FLORA LICHTMAN: Hey, it’s Flora Lichtman, and you’re listening to Science Friday. Today on the show, how one researcher’s persistence has changed cancer treatment. In cancer, you might think of the tumor like a seed of misbehaving cells taking root in the body, and whether it grows and where it grows depends on the conditions, the soil. This seed and soil hypothesis has been around for more than 100 years, and for most of that time, research and treatment has been focused on the seed, the tumor.

My next guest has spent nearly 50 years studying the soil. He argues that just like in a garden, the more you about the soil, the better you understand how the seed will grow. His research has often gone against the grain and sometimes led to his colleagues avoiding him in the halls, he says. The work has also led to 7 FDA-approved treatments for diseases, including lung and liver cancer, and earned him a National Medal of Science in 2016. Now, Dr. Rakesh Jain studies the biology of tumors at Harvard Medical School and Massachusetts General Hospital. Rakesh, welcome to Science Friday.

RAKESH JAIN: Thank you so much, Flora. I’m a big fan of yours, so I feel very honored that you have chosen to speak with me today. Thank you.

FLORA LICHTMAN: That’s too kind. Thank you for joining us. Now, in that intro, I set you up as a kind of outsider, at least someone who marches to your own beat. Is that how you think about yourself?

RAKESH JAIN: Yeah, I always been– my ideas have always been very counterintuitive. They’ve been against the grain. And anytime you go against the grain, it’s a fight. It’s an uphill battle. But when you reach the peak and you see the benefit, it’s very gratifying.

FLORA LICHTMAN: Let’s dig into this. So I want to start with a visual. When I think of a tumor, the seed, I picture a bag of messed up cells. Am I right? How wrong is that?

RAKESH JAIN: That is what most people think. But a tumor is more than a bag of cancer cells. It’s like an organ which has gone awry. It’s an organ which has its own rules. And if you can figure out those rules, we can improve not only detection, but treatment of cancer and improve lives of patients.

So when I entered the field, and even today, most people focus on the cancer cells. But I decided to focus, as what you call, the soil. And I found out the soil, it not only helps tumor grow– that’s understandable– but also confers resistance to every form of therapy– radiation therapy, chemotherapy, immunotherapy, and all the future therapies which will be coming along.

FLORA LICHTMAN: And when we talk about soil, what should I be thinking of? Is it just the area right around the tumor? Is it larger than that?

RAKESH JAIN: So if you think of a tumor such an organ, such as liver or kidney, what tumor is made of is cancer cells. And these cancer cells cannot grow without nutrients– oxygen and nutrients. And for that, they need blood vessels. But unlike normal tissue, these vessels are abnormal. And we were the first to identify their not only abnormal structure, but most importantly, their abnormal function.

But in addition to the blood vessels, even if the drugs get out of the blood vessels, they have to cross a distance between blood vessel wall and cancer cells. And that distance is covered by all kinds of things, the most important one which blocks the movement of drugs is matrix, which is made out of collagen and hyaluronic acids.

But in addition to that, there are all kinds of cells from the host, from the patient in there. They include all kinds of immune cells that kill cancer bugs and other things. They follow neuronal cells, and now, the new research is showing there are a lot of little bugs, the microbiome. And so each of these affect the outcome of treatment.

FLORA LICHTMAN: There’s a microbiome even within the tumor?

RAKESH JAIN: Oh, yeah, yeah, yeah. Yeah. We know it’s there, but the question is, how does it get there? And this is something that has fascinated me in the last 50 years. How do things get into the tumor, and what do they do when they get there?

FLORA LICHTMAN: Yeah. I wanted to ask about this because You’ve been thinking about the soil, this environment, this complex environment you just described since your PhD, which was, am I right, in chemical engineering, not cancer biology, by the way?

RAKESH JAIN: You’re 100% correct. I was trained as a chemical engineer in India. I did my undergraduate at Indian Institute of Technology in Kanpur. I came to this country in 72′, did my master’s on mathematical modeling of Delaware River pollution control.

FLORA LICHTMAN: A different kind of waterway, a different kind of landscape.

