Lab Meeting: Harvey Lodish
“The secret is always picking a scientific problem that is important, and developing whatever techniques you need to solve the problem.”
The year is 1968. Salvador Luria, MIT professor, famous biologist (Nobel Prize ‘69), mentor to four future Nobel laureates, and passionate political activist, pulls aside his department’s new hire—a brilliant 26 year old named Harvey Lodish. Having trained with Norton Zinder, Sydney Brenner and Francis Crick, the young Harvey needed no help—at least scientifically.
It was on other matters that Luria was seeking to provide advice: “I don't know how many times he [Luria] took me aside and said, ‘you know, you really shouldn't have said that to so and so.’ Or ‘this was confidential information, and you shouldn't have spread it’ or, ‘here's how to deal with the student in your office.’ He [Luria] was an exceptional person and taught me a great deal about mentoring students and running a laboratory.”
Whatever guidance Luria provided in the MIT hallways, it worked. As of 2022, “young Harvey” has mentored over 200 students—two of whom have received the Nobel Prize, and 8 who are members of the National Academy of Science or Medicine. He has taught biology at MIT for 55 years, and is among the institution’s most popular faculty (his classes perennially oversubscribed). His seminal textbook series Molecular Cell Biology has been translated into 14 languages and has educated generations of graduate and medical students—including three of Lodish’s own children and grandchildren (Q#5). His research lab (1968-2019) is legend: they made seminal contributions to our understanding of gene regulation and translation, cloned the GLUT1 and GLUT4 transporters, cloned the EPO receptor and mapped downstream signal transduction pathways, characterized how miRNAs and LncRNAs regulate erythrocyte development and how thyroxine promotes red blood cell maturation. The Lodish lab has also made countless contributions to understanding how hormones, such as adiponectin, influence fatty acid and glucose metabolism.
Along the way, Lodish has helped shape biotech in Boston and beyond—he has co-founded companies such as Genzyme, Millennium Pharmaceuticals, Allozyne, Rubius and Arris Pharma. He is currently the co-founder and board member of several early-stage biotechs: Tevard, Carmine and Cerberus (Q#2). He was previously chair of the Scientific Advisory Board of the Massachusetts Life Sciences Center, and had oversight of the state’s 10-year, $1 billion investment in the life sciences; he currently advises cities and governments on how to build durable biotech industries based on local university research (see Q #8). During local conferences, lab retreats and hikes with his children and grandchildren, Lodish has found time to climb all 48 peaks over 4,000 ft in the New Hampshire White Mountains (Q #1) and 20 others in Maine and Vermont.
In our interview, Harvey sums it all up with a wide smile: “I’m here. I'm 80 years old. I’ve been in biology for a long time.”
Below is an interview with Professor Harvey Lodish from August 2022:
1. You are part of the “4,000 club” where you have climbed all 68 peaks in New England above 4,000 ft in altitude. When did you start hiking?
In 1975 a group of graduate students took me on my first hike in the White Mountains, it was a three-day traverse of all the high peaks. We stayed in Madison and Lakes of the Clouds Huts. And in three days, we climbed Mts. Madison, Adams, Jefferson, Washington, Monroe, Eisenhower and Clinton. So, we did seven of the highest mountains in three days. In the hiking group was my colleague Mary Lou Pardue. We spent the Saturday night in a hotel because we were going to a Gordon Conference on Sunday—and we woke up on Sunday and said, well, what are we going to do? The conference doesn't start until six o'clock at night. So, we climbed Mts. Tom Field. So, by the end of the weekend I'd already done nine of the 48 peaks. And then I started taking my kids and my students and postdocs on these various hikes. So, it was wonderful. I've taken my lab, probably on dozens of hikes. It's a very good team building experience.
2. Your lab closed in 2019, but you are still very active in teaching and industry. What do your days look like now?
I am quite busy. I work with several small biotech’s in Boston I helped found. And de facto, I've been the Chief Scientific Officer for three of them. I'm on the board all three and I chair the SAB of two. They're all doing really cool science. Very different areas. One of them is in neurology, and epilepsy, developing gene therapies for haploinsufficient genetic brain disorders, of which there are hundreds. Another is developing a novel gene delivery system using membrane vesicles derived from red cells. A third one, called Cerberus, which was started by one of my former students, is developing very specific ways of inhibiting autoimmune reactions to foreign proteins, and potentially treating autoimmune diseases without shutting down the whole immune system—inducing tolerance to specific antigens. So, it's all very exciting. I work a lot with these companies. I help them all raise money. That's one big part of what I currently do.
