Lab Meeting: Edgar Engleman

“Choose a great question to pursue and be stubborn and persistent.”

In 1966 the Harvard Radcliffe Orchestra opened its season at the Sanders auditorium. They attempted Bach’s Brandenburg Concerto No 1, a piece meant for a group of soloists accompanied by a small orchestra. The conductor elected to use the entire strings section, and things got messy. The Harvard Crimson reported: “The first movement was too heavy and the violins never agreed sufficiently on any phrasing -- or even the precise location in time of the beat.”

The saving grace? Concertmaster (and Harvard senior) Edgar Engleman “played the solo part in the third movement clearly and sensitively.” Ed Engleman’s transformation, from an excellent violinist but “average student” (Q#1), into one of our nation’s most impactful immunologists is indeed the mark of a virtuoso. His early work, which established the tools first used to probe human immunology on a molecular level, was largely a solo-endeavor: “I was a bit of a lone-wolf,” reflects Engleman, now a Professor of Pathology and Medicine at Stanford.

After his days as concertmaster of the HRO, Engleman completed medical school at Columbia, internal medicine residency at UCSF, biochemistry training at the NIH and a brief postdoctoral fellowship (Q #4) in Hugh McDevitt’s group. He started his own lab at Stanford in 1979, dedicated to studying the human immune system: “I was told that it was a ‘waste of time’ [to study human immunology], because there were no reagents and no genetics. But I made my decision.” It was an excellent one.

Within a couple years, in collaboration with Robert Evans, he created the first monoclonal antibodies against human CD4 and CD8 (Q#4). With these powerful reagents in hand, his group uncovered that HIV uses CD4 to invade T-cells—at the height of the US AIDS epidemic. In the 1990s Engleman turned his attention to another component of the immune system: dendritic cells. His group studied how to collect and harness the ability of these antigen presenting cells to invoke an immune response against cancer. Engleman’s advances in isolating and loading human DCs with tumor antigens led him to co-found Dendreon, which developed the prostate cancer vaccine Sipuleucel-T (Provenge). In 2010, Provenge became the first FDA approved precision immunotherapeutic, and planted seeds for companies like Juno Therapeutics, Kite Pharma, and many other cell therapies. After the approval of Provenge, Ed’s father Ephraim Engleman—a legendary “old-school” rheumatologist, staunchly opposed to industry involvement—gave his son a phone call. The elder Dr. Engleman admitted that “there may indeed be some value in working with companies after all.” The younger Engleman lab’s current work focuses on understanding the molecular mechanisms of immunologic tolerance, and how this process is co-opted by cancer cells to evade the immune system and metastasize. Engleman considers his current studies to be among his most exciting and impactful, to date (Q#7).

In parallel to his career in academia (> 350 publications), Engleman has been a major force in biotech. In addition to Dendreon (acquired by Sanpower), he founded Cetus Immune (acquired by Novartis), Genelabs (acquired by GSK), and more recently Bolt Biotherapeutics, Medeor and Tranquis. In 1996 he co-founded VIVO Capital with his longtime collaborator, and biotech trailblazer Frank Kung. Engleman humbly characterizes these decades of scientific discovery and biotech creation by saying: “things came my way.”

His career, in both research and industry, has been defined by a pursuit of big problems—high risk and high reward projects that challenge dogma. A true physician-scientist (who practiced medicine for decades) his work is intensely focused on helping advance patient care.

Precision and rigor, in classical music and science, are key. But creativity and a dash of bravery are the sine qua non of excellence in both disciplines. Engelman’s early work establishing the nascent field of human immunology, bold decision to work with industry and VC in the ‘80s-‘90s, and current quest to find conserved mechanisms of tolerance, exhibit these qualities in spades. A self-described “late-bloomer”, Engleman’s most exciting contributions to medicine, science and biotech certainly lie ahead.

