Ben Greenfield [00:00:00]: My name is Ben Greenfield, and on this episode of the Ben Greenfield Life.

Dr. Azra Raza [00:00:03]: Podcast, this whole drug development model is so artificial. This is what forced me to actually write the book, to bring all this to attention. The first cell and the human costs of pursuing cancer to the last. The subtitle of the book is a direct criticism of this system of drug development because cancer scientists who are PhDs, mostly, they never see patients. They miss completely what the patient is going through. Cancer scientists are studying a disease they never see in animals who don't get the disease.

Ben Greenfield [00:00:44]: Fitness, nutrition, biohacking, longevity, life optimization, spirituality, and a whole lot more. Welcome to the Ben Greenfield Life show. Are you ready to hack your life? Let's do this. I was at a longevity conference way out in the mountains. I'll have to actually ask my guest, where was that? It was Sundance, right?

Dr. Azra Raza [00:01:17]: Sundance, yes.

Ben Greenfield [00:01:18]: Yeah, Sundance. And this conference, it was called Da Vinci, and it was all about different ways to extend lifespan and live healthier. And a lot of cutting edge technologies and really cool investors and medical practitioners and the like were there. And I met today's podcast guest while I was there because she actually gave a talk. She gave a talk about cancer, and it was so unique and compelling in terms of her approach that I wound up getting her book. I'm going to hold it up here for those of you who might be watching the video version. The book is called The First Cell. The First Cell.

Ben Greenfield [00:01:58]: As a matter of fact, all the show notes I'll put over at bengreenfieldlife.com/firstcell because I think you're really going to want to read this book, especially after you listen to today's show. Azra is a professor of medicine and clinical director of the Edward P. Evans Foundation MDS Center at Columbia University in New York. So she's joining me from Manhattan. She is a practicing oncologist. She sees 30 to 40 cancer patients weekly. She directs a cancer research lab and has hundreds of original publications in high profile journals.

Ben Greenfield [00:02:33]: So her entire life is dedicated to the prevention of cancer, specifically with some early detection approaches that we're going to talk about in today's show because she has a very unique approach and honestly, a very interesting and quite emotional story about some things that have happened in her journey with cancer research. So again, the show notes are going to be at bengreenfieldlife.com/firstcell. Azra, welcome to the show.

Dr. Azra Raza [00:03:07]: Thank you, Ben. Delighted to be here.

Ben Greenfield [00:03:09]: Yeah, yeah. You really turned a lot of heads at that conference. And I believe in your book when you shared about how cancer became a lot more intimate and personal for you. So I would just really love to hear a little bit more about that, if you could share with my audience what happened to you after treating cancer for a couple of decades.

Dr. Azra Raza [00:03:37]: What happened is that I had been an oncologist taking care of a lot of patients for 20 years until cancer entered my own home and basically laid waste many, many lives as a result. My own husband, Harvey Preisler, who was the director of the cancer center in Chicago, got his second cancer. The first one was a solid tumor, which he had when he was 34 years old. And then he survived that. But at 57, he got a liquid cancer, leukemia, and then died of it. So that's what happened to me. That cancer became a very personal story suddenly.

Ben Greenfield [00:04:29]: What was that like for cancer to be something that you studied as a disease, you know, as a cellular mechanism, and then experiencing it actually happen on a personal level?

Dr. Azra Raza [00:04:44]: When I grew up in Pakistan, Karachi. And at the time I was growing up in the late 50s, early 60s, we didn't have that much entertainment except reading and sports, basically. And so I was naturally driven by curiosity into the sciences, and I was reading a lot and interested in cancer all my life as a result, and had decided by the time I was really in my late teens that I'm going to study and try to unravel the mystery of cancer. And the two intellectual questions that fascinated me to begin with were the fact that within our body, we are giving birth to a cell that can live forever and literally a new species. And I felt like, oh, this is interesting. If we can unlock the secret of a cancer cell, we might be able to unlock the secret of aging, immortality. But the second thing was equally interesting to me, because it turns out that cells in our body have a rule to follow. If they are born in the lungs, they stay in the lungs.

Dr. Azra Raza [00:05:55]: Ovaries stay in the ovaries, brains stay in the brain, but only in one condition. They become mobile. They walk out of their organs of origin. So a breast cancer cell can land in the bones, a liver cancer can land in the lungs. And so immortality and mobility, these were two questions that had been intellectually of interest to me. But an intellectual interest doesn't really become a quest until you combine it with some emotional investment, of course. And that's what happened to me, because in Pakistan, where I grew up, the only way I could pursue my interest was to become a physician, because we didn't have postgraduate PhD programs in molecular biology and things like that. Had I gone to school in the West, I'm sure at that point I would have pursued a PhD in molecular biology.

Dr. Azra Raza [00:06:52]: But I was growing up in Pakistan, so I go to medical school. That's where I saw my first cancer patients. And immediately it became clear to me that from that moment on, I have to spend the rest of my life in trying to reduce the suffering of these patients. And the reason I'm telling you this long background, Ben, is that it wasn't like cancer is something new for me. I had been obsessed intellectually, had an emotional investment. Came to America at 24. Started my journey immediately by joining a fellowship in oncology. Even before I started my residency in medicine.

Dr. Azra Raza [00:07:31]: So I was pretty serious about this whole thing. And yet it made a difference to have a personal story. Why? Because the moment I started seeing patients in the US, I realized that narration is a very important part of medicine. Narrative medicine is very important because patients have to report their histories to us. They have to tell us their symptoms. But all these things change from mouth to mouth, from patient to family, from week to month. And it's kind of a chaotic, fragmented story. And you're supposed to make a sense out of it.