I also teach. I'm in my 55th year on the MIT faculty. I still like it, and I teach an undergraduate course in the Fall - a biotechnology seminar, which has about 15 students. Then in the Spring I organize and teach a graduate course called The Science and Business of Biotechnology, which brings together ~80 students from the Sloan Management School, getting MBAs or PhDs, with biology, bioengineering and chemical engineering graduate students. There are lots of lectures on current developments in biotech. Lots of discussion about starting companies and building companies.
In the middle of the class, the students form small groups and each develops a business plan for a start-up biotech company. They then present these at the end of the class to the whole class, instructors and for four outside VCs, who grade them.
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. What were the killer experiments?
Well, he has a Nobel Prize, but few know who he is now—his name is Salvador Luria.
He and Max Delbrück did a demonstration that bacterial mutations causing penicillin resistance pre-existed before penicillin was added to the cells. But if you read the paper, it was really a mathematical analysis--Max Delbruck was a physicist – of the rates of mutations. It was a brilliant experiment, which is the basis of a lot of understanding of stem cells and everything else [such as cancer biology]. In brief, the current notion in 1943 was that addition of penicillin induced bacterial resistance to penicillin. Nobody had any idea what genes were back then. And what they did in a simple experiment was they set up say 100 tubes and inoculated each of the tubes with one bacterium, and grew it to, say, a million bacteria. If penicillin induced a mutation to penicillin resistance, then each of the tubes would have about the same number of mutations—roughly 1000 in each tube of a million cells. That's not what they found. What they found fit their mathematical analysis, which is you have a certain probability of a mutation during every cell division. So if it occurs during the first cell division, you'll get 500,000 [resistant bacteria]. But that will be rare. If it occurs during the second division, you'll have 250,000—and that will be slightly more common. And it predicted a distribution, which is exactly what they got, which led to the notion that bacteria have genes that undergo random mutations. But that mathematical analysis applies for any kind of cell division, including cancer. You see where it goes? In other words, it's the probability of mutation during every cell division, and what the consequences of that are. So, you realize that it really underlies many current studies, for instance, on development and on cancer. And, I mean, for years, we had our graduate students read that paper, but then they get bored with it. Now, of course, we know all about genes. But it's the analysis that’s really cool.
You know, I mentioned haploinsufficient genetic disorders [Q#2]. As you know, there are a huge number of genetic disorders that are somatic mutations of one sort or another, and these underlie a lot of epilepsies and other neurodevelopment disorders. And it's the same formal analysis that applies to these conditions.
4. What are you reading in your free time?
I'm reading a lot of literature on treating psychiatric disorders. And I get into things that have no business getting into, about how we go about clinically testing a lot of these apps that being used because of the shortage of clinicians. My wife is on the board of the Brookline Center for Mental Health. And, we're financially supporting the clinical testing of a lot of these kinds of apps and programs that can help a clinician do their work better – something that desperately needs to be done. We will be working with a number of hospitals and centers on this. So, I spend a fair amount of time reading some of this literature – for instance ways of using natural language processing to identify early-stage schizophrenics.
I'm on the board of Boston Children's, where they have, like most pediatric hospitals, a crisis of children and teenagers with mental health disorders, where they just don't have the beds to accommodate them. And how one deals with this, and how one can improve the efficiency of the clinicians is a huge problem. We can't train enough clinicians and social workers. You know, our oldest daughter is social worker, and, you know, she's now working with 20 patients a week at home. There she can do many more, there's just a huge demand. So anyway, that's what I do in my spare time, because I found that interesting and rewarding.
[DN: “So light reading?”]
This is what I do. I read highly technical papers that I try to sort through to see if they might be useful, and then make contacts with the clinicians to see if we could test them at the Brookline Center. Because unless they work out in the field [they won’t work]. You can't do it all in a hospital, you need more of a community setting [to deliver treatment]. I haven’t watched television in over 40 years and I shy away from social media – freeing up time I can work on these important projects.
5. What was your first taste of science? Briefly, what about this initial experience drew you in? Who was your first great scientific mentor?
