In the United States, more than one in five deaths is caused by cancer. The medical community has put enormous resources into fighting this disease, yet its causes and best treatments continue to be a puzzle. Azra Raza has been on both sides of the patient’s bed, as she puts it — both as an oncologist and expert in the treatment of Myelodisplastic Syndrome (MDS), and as a wife who lost her husband to cancer. In her new book, The First Cell, she argues that we have placed too much emphasis on treating cancer once it has already developed, and not nearly enough on catching it as soon as possible. We talk about what cancer is and why it’s such a difficult disease to understand, as well as discussing how patients and their loved ones should face up to the challenges of dealing with cancer. Support Mindscape on Patreon. Azra Raza received her M.D. from Dow Medical College in Karachi, Pakistan. She is currently Chan Soon-Shiong Professor of Medicine and Director of the MDS Center at Columbia University in New York. Previously she was the Chief of Hematology-Oncology and the Gladys Smith Martin Professor of Oncology at the University of Massachusetts. Her Tissue Repository contains over 60,000 samples of samples from MDS and acute leukemia patients. She is the co-editor of the celebrated blog site 3 Quarks Daily. Web site

Columbia University Medical Center page

First Cell Center

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The First Cell

Conversation With Siddhartha Mukherjee

Twitter Click to Show Episode Transcript Click above to close. 0:00:00 Sean Carroll: Hello everyone, and welcome to the Mindscape Podcast. I’m your host, Sean Carroll. And today we’re talking about a somewhat difficult subject which is cancer, and how we can try to treat, and prevent cancer from taking lives. It’s a difficult subject, of course, because I, and I’m sure many other people in the audience are familiar with people who have passed away because of cancer. The two leading causes of any kind of death in the United States are heart disease and cancer by a wide margin, these two things. And I think, at least, informally, I don’t have any data, and I don’t wanna valorize one way of dying over another, but my informal impression is that cancer is much crueler than heart disease in many ways. It can come on people who are otherwise perfectly healthy. It can appear in people relatively young, I know people in their 40s and 50s who have been diagnosed. And the way that we have of treating it is not very good. It involves a very painful process, a very drawn out long process that often fails, that often, even though we do everything we can, cancer still claims a victim. 0:01:05 SC: So today’s guest on Mindscape is Azra Raza who is the Chan Soon-Shiong Professor of Medicine at Columbia University, she’s an oncologist, she’s been doing cancer research for a long time. She has a new book out called, “The First Cell: The Human Costs of Pursuing Cancer to the Last”. And as I said, we all know people who have died of cancer, Azra’s husband who was also an oncologist was diagnosed with cancer, and it eventually claimed his life. So no matter how much you know, no matter how expert you are in the field, this can come to get you, and there’s really nothing you can do about it. So Azra’s angle is that we should shift a lot of our resources from fighting cancer once it’s already spread through the body, to finding cancer as soon as it appears. That’s the name of the book, “The First Cell”, the first cell in the body that goes cancerous. Of course, many people would agree, many doctors, many oncologists would agree that, that would be great if we could do it, but the argument is that we can do it, there are things that we know that would improve the rates at which we find cancer very, very early, but we’re just not putting in the resources to doing that, that we could. 0:02:16 SC: And one of the wonderful things about Azra’s book, and it’ll come out in the conversation, is that she’s a very warm, human kind of doctor, and there’s a lot of stories in the book about individual people, and their struggles with cancer. And we talk a little bit about the fact that I would have a tough time being an oncologist, talking with people who had cancer all the time. But Azra really appreciates it, thinks it’s a privilege that she gets to help people in this crucial moment in their lives, going one way or another. So it’s a very uplifting conversation despite the gloomy topic, overall. 0:02:52 SC: So this is the last Mindscape Podcast, my last regular one anyway, of 2019. I take a two-week break for the holidays. There may or may not be another holiday message like I did last time. But one way or the other, I wanted to thank everyone who’s been listening, Patreon supporters especially, but really anyone who is listening to Mindscape once or every single week, my thanks goes out to you. It’s amazing to me that I can sit here, and talk, and I can send an email to some brilliant accomplished person somewhere in the world, and say, “Can I talk to you for an hour or two?” And they will say yes, because I have this podcast. I hope you’re enjoying it as much as I am, and I know that I have some really good guests lined up for the schedule next year already. So 2020 is gonna be another great year for Mindscape. Enjoy your holidays, and let’s go. [music] 0:04:00 SC: Okay. Azra Raza, thanks for coming on The Mindscape Podcast. 0:04:03 Azra Raza: Delighted to be here, Sean. 0:04:05 SC: This is, just so everyone out there in Podcast Land knows, we’ve never met before, but we have knowledge of each other over the internet for many years now. You’re part of the collective that makes 3 Quarks Daily, the famous blog site, is that right? 0:04:20 AR: Yes, my younger brother, Abbas Raza, is the editor-in-chief of it. 0:04:25 SC: And what kind of things do you contribute there? 0:04:27 AR: For the last 15 years, I’ve been posting two stories daily, very occasionally one. And one of them is a story related to some kind of scientific news that’s just been released, or a scientific article. But the other is general interest, because I have many other interests, so it could be literature, philosophy, music, art, anything. 0:04:55 SC: Well, that’s what’s great about the website. It really does bring things together in a way that is reminiscent of the Mindscape Podcast here, so that makes you a perfect guest. And also, what makes you perfect guest is you have a book that just came out, is that right? 0:05:09 AR: Yes. 0:05:09 SC: Or is it coming up called “The First Cell” and it’s not about the origin of life, it’s about cancer. And you’re an oncologist, and I thought… I wanna get into what cancer is, how we treat it, and so forth but I can’t help but ask about the very moving personal story that you open the book with. Could you tell the audience about that? 0:05:29 AR: Well, the book is titled “The First Cell”, but equally important is the subtitle of the book which is, “And the Human Costs of Pursuing Cancer to the Last”. So this is a book not about cancer, it is about cancer patients. 0:05:47 SC: Yes. 0:05:48 AR: And the purpose of this book, Sean, is to bring back the patient, front and center, into every discussion we have about cancer, no matter how deeply, and rigorously scientific it is. We have to ask the question at every point: Where does the patient benefit from this or is hurt by it? And so as a result of having this goal in mind, I have told many patient stories as well as patients who are in the treatment with me right now, their stories they have told in their own words. But after I started to write it, I had realized that it would be insincere of me if I did not include my own. 0:06:40 SC: Right. 0:06:41 AR: Because if I’m going into such granularity about people’s suffering and pain, it’s not fair to shield myself. 0:06:50 SC: If you’re asking other people to open up in this way, then yes. 0:06:53 AR: That’s exactly right. And so it has been 18 years now since my husband, Harvey Preisler died. I have never spoken about it to anyone or written about it. But what made me come out and write it and then write in as much detail as possible, because that’s what I was demanding of my other patients and their families. Now, this personal story became like a red line running throughout the book, through every chapter, and then there’s a whole chapter devoted to Harvey. You asked me to tell you something about this personal story I opened the book with. So this is the background on of why I put it there. And then, of course, Harvey was my mentor since I’m 24 years of age, we later got married, he was the head of the cancer center. And in an ironic and cruel twist of fate, he got the very disease he had dedicated his life to cure since he was 15-years-old, cancer, leukemia. 