Dr. Azra Raza [00:08:12]: And I didn't know how many of the nuances I'm missing. Because patients are forgetting to report something. And they're not telling me everything they should be reporting. Or I'm not hearing something which they are saying. And it became clear to me that it's not just a matter of perhaps a cultural or a language difference. Because, in fact, I was speaking fluently in English. It was more the disease oriented problems. Because there's disorientation, confusion.

Dr. Azra Raza [00:08:48]: And you have to make sense of it. And I always used to wish, Ben, that I somehow I have to develop better hearing. I have to hear more hearingly. You know, the kind of hearing that the blind develop. Where they can read between the lines. They can hear what is not being said. These are the gaps that got filled when Harvey had cancer, my own husband. Because now I can witness that one morning he wakes up, and the joints in the right hand are swollen and inflamed.

Dr. Azra Raza [00:09:22]: And dread and hot and burning and literally sizzling. And he's writhing in pain. And no sooner does that disappear over a week. That something appears in his knee suddenly. Or he develops night sweats. And when he is reporting to the doctor. And he is not exactly explaining everything, or I am unable to report every single thing. You know, these things start becoming suddenly fall into place.

Ben Greenfield [00:09:54]: When you experience that with Harvey leading up to that point, you'd obviously given a lot of thoughts to this two factor approach of mobility and immortality. And in experiencing what you went through with Harvey, did that further influence your hypotheses or your theory on the best way to detect and treat cancer?

Dr. Azra Raza [00:10:21]: Absolutely, Ben. In fact, that has led my path since that point on. I initially began my career by studying acute leukemia, acute myeloid leukemia, which is one of the deadliest cancers known to mankind. But within a few years, it became apparent to me that in my lifetime, this disease is not going to be cured. Why? Because it's. By the time we diagnose a leukemia, there are billions and billions of cells circulating all over the body via the blood because it's a bone marrow cancer. And so I had said to myself, the only good news we can give patients is that we found your cancer early and we can take it out or we can treat it effectively.

Dr. Azra Raza [00:11:08]: Well, how do you treat leukemia effectively? Because you have to find it early. And I realized that leukemia can't be found early. We have to find individuals who are at risk of getting leukemia and start following them till they develop it. And so there were people like that who already have some abnormal blood counts. They're called myelodysplastic syndromes. So in 1984, I turned my attention to focus on studying, treating and seeing patients with myelodysplastic syndromes, or pre leukemia, and then following them as they developed acute leukemia. So that was my trajectory going forward anyway. But then Harvey suddenly develops this second cancer at 57 years of age.

Ben Greenfield [00:12:01]: And by the way, was it completely separate from the cancer that he had at 34?

Dr. Azra Raza [00:12:06]: Yeah, because the first one was a solid tumor, a testicular cancer. And then the second one, which came a couple of decades later, is a leukemia. No relationship at all. So I realized instantly at even before that, I had been trying to study people who have had one solid cancer. Because their chances of developing a second one is high. In fact, think of this, Ben, that of all the new cancers that are diagnosed every year in America, one in five or 20% appear in a cancer survivor. I'm not talking about a recurrence of the same cancer. I'm talking about a completely new cancer like Harvey.

Dr. Azra Raza [00:12:56]: Now, a lot of people who are listening to me might get anxious because they may be cancer survivors, they may be people in their family who have had cancer. I don't want to scare anybody, because, in fact, the risk for an individual who has had one cancer of having a second one is only 13% higher than compared to a healthy individual. So it's not that high. But if you look at the actual number of people who have been diagnosed, let's say in America this year, we are diagnosing 2 million new cases. If you look at those 2 million new cases, then 400,000 of them are occurring in someone who had a previous cancer of some other kind before. So that has been known for a while. And I was concerned always that we need to find cancer really early. Even stage one is not early enough, because that requires removal by brutal treatments of slashing women's breasts or removing.

Dr. Azra Raza [00:13:58]: Undertaking surgery of some sort to remove it. And that was the issue. To find cancer early, you need to find it before it finds the patient. Meaning, try to find it at such an early first stage, at inception, at initiation, rather than waiting for the cancer to declare itself. So Harvey, having had one cancer, always we were worried that he might get a second one. But slowly you get lulled into a complacency because nothing was happening, and he was doing really well. And one fine day, the second cancer came.

Dr. Azra Raza [00:14:42]: However, I wanted to tell you that I had already established in Chicago a center called TIME center - therapy-induced malignancy evaluation - that there is a concern that perhaps some of the treatments we are giving for the first cancer has induced a second cancer.

Ben Greenfield [00:15:02]: Therapy-induced malignancy evaluation. Evaluation. Okay.

Dr. Azra Raza [00:15:08]: Yeah, that's the TIME, I called it. That's an acronym for this center. And I got a big grant for it and established it. And I started just taking samples of blood, saliva from people who have had one cancer. That's it. And they're in remission. They are cancer survivors. And I started banking these samples back in 1990s.

Ben Greenfield [00:15:34]: And all of these people had received therapy for their cancer. And you were evaluating whether or not that therapy might increase their chances of getting cancer again?

Dr. Azra Raza [00:15:44]: Yeah.

Ben Greenfield [00:15:44]: Okay.

Dr. Azra Raza [00:15:46]: So I saved thousands of samples from patients serially. Every six months, I would obtain these samples, breast cancer, lymphomas, lung cancers, all kinds of solid tumors. And at the same time, I have been saving samples from, of human tissue from my patients with pre-leukemia, following them longitudinally since 1984. So I go back a long way for two things. One, my search for the first cell, finding cancer at initiation, and number two, trying to save human samples to develop an understanding of what are the factors that lead up to the development of the first cell. What are the biomarkers that would indicate that a cancer is now imminent?

