 Hello, everyone, and welcome. I'm so glad to see so many of you here today. We have a stellar lineup of scientists and thinkers and physicians and experts all on a very important topic of cancer and health. I'm Catherine Bowers. I write about ecosystems and the ways that biology can disrupt our perfectly good human lives. I wrote a book called Zubiquity that looked at the connections between human health and animal health, essentially what physicians and veterinarians can learn from one another. And I looked at a lot of different health conditions from heart disease and mental illness and cancer. I'm also a Future Tents fellow here at New America. Future Tents is a partnership of three organizations that prize the creative, multidisciplinary kinds of conversations that we're going to be having here today. And it is a partnership of three organizations. It is New America, Arizona State University, and Slate Magazine. Future Tents explores emerging technologies and their transformative effects on society and public policy. And central to this partnership is a series of events in Washington DC and New York City and the Future Tents channel on Slate. You can follow the discussion online today using hashtag FTC, oh, FT Cancer, Future Tents Cancer, and follow us at Future Tents now. So a little bit of housekeeping before we get started. Please silence all your devices. During the Q and A, please wait for the microphone before asking your question. And since this event is being live streamed, please ask your questions in the form of a question. Now I would like to introduce Athena Octopus. Dr. Octopus is an assistant professor. You can come on up in the psychology department at Arizona State University. She's a cooperation theorist, theoretical evolutionary biologist and the co-founder of the International Society for Evolution, Ecology and Cancer. Welcome. Thank you, Catherine. And thanks to all of you for the invitation to come here and speak and for taking time out of your busy schedules to join us all for today. So I wanted to begin by just pointing out that all of us, we are each made of 30 trillion cells that are cooperating with each other, coordinating cellular behavior in order to make us all function. This is kind of spectacular, actually, if you think about it. It's orders of magnitude more individuals than there are humans on Earth, and somehow they're all coordinating in order to make us work. In fact, we can think about multicellularity, about multicellularity itself as this really highly cooperative system, and it has a lot of components of it that really are ecological. So cells in a multicellular body, they basically work together to gather resources, share those resources, and they help each other in a sense manage risk. Because if you're a lone cell going at it on your own, there are many more challenges, many more threats, and when there was a transition from unicellular life to multicellular life, those cells that teamed up were better able to take advantage of opportunities like dividing labor so that they could be more effective, and also avoiding threats like predation. If you're larger, you can have some of your cells specialize in making you more mobile, some specialize in reproduction, and that gave a big advantage to multicellularity. So what does all this have to do with cancer? We know multicellularity evolved because there were benefits to cells being cooperative. Cells basically evolved to constrain sort of selfish individual cell level behavior. They inhibited proliferation, regulated cell death, transported resources, divided labor, and also started taking care of the extracellular environment, getting rid of waste products and not producing too many waste products. Well, what we see in cancer is basically that this cooperation is very vulnerable, and this is a general phenomenon with cooperation. When you have cooperation, exploiters that can benefit from taking advantage of cooperators tend to do better on a short term, on a small scale, than individuals that are being more cooperative. So cooperation is vulnerable, and this is the case with cancer as well. We see that multicellularity is essentially a breakdown of this multicellular cooperation. So cancer cells actually don't inhibit their proliferation as much as they're supposed to as part of a multicellular body. They monopolize resources, they don't die when they should, and they also trash the environment in which they exist and that they share with all the other cells in the multicellular body. So what happens is these cancerous cells out-compete the more cooperative, normal cells, and that means that over the course of our lifetime, that evolution by natural selection actually favors those cheating cells, those cancerous cells that actually take advantage of the cooperation of our multicellular bodies. So we put this into a framework that basically lets us see how each of these five components of multicellular cooperation breaks down with cancer. And there's a famous and well-accepted framework for looking at cancer, the different characteristics of cancer called the hallmarks of cancer. It turns out that if you take this framework based on the evolution of multicellularity and you match it up with the hallmarks framework, you see that all of these components of multicellular cooperation break down with cancer. And this also suggests that a breakdown in division of labor is potentially another important component of cancer and maybe a hallmark that we should be looking at as well. And what all this means is that in order for us to be viable multicellular organisms, in order for multicellularity to be possible at this scale that it's possible with us today, our bodies actually had to evolve systems for detecting cellular cheating and suppressing it. And those are our cancer suppression systems. There are a lot of ways that our multicellular bodies do that. One is quite interesting, is intrinsic to every cell in our body. It's almost like the cellular conscience. So these cell intrinsic mechanisms basically monitor each cell for DNA damage and stop the cell from dividing if there's too much damage. And if that damage can't be repaired, it actually induces the cell to commit cellular suicide so that it doesn't damage the host. There's also neighborhood mechanisms. So cells actually are listening in on the sort of molecular chatter of their neighbors. And if they detect something going awry, then they can send a signal to have that cell commit cellular suicide as well. And if those two systems don't work, we have another system, which is a body-wide set of mechanisms. Many of them use our immune system to actually monitor the whole body for any regions where there's suspicious cellular behavior. So together all three of these systems help our bodies suppress cellular cheating long enough that we can live to reproductive age and hopefully far beyond without getting cancer. So we are very interested in understanding cancer as a problem of multicellularity. So we conducted a review of the existing literature on cancer looking across species. And we found that cancer was much more common in complex forms of multicellular life. So here we have up on top vertebrates, which are animals. So what we usually think of as the kinds of organisms that are susceptible to cancer. But it turns out that we see cancer across all of the branches of multicellular life. So it really is a vulnerability that we have as multicellular organisms. Cancer is not just sort of this problem that occurs because of cooperation breaking down. There's also these interactions between the evolutionary and ecological dynamics during progression. These are results of a model that I did during my postdoctoral work with John Pepper, who's actually sitting here in the front row. And we found that when cells monopolize resources as cancer cells do, that this actually favors cells that are more likely to move. This has important implications for understanding why invasion and metastasis occur. Because this overuse of resources is actually contributing to selection for cells that move. And in general, we think that there are a lot of reasons based on ecological theory. Why this destruction of the environment around the tumor should be actually favoring invasion and metastasis. One of the most exciting frontiers I think for the future of looking at cancer is seeing how cancer may actually re-evolve the capacities for cooperation that our multicellular cells are able to do, but to our detriment rather than to our benefits. So can cancer cells actually re-evolve cooperation to metastasize more effectively to start a new cell colony and a new tissue? Do they cooperate in order to actually resist our treatment? So we know that it can be more effective if cells work together to pump out toxins than if they do it individually. This raises a possibility of cellular cooperation contributing to drug resistance. We know that resistance, drug resistance is actually an ecological phenomenon. It's not just that the cells are mutated in a way that allows them to resist the drugs, but also that the environment that those cells are in makes a big difference. So if the environment is quite degraded, that can affect the opportunities for cancer cells. If the cells are in an area where blood can't flow, then they're not even going to get the drug. So I just want to end by pointing out that there may be many new strategies for cancer control that could involve disrupting cellular cooperation, and that really we're all vulnerable to cancer because we are multicellular organisms. And what that means is that we can't completely ever escape from that vulnerability to cancer, but if we understand the evolutionary dynamics, the ecological dynamics, and how cooperation among cells helps support our health and well-being, we may be able to find new solutions to help us deal effectively with the problem of cancer. Thank you. Thank you, Athena. I'd now like to invite Kate Hunt to come up for a conversation on ancient cancers and learning from the ailments of our ancestors. Kate is a bioarchaeologist with the 106 group and the Paleo-Oncology Research Organization. She has a special expertise in the analysis of human remains in an archeological context. Kate has received several international honors, including being named a TED Fellow in 2014, one of Fast Company's 100 Most Creative People, and one of Foreign Policy's 100 Leading Global Thinkers. So Kate, you are a paleo-oncologist. This is a little close, let's sit here. So who are your patients or study subjects if you're a paleo-oncologist? So as a paleo-oncologist, I look primarily at skeletons and mummies in the ancient and historic record, and I don't think I would call them my patients at all, but they're definitely individuals that I study in bioarchaeology. Are these mummies like we're used to seeing, like King Tut and the Egyptian tombs, those kinds of mummies? Yeah, I think in the best case scenarios, yes. But oftentimes, we are studying more of the skeletonized remains of individuals in the past. You have to be under quite specific conditions to be mummified, and sometimes that'll happen naturally, sometimes that'll happen culturally. But most of the time, what we come across are individuals that are skeletonized, and so we look at cancer in the dry bones specifically. And how far back are you looking? Like how many thousands of years are we talking? Well, evidence has been recovered from individuals, pre-human ancestors, as early as 1.7 million years ago. This is just very recent research coming out this year. And so that in pre-human ancestors, and then we have evidence as late as, or as early as 