It was during the summers of three years, in 1958 after 11th grade, 12th grade, and my first year at Kenyon - working in a lab at Western Reserve Medical School in Cleveland - on trying to understand what potassium uptake in red blood cells. Obviously, we now know it's a sodium potassium pump powered by ATP. But we were trying to figure out which intracellular metabolite might power the uptake of potassium. And that started me thinking in high school, back in 1958, that we had no idea what cellular membranes were. We had no idea that there were proteins embedded in membranes that transported things in and out. We really didn't understand the phospholipid bilayer structure. So that was ‘58. You know, by 1968, I was already a faculty member at MIT. And we started working on the biogenesis of plasma membrane proteins. This was work we did with students like Flora Katz and David Knipe and postdocs like Jim Rothman, who used the technology we developed, the vesicular stomatitis virus glycoprotein, to win the Nobel Prize in Medicine for elucidating the mechanism of vesicular transport. But the system we all worked out in the lab, which is following the biogenesis of the viral glycoprotein, because it was the only membrane protein we could follow. We elucidated the ER- to Golgi- to plasma membrane biosynthesis pathway in the 1970’s. And then later, of course, we started cloning all these proteins, the first glucose transporter and ion transporters, and so forth. But it really started when I was in the 11th grade in Cleveland heights High School.
And I was hanging around with a lot of medical students and researchers [as a high school student in the lab]. I would go to biochemistry lectures, and it was these people that discouraged me from going to medical school. Instead, they encouraged me to get a PhD. And since biology then was totally descriptive—I’ve never taken a biology course. I mean, in graduate school, I took biochemistry, of course. But at Kenyon I majored math and chemistry and decided to give myself a rigorous training in the mathematical physical sciences, knowing I would always go to graduate school in biology. I was at Kenyon in 1961, when Marshall Nirenberg showed that poly-U directed the synthesis of phenylalanine, and that UUU was the first letter in the genetic code. And my biology professor at Kenyon tried to explain in a seminar what that was all about--and got it all muddled up. And then I decided, okay, this is an area I really want to go into.
[DN: It is amazing that the author of the seminal biology textbook, never formally took a biology course in high school or college]
Exactly. My kids used it [Molecular Cell Biology] in college. And I have a grandson who just graduated from the University of Virginia, who used it in a cell biology course at UVA. But his last name is different from mine. And to this day, his professor has no idea that the grandson of the lead author was in his class.
6. 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 mean, there are many of them and, you know, some I did myself. It [high point] was really all the cloning we did in the 80s. The glucose transporter, the anion transporter in red cells, the galactose receptor on liver cells, the erythropoietin receptor, the TGF beta receptors, because each of them opened up a huge field research. And each of them [discoveries] was exploited by generations of my postdocs who ran with them in their own laboratories. I've always let my postdocs take work with them [to start their own groups].
[On Alan D’Andrea cloning the erythropoietin receptor]
He did it with a technology that we had to develop. Because we knew nothing about the receptor. And we did it [cloning] by functional expression. Briefly, we made libraries of cDNA, and pooled them into groups of 100 clones or so. And we looked for pools that would enable a few of the transfected cells in the pool to bind radioiodinated EPO; where the background of radioiodinated EPO binding was like 900 counts and the positive pools were 1200 or 1300 counts. But we got it. And he [D’Andrea] became very famous, and the paper has only three authors.
7. The number of students and postdocs you've trained is incredible, over 200. Two of your trainees have Nobel Prizes and 8 are National Academy members. What makes a good scientist?
It's curiosity. It’s also the ability to see into the future and identify problems that are important and that can be solved by current or future technologies. So, when I had a lab, I would get letters two or three times a day, from people who wanted to work with me. And the interesting ones, I would just ask them very simple questions. Why do you want to come to my lab? Tell me. And, you know, many of them had no idea why want to. They say, well you're a leader in the field, and I want to work with you, or I read your textbook, and I want to work with you—and that's meaningless. But you get a few that say: ‘can I just share with you an idea I have?’ I say, ‘sure.’ I sit back and listen. Do they know what my lab did? Or currently does? Do they have an idea for a problem? I mean, that's how Alan [D’Andrea] essentially came to me, wanting to clone the EPO receptor.
The secret is always picking a problem that is important and developing whatever techniques you need to solve the problem. You know, as opposed to many students that say I want to come to your lab because you do cloning, and I want to learn how to clone. That's very different.
