Ben Stanger Interview Transcript

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BRUCE MCCABE:  Welcome to FutureBites. I'm here with Dr. Ben Stanger, professor of Cancer Research and Professor of Cell and Developmental Biology at UPenn here in Philadelphia, and a bunch of other things besides, so I'm going to link your bio to this, [laughter] with all the other things you're doing, and the author of a book am reading right now, I bought it the other day, From One Cell, so I wanted to talk about that. But welcome and thank you for making time for me.

BEN STANGER:  Well, thank you so much for having me. This is great. It's great to meet you and love what you're doing.

BRUCE MCCABE:  Yeah. Love getting the word out about the wonderful science here. I mean, two new Nobel laureates yesterday, out of this medical research facility, and I've been meeting people who are pushing the boundaries in CAR-T cell therapies, Bruce Levine the other day, and Kiran Musunuru who's looking at gene editing for people with high cholesterol and to prevent heart disease. It's like all the magic's happening right here, and so it's a heck of a place. So, well, I wanted to ask you first about your book, because I'm enjoying it immensely. So From One Cell does something that I especially love, which is combining the history of the science with the science. So it's real storytelling. Where's the background on that? What made you want to do this, the story of a cell from first principles? 

BEN STANGER:  Well, thanks again. Thanks so much for having me. This is great. I'm really glad you're enjoying the book. So my background, I'm mostly a cancer researcher, but my background as a postdoctoral fellow was in developmental biology, and I really fell in love with the field and just the concept of how do we all get here? We all start out, whether we're human beings as we are, or animals as a single cell. And when you think about it, that one cell dividing again and again and again to create a human being that's capable of all the things that we do, it's just a remarkable, remarkable thing. So I think I've been fascinated by the field of development. Now, why write a book about it? Well, I fell in love with science even as a kid by listening to scientists. I wasn't one of those people who spent a lot of time in nature who play around. But it was watching Cosmos with...

BRUCE MCCABE:  Carl Sagan!

BEN STANGER:  Carl Sagan, exactly [laughter]. That I was, you know, and I grew up in New York, so going to the New York Academy of Science and hearing scientists talk about their work, it not only filled me with a kind of amazement at the world of science, but also that the people doing it were so into what they were doing. And I think that instilled in me early on that there's a kind of almost responsibility as a scientist to share that knowledge, to share what we do. So I think those two things kind of came together for me, is a love of embryology, a love of development, just the complexity of it and the beauty of it, and the need to share that with other people. So...

BRUCE MCCABE:  Oh, wonderful.

BEN STANGER:  This is the result.

BRUCE MCCABE:  It's storytelling at its finest. Science is always like this great big adventure story when it's told well, and it must be like that for the discoverers, right? 

BEN STANGER:  Yeah.

BRUCE MCCABE:  These moments of just pure joy.

BEN STANGER:  It's true. But the challenge, and I think this is why there aren't as many books about science written by scientists as by science journalists, is how do you give that excitement, like the pleasure of doing science, of discovering things and the knowledge that comes along with it without writing a textbook? That was the challenge for me. It took quite a while to sort of figure out how do you make it interesting but still get to the meat of the matter? 

BRUCE MCCABE:  Yeah. Well, I'm loving it. I'm loving the moments where they're grasping for explanations where we're just groping towards mRNA as a mechanism and there's alternative viewpoints, which you've canvassed in the storytelling. Love it very much. It reminds me, that sort of storytelling, of one of my favorite books was by Richard Rhodes. It won a Pulitzer. So, hey, it's all possible here, [laughter] but he wrote a history of the atomic bomb, and he wrote it on a human level. And the opening chapter is so gripping. It's Leo Szilard crossing the road in London, and it's the moment, it's trying to capture the moment when he understood, before crossing the road, before he reached the other side, the chain reaction, the possibilities in the energy release, in a chain reaction. And it's just gripping, your hair stands up on your head as he stops, he literally stops, this sudden jolt of understanding. And I've already come across a few moments like that in From One Cell. So...

