Julie Losman, MD 00:07
I do remember the very first time that I got the results of the experiment. I brought it to Bill and I showed it to him and I was very…I don't think we even were supposed to meet. I was so excited to show it to him that I sort of popped into his office. And he looks at that and he said, “Julie, this is your Da Vinci.”
Ken Shulman 00:26
That's Julie Losman, an assistant professor at Dana Farber. The Bill she's talking about is Bill Kaelin, her former mentor at Dana Farber and the winner of the 2019 Nobel Prize in Medicine, and Da Vinci. That's Leonardo da Vinci. Painter of the enigmatic portrait known today as the Mona Lisa. So, what do cancer researchers and 15th century Florentine masters have in common? Well, for one, a culture of mentorship, both came of age in a culture where knowledge is transmitted from Master to pupil. In this episode, we'll take a closer look at that culture, and at the crucial role mentorship plays at Dana- Farber. I'm Ken Shulman, and this is Unraveled, a Dana Farber Cancer Institute podcast. If institutional memory could take human form, at Dana Farber, it would look a lot like David Livingston. He's professor of genetics and medicine at Harvard Medical School. He's won many major awards during his nearly 50 years at Dana Farber. He's also served as mentor to dozens of post-doctoral fellows, young scientists who've honed their craft in this lab, young scientists including Bill Kaelin. Livingston says, mentorship is a big part of the job.
David Livingston, MD 02:00
Which becomes for me and the vast majority of my colleagues, a dedicated pleasure of interacting as a mentor, for a young person who is working on difficult but very important problems. Then there is nothing like watching a young person grow, watch them sprout their mythical wings, and begin to think on their own, and begin to ask questions that simply take your breath away.
Ken Shulman 02:33
Livingston caught the science bug early on in life at 11 years old, when a physician cousin gave him a subscription to The New England Journal of Medicine.
David Livingston, MD 02:42
Well, I tell ya, whatever it was, I couldn't understand the words, naturally. I didn't know any anatomy even. But I could look at the pictures. When the New England Journal came out, there was a case report from the Massachusetts General Hospital that I would read. It was like a magnet. Hmm. I couldn't wait to read one. Even in hard, even when the weather was crummy, even when there was something fun to be done.
Ken Shulman 03:08
The pull of science and medicine, the magnet, Drew Livingston on to medical school, and then in 1971, to the National Cancer Institute, where he worked as a research fellow. At the time, the cancer research field was still largely a mystery. It wasn't exactly a blank slate, but it was pretty close.
David Livingston, MD 03:28
Almost everything we didn't know. We knew something about cancer cells, we knew that they grew in ways that normal cells didn't, that they had capacities that normal cells didn't, like to cause disease. And we knew that cancer cells came in various, I would say, they wore different clothing. No two cancer cells necessarily wore the same clothing. They didn't look the same, nor did they replicate at the same rates.
Ken Shulman 03:58
Scientists did know about DNA in the early 70s. But they hadn't come close to decoding it. They hadn't sequenced the human genome.
David Livingston, MD 04:06
And we had very little knowledge of how genes were built. Except we were pretty sure they were built with DNA. We didn't know much about the punctuation in genes, not nothing, but almost nothing. It was just being worked out in those days. And what made them cancer cells was a total mystery.
Ken Shulman 04:29
Livingston came to Dana Farber in 1973, when it was still called the Children's Cancer Research Foundation. He immediately opened his own lab, and he began studying a virus found in both monkeys and humans. The virus is called SV40. SV for simian virus, and it's tiny with only a handful of genes.
David Livingston, MD 04:52
I knew that this virus when it was injected into a rodent, typically a hamster or a mouse, or a rat that lacked a normal immune system... could not grow. But what it could do was live long enough to make a tumor. And that was amazing.
Ken Shulman 05:13
The SV40 virus had another amazing thing to reveal. Researchers found that its cancer-causing agent was located in a single gene. And that single gene contained the code for a single protein. And when that single protein was added to cell cultures in a laboratory, it formed micro-tumors.