RAKESH JAIN: Exactly. And then I was shopping around for a PhD project, and I got very fortunate accident that my PhD advisor, Professor Whey, introduced me to one of the most distinguished human pathophysiologies at the National Cancer Institute. And he had developed a tumor with a single artery in a single input, single output. And I study using that tumor to look at, if you inject a drug in the artery, how much goes into the tumor? It comes out of the vein.

FLORA LICHTMAN: Wait. Because this was the fundamental question, right, that you were asking?

RAKESH JAIN: Yeah. Yeah.

FLORA LICHTMAN: Does the medicine get to the tumor?

RAKESH JAIN: Get in. Yeah. Does it get into the tumor? If it does, where does it get in? What part of the tumor? And what I discovered is most of it bypasses the tumor like beltway around the city. And two, it gets in highly heterogeneously– not uniformly at all. So some cells are going to get the drug, and they’re going to respond. Others are not going to get it. And what is even later on I discovered, is that when the blood supply is poor, it creates hypoxia. That mean low oxygen level and acidity. And combination of these two makes a lot of drugs ineffective, even if they can get there.

So you see, the blood vessels when they are bad, not only they block the delivery, but they also impair the effectiveness of the drugs such as immunotherapy. I mean, not all patients don’t benefit from it.

FLORA LICHTMAN: Does the medicine get to the tumor, feels like a very good and fundamental question. Why were you, a chemical engineering PhD student, the first person to ask it?

RAKESH JAIN: Well, I’m an engineer, OK? I have to– so in engineering, there is a subject called mass transfer. That means, how do things move from one place to another? And that’s what we study for our living. All right. And I said, OK, this drug delivery is like a mass transfer problem. So I asked my advisor, could I study that. Because that’s what engineers do. You look at input, output, and then using mathematical modeling, try to figure out what’s on the– inside the black box.

So I used that approach, and I say, this black box– but that was not very satisfying, even though I realized from my work, the blood flow is a problem. But I wanted to visualize it. I wanted to see the drugs coming in and seeing what’s happening to them.

FLORA LICHTMAN: I’m guessing an engineering approach comes in again.

RAKESH JAIN: Yeah. Right. So, yeah. So what I did is I developed these glass windows where you can surgically implant them on the brain, so look at brain tumors or brain metastases or breast, look at breast cancer, or you can look at liver, et cetera, many organs. And then we developed special microscopes so you could visualize when you see a drug coming– first, you could visualize the blood flow. And the first thing you see, the flow is not nice. It’s good in some parts of the tumor. Others, it’s not flowing at all.

But we discovered the mechanism for that too. And that’s an engineering problem. Why?

FLORA LICHTMAN: It all goes back to that Delaware waterway, doesn’t it?

RAKESH JAIN: You got it. Yeah. Exactly.

FLORA LICHTMAN: So had anyone watched a tumor in an animal over time like this before?

RAKESH JAIN: Well, actually, there was a study at NCI, National Cancer Institute, by a person named George Allgaier who had developed something like this. But they didn’t have the sophisticated microscopes at that time. So they didn’t pursue it. But that was many years ago. And I saw that, and it was back of my mind. But the very first time I studied that was in the rabbit ear.

I put a window in the ear of a rabbit when I was an assistant professor at Columbia University in New York in chemical engineering. And there was a professor who was developing these windows not for cancer. I tried to convince him to put cancer cells there, and I couldn’t convince him. So that’s when I said, OK. I need to do this in my own lab.

FLORA LICHTMAN: OK. So you have this window now in mice, primarily?

RAKESH JAIN: Well, I started out rabbits, but now only in mice. Yeah.

FLORA LICHTMAN: OK. And what did you see about the blood flow? What was going on with the blood flow in tumors?

RAKESH JAIN: It’s very fascinating. I wish I could show the video to your listeners, because that’ll blow their mind. Because it will completely change their thinking about cancer. Essentially, what you see is that some part of the tumor, the blood flow is quite brisk, pretty good. And other parts of the region, there’s no blood flow. If you gave that tumor to a pathologist, they’ll tell you there are blood vessels everywhere.