7,000 BC coming out of Southern Europe. Aren't there some in the Andes also? I think there are some possible, some probable cancers coming out of the Andes. And I think we are awaiting published research. And what are you looking for? When you have one of these remains, what do you see? What do you do? Well, there are a lot of different scenarios. So one of the things that we look at with any human remains are identification factors such as age and sex. But then we also look specifically at disease. And it can be any type of disease that you can see in the dry bone. And I think it's important to point out that most bio-archeologists have to rely on visual analysis. We don't necessarily have resources in the field to look at dry bones radiologically or microscopically or bio-molecularly. So we really have to rely on our macroscopic visual analysis. And so when we do that, we are looking for signs of disease that can be reflected on bone, where that individual has had to survive long enough for that disease to manifest in the dry bone. This is somewhat of a new field, would you say? Paleo-oncology? I think that it is a new field in that it's recently gained more attention in the academic and scientific sphere. But we do have bio-archeologists who have identified cancer in 1909 and 1924. And so this was definitely happening a long time ago. So I would not say it's necessarily a new field, but I would say that we are starting to synthesize the data in the last five years, really. And we're starting to really use technology that has made leaps and bounds to do more specific empirical analysis today that we weren't able to do in 1960s, 1970s. Is that using new machines, new ways of synthesizing the data? What's the difference? Yes, both of those. Specifically when we were just talking about this earlier, next-gen sequencing, and H-DNA sequencing has really expanded the opportunities to look at mutations. And mummified remains specifically. We've been able to make some really incredible progress in the last five years in proteomic analysis. And so these are more of the biomolecular techniques in those scenarios we, as archeologists, have to have the funding and the opportunity and support in order to do those analyses. But even in macroscopic analysis, we are creating more standardized definitions, standardized methodologies for diagnosing cancer in ancient human remains, although we have a lot more to go. This is still rather new. So the terms are different across different contributors to the field? Yeah, right now the terms are pretty different. And it's really important to come together and standardize, and I think that's right now. It's a very common goal among bioarchaeologists, not just in terms of paleo-oncology, but in terms of looking at infectious diseases as well. But we are just now kind of getting over that bridge in entering this new world of looking at cancer in the past as people are beginning to discuss the fact that cancer did exist in the ancient world and is not necessarily, not at all, a modern man-made disease. So you have sort of a personal, not sort of, you do have a personal connection to this topic. Can you tell us how you decided to go into this field? Yeah, yeah, so I started out as an Egyptologist working, an Egyptological student, I would say, working in the Nile Delta and the Valley of the Kings. And we were specifically looking at individuals in these tombs, two or three stories beneath the limestone, that were interred there in the 18th and 22nd dynasties, and some of these individuals had evidence of disease. And so when we came back from the field, I went back to school as an undergrad at that point, and I was diagnosed with cancer later that year, ovarian cancer, and I started to, I think this is such a typical nerd thing that I did. As I sat there getting treatment, thinking, hmm, I wonder, I wonder what sort of experience ancient people had with cancer. Are they, you know, were they feeling the same emotional difficulties? That I was feeling what sort of treatments did they have available to them, if any. And then the question was posed to me by a colleague, well, how do you even know cancer existed in ancient society? And from there, for my undergraduate thesis, I looked into the historical and literary references for cancer, because I figured cancer existed. Ancient physicians will be talking about it. They'll be writing about it. And sure enough, we have ancient physicians all over, Greece and Rome and Persia and Egypt, that are talking about cancer, Hippocrates, Galen, Celsus. What kinds of things are they saying? What kinds of cancers are they seeing? So a lot of reproductive cancers, and this is interesting too, because then we have to go into the word analysis and get linguists and historians involved, because they're not referring to cancer in terms that we necessarily refer to cancer, although eventually cancer became carcinose, and then Galen started to translate that into cancer, and so we are seeing that a little bit more, but mostly what was called carcinose, that's the first mention that you see. Yeah, so that was by Hippocrates, and he called malignant tumors carcinose. And of course, these are mainly based on symptoms that we, if we're gonna objectively look at this in the historical record, we can't just say, oh, if Hippocrates said it was cancer, it must be cancer. You know, we're actually really solidly looking at the symptoms that are described in detail, and many of these symptoms are reading a textbook for breast cancer specifically, which was talked about quite a bit in the historical record, and then a lot of other mentions of cancer in the historical record are quite vague, and could be other swellings and abscesses as well, so it's important to consider that. But it is a little hint that, okay, they were thinking about this, they were seeing cancer, so now let's find the biological evidence, and see if there is biological evidence, and that was the next step in the journey. And how do you cross-reference that? Do you use diaries and other accounts from other areas? Yeah, well, mainly primary sources from physicians who kept extremely detailed records at that point, and there's currently, there's not a lot of cross-referencing happening, being that there are still few people who are looking into the history of cancer. And so we've got some historians that are kind of doing one-off studies, and then archeologists who are doing the same, and we're really trying to push for a more comprehensive, collaborative approach with researchers from all different fields coming together and sharing this information. Are they gonna be part of the database that you're working on? Not this database, but the next database. Could you tell us a little bit about that database that you've put together? Absolutely. So when I started to look into the biological evidence of cancer and archeological human remains as pure curiosity, more than anything else in grad school, we expected to find maybe 15 instances of cancer throughout the published material. We ended up finding, well, I ended up finding, three years later, 259 published incidents of cancer, evidence of cancer and archeological record. And those right now make up a database that I'm putting together that will allow people who cannot access necessarily these articles. Some of these articles are very, very difficult to access because it's taken me three years to be able to access. And not everyone is going to have that time. And if we want grad students or other researchers to dig into different aspects of paleo-oncological research, we need to make sure that that information is open and accessible to kind of keep progressing. So this database will be open source, and it's a collection of a lot of different information, demographic information, diagnostic methods that were used for these, for this evidence, publication types, description of lesions, and it's fairly large and it's growing, and we are going to keep it growing with every published work of cancer diagnosis in the archeological record will be added to the database. And eventually, we're hoping to create a forum around this because a lot of this evidence is contended and should be, we should be looking at this evidence that especially that we're getting from the last, from 1909 to 19, or to 2000 really, we should be looking back over that evidence and making sure that we are seeing what we think we're seeing. And we'll be able to do that through this database and a forum of multi-disciplinary researchers. Is that database going to be open to patients? Because I'm sitting here thinking that, you know, how is this relevant to a current patient? Yeah, absolutely. It's going to be open to the public. Anybody is going to be able to access it. And in terms of relevancy to a patient coming from my own perspective, and just not necessarily all patients' perspectives, I remember asking myself a lot of the time what I did to develop ovarian cancer. What did I do wrong? Was it the soda that I was drinking when I was younger? Was it, you know, all of these things that really have not a lot of relevance? But that's, I think that's one of the first, that's one of the first things a lot of patients start thinking. And then my mom, my mom was thinking that too. What did I do wrong so that my daughter has ovarian cancer today? And I think it's really important to make sure patients and caregivers know that it's no one's fault, necessarily. This is something that humans have lived with for a long time. There are environmental factors, sure maybe. But there's also, we need to really be considering the genetic factors behind cancer. And to take that load off is, I think is huge. I have heard, and I'm sure there's people in the room who've experienced this, that the stigma or the fear around cancer can actually prevent people from seeking treatment. So you're seeing that this might be another way in, another way for people to get the help that they need. Have you found that kind of resistance or stigma in some of the ancient writings that you've looked at? It's hard to say because most of the ancient writings that I'm seeing are told from the physician's perspective. So they're very clinical, very descriptive. They don't really talk about the sociocultural factors that are also occurring with their patients. And you see this a lot in ancient physicians' records as well, it's for collecting data and not necessarily patient-centric. So we're not necessarily seeing this stigma in historical records yet. But again, we haven't looked at historical records with the depth that we need to. And hopefully more historians and linguists especially can kind of dig in to the historical records and to the word analyses as well. And perhaps there is evidence. In your travels, in your field work, have you encountered any sort of suspicion or curiosity about what it is you do? Or reaction to the idea of looking for cancer? Absolutely. Absolutely. I actually went back to the Valley of the Kings two weeks after my treatment ended to do another field season. And this was really important for me for my recovery but also because it's my passion and I thought I needed to, that was kind of one of the things that really got me through the treatment. So I'm in Egypt and I'm completely bald and I'm limping because they had accidentally severed an artery in my leg during the second surgery. And so I'm just kind of recovering and I'm looking pretty scary. And I was met with a lot of curiosity from my friends who are Egyptians and who are working with us and a lot of sympathy. But I also noticed that they didn't hang out with me as much as they usually do. Cause they