 Good morning, everyone. I'm Jeff Drazen, and this is the panel on decoding cancer. So when I was 16, my father was diagnosed with gastric cancer. He was dead within a year. The doctor said there was nothing that could be done. That was 1963. In 1984, I was junior faculty at the Brigham Hospital. And I had a patient with lung cancer. That was my specialty, was pulmonary disease. And when we diagnosed his cancer, there was surgery and some chemotherapy. But it did very little for him. Then within the past year, I've had a patient who was in his 40s. It never smoked cigarettes and developed lung cancer. And he thought he was going to die within a month. But it turned out that his particular tumor was a responsive tumor. And now two years later, he's doing remarkably well. And part of the reason for this success is that we as a community have begun to decode cancer. It's no longer a monolithic thing. It's no longer a simple death sentence for everyone. In this morning's panel, we're going to be talking about the progress that's been made. And in the past 10 years, the progress has been tremendous. And so what we'll do now is we'll introduce our four panelists just briefly. And then we'll get into the meat of it, how we've begun to decode cancer. So first to my left, Textu Chao. Good morning, ladies and gentlemen. I'm Shiloh Chao from Chinese Academy of Medical Sciences. So pleased to be here. I studied and worked in Shanghai for 30 years. Actually, I'm the immunologist. Two million area, I worked. One is the innate response and inflammation. Another one is about the cancer immunotherapy. As the immunologist, I'm so pleased to see the movie demonstrated by Francis. How the T-cell can recognize the cancer cell and then cure it. And so we have to understand what's the. Just a brief introduction yourself. Yeah. So now the major task of my now is being the president of Chinese Academy of Medical Sciences. So trying to work with the medical communities in China in the world to benefit the people. Thank you. Catrine Bosley. Catrine Bosley. I'm the CEO of Editas Medicine. And I've been in the biotechnology industry for about 25 years. I studied science as an undergraduate, but I've been in companies ever since really working to translate new science into medicines. And in cancer, I've done a lot of work, but a number of other therapeutic areas as well. Lydia Sohn. Hi, I'm Lydia Sohn. I'm at UC Berkeley, the mechanical engineering department. My background is in physics. And I've made a translation over into medicine and biology. It's a very exciting time for us all, I think. In Francis Collins. I'm Francis Collins. I'm the director of the National Institutes of Health in the United States. I started out as a chemist, changed my mind, went to medical school, got interested in genetics. Had the privilege of leading the Human Genome Project, which produced the first complete sequence of the human genome in 2003. And now as the person who in the US oversees the government's investments in biomedical research, I find that cancer is one of the areas that is of the greatest excitement and the greatest rapid movement scientifically. So it's a thrill to be part of this panel with these other distinguished folks. I'm going to ask the technical people if they could turn off the background movies here. And Francis, start off. How do we decode cancer? Well, let me just do a quick little setting of the stage of why this is such an exciting time in cancer and what we have learned about it. So if we can have the PowerPoint, I'm just going to walk you through very briefly. This is not going to be a lecture. Don't panic. What it is that leads us to say that cancer is a disease of DNA. So can I have the PowerPoint up on the screen on the side, please? Basically, we have learned as a process over the last 30 years that what you see here in this microscope slide, which are cancer cells growing, which is about the only thing that we could have said in the past about cancer, is that you could look at it under the microscope and it looked abnormal. And the cells were invading where they weren't supposed to. What's really driving that? Well, it happens because of mutations, misspellings in DNA. Here you see DNA spilling out of the nucleus of a cell. And if you zeroed in on it, of course, it is this amazing information molecule of all living things. It has a simple language. There's four letters in its alphabet, A, C, G, and T. But if there's a mistake in that DNA in a place that causes a cell to grow when it really shouldn't have, then you could have cancer as a result. Very important to keep in mind, though, that takes usually more than one glitch in a cell to cause it to go from being normal to being malignant. It's a multi-step process. So most malignancies have multiple mutations, invulnerable places, each of which is giving that cell an advantage over its neighbors and ultimately the potential of spreading outside of the organ where it started. So as we now really try to do what we can to take apart cancer and figure out better strategies for treatment, we're able to use this kind of information to really see what are the drivers at the basic molecular level of the malignancies that happen in people. And what we're learning is that it really doesn't matter so much what organ system your cancer arose in. What matters is what are the mutations that are specific for that cancer. Because we have now an increasingly long list of drugs that specifically target some of those mutations. Jeff talked about his patient with lung cancer. I'm guessing that patient who's now lived for two years had an ALC mutation or maybe an EGFR mutation, which is one of the ones that would be driving that in a lung cancer for which we have a targeted therapy. And so when you are in that situation and you know you are, this is moving away from one-size-fits-all chemotherapy to a specific, smart kind of bomb that goes straight to the heart of the problem. We will talk, I'm sure, about whether that is sufficient or whether you can get remissions out of that, but you often don't get cures. The other thing I quickly want to touch on is this revolution that's happening in cancer immunotherapy. Because your immune system's pretty good at finding abnormal cells and getting rid of them. Some people say, we're probably getting cancer every day, but we don't know it because the immune system cleans up those cells before they have a chance to grow very far. But cancers have a diabolical ability to be able to suppress the immune system and cause it to go to sleep. And we have new therapies that are now making it possible to release the