Systemic thinking about cancer

SALMAN KHAN: This is Sal here. And I have Dr. David Agus visiting the office. And I want you to introduce yourself because you have kind of an interesting life. DAVID AGUS: Interesting life is scary. But I'm a professor of medicine and engineering at the University of Southern California. I treat cancer patients. And I have a lab that looks at new ways and technologies to understand and treat cancer. SALMAN KHAN: And that's what's really interesting, the fact that you're a professor of both medicine and engineering. And I guess that's kind of what we're going to touch on a little bit here. DAVID AGUS: Yeah. SALMAN KHAN: And so this is clearly a picture of eggs. Why are we looking at eggs? DAVID AGUS: Well, if I gave you those eggs, and I put them in your office, and I say come back in three weeks, what would you have? SALMAN KHAN: They would go bad. I'm not putting them in a fridge, I'm assuming. I'm just-- DAVID AGUS: You'd have a rotten egg. Exactly. But if I was clever and I changed the temperature in your office to 99.5% degrees Fahrenheit and I rotated those eggs three times, it has to be an odd number, then at the end of three weeks, I'd have a chicken. SALMAN KHAN: So that's what this other picture is. You'd have this. So you could either have a rotten egg, so this kind of crazy mess, smelly thing, or you have this cute, adorable chicken. DAVID AGUS: Although they call babies, chicks. SALMAN KHAN: Chicks, or chick. Yes. DAVID AGUS: Yes. So a small change in temperature and gravity goes from chaos to order. SALMAN KHAN: Right. Right. DAVID AGUS: And so we're going to talk in a minute about cancer and all the chaos that's involved with it. But realize that that egg, I changed the temperature and the gravity and I went from chaos to order. So while will it seem incomprehensible and unable to model cancer, you're going to start to see little changes can have a major effects. SALMAN KHAN: I see. And this is what's a little bit unintuitive. So when think about things like cancer, I mean cancer is not the only one, we imagine that we just have to kind of-- we have to kill it or we just have to kind of have to take it out. But what are saying is, hey, maybe there's these subtle things, analogous to rotating an egg three times and getting the temperature just right, that can make it automatically do different things. DAVID AGUS: Exactly. To me, cancer is a verb, not a noun. So you're "cancering"-- SALMAN KHAN: Cancering. DAVID AGUS: --when you have cancer. It's not that you have cancer, you're cancering. And so my goal is to change your state of your body from a cancering to a healthing. And so the first question is how do you quantity the state? How do we say who and what you are? And so technology is giving us the opportunity to do that as we go forward. SALMAN KHAN: Right. I just want to get my head around that because you never hear that word "cancering." I think you probably invented that word, [INAUDIBLE], or healthing. Once again, when I imagine cancer, I think this is the way most researchers think about cancers, is the set of cells that have just gone berserk. And you have to remove them or kill them somehow or stop them from spreading. And what you're saying is, no, there's something going on systemically in your body that is cancering. It's allowing the cancer to thrive. DAVID AGUS: That's it. So your first definition of something you have to cut out, a different organism, that's bacteria. SALMAN KHAN: Right. DAVID AGUS: That's an infection. So if something from the outside comes inside of you, I give you the right antibiotic, it doesn't care if you're a man or a woman, you're six feet or you're three feet, if that antibiotic targets the bacteria, it goes away. The difference in cancer, it's your own cells that have gone a little bit crazy. And so we have to change the interaction of the body and the cells in order to make that patient better. Very different than something without, this is within. SALMAN KHAN: I see. In other words, I'm just-- it's fascinating because there's all sorts of parallels in, I guess, everyday life, depending on what you believe. But some people, if there's crime in an area, there's one point of view that you need to police it. You have to arrest all the criminals. But then, hey, maybe the criminals keep coming because there's certain environmental factors. Maybe there's just a lot of poverty and there's lack of education. And so you're saying, hey, let's look at the things systemically, as opposed to just-- DAVID AGUS: Hunting. Put