just didn't know how to talk about it. I think in a lot of areas, in Egypt and the Middle East, there is a rather large stigma associated with cancer. It's seen in a lot of communities as a death sentence. And it's, I think especially women have a very hard time going to the doctor when they suspect cancer, if they suspect cancer at all. Cause again, people don't talk about it because of that stigma. Does cancer have, is it described in different ways in different languages? Like the translation, is it? Yeah, yeah. Again, in Egypt, actually previous to my cancer diagnosis, I was working for the anti-cancer network for American University in Cairo when we were fundraising. And a lot of time, and I was just learning Arabic. So I'm just catching little pieces here and there. And when we talked about cancer, I often hear it referred to as the bad disease. Not that there wasn't a word for cancer cause there's definitely a word for cancer, many in fact. But it was a more acceptable way to refer to cancer in conversations. It allowed that conversation to continue. Whereas bringing up the word cancer and bringing up maybe a personal connection to cancer made that conversation more difficult to have. I wanna leave some time for Q and A that have one more question, which is how? I think that this can help patients kind of understand their situation, their condition. And it's interesting from a historical and medical perspective. In terms of treatments, do you think that your work has anything to contribute to that? I think that's a really good question and something that I've been thinking about for a couple years now, because I'm not sure. To be completely honest, I'm not entirely sure if we're going to be able to contribute to treatments necessarily. But I think that there is quite a large possibility that we might be able to contribute to prevention. And that is only because we can start to understand a little bit more maybe through these large impact events like the agricultural revolution and how cancer has responded to these huge events. And industrial revolution is a really good example too. Maybe we can start to understand a little bit more how the manifestation of cancer presents itself through these cultural changes. So are you saying that you see different cancer spikes at different historical eras? Not yet, but we are, well, we only have 259 individuals. So it's not a huge data set all around the world for all of these different time periods. But it is among our massive list of research questions that we are currently asking and pursuing. So something like the industrial revolution or introduction of tobacco, that kind of thing. Absolutely. Yeah, we expect to see a rise, but we are looking for the evidence and we can only assume so much. And then we've gotta go with the empirical evidence. Interesting. Well, I'd like to open it up to questions. Does anybody have a question for Kate about paleo-oncology, ancient cancers? Yes? Thanks. My question is about trying to do a comparison. And I realize it's gonna be the same problem with getting enough data. But have you or other people had the opportunity to try to compare groups of people that were either agriculturalists or horticulturalists with hunter-gatherers? Because I know that changes the picture for almost everything in human health and disease. And I imagine it must for cancer as well. Has that been done yet or not? It has not been done. And that is my number one interest right now is how we see cancer manifest in individuals before, during and after the agricultural revolution in different societies. Because we, I mean, of course, during the agriculture revolution, we're having this enormous shift in diet and what we eat and what we're consuming. But we also have this enormous shift in activity. We're going from a very pneumatic, a really active hunting-gatherers society to a more sedentary society. And this shift happens rather quickly. So it's gonna be very interesting to look at that more. Before we can get to that point, I think we really need to focus on standardizing how we diagnose cancer in human remains and making sure that we're doing a good job. Because we can go, we can look at these individuals, but if we don't have standardized ways, we're gonna have to come back and look at them again and again and again and we can't really trust our data. So that is one of the things that I'm trying to exercise a lot of self-control with and not look at that information quite yet until we make sure that the diagnostic methods that we're using are a good diagnostic method. Yeah. Thanks so much. This is so fascinating. I'm wondering, either related to the agricultural revolution question or any of your other interests in this space, what would be your sort of dream data trove or what kind of materials, if you had like a wish list that would really help you out and how come? There are so many ossoaries and these kind of wonderful collections of human bone all around Europe. And to me, I think that there's this amazing, it is a treasure trove essentially of information for someone like me who likes to look at the human bones. So I would really like to put together a team. I mean, it would have to be quite a large team of researchers to be able to go through some of these ossoaries and collect information, not just on cancer, but other co-existing diseases. Because that's just as important as well. And so that, I mean, that is on my list as well. There's a lot, it's a large list. Another question. Yeah. Wait, sorry, wait for the plan. Great presentation. Is there an opportunity to expand this to non-humans like different animals and fossils? Absolutely, absolutely. Traditionally, I haven't been doing zoo or archeological analysis and I'm just starting to get into that in the last two years. And I think that there is quite a possibility, or not a possibility, there's a lot of, there's a lot of potential there for information gathering, especially in prehistoric animals. And we have some evidence in the Jurassic period and the Cretaceous period of dinosaurs that have osteosarcomas. And it's really fascinating. And I think there's a lot that we can learn there. But I probably won't be doing that. Hopefully someone else will though. Yes, in the back. You're 259 cases right now. What kind of age distribution can you infer from them? And how do they compare to modern age distributions? Yeah, very interesting question. This is something that I was really interested in. And again, taking into account, there are limitations. Individuals that, this is something that we think about in paleo pathology a lot. Individuals that are older, and generally older females, we don't recover a lot of information from because their bones are more fragile and susceptible to decomposition. And so we have to keep that into consideration that maybe some older individuals and some very, very young individuals, we won't be able to see cancer in the bones, not because it wasn't there, but because we can't, we don't have the preservation required. But so what we're seeing right now is rather strange and pretty even. So young adults and non-adults, we're seeing 30% of the individuals that we have in that 259 are young adults and non-adults that have evidence of cancers. And generally the primary cancers, the bone, osteosarcomas and leukemia are two of the top for those. And then for middle adults, we're seeing again, right around 30%, it's more like 26% of individuals that have evidence of cancer. And these are generally metastatic carcinomas, secondary cancers. And then we're seeing a little over 30% in the older adult age range. And this is from, in the archeological record, this is 40 years and up. And we expected that we were going to see cancer around 60, 70% in these older individuals for you now. And we thought we might not see many much evidence of cancer and young people at all. But that's not what we're finding. And so there's a lot, there are a lot of, this is, there are a lot of limitations, like I said, so there's a lot to explore here. But it does raise an interesting question. Why are we seeing cancer in young adults in those numbers in ancient society? Is it just because they preserve, their skeletons have been preserved better? And so we can actually see disease in general in their bones more. Is it because they were manifesting cancer at young ages throughout the world? These are really good questions. We have time for one more question, yes? Thank you for all this information, it's great. You mentioned going through the historical records and I was wondering if any of the physicians commented on therapies they may have implemented and what types of results they saw. Yeah, absolutely. Yeah, they talked a lot about these different therapies. This was a, this is science at its earliest, this trial and error, trying to figure out what is going to work with this individual and what's not. So actually we've got a lot of different therapies in ancient Greece and Rome that were mentioned, such as a squirting cucumber, which sounds fascinating and is not, it's pretty boring, but it's something that was used a lot the autumn crocus was used a lot and What is the autumn, like the actual crocus flower? Yeah, yeah, so that was also used and the bark of yew trees was mentioned quite a bit as well and what's interesting about the bark of yew trees is that there's a derivative of this bark that we use in taxol today. So I mean it's, I find the pharmacopia side of it extremely interesting, although I do, you know, admittedly I do not have a background to the pharmacy at all, but you know, it was proof that we were, we were thinking about this for a long time and we were trying all sorts of different treatments and there was a common goal of how can we, how can we keep people with this disease living for a long time? There is not a lot that was said about the outcomes of these treatments, but for many of these historical sources it can be gathered that they weren't effective in that. Interesting, thank you so much. It was so interesting to talk to you. Thanks. I'd now like to welcome to the stage Jacob Brogan for a short presentation called Notes on a Small Thing. Jacob is a journalist and a critic and a member of the Future Tense team and he's also a frequent contributor to the Future Tense channel on Slate. Thank you, Jacob. Cancer has a funny way of dissolving the boundaries of the self. I don't mean that it makes us question who we are, though it sometimes can. To the contrary, I mean instead, I mean that I should say, instead in the most literal sense. To live with cancer is to live with the knowledge that part of your body has become other to itself, that one set of cells has become something else, something inimical to the surrounding tissue. No mere invader, cancer is the self already made other. Maybe it's the horror of that realization that has led us to speak of cancer in martial terms. To call for a war on cancer is to anticipate our agency, letting us reclaim some of our perloined power from the disease. But some of cancer's first metaphors, as we already heard today, were more animalistic. The word itself, as you just heard, comes from a Greek root meaning crab, carcinus. In his biography of cancer, The Emperor of All Maladies, Siddhartha Mukherjee attributes it, as again, we heard today. This is what happens when you write in advance and you're talking after smart people, attributes it to the ancient physician Hippocrates, he of the Hippocratic oath who lived in the fourth and fifth centuries BC, I should say fifth and fourth centuries BC. As Mukherjee tells it, quote, the tumor with its clutch of swollen blood vessels around it reminded