0:08:01 AR: And he suffered inexplicable indignities at the hands of this disease over a course of almost five years. Our daughter was three-years-old when he was diagnosed and eight-years-old when he died. And so in this sort of dizzying, disorienting period, what I experienced needed some distance of time as well, even to verbalize some of those things. So, in a way, the book is a combination of my personal story, but that of the people I take care of, and that of the disease I study. So it’s several books in one I guess. 0:08:48 SC: Yeah, yeah. I also had a very good friend, Michael, who was an oncologist, and was diagnosed with cancer, and eventually died of it. And if nothing else, it reminds us that we really don’t know so much about the disease, the people who know the most are still helpless in the face of it. And there’s something about cancer that is especially cruel how it happens apparently randomly, you can be relatively young, and it takes years. And you can reach a point where there’s not much you can do. 0:09:19 AR: And the greatest cruelty is that it is a silent killer, that it can grow to an advanced stage within your body and you have no inkling about it. In fact, there’s a very, very interesting study that was done some years ago, Sean, where people who have been long-term smokers try to quit many, many times. And when they finally manage to quit and not go back, because they quit, go back, quit, go back. Finally when they manage to quit, an inordinately high number of them end up with lung cancer. 0:09:52 SC: Really? 0:09:53 AR: So, a study was done to show why and it turns, the conclusion was that most likely they could stop only because something internal finally… 0:10:05 SC: Oh, that was a selection effect, right? 0:10:07 AR: So there is something but we tend to ignore it completely, and because it’s at such a subconscious level. So when you say that something very terrible about cancer, very unique about it, is that it is a silent killer. 0:10:23 SC: And just so hopefully many people in the audience have not seen cancer up close or had to deal with it, let’s back up, explain what cancer is. It’s not a simple even thing to explain what it is, there’s many varieties and many manifestations. 0:10:38 AR: To begin with, the very simple thing is that every living cell, which is normal, has a limited number of proliferations or divisions it can undergo. This is known as the Hayflick limit, that after 40 to 45 cell divisions, it will either undergo a process of committing suicide, or be killed by other things, or it will dial down all its activities and enter a state of senescence and be useful no longer. 0:11:08 SC: I mean, by the way, that’s worth a podcast all by itself, that fact. Because amoebas don’t have that property, they can just keep dividing forever. So, we, complicated multi-cellular organisms have built in a lifetime, a suicide mechanism for our own cells. That just fascinates me to no end, but okay, [chuckle] let’s not get too distracted. 0:11:28 AR: And cancer cells overcome this Hayflick limit and become immortalized, that they don’t die. So to me, the definition of a cancer is just that, that a cell which is now capable of infinite number of divisions. And what causes cancer? Really, there are some very specific events that can give rise to it, but most of the time it’s a random event. And probably I would say at least 60% of all cancers happen because of DNA copying errors as the cell is dividing. 0:12:01 SC: And is it correct to say that one thing we do know about cancer is that it involves a change in the DNA, it’s some sort of genetic mutation one way or the other? 0:12:01 AR: Only partly correct, because genetic change is one thing, but in inside the cell itself. But also, control of those a cellular function could come from an external source. However, ultimately, it is the cell gone rogue by itself, running amok. So, in the end, you are right that there has to be a genetic component to every cancer cell. 0:12:01 SC: And is it just, is it merely that it grows without bound or does the size and functionality of the shape of the cell also change? 0:12:57 AR: Probably as a result of the cancerous changes, everything goes haywire really, it serves no useful function anymore and it does change size, shape, form. 0:13:12 SC: When you have, I guess, since I know so little about this, my ignorance is going to show. When you have a tumor for a sort of cancer that is stationary in your body, does that grow because the cells simply keep dividing or because the individual cells puff up or is that a mixture of both? 0:13:30 AR: It’s because cells are dividing and making a big mass around them. I think of cancer as something which tends to evolve like life itself. The same constraints and the same principles that apply to evolution apply to initiation, expansion, growth of a cancer also. So, one cancer cell, let’s say, divides and becomes two. Each time a cell divides, it has to copy its entire DNA which is about three billion base pairs. So on the whole, at each division, a cell will retain three to four new mutations. Now, most of these mutations are passive which means they’re not… 0:14:21 SC: Harmless. 0:14:21 AR: They’re harmless. But some of these, if one of these happen to occur in a vital gene for example which is controlling proliferation or which is responsible for growth control, which are known as tumor suppressor genes, if these mutations happen in one of those vital genes, then the function of the cell is affected. But then let’s say it now overcomes growth control because of this mutation, that is mutation which will be termed as the driver or the founder mutation. So the first cell will have the founder mutation, but each time it divides into two, Sean, that’s the problem. It’s going to pick up new passenger mutations that may not change its proliferative or doubling ability but it can change its metabolism, its response to drugs, its ability to be more aggressive and it’s dividing so much more rapidly than normal cells that it starts making a mass, getting more and more blood supply to self, becomes a hot area because it needs nutrition to help itself. 0:15:33 AR: But the point is that this mass of cells now after like 30 doublings may have nothing or very little in common except the founding mutation with the original cell. So in other words, it’s a constantly, metamorphosing, mutating, transforming, dividing, selectively evolving sort of collection of cells. So what I say is that treating cancer as one disease is like treating Africa as one country. 0:16:05 SC: Yeah. [laughter] 0:16:06 AR: It is… And it’s a moving target because, let’s say I remove a tumor from my lung today to study its sensitivity to 50 drugs and find two drugs which are very effective. By the time I found the two drugs, it’s six weeks later because of all the tests I did. Cancer has moved on, the drug was… The drugs would have worked six weeks ago. And this is one of the reasons that we have not been able to control advanced cancers until now. The outcome for a patient with advanced disease is no different than it was in 1930s. 0:16:41 SC: Is there, is it… If you put into an evolutionary context, a biological context, is there any reason why cancer happens? Is there some purpose served for it biologically? I have this vague feeling that elephants don’t get cancer or something like that, there are different stories about different species having different susceptibilities. Is there a grand theory of all this? 0:17:03 AR: No, short answer is no, that’s… It’s called Peto’s paradox because the idea would be that if the number of mutations increase each time a cell divides then a larger organism should have a higher chance of having cancer, right? Just by that alone. 0:17:25 SC: More cells. 0:17:26 AR: And it’s exactly not true because… And it’s not the opposite either because, for example, mice and humans. Humans should have more cancer, it’s not true. Whales almost never get cancer for a different reason than elephants don’t. We think we know why elephants are not getting cancer because they have 20 copies of a tumor suppressor gene called p53 and that those genes are redundant, so that if one is mutated another one takes its place and another one and so tumor suppressor gene p53 which is known as the guardian of the genome because it’s constantly surveying the genome for mutations and forcing the cell which shows a mutation to commit suicide, if that gene gets mutated and it stops performing its normal guardian function then the cell can become cancerous. But if you have redundant copies of that gene, then the opposite would happen. That is this next copy would kick in even if one is mutated. However, when this was replicated in animal models to produce, to overexpress this gene or to have insert multiple copies of these genes, the results were not so great because you know what happened. The animals, number one, didn’t get cancer but aged dramatically. 