Lab Meeting: Deepak Srivastava

“In the coming decade, we will be able to assess human genetic variation on a massive scale.”

Deepak Srivastava’s scientific career began in earnest, on a sailboat.

As a 24-year-old medical graduate, the newly minted Dr. Srivastava went on a sailing trip with his research mentor, Professor Brad Thompson, in the summer of 1990. At ease on the open waters and under a starry night sky, Thompson discussed the paradoxical nature of genome regulation with his student: “You start off with one cell [zygote]. And even though every daughter cell has the same genome, you get so many different cell types from that, which is just a huge mystery” (Q#1).

How does an undifferentiated cell transform into a highly specialized neuron or a cardiomyocyte during development? What molecular factors control this cellular “fate,” and how can this journey be derailed in disease?

With these questions swirling in his mind, Srivastava chose pediatric cardiology as his clinical focus—a specialty that served as a tributary to his scientific passions: “much of the disease you take care of is developmental birth defects involving cells during embryogenesis that do not acquire their correct fate. So, it turned out that conversation [with Thompson] was directly applicable,” reflects Srivastava, now President of Gladstone Institutes and a Professor of Pediatrics at UC San Francisco (UCSF).  After completing pediatrics residency at UCSF and cardiology fellowship at Harvard, Srivastava chose Eric Olson (then at MD Anderson) as his postdoctoral mentor—though only 37, Olson was already well known for his groundbreaking work on skeletal muscle: “I wanted to figure out how cardiac cell fates are being determined. Eric was a relatively young scientist at that time…and on a steep upslope of his career” (Q#5).  The rest is history: Olson and Srivastava mapped key transcription factors dictating heart development.

Srivastava established his own research group at UT Southwestern in Dallas, and later returned to San Francisco to lead the Gladstone Institute of Cardiovascular Disease in 2005. His lab is dedicated to tackling the questions first broached on Thompson’s sailboat: “what I work on today is how you get such diverse cell types with the same genome…it’s all through regulation of epigenetic and transcriptional factors during development.” His lab employs animal and iPSC models to study heart development and disease, with a focus on mapping the complex transcriptional networks that underlie these processes. For his efforts, he is an elected member of the American Academy of Arts and Sciences and the National Academy of Medicine. 

In addition to running his lab, Srivastava wears another hat, as President of Gladstone Institutes: “we are overtly organized around disease…we have institutes that are explicitly focused on disease such as heart or neurodegenerative diseases. Part of our mission is to not only understand the diseases, but to also solve those conditions.”  At Gladstone, Srivastava has championed academic and industry collaboration to hasten the development of new therapies: “The goal is to impact people in the fastest way—because we all should be working with a sense of urgency, I believe.” To this end, he has co-founded two biotech companies, iPierian Inc. and Tenaya Therapeutics—focused on the treatment of cardiovascular disease.

Above all else, Srivastava is the rare breed of scientist who does not separate rigorous science and human connection: “when new postdocs or graduate students join my lab, I tell them that our goal over the next few years is to develop a deep enough relationship to last a lifetime.” It’s likely that this attitude has made Srivastava such a productive lab head and mentor, caring physician and effective leader at Gladstone Institutes.

Below is an interview with Professor Deepak Srivastava from December 2022:

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1. What was your first taste of science? Briefly, what about this initial experience drew you in? Who was your first great scientific mentor? 

I was first exposed to science by my father, Satish Srivastava, who was a biochemist and I got to see his passion for discovery and his love for training the next generation of scientists. My own first experience in science was the summer between college and medical school, when I spent three months in the laboratory of Benz Wermuth in Switzerland [Bern]. I sort of got “the bug” there, and I really enjoyed my time in the lab. Even though I was in a beautiful setting, I found myself in lab till 10 or 11pm at night, even on the weekends, because it was just so fun trying to pursue a question. When I started medical school, I knew that I was going to go for a career in both science and medicine. Even though I wasn't actually in the MD-PhD track, I knew that I was going to do both from the start.

Medical school is really when I had my first prolonged laboratory experience that solidified my desire to become a physician-scientist. My mentor there was Brad Thompson, who studied nuclear hormone receptors and their role in gene regulation. This was in the late 80s, and that experience got me thinking about how to understand transcriptional control of genes. Those were the days when Hox genes were just being discovered and the remarkable observations were being made that, by influencing transcription, they guided cell fates and organ patterning.

