Proactive cancer treatments – why are we targeting the last, instead of the first cell? with Dr. Azra Raza

56 minutes minute reading time
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Episode summary

Conversation timestamps

About the guest

Azra Raza

Dr Azra Raza is a highly accomplished Professor of Medicine and Director of the MDS Centre at Columbia University in New York. With a career spanning over three decades, she began her research in Myelodysplastic Syndromes (MDS) in 1982 and went on to hold prominent positions at Rush University, where she served as the Charles Arthur Weaver Professor in Oncology and Director of the Division of Myeloid Diseases, and at the University of Massachusetts, where she was the Chief of Haematology Oncology and the Gladys Smith Martin Professor of Oncology. Dr Raza's research and clinical trials have been published in prestigious peer-reviewed journals such as The New England Journal of Medicine, Nature, Blood, Cancer, Cancer Research, and many others. She is a highly sought-after consultant and reviewer and has served on numerous national and international panels. Her numerous accolades include a Lifetime Achievement Award from APPNA, two Awards in Academic Excellence from Dogana, the Woman of the Year Award from Safeer e Pakistan, CA, and The Hope Award in Cancer Research 2012, which she received alongside Nobel Laureate Dr Elizabeth Blackburn In her best-selling book, The First Cell - And the Human Costs of Pursuing Cancer to the Last, Dr Raza offers a thought-provoking critique of the medical, scientific, societal, personal, and cultural treatment of cancer. She argues that pursuing the first cancer cell rather than killing the last is the future of cancer treatment.

Articles, books, and other media discussed in the show

Azra’s Website
Twitter: @AzraRazaMD
Who wants to live forever? | The Express Tribune (2022)
Cancer Is Still Beating Us—We Need a New Start | The Wall Street Journal (2019)

Azra’s Book:
The First Cell - And the Human Costs of Pursuing Cancer to the Last

Recent Research:
Mutation in SF3B1 gene promotes formation of polyploid giant cells in Leukemia cells | Springer (2022)
Subversion of Serotonin Receptor Signaling in Osteoblasts by Kynurenine Drives Acute Myeloid Leukemia | Cancer Discov. (2022)
SF3B1 mutant-induced missplicing of MAP3K7 causes anemia in myelodysplastic syndromes | Proc Natl Acad Sci U S A (2022)
Opinion Paper by the Oncology Think Tank – We Must Find Ways to Detect Cancer Much Earlier | Scientific American (2021)
Survey and evaluation of mutations in the human KLF1 transcription unit | Sci Rep (2018)
Severely impaired terminal erythroid differentiation as an independent prognostic marker in myelodysplastic syndromes | Blood Adv (2018)
Clinical effect of point mutations in myelodysplastic syndromes | N Engl J Med (2011)

Conversation highlights

Episode transcript

Rina’s Intro

Rina Bogdanovic [00:19] Hello, hello, and welcome back to The Age of you podcast - A Sweet Secret to Longevity. My name is Rina, and I am your host. We are quite used to hearing news stories and reading articles about novel cancer therapies which are showing great promise. And frankly, this makes it very easy to believe that the cure for cancer must be just around the corner. Sadly, this is far from the reality with most of the newly approved drugs prolonging life expectancy by a few months at best. My guest today has been insisting for over three decades that the best chance we have of beating cancer is by catching it early. I first had the pleasure of getting to know her through her book, The First Cell. Having dedicated her entire career to researching and treating cancer, as well as losing her husband from the very same disease, she was able to explore this disease from every possible angle. She has spent the last 35 years collecting samples from patients with myelodysplastic syndromes, or MDS, at risk of developing leukaemia. In an effort to catch the first cell. As a result, she has created one of the oldest and largest tissue repositories collected by a single physician. She is a Professor of Medicine and the Director of the MDS Institute at Columbia University in New York. A warm welcome to Professor Azra Raza.

The interview begins

Rina Bogdanovic [02:13] Hello, and thank you very much for making time to join our podcast today. You have dedicated your career to studying myelodysplastic syndromes or MDS from both an academic perspective as a scientist and a clinical perspective, as a practising oncologist. In your book, The First Cell, which I have right here. You are very critical of the current state of cancer research, as well as the way these findings are being translated into clinical application. So, I'm interested in what was it that convinced you that MDS was worth investing decades of resources, energy, funding into ,what was it about MDs that was special?

Azra Raza [03:01] Well thank you, first of all, for having me on this incredible podcast and all the work you're doing congratulations. I'd like to begin by answering your question and say, If I had 72 more lives, I would do 72 times the same thing with MDS. I hope that convinces you of my passion. And the reason is actually very simple. As a teenager, I got fascinated by the idea of cancer intellectually because I realised two things. One is that within our body, we give birth to a cell that can live forever. No other life form on this world has accomplished that feat. And I thought if we can unlock the secret of cancer, we can unlock the secret of ageing we could become immortal ourselves. And second, the body is supposed to be like a nation, a state, and the cells are its citizens. And they are supposed to follow rules, like liver cells have to stay within the liver, ovarian cells in the ovary, pancreatic cells in the pancreas, only in cancer they walk out. In no other disease can cells walk out of the organs. This intellectual fascination led me to medical school because that was the only way into science and then in med school I saw patients and that combined my passion with intellect. From the moment I saw my first cancer patient, I knew that the rest of my life has to be dedicated to reducing their suffering. That's how I began. I come to America I start studying acute myeloid leukaemia and treating patients with it. And very quickly, it was apparent that in my lifetime, this disease won't be cured. So, I realised I should study the only thing that works in cancer treatment which is early detection. So how early can you go? I said I want to go to the first cell. I want to not study acute leukaemia but people who are at risk of leukaemia. Who are they? MDS! MDS stands for myelodysplastic syndromes. It is a pre-leukemic condition, a third of the patients march towards leukaemia That was my idea and I think it was a good idea 35 years ago, I think it's a good idea today. We should be studying people at risk of cancer to identify what are those phase transition factors that account for a cell going from pre leukaemia to becoming leukaemia, precancerous to cancerous, and that's how then we can go to healthy individuals and try to prevent cancer. That's the whole idea of MDS. And yes, it's been worth every penny, and every grey cell in my brain to work on this.