brakes and let the immune system do what it needs to. And I just wanted to show you a rather cool video of what that looks like when a T cell, which is part of the immune system that's particularly aggressive at going after a cancer cell, gets activated. So can we run the video, please? That's a T cell, all lit up and red. And you can see how busy it is. This is migrating around in a laboratory culture dish so you can watch it. And it's searching its environment. It's moving constantly. It's got all these ruffles. Now it's found a cancer cell. And it's really getting excited. It's lighting up its membrane with all of those ruffles and trying to figure out how can it pull together its armamentarium to actually do that cancer cell in. And what it has going for it, see those red globules though in there? Those are granules which are capable if they get released into the cancer cell to basically rupture its membrane. And you can see those granules more clearly here. They even line up appropriately when they get close to a cancer cell and get ready to blast it. Now I'm going to show you what happens when we let this whole thing happen. The T cells are in green. The cancer cells in red. You see that bright flash? That was when the T cell ruptured the cancer cells membrane and the dye that we're using slipped inside the cell and gave you a big bright flash. There goes another one. These are really fun to watch. This is like a video game except this is serious stuff. This is about life and death. And this is happening all the time, probably, to prevent cancers in each of us. But if it gets out of control, we need to unleash those green T cells to do this. And that's what some of the new immunotherapies are all about. One of those, in fact, was the result of the Lasker Award, the US Nobel Prize, being awarded just a couple of days ago to James Allison. Well, I could let this run for a while, but I think you get the idea of what's happening here. It's almost like 4th of July fireworks where those T cells are showing those cancer cells what for. So between the therapies that are being developed in terms of targeted drugs that go after specific cancer mutations and the immune therapy, we're in an exciting place. But we need to scale this up. And one of the goals of the President's Precision Medicine Initiative in the US is, in fact, focused specifically on cancer. And starting in the next few months, we're going to see what we could do to really push this much harder than has previously been possible. Thank you, Francis. So Lydia, we've sort of seen the Star Wars video. Those T cells, they were, gee, you got it. That's amazing. So how can you help us with that? What I do in the lab and many of my colleagues is we're building new tools to help monitor, to help detect cancer. And one of the focus in my own research is to look at circulating tumor cells. Those cancer cells shed from the primary tumor and circulate in the bloodstream. And I think what's interesting, it goes to how individualized everyone's cancer is, the uniqueness and the fact that we now know that some people, our EGFR, have the mutation that actually is my mom who has that lung cancer form. And the question is really, since there's uniqueness in cancer patients, there's also uniqueness in the circulating tumor cells that are in the individual body. And I think it's quite fascinating at some level. So we have, in the US, one FDA-approved system, Cell Search. And that's focused solely on one type of circulating tumor cell that's expressed one particular type of protein, EPCAM. And now we know that these circulating tumor cells, they're heterogeneous. They have a heterogeneous population. And it's a question now of which cells are the ones that might lead to that metastacy in the body? And can we actually capture those cells to give it to, for instance, my colleague, Amy Her, at UC Berkeley, where she can actually lyse the cells and start to look at the proteins and looking heterogeneity. But we still need to be able to try to isolate these cells and try to at least give a first pass in saying you have a whole range of different cells expressing different markers, whether they're a stem cell like or they're showing EMT and everything. And that's something that we're focused on right now in the lab. And I think that helps overall this whole idea that everyone's unique. They're going to have different subpopulations. What do those subpopulations mean for that person's cancer? How does it change during the course of therapy and so forth? And to be able to track that, I think, is powerful on the clinical side. But it also could be powerful towards studying cancer, developing new drugs and so forth. Great. So, Katrina, Francis told us that cancer results from spelling mistakes. I would be in big trouble. So is there a way we can correct these mistakes? Well, if I may have the slides one more time, there's an additional slide to give you a picture of the tool that is currently really capturing the imagination and really tremendous amount of effort within the scientific community called CRISPR-Cas9. So this is a tool to do what's called genome editing. The idea that you could go in and in that sequence of DNA where you have a mistake be able to fix it. Very simple idea, a little bit more complex in practice. But the concept is to be able to, if you have a mistake in that sequence, it could be a small mistake or a large mistake, can you go in and either delete it or correct it, paste in the corrective DNA. Now, in the world of genetic diseases like cystic fibrosis or certain forms of retinal disease, you would want to work directly in the patient's cells where the disease is occurring. In something like cancer, as you mentioned, this cancer cells are very heterogeneous. They're not all the same as one another. And so figuring out which exact mutations, which mistakes in the DNA you want to correct, that does make directly applying this CRISPR approach to cancer is challenging. However, what people are doing right now is putting together what Dr. Collins mentioned with the T cell attacking the cancer cell. And I'm sure something you're very deeply involved with. The idea to, how can we better train T cells to do that job? So there's been some spectacular work that's 20 years to be an overnight success. This is what it takes. But this idea of engineering the immune cells of the body, the T cells of the body, to go find the cancer cells. There has been amazing progress in that fairly recently such that now a lot more folks have come together to say, OK, how do we improve on that? How do we make that more successful? So it