0:18:53 SC: Ah, okay. 0:18:53 AR: And died of aging. 0:18:54 SC: Well, I was going to ask ’cause I’ve never heard of the tumor suppressor gene and again, I’m not an expert in this area but it sounds like we should just have lots of tumor suppressor genes but it’s not that simple either. 0:19:04 AR: It’s not that simple. And so, it would be simplistic to think that elephants who are large animals and should be getting lots of cancers don’t get it, it’s all because they have 20 copies of p53. We’d like to think so but probably it’s not true. 0:19:16 SC: Yeah, it’s very tricky. [chuckle] So, aside from the grand biological theories, what about human beings? Cancer is quite common on the scale of things that kill us in the world today. What should a typical American, let’s say… Sorry, let me back up, are the numbers very different from the US to Europe, to Africa, to Asia, etcetera? 0:19:41 AR: Actually, no. 0:19:42 SC: Okay. 0:19:43 AR: The only difference in numbers that appears is because some places keep good statistics, others don’t. So the only numbers we can rely on, unfortunately, are only Western countries and a few countries in Asia and Africa. But, in general, wherever it has been looked at, a few things are very clear. Number one, no age is immune from cancer, so from birth to death, a person can get cancer any time. However, it’s much more common as age advances. 0:20:14 SC: So not just because you’re older, but because the likelihood per year goes up when you’re older. 0:20:19 AR: I actually call it “the MIST of aging” to remember it easily. It’s an acronym, MIST. “M” stands for mutations, so just remember that, by the time you are older, each cell has now gone through multiple mutations, so each cell has more mutations in it. And if you think about this great sand pile game that Per Bak, one of my patients, that I describe in great detail in the book, came up with, was that if you are dropping grains of sand, it forms a little pile. But the sandpile, after you keep dropping the sand, will eventually collapse. The last grain of sand, which caused the pile to collapse, was no different than thousands of grains that came before it, it was the pile that had become unstable. So, it’s not necessarily something a mutation that causes cancer, it could just be that with age, many things are becoming unstable in the body. So, one of them is the number of mutations have increased per cell. A second one is the immune system may be a little more decrepit now. It’s not as efficient in eliminating the abnormal misbehaving cells. 0:21:38 SC: Right. So, immune is “I” in MIST? 0:21:41 AR: Yes. And then the “S” stands for senescence, which we mentioned this briefly earlier, that after the Hayflick limit is reached and cells dial down their activities and enter a quiescence period, in which they are really not performing any more useful function. They’re incapable of dividing anymore, so they’ll never become cancerous, but they have a minimal level of metabolic function going on to stay alive. So now more and more cells are entering senescence with age, and what is happening is they are producing a ton of garbage, and the garbage system in the body is becoming… 0:22:19 SC: I can feel it. [laughter] 0:22:19 AR: You’re too young. The garbage system is now becoming overwhelmed. 0:22:25 SC: Yeah. 0:22:26 AR: And what happens then is that more and more of this toxic material starts collecting and poisons the soil or the microenvironment in which the seed or the cell is living. So the “S”, really, is not just senescence, but the soil, as well, of the body becomes more pro-inflammatory, which means these inflammatory proteins, cytokines, are accumulating and causing normal cells to have less than robust existence, whereas supporting the proliferation and growth of something which is even slightly out of balance but has a selective growth advantage in that setting. So, it’s fitness of the landscape to the seed that’s existing in it. And the last… 0:23:20 SC: So, sorry, just to make that clear, the senescence cells, as you say, they’re not the ones that’re gonna become cancerous, but they make all the cells around them more prone to it, by weakening them in some sense. 0:23:29 AR: Yes, by poisoning the atmosphere in which they are living, poisoning the soil in which they exist, that’s exactly right. And the last thing, “T”, that… You see, one of the problems is that… I’ll give you the example of the bone marrow. In a normal healthy adult, half of the marrow is fat cells and the other half is hematopoietic cells, which means the cells which make blood, which do all the things blood is supposed to do. By the time we are, let’s say, 70 years old, this ratio changes, so that 70% of it is now just empty space, which is filled with fat cells, and only 30% are active cells. So, in this setting, what happens is that every living cell is under the control of signals from other cells, from within itself, from the soil in which it exists, from blood vessels that are coming, from nerve endings that are feeding on to it. 0:24:42 AR: The increase in distance between controlling cells and those that are the targets, the effector and the effector cells, just by increasing that geographic distance, you know, that can also lead to slight change in, for example, a suppressive behavior. If a cell is growing too much, then it would be controlled and it would be told not to, and yet it’s suddenly taking off. So, I do think that with age, the incidence of cancer increases, because you asked me about, “Is it the same all over the world?”, and, “Is it the same disease all over the world?” What we see is… In America, for example, 1.7 million new cancer cases are diagnosed in adults. In children, 14,000. So you see the difference that age makes. 0:25:39 SC: They’re there, but there’s a big difference. Yeah. 0:25:41 AR: Yeah. So, there is a big difference in age and… But as I said, no age is really immune from it. 0:25:49 SC: I mean, all these facts about aging… Tangentially to this conversation, but I’ve had previous conversations with experts on aging and there are people out there who want to stop or reverse aging and this reminds us how hard it is. How many things are going on under the umbrella of what we call, aging. 0:26:08 AR: No, I don’t think… Of course, it’s going to be very hard, like curing cancer is like, you’re going to cure aging basically but one thing we can target is instead of always running after disease and treating disease preventing it. 0:26:25 SC: Right, sure absolutely but… I wanna get there but just to drive it home, how important that is, again, for the folks in the audience who haven’t had to go through this personally, how do we treat cancer in a typical patient these days? Is there a standard way of… We’ve all heard of radiation therapy and chemotherapy and so forth. 0:26:44 AR: Yes. So, the good news is that 68% cancers, we are… That are diagnosed today are cured. But cured with what? The same things we were using like 60-70 years ago. “Slash, Poison, Burns”, surgery, chemotherapy, radiation therapy. The same things. Of course, there are very small pockets of rare cancers for which other things are used. Two of them have targeted therapies, one is chronic myeloid leukemia being treated with the Imatinib which is one gene causing a problem and one magic bullet that targets it. That’s the one cancer that has been really paradigmatic in the sense that it seemed to establish a model that cancer is a disease that is caused by a genetic change, which can be targeted by a drug. 0:27:40 SC: Right. 0:27:40 AR: Successfully. Sadly it turned out that for all other cancers, there’s many, many genetic mutations and no single drug seems to be working. So, basically chemotherapies and indiscriminate killing of normal, as well as abnormal cells and that’s what we are still using. The 32% patients that we are not curing, their outcome today, is as bad as it was 50 years ago. 0:28:09 SC: And so, what should we do? [chuckle] Part of the message of your book is that of course, we don’t have all the answers. You don’t have all the answers either but we do choose to spend our resources trying different things and you have a specific angle you think that we should be pushing towards. 