So you’re going to ask the question, OK, what’s going on? So just visualize like you have a highway and traffic is not moving. You see what I mean? I’m sure–

FLORA LICHTMAN: We’ve all lived it. Yeah.

RAKESH JAIN: So we realized this. And then, obviously, I began to think about when I was a professor of chemical engineering, why would flow stop in a vessel, in a tube?

FLORA LICHTMAN: You had asked this question. Is medicine getting to the tumors? Because if we’re going to treat cancer, we want the medicine to get there, right?

RAKESH JAIN: Right.

FLORA LICHTMAN: You find out that the arteries that would take the medicine there are not working, at least not working very well and definitely not working very well across the tumor. This feels very promising. So are people– are the grants rolling in at this point? What do people think about this? How does the field think about this?

RAKESH JAIN: Are you kidding? So when I proposed this, my first six grants were rejected in a row. When I proposed this, I want to study drug delivery and tumors. This is not an important problem. You need to focus on cancer cells and its genetics. Why are you wasting your career? So it took quite some time.

I finished my PhD in ’75 December, and I got my first grant in 1980 from NIH. So that was very gratifying.

FLORA LICHTMAN: I bet.

RAKESH JAIN: Yes, yes. So it was very hard. But I kept at it because I knew if you’re going to make a difference in treatment of cancer, we need to figure out what’s stopping blood flow and how to improve it.

[MUSIC PLAYING]

FLORA LICHTMAN: We have to take a quick break. But when we come back, how Rakesh Jain’s research went from heresy to canon, and what it might mean for the future of cancer care.

[MUSIC PLAYING]

OK, Rakesh, so we left off with this idea that this work was outside of the box, because you are trying to make the blood vessels that lead to the tumors work so that they can bring medicine to the tumor. But there’s also this dogma in cancer research of starving the tumor. So is that partly why it was heretical?

RAKESH JAIN: It was, partly, because of that definitely, first because I was not working on cancer cells. That alone was a problem. All right.

FLORA LICHTMAN: Not the seed.

RAKESH JAIN: Not the seed, yeah. They said, you’re working on hubcaps instead of the engine. OK?

FLORA LICHTMAN: Literally, is that what they said?

RAKESH JAIN: Yeah. So, anyway, so since 1971, a very distinguished colleague of mine, late Dr. Judah Folkman, had put forward the idea that we need to starve tumors. And it’s a good idea, because that’s what surgeons do. When you cut off the tumor from a patient, you cut off its blood supply. It’s sayonara. Tumor is dead. And he was trying to do that in patients in situ.

And so he was trying to develop what are these drugs called anti-angiogenic drugs. And the very first such drug was anti-vegf drug known as bevacizumab or trade name is Avastin. It sells for $10-plus billion per year and used by a large number of patients. So this drug was originally developed to starve the tumor to death. The reason was because VEGF stands for vascular endothelial growth factor– vascular, I mean, for the growth factor–

FLORA LICHTMAN: So it seems like it’s going to make them grow, right?

RAKESH JAIN: Yeah. And now, if you cut it off, they’re not going to grow, right? It’s a very cool idea. Think about it. And except when they tried this in patients and when mice had, of course, starved the tumor. But when they tried this in patients, it didn’t work. The trial failed. But when they combined with chemotherapy, it worked like a charm.

FLORA LICHTMAN: Oh, that’s strange, right?

RAKESH JAIN: Yeah. So I said to myself, hold a second. How can you deliver a drug if you cut off the blood supply? Why would it make work better? So in the meantime, while I was doing experiments in mice, I was seeing that when you give this drug, you actually improve the blood supply.

FLORA LICHTMAN: So it does the exact opposite–

RAKESH JAIN: Opposite. You got it. You got it.

FLORA LICHTMAN: –that people thought it did.

RAKESH JAIN: Exactly, for a short time. Not permanently. So anyway, so originally, when I proposed this idea in an article in 2001, in an article in Nature Medicine, normalizing vessels using drugs that were developed to kill them, I was not–

FLORA LICHTMAN: How’d that go?