works in more patients. So it works in more different kinds of cancers. And then so that you can have more easy to use versions of it for patients. And that's where, right now, putting this CRISPR technology together with this engineered T cell technology. For those of you who read this literature, it's the CAR T or the Camaric Antigen Receptor T cells, putting those two things together so that you're using CRISPR to really engineer much more advanced versions of this T cell. So I think you're putting together two of the most exciting technologies in biological research right now. But that is absolutely the direction that makes scientific sense to put these two together and take cancer immunotherapy to the next level by using CRISPR. So you can use it to create the commando T cells, which are separate from the kind of run-of-the-mill soldier. Exactly, yes. We want the advanced, the Army Rangers, the very specialized. They're ninja warriors. Ninja warriors, these cells, exactly. And partly because as many of you may know, some cancers are tougher than others. Some cancers have responded well to the various traditional kinds of medicines. And some are just very, very, very tough. And so finding ways and also patients may do well for a while. And then the medicines stop working and the cancer comes back. So finding ways to create these very durable, long-lasting remissions is one of the things that makes people very excited about this CAR-T approach is while it doesn't work for everybody in that way, seeing patients have that very, very long, durable remission tells us, OK, this version of the T cell was the right answer for these patients. How do we figure out the next version that will work in more patients? And that's where we're wanting to push this kind of approach. So it's the precision personalized medicine that Francis talked about at that interface? Absolutely, absolutely a piece of it. Because in the version of this technology that's being used today, what you do is the patient, you take cells from their body, you work on them outside of the body to essentially change them and train them to be able to go after the tumor. And then you give them back to the patient. So it is a very, very personalized therapy in that regard. And that way you're understanding the nature of their cancer, but you're also using your own cells to get back to them to attack the cancer. So how can the immune system help us more? What can we do to take it to the next level? So we have so much at the tour now to engineer immune system and empower their capacity to care the cancer cell. Just mentioned, we can have the CRISPR-9 technology to relieve the suppressive status of the T cell from the cancer patients. As we know, there is an immune suppressive status in the cancer patient, not only in the tumor microenvironment. So the T cell, freshly isolated from cancer patients, cannot cure the cancer efficiently. So we have to re-indicate them in vitro, expand them to enough members, then adopt a transfer to the cancer patients. So this way we can amplify the specific anti-tumor immune response against cancer in vivo. So I think we can re-indicate the T cells in vitro. I think this is one approach. I think another approach is to identify the tumor antigens expressed by the tumor tissue. So this is the target. This determines the specificity of immunotherapy. So by identifying the tumor antigens by the genomics, so we can prepare the therapeutic antibody against the cancer. So this is another approach. I think surprise and surprise or regulating and regulator is the smart strategy of our immunologist to fight cancer. As we know, the immune system want to recognize cancer cells and kill them. However, cancer cells are very smart. They can indicate the immune system to be favorable of their growth, their metastasis. So cancer, not cancer cells, I think the cancer tissue, can release so much kind of factors, indicates the immune system to be suppressive. So they cannot recognize the cell. So another approach, I think, we can use the combination therapy to relieve the suppression by the in combination with chemo therapy, radiation therapy, and something like that. So we should use the competitive strategy to fight cancer, I want to say. And as to the precision oncology, so we should have the precision research first, identify the biomarkers, how to predict the population of the patients who are responsive to the immunotherapy you want to use. So last year, we identified one markers of the liver cancer. Only a few preparation of the cancer patients as a liver cancer are responsive to interferon therapy, adjuvant therapy. So why? Why most of them are not responsive? Why some of only a few of them are responsive? Finally, we identified the one protein rig I. So at the high level of this protein, the patients are responsive to the interferon therapy. So through this way, next time, if you want to use alpha interferon therapy, we should detect or scanning the rig I level from the tissue. Then if the rig I level is relatively high, we can use the interferon therapy. If it's very low, we cannot use the interferon therapy. So the precision oncology, one of the strategies is to identify the markers to predict the responsiveness of the patient to the therapy you want to use. And also, we identify the target for the drug design, I think next topic maybe. So the big change that's occurred is that we've begun to understand, or actually a pretty good understanding, how cancer cells go from quiescent normal cells to ones that are kind of getting aggressive. And they're sort of sneaky about it because they realize that the body's got its own immune surveillance, and they put it to sleep so that they don't get picked off by the immune system. Every time we come up with a way to kind of beat back the cancer, you said the cancer cells were smart. Are they smart, or are they just changing all the time? And it's Darwin at work. When you change a way that helps you survive, that there's a fire out there, and one of the genetic changes makes you immune to fire, then you're fine. So is this a sarcastic process, one that's kind of just random, or is the cell smart enough to know what's going on out there and to try to beat it back in an organized way? Yes, if you're worse about this. So during the interaction of the cancer and the host, host want to recognize another part. So I think adapting to the killing by the immune system is one of the strategy of the cancer. So they want to lose some tumor antigen, just as you told us. So they want to change themselves to adapt to the survival environment. So this is the very