Azra’s First Patient

Rina Bogdanovic [05:56] You mentioned that from the first cancer patient you worked with you were convinced that working with cancer was the right path for you. I'm curious, what type of cancer did that first patient have?

Azra Raza [06:09] Amazing that you asked, it was a bone marrow cancer. It turned out to be a case of myelofibrosis, a 30 something, 32 or 35, year old woman who had travelled from one of the North-west Frontier Provinces in the north of Pakistan, all the way to Karachi, which was the largest city it still is, and seeking treatment. She had a huge spleen; the spleen filled the whole abdomen. And the main point my teachers made was that you could not take the spleen out because the spleen is doing the work of the bone marrow in this moment. And if we remove the spleen, the liver will enlarge, and you can't remove the liver. This whole thing fascinated me very much. That from the bone marrow, suddenly you're transitioning to a kind of embryonic bone marrow formation, because in utero, blood is made by the spleen and liver. So, we're reverting to those because the bone marrow is failing. So, the body reinitiates some of those earlier programmes. So that was it.

Rina Bogdanovic [07:30] Before we go into more detail, I think that one very open but crucial question here is what is cancer? And I have to say that reading your book really helped me appreciate the sheer complexity of this disease, and by extension, the problem it poses. How has our understanding of cancer and its causes changed over the last few years?

Azra Raza [07:59] Sadly, not very much. And, thank you for reading the book because 99% of people who interview me immediately say, well we haven't read your book but we want to ask you. So here's the exception, you've read the book, thank you. It is an extremely complicated disease. But on the other hand, remember that there is something called convergent evolution, which means things tend to converge also, as they evolve. So, let's say a liver cancer is very different than a leukaemia, a bone marrow disease, or let's say a pancreatic cancer is quite different than cancer of the ovaries. But what's common in all of this is two things really, one, that the cell that becomes cancerous no longer responds to growth inhibitory signals, that is common to every cancer. And a second property that's common to every cancer is that it can literally, as I said, walk out of its organ of origin. It can invade other organs, it becomes very metastatic, invasive. Those are properties of all the cancer cells. So there has to be something in common, right. And that's convergent evolution that leads to something common and so the prime cause may be common as well is my point.

The impact of losing her husband to cancer on Azra as an oncologist

Rina Bogdanovic [09:49] Coming back to your book, which was incredible to read. The urgency for a new approach to cancer diagnosis and treatment is so beautifully portrayed in your book, through relationships you develop with your patients and obvious agony and frustration you go through every single time that the available treatment methods do not suffice. I think that your empathy and your dedication to a field which in your own words, is in a crisis is truly admirable. So, I was wondering, would you say that having been on the other side of the hospital bed, as a wife of a patient has changed the way you work with your own patients?

Azra Raza [10:44] That's a deep question you asked. It's a very important question. I have thought about this myself a lot. And I don't think I changed really as a doctor as much as all my perceptions changed as a result of the experience of seeing someone you feel like your life depends on you loved them so much, and yet you over a period of five years see them slowly die. And that experience leaves you, the word changed or evolved or metamorphose, none of them suffice to say, to describe to you the kind of soul shattering insights that suddenly become a natural part of you. So, everything you look at now, is still the same, the things are the same, but your eyes have changed so much by the insights you've developed, that your sight is now very different. And that's an experience that, I must say, left me in a wind, numbed for a while. After taking care of someone, where every sulcus and gyrus in your brain is constantly focused on a cancer and a person who's dying of cancer. Every action I made, you know, should my daughter who's five years old have a playdate? Well, it was affected by what time was Harvey getting chemotherapy? So, everything is ruled by that for five long years. And then suddenly he dies, and you have nothing. It's like emptiness, I couldn't even listen to music for two years. It meant nothing to me. It used to irritate me in a way, and I love music. So, when you ask me, did it change me as an oncologist, I have to say that it's impossible not to change as a result, because as a person, I changed so much. So, whether I had more empathy now, I don't know. I'm the same person, but because my perceptions are different, the empathy level must be different. I hope I'm making sense, but it's a difficult question to answer. The short answer is, absolutely it has changed me as a person. And it has changed me in every way in which I react to things.

Ageing is the most potent carcinogen

Rina Bogdanovic [13:34] I think through your book, it's just so obvious how empathetic you are as a person and as a doctor. And I don't doubt that even prior to this experience, you had ample empathy for your patients. But on this podcast, we predominantly focus on topics of longevity and chronic inflammation. In your book, you said something that I found very interesting, which was that ageing is the most potent carcinogen. You explained this by using the MIST of ageing, and I really liked the acronym. Could you explain it for our listeners?

Azra Raza [14:13] Why don't you read that little thing? You have such a beautiful voice.

Rina Bogdanovic [14:17] Thank you.

Azra Raza [14:18] That would be lovely.

Rina Bogdanovic [14:20] For the listeners who have the book next to them, this is on the page 81.At least four major areas of profound biologic alterations turn the aged body into a hotbed where malignant cells can thrive. I call it the MIST of ageing. First are mutations. In addition to heredity and exposure to toxic environments, each new round of DNA replication as a cell divides causes fresh copying errors. Cellular metabolism also causes DNA damage. Mutations from these sources add up over time. The second is the immune system’s increasing inefficiency. All bodily processes become more decrepit with age, causing the immune system to falter and miss eliminating a cancer cell at its very inception. Third is an increase in the number of senescent cells with age. Senescence by itself is anticancer because the cell stops dividing. However, it is carcinogenic for other cells because it is still metabolically active, producing waste materials that accumulates, causing the natural habitat of cells to turn toxic. This inflammatory microenvironment provides the ideal soil for the abnormal cancer seed. Finally, there is the problem of tissue loss with age, dramatically visible on the face and neck but equally disfiguring internally. Tissue depletion leads to geographic reorganization in organs such as the bone marrow with resulting spatial renegotiation between cells whose activity depends upon precise physiologic gradations of chemical signalling. These four factors descend like a mist that cloaks the elderly in the possibility of cancer. Where in the Per’s mode, a grain of sand is eventually enough to tip the system into an avalanche, the bodies of the elderly are engulfed in a swarm of them.