BEN STANGER:  You'll come across more, I'm sure. And towards the very end there's a chapter about Day Science and Night Science, it's called, this is a phrase that was coined by François Jacob. He was the discoverer of mRNA.

BRUCE MCCABE:  Yeah.

BEN STANGER:  And he talks about, Day Science is when you're a scientist and you're kind of doing things that make sense, you have a clear hypothesis and you're just trying to prove or disprove it. I think that's how most people think about what we do in the laboratory. Night Science is where you make an observation and you have no idea what it freaking means [laughter] That it's just okay. And you start going through basically this fog, you can see maybe 10 feet ahead of you, but you don't really know where you're going. And it's those moments that are where the big impact comes. But it's extremely uncomfortable as a scientist to be there, to be in uncharted waters, to not really know whether this is going to lead to something interesting or, you know, a kind of a dead on arrival PhD kind of thing. [laughter]

BRUCE MCCABE:  Yeah. Was he the guy that was with his wife at the movies? And then he left and he said to his wife at the end of the movie, I think I've just come up with something big. [laughter]

BEN STANGER:  Probably the understatement of the century. Yes, ‘I think I just came up with a good idea.’

BRUCE MCCABE:  See, that's the magic in this. So, yeah. Thank you for writing it. It's extraordinary. Now, if we can switch to the research, the opportunity, I've got to talk to you here, I really want to just kind of explore a little bit about the hopes and dreams. Because there's so much going on in cancer at the moment with different therapies. Blood cancer therapies in particular have had great success out of UPenn. And I'm really interested in just the pathways you are seeing in your research that are exciting as we push forward, where you see particular possibilities. And I know you said just before we start, it's a huge question, [laughter], but you know, even if we captured a few of the things that just are top of mind for you that you go, ‘You know what? That's got a lot of potential,’ in your mind, I'd love to know about that.

BEN STANGER:  Well, let's start with immunotherapy. CAR T-cells. You know what they are, they are these T-cells that have been engineered to go and kill cells, with a specificity that are expressing some molecule that a T-cell can recognize. And that has been really successful for liquid tumors, for blood cancers, for a couple of reasons. One, the target cells, the cancer cells are, they're there in the blood. They're easily accessible to the killer T-cells. And the targets that scientists, Carl, June, Bruce Levine have been able to figure out, and others are, have been relatively easy to find. So the first and most prominent CAR T-cell, the CD19 CARs, the CD19 molecule is present on B cells and it is on most of those cancers, most of the cancer cells. So it makes it relatively easy for the CAR T-cells to find those cells and kill them.

The next challenge and where I hope we're headed, and we're doing some work along these lines in my laboratory as many people are, is figuring out how to apply that model to solid tumors, to the big cancer killers, breast cancer, lung cancer, pancreatic cancer, and so on and so forth. And all the things that made CAR T-cells, I certainly won't say easy for blood cancers, because that was an immense effort and an immense achievement, but that was in some sense the low hanging fruit.

Because when it comes to solid tumors, you have problems of access. The cells aren't sitting right there. They're embedded in a very hostile environment that doesn't want the immune system to recognize it and has built up all of these defenses. And then the targets are not so great. We don't have a CD19 equivalent that's present just on the cancer cells that we can do without in other normal cell types.

BRUCE MCCABE:  There's not a clear targeting mechanism in solid tumors? 

BEN STANGER:  No. So the way that the CAR T-cell works is it finds a molecule that's present on the target cells. And that molecule may also be present on normal cells, but in the case of CD19, the target for current CAR T-cells, you don't care whether it kills cancer cells and normal cells with CD19. The result of a successful CAR T-cell treatment is you lose all of your B-cells.

BRUCE MCCABE:  Right.

BEN STANGER:  But you can live without B-cells.

BRUCE MCCABE:  You can live without them, yeah.

BEN STANGER:  Right. But if you imagine you have a solid tumor cell that has a molecule that you'd like to target with a CAR T-cell, that molecule may also be on normal solid tissues elsewhere in the body. So now at the same time that the CAR T-cell is killing the cancer, it has the potential to kill lots of normal cells and because lots of toxicity. So the search is on for that perfect target molecule that's specific to the cancer, and there are lots of candidates, but so far we haven't found one.