Ben Greenfield [00:16:43]: So, before addressing this idea of the first cell, I'm curious, with TIME, did you actually find that there are therapies that one gets when treating cancer that could increase their chances of getting cancer again, or even getting a second, unrelated cancer similar to what Harvey experienced?

Dr. Azra Raza [00:17:01]: Yes, there is definitely epidemiological studies to show that. And there are a lot of drugs, particularly chemotherapeutic drugs, radiation, etcetera, that have been directly related to certain types of leukemias, lymphomas, etcetera, that developed. But it's not just that, because, for example, in Harvey's case, he only had surgery. He didn't receive any radiation or chemotherapy, yet he developed a second cancer.

Ben Greenfield [00:17:33]: For the testicular cancer, all he got was a surgery. Is there a possibility that even increased his chances? Or is that completely unrelated?

Dr. Azra Raza [00:17:42]: Given that second cancer was completely unrelated, I doubt that surgery alone would have caused enough stress for something to show up 20 years later.

Ben Greenfield [00:17:53]: So when you say the first cell, explain to me what you mean by that.

Dr. Azra Raza [00:17:56]: The idea is that cancer begins in one cell, and that cell acquires a life of its own, and it starts to proliferate extensively without serving any purpose which is useful for the body. Every cancer that has ever been looked at begins in one cell. And then that cell divides and forms a clone. And so it's always monoclonal. One cell gives origin. And I thought to myself that if that is the case, that something goes wrong in one cell that was normal until yesterday, and today, it suddenly become cancerous. What could be causing that? And there are a lot of hypotheses around, but nothing has been surely proven. Saying that it is damaging agents in the environment. It is aging can cause all kinds of chronic inflammation that can put cells into stress.

Dr. Azra Raza [00:19:01]: And it could be an infection, and inflammation and exposure to toxins. It could be hereditary susceptibility. All those things are possible that can cause a cell to misbehave. But if you narrow them down, basically each of those are stressing the cell in some way or another and telling the cell that, hey, fight or flight, either develop a strategy to survive or you're gonna die. And in this condition, cells start to develop all kinds of strategies to survive whatever stress they're facing. And one of these stresses. Sorry.

Dr. Azra Raza [00:19:39]: One of these survival strategies is that the cell can throw its program back to almost like an embryonic stage, where its only purpose is to just keep multiplying and treat the body as an adverse environment.

Ben Greenfield [00:19:56]: Now, one quick question I have about that. When you say stress, a lot of times my listeners have heard me talk about so called hormetic stressors. You know, exercise or sauna or cold or eating a wide variety of plants or herbs or spices, etcetera. Is there a certain kind of stress that would seem to shift the cell into the type of survival response that would cause this type of monoclonal reproduction. Because I wouldn't imagine that, you know, exercise would cause a cell to want to become cancerous, for example.

Dr. Azra Raza [00:20:31]: I see what you're saying, but no, those things are all pretty safe. The things that we know of that put people under stress are well known, which is the opposite of exercise. Sedentary lifestyle, rather, will put people at risk, or the wrong kind of diet.

Ben Greenfield [00:20:50]: Toxin exposure, relationship stress, poor sleep, maybe electrical or air or water pollution, etcetera.

Dr. Azra Raza [00:20:58]: And most recently, Ben, which has shocked me what is being shown is that climate change.

Ben Greenfield [00:21:05]: Climate change, yeah.

Dr. Azra Raza [00:21:07]: Directly related to the temperature rising is related to childhood leukemia, for example. Definite increase in that.

Ben Greenfield [00:21:18]: Do you think that's because the increase in temperature and the climate, or the factors such as industrial emissions that would cause that increase?

Dr. Azra Raza [00:21:26]: I think it's all of those things together. I don't think there's any one reason for these. And there are so many increased stresses in every way right now. So many pollutants, so much of the exposure to the kinds of things that our bodies have never seen. But clearly there are epidemiological studies now coming out showing that especially mothers who, I mean, women who are pregnant, if in the first eight weeks or twelve weeks of their pregnancy, in the first trimester, are exposed to high temperatures in the climate, then their babies have a much higher incidence of developing acute lymphoblastic leukemia. I never heard of this before. But there's another kind of stress. So we know that stress can make cells behave differently.

Dr. Azra Raza [00:22:21]: And cancer is directly related to aging. And aging puts in a lot of stress on every organ in the body. So that all kinds of chronic diseases, not just cancer, but heart disease, dementia, lung pulmonary problems, arthritis, all kinds of things start to happen with increasing age. Why? Because there's a lot of stress inside the body. And I think, I don't want to underestimate the psychological stress here because, as you said, psychological stress, lack of sleep, anxiety, all these hormonal disturbances related with these things can put cells on under stress, too. You asked me to clarify the concept of the first cell. So I was saying that even before the first cell. I'm saying that there has to be all these kinds of stresses that any one of them can tip the cell over.

Dr. Azra Raza [00:23:23]: And I think of it basically, I think of it like a cell suddenly becoming so stressed that it throws its program or does something, whether it's a mutation, DNA damage, whatever happens to it immediately starts to treat the rest of the body as foreign, and it has to survive against it, as if it's an adverse enemy that has to be kind of kept away. And this particular cell then only will expand its own population in a very selfish way and ends up killing the host and killing itself. But I wanted to always find what those stresses are and how that first cell is being produced and how is it becoming mobile, how is it getting out of the organs of origin? And all that had been going on way before Harvey got sick.