Azra Raza [17:00] You did a perfect job, and that's exactly it. I call it the MIST.

Azra’s new cancer model

Rina Bogdanovic [17:06] I think it was perfectly described in your book as we've just heard. Moving on, since we've mentioned the microenvironment. One of the points which you make very clear, is the limitation of the reductionist approach, which is used by many cancer researchers. One of the examples of this, as we've just heard, is that the importance of the microenvironment of the cancer cells is often overlooked. So that brings into question how accurately can the cell lines actually represent the tissues or cancers they come from?

Azra Raza [17:41] Brilliant question. Not only have you read the book, you have really grasped the input of what I'm trying to convey. Thank you so much. It's such a pleasure to talk to someone who is knowledgeable and is interesting. So, here's a very interesting answer. As we just discussed, with age by itself there are areas of chronic inflammation that start developing in various organs because cells don't age and simply die. Many of them just hang on as senescent cells. They're not doing any useful function, they're not performing it, but they continue to excrete, exude toxic material that poisons the environment. Another way that microenvironment can get very toxic is if there's a let's say, in the liver, there's an infection by Hepatitis B virus. And so, it causes chronic inflammation, lots of cells are dying. In these states, when the microenvironment is poisonous cells start getting a signal fight or flight, either you're going to develop a strategy to survive, or you're going to die. And my new cancer model, which you will love hearing about is that because of the stress of the microenvironment, cells get signals to develop strategies and the strategy that biology uses is to throw out 1000 different diverse responses, and then one of them might work. So, in the stressed environment, one thing that can happen is that a blood cell has arrived, let's say, an immune cell from the blood like a macrophage to eat these dying cells, but a dying cell from the liver that gets into the blood cell doesn't die. So, If it doesn't die, it fuses its DNA with the DNA of the blood cells

Rina Bogdanovic [20:07] forming giant cells.

Azra Raza [20:09] Yes, exactly forms a giant cell, a big cell. But now it has endowed itself with two of the basic properties of a cancer cell. Number one is, because it's inside a blood cell, it's mobile. Now it can walk out of the liver. And number two, why isn't that cell, which has walked out of the liver being recognised as a foreign cell by the blood and immediately killed? Because it's inside of a blood cell, so it evades the immune system. So, my new model of cancer is that the first cell is really two cells.

Rina Bogdanovic [20:55] And your new model cannot be investigated with the cell cultures we are using at the moment.

Azra Raza [21:03] Absolutely not. Because the result of pursuing those artificial things is that today, the mortality from cancer is the same as it was in 1930. And that is something which we should be really ashamed of. We're refusing to take the blinders off our eyes, we keep investing in these schemes that really are so complicated, and so toxic in the end and benefit so few patients and financially are bringing the whole healthcare system on the verge of a collapse.

Rina Bogdanovic [21:48] I just want to repeat what you've said. You are saying that our methods of treating cancer have not improved life expectancy since 1930s. That's 90 years, just for our listeners to realise what we're saying, that's an incredible amount of time and incredible amount of money invested in research and therapy development.

Azra Raza [22:16] Let me be very clear, 68% of cancers we diagnosed today we can cure. But we are curing with what is the question, slash poison burn. Why? We were doing that a 100 years ago? Why are we doing the same thing today? And then second, the 30% patients who present with advanced disease, their outcome is no different than it was in 1930 and 1930, only because that's when statistics started to be collected. You can go back 1000 years, or at least 100 years easily when we started to do operations and radiation was already available. So those are my points. Why are we using the Stone Age Palaeolithic Technologies today? We were slashing breasts 2500 years ago for breast cancer. What are we doing today for breast cancer? Slashing. So, what are we doing wrong? Why aren't we able to get better? I think it's because we have been targeting the wrong goal. We have been targeting the last cell, we try to kill the last cell. No, I'm saying we should be proactive, not reactive. We should go for prevention rather than cure; we should go for the first cell rather than the last cell. And as you wisely pointed out, sighting that first cell is impossible in a petri dish. So how do you sight it? Well, by the time cancer declares itself, there's already hundreds of millions of cells. So, the only way to sight it is try to do what I've been trying to do, which is go and study people at risk of cancer.