8. What set of research questions or projects has you most excited about working in science today?
I spend a lot of time on two things. One is the science—a lot of time thinking about therapies, and gene therapies particularly. What are the good systems? What are the real problems, and how are we going to avoid them? What are companies doing, and does their research actually make sense? That kind of thing. So that's one. The second thing that I'm heavily involved with, is really on an international policy level. I working with governments to try to build biotech ecosystems around great university cities. This is a whole different issue. But I seem to have some credibility. I mean, I'll give you an example. I was just in Paris. There are some great research centers in and around Paris, particularly in the cancer field. There are essentially zero biotechs. So how can you build an ecosystem where you can take research out of, say, a cancer hospital or research institute in Paris, and build companies that over time will actually produce therapies and contribute to the French economy. So, this is an example of what I do. A month before, I was in Singapore with pretty much the same question. In other words, both places [France and Singapore] have outstanding research facilities, but do not have a tradition of faculty entrepreneurship. You see the difference? And there are many American cities that fall into this same category. I've spent a lot of time with Cleveland, where I grew up. They have Case Western Medical School, which is one of the top 15 in NIH funding. And they have the Cleveland Clinic, which is often considered the number one hospital in the United States. And yet there's no biotechs in Cleveland
As I said, I'm 80 years old. I'm still on the active faculty. The point is: I'm really privileged to be able to get involved with this stuff.
[on building and then scaling a biotech]
As I point out to these clients--it's very easy to start a biotech company, you need about $1,000,000, 6 people and a couple of lab benches. That's easy. The challenge is growing the company to 200 people. That's the hard part. Because then you need whole different types of people. And the people that are running the company at the beginning, are often not the people that you want running the company when it's much bigger.
9. Which areas of science, outside of your direct area/field, are you most excited about seeing develop in the next 5-10 years?
I am very excited about clinical work on autism, schizophrenia and other mental health conditions. I have a granddaughter that's going to wind up getting a PhD in Clinical Psychology. And she's currently working at a school with autistic children in the Bronx. And I told her, when you get there [to grad school], you must take a course in human genetics. Because at some point, every kid with autism will come in and have their whole genome sequenced. And hopefully, or almost certainly, there will be a clue in that diagnostic as to what the best way of treating that child will be. Right now, it's a huge black box. But what I hear—I have two granddaughters working in schools for neurodivergent children—and they told me the same thing: each kid's different. Well, come on. Genetics has not [yet] made an impact on that.
10. What is one piece of advice for a young scientist aspiring to have a career in academia, and make some important discoveries?
When I tell them is: do not get involved with biotechs until you have tenure. Focus on your own research, and once you're a little more security in your job, you can start playing around with companies. And really the underlying advice is to focus. Focus on specific problems, because when the tenure decision comes up, it's basically the answer to a very simple question: you know, what have you done? What have you done that's important?
11. Who was your biggest scientific mentor? Why were they such a great mentor?
I've talked about this publicly. I had lots of good mentors when I started at MIT. I mentioned Salvador Luria, I don't know how many times he took me aside and said: Harvey you really shouldn't have said that to so and so. Or Harvey, you know, this was confidential information, and you shouldn't have spread it or, here's how to deal with the student in your office. All of this kind of stuff. I mean, he was an exceptional person.
He also led on the Boston Common, the largest anti-Vietnam war protest in Boston. That happened to be the day before he won the Nobel Prize. Okay. So, when you have those kinds of people around, you'll learn from them. David, Baltimore was another one. He was my roommate in graduate school. But David, being much more senior than me, gave me lots of advice as to how to run a lab. I mean, I was 26 when I had my own lab, and that's a little young. But there's advantages in being young and doing this. Scientifically I was fine. But in terms of all the psychology of running a lab, I had little idea what I was doing. So, I had some very good advice, which I've hopefully passed on to my trainees.
I'll just tell you one vignette. When I visited Carleton College, in 2004, I flew in the night before and my host was a guy who was writing a biochemistry textbook and I was helping him.
Anyway, I got up in the morning, I was scheduled to meet a group of students for breakfast at 8:30am and then meet a class at 9:30. So, I went running, and came back to my room. I said, let me quickly check my email. So, I had about 200 emails, almost all of which were congratulating me on Aaron Ciechanover’s Nobel Prize. Okay. So, I was interviewed on NPR, I talked to the New York Times, I talked to several other newspapers. I was about 20 minutes late to show up for breakfast, and another 20 minutes late to show up for the class. I walked into the cell biology class and the young professor looks at me, thinking “who's this big shot who comes in 20 minutes late.” Anyway, he introduces me, and I begin by explaining why I'm late: ‘my student just won the Nobel Prize.’ And the whole class was completely transformed. And without asking the Professor, I said: look, I need a show of hands. I can give the lecture I was going to give on G protein coupled receptors, or we can talk about Aaron Ciechanover and what he did to win the Nobel Prize. We used the hour to talk about Aaron and his research.