Hippocrates of a crab dug in the sand with its legs spread in a circle. Mukherjee is seemingly non-plussed by this origin story and he notes, few cancers truly resemble crabs. Fair enough, but if the word has stuck, it may be because it is apt in ways that go beyond mere material similarity. I thought of it last week while walking through a high-end Manhattan fish market with my girlfriend Catherine. On the shelf of a cold case, someone had displayed three or four elegant, beautiful, and very expensive crabs on crushed ice. As we got closer, we noticed that they still seemed to be alive. Maybe this was just some kind of autonomous reflex, but their cartilaginous mouths were yawning open and shut as we approached, gasping seemingly in the unwelcoming air. Strikingly, their eyes had been removed, presumably because none of us wants to see our next meal watching us, least of all on motile eye stocks. Now, our species treats many animals monstrously. We do terrible things to almost everything we eat. Watching the crabs, though, it occurred to me that we rarely present such treatment as a signpost of the commodified creature's quality. A modern market could not have shown the crabs this way, I think, unless we thought of them as profoundly distant from our own form of life, which I believe we do. While things were likely different in Hippocrates' day, I confess that I know relatively little of animal welfare in the ancient Agora. Perhaps his image stuck for its metaphorical implications, despite its anatomical inexactitude. Cancer, like the crab, strikes us as fundamentally alien. Where cancer is concerned, though, a paradox of sorts hides in this alien quality. If cancer is alienating, there is nothing that cancer patients want more than to be alienated from it again. I know this feeling all too well. Almost exactly three years ago, I learned that I had papillary thyroid cancer. As diagnoses go, it could have been far worse. Papillary thyroid cancer is, I soon learned, one of those cancers that you are more likely to die with than from. I suspect it is, there's a lot of it in the ancient record, if you're looking for it. Objectively, I knew it had been there for months and maybe years. In the blog I was maintaining at the time, I called it a small thing, and sometimes referred to it almost affectionately as my slow-growing stranger. Still, I was horrified by the mere knowledge that it was there and desperate to have it out. My doctors were eager to oblige. That's what doctors do. They like to remove cancers, especially when it's easy. In June 2014, just a month after my diagnosis, a team of surgeons at the Washington Hospital Center put me under and made a small incision, maybe an inch and a half long, at the base of my throat. While I was down, they carefully extracted my entire thyroid, which is a globular mass that, as my surgeon told me, arguably resembles a butterfly, but only if you squint. Recommend going and looking at a thyroid sometime and seeing if you agree. They also took out a few smaller glands called parathyroids, I think we have four of them or eight of them or something, and they took out two that apparently didn't look quite right. Much later, I asked if I could see a picture of the cancerous tissue that they'd taken out. I'd heard that surgeons sometimes pose for pictures with particularly impressive tumors, like fishermen showing off a catch. I knew mine wasn't much to look at, so I probably shouldn't have been surprised when my own surgeon responded with a simple bafflement at this question. They had, of course, just thrown my thyroid and the accompanying tumor out shortly after removing it. I think, though, that I just wanted to know that it really was gone, that it really was outside of me, somewhere, anywhere, not in my throat, and it was. But, of course, you don't just take out a thyroid without consequences, it is actually an important organ. The hormones that it secretes are crucial to the body's functioning, variously regulating energy levels, mood, even weight loss and gain. Small, as this organ is, small enough, remember, I mean, you can perhaps even see it, that the incision on my neck was quite short. The body can barely carry on without the thyroid. Treatment, fortunately, for me and many others, is simple enough. In my case, is just a massive daily dose of a hormone replacement drug called Levothyroxin, which is, I think, the generic of a drug called Synthroid, that effectively jump-starts much of the endocrine system. I consume 300 micrograms of it every morning, which, if you are an endocrinologist, you know, is a lot for someone of my build. I do that well before I do anything else. It's the first thing I do every day. So long as I remember to do that, everything is fine, but without it, I would be a puddle before long. The slight irony of this does not escape me. Extracting the alien tissue took just a few hours, but now I ingest an alien substance every day. Today, my body barely turns on without this daily reminder of the cancer that I had. This reminder also to the parts of my body that they belong to a more meaningful whole. In, this is another one of those moments where you're talking after smart people. In a recent article for Slate, and also her talk today, Athena Actopus asks us to imagine the human body with its 30 trillion cells. I miswrote that number twice while I was, it's a lot of sales, twice while I was writing this, as a fundamentally collaborative organism. Though not every element of the system interacts directly, every one of those pieces and parts that makes us up supports the others, at least under ideal circumstances, if only by helping to guarantee the survival of the whole. But if collaboration, as Athena told us, is in their collective interest, it isn't always in their individual cellular nature. Sometimes a cell here or there figures out that it can divide faster than it should, take more resources for itself. This, Actopus writes in her article, is this cellular version of the tragedy of the commons. Or to put it another way, this is cancer. What cancerous cells lack, in other words, is the same thing that we all lack. A totalizing understanding of the world of which we are a part. A world that needs us almost as much as we need it to remain a whole. Few thinkers have understood this problem better than the 17th century philosopher Baruch Spinoza. A theorist of totality, Spinoza would nevertheless protest in his correspondence, which was copious with the scientists of his day, that he was incapable of describing how exactly the whole fit together. To know this, he wrote in a 1665 letter to Henry Oldenburg, it would be necessary to know the whole of nature and its parts. Needless to say, Spinoza, a humble man, who was a lens grinder by day, did not believe that he knew the whole of nature and its parts. In order to explain, though, what he meant, he offered Oldenburg what may be the most simultaneously disquieting and adorable animal example in all of philosophy. Now, let us imagine, if you please, he wrote to Oldenburg, a tiny worm living in the blood, capable of distinguishing by sight the particles of the blood, lymph, et cetera. He, if you go read the full letter, he names a lot of parts of the blood that we don't call parts of the blood anymore, I think. But it was the 17th century. And of intelligently observing how each particle on colliding with another rebounds or sometimes communicates some degree of its motion. He thought of this worm as a sort of scientist, an observer of the system it was in. But where we humans see the blood as a whole, recognizing blood as blood, Spinoza's nematotal scientist lacked such adequate knowledge to use Spinoza's term, adequacy. Capable of recognizing only the relationship between the distinct bodies amongst which it swam. That worm, Spinoza writes, would be living in the blood as we are living in our part of the universe. For we, too, he suggested, see only the relationships around us and not our relationship to the whole. But where Spinoza's worm swims peacefully, cancer, we might say, revels. Cancer, we might say, reveals in miniature the possible consequences of inadequate knowledge of the whole, of the total, of the systemic. It kills us because it cannot see that it is killing itself in the process. Let me admit some inadequate knowledge of my own now. Though I am endlessly grateful to the doctors who treated me to my wonderful endocrinologist, to the endocrine surgeon who led my surgery, even to the cranky German anesthesiologist who put me to sleep. Though I hope I never see him again. I genuinely don't know if they should have taken out this cancer that was growing inside of me. It was not, as far as I know, killing me. There are dangerous varieties of thyroid cancer, but mine did not count among them. It does not count among them. I sometimes suspect that it was my relationship to the word cancer rather than my diseases relationship to my body that horrified me most at the time. It's a horror, as I've suggested, that inheres in Hippocrates' founding metaphor for this mess, this morass of diseases that share a single name, carpinos. If my cancer hadn't been called cancer, would my doctors have rushed to remove it? I don't know. I know this though. A few weeks ago, I visited the National Aquarium in Baltimore to talk with a veterinarian for the Slate podcast that I host, Working, where we just talk to people about what they do all day. My producer and I, even though we were just looking for daily details, still like to get exceptional ones, so we asked if she could tell us about a particularly memorable surgery. And to our surprise, she didn't bring up really cool fish or what it's like to fix a sick dolphin or sea turtles or any of the fun stuff that you think of when you think of an aquarium, but she brought up a surgery that she performed on a gecko. They had this one lizard, she said, with a large ventral neck mass, a lower neck mass. At first, they couldn't figure out what was wrong, but when they opened up the creature's neck, they realized that there was something off about its thyroid. Not cancer, necessarily, but something bad. As in my own case, it sounds like it was easy enough to remove the organ. It's complex, but it is removable. But afterward, they had to figure out, as they do with human patients, how to replace the thyroxin that their small reptilian patient was no longer producing on its own. The solution, it turned out, was to give it the same drug that I take. Take an extremely, extremely small dose of levothyroxin or synthroid or something like it. You grind it up really small and feed it every day, just as I am fed, by my own hand, every day, the drug to it. So the synthetic hormone replacement that now regulates my body's basic functioning also maintains the liveliness of this lizard, a creature separated from me and from you by millions of years of evolution. We hear all the time from scientists that we share huge amounts of our DNA with all other living things, but that legacy had never really come home to me before. In so many ways, homo sapiens and ghakata couldn't be more distinct, but I was oddly heartened to learn of the things that we have in common. This is the lesson I took from my distant quadrupedal sibling. Otherness and strangeness are always more finite than we realize. It's what we have in common, ultimately, that saves us. Long after my surgery, I wrote in my blog of a dream I'd had. I wrote that in the dream, my tumor had become something else. No longer cancerous, no friend, it was not a monster either. It was just a lazy roommate. It's unwashed dishes piling up in the sink. Though that image lingers, I'm still