Below is an interview with Dr. Edgar Engleman in August 2022:

1.     What first got you interested in medicine?

My father [Ephraim Engleman] was a professor of medicine at UC San Francisco [a renowned rheumatologist]. He was old school, and I mean really old school. He died at work shortly before his 105th birthday. He commuted 30 miles to UCSF from the house where I grew up, every single day. He loved working, and so was a great role model in that regard.

On the other hand, I never considered pursuing a career other than medicine. None at all. Because I had this very strong role model. Importantly, too, I didn’t develop an interest in science until late in medical school.

[On going to Harvard College and the Columbia University Med School]

I came from a pretty average high school. But my claim to fame was that I was a good musician—a violinist.

When I got to Harvard, I was pretty turned off by the preppy social norms. As a result, I decided to just spend my time with my fellow musicians—I was the concertmaster of the Harvard-Radcliffe Orchestra [HRO]. I majored in Social Relations/Psychology and took the minimum required pre-med courses, which I did not particularly enjoy. So thought I would go to medical school, because it was a family tradition, and not necessarily for the ‘right’ reasons.  

When I arrived at Columbia [medical school], there were two people out of the class of 110, who had not been science majors in college. As one of these two, I was ill prepared. The first day of medical school the Dean said to our class: ‘we're going to flunk about 15% of you. But don't worry, we'll let you take the first year over again.’ So medical school in those days was not like medical school today—there was really a bootcamp type of mentality.

Initially I didn't like medical school at all, in fact I hated it. The reason is because we had to memorize a lot of stuff. Eventually, it occurred to me that we were memorizing things that made absolutely no sense; it also seemed as if there was little real understanding of the human body or disease pathogenesis. So, I became very skeptical [of the traditional teachings].

I was smart enough to be able to catch up and do reasonably well [in med school]. But I became extremely skeptical, and I thought: ‘there’s got to be a better way.’ So, I started tinkering in faculty research labs at Columbia. I enjoyed working in those labs—trying to find answers to how a drug or a hormone affected a chemical reaction was like a treasure hunt. It was fun to try to see if I could solve interesting problems. But scientifically I was a late-bloomer, relative to many others who had a passion for science very early-on. I did not. After medical school, I continued to follow the family tradition by completing an internship and residency in internal medicine.

2.     What was your first taste of science? Briefly, what about this initial experience drew you in?

[After graduating medical school] the Vietnam War was going on and all physicians were subject to the draft. On the other hand, physicians interested in research training could apply to the NIH for the equivalent of a fellowship there that would fulfill their service obligation. So, I applied and was accepted. At the NIH I performed basic research in biochemistry under the guidance of an eminent chemist, ER Stadtman. But again, I was in the wrong place. I was purifying enzymes from E. coli and analyzing their properties, and for me this was not quite translational enough.

So at this point, I was becoming increasingly concerned about where my career was headed. I'd already finished my clinical training and the research I was performing at NIH was not inspiring, and at this point I was married with a child and needed to figure out what I was going to do longer term. So, I started reading. I discovered this very nascent field called ‘immunology’. Immunology was interesting, because some studies suggested that the immune response is controlled by major histocompatibility genes that were strongly linked to disease susceptibility. Some of the most exciting discoveries had been made by Hugh McDevitt, a professor at Stanford. I ended up contacting him [McDevitt] and asking if I could do a fellowship in his lab. I had some ideas that I shared with him and thought he would welcome me with open arms. But instead, he said: ‘well, yes, you can come but only if you first get your own fellowship.’ So, I had to get a fellowship to cover my expenses and lucky for me, I got one. 

3.     Name an overlooked scientist, whom you feel strongly that every grad student (or med student) should know and be able to describe their major findings.

Hugh McDevitt would be someone I would mention. He discovered that MHC II genes could influence the immune response. He got some recognition for this discovery. But, he didn't get the Nobel—Benacerraf and others did. But many people felt McDevitt deserved more credit. He was a great scientist.

