Science Friday - How A Fringe Idea Led To Lifesaving Cancer Treatments

Episode Date: December 10, 2025

In cancer research, the “seed and soil” hypothesis posits that the tumor is like a seed of misbehaving cells taking root in the body. Whether it grows—and where it grows—depends on the conditions, or soil. Since this hypothesis was proposed more than 100 years ago, most research and treatments have focused on the seed, or tumor. For nearly 50 years, Rakesh Jain has been studying the soil. But in a seed-focused field, his work was seen as wasteful and radical. Now, that very same research has led to seven FDA-approved treatments for diseases including lung and liver cancer, and earned him a National Medal of Science in 2016. Host Flora Lichtman talks with Jain about how his fringe idea led to lifesaving cancer treatments. Guest: Dr. Rakesh K. Jain studies the biology of tumors at Harvard Medical School and Massachusetts General Hospital as a professor of radiation oncology.Transcripts for each episode are available within 1-3 days at sciencefriday.com. Subscribe to this podcast. Plus, to stay updated on all things science, sign up for Science Friday's newsletters.

Hey, it's Flora Lichten, and you're listening to Science Friday. Today in 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 know 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 seven 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. Thank you so much, Flora. I'm a big fan of yours, so I feel very honored that you've chosen to speak with me today. Thank you.

That's too kind. Thank you for joining us. Now, in that intro, you know, 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? Yeah, I have always been, my ideas have always been very counterintuitive. They've been against the grain. And any time 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. Let's dig into this. So I want to start with a visual. You know, when I think of a tumor, the seed, I picture like a bag of messed up cells.

Am I right? How wrong is that? 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 rye. It's an organ which has its own rules. And if you can figure out those rules, we can improve not only detection, 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 is what you call the soil. And I found out the soil, it normally helps tumor grow. That's understandable, but also confers the resistance to every form of therapy. radiation therapy, chemotherapy, immunotherapy, and all the future therapies which will be coming along. And when we talk about soil, you know, what should I be thinking of? Is it just the area right around the tumor? Is it larger than that?

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, right, 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 normal 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 haleronic 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 ten. cancer, bugs, and other things. They're full of neuronal cells. And they are now, the new research is showing there are a lot of full of bugs, the microbiome.

And so each of these affect the outcome of treatment. There's a microbiome even within the tumor? Oh, 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? Yeah, I wanted to ask about this because I know 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.

You have 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 70 to do. Did my master's on mathematical modeling or Delaware River Pollution Control. A different kind of waterway, a different kind of landscape. Exactly. And then I was shopping around for a PhD project, and I got a very fortunate accident that my PhD advisor, Professor Way, introduced me to one of the most distinguished tumor pathophysiologists at the National Cancer Institute. And he had developed a tumor with a single artery and 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. Because this was the fundamental question, right, that you were asking?

Yes, yes. Does the medicine get into the tumor? 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, A, 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 means 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're bad, not only they block the delivery, but they also impair the effectiveness of their drugs such as immunotherapy. Once immune, I mean, all patients don't benefit from it. You know, does the medicine get to the tumor?

Feels like a very good and fundamental question. Why were you a chemical engineering PhD student, like the first person to ask it? Well, I'm an engineer, okay? 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, okay, this drug delivery is like a mass transfer problem. So I asked my advisor, could I study that?

Because, you know, that's what engineers do. You look at input, output, and then. using mathematical modeling, try to figure out what's in the outside of the black box. Right. So I use that approach and I said this black box, but that was not very satisfying, even though I realized for my work, the blood flow is a problem. But I wanted to visualize it. I want to see the drugs coming in and seeing what's happening to them.

I'm guessing an engineering approach comes in again. Yes, yeah, right, 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 metastasis, or breast, and look at breast cancer, or you can look at liver, et cetera, many organs. And then we develop special microscopes. So you can visualize when you see a drug coming. First, you could visualize the blood flow.

And the first thing you say, the flow is not nice. It's good in some parts of the tumor. This is not flowing at all. But we discovered the mechanism for that, too. And that's an engineering problem. It all goes back to that Delaware waterway, doesn't it? You got it. Exactly.