glad my cancer is gone, even if my life is a little more complicated for its absence. And yet, when I think of that small thing now, I try to approach it as I do the gecko, inclining toward that more adequate knowledge, a knowledge of association and interdependence, that my cancer and I both lacked. Cancer terrifies because it forces us to consider that our own bodies have become other. Countries divided against themselves. For me, at least, recovery and life after tell a different story, suggesting that our others are closer than we realize. Thank you. Thank you, Jacob, that was magnificent. To kick up our final conversation, changing the way we think about beating cancer, please welcome our moderator, William Salatan. William Salatan is a national correspondent for Slate. Come on up, and your panel can join you. Come on, folks. Katherine, how much time do you wanna save for questions? Just give me a signal. Okay, okay. You got it, thanks. So this, first of all, we've got a lot of smart people up here, so my job is basically to get them started and then get out of the way. Let me first tell you who they are. I will, I'm just gonna do this alphabetically because that's the way I put it down here. First of all, actually, Athena's down at the end. I wrote a bunch of stuff about her, but you already got an introduced to her. So the only thing that I had written down that wasn't already said is that she has an appointment in psychology, so at some point I wanna hear how that relates to everything. The, she did kind of mess up my whole understanding of this because I came in thinking that we were gonna build a big, beautiful wall to keep out the cancer, and it turns out it's more like a corporate polluter, so my whole model is messed up. Next to me is Donna Marie Manassi. Did I get it right? Okay, good. She is the director of breast surgery at the Maimonides Breast Cancer Center. If I get anything wrong, let me know right away. She's an advocate for empowering women by educating them about breast health and disease with the idea of detecting disease earlier and improving prospects for treating it. Next to her, actually not, oh yes, next to her is David Rees. He is Senior Vice President of Translational Sciences and Discovery Research at Amgen. He heads up the company's drug and therapeutic development sector, and he serves on the board of the Amgen Foundation, and before that he directed clinical research at the Breast Cancer International Research Group, and he co-founded and was President and Chief Medical Officer of a not-for-profit academic organization, Translational Oncology Research International. Last night I was driving home and I was listening to a panel that he did with some other folks last year on immune, what was it, immune checkpoint blockade therapy, a term which many of you probably know, but all I can say is I didn't drink anything and that was the most dangerous drive I had, just listening to this panel and trying to understand the complexity of it. And next to him is Joshua Schiffman. He's Professor in the School of Medicine at the University of Utah and the Principal Investigator at the Huntsman Cancer Institute. He works with high-risk pediatric cancers and leads a lab that studies evolutionary medicine and comparative oncology with the goal of identifying universal drivers of cancer risk and cancer development. So the topic we were given was changing the way we think about beating cancer and I had a bunch of stuff to say about it, but Jacob said whatever hadn't already been said by Catherine so we're gonna discuss some of these new models and how we can think about it. Before we start, I just wanted to lay down a couple of ground rules. The first one is the Kellyanne Conway Rule, which is if you don't like the question I asked you, answer a completely different question that you wish I'd asked. Okay. The other one is the Donald Trump Rule which is you don't even have to wait for the question. If you have something you think that the American people need to hear, you can just interrupt and say it. But I thought that I would start off by asking a general question to Dave about because you work in clinical research and therapy development and we've had some theoretical discussion here, but can you talk generally? Can you just give us an overview of where we are? The limits of our progress in studying and understanding and treating cancer in recent years and the crisis of reproducibility and research and how to think about where we are and what we need to do differently in terms of rethinking, reconceptualizing the disease and investigating new ways of approaching it. Okay, so that's about a seven hour answer. So where are we? I actually think we're at an inflection point. If you want to take the long view over the last half century or so, we've devoted an enormous amount of effort to actually trying to understand what makes a cancer cell tick and that understanding was covered by a lot of the things Athena said earlier, for example. And we have a pretty good understanding of what that is right now. It's not perfect, it's hardly perfect, but it's pretty good. I think also what we now understand is cancer in the sort of broader ecosystem of the body or the body's ecology and that has led us, I think, directly to where the most interesting developments are now occurring, which is in the area of what we call immuno-oncology or harnessing the body's intrinsic immune system to fight cancer. If you want to ask a very basic question, it would be why do we get cancer? So one answer is bad luck. We're multicellular organisms, those cells divide a lot of times, they can accumulate mutations. There's another side to that question, which is why does the immune system actually not recognize those tumors and eliminate them? And it turns out that a large number of cancers really have devised a variety of clever ways to evade the immune system. They basically can fly under the radar. And so in simple terms, a lot of our effort now in new drug development is making that cancer visible to the immune system again and then activating that immune system. There's no question in my mind that we're at a watershed moment. I mean, the things we're doing now, when I was in training 20 years ago, we couldn't really have thought about doing much of that enabled by rapid inventions and technology. 20 years from now, I think things will be much different as well. Let me go to Athena and ask, most of what I wanted to ask you, you've already just did in your talk, but there's one thing that I really was curious about that you didn't get to in the talk. And by the way, if you want to add in anything that you couldn't squeeze into it, just throw it in here. That the idea that cancer is not a coherent enemy, that it is the plurality of cancer. And I think this was from your article in Slate that I saw this, the idea that it's an evolutionary environment in which different cancer cells are actually competing with one another. And there's a concept called competitive release that you introduced there. Can you explain how this plurality affects, for example, drug resistance? Sure. Yeah, so cancer itself is a really diverse entity. Even the normal cells in our body are not genetically identical because mutations just can arise during normal cell replication, but cancer is often very genetically diverse. Sometimes it has actually breakdowns in the parts of the genome that regulate the DNA repair also. So you can have hugely diverse tumors. And what that means is that when we go to treat cancer, that it's very likely that there will be cells that are already that are resistant. And they may be just a few, but when we treat cancer with a drug that kills 99.99% of the cells, we still have 0.01. And when you have millions of cells in the teeniest tumor you can imagine, that's still quite a few cells that remain. And in ecology, there's this phenomenon of competitive release, which you mentioned. And that basically is a mechanism where when you remove competition, then the individuals that are left have space, have resources that they can then use. And we think this might be what's going on sometimes during relapse is that there'll be maybe pre-existing resistant cell clone that's there we treat and then we leave the planning field open for that resistant cell to basically take over. And then when you try to treat it the next time, it turns out that the drug is either not as effective or possibly not effective even at all for the second round. Is there any connection between this and metastasis? Do we end up favoring metastasis with some of the drug interventions we do, or is that a completely separate phenomenon? There's some very suggestive evidence that some of the therapies that we use, like for example anti-angiogenic therapies, those are therapies that were sort of designed to decrease the amount of blood flow that the tumor would get. Actually that kind of treatment was associated with smaller tumors but more metastasis. So the ecological dynamics that are happening as cells are leaving the primary tumor, growing, basically colonizing new environments within the body are really complex. I think it just now really is ecological theory, really meeting our understanding of how cancer starts in the body and then how invasion and metastasis occur. But to me it's a really exciting time because we have so many tools in ecological theory that have been developed by really smart people over so many decades now and we can really leverage that I think to better understand what's happening in cancer. I think we get even more complex because we're now learning with the biology and the science that there are some cancer cells, an individual cell that can switch its phenotype, meaning it can stay part of the tumor, then it can change molecularly, float through the bloodstream, go where it needs to go and then change again so it can set up shop. So how are you gonna attack something that's changing on you like a chameleon? And it's really, it's like a chess match. Well it's classic evolutionary biology. You can think of the treatment as applying a selection pressure and cells that are able to survive those selection pressure, that selection pressure are the ones that move forward. So much of what we think about when we're trying to develop new drugs are how do you just cut it off? How do you corner that cancer cells so that it can't escape? Cancer cells are actually very inefficient. They're metabolically inefficient because of all the mutations, I mean they're messed up and we need to try to take advantage of that as well. How ambivalent are these cells you're talking about? They can't be persuaded to become, they can fake being a normal cell? They can... Well so the flexibility of all the cells in our body is kind of amazing but cancer cells in particular can be very, very flexible in terms of changing. And in fact there have been studies where they take a cancer cell and put it in I think a mouse or a frog embryo that's growing and the cells will behave completely normally even though they're totally cancer transformed. So the environment makes a really big difference for whether what we see looks like cancer or not. And remember the immune system actually has a major role in this. I mean as David alluded to, some of the drug therapies that are coming out are trying to get the immune system to do its job. Basically the cancer cell has figured out how to basically use the immune system against itself. So our immune system's job is to protect us from foreign invaders. But part of that job is also not to consume our cells. And so cancer cells are actually using that mechanism so they can stay under the radar. So