David Livingston, MD 05:33
That was almost a matter of addiction for those of us who entered the field, because it meant an enormous leap had taken place in cancer science that gave us an inkling, an insight, and tools that made it possible to study cancer for the first time, much more simply than ever before. Intoxicating discoveries don't come in big bushels. You know, this series of observations that others, many others observed in the world, and I was privileged enough to be one of them, was intoxicating to all of us.
Ken Shulman 06:10
That sense of wonder, the sense of intoxication grew as Livingston and the post-docs in his lab began to unravel the mystery that was cancer. He soon found a promising area to explore: tumor suppressor genes. These are genes that single out potentially cancerous cells and neutralize them. One day in 1987 Livingston got a call from Bill Kaelin. Kaelin told him he'd been working in another Dana Farber lab, but that lab had shut down. Now he, Kaelin, was orphaned. He needed another lab where he could finish his postdoctoral fellowship. Livingston agreed to meet with him.
David Livingston, MD 06:53
I thought he was one of the tallest people I'd ever seen. I come from a family of short people. And this large, tall, very gracious, well-spoken young man came on and knocked and came in. And I thought to myself, “Boy, Americans are making them tall”. It's great. It's absolutely wonderful. And he was obviously extremely intelligent, quite gracious, and he asked great questions.
Ken Shulman 07:21
Kaelin was also taken with Livingston, with his infectious enthusiasm for science. And there were some interesting things going on in Livingston's lab. They’d just begun studying a tumor-suppressor gene, known as the RB gene. Children born with a defective copy of this gene develop a rare eye tumor called retinal blastoma. It's where the RB gene takes its name. Kaelin was eager to dive into a project with such a direct link to cancer, especially with Livingston as his mentor.
Bill Kaelin, MD 07:52
But what never changes in science is the ability to sort of see a good question, ask a good question, to have sort of the nose or the instincts to decide where you're going to work, what problems you're going to tackle. And so, I think the first job of a mentor is to kind of imprint upon you that sort of scientific taste and scientific intuition on you know, what might be a good thing to work on what might be a fertile area to start working on it. So, I certainly learned that from David, he has incredible scientific taste. David also taught me, you know, the art of experimental design, how to design really effective penetrating experiments that would get to the heart of a question and will hopefully give you a relatively unambiguous answer. So, you know, I say that, you know, thinking never goes out of style. I mean, David really helped me to think like a scientist.
Ken Shulman 08:43
Thinking like scientists. The pair found a project for Kaelin. Genes, as we know, are molecular blueprints, they contain the instructions for making proteins. The RB gene that Livingston's lab was looking into contains the instructions for making the RB protein. And it's that RB protein that actually suppresses tumors. What Kaelin set out to do was understand how the RB protein worked, what biochemical properties that this protein has, that enabled it to block cancer. It was an ambitious project. And Livingston says Kaelin absolutely nailed it.
David Livingston, MD 09:26
And even in some detail. That's a hell of a thing for a postdoctoral fellow to do. And it wasn't the only accomplishment he had made. He made a number of them in my lab, and others had too. So that was a happy moment. That was a good moment. That was a self-satisfying moment. And the entire lab was thrilled. And of course, Bill was thrilled. It was a great discovery.
Ken Shulman 09:52
Kaelin is quick to share much of the credit for this early triumph with his mentor. He says Livingston constantly challenged him to ask more daring questions, and to design even more bomb-proof experiments that could answer those questions beyond any doubt. But Livingston wasn't just a hard-driving coach.
Bill Kaelin, MD 10:12
So, David was just a fantastic cheerleader. psychotherapist, at times, I know myself, and I'm sure this is true for most young people doing science, there are days when it's all very frustrating. And you're wondering whether you're just a square peg going into a round hole. And David was very, very good at giving me perspective, encouraging me, keeping me moving forward. So, I'll always be very grateful for that. Again, in addition to asking great questions, David was a fantastic cheerleader, no matter what you discovered, David made you think you were going to Stockholm, which is sort of ironic that I eventually did go to Stockholm.