Ben Greenfield [00:24:25]: So there's kind of two problems. It sounds to me like you're trying to tackle. One, the early detection or identification of this first cell in the first place, and then two, the actual mechanism by which it could become mobile. Rather than being localized in certain tissue areas.

Dr. Azra Raza [00:24:42]: I would add a third one. What were the stresses that caused that cell to misbehave?

Ben Greenfield [00:24:47]: Yeah. The triggering action. Yeah. So a lot of people who hear discussions about early detection technologies might actually think that something like, oh, let's say like a Galleri blood cancer biopsy or what's it called, a GRAIL screening or maybe a full body MRI or something like that, would be adequate for early detection. What's your take on current early detection technologies?

Dr. Azra Raza [00:25:17]: Grossly lacking in accuracy is what my opinion is, because any imaging scanning device only at best, picks up stage one. And stage one means already you need slashing approaches to treat it, surgery of some sort. And the kinds of tests that you mentioned, Galleri, for example. I love that test. But the problem is, Galleri is a test in which it started because scientists realized that when you are worried about a pregnant woman who is in her late thirties and is conceived a child, is the fetus normal or not? Because developmental abnormalities and congenital issues are more common with maternal advancing age. So, for example, I became pregnant when I was 39 and gave birth when I was 40. So I was very concerned that I want to make sure my, the baby I'm carrying is normal.

Dr. Azra Raza [00:26:29]: So I underwent an invasive procedure that was called amniocentesis, where a long needle was inserted through my abdomen into the uterus and some fluid, amniotic fluid was drawn in which the baby is bathing. And from that, you can pick up fetal cells and perform DNA and chromosome studies to show that this is normal. Well, it occurred to some scientists that perhaps we could detect those things in mother's blood rather than having to insert a needle into the uterus. Can we just take a blood sample? And indeed, they started to find rare cells, but a lot of DNA pieces that had been shed by the fetus. And those pieces of fetal DNA could be distinguished because, for example, if the mother is carrying a male fetus, they would be 46 XY, whereas her DNA would be 46 XX. So based on that, it turned out that today all we have to do is a few drops of blood from the mother who is pregnant, look for cell free fetal DNA in that blood, and say that this cell free fetal DNA is normal. What if.

Ben Greenfield [00:27:53]: What if it's a female, by the way? What if it's an XX and it's a mother?

Dr. Azra Raza [00:27:57]: So there are ways to tell maternal and fetal differences that are. Okay, I'm just saying how. That's how it began. But now we have more sophisticated technology to tell fetal DNA from maternal DNA. But you find pieces of cell-free DNA, meaning DNA just freely floating. It's not inside any cell, in the mother's blood. And this DNA can tell us whether the mother is, whether the baby is healthy or not. And when that was happening, then, of course, it became apparent and obvious that if we can detect abnormalities of the fetus from this simple two, three drops of blood, maybe we can detect cancer by looking for cell-free DNA from cancer cells.

Dr. Azra Raza [00:28:45]: And indeed, that turned out to be true, that you could. So this company, Illumina, started the testing for cell free DNA to look for cancers. But then if you found that cell free DNA with mutations that are associated with, let's say, lung cancer or a pancreatic cancer, that was good that you could tell, oh, this is where the cancer is coming from? Possibly. But then there were DNA mutations or cancer DNA that was being found, and we didn't know where it's coming from. So that produced a lot of anxiety. What is the tissue of origin? Is it from the ovaries or the lungs? And so this company, GRAIL, brilliantly developed a new technology. And just full disclosure, I'm an on the board of advisors for GRAIL, but they developed a technology of looking for methylation markers on these pieces of cell free DNA to say where it's coming from. And it's a beautiful way to test and show 99% or something accuracy in stage three and four cancer.

Dr. Azra Raza [00:29:56]: But that accuracy starts going down. So that sensitivity of the test at stage one is 24%, even though the positive predictive value is about 43% to 50%. That is, if a DNA is there, then the positive prediction that it will be cancer is 50%. Even that is not the best. But if for stage one, at best, you are detecting maybe 30% of the stage one cancers. But missing 70%. That is not a very accurate test, and we need to improve it. I'm very much in favor of Galleri tests because it is detecting cancers for which we don't have screening tests.

Dr. Azra Raza [00:30:45]: And I want to say something here, Ben, about the screening tests we have right now. We have five screening tests that are really acknowledged. Pap smears, psas, mammograms, colonoscopy, and CT scans of the lung for patients, for individuals who have history of smoking. So they are at high risk of lung cancer. Now, on these five screening tests, we spend something like $34 billion annually. And out of those, let's say we detect 9 million positives results. We get positive results mean that colonoscopy found a tumor, or mammogram found a mass, etcetera.

Dr. Azra Raza [00:31:32]: But that doesn't mean that it's cancer. So then you have to go and do a biopsy. So let's say 9 million tests conducted at the cost of $34 billion are found to be positive. When biopsy is done, 8.8 out of 9 million turn out to be false positives, that they are benign. So, basically, at the moment, we are spending $30 billion to diagnose 204,000 individuals with stage one, earliest cancer. And that shows us that the efficiency of. Not that the search for early detection should go away. Rather, we have to improve our technology.

Dr. Azra Raza [00:32:25]: And I think that a test like GRAIL is offering the Galleri test is a dramatic improvement on that. Or cologuard or any of these exact sciences is offering tests. Now, multiple tests are coming out, which are steps in the right direction, but they still need to be improved.

Ben Greenfield [00:32:46]: One of the conversations that inevitably arises when talking about early detection is the potential for false positives and the worry that that creates in patients as a result. Are you concerned at all about that, with the rollout of all these different early cancer detection technologies?