BRUCE MCCABE:  I see.

BEN STANGER:  And then there's this whole problem of how do you overcome the immunosuppressive nature of the tumor, the fact that it doesn't want the T-cells to get in there and kill the cancer cells? How do we allow the T-cells to do their job? So I think there's a lot of progress there. I think we'll get there, but it's a lot of night science. [laughter] A lot of slogging your way through, to get to that.

BRUCE MCCABE:  A lot of data related work? I mean, I think now something I saw years ago, at The Cancer Atlas, I think this is at Broad, they were talking about it and they were sequencing every known variant of every known cancer and trying to get biopsies from around the world and build a library and make it open source. Maybe it's almost complete now, I'm not sure, but is the problem one of basically brute force and lots and lots of data to find that sort of target? 

BEN STANGER:  So that's a slightly different angle on using the immune system to target cancer. So in the CAR T-cell, we're just looking for a molecule, typically it can be an abnormal or mutated molecule, but in the case of CD19, it's a normal molecule, present normally on cells. What you're describing is these large scale efforts, international efforts, to find all of the mutations that happen across cancers.

BRUCE MCCABE:  Okay.

BEN STANGER:  Right? Cancer is a genetic disease. Each cancer has a different spectrum of mutations. And knowing what those mutations are and figuring out how to target each one individually is the notion behind so called precision medicine.

BRUCE MCCABE:  I see. As opposed to the molecule that's just common.

BEN STANGER:  That's just common. Right, exactly.

BRUCE MCCABE:  I understand.

BEN STANGER:  So what that effort enables as far as immune therapy is concerned, is if you find that there's been a mutation in a protein that normally is not recognized by the immune system because itself, it's part of us, but that mutation causes it to now no longer be considered self by the immune system, that means the immune system can mount a reaction to it, and we can help the immune system by making a vaccine that's based around that now altered protein. So that's yet a parallel effort that's going on right now where we try to use the information that is coming from all of those sequencing efforts and design better ways to get the immune system to recognize those altered peptides.

BRUCE MCCABE:  So moving from liquid to solid tumors, lots of hope. Do you feel optimistic about those pathways? 

BEN STANGER:  Absolutely. And we're thinking outside the box more and more. Before you came into my office, I was just talking with a couple of students, medical students, who are putting together a presentation in a whole new area of biology. That's kind of fascinating. So I'll digress into it for a second if I may, called endogenous retroviruses. Endogenous retroviral elements. So retroviruses are a type of virus. HIV is an example of one, that infect cells and their DNA gets integrated into our genome. Alright? And over millions of years of evolution, these viruses have scattered and spread throughout our genome. So we have thousands of viruses from evolution embedded in our genomes. And over time, this has led to our, we have figured out ways to silence them. Right? So they're in our genome. They generally don't cause trouble because through a combination of immune system and gene regulation and so on and so forth, they just sort of sit there and they don't cause trouble.

But when a cancer cell emerges, some of these retroviruses that are silent now become expressed. They're able to make proteins, and those proteins are also not going to be recognized by the immune system. So there's the possibility that these ancient viruses that have been sitting around silently for years could also become targets that we can use to leverage the immune system.

BRUCE MCCABE:  Interesting. Almost like a tangential way of identifying and finding the cancer.

BEN STANGER:  Exactly right.

BRUCE MCCABE:  Wow. Okay. Interesting.

BEN STANGER:  So, yes. So to answer your question, lots of movement. It's a rapidly changing field with immunotherapy and cancer and solid tumors. I expect great things in the next 10 years.

BRUCE MCCABE:  And specifically on pancreatic cancer, I believe that's a big focus for yourself? 

BEN STANGER:  For my lab. Yes.

BRUCE MCCABE:  Yeah. And I believe also I think I read on your website that it's about to be the number two killer, I guess cancer killer. Would that be...

BEN STANGER:  In the United States, it's predicted in the next few years to become the second leading cause of cancer death behind lung cancer. Yes.