My project in the Thompson lab was really to try to understand how certain steroid hormone transcription factors were functioning in cancer. When I graduated from medical school, and this is a great story in mentorship, Brad [Thompson] took me out on his sail boat—he had taught me how to sail. We did an overnight trip, just he and I, which was pretty special.  It was dark out and we were under the stars having a conversation about the future. So, I asked him: “if you were a hotshot young scientist, what are some of the big questions for the future you might pursue?” This was in 1990. And he thought about it, and said: “just trying to try to figure out how the genome is regulated. You start off with one cell [zygote]. And even though every cell has the same genome, you get so many different cell types from that, which is just a huge mystery.” I thought about that, and then ultimately went on to do pediatrics, and then pediatric cardiology as a clinical specialty. And there much of the disease you take care of is developmental birth defects involving cells during embryogenesis that do not acquire their correct fate. So it turned out that conversation [with Thompson] was directly applicable to the clinical area I chose to study. It certainly turned out to be a somewhat linear trajectory, because what I study today is how you get such diverse cell types with the same genome and how human mutations disrupt that process resulting in disease.  Of course, it’s all through regulation of epigenetic and transcriptional control during development.

[Were you always committed to medicine and becoming a doctor?]

As a kid, even in grade school on the playground, if anybody got hurt, I was always the first person to try to help. I was also always interested in reading a lot about science and medicine. Actually though, when I was in college, I was an economics major. I thought I was going to go to Wall Street and be an investment banker.

While I was always interested in science and medicine, I was less interested in being a doctor in private practice.  Although it would be very rewarding and great in so many ways, I wanted to have a broader impact, which I thought would be harder to do in private practice. But at the time [college], salaries in academic medicine were so much lower that I feared I would succumb to financial pressures and that made going into medicine less attractive.

But I remember one discrete day halfway through college when I recognized that that to me, money is much less important. I realized that I really love doing science and medicine, and I'd be fine no matter what. So the next day, I changed all my classes and went down the physician-scientist path and it was totally the right decision. The decision came after a fellow student, who was actually an English major, followed the Socratic method and asked me questions about why I was doing what I was doing [which at the time was finance]. We talked until like 4am, at which point it just became crystal clear that I should pursue medicine. After I changed all my classes, I never had any doubts again. I love what I do now.

2. What has been your scientific high point? — What do you consider to be the most exhilarating discovery or set of discoveries you have been involved in throughout your career?

The arc of discovery that has been most satisfying in my career, particularly as a physician scientist, has come from a patient and family that I took care of in the early 2000s. This patient and family had a particular form of heart valve disease where one of the valves becomes calcified and needs to be surgically replaced. This is among the most common forms of heart disease.

Even with our primitive technology at that time, we were able to map a single gene [NOTCH1] that was responsible for causing the disease in 11 family members across 4 generations. We subsequently figured out the mechanism underlying the disease by making induced pluripotent stem cells from the family members. It turned out that when NOTCH1, a transcription factor that regulates cell fate, was present at 50% levels, the valve cells were getting “reprogrammed” to become more like an osteoblast and therefore laid down calcium as they are supposed to do. After understanding the mechanism underlying that disease, we were able to do a novel high content drug screen in the lab, evaluating how gene networks were dysregulated in the patient cells. We found a drug that corrected the dysregulated gene network in the patient-derived iPSCs, and then took that drug in vivo to a mouse model that we made in our lab. We found that the drug worked in vivo, and are now taking that compound towards clinical trials. So that story goes the full arc from taking care of a patient to finding a drug for that disease. I think it often takes persistence; in science you have to be willing to go deeper and deeper. Sometimes you are waiting for technology to catch up. For example, if we had discovered this family today, I think we would have been at the same spot within four or five years. We found the disease in the early 2000s but couldn't figure out the mechanism until we could make iPS cells. Even once we could make iPS cells from patients, we found that there was too much noise in the culture system [to study dysregulated transcriptional networks]. Again we had to wait until we could make isogenic controls, using gene editing to correct the mutation on an identical genetic background—create cells with and without the single nucleotide change. All the biology suddenly laid itself out beautifully once we got rid of the “noise” by using an isogenic control line. So I learned that sometimes the time is right to ask a question based on the technology available. Sometimes it's not. When it's not, you may not be able to address the question, but you should never forget about it. When technology makes itself available, you need to go back to it and figure it out.

I should say, the last few phases of this research story were led by an MD-PhD student: Christina Theodoris. In my lab, she published papers in Cell, JCI and recently in Science describing these findings. Then she was a pediatric genetics resident at Boston Children's Hospital (where I also trained in cardiology) followed by a postdoc with Shirley Liu in Boston [at Dana-Farber Cancer Institute] where she learned more computational biology skills. We've just recruited her to come back to start her own lab at Gladstone and she represents the other passion I learned from my father, which was active and close mentoring to help young scientists succeed.