Dr. Azra Raza [00:33:03]: Look, I mean, I just gave you statistics that things we keep doing, like mammograms and like colonoscopies and like PSAs, etcetera, they are, yeah, they cause anxiety in people because most of them turn out to be either negative or false positive. I just quoted the statistic. But that doesn't mean that it shouldn't be done. What it means is we have to keep working more and more to improve the technology. So I am concerned that it causes anxiety. But on the other hand, it's at least that, that causing that anxiety is better than having a diagnosis of late stage cancer when you die.

Ben Greenfield [00:33:42]: Well, obviously, a big part of this raises the question of what that early cancer technology, early cancer detection technology would look like. I mean, have you made any inroads in that respect, or come up with any solutions as far as better detection technologies?

Dr. Azra Raza [00:33:58]: I think dramatic inroads are being made. And the idea, Ben, now that we have advanced so far into the biotechnology world, that we can detect not one or two proteins or their metabolites, but rather, if not hundreds of thousands, then millions of pieces of proteins and DNA and RNA and metabolites, etcetera, just from few pieces of, few drops of blood. Not just that. I have been working on trying to find, as you know, the first cell. I'll give you my own story that I started studying pre-leukemia patients, and the idea I had was, let me try to find the first leukemia cell. Well, how do you find the first leukemia cell? Because if you wait long enough for it to show up in the bone marrow, and you can't do bone marrows more than once a year, at best, you can miss, and it's too late already, then they basically, the mortality is 100% for finding leukemia at that stage. So I wanted to find it earlier. So in 2015, I set up my laboratory with a filtration device, which means that I said, okay, if these leukemia cells are being formed, these leukemia cells are larger than normal blood cells, and if they're circulating, released into the blood, maybe we can trap it and capture it from blood by simply using a coffee filter-like technology.

Ben Greenfield [00:35:42]: So you're saying that's because they're a slightly larger size, even in the pre-leukemia stage, before they've become problematic?

Dr. Azra Raza [00:35:49]: No, pre-leukemia would be the small size, but if leukemia first cell is appearing, that is large.

Ben Greenfield [00:35:56]: Okay, got it.

Dr. Azra Raza [00:35:58]: So can we trap that first leukemia cell from the blood? And not only did we start trapping leukemia cells from the blood, but we started to trap all kinds of abnormal cells, like giant cells, which have many nuclei. And of course, it turns out that a lot of people have been working on this field for decades, and the literature is quite advanced, where people have been seeing and trapping these abnormal kinds of cells that are associated only with cancer recurrence and cancer metastasis and now leukemia spreading. So it's a very exciting area that not only biomarkers like Galleri has or exact sciences has, but also abnormal cellular markers that were previously completely unknown are emerging on the scene. With the modern technology. And not just biomarkers and cell markers, there are advances being made in wearable and implantable devices that can detect deep into the tissues, abnormal signals that are happening or things like, instead of doing yearly mammograms, there is a smart bra that is being tested at Stanford, where women just have to wear this bra for 2 hours a week and it's got these tactile sensors in it, which can record changes in pressure and temperature and heat, etcetera, that is being generated and can detect early breast cancers, for example. So there are all kinds of new devices, new technologies, new biomarkers coming out. I'm terribly excited about it.

Ben Greenfield [00:37:53]: So if these new technologies become more accurate, more accessible, and we can detect cancer at an earlier stage, does that affect the nature of drug development as far as the way that we approach that? Because obviously we're targeting cells at a different stage, of a different size. And so how does this affect drug development?

Dr. Azra Raza [00:38:12]: Yeah, you know, that's such a good question, Ben, because a lot of people ask me, well, so what if you find the first leukemia cell? Are you going to give the patient a bone marrow transplant for that one cell? And the answer is that you can't give therapies that you've developed for end stage cancers to take out the first cell. Of course not. The therapies have to co evolve, and these would be much gentler than the therapies that we are using right now, trying to kill billions and billions of cells. And let me give you an example. Our bodies seem to cooperate well with us for 60, 70 years, and we generally function well. Everything is going on, and we get lulled into some kind of complacency that everything is hunky dory, but it's not because little changes are happening all over in the body that can lead to dramatic, catastrophic big events. And I think of it like dropping grains of sand. If you drop grains of sand, they will form a pile.

Dr. Azra Raza [00:39:17]: But a time will come if you keep dropping grains of sand, when the pile will collapse. But the pile collapsed not because there was something unusual or unique about the last grain of sand that caused the pile to collapse or cause the avalanche, but in fact, the pile had become unstable. It had become a complex system. What is a complex system? Where small events can lead to larger events. And so these small events, these small disturbances are going on in our body when I, we think we are functioning perfectly well, I tell myself, oh, I'm running 3 to 5 miles a day. There can't be anything wrong with me, even though I'm so old. But no, there's a lot going on because when I look at myself in the mirror, I can't recognize myself. I think, wow, this is what's happening on the outside.

Dr. Azra Raza [00:40:11]: Imagine what's happening inside, in my body. So, so many things are going wrong. So many things are changing inside the body. The best way to deal with it is not for it all to come crashing down on us one day and cause a heart attack or cause a solid tumor somewhere, or a leukemia. Rather, we need to detect these early changes constantly treating the body like a machine and monitoring it 24/7 for these minor changes. And keep correcting the minor changes to prevent the larger catastrophe.

Ben Greenfield [00:40:53]: Keep the sandpile stable.