even though these cells may change genetically and can try to evade if we get the immune system to do its job through certain mechanisms, certain drug therapies that we use, certain environmental changes, the immune system can actually attack some of these cells that are actually changing on the fly. One of the themes that I'm hearing in the conversation is that there is sort of a purge model. Get rid of it, right? And then it sounds like there's another model which is to manage it if you can affect the environment so that it is not. So for example, we don't have to take your thyroid out, in Jacob's case, if we can somehow manage the environment or affect influence the cells rather than destroy them. Is that correct? Yeah, I think there's a really exciting opportunity to leverage the body's sort of innate cheater detection systems. And the exciting advances in immune therapy, I think are an example of this because our immune system is one of the most important lines of defense against cancer. And cancer manages to somehow get around so much of what the immune system does. I mean, in a way, it's kind of like paying off the police or something, right? You know, our immune system is trying to make sure that those cancerous cheating cells don't get out of control, but they manage to somehow still get not just the immune system to leave them alone, but sometimes the immune system to actually help them. So I think that is one great example of how we can sort of take the body's natural ways of dealing with cancer and potentially enhance those. And then also targeting genes that are associated with the more intrinsic cellular cheater detection mechanisms like P53, which Josh has worked on a lot. That really is sort of the cells' intrinsic way of policing itself, right? So that it isn't cheating. You mentioned my favorite genes in Amman. Yeah. But I will just to correct one thing you said earlier. So I'm actually not the principal investigator of Huntsman Cancer. I'm one of many investigators. I don't want people to know. Not even a principal. I'm just an investigator among many. But let me tell you about P53 because this is really exciting. And I think the other aspect that's really interesting now and is taking up steam is the field of comparative oncology, which I'm very involved in. So I'm a pediatric oncologist. I'm a clinician, but I have a laboratory as well. And so we try to merge this idea of translational science, which David does. And it turns out that there are animals that naturally avoid cancer. They've evolved over millions and millions of years to become cancer resistant. And I always talk about my friends and colleagues in Big Pharma who spend, what is it, about $100 billion a year on drug development overall, which is a lot of money. And usually after, for the most part, three to five years, if a drug doesn't work, you have to change direction and you have to keep, is that a fair statement? A little longer, but you're in the ballpark. In the ballpark. Well, animals have had millions and millions, tens of millions, hundreds of millions of years to evolve different strategies for avoiding or resisting cancer. And so the ones that Athena and I have worked on together and others are elephants, for instance. So elephants are 100 times the size of people. That means instead of 30 trillion cells, they have 300 trillion cells. And that many cells dividing over and over again, elephants live 60, 70 years. So 300 trillion cells dividing decade after decade after decade, just by chance alone, all of these elephants should be dropping dead of cancer. In fact, dying before they could even go on to have more baby elephants, and then they'd go extinct, right? And so extinction isn't a good strategy for survival. So the elephants must have had some way of avoiding cancer. So it turns out, working with Dr. Maley and others at Arizona State University and collaborators across the country, we learned that instead of two copies of this P53 gene that humans have that help us to avoid cancer for the most parts on 100%, instead of two copies, like in humans, elephants have 40 copies. And so that's just one example, 40 copies, right? And this is what we think potentially is helping to keep the elephants for the most part resistant from cancer. They do get cancer, but at a much lower rate than expected. So that's just one example. Whales don't get cancer, naked mole rats don't get cancer. So does nature have a prescription for us of how we as humans could start avoiding cancer or treating cancer? Well, behind your question, Whale is actually another probably very fundamental question, which is what is our notion of cure? And so you could kind of take two broad views. Cure is elimination of every last cancer cell from the body. That's our traditional description. And I think we're evolving more towards a notion of cancer control and what I might call a functional cure. If we harness the immune system to attack a widely disseminated cancer, eliminate much of it, but not all of it, but it's just sitting there and it's not doing anything. And it's not doing anything for a long time. Does it matter that there are cancer cells? That may be a functional cure and one of the goals may be to have that patient live a long natural lifespan. They may never be technically cancer free, but we want it not to matter. Okay, Donna Marie actually deals with patients. So you just heard this, do you buy this? Is this a way you can actually work with people? It's interesting because the number one question I get from my patients when I treat breast cancer is, will I be cured? And I often say in trying to be hopeful that depends on what you define as cure, but you will not have to deal with this disease for a very long time. You will see your grandchildren, you won't deal with this disease. And that's not a bad thing. I do buy exactly what David said. I wouldn't be in this business if I didn't. But I think his point is more relevant today than it used to be say 10 years ago where we approached cancers as I'm a surgeon. I'm gonna go in there and cut this thing out. You're not gonna deal with it at all. It's coming out of you and I'll walk out there and I'll be the hero. And then somebody else is gonna poison it and then somebody's gonna burn it and all those wonderful things were happening, but then there's a person there who has to survive what we're doing. And that was one way to do it and we did it that way for centuries. And the problem was that some people survived, some people didn't, but did we really do anything? And we were looking at cancer as something to take out of the body. When it really is just a distortion in the system and it wasn't just the cancer with this foreign invader or this bad cell that changed. It was also that our immune system or the environment around us was not interacting and talking and communicating in a way that allowed that person to survive or not have this disease. So today, a lot of the therapies that we use in breast cancer that are very effective work on the notion that we're effecting using the immune system to treat those diseases and person to live with their cancer. 10 years ago, somebody who was diagnosed with stage four, they were planning their funeral. They walked out of the doctor's office and they planned their funeral. Today we have people who are stage four disease where disease has gone everywhere. We give them a drug therapy. Most of the disease you won't see and they'll live 10 years, 15 years out without a problem. And so yes, they have to be on some maintenance therapies, but they live a healthier quality of life even though there are cancer cells that are actually still living in their body. So I definitely buy the scenario that we have to learn how to live with this disease or live with these cells. I don't even know if we can even refer to it as a disease per se, it's just a state. You're in a cantering state per se. Not to say that this is foreign invader we have to attack or fight with. So psychologically and socially, what does this new era look like? You're seeing it now. What is it like for people now? Is it, how is it different from the way it was 10 or 20 years ago for someone to be told and to think, I have this, how are they treated differently? We heard Kate's story. Are people socially going to be regarded as not the walking dead the way that used to be? It's a great question. I think it depends partly what culture you're in, what society you're in, if you're in a city area or a non-city area. I think, especially in breast cancer, I think one of the things that led to breast cancer happening the way it did for generations is that women didn't talk about it. There was a fear. Your grandmother died of something. I don't know what it was. It was kind of a pariah scenario, which to me has always been one of the things that I emphasize when it comes to educating women is by you telling somebody else you're saving somebody else's life. Go get an exam, do your mammograms. You can survive cancer by doing that. And I think today there's much more of a conversation if you just hit the month of October, which happens to be one of my favorite months because it's my sister's birthday. But other than that, the entire world is pink. People are talking about breast cancer, talking about what breast cancer is. It can be treatable, it can be cured. Because of that, we have Susan G. Coleman who rates a lot of research money, et cetera, et cetera. Women do well. You take prostate cancer for men who never do anything when it comes to their healthcare. Someone like Mike Mokin gets prostate cancer, puts a lot of research to it. Now we have a blue month for men for prostate cancer, which I know most of you guys probably may or may, well, you guys will, because you're cancer docs, but some people don't even know about. And so I think cancer today is not a dirty word. I think that some older cultures may still kind of sense it. I actually happened to practice in Brooklyn where there are a lot of different cultures. Muslim, I think, exactly what Kate said is exactly true. For some of the other populations, I can't even tell the person they actually have cancer. They have this thing growing that I'm going to take out. And I appreciate the cultural reasons behind it, but it's actually doing them a disservice because in order for you to be able to do what you need to do with that disease, which by the way is not just what I do, but eating healthier, exercise, all those things actually contribute to helping the immune system do its job. Just to pick up on a really important point about sharing family history and who has what. As trained as a pediatrician, I said pediatric oncologist, but a pediatrician first, I'd much rather prevent cancer than treat cancer. And we don't yet have a way of preventing cancer, but we can catch it early. And we know the earlier you catch a cancer, the better the outcome, whether it's immunotherapy, surgery, chemo, radiation, or combination. So how do you figure out who's going to get cancer and when? Well, the number one predictor really is family history. So if you're able to collect your family history, you know if cancer runs in your family, you could get the appropriate screening before you have symptoms. The other flip side is genetics, right? There's a very large genetic risk for cancer. In fact, at least one in 10 of every cancer is caused by an underlying inherited gene. And if you could identify that gene before you get your cancer, then you can intervene. And that's gonna change outcome. And the number is even higher in children who develop cancer. I gotta ask you about a puzzle here that's killing me as you're talking. You