3. What set of research questions or projects has you most excited about science today?

What I'm most excited about broadly, which applies to every area of science, is the fact that in the coming decade we will be able to assess human genetic variation on a massive scale…because the cost [of sequencing] has come down enough. There are enough systems set up now that we'll have data about whole genomes on hundreds of millions of individuals, or maybe far more, in the next decade. When combined with information from electronic health records to track outcomes, and AI approaches to analyze these datasets, I think we'll really begin to assign genetic variation to clinical outcomes. And if that's all we could do, I'd be less excited. Because then it's just an association, right? But if you know a certain genetic variation is associated with disease, the real question becomes: which cell type is that variation affecting?  The DNA variation is in every cell in our body, but only a subset of cells will have a problem with it [and contribute to disease].

Today, we can assess which cells are affected at single-cell resolution with new technologies. So, the merging of large-scale DNA sequencing, EHR integration and mechanistic single-cell resolution studies can allow us to map cause and effect relationships between genomes and disease. I think that opportunity is really exciting to me, within my own lab, but this same opportunity applies to every area. We just didn’t have this ability a few years ago.

4. What is one piece of advice for a young scientist aspiring to have a career in academia, and make some important discoveries?

My advice would be for people to find an area of science that they can care about enough to really give it their all. As they do that, also be fearless about incorporating new technologies as they come online, in order to try and answer questions. One must be willing to go deeper and deeper into that area, while also sort of keeping your “antennas” up for where interesting and unexpected offshoots might arise. The reason I say that is, generally as you dig deeper and deeper into the mechanism of any problem, there's the potential to uncover novel ways that cells or organs work. One could just observe that and then move on. But if your “antennas” are up, you might see that and deduce a more general phenomenon that is affecting other areas of biology. If you pursue that further, your impact on science can go beyond your own field. As people develop their careers to have a deep impact within their own narrow area, also think about how findings can influence the way people think in all areas of science.

[How do you personally keep your “antennas up?”]

It is key to read about findings outside your narrow area or field. People will naturally hear and read about discoveries in their own field because they're going to go to those kinds of meetings. They're going to read things in their own field, because they have to. So try to religiously attend seminars and read articles about topics outside your own field. That may actually make the biggest difference in your science.

[And advice specific to physician-scientists?]

One piece of advice that I give to MD-PhD trainees is that it is possible to be a high-quality physician and a high-quality scientist. I say that because I think so many people are advised today that it's not possible—they need to choose one or the other. I think you can do both.

But it doesn't happen by chance. And the only way to be good at both is that during your training, you have to fully focus on mastering what you're doing at the moment—getting more learning per unit of time than your peers. If you do the math, that's the only way it works, right? The amount of time spent in training can't really change. So you have to be able to extract more knowledge and more learning than your peers [pursuing just science or just medicine]. Finding ways to do that in clinical training and finding ways to do that in lab is key if you want to excel. You have to really focus and choose what you want to do with your time.

I'll give you an example for how to do this on the clinical side. When you see a patient you will learn about the patient on rounds, as part of the team. And somebody might say: “here's an article, read about it.” But I'd say by and large, what you find when you're a resident is that you're really busy. And you get really sleepy. It’s really easy to see a patient, learn what you need to learn by discussion and what happened to them--which we'll never forget. But it might be this narrow part of the disease, compared to everything else you may need to know. And it's unlikely that you'll read a primary article, even if somebody gives it to you, because you won't have time. But if you religiously decide to spend 10-15 minutes every day reading about a new disease by reviewing a standard textbook—it will make a huge cumulative impact. In most textbooks for medicine or pediatrics there is about two to three pages on every condition…a digestible amount. Textbooks now are so beautifully constructed that you will actually learn all the key points you need to know about that disease, which you may miss on rounds. The key is to pair that reading [temporally] with seeing a patient—then you will never forget what you read in those pages. I guarantee you whatever field you go into, you will remember the facts you read, because you saw an [affected] patient the same day. But you've got to be religious about it and do it every day, no matter what. And if you can do that, you have 365 days in a year and you are in clinical rotations through medical school residency for 5-7 years, or more. If you add that up, it becomes around 2000 disease states in your head permanently—that’s a lot. And it's with that fund of knowledge that you can connect the dots and become a good scientist and physician. And so that’s a small example of how in that clinical timeframe you can do more.

5. Who was your biggest scientific mentor? Why were they such a great mentor? 

I mentioned my father. As a scientist, I patterned a lot of how I run my lab and deal with people based on his example—I make the lab a part of our family. I learned a lot of that from my father, and so he had a huge influence. The other major mentor is Eric Olson, who I did my postdoctoral training with when he was at MD Anderson. And he has continued, even 25 years later, to be one of my closest friends. Our families are close, and we started companies together. I think I learned from him to always be thinking deeply about mechanism [of disease]. That's probably the most important thing: to be relentless about getting to the core of how things work mechanistically.