smart, this is just the Darwin's rule. But at the same time, the cancer is actively indicating the immune system. They really so much feathers to suppress the immune system. So adapting themself to the change themself to escape the immunological surveillance, it's one strategy. But at the same time, they also indicate to the system to be favorable for their survival. So I think this is another very smart strategy. Yeah, your question is very appropriate, Jeff, because I do think cancer is a pretty good model of evolution except happening in the individual level over a measurable period of time as opposed to evolution over hundreds of millions of years. So yeah, cancer cells are going to survive if by some random process they develop some attribute that allows them to escape the immune system and to keep growing. And particularly if they're able to leave their original home and spread to some other part of the body, then they've got a real advantage. There's lots of them out there. This has a real consequence for when we try to design drug therapies for cancer. There are this really wonderful growing list of targeted therapies like the Tarsiva against EGFR that you mentioned with your patient or Crizzotinib, which works against lung cancer where you have an alkymutation and a long list of others. Melanoma, all the drugs that target the oncogene called BRAF, gave wonderfully exciting results. You'd give the drug to somebody with metastatic melanoma. The tumors would melt away. People would go back to work. But then about nine months later, it was back again. So what's that about? Well, it's really a matter of mathematics. By the time you've been diagnosed with metastatic malignant melanoma, there are more than 100 million cells, cancer cells, in your body. The mutation rate for each letter in the DNA code is about one in 100 million. So somewhere in that group of cells are some that have already, just by random chance, developed a mutation that's going to make them resistant to your drug therapy. So you give the drug therapy. It looks like everything melted away. But those resistant cells keep on growing. And pretty soon they recreate the entire scene. So what's the answer? The answer has got to be that you hit them not with one drug, but you hit with two. Because the chances that you're going to have so many cells that two drugs have, by chance, a resistant cell in there somewhere is much lower. Three would be even better. You may be recognizing a resonant theme here with how we figured out how to treat HIV-AIDS. Remember HIV-AIDS? And originally we started with one drug, AZT, got people in pretty good responses, but it came roaring back because the virus was resistant. Same problem of mathematics. Now we treat HIV-AIDS with three drugs and we keep people in remission for life. We need to move our cancer therapy in that same direction, figure out how to use combinations. But you know what? The combination, if I had cancer, might be a different set of three drugs than for you, even though you might have cancer in the same organ that looked the same under the microscope, but you had a different list of molecular drivers than I did. And you wanna be able to personalize or precision-orient that therapy. The challenge is, how do you run trials like that? Where everybody's on a different combination and then figure out whether it worked or not. The FDA is, you know, their hairs on fire, trying to figure out exactly how they would decide whether to approve something. They're getting there and they have some pretty good ideas about it. That's the direction I think we have to go, is to go from monotherapy to multiple approaches, maybe including both a targeted drug and an immunotherapy. There's no reason to do one or the other. Why don't you do both? That's, I think, our challenge for the next half decade is to figure out how to put all of those tools in place and go after some of those most recalcitrant cancers like pancreatic or brain tumors, which we don't do very well with. We ought to be able to win those battles. I think the other thing that I might add to that is that there's a dimension of diagnosis to this, which really, the concept of personalized medicine, it goes directly to that. So for a given patient, how do you know what their exact kind of tumor is? The reason that we can actually approach it now in a DNA sequence-driven way is because of what Dr. Cullins and all his colleagues did in terms of doing that first sequence of the human genome. Now, the first sequence took a lot. Only 13 years and $400 million. The first one was expensive. But because the first one was done, we can all now send a cheek swab to 23andMe and get it done. Or more particularly, if you have cancer, you can get a very high quality, rapidly done, pretty inexpensive sequence of your tumor. In fact, so in the United States, there are advertisements on television for this cancer treatment healthcare company. And they talk about, in their advertisement, we sequence your tumor. Now, I don't say that because I'm trying to make an advertisement for them, but I think it speaks to the degree with which the concept of cancer as a disease of DNA has really fully taken hold in the medical community. And that's a spectacular shift conceptually, I think for physicians, because we didn't used to think of it as a DNA disease. We used to think of it as many different things before we kind of understood the real underpinnings. And now have the tools to address it at that level as well. So I think that equally important to what drugs are we making, is the ability to actually diagnose and leverage the human genome project as a critical part of that to be able to apply this concept for real patients today. If I might add, for someone like me who's more of an engineering applied person, it's up to us to try to help all of you develop the more sensitive techniques to detect the cells that have changed as early as possible so that we could hand it over to you, hand it over to your institute so that you could start seeing what are the mutations because things will happen quickly. And the question is, do we right now have the tests that can be sensitive to detect these changing cells to be able, in the body from which then? And so that's something that is an objective for people writing. And that's really important also when you're trying to decide whether you're on the right track. So you are giving that first blast of drugs to somebody who has a cancer and you think you've chosen the right drugs. If you have the ability to see what's happening to circulating tumor cells, you're in a much better position to know