Ken Shulman 10:52
Livingston doesn't remember it quite that way.
David Livingston, MD 10:55
Well, in those days, the only thing I knew about Stockholm was that some of my relatives were born not far away. That was about it. I mean, I knew all a lot of the myth and, and I knew that the Nobel Prize had its home there with the royal family and on and on, but that really wasn't something that crossed my mind in a serious way, until a year ago.
Ken Shulman 11:18
What he does remember is the thrill he felt when he first saw the results of Caitlin's work, the thrill and the pride that only a mentor can know when the student paints his first masterpiece, his first Da Vinci.
David Livingston, MD 11:31
To encounter someone with a mind that's golden, that can approach a really complicated problem in medical science, really complicated, you know, it's largely shrouded in endlessly deep mystery. And crack it open in one experiment. Excuse me? You see that on the fingers of one hand in your lifetime.
Ken Shulman 12:00
Many of Livingston's former postdocs have gone on to make major contributions in cancer research and treatment. And many, including Kaelin are now mentors to one or more generations of researchers.
David Livingston, MD 12:12
Now reaching the success that Dr. Kaelin did is of course, not a daily event. But may I say that Bill Kaelin has a laboratory now and for many years now, and he has also earned the right to be viewed as a great mentor. No question. He has a right to be viewed as a great scientist, unequivocally. He also has, in my view, the right to be viewed as a great mentor. And as some of us would say, a mensch in the truest order of the word.
Ken Shulman 12:54
In 1992, after five years in David Livingston lab, Bill Kaelin opened his own laboratory, he began what would become his life's work, a study of the body's oxygen-sensing system. That study would yield fascinating information about cancer and metabolism and would eventually lead to the Nobel Prize. As head of his own laboratory, Kaelin also became a mentor, and helped to shape a new generation of researchers at Dana- Farber, a generation that impressed him right off the bat.
Bill Kaelin, MD 13:27
A lot of young people are doing everything they can to come to Boston, and they're interested in cancer and to come to the Dana-Farber to do their work. So, I like to say I think the Dana-Farber and Harvard generally, you know, they've set up this sort of nice, positive feedback loop where they have, you know, great young people beating on their door. And that's what makes them a great institution. And because our great institution, they have great young people beating on their door. So, it's almost self-fulfilling. It's a little bit like Silicon Valley and computer science, I think we really attract some of the best and brightest from around the country, and around the world. So, you start with that, I think as being part of the secret sauce.
Ken Shulman 14:08
Kaelin often says that David Livingston made him into the scientist he is today. He also credits Livingston with making him an effective mentor. From Livingston, he learned that one of the first and most important things a mentor can do is help a mentee decide what question they want to answer.
Bill Kaelin, MD 14:27
What problem am I going to work on? Because there's an opportunity cost to everything you do. So, I think that the first decision of what I'm going to work on turns out to be quite critical. In fact, getting back to David Livingston, he used to say that the most important thing for a young scientist is just plant them in a fertile area and water them once in a while.
Ken Shulman 14:45
Kaelin also learned that a good mentor needs to help a mentee stay on mission, to focus on the initial question and avoid distractions and dead ends. It's a problem that plagues today's postdocs in particular, postdocs who have tools that Kaelin and his generation could only dream about.
Bill Kaelin, MD 15:03
You know, there's always some shiny new technology or toy that it's easy to kind of focus on. I want to learn how to do this approach. I want to learn this technology. And so, one of the other things I learned from David Livingston is that every good experiment actually starts with the question, you know, what question are you trying to answer? And if you start with the question, you can figure out what technologies you might need to answer the question. I think with some of these shinier and newer and in some cases, sexier technologies, there's a temptation to start with the technology and try to figure out what questions you can answer with that technology.