BRUCE MCCABE:  It's very aggressive, isn't it? It's fast, and it also returns quickly. I'm sort of dumbing it down, I guess, in the way I talk about it, but yeah, so where are we at with that and what are some of the pathways there? 

BEN STANGER:  Yeah. So pancreas cancer is so lethal because it's kind of a perfect storm of all of the problems of different types of cancer. It spreads early, so it's metastasized through the body most of the time when it's discovered that just intrinsically makes it hard to treat. There aren't really good drugs, just the cancer cells have figured out ways to not be particularly responsive to chemotherapy. So where is the promise? So the promise is in immunotherapy is one area. All of the things that we talked about just a moment ago, those are all areas that we're tackling.

BRUCE MCCABE:  Yeah.

BEN STANGER:  In pancreas cancer, there's some really exciting data that came out just in the last year using what I just described, the finding of mutant peptides or mutant proteins that are abnormal in the cancer cells. Then designing a vaccine, giving that vaccine to a patient who's had their tumor removed, and seeing if that immune response that comes from that vaccine can prevent the tumor

And what's kind of cool and puts lots of pieces together is, how did they make that vaccine? They used the mRNA technology that just won the Nobel Prize here yesterday. And that's only possible... This vaccine approach is really only possible because of that technology. Because if you imagine it, you have to go from the patient sequence to having the tumor out, to making the vaccine and giving it to the patient in the span of about two or three months.

BRUCE MCCABE:  It's going to be quick.

BEN STANGER:  It's going to be quick. And this mRNA nanoparticle technology is fast. That's why the COVID vaccines could come together within a year.

BRUCE MCCABE:  And the early results are very promising, aren't they? That vaccine, the early trial results.

BEN STANGER:  The early trial results are very promising, but it was phase one trial, with all of the limitations. Right? We really need to be cautious...

BRUCE MCCABE:  Of course.

BEN STANGER:  Especially in clinical medicine, but yeah. Very promising. Very exciting. It's going on to phase two.

BRUCE MCCABE:  Yeah. And just backtracking slightly, but when a cancer like pancreatic cancer metastasizes and appears in all kinds of places, are all the same markers evident in all of the different tumors or is each one potentially different? This is, sorry, a dumb question.

BEN STANGER:  No, no, it's not a dumb question at all. In fact, that's one of the big problems. And so each metastatic site, each tumor in different parts of the body can be different.

BRUCE MCCABE:  Okay.

BEN STANGER:  And even within one tumor there can be different properties. And that's referred to as tumor heterogeneity. And so tumor is an evolving... It's an evolving organism, if you will. And so if we have a therapy that works on part of the tumor, but another part of the tumor is different in such a way that that therapy doesn't work, of course getting rid of half a tumor isn't really going to get you all that far.

BRUCE MCCABE:  It's not enough.

BEN STANGER:  So this is why we haven't done quite as well with cancer as we have with other problems, but again, we're getting there.

BRUCE MCCABE:  Yeah. Now, this is a bit of a tough call, but if you were to sort of step back and say 20 years from now or even 30, pick your timeframe, but could you draw a picture for us to how you think of the progress? Do you feel like it's almost a random, where are the easiest pathways? It seems like that to me, that we follow the easiest pathways. So then, low hanging fruit, effectively. Sometimes we make an occasional discovery about a rare disease or cancer. But when it comes to the myriad forms of cancer, are there particular flavors which we will probably have defeated first? Or is there a way of kind of drawing the landscape of how you think about this? Are they all going to be manageable diseases rather than curable diseases? That's been put to me as well.

BEN STANGER:  Yeah. I think that's one good way about thinking about cancer, the more we understand about the genetic and epigenetic changes that happen in cancer, the more we have an arsenal of drugs so that when one drug stops working, we can bring another one on board. We can bring another one on board. So that is slowly converting cancer to a chronic disease that's less lethal. So that's one approach. That's a little bit incremental. The reason there's so much excitement, that I'm so excited about immunotherapy is that the cancer can evolve around therapies, but the immune system can evolve around cancer.

BRUCE MCCABE:  I see.