0:28:26 AR: Yes. The angle is of course that of the first cell, that instead of forever chasing and trying to kill the last cell, we have been trying to do that for 50 years. We have done it successfully in a very small number of rare cancers but for the majority of patients who present with the common types of cancers, GI, colorectal, lung, ovarian, kidney cancer, I mean for these types of cancers, we really haven’t made a big striking blow against them in using the same, “Slash, Poison, Burn” approaches. 0:29:09 SC: Let me… I should have asked this earlier, but we speak of cancer being in remission, we typically don’t speak of cancer being cured, right? Can you explain the difference there? 0:29:21 AR: I mean, it’s a technicality where oncologists insists that if someone has been cancer-free for five years at least, then we call them cured. 0:29:29 SC: Okay. 0:29:30 AR: But otherwise, if there is no evidence of even microscopic disease, we only will call it remission. 0:29:35 SC: And that’s because we are never sure whether there’s still a little bit of cancer there? 0:29:40 AR: Yes, that it may recur but after five years, if it recurs the chances are that it’s a new cancer. 0:29:47 SC: Right. Okay, that’s fair. And, is it… If there are genetic components to turning a cell into a cancer cell, is it just one mutation would be enough or do you need a combination of mutations? Because if the latter, then you can imagine that even if you get rid of all the actually cancerous cells, there’s still a bunch of cells left over that are ready to become cancerous ’cause they have all but one of the mutations. 0:30:11 AR: Yes. That’s… The answer is yes, that there is always that danger. So you were talking about… We have a certain amount of resources, how are we going to spend them? I think before we get into it, I want to give you a few statistics. 0:30:27 SC: Sure. 0:30:28 AR: The first is, as I said, our strategy has been since time immemorial to get rid of the cancer somehow. So, we see a disease. 0:30:36 SC: Once it’s already developed… [overlapping conversation] 0:30:36 AR: Once it’s already developed. Yes, we see it we want to get rid of it. And if we get rid of what we can see, then we still assume that microscopic disease may be present. So, we try to kill it with supplemental adjuvant therapies like chemotherapy, radiation therapy. So, we not only remove a woman’s breast, we’ll now give her tons of both of these as well. Overtime we have learnt to use these things better, and that has changed but I wanted to give you some statistics. First of all, patients were diagnosed with early stage disease, 90% can be cured, but those who are advanced with advanced disease, 90% or more… 100% are going to die with the common kinds of cancers, really. 0:31:23 SC: That makes sense, but it’s a dramatic shift. 0:31:26 AR: Yeah. So, we know that early detection is more amenable to treatment. It’s true for every disease. The earlier you detect the better you are able to treat it before you let things go completely out of hand. Now, I started my career, Sean, in 1977 by studying and treating patients with acute myeloid leukemia. Today in 2019, I’m using the exact same combination of two chemotherapy drugs, popularly known as 7+3 to treat acute myeloid leukemia. I was using 7+3 then, I’m using it now. Can you imagine, I see 30 to 40 patients every week for all these years. Can you imagine the same conversation with the same side effects and the same dreadful results over and over? 0:32:18 SC: Honestly, I cannot imagine being an oncologist. [chuckle] I think that you need a sort of strength of will and generosity that would tax me a little bit, but I give you credit for having all those conversations. 0:32:29 AR: Thank you for saying that, but I have the opposite view. You have such exquisite sensitivity, because I listen to your, all your great courses, as well as your podcasts. And I think you have exquisite sensitivity and you would make an excellent doctor. And we all have to do what we have to do in life. 0:32:49 SC: That’s right. 0:32:49 AR: And when a human being needs us, then it is actually an immense privilege, Sean, to be there for someone. 0:32:57 SC: That’s true. 0:32:58 AR: And help them. If we can’t help them live better life, we help them have a better death. We help them at every step of the way. And to me, that is the most sublime form of grace that you can see. The most, the greatest acts that you witness and are seen in the nobility of endurance that is manifested by these patients. 0:33:26 SC: And a corresponding level of frustration that you’re having the same conversation with them about the same treatments 40 years later. 0:33:32 AR: Yes. 0:33:32 SC: And we should be able to do better you think? 0:33:34 AR: I’ll give one example. My daughter Sheherzad’s best friend, Andrew, three years ago, at 22 years of age, got diagnosed because he had pain and tingling in an arm. By the time he reached the emergency room, he was already quadriplegic. The neurosurgeons, when they operated on him, found a 9-cm brain tumor, which they could only partly remove. So every oncologist knew from day zero that this poor boy’s chances of survival are 0.00. Do you know the first thing he said when he woke up, Sean, from the anesthesia? He said was, “Mom, don’t worry. Just call Azra, she’s on the cutting edge. She’s gonna find a cure for me.” 0:34:22 SC: Oh no. 0:34:23 AR: How ashamed I felt. How can I ever look at myself in the manner that this poor boy, I stood by his bedside realizing how badly we have failed Andrew. And the question I ask myself is: How many Andrews will it take? And to address that last point, I wanted to bring you up to date about Andrew that three weeks before he died, which was two years ago now, they brought him a form to sign: Do-Not-Resuscitate. We call it a DNR form. 0:35:01 SC: And how old was he? 0:35:03 AR: Twenty-three now. Diagnosed at 22, he’s 23. How is a 23-year-old supposed to sign his own death certificate? He sent it away, he said, “I’m not signing it.” So they took it away. That night, his father came over to spend the night with him. As soon as his father came, he called the people back to bring this form, signed it, saying, “I could not sign it in front of my mother and sister.” This is the grace I’m talking about that this 23-year-old young man who’s dying is protecting his mother. 0:35:42 SC: Well, we’re all going to die some day, we all know it intellectually, but you can, there’s a certain point you reach as a cancer patient, you know it in a slightly different way, in a more visceral way that it’s coming. And how you react, how you behave says something about who you are. 0:36:00 AR: Definitely. It is my opinion that the kind of lonely courage that this boy and that all the patients that I’m taking care of really show at one point or another in the course of their illness, that’s the kind of courage that needs nations to dedicate monuments to. And you know, some of it is it’s the kind of courage that Harper Lee has defined beautifully. She says, Sean, “Courage is knowing that you are licked before you start, but you start anyway. And you see it through to the end.” 0:36:41 SC: Right. 0:36:42 AR: And that is what Andrew did. From the start, he knew he’s licked, but he went through round upon round of chemo, radiation, more surgery, immune therapy, more chemo, more radiation, more immune therapy, more surgery. He went through everything, and saw it to the very end. And that’s the kind of courage that really is what I’m talking about. After my husband died, we found in his wallet a beautiful saying, a beautiful line that he had written. Something to the effect that, “I know there is no good end for what I’m going through, but I have to do it, because I’m a man and a man is responsible for himself.” 