Azra’s revolution – coalition of 8 institutions

Azra Raza [24:45] By the way, during this pandemic, I put together a coalition of eight institutions, the top institutions in America: Columbia, Harvard, Johns Hopkins, MD Anderson, University of Chicago, Northwestern, Memorial Sloan Kettering, and Montefiore, eight of the top institutions in the country. I said to them, point out the fatal flaw in my argument that we have to go for early detection, which is much earlier than stage one. And if you can't, then you have to join the revolution. Guess what, everyone joined the revolution. Two things resulted from it. One we wrote an opinion paper, all of us agreeing that indeed going after the first cell is the future of cancer research and treatment. Prevention is the way to go. And we published this in Scientific American, January 8, 2021. There are 30 authors with me as the lead author. Then I said, okay, talk is cheap. Let's do it now. I convince my colleagues around the country to start collecting samples on cancer survivors. Now, I don't want anyone to get scared. If you are a cancer survivor, you're fine. Your risk for getting a second cancer, not recurrence of cancer, I'm talking about a second cancer is very small. However, if you look at individuals who actually are diagnosed with cancer, then 20% of them are cancer survivors. And you read the story of my husband Harvey, at 34, he got one cancer, and survived that horrendous experience. And then at 57, he got a second completely unrelated cancer from which he died. So, if one in five new cancers appear in a cancer survivor, and cancer survivors regularly come for follow ups and check-ups to their hospitals, where they got treatment for the first cancer, my suggestion was, why don't we just draw some non-invasive samples. Like 30 Cc of blood, saliva, urine, faeces, hair, nails and save them. If eight institutions work like this, in the first year, we'd have 16,000 samples. 500 of them will have developed a second cancer, now imagine we have all these samples from before they got cancer. So, what am I looking for? Number one from the blood, I'm looking for that first cell. But it brings me back to the most important thing, my opinion is that in the future, we will not be treating cancer by targeting even the first cell but trying to reduce the stress that caused the appearance of the first cell. Whether that stress is coming from ageing, or an infection, or an autoimmune disease or exposure to something toxic, we don't know. But we want to fix stress markers, metabolites and proteins of chronic inflammation and stress, that are responsible for the phase transition once again from going from a precancerous state to cancer. What is the change in them and in the metabolites that are being shared in the blood and saliva and urine? Why hair and nails? Because my friend Kenneth Pienta at Johns Hopkins convinced me. He said Azra, think of it like this, you can tell the constituents of an ocean by examining a cup of water that you skim from the top, and you can tell what's half a mile down deep into the ocean. So he asked why not hair, why can't hair and nails tell us what's going on. And he's right, I'm not going to say anything more because he hasn't published the papers yet. But it's dramatic what he's finding, especially in people getting chemotherapy. So, the point I'm making is simply that eight institutions have come together to start saving samples on cancer survivors. Within two years, we have enough samples, we'd have caught the first cell and the stress markers in 1000s of patients who have developed a second cancer, so we have their samples from before and immediately after. And now we can compare for the phase transition through all the studies I'm talking about. It required $22 million, but I raised it.

Rina Bogdanovic [29:28] Congratulations, that's amazing.

Azra Raza [29:32]Thank you. I think it's going to be a game changer.

Rina Bogdanovic [29:36] I absolutely believe in you.

Azra Raza [29:39]And you know, science is something very interesting. I want to say one last thing here. Art is I; Van Gogh could stand and paint the starry nights by himself. But science is we. There is great strength and power in consensus building because each of us bring complementary strengths to the table. And all of us are standing on the shoulders of giants. So, it is not as if we started you know, I, me, mine, I, me, mine. No, science has to be we. And I'm a firm believer in going to the top scientists, the top clinicians, the top oncologists, the top researchers, and getting them convinced. Okay, tell me, what am I saying wrong, and I'll believe you, and I'll do what you are doing. And so, I think that this consensus, this kind of a group effort to really turn the entire cancer paradigm on its head, go from the last cell to the first cell, is the way it's going to change I'm very excited about it.

Mice are the real elephants in the room

Rina Bogdanovic [30:51] So am I. And before we come back to giant cells and biomarkers, I want our listeners to understand the problem with the current model. And I have to say, I feel very grateful for having a chance to talk to you, because as a young student of science, I think I am much more at risk of idealising the current medical and scientific paradigm. And seeing as I'm spending so much of my time studying and striving to be a part of this world, it's quite unlikely for me to critically assess our current scientific system. So, thank you for opening my eyes, especially to the fact that the hype I hear about cancer therapies, very often is just that, a hype. Mouse models have, for decades now been the norm. And yet humans and mice differ quite extensively from each other, from our life expectancy to our metabolism, our immune systems. Why do you think mouse models continue to be the norm for developing therapies?

Azra Raza [32:01] Do you know, how I ended up actually writing The First Cell? Because there is an interesting challenge that's given out by my friend John Brockman, who is always trying to bring together what he calls the third culture. Which is the culture of science and the culture of the humanities together into a third culture. And annually, he gives to about 150 people he thinks are worth asking a question, and luckily, I'm one of them. He sent this annual question out. And one year, like back in 2014, or 15, he asked the question, in your opinion, what scientific idea will make the biggest change if it's given up? I answered the mouse models, and mice are the real elephants in the room. And I said, just look at the data, 95% of everything in cancer is failing to help patients. Because look what we do, we take a mouse, and we kill its immune system. The mouse doesn't get the kind of cancer, for example, I'm studying. So how am I going to have a mouse model of MDS or acute myeloid leukaemia? Well, I kill the immune system of the mouse, then I transfer some cells from my patients to this mouse. 90% will die immediately some will try to survive and one or two will take off and start growing. And now we treat this mouse with a drug we think should work and it works, and the mouse is cured. Now we claim that this drug is curing acute myeloid leukaemia and bring it back to the bedside. Well, 95% times it fails and the 5% times it gets approved. I think it should have been considered a failure because it's extending survival by two or three months for 20 to 30% patients. That's it. And it costs millions of dollars, $100,000 a year. Now if I don't prescribe this drug, I'll go to jail. Why? Because if my patient dies, the family can sue me and say this drug was approved, why didn't you give it. And I'd say well 70% Chance was that it wasn't going to do anything and 30% chance is that median of two months. Well, one person out of those 100 live for two years, maybe it could be my father, my son, my brother, and you withheld the drug. So those are the issues. Mouse models are so popular because they're very easy to use. You can do anything to mice can kill their immune system. You can't do that to humans. Secondly, 90% of researchers who are studying cancer, they are not oncologists, they are PhD doctors, so they don't have access to patients. So, they have created this whole castle in the air, basically, a house of cards, claiming that they are studying cancer, but yes, of course, they're studying cancer, but it's not even a cancer that the mouse gets, they're studying something completely artificial, that they have created and claim that it works. It's horrifying. I don't understand why people are not looking at this seriously. I don't know. I can't answer, you tell me why you think this is true?