RAKESH JAIN: It did not go too well. I will not dwell on it because I could give you a long history about my grand rejections paper, on and on. But anyway.

FLORA LICHTMAN: What was the worst review? Just give one example.

RAKESH JAIN: Well, somebody wrote to me, what’s Dr. Jain smoking? Example. I still would like to know what Dr. Jain is smoking because I’m a non-smoker all my life. So anyway, that was a tough time for me. Friends wouldn’t talk to me. They would turn around because– and I had so much respect myself for Dr. Folkman. He liked the idea, eventually, when I met with him, explained to him. Because it explained why this therapy is working.

But the interesting thing is, what is even cooler is that I found out that later on and showed in 2012 that when you repair the vessels, immune therapy works better.

FLORA LICHTMAN: Wow.

RAKESH JAIN: And that’s what led to many trials of combining these anti-vegf drugs with immune checkpoint blockers and other things. And guess what? That’s how led to they write another seven approvals by FDA for lung, liver, endometrial, and lung cancer.

FLORA LICHTMAN: Lung, liver, endometrial–

RAKESH JAIN: And kidney. Sorry. Yeah.

FLORA LICHTMAN: And kidney cancer, all now use this protocol.

RAKESH JAIN: Yes. Now this is approved now, yeah. But not only that. There were 200 trials going on as we speak with such a combination. So I think this is transformational for immune therapy. So anyway, this is so gratifying. I cannot tell. Because this also is helping kids with the benign tumor in the ear, Schwannomas, they’re hearing. That’s become the standard. Their hearing comes back they don’t have hearing. And then suddenly, boom. You give this drug at a homeopathic dose, and boom. Their hearing comes back. And potentially, it will help about half a billion people worldwide with many diseases.

FLORA LICHTMAN: You spent a long time working on this when people were skeptical of it. Did you ever want to quit?

RAKESH JAIN: Are you kidding? No. It’s just not in me. Yeah.

FLORA LICHTMAN: That’s not who you are.

RAKESH JAIN: No, I can’t quit. Because look, I shouldn’t say that. I’m turning 75 next week. I’ll be on December 18. I ain’t quitting. As long as this brain keeps functioning, as long as my neurons keep firing, I want to make a difference in other diseases too, besides cancer. And I’m working on a microbiome, how that can help. I’m working on how neuronal cells help cancer cells grow, how to block that in tumors of the kids.

So I don’t have enough hours in the day to pursue my work. That’s my problem.

FLORA LICHTMAN: You want to make the most of your time.

RAKESH JAIN: Yes, I do. I do.

FLORA LICHTMAN: So back to your research. The other problem that you found when you were looking at these blood vessels is that they were crushed, collapsed. What was happening there? And how do you fix a crumpled up blood vessel?

RAKESH JAIN: So the first question we asked is, hey, who’s doing this? Two, how much force is being applied, and number three, who’s applying it? And number four, how do we get out of it? That’s a good engineering problem, too. We like to measure forces. All right? So.

FLORA LICHTMAN: That’s the bread and butter of an engineer. Yeah.

RAKESH JAIN: OK. So human tumors apply pressures higher than 120 millimeters of mercury. Do you know what a mean arterial blood pressure is? 100. So a tumor can compress, apply pressure more than your heart can pump.

FLORA LICHTMAN: So it’s a high pressure zone–

RAKESH JAIN: Collapse. It collapse.

FLORA LICHTMAN: –which explains why your blood vessels are crimped.

RAKESH JAIN: You got it. Collapse it. So the next question is, who’s collapsing it? So the first thing that collapses are cancer cells themselves. They will do that because they’re growing in a confined space. But the tumor where this is the worst is pancreatic cancer. There’s no treatment for it. Or all the treatments are generally very ineffective. And you know what, the tumor, pancreatic cancer, has? Has only 5% of seeds. Only 5% cells are cancer cells. That’s it.

FLORA LICHTMAN: Wow.