4.     You became faculty relatively quickly after finishing internal medicine residency. What did you initially set out to study?

I was only in McDevitt’s lab for a year. I was offered a faculty position at Stanford very early on to join the Department of Pathology. I was no pathologist, but I had been boarded in medicine and they liked that. The department also wanted expertise in organ transplant clinical testing: ‘how do you find a match between a potential donor and the recipient?’ At the time such testing was based on a very primitive immune assay called the mixed lymphocyte reaction. I had experience performing this assay, and based on that and my clinical training, they offered me a faculty position. I couldn't believe it. I told McDevitt that I had this offer, and he was upset, actually furious, partly because I hadn’t completed my fellowship (not even close) and partly because he was concerned about my competing with him in the burgeoning field of immunogenetics.

I reassured him that I wasn't going to compete with his lab. McDevitt was studying the immune system using the mouse as a model organism, and by exploiting mouse genetics. I was interested in translational human immunology. I wanted to study the human immune system. He [McDevitt] said: that's a ‘waste of time, there are no reagents, no genetics.’ But I made my decision and left the lab to join the faculty. Then things came my way. I was a late bloomer, because my knowledge of immunology was primitive, but I made a good guess. There was this new hybridoma technology out there, which allowed you to make mouse monoclonal antibodies against targets of interest, which had been published in Nature in ‘78. When I joined the faculty in ’79, I said: ‘why don't I try to make monoclonal antibodies to human white blood cells that could distinguish different types of these cells from one another?’ And damn, if it didn't work! Once we got those reagents [anti-CD4 and anti-CD8 mAbs] they enabled me and others to perform lots of very straightforward experiments that defined the functions of T cell subsets. In addition, the antibodies were especially useful during the HIV epidemic when the Stanford Blood Center successfully used the antibodies to screen blood donors]. After these discoveries, I gained confidence, wrote and received grants from the NIH and started to bring in postdocs and grad students. I found that I really enjoyed the mentorship element of science, as well as the discovery process.

5.     You have had quite an impactful career in biotech and venture capital –both co-founding and investing in companies. How did you first get involved in “industry?” 

I was approached in 1979 by Frank Kung who was working with a company, now long since gone, called Cetus. The first two or three big biotech companies were Cetus, Genentech and Biogen. Cetus’ leaders felt their arch competitor was Genentech, and they would do almost anything to compete. Frank [Kung] had gotten his PhD in molecular biology and an MBA at UC Berkeley. He and his wife, who was a chemist, were immigrants from Taiwan.

After coming to the US and going to grad school, he went to work for Cetus. They told him to find some people with ideas in new fields like immunology and gene cloning. And so he found me at Stanford, as a first-year assistant professor.

He asked: ‘do you have any good ideas regarding immunology?’ I said: ‘ideas, I have 1,000 ideas!’ One was a strategy to make human monoclonal antibodies before there was established technology to do it. Another was to clone human cytokines. I thought these were goals that we should pursue. In 1980 or 81 I was invited to visit the CEO and chairman of Genentech. Genentech was clearly the leader in using gene cloning to produce therapeutic proteins and would soon become the first public biotech company. At the meeting, I told them about a few of my ideas and they said that I should work with them because there was no need for any other biotech companies, especially since they owned all the key technology. After that meeting, I decided that I didn’t want to give my ideas to Genentech. So, Frank and I got together, and started a subsidiary of Cetus [Cetus Immune]. Before Cetus went public, about a year after the Genentech IPO, in the early 80s, the company acquired all of the shares in Cetus Immune and encouraged us to join the company as exclusive advisors. Cetus had really benefitted from work that we had done, and they told Frank and me: we'll give each of you a million dollars’ worth of Cetus stock, if you stay on as exclusive advisors for seven years. A million dollars is a lot of money today, but in 1982 it was a huge amount of money, Dylan. But ultimately our decision was easy—I didn't care about money and Frank wanted to do his own thing. So, we formed a new company called Genelabs. Frank became the iconic first East Asian public biotech CEO. I was the chief scientific officer. After a while, I wanted to get back to the lab. I was having a lot of fun [in industry] but decided I didn't want to be based in a company—because there was too much focus on product development rather than scientific discovery.