without having to wait for a couple, three months to see if the scans change, you get a more immediate idea. And likewise, when you're trying to find out, okay, somebody looks like they're in a complete remission. Are they really? Are they, is it starting to come back? Because if so, you ought to jump right on it. If you wait until you see some sort of big picture on the CT scan, you probably waited longer than you should. And having the kind of thing that you do to do that very early detection, circulating tumor cells is a real advance. So one of my mentors in my youth used to say that one man's noise is another man's signal. So you study individual cells, Lydia. What's the variance, right? You've heard that not all these cancer cells are alike, that there's one of them that's hanging out and if you kill all its brothers and that one happens to be immune to what you're using to kill its brothers, it's gonna survive. So do we have the capacity to determine what the variance is when a patient rolls in with the tumor, or do we have to wait for the process of selection to tell us what's going on? Can we be smart enough to pick it out in advance? So as Francis suggests, we have drug A, maybe even have drugs B and C, but we have many choices for B and C. Do we have a way of knowing in advance what the choices should be to pick up that rare cell that when you kill the rest is gonna bring the tumor back? Well, that's a loaded question. I think right now the state of the art in engineering and clinical diagnostics is such that we're just now understanding that there's a whole bunch of different cells and which one is it? I don't think we know right now. I understand that it's definitely not, for instance, the epithelial cells, those are transitioning in going through a process of transition to EMT or a stem cell like, but even then, I think it's still out there. And I thought what was best said to a student of mine had said, if you think about it, there's one to 10 cells and 10 mils of blood. That's what everyone anticipates as a CTC range. But then you have how many liters of blood in your whole body? But then there's only one or two metastatic tumors initially at start. So it's like one or two cells or a clump of cells. So how do you know which one it is? And I don't know and I ask all of you, how can we know that? There's a lot about the microenvironment and everything and that would help inform someone like me to be able to help figure out what's the best way to pinpoint and isolate these cells. So I think hopefully I've answered that question. So how did those tumors, the cells express something on their surface that we could monitor immunologically? The immunology is a great way to find a needle in a haystack. Can we employ that technology to help in this battle? So there are two strategies to, early diagnosis of cancer. I think when from the blood sample, we can detect the protein and the microRNA in the blood to show the progress of the cancer and what's the types of the cancer, the patients. And I think another very important approach, now we are utilizing is bicepine. So we can get the very small tissue to know, through the gene detection to see if there are any pre-cancer type. So I think by the standing of the small tissue, we can know the cancer status, a pre-cancer or advanced cancer. I think two ways we can use to distinguish the normal cell and the cancer cell. So we've seen that this thing we've called cancers, really many things. And you've been in the business of developing therapies. And sort of the therapeutic development nightmare is that I don't want one drug, I want 100 million drugs. Is there a way to kind of fine tune this? Is there a way that we can develop a therapeutic approach that would be applied rather than a specific drug and that would have many different outcomes? How can we beat the cancer at its own game? So it's a great question because I think what we want to, we want to be careful to still be objective and rigorous in the data that we develop. And I think that the regulatory authorities, the FDA, the EMA, Cossetia, et cetera, care very deeply about that too. So one of the challenges in developing drugs, particularly in such a serious disease as cancer is balancing that real urgency and need of the patient with the need to be objective and not be anecdotal. The plural of anecdote is not data, right? And so we really do need to find a balance there. Certainly in any drug development and most importantly in cancer, you always want to work looking at your new therapy on top of or on a background of other therapies. That's usually how you start. One of the interesting challenges here is, so think about how are most cancers traditionally treated. Traditional chemotherapy, which has to do with interfering with dividing cells. So any dividing cell in the body, that's why, for example, hair falls out with a lot of traditional chemotherapies because the hair follicles are dividing and if you're interfering with all dividing cells, you're gonna hit the cancer cells, but you're gonna hit things like your hair follicles and other things. You're gonna hit the lining of your gut, things like that. You know this far better than I do. But those are the original approaches in terms of what we call traditional chemotherapy or traditional cancer drugs because you were hitting every dividing cell in the body because cancer is dividing that rapidly. Now, there are a lot of good drugs like that. We still use those a lot because they actually can help patients quite a lot, but they do have a lot of serious side effects and they often aren't sufficiently efficacious. We also use radiation therapy, so literally x-rays, usually focused on a particular part of the body. But again, you're trying to kill cells and that has a lot of side effects too. So these sorts of therapies, they have helped patients tremendously. They do have a lot of side effects. Ideally, you'd like to have a targeted therapy and do it in place of. Not have to go through those very difficult therapies. So I think it's partly how do you do the combinations? That is absolutely one of the challenges. But also, if a person has been newly diagnosed with a cancer, there are traditional therapies, let's say, let's say lung cancer would have you, there are traditional therapies available, and then there's something new. Do you try that early on or do you try it in the patients that are most advanced where all the other therapies have failed? There's an ethical aspect to that, but then there's also, there's an ethical scientific aspect of if your therapy is gonna probably work best if you get early