were talking before about the elephants. The elephants evolution has weeded cancer out of the elephants almost not entirely, but close to it, right? Meanwhile, you deal with pediatric cancers. This is killing people before procreation. So how is this still around? Why? Well, there are about 1.6 million new diagnoses of adult cancers in the US every year. Do you know how many children there are who develop cancer? It's about 16,000. So much, much fewer. And so that's a problem for resources and other areas of research because we have to try to get everyone together to focus on these kids. The number comes out to about one in 300 kids will develop cancer. Do you know how many adults will develop cancer in their lifetime? Half of all men and a third of all women. So that means if we divided this room in half right now, everyone on? Yeah, don't do it. Ah, I don't know. Well, they invited us over here because everyone on this side in the room, you're gonna have cancer if you haven't already. Don't do it. You're looking nervous. You can switch, there's an MPC right there. But so half of all men, a third of all women. So cancer is part of life. But in kids, it's much rare. It's much less likely. So although it does happen, although there is a large genetic component, it's not enough to wipe out the human species. I remember with genetics, which is a very important thing, especially in, for example, in my case, women with the block of gene, the gene that increases yours for breast cancer. Just because you have that gene, it is not guaranteed every single person with that gene will have that disease. There is a concept of epigenetics, which basically is that even though your gene may say you could get breast cancer with this defect, depends on how that gene's activities actually manifested. Is it influenced by things in your environment, the internal environment as well as the external environment? You know, if you take two women who are bronchopositive, one lives a really healthy lifestyle, she's less likely to get breast cancer compared to that same sister with bronchogene who lives an unhealthy lifestyle. So there is a lot of hope in the essence of cancer when you try to think about, instead of just like here's this invader that we're trying to take out and poison or burn, but there's actually things that the individual can do and the community can do to kind of enhance the fact that this disease is something you can live with. And you can couple that with surveillance. So come back to this P53 gene, my favorite gene. So I told you humans for the most part, we have two copies and we have about a 50% lifetime risk of cancer. Elephants have 40 copies and have about a 5% risk of cancer. Some of the patients that we take care of also with breast cancer, actually instead of two copies, they only have one working copy and they have something known as leaf romani syndrome. And if you only have one working copy, your lifetime risk for cancer approaches nearly 100%, often at a young age. So imagine that sort of Damocles hanging over your head. But we've recognized the genetic risk and now we're actually doing, this is part of the NCCN guidelines, national guidelines for cancer screening. We do whole body MRI, head to toe. And you know, we're finding patients with cancer before they even know they have cancer. So they're walking around with cancer but we're finding it while it's small and we take it out with surgery alone and they go on to live a long, healthy life where otherwise they would have died. So coupling the genetic risk with surveillance, family history and then good drug development, I think we're turning the tide or we're on the cusp perhaps, hopefully we're turning the tide. Probably be remiss if we didn't point out that we've been talking about cancer as a monolithic thing but it's actually 200 different diseases which can be very, very different on a molecular level, one from the other. So the challenge is understanding all of those and then customizing what we do. There are common pathways and common themes but there are unique features, both among tumors and actually within tumors. I do wonder if in retrospect the people will look back at our era and say that's the number one thing. The way we talked about cancer as though it was a thing, it turned out to be a whole world. Yeah, I mean an oncologist doesn't think of cancer. We actually don't even think of breast cancer or ovarian cancer. We think of molecular subsets of each of those, many of which are actually now precisely defined. What, sorry. I wanted to expand out to thinking about this question you brought up earlier of how do we think about curing cancer in the context of all this complexity and one thing that's been really striking to me from looking at cancer across species and thinking about what happens across the lifetime of an individual whether it's a human or an elephant or a mouse in terms of cancer susceptibility. I'm really struck by the fact that cancer is not so much this all or nothing proposition like we often categorize it as, right? Like either you have cancer or you don't. Well, actually all of us have many, many mutated cells. Some of us have cells that if we could pull them out and look at them they would look like cancer but they're not doing anything that's damaging because the cells around them are keeping things under control or the immune system is policing effectively. And many people when they die they have prostate cancer or breast cancer and didn't know it and weren't symptomatic. So I think more about not how can we get rid of cancer or how can we destroy it but how can we live with it and die with it but at the time we would have died otherwise. So how can we keep it under control in the way that allows us to live the long, happy lives that we can? Well, cancer is a good example. If all men lived to age 120 the rate of prostate cancer would be close to 100%. Now the vast majority of those wouldn't be bothering anyone. Right, right. I had a bunch more questions but I wonder whether we should bring in the audience at this point. Do you want to, okay. Yeah, so I'm wondering with Esther Dyson, I care a lot about this. I'm on the board of 23andMe and I had cancer and so forth. First, in terms of talking, maybe it's not genes causing but genes increasing the vulnerability of the cancers that are all kind of late in there but the specific question was about P53. What bad things does it do presumably that means that we don't have 40 copies? Yeah, sure. Why would we not want it? Yeah, why don't we have 40 copies? Well, this actually gets a lot to what Athena's work is and so you have to take a step back and understand things in an evolutionary context, right? And so what is the life history? It's sort of like bringing coals to Newcastle sitting next to Athena and talking about life history but what is the life history of an elephant versus a person versus a mouse, okay? So you start with an elephant. An elephant gives birth. I said to 300 pound baby elephant. It takes about 10, one elephant at a time. Usually it takes about nine, 10, 12 years before the elephant retires then they have another elephant. It's very slow, long-lived life. And so the grown-up elephants need to be around also to sort of help raise that baby elephant. Now you look at humans, right? And in sort of the evolutionary context and life history of humans, you know by the time we're 20 or so, you know it's already we're ready to have kids and by the time we're 40 or 50 we're not having kids anymore and if the grandparents die of cancer well we've already propagated the species. And then you look at a mouse. A mouse only lives a couple of years but they have many, many baby pups at a time and they're actually picked off in the wild before they reach the age two or three so their cells aren't around long enough to develop cancer. So if you take those three examples a mouse hasn't really developed a lot of resources to prevent against cancer because they're gone before they already have cancer and they've already reproduced a lot. On the other extreme the elephant needs to be protected from cancer because of their growth and their size but also the way they raise their one baby elephant at a time and humans are somewhere in the middle. So the reason that humans don't need to be more protected from cancer is they've already passed on their two copies of P53 as they reproduced. But the other thing that's important is to recognize what happens with extra P53 because there's always a cost. So they've done experiments in mice actually and they've created what they call super mice, right? And these aren't mice in underpants with a cape behind their back but these are mice that they've actually put in extra P53. So they're almost like the elephants in that sense. And these mice where they put in the extra P53 the super mice, guess what? None of them got cancer even though they tried to do all sorts of things to give them cancer. So they were protected from cancer. But what was the cost? They actually all aged prematurely. So they actually died of old age in an earlier timeframe because that extra P53 was killing any cell that had a mutation but then their cell turnover was quicker. But then they redid the experiment and they put the P53 in in a way that would only be turned on when it needed to be. Those mice lived the right age and didn't get cancer. Now the one follow up question that I'll turn back to you guys because we think about this when we discuss prevention and what's the cost. What if there was a pill where you could just like take elephant P53, right? And actually we're working on that but that's another story for another time. But what would be, but it's a long way away from development. It's a long way. We're not quite at the Amgen stage. We got, yeah. Yeah. Talk to me. Yeah, anyways. But what would be the acceptable cost? And I've had students and we talk about personalized medicine. I should have, if we had a pill elephant P53 or other ones it doesn't matter what the drug is. And I told you this drug would 100% prevent cancer. 