After all my clinical training in Boston, I started my postdoc but the lab I was in unexpectedly had to close. I needed to change labs, and could have chosen an alternative lab in the Harvard system. There are many good labs there, but I had a very specific question at that point: I wanted to figure out how cardiac cell fates are being determined. I had a fellowship through a special national program for pediatric-scientists that was mobile, so that made it easier to move. Eric was a relatively young scientist at that time, he was perhaps 37, and on a steep upslope of his career. He was at MD Anderson and was working on myogenic transcription factors in skeletal muscle, but not doing much work in the heart at that time. But I called him and asked if he'd be willing to take me on, and that we could use a lot of technologies he had already pioneered in skeletal muscle on the heart. And he agreed, so I moved down there to train with him. As you can imagine, the people at Harvard were surprised when I said: “I'm leaving Harvard to go to Houston.” But it turned out to be a great decision – we discovered new transcription factors that control cardiac fate decisions.

6.     What should trainees look for when choosing a PhD or post-doc lab?

I would look, most importantly, at the values of the mentor and how they view the relationship between the mentor and mentee. The greatest predictor is to look at their track record. So when new postdocs or graduate students join my lab, I tell them that our goal over the next four or five years is to develop a deep enough relationship so that it can last a lifetime. Because ideally, your mentor will be somebody who will be engaged with you, not just during the time in that lab, but for the rest of your life. That doesn't happen by chance, it happens only with an investment of time, and experiences together. I would look for a mentor who is interested in doing that. Not everybody is…so find somebody who values and is interested in that. And if the mentor does value this, there’s a good chance it's going to be a strong lab environment. I would also look for a mentor who's created a lab environment that is one where people have a high degree of intensity, because that's what's going make them more productive. But also lab members who really like being around one another and like to have fun. Because I believe you are going to do your best work if you're really loving it. Making sure it's an environment where people love what they're doing, I think is really important.

7. How do you view the role of a physician scientist in working with the biotech and venture community in SF? How has this relationship changed over time, and what implications does this have for therapies reaching patients? 

Particularly as a physician-scientist, the reason I do what I do is to impact human disease. At the end of the day, if our lab keeps making great discoveries that just sit on the shelf…well that is not fulfilling because I want our work to reach patients.

But I'm not in the best position to make a therapeutic. Nor do I want to be the one who does that. Rather I see myself and our lab as a discovery engine. But I'm very interested in seeing those discoveries have an impact. The only way it's going to have an impact is through investment from the commercial sector. I see [industry engagement] as very much a part of the same mission to cure diseases. Scientists need to be engaged if they want to have their discovery go to the next step. It used to be that if you published a great paper and described a great new target for disease, somebody would come in from the commercial sector, license it and develop it. But I think that started to fundamentally change during the financial crisis [2008].

There was a big shift in risk appetite. So, unless you became proactive about taking that discovery to the next step, de-risking it further and then getting it into the hands of the commercial sector, the work just sat there. That was unsatisfying. I think because of that [investor skepticism] it made sense that scientists have found creative ways to interface with the commercial sector to advance the discoveries themselves. That is what I've tried to do at Gladstone. I wear another hat, in addition to running my lab, as president at Gladstone Institutes. I’m in a position to sort of affect how we interact with industry more broadly. We’ve been very active in doing that at Gladstone—unlike other high-quality independent research organizations, we are overtly organized around disease. We have institutes within Gladstone that are explicitly focused on heart disease, neurodegenerative diseases, as well as viral and immunologic diseases. We feel like part of our mission is to solve those conditions. As part of that, we have recruited talents that help achieve that mission, including Shinya Yamanaka, who invented iPS cells, and Jennifer Doudna, who co-invented CRISPR technology—two technologies that together really impact all our science.

The main point of co-founding a company or interfacing with industry is to transfer the knowledge when a discovery in our lab has gotten to the point where we're no longer the experts in the next step toward a therapeutic. The goal is to impact people in the fastest way—because we all should be working with a sense of urgency, I believe. When it comes to actually making a drug, we want to get it in the hands of experts. There would also be an opportunity cost of us doing drug development in our own lab—the opportunity cost is the next big discovery, because now we're trying to do translational work that could be better done elsewhere. We should stick to what we do best, which I think in an academic setting is discovery. If you are an assistant professor, and you happen to have made a discovery that is at that point [of drug development], then you should put it into a company and go for it. But if you're just doing it because you want to create a company, then that's not a good reason. That's just a distraction.