Ken Shulman 15:40
In 2001, almost 10 years after he opened his own lab, Kaelin published a blockbuster paper, the paper described in exquisite detail the mechanisms the human body uses during hypoxia, during times when oxygen is low. This and additional work on oxygen sensing and metabolism would eventually earn him the Nobel Prize in Medicine. Most postdocs came to Kaelin's lab to work on those specific problems, or on closely related ones. Enter Julie Losman.
Julie Losman, MD 16:13
When I started at Dana Farber, I was reasonably sure that I wanted to study, research-wise I wanted to study leukemia. There's really good treatments for a lot of patients, but there's still a huge unmet need. So, it had that resonance for me.
Ken Shulman 16:25
Julie Losman started at Dana-Farber in 2006. As a resident at Johns Hopkins, she'd worked on leukemia. The biology of the disease fascinated her. So, it followed that at Dana-Farber, she joined a lab that studied leukemia, but that lab closed a year and a half later. Orphaned, Losman started looking for a new lab where she could work. She met with several scientists, including Bill Kaelin. He liked her immediately and her story was touchingly familiar.
Bill Kaelin, MD 16:55
I actually did not start out working with David Livingston. I started out working with a young faculty member named Shelly Bernstein. I was Shelly Bernstein's first postdoctoral fellow. And it turned out I was also his last postdoctoral fellow because four or five months after I worked with him, he called me into his office and told me he was shutting down his laboratory and he was going to go into clinical practice. And likewise, Julie, started out working with a wonderful scientist named Gary Gilliland. But then Gary decided to leave academia to go work at Merck. And so, Julie arrived at my doorstep an orphan. And it made me think back of my time, looking for laboratories and landing with David Livingston. And Julie is just a superstar.
Ken Shulman 17:37
But sympathy and shared history weren't enough of a reason to work together. They needed a plan.
Julie Losman, MD 17:43
Bill doesn't study leukemia, and I definitely did not want to switch out of the leukemia field. So, I actually ended up meeting with Bill early on in 2009. And then sort of mid-2009, making the decision to join his lab, because basically, what he told me was look, as long as you're studying an important question, as long as you're sitting an interesting question, and as long as you're studying a question that I feel that I can bring some knowledge and some insight to, you can work on whatever you want in my lab.
Ken Shulman 18:14
The pair came up with a suitable project shaped by their shared expertise. The work went well. And then things got even better. Another postdoc in Kaelin's lab was studying a genetic mutation that just been identified in brain tumors. The mutation was called IDH. IDH was of great interest to Kalin because it plays an important role in metabolism. Then there was an extraordinary stroke of luck. Researchers at Washington University found that same IDH mutation in leukemia.
Julie Losman, MD 18:49
This is the perfect storm - these things are not supposed to happen in nature just where all of a sudden, you know, this enzyme involved in metabolism that Bill and the entire lab was very interested in, had been working on in brain tumors, and all of a sudden I joined the lab wanting to study leukemia, and this mutation pops up in leukemia.
Ken Shulman 19:07
Kaelin asked Losman to investigate the role that this specific enzyme, the mutant IDH, played in leukemia. It started off as a side project. Within a few weeks, it took over her work life, the perfect storm morphed into the perfect project. In its natural state, the IDH gene is a fundamental part of the cycle that generates energy for cells. Losman knew that the mutant form of IDH changes a cell's metabolism. It changes the way a cell produces energy. The mutant IDH also changes the by-products the cell emits during metabolism. These byproducts are called metabolites.
Julie Losman, MD 19:50
And so instead of basically converting one metabolite to another, it produces a completely new metabolite, this metabolite called 2-hydroxygluterate or 2HG. This metabolite normally is found at very, very low levels in cells. Cells kind of get rid of it because it's considered to be somewhat toxic. But in these IDH mutant cells, you have these massively high concentrations of this metabolite.