6.     You have mentored many (hundreds) students and postdocs yourself. Did you have a key scientific mentor?

I have to be truthful. I didn't have a scientific mentor that I can really point to. I think the reason why it took me such a long time to figure out things was because I was on my own—a lone wolf. I'm not recommending this approach, I'm just describing my reality. On the other hand, I didn't burn out early. In fact, I'm more inspired and excited today about what we're doing in the lab than ever before. While I admired other scientists, and I always thought that some were brilliant, I never had a true mentor. It’s probably as much my fault as anyone else's—because I was searching around for quite a while, trying to figure out what I wanted to do.

When I first came to Stanford, Hugh McDevitt was a very hot commodity and a lot of people wanted to work with him. I’ll tell you the story of when I first got to his lab. I arrived, and I was so excited. I had secured my fellowship and I went into meet him. He [McDevitt] said: ‘Oh, you're here. I hate to tell you this, but I don't have any space in my lab.’ And sure enough, there was no space in his lab. But then he told me: ‘well, I have this lab in another building. There are a couple people in there that are finishing up their fellowships, and will be gone soon so you can use that space.’ So, I went over there to claim some space. There were in fact great postdocs who were in the process of leaving—one of whom was Andrew McMichael, who became a professor at Oxford, while the other, Takehiko Sasazuki, became a professor in Japan. But they both left within a few weeks after I arrived, and then I was totally on my own . So that's my life. As a result, I ended up doing experiments that were really interesting to me and had nothing to do with the fellowship I had originally proposed.

7.     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?

I’ve got to be honest with you, Dylan. I'm more excited about what I'm doing right now than anything I've ever done.

I got lucky by choosing to pursue immunology, which at the time [early 80s] was a nascent field. I had no idea it was going to become so wildly impactful. The bottom line is: I believe that the immune system is affecting just about process in the body and most diseases, too. Certainly [it impacts] the vast majority of chronic diseases such as cancer, autoimmune disorders and aging. It's taken a long time for me to fully appreciate this. What I’m working on right now is trying to understand the mechanisms of how the immune response is switched on and off—a process that we call immune tolerance. This refers to antigen specific immunity, whether it's in cancer, organ transplant, autoimmunity or maternal fetal tolerance.

Based on discussions with colleagues, I've come to believe that there's a common set of mechanisms underlying immune tolerance. If we can understand and control them, I believe we can manipulate and potentially cure or prevent a wide range of diseases. I'm extraordinarily excited about this. We just published a paper three months ago in Cell, which begins to address this question in cancer.

It’s work that was led by a brilliant postdoc, soon to be a faculty member, Nate Reticker-Flynn. When he arrived at the lab eight years ago, we talked about projects. I mentioned [in this interview] how important it is to choose a great problem, but how difficult it is solve such a problem. [Reticker-Flynn and I] talked and we came up with a question, which is: why does cancer almost always start to spread by colonizing the draining lymph nodes? There is 100 years of clinical knowledge suggesting that once tumors get to the lymph nodes, it's bad news for the patient. It is the first step in metastasis. And yet, the assumption has been that lymph nodes are just the places where our lymphatic system (our plumbing) drains—you know everything, including tumor cells, drains into lymph nodes. The question that Nate wanted to pursue, was: what if tumor cells don’t end up in nodes just due to plumbing? What if they go there on purpose?

Our hypothesis was that tumor cells do something nefarious in the lymph nodes that causes the immune cells there not to attack the tumor and results in systemwide immune tolerance. The question of why our immune systems do not attack and eliminate cancer is a fundamental issue that has been in our minds, in everybody's minds, for years.