Rina Bogdanovic [36:12] I think it comes back to what we mentioned earlier, we are so accustomed to this reductionist approach where we're looking at one gene, we're looking at one protein, we're looking at one signalling pathway.

Azra Raza [36:25] Well, here, I think our institutions have failed us. Why? Because they could have provided human samples to these individuals, it isn't like people are not getting cancer, millions of samples are available. They're sitting rotting away in pathology departments in freezers. Why? Because these very people themselves don't want to go and even bother. They are the ones who sit in study sections and give all the grants and it's easier to study mice everywhere. Institutions should have been more strict and say no, this is artificial. You can't do that we will provide you with the samples that you need. But they haven't done it. So, I think it's not just the failure of scientists or academia or our pharmaceutical industry. I think the very institutions that are supposed to protect patients are not protecting patients. So, John Brockman liked my answer very much. And by the way, that year, my answer made the headlines in The Guardian, The Observer, and everywhere newspapers picked it up. Then I went on this Freakonomics NPR programme. It's called Freakonomics Radio Hour. And I gave a long interview back in 2014. And they replayed the whole thing when The First Cell came out in 2019, saying you were right, you were oppressed back then, so we're going to play it again. But John Brockman, who gives the question liked my answer so much, he's a very good friend, so he and his wife Katinka Matson, came one evening to dinner to my place. And they said, well, you have to write a book. Because he's also an agent, a book agent. And he said, no, your idea was the most important one. You keep telling us all these issues with cancer problems. So, I insist that you write a book, and for two years, I didn't listen to him. I kept saying, I'm not a writer, I can't write I'm not a writer. I'm a scientist. I'm an oncologist, I don't have time, he wouldn't listen to any of my excuses, and made me do it.

Rina Bogdanovic [38:38] One of the things I disagree with what you said, and that is that you are not a writer. I have really, I have not been able to stop thinking about it for days after I read it. So, thank you for writing it.

Azra Raza [38:50] Well, you know there are multiple authors in the book, like Chapter Six is basically written by my daughter and Andrew's sister. And then at the end of the book, I have done something which no one has done, which is go back to families who lost their loved ones to cancer and ask them 10 years later, thinking back, what decision would you have changed? And then they wrote, the last part of the book is by these family members. And that I think, is the most deeply moving part to me, what they have to say.

Who pays the cost of cancer treatment?

Rina Bogdanovic [39:21] Exactly, because I think this book is so rich, in a sense, you completely deconstructed the cancer paradigm, from a scientific, from a clinical perspective, but then you also allowed these families to tell their stories. So, I think I want to come back to something you mentioned, which is the price of these medications. The financial burden on these families and these patients is undeniable. So how do you reflect on this as a clinician and as a wife of someone who was treated?

Azra Raza [39:54] I think you're pointing out a very sensitive area here because we don't want to discuss costs of drug when we are prescribing it for a patient. And that's a disservice to the patient because if I tell the family, well, this is the next drug I want to give them, they find out that the co-pay is something like $7,000 a month, they mortgage their house to give it. But they don't realise what a small chance this drug has and what outcome is expected as well as we do. These are very sensitive issues. But as a result of not being completely able to discuss with the families and the patient, the result is that today 42%, and that's a huge number, that's like half of all cancer patients diagnosed today completely become bankrupt by the second year. They lose every penny of their savings. In America, we loot them of every penny, they have saved all their lives by the second year. And you can't make up these statistics. They're all there in my book. So, the questions are so profound. Everyone is paying the price for this. But the most profound effect is on the patient. And then once the patient dies on generations of that patient to come, because the next generation's life is ruined also. 80% of healthcare costs are because of the last few months of life. And in that 80% we managed to fleece every last hair from them. I think that it's an obscene and a horrifying system in which the only people who are really benefiting are always the people on top of the business and the ones who are losing are at the bottom. If you think about it in a health care system, the two people who have skin in the game are doctors and patients. Well, doctors are overworked and underpaid, and patients are always having to meet the cost of ineffective therapies. So, the system is taking advantage of both. And the only way to change it is to completely overturn the system. How? Once the word processor was introduced, no one thinks of the typewriter. We need to show success of the new model, early detection, the first cell, the stress markers, if we can find those, are we able to prevent? If we can show that no one will worry about these therapies tomorrow or these mouse models.

Azra’s tissue repository – 35 years in the making

Rina Bogdanovic [43:20] And you as a perfect example of someone who has been advocating this for decades now. And our listeners will be happy to know that you have not spent these decades sitting around and waiting for someone else to listen to you. You have spent these 35 years collecting over 60,000 samples from your patients. And I want to stress this, you collect them yourself from every single patient. How are these samples now going to be used for your new model?