0:37:39 SC: And it’s difficult because we don’t either sort of, narrowly as a medical establishment or broadly as a society, deal very well with how to die, how to help people dying, how to admit that death is coming, and how to face it. There’s individual moments of courage and grace, but there is not… We tend to avoid it. We tend to live in denial. Do you think think that we can change that? Do you think that… How bad is it or is it better than I think it is? 0:38:14 AR: First, I want to quote Emily Dickinson. Beautiful, beautiful writer. “I measure every grief I meet with analytic eyes. I wonder if it weighs like mine or has a different size. I wonder if they bore it long or did it just begin? I cannot find the date of mine. It’s been so long a pain. I wonder if it hurts to live and if they have to try and whether could they choose between, they would not rather die.” You see death is not an option, death is not a choice. As you say, death is coming for all of us, but for those individuals who start hearing the footsteps of death approaching, what goes through their minds is impossible for us to imagine unless we are in those shoes. So, I think it is impossible for us to switch places easily. However, one of the main reasons to write the book for me was exactly what you said that I’m getting tired of everyone only promoting the positive anecdote as if dying is a failure. Dying is not a failure, denying death is a failure. And the main difference between humans and Greek gods is that we accept mortality in the final analysis. Look at Andrew, at 23 he accepted mortality and is trying to protect the living, because he knows he is dying but he’s trying to shield his mother and his sister. That is the sublime grace of humanity and that is what makes my life of privilege to live. 0:40:19 AR: Instead of people feeling sorry that I have to take care of dying patients, they should be envious that I get to see humanity in its noblest of forms. Basically it boils down to are we prolonging life or prolonging death by the current techniques? That’s the question I’m asking in the book. That if the 68% patients we are curing today with cancer, why are we curing them with paleolithic treatments that belong in the Stone Age? Why are we still using chemotherapy for God’s sake? It’s like taking a baseball bat to a dog to get rid of its flees. It’s so horrifying, the toxic effects. And the 32% patients who present with advanced disease, who we know we are not benefiting, we are being bringing drugs to their bedside which have a failure rate of 95%. And the 5% that are FDA approved and are ostensibly great successes, they should have failed because they are only prolonging survival by a few months for a small minority. So if 100 patients are given this Drug X, 20%-30% will respond for a few months, 70%-80% will never respond and suffer all the toxic side effects, 100% will suffer physical toxicity of the drug and financial toxicity. Do you know, Sean, that today in America, 42% individuals who are diagnosed with cancer, 42% become financially ruined by two plus years. 0:42:13 SC: I was gonna ask about that. I do know that and that’s an astonishing number. 0:42:17 AR: It is untenable. It is unsupportable. It is unconscionable. 0:42:22 SC: It’ll be one thing if, “And then, they live happily ever after.” 0:42:25 AR: Yes, they’re not even living. So why are we bringing drugs to the market or to the bedside which are benefiting a small fraction of patients for a few days and hurting everybody and ruining 42%, not just themselves, their next generation to come. So, the question is what should we do then? We have present patients to worry about, and then what are our plans for the future? Either we can keep doing the same thing, and there is some benefit to hanging on to your ideas for ever, but sometimes giving up bad ideas can also help. Okay, we have milked the most out of chemo and radiation. Even for the 68% we are curing, there should be better solutions in my opinion. We don’t have to torture people. And for this 32%, we shouldn’t be saying, “Either you die of cancer or you die of the drugs we give you and also be financially ruined.” But we have a limited number of resources. How are we going to spend it? 0:43:26 SC: Actually, let me interrupt you just there, because I don’t want to let this terrible fact about financial ruin and the grim mortality rates go by without wondering about the causality just a little bit. Let me just put this on the table. Are some people or groups benefiting financially from the current regime? Do they have a vested interest in keeping it like this? 0:43:49 AR: My answer is not some people but everyone is benefiting except the cancer patient. Why do I say this? I think it’s very easy for the public to imagine the worst possible things about the evil pharmaceutical companies, but I ask you this question. If you go to the corner drug store and buy a packet of 100 Band-Aids, it’ll cost you $3.99 or something. If you go to a hospital and they put a Band-Aid on you, one Band-Aid will cost $75. So where’s the drug company in this equation? 0:44:24 AR: And what about all the extra imaging or extra scanning people are getting? And what about all the therapies that oncologists are giving to patients who they know will not be benefited, 80% chance is they will not be benefit… Why aren’t we holding them responsible? The question is, I’m one of them. Every criticism applies to me as much as it does to any other oncologist. Why am I doing it? When I know 7+3 is so bad, why am I giving it? Because otherwise I’ll go to jail, because a group of key opinion leaders in the field have reviewed all the data and come up with guidelines and it’s a good thing to try to make something more uniform, try to bring some method to the madness so that, let’s say, if a pancreatic cancer patient is diagnosed with stage four disease, these three drugs will be used in first-line treatment, then these three in second line, these two in third line treatment, that is the guideline. 0:45:26 AR: If I deviate from doing that, then I’m opening myself to legal challenges. So I’m also giving those drugs knowing full well that it will only hurt 80% of the people, practically 100% in the end for a benefit of a few… The other thing is we tell everything to the patient, it’s not like we are doing it without signed consent forms and they are the ones choosing it also because life is so precious and dying is so scary that most of my patients will tell me even if there’s a one in a million chance, what do I have to lose? Let me sign up for it and do it. So it’s a very strange kind of system where everyone is to be blamed but no one can actually assume the blame. So where does individual responsibility end and society’s responsibility begin? These are the fundamental questions I’m raising in the book. 0:46:23 SC: And it is fundamentally difficult. If you’re told there’s a 1% chance of survival, a 99% chance that you will die and your family will be financially ruined, saying, “No, I’m not even gonna try to take that 1%,” is difficult. Or more, in terms of policy saying, well we should spend less because most of what we’re spending is being wasted, people are going to worry that if you’re spending less, you’re not doing as good a job and it’s honestly hard to balance these. 0:46:55 AR: So here’s the thing, I’m saying that if 95% of the drugs we bring to the bedside are failing, the first question is why are they failing? Because whatever we did to bring them to the bedside is a failing model. What is that failing platform where we are even developing these drugs to bring to the bedside? Mostly in animals, or in in-vitro petri dishes or in extremely artificial conditions that we keep insisting will be extrapolated to humans. Well, over and over, it’s been shown that doesn’t happen. So there’s a time to simply take off the blinders and admit the truth. Cancer is too complicated for us to understand every intracellular signaling pathway, and then try to fix it because it keeps… It has moved on also. 0:47:46 SC: I know you have strong opinions about studies being done on mice. 0:47:49 AR: Very strong opinions. [chuckle] 0:47:52 SC: And mice are the model organism in which we test our ideas about cancer, right? 0:47:58 AR: So I don’t want to be misquoted here, I’ll make myself very clear because very often I am misquoted and then I get hate mail for months, years. 0:48:10 SC: Not from my listeners, they’re all very sweet. 0:48:11 AR: I hope not. [chuckle] The main point I want to make is this, animal models are excellent biologic tools where we can test a large number of very intricate questions about all sorts of biologic phenomenon. There’s no question about it, or most of the advances have occurred even in cancer, because of studying animals. The only thing I object to which I try to be as specific as possible, and I’m glad you’re giving me this chance to explain my point of view accurately. The only thing I object to is you can’t create a tumor in an animal treated with some drug and think now when you use the same drug in the human tumor, it’s going to have the same results. So for drug development, animal models have not been helpful. This is the point. 0:49:08 SC: But they’re used all the time? 0:49:10 AR: But they are used in these pre-clinical testing platform. In fact, you can’t bring a drug to the market unless you have tested it in a mice. And my question is, why is that giving the FDA any level of confidence that if we don’t see toxicity in mice, we won’t see toxicity in humans or if we see efficacy in mice, we’ll see efficacy in humans because the actual evidence is contrary to that, that there is no possibility of this flip-flop exchange of information from one species to another, yet we keep doing it. 0:49:47 SC: Do you know about the Twitter account called “In Mice”? It takes headlines. [chuckle] You know, “Study shows eating ice cream cures heart disease”, and then it just re-tweets it with the words “in mice” added. 