So had anyone watched a tumor in an animal over time like this before? Well, actually, there was a study where at NCI, National Cancer Institute by a person named George El Jair, who had developed something like this, but they didn't have the sophisticated microscopes at that time, so they didn't pursue it. But there was many years ago, and I saw that, and it was sort of back of my mind. But the very first time I studied that was in the rabbit ear. I put a window at the year of a rabbit when I was an assistant professor at Columbia University in New York and 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 say, okay, I need to do this in my own lab. Okay, so you have this window now in mice primarily? Well, I started our rabbits, but now only in mice, yeah. Okay. And what did you see about the blood flow? What was going on with the blood flow and tumors?

It's very fascinating. I wish I could show the video to your listeners because that will blow their mind because it will completely change their thinking about cancer. Essentially, what you see is 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 he gave that tumor to a pathologist, they'll tell you their blood vessels everywhere. So you're going to ask the question, okay, 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. We've all lived it. Yeah. So we realized this. And then obviously I began to think about when I was a professor of chemical imaging, why would flow stop in a vessel and a tube?

You 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? You find out that the, 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 sort of like rolling in at this point?

What do people think about this? How does the field think about this? 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 it's 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. I bet. Yes, yes. But 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. We have to take a quick break, but when we come back, how Rakesh Jane's research went from heresy to canon and what it might mean for the future of cancer care. Okay, 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 and cancer research of starving the tumor. So is that partly why it was heretical? It was partly because of that definitely. First, because I was not working on cancer cells, okay? That alone was a problem, all right? Not the seed. Yeah, not the seed. Yeah. They said you're working on Hup caps and sort of the engine, okay? Literally, is that what they said? Anyway, so since 1971, a very distinguished colleague of mine, late Dr. Judah Fookman, 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 a cyanide. Tumor is dead, right? And he was trying to do that in patients in situ, right? And so he was trying to develop what are these drugs called anti-angiogenic drug. And the very first such drug was anti-vegef drug, known as Bevasuzumab or trade name is Avastin. Well, it sells for $10 plus billion per year and used by 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.

So it seems like it's going to make them grow, right? 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, starve 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 charm.

Oh, that's strange, right? Yeah. 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 and mice, I was seeing that when he give this drug, you actually improve the blood supply. So it does the exact opposite. You got it.

That people thought it did. 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 anti-drugs that were developed to kill them. I was not... How'd that go? No, it did not go too well.

I would not dwell on it because I could give you a long history about my grand rejections, paper, on and on. But anyway. Wait, what was the worst review? Just give one example. Well, somebody wrote to me, what's Dr. Jane smoking? I still would like to know what Dr. Jane is smoking. Because I'm a non-smoker all my life. Anyway, there was a...

a tough time for me. Friends wouldn't talk to me. They would turn around. Because, you know, and I had so much respect myself for Dr. Focoman. He liked the idea eventually when I met with him, explained to him, because he 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. Wow. And that's what led to many trials or combining these anti-vege of drugs with immune check-bom blockers or other things. And guess what? That's how led to their right another seven approvals by FDA for lung, liver, endometrial, and lung cancer.

Lung liver, endometrial. And kidney, sorry, yeah. And kidney cancer all now use this protocol. Yes. Now, this is approved now, yeah. But not only that, there are about 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 you,

because this also is helping kids with the benign tumor in the ear, show anomas, their hearing, that's become the sten. The hearing comes back when they don't have hearing, and then suddenly, boom, you give this rugged homeopathic dose, and boom, their hearing comes back. And potentially it will help about half a billion people worldwide with many diseases. You know, you spent a long time working on this when people were skeptical of it. Did you ever want to quit?

Are you kidding? No, it's just not in me. That's not who you are. No, I can't quit because, look, I shouldn't say that I'm turning 75 next week or be on December 18. I ain't quitting. As long as this brain keeps functioning, as long as this brain keeps functioning, as long 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 neuronal, how neuronic cells help cancer cell grow, how to block that in tumors of the kids. So I am, so I'm, I don't have enough hours in the day, too. to pursue my work, that's my problem. You want to make the most of your time. Yes, I do. I do. 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? Okay. So the first question we asked is, A, 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? Right. Now, that's a good engineering problem, too. Okay? We like to measure forces, all right? That's the bread and butter of an engineer, yeah. Okay, so human tumors apply pressures higher than 120 millimeter mercury. You know what are mean arterial blood pressure?

It's about 100. So a tumor can compress, apply pressure more than your heart can pump. Okay. So it's a high pressure zone in your body. It collapse. Which kind of explains why your blood vessels are crimped. You got it. So the next question is who's collapsing it, right?