Azra Raza [43:51] Thank you for bringing that up. Yes, these samples come from my patients, every vial is meaningful and has a poignant story which brings back memories with the patient that I took it from. And you are right, I do the bone marrows myself in clinic, I'm working like an intern to this day. And I draw all the bloods I asked the patients, and no one has ever refused me. I can't remember anyone in 35 years who said no. And I started saving samples. No one was thinking about it in 1984. People thought I was mad, but I just kept saving them in my freezers. And continuously I have used these samples to develop new biologic insights into the disease and collaborated with scientists from NIH to Stanford to Yale to MD Anderson to Harvard, given hundreds and 1000s of samples. Shared them with others because as I said, science is we. And if somebody else has a better technology, then of course we collaborate, and these are the very samples that have allowed me to learn so much about this disease and be able to be so confident today. To say all these things, challenging the very fundamentals on which cancer enterprise has been erected. And yet I'm able to survive all of this and not be blown out of this universe as this brown immigrant Muslim woman coming from God knows where trying to challenge us. No, I survive it because of the confidence I have in knowing that what I'm saying is correct. And all that has come from studying human tissue constantly, properly with colleagues, and publishing in high profile journals. However, the technologies were not that great in the past. Today, I can do proteomics, genomics, metabolomics, transcriptomics, glycome studies, everything on few cells, few drops of plasma, serum. And so today, what I'm doing is something more exciting, I'm using the entire tissue repository to try and study number one, it has already been studied for whole genome sequencing by Regeneron. And the data are in the cloud already. Now we are developing the next steps to do proteomics and transcriptomics on the whole tissue repository. But with a company Grail, which is based in San Francisco, this company is dedicated to early detection of cancer by looking for pieces of shared DNA, which are mutated from cancer cells into the plasma of serum. And they have a methylation platform by which they can determine what organ is this piece of DNA coming from. So not only can they detect cancer early, but they can also say it's coming from the pancreas or the ovaries or the lungs. So, I'm working with this with Grail, and they are studying my whole tissue repository, all those samples from pre leukaemia and then comparing to leukaemia. What changed? How exciting is that! So, I have big plans for studying now the entire tissue repository, and big plans to bring the latest technology to date and I can't do it alone. So, I was in Chicago two months ago, and we are signing a contract with this company called Accentedge, which is an AI company. Because AI is at the heart of this whole thing. Let's say I do metabolomics and proteomics; I've already done the genomics on the whole tissue repository. Only AI has the power to go and do this big data analysis. So, I've already made that deal. So, I think this tissue repository is going to yield some incredible biologic insights about how to target that phase transition, but also the new tissue repository we are collecting for cancer survivors. So, we have now two collections, both in which pre leukaemia to leukaemia and pre cancer to cancer of any sort, and study everything. Do you like that model?

Why is early detection the way forward?

Rina Bogdanovic [48:42] I could not imagine a better approach. I think for our listeners, could you explain what is the meaning of a biomarker and how early detection could change the approach to cancer treatment?

Azra Raza [48:56] Thank you so much, biomarker is a very important word. So, what happens is that as cancer is forming, the cells start shedding pieces of proteins, pieces of DNA, pieces of RNA, pieces of metabolites, which are also proteins, but resulting from various chemical reaction that have occurred in the cell. And we think that the metabolism of a cell, the chemical reactions in a cancer cell are quite different from a normal cell. So, the metabolites and proteins that shed are different. Where are they shedding? They shed everywhere. They can be detected in the urine, in the faeces, in the blood, in the saliva, any compartment of the body. So, these together are called biomarkers. Biomarkers are simply biologic markers of the presence of a certain kind of cell, and we think that the malignant cell has different biomarkers, for example, has more mutated DNA. So, when DNA is chopped up and thrown out, some of it escapes into the blood. Can we pick that piece of DNA and find that mutation? And then when we have a mutation say, aha, this is definitely indicating the presence of cancer. Well, where is the cancer because it's so early that no amount of imaging devices we have right now will be able to detect it. Then we look at its pattern of methylation, what genes are turned up what genes are silence, and by knowing that, we can tell which organ it's coming from. So, for example, the company Grail, I'm a big fan of that company, simply because they are doing this methylation marker in the blood. Their results are there they can detect 29% of stage one cancers already. And 99% of stage four. Well, my criticism of this approach is that you don't have to be a weatherman to know it's raining outside. I don't need some special tests to tell me that this patient has stage four cancer, it's obvious. I want to detect stage one. Well, in stage one, you're missing 71% of the cancers, you're only detecting 29%. But there is a very important point they make. The point is that they are detecting by doing this test number one, with few drops of blood. They are looking for 50 cancers. So, it's different than doing one mammogram a year or doing one colonoscopy a year. You are now using one drop of DNA to look for 50 cancers. And you can detect 30% of those cancers. Yes, you're missing a lot right now. But of course, we can always improve on this technology. It's called MCED, multi-cancer early detection. I wrote a paper about this, and it was published in Scientific American. But MCED multi-cancer early detection, not one cancer at a time, but many cancers in one patient at one time. That's the approach that's going to be the winning approach. Secondly, another important thing is that they are picking up cancers for which there are no screening tests. You see, you can do a mammogram to pick up breast cancer. But we don't have good screening measures for brain cancer. We don't have good screening measures for ovarian cancers, killing so many women. So, they're detecting these cancers early for which we have no screening measures. Is it worth doing? Absolutely. Absolutely. And with improved technology, we'll be able to detect 70 or 80% of stage one. And stage one is curable as you know, we can cure 70% easily. So, I feel that biomarkers are the ones that are going to lead us to instead of examining one cancer, per patient screening, we can do multi cancer, early detection through biomarkers.

In search for the giant cell

Rina Bogdanovic [53:34] Bringing it back to giant cells and what you've mentioned about different screening methods which are available today. I was listening to your lecture for the Human Glycogen Project. And I really liked it, I think there were two examples where you show that you were able to detect giant cells years before screening methods would have detected them. Could you talk a little bit about that?