100%. So instead of having a 50% lifetime risk you never get cancer. But you die one year earlier. Would you take it? People are raising their hands. What if I had a pill and you took it every day and you never would get cancer ever but you'd die five years earlier? Would you take it? Well now some people are not in there yet but not out. What if you died 10 years earlier but you never die of cancer? And so you can keep playing that game. So there's a cost and a benefit of all of them. But thank you for a great question. I'll also add that there are some cancer suppression genes that seem to also be associated with lower fertility. And this is an area where it's sort of actively being researched but for example in the Utah population database there are women who have BRCA genes that basically what this suggests is that having more susceptibility to cancer can also be associated with greater fertility in some cases which could actually tip the evolutionary scales in favor of cancer suppression in some cases. So this is all really exciting and interesting. It brings epidemiology, evolutionary biology, cancer prevention, cancer treatment, sort of all together in a very exciting interdisciplinary context where I think we're now all starting to operate realizing we need to be all sort of working together to understand the multifaceted nature of cancer. Sometimes you read in the popular science literature things like, well, sickle cell anemia is like a terrible disease but it had a kind of evolutionary benefit because people who carried the mutation, I guess, didn't get as much malaria so in certain regions of the world it was a good thing and I'm just wondering if since you're talking about all the overlaps between some genetic aspects of cancer suppression and some other aspects of animal life or the human life, whether it's possible that there could be some, I'm gonna put it in air quotes, benefits to having some genes for cancer susceptibility? That's a great question. So we can all agree that cancer is a bad thing, right? Cancer is not a good thing but I think there is an open question of whether susceptibility to cancer may be there because of other benefits that our ancestors thought as a result of having those genes. So if higher fertility was associated with those genes or having a longer lifespan if you didn't get cancer was associated with those genes. As long as there's some mechanism for a reproductive benefit to happen then evolution could actually select for susceptibility to cancer. It seems so counterintuitive, right? Like how could evolution select for susceptibility to a disease but if the sort of evolutionary calculus works out that you get more individuals reproducing who have that susceptibility then you can actually get selection for, yeah. I think one way to understand the amazing question is cancer oftentimes hijacks cellular mechanisms that we have for normal life circumstances. So the one that we talk a lot about is wound healing, right? So I've got a little cut on my palm here and it's been healing over the past couple of days and that's a good thing for me because the cells are dividing and then it will scar up and the scar will go away and I'm fine. But a cancer cell, what it does is it uses the same mechanisms but then it doesn't turn off when it should and it basically just keeps going and going and going. So it's not so much, it's a genetic susceptibility in terms of taking advantage of our genetic systems that are already in place to make us who we are today. Yeah, the wound healing is a great example because cells also need to be able to move in order to close a wound so it doesn't get infected. And lo and behold, all of the cells in our body then have this ability to move that can be turned on with the right circumstances. So we have this susceptibility that may actually make it more likely that invasion and metastasis occur because our cells are ready to heal a wound if necessary. Other questions? Somebody got one for the clinical side of the panel. Let's go, let's go. Yes, I'm wondering if any of you are familiar with the tropoblast theory of cancer that was first enunciated, I believe by Dr. John Beard about 100 years ago, the British embryologist. And I'm biased in asking the question because the foremost practitioner of his theory or of curing cancer is a doctor who I went to 25 years ago because I had advanced metastatic cancer and here I am. So, as well as hundreds of other people have had equally wonderful success with that theoretical and practical approach to cancer. So, I am familiar with the trophoblastic theory. I think now, what we understand about cancer is that many cancers sort of recapitulate programs that our cells run during embryogenesis. So they are embryological programs. They're some of the things that actually allow those cells to survive. In adverse conditions and to migrate in particular because when you are growing a body, many cells are moving in a coordinated fashion to different areas. So, there is actually a fair amount of overlap if you look at the molecular level between what's happening in embryogenesis and what cancer cells are doing. Yeah, I'll add there's another really exciting and interesting development related to the kind of trophoblastic sort of phenotype that cancer cells can have, which is we know now that during gestation there's a lot of transfer of cells between the mother and the fetus. So, fetal cells go back into the mother, maternal cells go back into the fetus and those cells lodge in the breast, in the brain, in the tissues all over and they actually are metabolically active, they're expressing genes, they're doing things. And this has been going on since, at least the beginning of mammals. And so, to the extent that this microchimerism, these sort of trophoblastic cells that don't just go into the uterus but go throughout the body and survive in those areas of the body, that actually looks a lot like certain things that happen during cancer progression in terms of invasion and then that metastasis. So, we may be able to learn some really interesting things about how to keep metastasis under control from looking at this microchimerism where you have these cells and these colonies of cells that are living throughout the body, expressing genes but not necessarily contributing to disease. Sometimes they do but sometimes they're also associated with health, so. We have time for maybe one more question and then I want to get the folks on the side of the panel to give us a verdict on the utility of some of this stuff or how we might apply some of these concepts we've been talking about. Thank you. First, I'm actually going to be in trouble as Katie Hunts can be mortified that she's looking for a doctoral program that has a healthy, I mean healthy, stipend. So, if you know anyone, please. My question, epigenome has been mentioned a few times and along the vein of these last few questions and the work of Eski Velaslav over in Copenhagen. He is now to the point with epigenome evolution and studying it that he is pointing out that there's environmental stressors, emotional stressors in life that he thinks are triggering susceptibility to diseases and cancers. Has there been any work outside of his that you know of or is that a road that is going to follow down? Well, I mean I think it kind of goes along it's along that whole epigenetics that I was mentioning earlier that we have genes that code for specific proteins that then if you follow the theory go all the way down to producing cancers, et cetera, et cetera. If you can modify how those gene activities actually expressed which is what epigenetics talks about whether it be through emotions, stress levels which is where that would fall under, stress that by the way that's not stress that's helpful stress but out of control stress or you don't feel like you have control stress you can actually change how that gene is actually expressed because now it's responding to something in its environment. I think the communication between the genes and the environment and the cells in the environment is actually what really is what's going on with cancer rather than what we thought it was in the past where it's just a cancer cell that's gone awry and it's just running amok in the body. So I definitely would agree that emotions can definitely play a role in that if you think about some individuals who had very stressful situations, the loss of a loved one, a traumatic situation, war, they may develop diseases, not just cancer by the way but cardiac diseases, other diseases that affect humans can definitely happen as a result of that. We're just about out of time but before we part I just wanted to get some thoughts. I'm personally very excited by a lot of stuff I heard today but at a theoretical level and I wonder what can we look forward to? How can we apply this, where does the rubber meet the road in terms of how this will affect therapies, how long it will take and how it affects treating patients? I think we're seeing a lot of it right on the front line right now. I think if I look at the career of breast cancer of my older partners, in the past we really had one method of treating breast cancer and it lasted for decades. I think with the efforts of Amgen and other organizations that we now see a lot of these therapies being put into place very quickly so we can actually see a true response. Furthermore, I think that if you don't know what you're actually looking, you can't really treat and we thought of cancer as just this one invader either it was our own self that kind of just went awry and we have to get it somehow and get it out of the body. Instead, we're now understanding that there's actually an ecology, a microenvironment that actually is happening there's actually communication and signals that are actually from our own other cells and our own systems that are meant to control these things they're actually cooperating, as Athena mentioned in some cases, with kind of being part of the cancer team if you will and I think it's really looking differently when I see a patient sitting in front of me and I don't think, okay, I got to cut this out to help her, there actually is a lot more that goes at play, there's actually more of a team approach in addressing this disease. So I'm a pragmatist, my title, Translational Sciences means translating things from the laboratory into the clinic. I mean, we have dozens of drugs either in the laboratory or undergoing clinical trials now that really try to take advantage of the concepts that we have discussed today. So I would say we are translating from the theoretical to the practical. The biggest area is immunotherapy or immuno-oncology and that is breaking open a lot of things. I very much believe we are at an inflection point and in 20 years we will look back and things will be different. It won't be two months, but we actually have pretty good insight right now into the problems and the questions that we need to solve. And 10 years ago even in my career it was hard to say, I have a line of sight into what I need to do. Now we actually have a decent idea of what we need to do. We need to solve the technical challenges to get there. But those are solvable problems. I'm gonna stick with my concept of cancer prevention and I'd say what excites me the most these days is our lab and others. We're really going around the animal kingdom trying to understand how is nature solved the problem of cancer resistance and how can we emulate that and translate that to people. But again, that's a ways off. We're working on it now. But I think in terms of the clinically, what excites me is really this integration of cancer genetics, cancer predisposition, family history, putting it all together in order to actually have something tangible to offer our patients for early tumor surveillance and really think about precision prevention and how do we identify tumors early and intervene before they get large, before they spread, before they even cause symptoms. Now for me, the most exciting clinical opportunities right now are really developing quantitative measures of the evolutionary dynamics going on in tumors and of the ecological features of tumors. And we actually have a consensus statement that Josh was involved in as well where we basically said, well, if we look at the diversity change over time as evolutionary components, we look at the resources available to the tumor and the hazards that are present for the cancer cells that we can actually start to quantify what those dynamics are going to be and start to categorize tumors based on their evolutionary and ecological characteristics which may help us figure out which ones we can treat to control, which ones we might want to treat a little bit more aggressively and sort of utilizing that approach as well as thinking about how can we measure these aspects of cellular cooperation when they break down? How can we detect if cancer cells are re-evolving cooperation and if so, interfere with it? I think those are really the exciting ideas for the future for bringing this into the clinic. I want to thank you all. This has been a really enlightening conversation. I think you've taught us a lot. And can we have a hand for these partners? Thank you. Thank you.