Dr. Azra Raza [00:40:55]: Keep the sandpile. Keep fixing the unstable parts of the sandpile. I have a website called with my brother called 3 Quarks Daily. And for the last 20 years, we have not missed a single day when we did nothing. Post ten or so interesting stories in medicine, science, engineering, music, philosophy, literature, all kinds of things. And just this morning, I have posted two stories about Alzheimer's disease, one in the New York Times this week that shows that now Alzheimer's disease can be detected years in advance of through a blood test. You don't need scans of the brain anymore through the blood test, it's picking up proteomics markers. It's picking up markers that tell you that early Alzheimer has started.

Dr. Azra Raza [00:41:51]: And the second story is that, you know the drug ozempic?

Ben Greenfield [00:41:55]: Yeah.

Dr. Azra Raza [00:41:56]: This weight loss drug that Ozempic is, seems to be a miraculous drug because not only are people diabetes being helped, but it's also helping people lose weight. And losing weight means all kinds of benefits are coming from it. Well, today, the report I have posted is that ozempic can help early cognitive changes in Alzheimer's.

Ben Greenfield [00:42:25]: Interesting.

Dr. Azra Raza [00:42:26]: So, when you ask me such an important question that what kind of treatments will be, will there be for the first cell? I'm saying that even treatments like lifestyle changes. So, yeah, I mean, the changes we'll have to make to fix the little problems will also be much gentler, nuanced, and much easier to do, even at those stages. Things like ozempic, aspirin, metformin, all these things could work better then.

Ben Greenfield [00:42:54]: So when it comes to the actual drug development, I think I read this in your book that you seem to think there's a little bit of a problem with translating rodent studies into human models. Am I correct about that?

Dr. Azra Raza [00:43:11]: To say the least, yes, I think it's a gargantuan problem.

Ben Greenfield [00:43:17]: Yes, I think it's an important topic to address. Can you explain that to people? Because so much of what we do is based on studying supplements. We take medications, etcetera. But a lot of it is done in rodents.

Dr. Azra Raza [00:43:27]: That is one of my pet peeves, actually. I want everybody to know some crazy statistics that today, 95% of all experimental drugs that we bring to the bedside, 95% fail outright in cancer. The 5% that get FDA approval and that are actually supposed to be helping patients, they only help 20% to 30%. Patients extend their lifespan by a matter of weeks.

Ben Greenfield [00:44:04]: Wow.

Dr. Azra Raza [00:44:05]: 2.1 months or something. So it's such a horrible statistic that I can't even make it up right now.

Ben Greenfield [00:44:12]: I would imagine that you didn't even just take into account the number needed to treat I to see those changes.

Dr. Azra Raza [00:44:18]: And the amount of money and the amount of physical toxicity we caused to hundreds of thousands of millions of people to get those results. It's completely atrocious. How has all this happened? Why are the results of experimental trials so bad? Well, how are experimental trials brought to the bedside? Why is a drug suddenly thought of as possibly helping cancer? The way it happens is, let's say, funding agencies like the National Institute of Health will give a grant to me and say, okay, Doctor Raza, you have a good idea about developing this particular drug x for your patients. Show us how you'll develop it, we'll give you the money. So I'll go ahead and do some research in my lab on first cells that I obtain, which are growing in cell lines and try to treat them, and then use animal models, like mouse models, to create artificial tumors in these mice. How do we create those tumors? Because mice don't get the kind of cancer we are trying to study. So we kill the immune system of the mouse and put some cancer cells from the patient into the mouse. Well, they grow into the mouse.

Dr. Azra Raza [00:45:50]: Without the immune system, they grow some kind of a tumor. And now we come in with a thousand drugs and keep testing them until we find one that works. And we say, oh, this drug works.

Ben Greenfield [00:46:02]: And you're saying that the mouse is basically turned into, essentially like a fake human by suppressing the immune system and then inducing a tumor that would normally appear in a human?

Dr. Azra Raza [00:46:10]: Yes, that is so artificial. Now then we will say, okay, now this drug is helping the mouse. In fact, it's curing this tumor in the mouse. So we first of all make this claim that a great cancer treatment discovered for pancreatic cancer, and in only fine print, we learn in mice. But now everyone all around the world is excited by reading the headlines. Nobody is going to read that fine print at the end that it's only happened in mice. So, first of all, the public gets duped into thinking that great new treatments are coming and they get lulled into, oh, if I get cancer. I have read somewhere that there is treatment for pancreatic cancer, stage four.

Dr. Azra Raza [00:47:01]: In the meantime, now I can't take this drug to the bedside, and no one can give me a grant to do it because it's going to cost a billion dollars to get this drug approved. At least it costs hundreds of hundreds of millions of dollars even for one trial to test it in humans. So the only entities that can now take over this drug that I think is working will be a pharmaceutical company which will come and say, okay, doctor Raza has good credibility, let me take this drug and now sponsor a clinical trial in which 50 cancer centers in the country will put patients on this drug and let's see what happens. This is how drugs are brought from NIH support, through an academic person's lab research, to now pharmaceutical companies, then to the bedside. By the time it's reached the bedside, hundreds of millions of dollars have now been spent. When this given is given to the patients, 95% of the time, it's going to fail completely. And the 5% of the patients who might actually, 5% of the drugs that are approved is because they showed something in some patients. Now, none of these are curative at all, so they help people for a brief period of time and then stop helping.