on, can you do that trial? How do you do that trial? Is that something that's feasible to ask somebody to agree to do if there are traditionally approved therapies available? So I think there's a couple different dimensions to this. I don't have an overarching answer for you. In my experience, you need to look at each type of cancer you want to address. What is the hypothesis you have for what you're trying to develop? See if there is a scientifically legitimate and ethical way to do an objective trial so that you get a clear readout. I don't think we can escape from the need to do those real experiments in patients. So I'm gonna pick up on one phrase that you used and ask your three co-panelists. You said the specific type of tumor that you have. And we've thought of the specific type of tumor like you have lung cancer, but I have a patient with EGFR mutant lung cancer and there'll probably be seven or eight different kinds of that. So we're gonna take a lot of patients and subdivide, take something we've called lung cancer instead of calling it one thing. It's really 50 diseases or 100 diseases. And as a biotechnologist, you might want to attack the most frequently occurring of those. So how do we begin to give labels to these different kinds of cancers so that the treatments can be designed to hit them? So I think our taxonomy for cancer is undergoing a significant revolution and it should because I think that the organ in which the cancer arose is gonna be a lot less important than what's happening in those cancer cells that's driving their malignant behavior. We are just starting at NIH a trial called the MATCH trial and they're aimed to enroll 3,000 patients and they're enrolled on the basis of what DNA changes are found in their tumor. It doesn't matter whether it was lung cancer or breast cancer or prostate cancer or pancreatic cancer. What matters is what were the DNA mutations that were identified. And then you get assigned to the targeted therapy that seems most appropriate for what we know about the molecular details of your cancer. And ideally we try to do combinations in this and 20 drug companies have actually agreed to take part which is a big step forward. Drug companies traditionally have not been too excited about having their novel therapy given to a patient who's also getting a novel therapy from another company because suppose there's a toxicity, how do you figure out which is which? They've generally preferred just to have one drug at a time but as we've been talking about that may not be the way to cure people. So we're gonna have to have this new dynamic of companies being willing to share the risks and they have agreed to do so in this trial. So over the course of the next two or three years thousands of people will be enrolled in this. It's a very different mindset than what we've traditionally done but I think it is the way to kind of get past our old ideas about what matters and focus on what really does matter which is what's driving that malignancy, what tools do we have to go after it, can we in fact do better than we have with the old ways and attack this in a purely rational strategy. I suspect there gonna be some pretty significant exhilarating moments and I suspect there also gonna be some real failures and a really important part of this is to figure out when it doesn't work, why didn't it work? If you had this tumor and it had these characteristics and you had these drugs and man it should have been just the right thing and the cancer just keeps growing anyway. Why was that? If you could figure that out, learn from that then the next time you could do better. That's a big part of our challenge right now. And that's going to sort of take a paradigm shift in research when you recruit patients with lung cancer into clinical trials they're desperate, right? They know that 10 years ago they were going to have a very short, pretty terrible life and yet my patient was able to do things that he wanted to do that he hadn't thought of doing because he didn't realize the time was short and in pretty good health. So we've talked now for almost 40 minutes among ourselves. It's time to bring you all in, our audience. So I'd like to get a show of hands. How many of you know somebody that's had cancer? And do they talk about it this way? If they, if their cancer is new, is this, do they think about, oh I have a cancer that's responsive or is the same story, it's terrible. I need to think about what my life is going to be ending soon, what I need to do to make it better. Have you seen among your friends or even yourselves and your family members a change in the past three or four years when you hear that somebody has cancer? Tell us your stories and ask the panel how we can help you understand them. Raise your hands and we'll bring you a microphone. Now I can't, yes please. Then tell us who you are. Hi, my name is Piro Skarnagia, I work for LSE. First of all, thank you. You all saved lives with your work. Thank you so much. The story is that I think the perception has changed my one of how cancer can work and how medicine and science can help us through the past years. I think there's much more hope and in family more discussion, not only of what's happening, what happened in the past. We didn't know in the family that there was cancer, that was a forbidden subject. I think there's much more openness which is critical if I understand the new genetic dominance of this treatment. Can I have a question? What is the role of the environment? We have heard in the past so much about carcinogens, exposure to sun and all that. So in this new framework where gene is the driver and then the mispelling of the gene, what's the role of the environment? It's causing the change in the genes causing the mispelling, what is the role? How should we think about it now? I'm glad you brought it up because I was getting a little worried that we were getting very deterministic here about the DNA role. Like most conditions, cancer is a mix of genetic predisposition and environmental exposure and just random changes. We shouldn't forget the random change part because every time you have to copy the entire genome of a cell, it's possible to make a mistake. And so some parts of cancer probably are simply on that basis. But we certainly know some very dramatic examples of environmental influences on cancer, smoking. It just amazes me that we are still at a point where whatever country you look at, there are a lot of people still smoking cigarettes when we have such compelling evidence of the connection of that to lung cancer and to the kind of lung cancer that's really very