It turned out after [almost 8] years of research that our hypothesis was correct. In fact, tumor cells use genetic tools to escape initial attack by the immune system while they're journeying to lymph nodes. Once they arrive, they reprogram the immune cells there not to simply not attack the tumor but to become supporters of tumor growth. Certain of these [immune cells called Tregs] then leave the lymph node, migrate to distant tissues, and set up shop to help the tumors invade. It's truly remarkable. Nate had to develop a new tumor model in mice just to study this process (which took two years), and using this system, he eventually solved the problem.

He [Reticker-Flynn] identified a conserved genetic program in the tumor cells, regardless of tumor type, and showed where in the lymph nodes they encounter and reprogram immune cells. Now, we don't yet know all the details of how this happens, but the basic steps are pretty well described in that paper. Tumors aren't going to spread without the help of the immune system. The study is a remarkable demonstration of how cancer uses the immune system to survive and spread, which 20 years ago would have been thought to be nuts.

Ultimately, I think this question of immune tolerance is not just about cancer. Tumors have stolen this program and are using it to their advantage. But immune tolerance, or its loss, is fundamental in many diseases including cancer, inflammatory disorders, autoimmune diseases, transplant tolerance, aging and probably explains why mothers do not reject their fetuses. I think all these processes may involve the same [immunologic] mechanism. To the extent that we can discover the details of how this process works, and we have made some progress, that would be truly game changing.

8.     Which areas of science, outside of your direct area/field, are you most excited about seeing develop in the next 5-10 years?  

For me, it's neuroimmunology. I think that the neuroscience field has, until recently, ignored the immune system. Just like oncology field did up until 20 years ago, there has been huge skepticism about the role of the immune system in neurologic disease.

In the last few years has there been some initial recognition of the importance of  immune cells in the brain—not just the microglia, but other immune cells as well. And I believe that [studying these cells] is going to be critically important to our understanding of diseases ranging from Alzheimer’s and Parkinson’s disease to epilepsy and even psychiatric disease. I wish I had the time to pursue it because I think [neuro-immune interactions] are really fascinating. We have done a little bit of work in this area using mouse models, and I’m convinced that chronic inflammation is key to accelerated brain aging and neurodegenerative disease.

9.     Who are a couple up-and-coming scientists (lab < 10 yr old) in your area, or more broadly, whom you think we should watch? Why is their work so exciting to you?

I'm very excited about Nate Reticker-Flynn's future [Q#7]. I'm also on the graduate committee of Noah Greenwald, who's doing fantastic work [in the Angelo and Curtis labs]. He is developing/using very modern, cutting-edge multiplex methods, and is very talented. I'm also collaborating with Michael Angelo, a young faculty member who is very good at developing new engineering tools to solve biological problems. He developed a high complexity imaging tool called MIBI. Combining the power of transcriptional profiling with imaging, and being able to map where and how cells interact with one another, is very powerful. Our labs are currently collaborating in investigations of the mechanisms responsible for immune tolerance.

[MIBI video tutorial playlist]

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

Choose a great question to pursue and be stubborn and persistent. If I look back on all the trainees I've had and ask which ones have turned out to be truly successful in academia, they share one characteristic in common: resiliency. Their personalities are often completely different. I remember one former trainee who was very bubbly, very outgoing, and a fantastic networker with lots of collaborators. Another trainee who was in the lab at the same time was quiet, worked mostly alone and resisted talking about his data before it was ready for publication. But what these two shared in common was a determination to pursue big problems and not let other things get in the way. They did whatever it took to overcome technical hurdles. Typically, trying to solve a big problem is not something that takes a year, but much longer. Don't let somebody tell you what you can and cannot do. Be persistent. However, not every great idea turns out to be correct. So, you must also be able to know when to change directions, and a good mentor can help with this. Based on what I've witnessed with my trainees, and in our lab’s own work, there remain a lot of great unanswered questions, but the answers almost never come quickly or easily.