Dr. Azra Raza [00:48:27]: And what is the cost of this drug is $100,000 a year on average. Plus it has to be given to all hundred patients, out of which 20 might respond for a brief period. So what about those 80 patients who got no benefit from it, suffered financial toxicity and physical toxicity and died anyway? And these 20 who lived a bit longer? Of course, there are always anecdotal cases that are going to live much longer, and those are the positive cases that are constantly proclaimed from the rooftops that, oh, this person is living five years now, but look at the majority, what happened to the others? And so this whole drug development model is so artificial that I can't even. This is what forced me to actually write the book to bring all this to attention. The first cell and the human costs of pursuing cancer to the last. The subtitle of the book is a direct criticism of this system of drug development, because cancer scientists who are PhDs mostly so they never see patients, that means they miss completely what the patient is going through. Cancer scientists are studying a disease they never see in animals who don't get the disease.

Ben Greenfield [00:50:00]: Do you think there would be a better way to go about cancer drug development if you could wave a magic wand?

Dr. Azra Raza [00:50:08]: Yeah, absolutely. I came to the US when I was 24, and I was so anxious that someone will cure cancer before me. And I have six months waiting period for to start my residency, and this may happen before I can even start. So I showed up at Roswell park cancer Center, wanting to work there in oncology while waiting to start my residency. And so they had a slot in pediatric oncology. That's how I started my career with pediatric oncology. But honestly, Ben, I couldn't take it. I was crying the whole time.

Dr. Azra Raza [00:50:43]: It's so difficult to hold little kids down and do lumbar punctures and bone marrows on them and drill holes. Oh, my God. No, it was too much. I couldn't take it. I was crying all the time. So my attending took me aside and said, hey, you can't last in pediatric oncology, and then sent me to adult oncology. But the thing I saw immediately at 24 years of age was I start working in adult oncology. And the most shocking thing, Ben, was that the same combination of chemotherapy drugs that were producing excellent responses in childhood leukemias had basically no effect in adults.

Ben Greenfield [00:51:32]: Really?

Dr. Azra Raza [00:51:33]: And I realized that even a smaller version of our own selves cannot serve as a model.

Ben Greenfield [00:51:40]: So not only are mice not human or human adults, but even children.

Dr. Azra Raza [00:51:44]: Even children aren't. Yeah, because think a two-year-old cells are basically virgin cells. They haven't received any of the insults and injuries that we receive with age. The mutations that would accumulate as compared to a 70-year-old cell, which has received a thousand cuts by now. So the way it metabolizes drug is completely different than a virgin cell in a two-year-old. That's metabolizing the chemotherapy drugs. In other words, I think Norbert Weiner said it in 1940, the best way, way that the best model for a cat is another cat, preferably the same one, because that's how models are so, so artificial. And I think of it like, have you seen that painting by Magritte, the surrealist artist that this is? He paints a perfect pipe, a smoking pipe.

Dr. Azra Raza [00:52:49]: And then on the title of the painting is, this is not a pipe. And you are forced to think, well, it looks like a pipe. It looks perfectly like a pipe. Why isn't it a pipe? Because what you said, you can't pick it up and smoke it. That's the difference.

Ben Greenfield [00:53:05]: Yeah, it's a model. You could probably roll the canvas and figure out some creative solution. But, yeah, I heard. Just saying. Yeah.

Dr. Azra Raza [00:53:13]: So I think of the models that we have been using for the last 70 years are so artificial, so abnormal, and no one is willing to see that because all the money is being offered in studying those models. So until and unless we change the goal of cancer research to studying human cancers and studying human samples to find human cancers and to study cancers at inception, rather at end stage and financially incentivize these new goals of studying human samples and studying early cancers, financially incentivizing the goal, then the whole field would turn towards that study. Until we do that, everyone will be trying to study the last cell and using animal models.

Ben Greenfield [00:54:10]: Well, why, in your opinion, isn't that being done yet? The research approach that you've just described on human cancer or on human cells?

Dr. Azra Raza [00:54:16]: The answer is very complicated and very long. But let me just say this. Who has taken this? Either young researchers or older researchers. The older researchers have been studying mouse models for 30 years. They don't know anything better. But they are the ones sitting in all the committees deciding who gets money. So they keep giving money to only these. The names.

Dr. Azra Raza [00:54:43]: National Cancer Institute or National Institute of Health may be an institute, but it's composed of people like these now, young people who can take risks. The problem is that they're just starting their careers, and taking a risk means that there is a chance of failure. When you're trying to build your career, you can't fail. So you are not willing to take that many risks. But the biggest problem for both younger and older scientists is that in this country, it's madness. But our salaries depend on grants, which means if I'm not getting a grant, my child can't go to private school, can't go to university, I can't take a vacation with my family. So I call this paycheck oncology. So in other words, there is a dramatic limitation on my ability to think originally, except to follow whatever is being offered.

Dr. Azra Raza [00:55:46]: Hey, the grant is being offered to develop a mouse model for ovarian cancer. So of course I'm going to apply for that grant and try to develop a mouse model. Instead of thinking originally about what can be causing ovarian cancer, how can I study it?

Ben Greenfield [00:56:02]: It sounds to me like we need some form of independent funding then.

Dr. Azra Raza [00:56:05]: Well, this is why I'm forever groveling and begging and on my bended knees.

Ben Greenfield [00:56:10]: I know. Well, it's in your book. Did you write a letter to a bunch of billionaires or something like that?

Dr. Azra Raza [00:56:14]: Yes, I did. Because I became so incensed by the idea that a football player is getting $126 billion, million dollar contract track for five years. And I am trying to cure cancer and have my hat out and begging everybody for $100,000 a year. What kind of insanity is this when everybody has a stake in cancer? Who doesn't know someone who has had cancer or whose family has cancer? We are only one degree separated, by the way cancer will strike one in two men and one in three women. So it's also very personal for everybody. And yet money is not being given. And I was so depressed about so many people dying in my hands all the time, I realized one day that since 1977, I have been using the same two drugs to treat acute leukemia. Today, in 2024, I'm using the same two drugs that I was using in 1977 for this disease.