So the first thing that collapses are cancer cells, right? Themself, they will do that, right? Because they're growing in a confined space. But the tumor where this is the worst. is pancreatic cancer, you know? There's no treatment for it. Or all the treatments are really very ineffective.

And you know what the tumor pancreatic cancer has? Has only 5% are seeds. Only 5% cells are cancer cells. That's it. The rest is just soil. So soil is compressing. So the next question, what in the soil

is doing this? And it is the matrix. So the question is, how do you get out of matrix? Right? 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 or normalizing. Normalize it. Don't destroy it. I'm a Jane. We don't believe in killing anything. Okay. That's my religion. Okay. I try to fix things. So anyway, so how do we fix the matrix? Lo and behold, a few years later, we discovered that a highly effective anti-hypertensive drug,

a drug which is given to patients who have high blood pressure called Lassardin, costs less than dollar per day, it's cheap, safe, given to 20 million people, that can do it. Hmm. Okay, 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 sort of 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, Lassarton, that seems to re-inflate the blood vessels. Does that sound right?

Yeah, it removes them. Yeah. What does it do? Does it get rid of the matrix? Yeah, what it does, it reduces it. Same thing, normalize it. This sounds too good to be true in a way. A generic, safe, cheap drug?

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, you know, glioblastoma is one of the most deadly brain tumors. Yes. The last therapy that worked was nearly 20 years ago, not much as 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 of this kind of brain tumor is that there's a lot of edema in the brain. Adema 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, you know, this type of tumor, they get steroids for that. They don't like it, but that's only they 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 break at the same time. It's not going to do any good, right? what we discovered and published in 2023 that LaSartan can actually decrease edema. Decrease that swelling. Yeah, decrease that swelling. And I've been trying to get funding for it, and I'm unable to do that. You need to do a trial. I need to do a trial because I have compelling data in mice.

So we have enough evidence to move to a clinical trial. But? But I can get money. for it. Because? Well, number one, the multiple reasons for it, this is a generic drugs. So pharmaceutical company is not going to make money with it. There's no financial incentive.

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'm flora about them because of their way what's happening to our funding. You know, we are taking all these ideas, not only mine, but many other people's ideas, patients will never benefit from them unless the NIH invest money in it.

Let's talk about that a little bit. What do you think is the biggest threat to cancer research right now? 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 start 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 and medicine have gone to the U.S. than any country in the world. Maybe the rest of the world combined, you know. And yet, we are just handing over this leadership to other countries. And we are hurting patience by not investing in this.

What about attracting talent from other countries? Oh, that's hurting, too. I mean, right now, if you look at my lab, I have people in Germany, from many countries of Europe, many people from Asia. And if he stopped giving them visas and if you start charging $100,000. For the H-1B?

For the H-1B. I mean, it's going to hurt. Not only us, it's going to hurt industry, from school companies, It's going to hurt the hospitals. It's going to hurt all of us. Florida, we need to do something about it. And I think the foundations also need to step in.

You know, 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 scientist. And I just cannot tell you, Flora, how sad. that is. How do you think about mentoring right now when it seems so difficult for trainees and for young scientists?

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 error. So just hang in there. Just hang in there. And I'll continue to support you as long as I can. If necessary, you know, 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, you know, it's like seed and soil. We need to give some fertilizer to the soil. Fertilize. Yeah. Yeah. And these are just so smart people and dedicated and determined. You know, 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? Well, I feel, Joe. 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. What did it mean to you to win the National Medal of Science? I mean, that is, you know, among the biggest science recognitions. I cannot tell you how joyful it was to me with the President Barack Obama and the White House. Can he imagine? And look, I'm a foreign, I was born in a little town in India. Can you imagine this is like way beyond my dreams?

Coming and standing in the middle of White House. That was like beyond anything I had. imagine. What advice do you have for people who are pursuing an idea that is outside the box? 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 sort of figure out for yourself. And I am not stupidly stubborn. That's what I like to think. Yeah. Yeah. Don't be afraid to be wrong, too. 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, this is no, there's a little problem here.

What's the purpose of science? I think there are two purposes of science. For me, 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. Seeking joy and helping humanity. I think you've done that. Thank you. I've been very fortunate. Dr. Reckhash Jane is Professor of Radiation Oncology at Harvard Medical School in Boston. And happy early birthday to you. Thank you very much. Thank you. This episode was produced by Rasha Auretti.

Special thanks to engineer John Day and the folks at WGBH in Boston for hosting Dr. Jane. We'll see you next time. I'm Flora Lichtman.