RAKESH JAIN: The rest is just soil. So soil is compressing. So next question, what in the soil is doing this? And it is the matrix. So the question is, how do you out of matrix? Selectively. And that’s where the next chapter began in my career, looking for how to reduce matrix– not remove it completely, because if you do that, that’s bad news. How to normalize it. Remember, the word we use is not removal. We’re normalizing.

FLORA LICHTMAN: Normalize it.

RAKESH JAIN: Don’t destroy it. Amit Jain, we don’t believe in killing anything. All right. That’s my religion. We try to fix things. OK. So, anyway. So how do we fix the matrix? Lo and behold, a few years later, we discovered that a highly effective antihypertensive drug which is given to patients who have high blood pressure, called losartan, costs less than $1 per day. It’s cheap, safe, given to 20 million people. That can do it.

FLORA LICHTMAN: OK. Let me recap here. So you find out that there’s a lot of pressure inside these tumors that’s doing the collapsing. And you find out that it’s actually this matrix that’s in between the cancer cells and the other cells in there that’s applying the pressure. And you discover this cheap generic blood pressure medicine, losartan, that seems to reinflate the blood vessels. Does that sound right?

RAKESH JAIN: Yeah, it removes them. Yeah, it–

FLORA LICHTMAN: What does it do? Does it get rid of the matrix?

RAKESH JAIN: Yeah, what it does, it reduces it. Same thing. Normalize it.

FLORA LICHTMAN: This sounds too good to be true, in a way. A generic, safe, cheap drug?

RAKESH JAIN: Yeah. But we found out one more benefit of it, which is really what I want to talk to you about. This is a recent finding. So glioblastoma is one of the most deadly brain tumors.

FLORA LICHTMAN: Yes.

RAKESH JAIN: The last therapy that was work was nearly 20 years ago. Not much has changed. Can you believe that, in 20 years, after so much investment? Immune therapy has failed. Everything has failed so far. So what’s going on here? So one problem with glioblastoma is, or these brain tumors, there’s a lot of edema in the brain. Edema means swelling. There’s a lot of water. All right? Leaky vessels. There are no lymphatics that can come out, so the water accumulates.

And what happens to control the patients who have this type of tumor, they get steroids for that. They don’t like it, but that’s only thing that can control it. So guess what? When you give immune checkpoint blockers, this immune therapy, edema goes up. That means swelling goes up even further. So now, you have to give patients steroids. Guess what? Steroids are immunosuppressants. So you’re expressing both accelerators and brake at the same time. It’s not going to do any good, right?

What we discovered and published in 2023 that losartan can actually decrease edema.

FLORA LICHTMAN: Decrease that swelling.

RAKESH JAIN: Yeah. Decrease that swelling. And I’ve been trying to get funding for it, and I’m unable to do that.

FLORA LICHTMAN: You need to do a trial.

RAKESH JAIN: I need to do a trial because I have a compelling data in mice. So we have enough evidence to move to a clinical trial.

FLORA LICHTMAN: But?

RAKESH JAIN: But I can’t can get money for it.

FLORA LICHTMAN: Because?

RAKESH JAIN: Well, number one, there are multiple reasons for it. This is a generic drug, so pharmaceutical company is not going to make money with it.

FLORA LICHTMAN: There’s no financial incentive.

RAKESH JAIN: There’s no financial incentive. So I’ve tried to approach companies, but that’s not working. And with NIH, I don’t need to tell you what’s going on. I’m so worried about my students and my junior people. I cannot tell you. I cannot tell you how much worried I am, Flora, about them because of the way what’s happening to our funding. We are taking all these– not only mine, but many other people’s ideas. Patients will never benefit from them unless the NIH invests money in it.

FLORA LICHTMAN: Let’s talk about that a little bit. What do you think is the biggest threat to cancer research right now?

RAKESH JAIN: The biggest threat to cancer research is lack of funding. There are so many brilliant people, so many brilliant ideas. And just to give you an idea, when I started my career, about 25% of the grants were getting funded. You write your application. First round, about 25% or maybe second round. Under Biden administration, went down to 11%. Now, it’s 4%.