0:50:01 AR: I love that. [laughter] Yes. So I got tired of the promotion of this anecdotal person who has had remission for four years on this drug that had failed in everybody. The question I asked is that, yes, it’s true that there are unicorns who have superb inexplicable responses even to targeted therapies that have failed in every other patient and we don’t have an explanation of why they are responding so well. But we keep taking that as the anecdote that we’ll count over and over to say, “Well that could happen?” The question I’m asking is, at the expense of what? At the expense of 99 out of 100 patients suffering unbearable toxicities. And medicine’s one rule that we begin with is, first do no harm. So how can we justify ourselves in an enterprise where 95% drugs are going to just harm and the 5% that we think won’t harm will still harm the majority of patients? So instead of constantly trying to improve the typewriter, we have to invent something like the word processor to make that obsolete. In order to make the paradigm shift to a better one, we need to show a better way. Because no one is going to willingly give up what they’re doing. 0:51:32 SC: And there is sort of a naive logic about testing things on mice in the sense that if it goes terribly wrong and the mouse dies, it’s not as bad as it happening to a human being, but I think that you have this idea that we can test things on human cells or human tissues without testing them on human beings and maybe that’s a better way to go. 0:51:54 AR: Yes, that’s exactly well said. You should be giving this podcast because you are so eloquent. 0:52:00 SC: It’s a conversation. [laughter] 0:52:02 AR: No, I think that’s exactly right that yes, there are some things we can’t do in humans that we can do in animals, but we don’t have to do them. There are the things that we can do that we haven’t even interrogated yet. 0:52:15 SC: So how do we do that, how do we test things out on human tissues or cells without the whole human? 0:52:21 AR: I think it was in 1940s I think that somebody said the best model for a cat is another cat preferably the same one. 0:52:38 SC: The same cat. 0:52:38 AR: Yes. 0:52:39 SC: They are different, yes. 0:52:40 AR: Yeah. So in other words, what we need is we need to test individual humans for their disease, and if we want to diagnose, we know that the only thing that works in cancer is not… In fact 1903, Dr. [0:52:56] ____ in England set this, it’s not the cancer that kills, but the delay in treatment that kills. So if we know that the earlier we detect cancer, the higher the chances of cure, why not try and develop better techniques to detect cancer early? Well, this is not a new idea. Screening measures for cancer were put into place 50 years ago. Screening how? By mammography, by colonoscopy, by pap smear and by PSA measurements, these are the four most common screening measures used. And mortality from cancer has dropped by 26% in the last 30 years not because we invented some new magic bullet, but because… 0:53:44 SC: Not ’cause we’re curing it. 0:53:45 AR: No. Because of two things: One, anti-smoking campaigns and two, screening measures. Even with these four old screening measures we have brought down the mortality. But these have been milked dry now, this is the maximum benefit we will get. The present rate for cancer mortality is only declining by 1% a year, and only that is happening again, not because of new drugs coming on market, but learning to use existing chemotherapy, radiation therapy, better and diagnosing cancer earlier and earlier, through more sophisticated imaging, scanning et cetera, techniques. So what my point in the book is simply we’ve done enough by trying to chase the last cell. We have used artificial testing platforms, clinical drug development platforms, these have been spectacular failures. 0:54:45 SC: And by the last cell we mean the most recent cancer cell in this cancerous growth rather than the first one that appeared. 0:54:52 AR: The last cell means that after you have given all the treatment you still think some residual disease may be left behind. And that is the last cell I’m talking about. So we keep trying to develop sophisticated techniques to molecularly identify the last cell. I’m saying, why not go not for minimal residual disease, but develop techniques to determine minimal initial disease and diagnose it cancer early in fact, and try to prevent it. So instead of using the standard screening measures I described, why not in this day and age of God-like technology, cutting and pasting the DNA, why not develop technologies like you go to sleep in bed sheets that scan you overnight for the presence of a hot spot. ‘Cause remember I told you, a cancer when it begins divides faster than normal cells, so it needs more nutrition, it attracts more blood supply, area becomes hot, it can be picked up by scanning techniques. 0:55:52 SC: So the phrase “hot spot” is not metaphorical, it’s literally hotter… 0:55:54 AR: Hot, literally hot. 0:55:55 SC: A part of your body that is higher than average temperature. 0:55:58 AR: Yes. For example, a smart bra is now in clinical trials which is fitted with 200 nano sensors that detect changes in temperature and circadian rhythm. So the point is, or you can sit in on something, on the toilet in the morning, it’s called the Fit Loo, it takes part of your urine and examines it for the presence of biomarkers of malignancy that are being… Metabolites that may be secreted. Or you can do a liquid biopsy. If somebody has colon cancer, as soon as cancer cells begin and start proliferating, they start shedding their DNA into the blood. You know where it started actually? It started with mother-child placental bridge, because it turns out that since developmental abnormalities in an embryo increase with increasing maternal age. So an older women becoming pregnant, has a higher chance of having an abnormal, developmentally abnormal baby. In order to diagnose those kinds of syndromes like Down syndromes, etcetera, we used to put a long needle into the uterus of the mother, draw amniotic fluid and look at it. I underwent this amniocentesis when I was pregnant, because I was 40 years old when I was pregnant. But then this was discovered that the fetus is shedding its DNA into maternal blood. 0:57:33 AR: So, cell-free fetal DNA, cffDNA, is now the standard routine thing. All we need is a few drops of the mother’s blood now, and we have the health of the fetus reflected in those few drops of blood, or few CCs of blood. The same techniques have been applied to cancer. When cancer starts, it also sheds off cell-free DNA, cfDNA, into the blood, and so you get the… 0:58:00 SC: Oh, okay. I did not know that. And this the mutated DNA that is, [0:58:04] ____ cancer. 0:58:04 AR: That you can pick up. And just two weeks ago, it was announced by the company GRAIL, which is really going after early detection of cancer, they announced that not only can they detect cell-free DNA reliably, 99% of the time, they can also say which organ it’s coming from. So is it coming from pancreas, is it coming from the liver, is it coming from the lungs, based on the kind of mutations. 0:58:33 AR: So, this is the beauty of very different disciplines of knowledge coming together, in a consilience of cross-disciplines, to yield this kind of information. Because the human genome was sequenced 20 years ago, practically, but now we are seeing the dividends of it, because we know what the normal DNA should look like, we can pick up a mutation, we can now detect… I mean, think about it, 20 years ago, it took 15 years [chuckle] and $2.7 billion to do the first human genome sequencing. Today, it costs a few thousand dollars and three weeks of sequencing. 0:59:12 AR: So, we’ve become efficient very quickly, and I think that if we start paying more attention to these new types of techniques, we need to develop strategies to detect cancer’s footprints. In any secretion, for example, blood, sweat, tears, urine, stool, you can do… You can find biologic markers of DNA. For example, some cancers which are beginning, let’s say your bed sheets detected a spot in my head of pancreas one night. The next morning, it isn’t necessary for me to have an open abdominal procedure, and a Whipple’s procedure and eviscerate my whole belly. No, what it means is, first I should be monitored and then taken for maybe even more sophisticated, focused scanning measures, to make sure that this thing is growing, it’s a real presence. If it is confirmed it’s a real presence, one thing we can do is do a liquid biopsy, see if it’s shedding anything in the blood, in the urine, in the tears, in saliva. If we don’t find it, then we can still do another thing, we can yell at that spot. How do we yell? Using ultrasounds. We hit it with ultrasound, when ultrasounds hit this little mass, it wiggles, it shakes, and they shed off more protein, so you hit it… 1:00:36 SC: It becomes easier to detect. 