out there and learn new technologies. You guys are living in an era when we have all the cutting edge technologies, from genomics to new imaging technologies. If you want to ask a question, really the sky’s the limit in terms of the number of ways you can go about doing it. If you learn these things early on, it will take you really far.
What is an ugly truth of your research/job?
An ugly truth is that nothing is ever complete, No work is ever fully done, no story is ever the end. Basically, that there is no end. You have to define when you think you have found something significant, and when it’s time to put it out into the public domain. All the work you do today, someone could come tomorrow and find something else that says it doesn’t actually work this way, it works another way. That’s okay. We attach a lot of ego to our work, but it is an ugly truth that regardless of the amount of work you do, (you can put your best hypothesis and findings out there based on current knowledge) things change as knowledge grows. That’s why you have to change. Things will keep changing and you think you finish your work today, but no it’s actually not finished, something new will follow up on that. Maybe it will withstand the test of time, and maybe it won’t, but that’s just the fact. It’s still a drop in the ocean and it contributes to knowledge. You know that whatever you did, paved the next path of science literature that follows it. So, how do you cope with this? I think that you just have to be interested in science and keep learning and don’t have an ego attached to your science. Don’t be an egotistical scientist. Be open, think critically, and if you keep doing that, and are ready to go outside of your comfort zone, and are just doing the science, I don’t think those things will affect you. I think the way to deal with it is to accept that there is a bigger reason you’re doing the work that’s not just for one paper or one story. In research, the fact is that you’re looking for the truth in a maze. Now, who knows what the truth is? The truth is constantly being rewritten. However, if you do this for the love of learning, the work will never seem like work or a chore, regardless of whatever happens.
What research do you hope to continue or start in the future of your career?
Many things! I really hope to dig deeper into the immune system. There are so many emerging tenants that confer with the basic understanding of how the immune system works, so I hope that we will continue to contribute to our understanding of how pathogens impact hosts and vice versa so that we can win this arms race against pathogens. COVID-19 is a good reminder of the importance of immunology in today’s society. We have all had a crash course in immunology over the last year regardless of whether or not you’re an immunologist. You know some immunology today because of the pandemic. The pandemic is a great reminder of how important this work is, and how we need to win this armed race against pathogens, and to keep the good work going so we don’t hit another pandemic. Intracellular pathogens, things like viruses and the things I described to you, these are the very difficult cookies to tackle. I think we need to keep digging deeper and deeper into this before they get the better of us! More broadly, I also want to focus on the other side of the double edge sword, such as how do we keep the immune system in check to prevent human disease and promote the health of people, especially healthy aging. We would like to keep working to try and figure out what are the mechanisms that control and regulate immunity so that we can start to devise better strategies to try and prevent diseases, especially these long term chronic diseases that are really a big burden on the healthcare system. I hope we can continue to do both of these things.
Link to ISB Profile: Naeha Subramanian, PhD · Institute for Systems Biology (isbscience.org)
Link to Subramanian Lab: Home | Subramanian Lab (isbscience.org)