Azra Raza [53:56]When cancer starts shedding its markers into the blood, blood cells which are normal are also shedding their markers in the blood. So, a few cancer cells compared to 50 billion normal cells. The markers get so diluted that until the cancer is reached stage 2, 3, 4, you can't even detect it. That's the problem. How do we overcome this problem? Well, one way is, instead of saying that there are only 100 cells right now shedding markers, so we can't pick them, why not pick the 100 cells that are shedding the markers? Why wait for only the markers. And so, I was always very interested in going after the first cell. And as I was looking for that I befriended a wonderful scientist and haematologist who's Italian but lives in France, her name is professor Patrizia Paterlini-Brechot. Patrizia and I became friends instantly as we met, she developed a machine called ISET isolation by size of epithelial tumours. This ISET machine can detect one cancer cell from 50 billion normal blood cells. And I said, well, I'm trying to detect one leukaemia cell in a pre-leukaemia patient to try and predict when the patient will develop it. Because once they develop acute leukaemia, it's a universally fatal illness. And I said, it's diagnosed too late. We diagnose it from the bone marrow, and that means it's already too widespread. So, can I detect one cell? We started working together six years ago. And when we started working together, instead of finding leukaemia cell, I started to find these giant cells. Now, Patrizia has already published some 10-11 years ago studies of heavy smokers with lung disease who were at risk of lung cancer. And she found several cases where she had found similar cells in those individuals who did not develop actual cancer for three, four years. And when they developed it, it was the cancer that was predicted by the presence of those cells detected for three to four years. I think that this is a fantastic new area in which we are trying to catch the earliest cancer cells. And as I said, instead of cancer cells, very early markers seem to be these giant cells. We don't know what they mean, right now. We don't know what these giant cells are, what is their origin. However, over the last 10 years, a lot of insights have been developed. And it seems that the most important contribution of science in this area is that that cell is not one cell. It's a fused hybrid cell. So, four groups are really seriously working on this, one is ourselves. We just published our paper I am happy to send it to you about these giant cells. Second group is the father of this giant cell, this polyploid giant cancer cell is Jinsong Liu at MD Anderson. And another scientists there, Steve Lin, who's a radiation oncologist also interested in trying to trap these abnormal cells from the blood. He calls them CAMLs, which is cancer-associated macrophage-like cells, because they're finding macrophage markers. I think macrophage markers are there because it's the fusion of a macrophage with the tissue cell. So MD Anderson, these two scientists ourselves at Columbia, at Johns Hopkins, I think the finest scientist Kenneth Pienta is doing amazing work in this area. And the fourth is from the Oregon Health Science Centre in Portland, Oregon. Professor Melissa Wong doing amazing work in this area. So, guess what I did? I decided to bring us all together in one room and lock us up for two days and come up with some uniform ideas about what all this means, instead of each of us calling these cells by different names. Let's come up with some uniform nomenclature. Are they even the same? Or are we finding 10 different types of cells? What is all this? So, as I told you, I believe that science is we, so I'm bringing all these investigators together in one room July 26-27. My idea is let's get together. Let's come to some conclusions. And then write up and publish whatever conclusions we come to and then direct and focus our research in that area and collaborate. Do it together.

Rina Bogdanovic [59:34] Excellent, especially because, is each of these people studying a different types of cancer?

Azra Raza [59:39] Yes, exactly. Absolutely right. Kenneth Pienta is studying prostate cancer. Jinsong Liu is studying only GYN cancer. I'm studying leukemias, liquid cancers. And then Steve Lin and Melissa Wong are studying all kinds of solid tumours, but I'm the only one studying liquid tumours. However, with this cancer survival initiative now, Columbia University, all our cancer survivors are going in this study. So, the leadership is behind me. Again, I do the same thing with the Cancer Centre director, the dean, the head of medicine, the head of the division, look this is what I'm doing, I say, and if you don't support me, then why should I expect support from the outside? And so, they are wonderful people, I have to say this is the beauty of being in America for me, that literally a brown female can get up and come here and on the basis of merit alone, I can compete. And by law, no one can question that. That's the beauty of being in America, and I must say that I've been the biggest beneficiary of this meritocracy here.

The First Cell Centre

Rina Bogdanovic [1:00:52] I'm glad to hear that because you absolutely deserve it. But for our listeners, now, could you talk about the First Cell Centre?

Azra Raza [1:01:01] Yes, thank you, the First Cell Centre is aiming to identify, target and eliminate the first cell at its initiation. The goal of the First Cell Centre is making cancer's first cell its last. And so how do we do that? Right now, we are talking about taking blood from someone, passing it through a machine in my lab, finding the first cell then trying to study the first cell. Finding the right targets on it, then taking back treatment to try and only kill that first cell. And all this is happening simultaneously, by the way, but another way to do it is to work with biomedical engineers and develop a filter that's in the machine but convert it into one that can be used like a chip on the skin or under the skin, which can filter and catch any cell larger than its pore. And then all you have to do is have an ultrasonic device, just pass over it and say ah, there are five large cells today, oh, tomorrow, there are 5000. So, something is going on, you know, that kind of thing. The Frist Cell Centre I have created is really, for the purpose of developing prevention rather than cure of cancer. And for that, biomedical engineers, imaging devices, people who are doing all of this stuff has to be combined. The idea of the centre is to bring multidisciplinary approach, bring the experts together. And at 3:30 today, for example, I'm meeting again, with the biomedical engineering team, I have been mentoring PhD students with them for the last four or five years. Our collaboration has gone extremely well. And the PhD students are trying to develop this device. So, I'm very happy to tell everyone that the First Cell Centre, I hope, will be the centre that develops a humane, compassionate, non-toxic, preventive approach to cancer.

Rina Bogdanovic [1:01:28] What it sounds to me like is that this type of chip, once is developed, is going to be implanted in many, many people who will be able to monitor it themselves. Is that what the plan is, if I'm understanding it, right? Because the capacity I imagine is not big enough to screen hundreds of 1000s of people all the time.

Azra Raza [1:04:03] Billions of people. So yeah, it's very true. You know, in America right now, everything has been politicised, masks have been politicised, vaccines have been completely politicised. It is so pathetic. If I mentioned a chip right now, shhhhhh don't say chip, don't say insert it under the skin because everyone will immediately blame you of using a signal through which you can track their money. I don't know people have gone completely insane here.

Rina Bogdanovic [1:04:44] It's not only in America, though.