1:00:37 AR: It yells back, and then you just do another test of these liquid biopsies from various places and now see if you’re detecting it. And once you detect it, then you really confirm its potential lethality, because it may not necessarily be very aggressive, it may not need to be removed right away, it may not kill someone who’s 80 years for another 30 years, so there’s no need to go in. So all these markers of initial malignancy, its potential lethality, its ability to become invasive and aggressive, those are all pieces of information that can actually be investigated with the current sophisticated technology. So my point is, we have present patients, and we have future patients. We should divide up resources into half and half. Half we should be dedicating to the present patients, half to developing better technologies to prevent and to detect early, and prevent the disease from becoming its end-stage monstrosity. 1:01:41 SC: Whereas right now, it’s not fifty-fifty. 1:01:43 AR: No, it’s five and 95, right now. 1:01:45 SC: Five percent for future patients. 1:01:46 AR: For future… For early detection. And, for present patients, what we need to do also, Sean, which I feel very strongly about, is we have to stop hurting them. I mean, that is something we need to stop giving everybody. And the most obvious thing to do is try and identify which patients are likely to respond to which drugs. How do you do that? Well, any time a sponsor wants to propose a clinical trial, an experimental trial, they should be made to save every sample from every patient going on that first trial. And then, you’ll have some patients who respond, some who don’t. Now, you compare the responders and non-responders, using every technique you have available. Genomics, proteomics, transcriptomics, metabolomics, panomics. Test by every way and try to enrich the next trial for patients who are likely to respond, and so on, and so forth. Today, the clinical trials are done the same way they were being done in 1977. [chuckle] And it is horrifying to me that the agencies which have been charged with protecting patients and demanding this kind of rigor, are not doing it. 1:03:09 SC: I think that the… This sounds very provocative, and promising, and so forth. The idea though it is, the scientific idea, that I get from it, that is most exciting to me, is the idea of the footprints of the cancer. I mean, the wearing a blanket and finding a hot spot sounds interesting, but that’s literally looking for the tumor in your body, whereas the sort of indirect idea that once there’s a tumor in your body it leaves traces, either from DNA and, correct me if I’m wrong, from reading your book, but you can find tracers of the fact that your immune system is beginning to fight it, also in your blood. Is that another way of doing it? 1:03:46 AR: Yes, definitely. In fact, the best way that would emerge eventually is a collection of all of this technology which is imaging and scanning and devices and biomarkers and genetic markers. All these put together and all being read by something no bigger than your cellphone and all the information available on this, but then even implantable devices. I’m working with biomedical engineers at Columbia University on a chip that we want to implant under the skin from birth to death which constantly should be monitoring. The idea is that even the screening techniques we used so far brought down the mortality considerably, but it’s not happening anymore because they have reached their limit. But those were done annually at best. We want to treat the human body as if it is a machine and constantly monitor it for even the appearance of perturbations and disease-caused networks. And you see that and you step in and try to intervene. So many of the same drugs which are failing today can be applied in earlier stages of the disease and may be far more effective. And this has been shown as a paradigm in chronic myeloid leukemia, the disease I mentioned to you for which a targeted therapy is the ideal for every cancer. Well, in that cancer itself, as long as it is chronic myeloid leukemia, that drug is all, is curative. But if the disease starts to accelerate, becomes acute leukemia, the same drug is useless. So earlier stages, the same drugs can work. 1:05:27 SC: Well, that’s what I wanted to pinpoint also. It seems obviously true that if you can find the disease earlier you have a better chance of curing it. But how far can we go in saying that? If we find it very, very early, does our chances of curing the disease go very, very high or does it increase by 10%? 1:05:52 AR: My answer is it will be 100% more curable. Why? Because of all the statistics that are available. The earlier you find cancer the better you’re able to cure it, but the issue is how quickly are we able to do it? And then, technologies will also evolve for treatment of early disease, so if you diagnose… 1:06:14 SC: Is this a different kind of thing to try to do than cure the late disease? 1:06:15 AR: Yeah, totally different. Yes, so let’s say you have a million cells to kill rather than 150 billion cells to kill, there’s a big difference. So, I think, for example, if you needed radiation therapy to kill 100 billion cells, you may need just a targeted laser to knock off a few million cells quite confidently or you can use immune cellular therapies that if we have a biomarker, we can arm the killer cells of the immune system with it, and it will be able to distinguish then between the cancer and the normal cells. The current cellular therapies we are using are unable to distinguish between cancer cells and normal cells. That’s why the toxicities of CAR T therapy, because it will kill every cell that is expressing that marker which means normal cells as well as cancer cells. I’m saying that once we have biomarkers specific for cancer cells, we may have an address for the cancer cell also, that is more usable by the same techniques which are causing so much toxicity. 1:07:26 SC: And it sounds like this is great, because it’s not just an aspiration, it’s not just a sort of feel good motto that if we found the cancer earlier we could help cure it quicker, more effectively, but that there are very concrete steps being taken. How popular is this view in the community? Is this a plucky minority or is it catching on as this is what we should be concentrating on? 1:07:51 AR: All of these things I described to you are in various stages of development. So everyone has known for 50 years that the best strategy is to go early, and people have spent a lot of time in screening and trying to make those as accurate as possible. In the last 10-15 years, people have started developing all this new technology based on the evolving genomic information and proteomics, etcetera, that’s becoming available. So, clearly, those things are all in various stages of development. It’s not a pie in the sky, but the more resources we need, the more people will get interested. And young minds who are today wasting their time and talent and intellect on failing models, because they are working with mentors who for 30 years have used those failing models, and they’re the ones sitting in every granting agency deciding who gets the grant and who gets to scratch who’s back. This all has to stop and young minds and young intellect as well as resources should be better used, I think. 1:09:00 AR: And new technology, new ideas, new therapies will bring their own set of problems. So, I’m not someone who’s going to say, “Oh, all our problems will be resolved,” because I’m an old hag. I’ve been there, done that in all kinds of things. But I do think that it is time to recognize at least where we are failing, time to take off our blinders, time to at least describe the problem in its detail and see the problem for what it is. Right now, we are not even willing to see the problem. It’s not that we are just not finding the solution. We refuse to look at the details of what we are doing wrong. My insistence is to look at all of this through the prism of human anguish, because this is not just some cut-and-dried science. This involves humans. This involves the 22-year-old Andrew, or a 38-year-old Umar, or my patient, JC, who died at 34, or Harvey who was diagnosed with his first cancer and then at 34 and his second cancer at 57. 