It’s like one out of 25. Think about it. And you would think somebody with my track record would get their grant funded the first round. No, it’s not happening. No, it’s not happening. Now, think about the junior people. Think about that. So it’s so sad. I mean, we are world leaders. I mean, more Nobel laureates in medicine have gone to US than any country in the world, maybe the rest of the world combined. And yet, we are just handing over this leadership to other countries.

And we’re hurting patients by not investing in this.

FLORA LICHTMAN: What about attracting talent from other countries?

RAKESH JAIN: Oh, that’s hurting too. I mean right now, if you look at my lab, I have people from Germany, from many countries of Europe, many people from Asia. And if he stopped giving them visas and/or if you start charging $100,000–

FLORA LICHTMAN: For the h-1b, yeah.

RAKESH JAIN: For the h-1b, I mean, it’s going to hurt not only us. It’s going to hurt industry, pharmaceutical companies. It’s going to hurt the hospitals. It’s going to hurt all of us. Flora, we need to do something about it. And I think the foundations also need to step in. They have money. We know that. I mean, there are a lot of wealthy people in this country. We know that. We are killing our young scientists.

And I just cannot tell you, Flora, how sad that is.

FLORA LICHTMAN: How do you think about mentoring right now when it seems so difficult for trainees and for young scientists?

RAKESH JAIN: I sit with them, and I’m trying to support them as much as I can. And I keep reminding them my first grants were rejected in a row. So just hang in there. Just hang in there, and I’ll continue to support you as long as I can. If necessary, I’ll beg. I’ll do whatever it takes. Because these are such bright people. They have bright ideas, and they have bright future ahead of them if we just– it’s like seed and soil. We need to give some fertilizer to the soil.

FLORA LICHTMAN: Fertilize.

RAKESH JAIN: Water. Yeah. And these are just so smart people and dedicated and determined.

FLORA LICHTMAN: We started this conversation about how even pursuing the soil as opposed to the seed was an uphill battle. Do you feel vindicated? Do you let yourself feel any little bit of that?

RAKESH JAIN: Well, I feel joy. I’m not going to deny it. When a trial succeeds, when your concept works, when it helps people, how can it– you smile. You get this, and you forget about all your woes. You forget about all the rejections at that moment.

FLORA LICHTMAN: What did it mean to you to win the National Medal of Science? I mean, that is among the biggest science recognitions.

RAKESH JAIN: I cannot tell you how joyful it was to meet with the President Barack Obama in the White House. Can you imagine? And look, I’m a foreign– I was born in a little town in India. Can you imagine? This is way beyond my dreams, coming and standing in the middle of White House. That was beyond anything I had imagined.

FLORA LICHTMAN: What advice do you have for people who are pursuing an idea that is outside the box?

RAKESH JAIN: Hang in there. Number one. Just don’t give up. There’s a difference between being stubborn and stupid, but that’s the fine line you have to figure out for yourself. And I am not stupidly stubborn. That’s what I like to think. Yeah.

FLORA LICHTMAN: Yeah. Don’t be afraid to be wrong, too.

RAKESH JAIN: Oh, no, no, no. You cannot be. Yeah. Actually, if you’re not wrong, something is not right. Yeah, yeah. If everything’s going right full time, there’s just– no. There’s a little problem here.

[LAUGHTER]

FLORA LICHTMAN: What’s the purpose of science?

RAKESH JAIN: I think there are two purposes of science. For me, it’s more– one is personal joy it gives me. And the second, it’s the understanding the mystery of nature is what drives me, right? But second purpose of science is to serve humanity, to improve the lot of human beings.

FLORA LICHTMAN: Seeking joy and helping humanity. I think you’ve done that.

RAKESH JAIN: Thank you. I’ve been very fortunate.

FLORA LICHTMAN: Dr. Rakesh Jain is Professor of Radiation Oncology at Harvard Medical School in Boston. And happy early birthday to you.

RAKESH JAIN: Thank you very much. Thank you.

[MUSIC PLAYING]

FLORA LICHTMAN: This episode was produced by Rasha Aridi. Special thanks to engineer John Day and the folks at WGBH in Boston for hosting Dr. Jain. We’ll see you next time. I’m Flora Lichtman.

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