Ken Shulman 20:16
The mutant IDH gene causes cells to produce a metabolite called 2HG. And this metabolite 2HG, looks a lot like another metabolite that Kaelin's lab knew well. That other metabolite was part of the system that sounds the alarm when oxygen is low. You might remember that Kaelin had already shown how cancer games the oxygen-detection system, how it tricks that system into sounding a false alarm, and how that false alarm triggers a series of mechanisms that push tumor growth at the expense of healthy cells. Losman and everyone in Kaelin's lab expected 2HG to do the same thing, just like its chemical cousin did. They expected it to also trick the body into thinking that oxygen was scarce. That trick would help hijack the system and feed tumors. This was how many cancers grew. Many, but not all. Just after Losman joined the Kaelin Lab, another postdoc discovered that the false low oxygen alarm factors that drove so many cancers did not drive brain cancer. In fact, they stifled it.
Julie Losman, MD 21:31
And so this was all really interesting and very paradigm shifting. One of the questions was, is this all true, likewise true in leukemia? And so that's how I started working on this in the context of leukemia.
Ken Shulman 21:44
So Losman designed her initial experiment, she took a cell line, she removed the cytokine. That's the growth factor that cells need to grow. Then she introduced the mutant IDH. If the cells resumed growth, it would mean that mutant IDH caused cancer. But the initial experiments failed. The cells couldn't tolerate the mutant IDH. So, she found another cell line, a human leukemia cell line called TF1.
Julie Losman, MD 22:16
These cells could tolerate it. And when I put mutant IDH into the cells, and then withdrew cytokine, the cells grew.
Ken Shulman 22:25
Losman would repeat the same experiment more than 50 times during her five years in Kaelin's lab, the results were always the same. Mutant IDH was a driver in leukemia. And the lab work was exhilarating. With this model in hand, she was able to show that the Leukemia was indeed driven by the metabolite called 2HG. She deciphered how 2HG allows leukemia cells to grow.
Julie Losman, MD 22:53
It's really fun to do science that feels like you're going downhill, right? So much of science is going uphill, every once in a while, when you hit on a project where it actually feels like you're running to catch up with the science, it's really, really fun. I do remember the very first time that I got the results of the experiment, I plotted the graph of the growth of the cells that were expressing wild type IDH. So, the non-cancer associated form and the mutant form, and I brought it to Bill and I showed it to him and I was very - I don't think we even were supposed to meet, I was so excited to show it to him that I sort of popped into his office. And he looks at that and he said, “Julie, this is your Da Vinci.”
Ken Shulman 23:30
For Kaelin, Losman's result was as beautiful and timeless as the Mona Lisa. Perhaps even too beautiful. Like everyone else, scientists need to be wary of getting what they wish for. Kaelin remembered an important lesson he learned from his mentor, David Livingston.
Bill Kaelin, MD 23:54
So, David was very good after the initial wave of euphoria, when you thought you had discovered something, quietly suggesting that maybe there were other things you'd still be thinking about, maybe there was one more experiment you should do, one more thing you might have overlooked. And so, I'm very much the same way with my mentees that I'm pretty good at coming up with alternative explanations for their data that will then force them to maybe think about doing an additional experiment or two.
Ken Shulman 24:22
But it didn't take long to see there was nothing ambiguous in Losman's experiments, or her data.
Julie Losman, MD 24:28
And that was one of the you know, the beautiful thing about that experiment, and about that result was that the result was just plain to see, you didn't have to, there was nothing to interpret. He just looked at the result was there and that was really the result on which I built my entire postdoc, which was focused on understanding how this mutation, how this metabolite, how this 2HG promotes cancer specifically in the context of leukemia.
Ken Shulman 24:57
Kaelin knew Losman had made a major breakthrough, but neither of them were done. In science as an art, great work inspires more great work. Losman's Da Vinci asked as many questions as it answered. And the most obvious question was whether you could kill cancer cells if you somehow blocked the 2HG, if you block the toxic metabolite produced by the mutant IDH gene.
Julie Losman, MD 25:23
Now, I think, again, a lot of scientists who are maybe not quite as sophisticated as Bill would say, “Well, of course, right? Of course, you can, you know, you have a mutation, that mutation is important to drive the cancer. Of course, if you inhibit the mutant, you're going to kill cancer.”