BEN STANGER:  So we're only limited in, okay, what's the next drug that we can get for this cancer? But the immune system is constantly trying to keep up with the cancer as it's changing and recognizing it. So that's I think another avenue is helping the immune system along. 

The biggest impact I think in cancer will come not from treating cancer, but from preventing it from happening in the first place. We're here at Penn, our founder was Ben Franklin, he said, an ounce of prevention is worth a pound of cure. And that's where we can really have an impact. So how do we do that? So there is an emerging concept out there now called cancer interception. I don't know if you've come across...

BRUCE MCCABE:  I have not.

BEN STANGER:  This phrase before. It's a little subtly different from prevention. So prevention would be let's intervene in a way that the process doesn't even get started. So say smoking cessation, getting people to stop smoking, that's a form of prevention.

BRUCE MCCABE:  Yes.

BEN STANGER:  All your listeners, you should please ask them to stop smoking. That's a great thing to do. Interception is, the cancer has started, but we do something at a very early stage to reset the clock. To take it back in time. Perhaps one of the best examples of cancer interception that we're doing right now is colonoscopy. So I'm a gastroenterologist, I do colonoscopies. We see a polyp that's a pre-malignant lesion. It's on its way to becoming a cancer. We take it out, we intercept it just like a American football player intercepts that football before it can get into the end zone. So that I think is where we need to be headed to be able to detect or identify those at risk of developing an advanced cancer and giving some kind of drug or some kind of therapy at that early stage that prevents it from going all the way.

BRUCE MCCABE:  And chemically detecting rather than just physically detecting? I mean, we do a colonoscopy as observation, right? 

BEN STANGER:  Right. That would be an example of mechanical interception.

BRUCE MCCABE:  Mechanical. Alright, mechanical interception.

BEN STANGER:  Mechanical interception, but we could imagine if there was a drug. In fact, the same drugs that we give to patients with cancer because they target the cancer cells may also work in these very early lesions as well. So we may find ourselves in a point in time where we are giving cancer drugs to individuals who don't have cancer, but are at risk of developing it and halting the process.

BRUCE MCCABE:  Interesting. I guess where I'm going with that thought process is when I look at things like Sherlock and other technologies with CRISPR-Cas13, can we use these molecules to do very, very fine detection. Can we detect the pre-stages of cancer like that as well? Could you do a scan one day, perhaps a blood test, and it says, "You know what? You haven't got cancer, but you've got the preliminary [cells].” Is that possible?

BEN STANGER:  Absolutely possible. Absolutely possible. It's very, very difficult because to be able to find that needle in a haystack marker of a very early cancer, you need to do very large studies looking at many, many people and see what they do over time.

BRUCE MCCABE:  Yep. Yep. Okay. Now, we're running out of time and I'm very grateful for what I've got here. So is there anything else that you'd put on the radar for people, you'd say, “Watch out for this, not many people know” or “more people should know about what's happening” in a particular area? Or have we covered that ground? 

BEN STANGER:  Well, I think we've covered a lot today. I would come back one more time to this remarkable mRNA vaccine technology because where we've heard about it and where it's gotten most of its publicity is with respect to COVID. It enabled the COVID vaccines, but I think this is the way that we are going to be making most of our vaccines in the future. It allows the technology to occur rapidly. I gave you an example of how this is likely going to be applied to cancer and cancer vaccines. And it's also going to have the ability to introduce new genes into cells rapidly for gene therapy approaches. So, it's such an exciting time here at Penn ...

BRUCE MCCABE:  It's an exciting time in medicine. I think it really is a golden era of medicine we're moving into. It just keeps striking me how much is going on in parallel right now.

BEN STANGER:  It's so true.

BRUCE MCCABE:  Very, very exciting time, very optimistic time. Thanks for your time, Professor Ben Stanger. And I'd love to stay in touch and I'm going to do some more reading, not only of your book, but about the interception strategies, and I'll sort of take that on as well.

BEN STANGER:  Wonderful. Pleasure talking to you. Thanks so much!

BRUCE MCCABE:  Thank you!

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