Dr. Azra Raza [00:57:29]: Think about the number of conversations I've had with thousands of patients over the years, the same toxicities, the same dreadful results I have to discuss over and over. And it's so clear to me how to change the paradigm. And yet, for 40 plus years, I have failed completely and miserably to convert people towards this thinking. I don't know why it is, but most of it is financially driven, for various reasons. And so I wrote to billionaires 100. I went and bought the Forbes list of billionaires and wrote to the top 100, a handwritten letter, and sent it personally to them, saying this. And just in a one-page, not a polemic of any sort, but I said all this, and look, my life is devoted to this.

Dr. Azra Raza [00:58:20]: I can do all this. I can help turn the paradigm, if you support me. Of course, I didn't get any answers. Eventually I got eleven responses out of hundred letters. Ten of them were gee, thanks, but thanks, we are not interested. And then one person, Patrick Soon-Shiong, who is a physician, a surgical oncologist himself, and a man of great vision, he responded to me and he got interested. And so, in fact, he is the one who supported. Gave me the biggest present somebody could have given at the time, which is that he helped to provide me with protected time to devote myself to research, by giving an endowed professorship to Columbia University.

Dr. Azra Raza [00:59:18]: And I occupy that endowed chair because, which pays my salary, so that I can now invest all my time into this. And that's a huge deal. At least that came through. But Patrick and I couldn't work, haven't worked together, because his interest is treating the established cancers, whereas my interest is finding the first cell. So I'm forever applying to grants, I think, somehow. Tell me, Ben, how do I raise the money? It's not even that much money I have to raise.

Ben Greenfield [00:59:52]: Well, do podcasts like this, you know what? I should actually ask you, and I can put a link in the show notes at bengreenfieldlife.com/firstcell, is there a good website or website URL that people can go to to learn more about your work and how they could support it financially?

Dr. Azra Raza [01:00:08]: That's very kind of you. Yes. Azrazada.com is my website.

Ben Greenfield [01:00:13]: So my first name, my last name, azraraza.com.

Dr. Azra Raza [01:00:18]: Yeah. And as soon as you open that, there is a donate button. But you know, some years, like five years ago, I realized that why am I the only one saying all this? I have colleagues around the country. Let me call them and see. So I created something called the oncology think tank. Five years ago, I called my colleagues at Harvard, Yale, MD Anderson, Johns Hopkins, University of Chicago, Northwestern. These are the top centers in the country. And I asked them, look, do you think my two ideas, one, find cancer early, and two, study human samples.

Dr. Azra Raza [01:00:59]: Is there a fatal flaw in these, in my proposition? If yes, point it out to me. And if not, then you need to join the revolution of trying to find the first cell. Do you know, everybody agreed with me and joined me. And I have 30 people from these institutions who got together. We had 17 two-hour long meetings, weekly meetings, and we came up with an opinion paper. And the consensus in the opinion paper of all these institutional leaders in oncology is that the way of the future in oncology is to find cancer early. And we agreed that to find cancer early, we should not study people who, I mean, we should continue to study people who have cancer, but also at the same time, study a group of people who don't have cancer yet, but who are at risk of developing it.

Dr. Azra Raza [01:02:00]: And these are cancer survivors. These are patients with pre-leukemia and leukemia, etcetera.

Ben Greenfield [01:02:07]: Would that also include patients who have done genetic testing and might have genetic predispositions?

Dr. Azra Raza [01:02:13]: Yes, but no, but we are. Sorry, those are people who are at risk. Yes, Ben, but the proposition that the oncology think tank came up with was, yes, we should study those. But those are rare. So the most common group is cancer survivors. Each of these institutions, Harvard, Yale, MD Anderson, Johns Hopkins, University of Chicago, Columbia, Northwestern. We are ready to start banking samples on cancer survivors and filtering their blood, seeing when the first.

Dr. Azra Raza [01:02:49]: When the cancer appears, if a second cancer appears, like Harvey developed a second cancer, will there be the first cell trapped on the filters? Can we look at biomarkers in their plasma, saliva, urine, feces, hair, nails? We are saving everything. So, at Columbia, I started doing this some years ago, and believe me, it is shocking, Ben, how many people are developing second cancers. And we are able to have all these samples ready, but it needs more money to fund all these other centers to accelerate the progress, to catalyze this, to have not do the work in ten years, but in one year, we can't afford to waste so much time.

Ben Greenfield [01:03:32]: Yeah. Yeah. Wow. Well, I'll link to your website in the show notes and everybody, I'm going to hold this book up again because we're nearing the end of the interview here. But we've only scratched the surface of the technologies and the objections and roadblocks that Azra has run into. And a lot of what goes into this idea of going after the first cell. So again, the book is called The First Cell: And the Human Cost of Pursuing Cancer to the Last. The show notes are at bengreenfieldlife.com/firstcell, you can support Azra by going to her website, azraraza.com, and I'll also link to that in the show notes as well as her 3 Quarts Daily, which I'm going to have to check out and maybe add to my feed reader.

Ben Greenfield [01:04:15]: Azra, thank you so much for coming on, for sharing this with us, for writing this book, and for caring as deeply as you do about this.

Dr. Azra Raza [01:04:21]: Thank you for having me.

Ben Greenfield [01:04:23]: All right, folks, I'm Ben Greenfield from bengreenfieldlife.com/firstsell, signing out with Azra Raza. Have an amazing week. Do you want free access?

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