1:10:08 AR: And this is one thing I want to also recount to you, Sean, that my life has been committed to early detection since 1984. Do you know why? Because I started by studying acute myeloid leukemia and treating patients with it. Within a short space of seven years, it became clear to me that in my lifetime, this disease is so aggressive, we will not be able to cure it. And I was right, unfortunately, we were using 7+3 then, we are using 7+3 now. In 1984, because of a patient, JC, I realized that the best way to handle acute myeloid leukemia is to stop the disease before it becomes so aggressive. Are there patients like that? Yes, it’s a whole series of syndromes called myelodysplastic syndromes, which are pre-leukemic, because a third of these patients can develop acute myeloid leukemia. My idea was well, then we should study pre-leukemia, and follow these patients through. And had I gone to school in this country, at this point, I would have invested the rest of my life into making a mouse model of this pre-leukemia. [chuckle] 1:11:21 AR: But coming from Pakistan as a fresh immigrant, I trusted my instinct rather than followed custom. And I decided, “Oh, I’m going to study these patients, let me save their samples.” So I just started banking blood, bone marrow aspirate, biopsies, normal buccal smears, germ line controls on all my patients, and… 1:11:43 SC: So by saving them, you don’t mean saving the data, you mean literally saving the tissues, the cells? 1:11:47 AR: Both. No, I mean both the data as well as the actual samples. It’s the most well annotated tissue repository, which today has more than 60,000 samples from thousands of patients. And not one cell has come from a different doctor. Every patient is my patient. 1:12:07 SC: Do you want other doctors to contribute to this? Is there an ongoing… 1:12:10 AR: It’s very expensive. They can’t afford to do it. 1:12:11 SC: Oh, okay, so it’s a choice. 1:12:12 AR: I’m the only one who does it, because I pay for it. And how do I pay for it? No grant can support it. My patients support it for me. I asked them and they want to give me money, and I say, “No, I don’t want personal money, give it to the tissue repository,” because it costs almost a million dollars a year just to maintain the tissue repository. So point is that I have these samples, which were obtained in a longitudinal fashion serially on these thousands of patients as they progress from pre-leukemia to acute leukemia. Now, if we go in and study these samples and work our way back, we can at the end go and ask the question: Why did this, a healthy individual, even get pre-leukemia? Was there a genetic mutation that made them susceptible or at high risk for it? 1:13:06 AR: What was it about their exposome, environment, exposure? What was there about their background, their inherited DNA? And so those kinds of questions we can then take to the DNA sequences that are in the public domain from hundreds of thousands of healthy volunteers, and find out how many people fit our bill for being at high risk of developing even pre-leukemia. And then following those healthy individuals to find whether they develop it or not, and how quickly can we stop it there? This is the kind of thing we need to do. The problem is, so it took me so long to amass the samples. Even today, I’m doing five to 10 bone marrows every week in my clinic. With my own hands, I do the bone marrows and banking them. So I have all this tissue, the technology has got up. We need resources. Who’s going to give the resources? The government can’t afford it, because I need $100 million to study the whole repository. It isn’t as if I haven’t been studying it, Sean. 1:14:12 SC: Of course. 1:14:13 AR: Over the last 30 years, I have over 300 original publications, which are reporting on the results we find from limited samples we take out, study it for one gene, or that signaling pathway, or this drug, or that kind of thing with limited questions. Clearly now that all the technology has arrived and we need to go in and study the entire tissue repository, that is a thing that no one can… No government grant can support $100 million to one individual. And I don’t need the money to set up a building with 70 scientists working in it. No, this is money that’s needed to pay for the actual tests for the samples, to do the proteomics on 200 patients, it costs $4 million. This is the kind of… That’s where the money will go. So the other idea that occurred to me was… 1:15:11 SC: If there are any Mindscape listeners out there who would like to donate $100 million to… [chuckle] 1:15:16 SC: The tissue repository, we’ll encourage them to do that. Can you just, I’d like to try to give the audience a sort of visceral feel for what it’s like to be doing this kind of work. Number one, let me just mention this kind of longitudinal study is the gold standard in sciences, social sciences especially, and really hard and expensive to do, because you have to start young and continue to be dedicated and get the resources. But where is it? Where are these tissues? Are they in a room somewhere? Are they kept cold or do they still duplicate the cells, or is there a finite number of cells that we use up? 1:15:55 AR: So the entire tissue repository is housed at Columbia University, The Cancer Center. It moved with me from Buffalo to Cincinnati to Chicago to Massachusetts to New York now. 1:16:08 SC: It’s been around. 1:16:09 AR: And it has, since 1984, it’s travelled with me. And these are samples which are in freezers, but in addition, we have frozen viable tissue also which can be brought out and regrown in plates, in animals, in vitro, in vivo. So it’s an immense collection of samples. Everything belongs to Columbia University. I don’t have any companies to my name. I don’t need any personal money. This is all going to go through Columbia University. So one thing that occurred to me, Sean, is that the people who should be most interested in finding the first cell are the people who are at highest risk of getting cancer. Who are those people? They are people like Harvey, my late husband, people who have one cancer. Now, I don’t want to scare your listeners at all, but I do want to say that one in five new cancers is diagnosed in a cancer survivor because whatever was there to cause the first cancer is still there. 1:17:17 SC: The conditions are still there. 1:17:18 AR: Conditions are there and probably with our treatment for some of them we’ve made the conditions worse because Harvey did not die of his cancer, he died because we wiped out his immune system with the horrible chemotherapy we gave him. So the point is, the people at highest risk should be the most interested. Today, in this country, there are 20 million survivors from cancer. Even if one million of them just give $10 a month for a year, that’s it, that will fund the whole tissue repository. 1:17:49 AR: People ask me, “Dr. Raza, Why should we give you money and not to the American Cancer Society?” My answer is, where’s the tissue for American Cancer Society? Talk is cheap, Sean, but I’m the one who has the tissue, I’m the one who has the commitment to early detection because I’ve been going after not just acute leukemia but pre-leukemia. Since 1984, I have been saying the same thing since 1984. How much more credibility can I give? People are very quick to start criticizing me, “Oh, she’s talking about the first cell, she doesn’t know how much screening measures have fail… ” I know, nobody needs to lecture me about these things because not only do I see 30-40 cancer patients every week, I have had a cutting edge research lab for 35-plus years and I’m a cancer widow. 1:18:44 AR: So I have stood on both sides of the bed of a cancer patient, as well as a family member, as well as an oncologist. So, there is really very little that I have not experienced directly and first-hand, and I have been consistently committed to finding cancer at its earliest possible cell and try to take care of it to prevent the disease from happening. And if people don’t trust me by now, and don’t want to support this tissue repository, then I don’t know who will? All I can say is as long as there is one breath left in my body, I will keep saying the same thing and trying to work as hard as ever for my patients. 1:19:28 SC: I can’t think of a better place to end up than that. That was very eloquently said. Dr. Azra Raza, thanks so much for being on the Mindscape Podcast. 1:19:35 AR: Thank you, Sean, it has been an honor being on your podcast. [music]