Azra Raza [1:04:45] Oh, it isn't? That's even sadder then. Well, that's the problem that America is the leader. People when they asked me is Europe doing better in cancer. I say no, they can't be because they're looking up to us for leadership. And if this is what Americans are doing, yes, they are creating the same kinds of distrust and mistrust of science and scientists. And it's horrifying. So, I wanted to talk openly about the chip, but I'm afraid only because I don't want to be misunderstood. However, the idea is that from birth to death, we should simply have a chip installed that can detect not even the first cell very soon, but the stress markers, anytime there's increased stress in some organ. It may lead to multiple sclerosis, if it's in the immune system, it could lead to rheumatoid arthritis, if it's in the joints, every one of human diseases that we have failed to cure, basically, unless we can fix it surgically and unless we try to prevent it. For example, mortality from infectious disease came down dramatically once we introduced antibiotics. But the real change came when we introduced vaccines and prevented those diseases instead of treating them. And the same happened for heart disease. Yes, we can fix the coronary arteries, but anti-cholesterol drugs and better lifestyles are the ones that are changing really, by preventing heart disease rather than treating. Same thing has to be done for every disease. And cancer is, of course, paramount, the first in all of this. And the idea is that, yes, these kinds of devices, these kinds of imaging technology, and AI combined with the use of multiple kinds of markers that can be detected from saliva, or hair, nails, anything. These are the future of healthcare. And anyone who keeps sticking to the old model, believe me, they will be left behind.

Advice for young scientists and clinicians

Rina Bogdanovic [1:07:16] Now, thinking of the future, I would like you to put yourself in my shoes. I'm in my second year of studying biomedicine. Very passionate about science, I want to pursue science. But now I'm witnessing a paradigm shift not only regarding cancer, what advice would you give to young medics, young scientists who are just finding themselves in the scientific world?

Azra Raza [1:07:40]Where are you by the way?

Rina Bogdanovic [1:07:42] I'm in London.

Azra Raza [1:07:43] You're at the heart of high culture in science. What is it Albemarle Street on which the Royal Institute is? What is the address of the Royal Institute in London?

Rina Bogdanovic [1:07:59] I have to say, I don't know.

Azra Raza [1:08:01] Okay, I think it's Albemarle Street. And that street is the first street in the world to become a one-way street. You know why? Because a 100 years ago, the way that scientists would present their findings was like a story. They would stand at the auditorium of the Royal Society in London. And I have seen cartoons and pictures from those days, which showed that the people attending these kinds of scientific lectures, but they were told like a story, science as a story. Half the participants were women in the audience, society women in London, going to the Royal Institute to hear scientific discoveries, like nitrous oxide, what does it mean? So that street used to be so crowded with the horse carriages that they had to make it a one-way street, that was the first street to come. So, if you are in a place that really has given birth to the whole scientific revolution, and you are so fortunate, I don't know what you're doing. But whatever you are doing, pay full attention to that task for now. Your job is to learn as much as you can in every discipline and keep reading and keep educating yourself. I'm sure you have great mentors. But once your education is done, that will be the important decision for you. How are you going to use this technology and how will you keep improving upon this technology. Are you planning to become a physician as well or is it a PhD route?

Rina Bogdanovic [1:10:03] I think probably stick in science. But I would always want to make sure it has a clinical application.

Azra Raza [1:10:10] Oh good, that will be great if your application is going to be to directly affect our lives. I think that you are the one who's going to bring the real revolution now. I'm trusting and depending on you young people, because of the way you're being raised, the training, you're receiving the technology that is at your fingertips. You know, it used to take 80 years to double the scientific knowledge not long ago, then it took 20 years, and then it took seven years. Today, I think it's taking less than a few months, scientific knowledge is doubling. And interestingly, it is at your fingertips because of the cyber revolution, that if a question comes into your mind, you just type it in Google, and it's immediately answered from whatever technology and then you can apply it to yours. You are one of the most fortunate people. My advice to you is keep doing what you're doing and pay full attention to it. Keep reading as much as you can and read a lot of fiction. Because that tells you the human stories that really, I think centres and grounds you into the human side of things, and you'll find your passion, and will find your reason coming together very nicely.

Rina Bogdanovic [1:11:42] Thank you. Now as we are bringing this interview to a close, I would like to ask you for one final message for our listeners, be they doctors, maybe they're scientists, maybe they're individuals who themselves are dealing with cancer. What would be your one final message?

Azra’s final message

Azra Raza [1:12:01] I think my final message is always the same that never forget the human anguish angle that we may think we know a lot. And factually we may be correct, but it's important how you conduct yourself in life, not just what you know, but how you impart your knowledge. And I'll end by quoting Emily Dickinson and that advice I hope all the young people in the audience will remember the first line is so important and then how she continues: Tell all the truth - You see what she's saying? She's admonishing you right away. Her command to you is that you have to tell the truth. But now what comes next: Tell all the truth but tell it slant Success in Circuit lies - What is she saying by all this, you have to be sensitive to how you impart your knowledge, we have to tell the truth. There is no question about that she's not questioning:

Tell all the truth but tell it slant —

Success in Circuit lies

Too bright for our infirm Delight

The Truth's superb surprise

As Lightning to the Children eased

With explanation kind

The Truth must dazzle gradually

Or every man be blind —

Rina Bogdanovic [1:13:48]Thank you. And thank you for joining me today.

Azra Raza [1:13:54] An honour.

Rina’s Outro

Rina Bogdanovic [1:13:57] For all of our listeners, I think this conversation should have been enough to convince you to read Dr. Raza's book. But if it wasn't, and you were interested in what we were talking today, I think this is an amazing place to start. I will also put a link to your website down in the description, which I found very interesting. There was a five-year plan for the First Cell Centre. And for anyone who is questioning what the next steps in cancer should be, I think that is a very good place to start. If you're interested in finding out more about GlycanAge head on to glycanage.com where you can access a whole list of their scientific publications, blog posts, testimonials, and of course, this is where you can order your GlycanAge test kit. Please don't forget to leave ratings and reviews for this episode and engage with us on social media. All the links will be in the description. Thank you for listening and have a great day.

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