Ken Shulman 25:40
But they weren't sure. There are two basic models on how cancer develops. In the first model, a genetic mutation turns on an irregular growth program. And that irregular growth program drives the cancer cell. The second model, a model called the hidden run, also starts with a genetic mutation. But in this model, the genetic mutation sets off a series of changes, one after another. And it's these downstream changes that drive the cancer. The initial mutation, the hit and run mutation does ignite the chain reaction, but it doesn't sustain it. And you can't stop the cancer by targeting the hit and run mutation.
Julie Losman, MD 26:25
And there were reasons to think, very plausible reasons to think, that this hit and run phenomenon could be how mutant IDH functions. Because when you rewire the metabolism of the cell, you have a lot of secondary and tertiary effects that may not be reversible.
Ken Shulman 26:46
Losman spent her final two years in Kaelin's lab on this problem. She wanted to see if you could reverse the transformation from healthy cell to cancer cell by blocking 2HG. Through Kaelin's network, she connected with a local drug company that had just built an inhibitor that would block 2HG.
Julie Losman, MD 27:05
And so, we got our hands on these inhibitors. And I was able to use my assay to interrogate whether these inhibitors actually did reverse transformation. If indeed, leukemias are dependent on this mutant protein. And it turns out that they are.
Ken Shulman 27:21
Losman worked with drug company scientists to translate her research into a therapy for leukemia.
Julie Losman, MD 27:27
And I learned a little bit about, you know, how science and industry is a little different than academia. But really, how you can mesh those two approaches in a way that really brings out the strengths of both It was really incredibly fruitful collaboration.
Ken Shulman 27:41
The drug went into clinical trials. A few years later, the FDA approved it, to treat leukemia.
Julie Losman, MD 27:48
Which, you know, was incredibly gratifying and incredibly rewarding to have spent all that time, you know, digging in the weeds of the molecular biology, where I have to be honest, you know, from on a day-to-day basis, I wasn't really thinking about the translational implications, I was interested in understanding the biology. But once you really understand the biological underpinnings of a system like a cancer cell, you can really start to make headway in terms of targeting it. Bill and I shared a glass of champagne, you know, when the drug really you know, started working clinically because this is really why we do this.
Ken Shulman 28:31
In 2014, after five years working with Bill Kaelin, Losman opened her own lab at Dana-Farber. Over time, her focus has shifted from leukemia to cancer metabolism and epigenetics. In essence, she studies how a cell's metabolism can determine which genes are selected for expression. And like her mentor, Bill Kaelin, and his mentor David Livingston, she offers fertile soil and occasional watering for the newest generation of researchers at Dana Farber.
Julie Losman, MD 29:02
I have to say that the postdocs who work in my lab have generated really beautiful data. And I hope that I've conveyed to them that they themselves have produced their own Da Vinci's.
Ken Shulman 29:16
She still remembers the thrill she felt after painting her first great work in Kaelin's lab.
Julie Losman, MD 29:23
It's still to this day the most beautiful figure I've ever generated. I mean, I'm hoping to produce a few more. You know, Da Vinci was successful because he had more than one Mona Lisa, equivalents, but there is also something to be said for generating something like that for the first time. But on a personal level, you know, for the first time doing an experiment and just having this just sense of what's in front of me is important, is something that I love to say that it happens once a week. Unfortunately, it doesn't. If you're lucky, it happens maybe once or twice a year. But that was a very, very special moment.
Ken Shulman 30:14
Next time, one of Dana-Farber's youngest and most brilliant minds sheds light on one of biology’s hottest field, epigenetics.
Cigall Kadoch 30:22
Imagine a box of books. If you're packing a bunch of books in a box, and suddenly you want to access a book that's at the very bottom of that box, you're gonna have to do some unpacking. And so, the factors that we study are essentially the unpackers.
Ken Shulman 30:35
I'm Ken Shulman and this is Unraveled, a Dana-Farber Cancer Institute podcast.