hard to detect early and very hard to treat. Sun exposure. We're seeing a lot more melanoma these days in the southwest of the U.S. where there's a lot of sun. Well, it's very clear that that's not just a random chance. It is in fact ultraviolet light which can damage DNA. And if it damages in a way that actually causes that cell to grow, most DNA damage is harmful to the cell. But once in a while, you hit the place that actually activates an oncogene or knocks away a tumor suppressor and then the cell starts growing. So we know a lot about a couple of those things. We know radiation is certainly a risk for cancer. I mean, look at all the follow-ups in people who got exposures, whether it was in the atomic bomb blasts or other things. But there's still a sense that there's other stuff out there. And a great deal of effort going into that. We have environmental scientists constantly on the prowl to try to identify other kinds of exposures that may be contributing to cancer. And usually there's a big controversy about whether they've found something or not, whether it's in the air or the water. We obviously need very large studies, epidemiology studies to begin to identify those connections. And I think lots of research enterprises are aiming to do just that. But I should have mentioned also viruses. I mean, you might say that's an environmental exposure. Certainly liver cancer from hepatitis virus or cervical cancer from HPV, which is now pretty much a preventable disease with a vaccine. You should think about all those things as well. Those are caused by a environmental exposure. It happens to be a virus and not something in the air or the water. So I don't think it would be appropriate for us to have this session about cancer without talking about prevention because we've really been talking about treating people who have the disease. And a lot of the prevention is trying to be sure you avoid the environmental exposures that we know are bad for you. And also trying to identify what kind of screening tests are available for people at higher than average risk in order to pick up cancer while it's still as small as possible and as treatable as possible. We have a big controversy about whether mammograms are actually doing what we wanted them to right now or there's some debate about whether mammograms are finding things as often as you would like or whether we're causing an awful lot of anxieties and follow-up procedures and people have a positive mammogram which turned out to be a false positive. But it's the idea of trying to do that early detection. So yeah, I'm sorry, the long answer but environments critical, prevention's really important to think about we don't want to have people taking all these targeted therapeutics or immunotherapies. We don't want them to get cancer at all. If they fall through the safety net and get it we want to be ready but mostly we want to keep them from getting cancer in the first place. Other questions, yes. Because I don't speak English, so I speak Chinese. I would like to raise my question. I'm from China Business News. My question is for this lady. Lady, you mentioned about, you mentioned a very important information because different patients have different DNA so the cost is very, very expensive. 300 million, I'm not sure whether maybe it's not the correct information. For each person the treatment of that cancer is 300 million. We learned that for the rescue and the cleanup of those firefighters who have suffered the cancers during the blast event in Tianjin. So if it is so expensive, how could they afford that? Thank you. Let me try to rephrase the question to make sure that we have it correct. There are many potential targets and the 300 million refers to the number of letters in the alphabet. Actually, I think he's talking about the original cost of the first genome that was mentioned. Right, and that cost has now was dropped way down to maybe a couple thousand dollars and at the rate it's going to be less than the airfare flying from Boston to Beijing. In fact, it is already, it depends on what class of service you're in. So we think that it's possible to identify the tumors but let me, the rephrasing the question is for each of these firefighters exposed in Tianjin, will every one of them have a different mutation or are there in fact some soft spots or hard spots depending on your perspective where we can know to look to see whether somebody's at risk. So they've had an environmental exposure. Is there a way to check whether it's individual circulating tumor cells or to know whether one of their checkpoints has been modified by their environmental exposure. It's gonna be your problem, Joe. So this question about the expensive of the genome sequencing individually and how much for the personalized medicine for each person. I think this question maybe raised by the reporter. So I think now the expense of the whole genome sequencing is reduced remarkably and very cheap. I think now it's time to practically use this technology to benefit general people. And also we can use this technology for the population study to go to the big data and then provides the data for the policy makers to improve the, I think the quality of life for the prevention, not only for the treatment, but just now we talked so much about the treatment of cancer patients. But now we should, maybe by the sequencing we can also benefit the people, have curiosity of their sensitivity to be the cancer patients. Maybe we can provide them informations for them to take measures for prevention of the cancer. Yeah, with low price, I think. The other thing I might add with regard to your question is in developing drugs, we don't think about the market as this country, that country. We think about it as patients wherever they may be who have the type of disease that we're trying to address. And if you think about the medical community, the big international medical conferences, the big cancer conferences, for example, physicians from all over the world are there because they really are seeking to understand the application of the insight, the genetic insight, the treatment insight across wherever they might be treating patients. So this is why in every country you have the academic medical centers that are really at the forefront of knowledge, and those physicians are all going to the same conferences with one another and exchanging the most advanced insights. So for example, the firefighters that you referred to are part of, I'll call it a global community of patients and the experts that will seek to treat them will be working off of insights from patients in the US and patients in Brazil and everything else. So I think that the medical community at this cutting edge research level tends to be quite international. And I think just as we don't anymore think of tumors quite as much as a breast tumor or a prostate tumor, we give it a genetic basis. I think the same thing with regard to what is the genetic makeup of the person and where do they come from. What we really care about is the genetic signature of the tumor and that's the group that we put together to try to treat those patients. Thank you, I'm Vijay. I run a tumor profiling company in India for the last two years to do next-gen sequencing. Not a week goes by that I don't get calls from just my own social network that someone has been diagnosed and they want to know what we can do to help. So I think this is getting really universal now. I have a very specific question about transfer of knowledge from precision medicine into medical practice. And in particular, we find it very difficult to get treating oncologists to use this information at first line therapy, right? Even foundation medicine and carous and so on in the US today are really treating at second line, third line, sometimes really when therapy has failed and only then genomic signatures are being looked at. How do we get this into first line? So Catherine was referring to this as the dilemma and it's not just because oncologists are slow to pick up on new opportunities. It's because for many of these therapies we don't know yet sufficiently how they're going to work. And yet for many cancers we have a standard approach. It may not be that great, but it is what is offered to people with that diagnosis. I think you can kind of see the path that's been followed with targeted therapies that got started a little earlier and you can see where we need to go here, so I mean look at Herceptin, the very first sort of targeted cancer therapy based upon a molecular understanding of breast cancer and coming up with a way to make a monoclonal antibody. Initially that was tried on people who'd already failed chemotherapy, now it's first line. Look at Gleevec for chronic myelogenous leukemia. Initially seemed like this is gonna be a pretty risky strategy trying to block a kinase. Gosh, it really seemed to work quite well in the first 30 patients and now it's first line therapy and it's amazingly successful. So we have to kind of go through those stages and to get there you wanna be sure that you have the data to base it upon. I'm impatient just like you are. Hurry up already, let's get the data. Which means that we worldwide really need to mount these trials on a scale as quickly as possible so that we can begin to learn what works and what doesn't. Some things just aren't gonna work even though they sounded great and you had an anecdote or two that says, wow, this is gonna be the next Gleevec and then, you know, you tried on 100 patients and it's a big disappointment. But it's our obligation, I think, as patients, as providers, as researchers to be pushing this envelope. Now that we have a pathway, we have a strategy, we have a framework, we should not be waiting around to find out how to apply. This has to be brief. Thank you very much for a very impressive panel. My question is actually maybe to go back to the original video that Professor Collins has shown as can the panel envision designing or generating superimmune cells or superimmune T cells that can recognize all the antigens that we have so far in our data? So am I too optimistic or thank you? Well, in a way, that's what people are trying to do right now. I have a very good friend who has brain cancer, glial blastoma multiforme, the most aggressive form. She was diagnosed four years ago. Her brain tumor cells express on their surface a particular protein that normal cells don't have. So she was enrolled in a clinical trial at NIH and it was what you heard about earlier, taking out her T cells, putting into them an appropriate cassette to train them to go after that abnormal protein in her brain tumor that otherwise shouldn't be there and then giving those back and doing that repeatedly. And it's pretty unheard of for somebody to be four years out from that disease because the five year survival is about a year and on the average. And here she is way out there on the tail. Now I can't, that's an anecdote. Be careful here cause this has only been done a few times. I think what you're getting at is could we apply that in a general way and every kind of cancer know what the target should be, train the T cells to go after that. We're not there yet cause finding those sort of wonderful Achilles heel examples for every cancer doesn't come so easy. I will say, we touched on this, that the other immune therapy approach that doesn't require you to know that is the one that basically takes the breaks off of the immune system in a general way. So when Jim Allison gets the Alaska Award in a couple of weeks, it will be for figuring out that if you make a monoclonal antibody against something called CTLA-4, you unleash those T cells not just for one target but for all targets and you give a chance for a cancer that was run and wild to get tackled. And of course there might be a side effect from that. Oh yeah. Your immune system can be attacking yourself. So in the few minutes we have left, I think that in the past decade, the word cancer has evolved from a monolithic death sentence to a question of what type and is this something that we have worked out a way to deal with? I think it's important to think back to 1948 when Sidney Farber published his first paper on the treatment of childhood leukemia. He got remissions at that time and there were people who said it was terrible to treat these children because their disease always came back. But we have two elements here. We have scientists that wanna cure people and we have patients that wanna be cured. And putting them together to decode their disease and to kill it selectively and permanently if possible is the goal that we're making progress toward. And I think that you've heard the mechanisms. We use the immune system. We can fire it up to kill your cancer cells. We can identify the specific mutations in a person's individual cancer and we know what makes it susceptible to specific drugs so the tumor can't grow. We've made great progress and we have these two groups of people, scientists desperate to help people and patients desperate for help and that combination is gonna lead to progress. So come back to Dalyan in a decade and we'll have wiped this one off the map. We hope. Thanks for your attention. Thank you. Thank you.