some lights in the area, put some police driving by. But all of a sudden, the crime level goes down. SALMAN KHAN: Right. Right. It's not just about arresting the criminals. DAVID AGUS: Exactly. SALMAN KHAN: It's about preventing the crime. DAVID AGUS: Let me tell you about a clinical trial that was done a couple years. It's the coolest clinical trial. And they took women after optimal therapy for breast cancer, these they were women who were premenopausal, so really aggressive breast cancer. Half of them, after treatment, got placebo. And half of them got a drug that builds bone. SALMAN KHAN: Interesting [INAUDIBLE]. Let me write this down. So this is breast cancer. So these are people-- DAVID AGUS: These are young women with breast cancer. SALMAN KHAN: Right. Right. And half got a placebo, which means just like a sugar pill. DAVID AGUS: Sugar pill. SALMAN KHAN: And then you give that to patients just to make them think that they might-- because sometimes the psychological impact [INAUDIBLE]. DAVID AGUS: And this was ethical. And it's very important to talk about whether it was ethical or not. It was ethical because they already got their treatment for breast cancer. And normally in those women, we just wait. And hopefully, they're cured. And we see if it may recur. SALMAN KHAN: Right. DAVID AGUS: So in those women, we divided them into half. And we gave this pill. It was a placebo. And half, we give a drug for osteoporosis that builds bone. SALMAN KHAN: Osteoporosis, osteo-- DAVID AGUS: You say, why are you wasting someone with breast cancer's time by giving them a drug that targets bone. SALMAN KHAN: Right. Right. Right. DAVID AGUS: The reason is breast cancer metastasizes to bone. SALMAN KHAN: And it metastasizes, it spreads to bone. DAVID AGUS: It spreads to bone. SALMAN KHAN: And that's when cancer just goes, [INAUDIBLE]. DAVID AGUS: Right. It goes to the bone. It likes the bone. So the argument, if I change the soil, the seed won't grow. Because remember, when you have a garden, you can give your fertilizer or make that soil so those tomato plants love it. SALMAN KHAN: Right, right, right. DAVID AGUS: And so that's what we're doing here. We're making the bone different. SALMAN KHAN: Right. And so once again, the system thinking is that before, if you have these breast cancer cells that are just growing, the view is, hey, let's irradiate them. Let's slice them out. Let's get chemicals that will be toxic to these cells and kill them. What you're saying is cancer really starts to become a real negative once it spreads. And what you're saying is let's keep it from spreading maybe where it's the most common to spread, which is in the bone. So before the bone drug, the cancer spread. The cancer could kind of take root in the bone and then start spreading and metastasizing. This is what metastasis is. DAVID AGUS: Um-huh. SALMAN KHAN: And instead, you're saying maybe if you have this special drugs, this osteoporosis drug, it makes the bone that much stronger and less susceptible to this type of thing. And then that won't be able to happen. DAVID AGUS: Exactly. SALMAN KHAN: Right. Right. Fascinating. DAVID AGUS: So at the end of that trial, the cancer recurrence was reduced by 40%. SALMAN KHAN: Wow. DAVID AGUS: At the end of that trial, new breast cancer, so a separate breast cancer-- because once you have one breast cancer, you can get another breast cancer-- that was down by 35%, SALMAN KHAN: Wow. DAVID AGUS: So this notion of changing the system-- because remember, this is a drug that didn't even touch the breast cancer-- had a dramatic effect in the survival of these young women. SALMAN KHAN: Right. Right. DAVID AGUS: So again, it just makes this a whole new way of thinking about disease. SALMAN KHAN: Right. Right. So if we were putting words on things, the way that most people think about disease right now, you call it kind of a reductionist, where they're just going to focus on one narrow part of it. They're trying to focus on this thing right over here. And you're advocating for kind of a more systemic way of thinking about it, where you think about everything that this might involve or that might affect it. DAVID AGUS: It's so wild is that for the last several decades, we're trying to focus on the individual cell, and then the individual gene, and then the piece of the gene. And we forgot to take that step back and look at the whole system. And so remember, the cancer is your normal cell that's gone a little bit crazy. So we have to model that whole system and figure out a way to control it so the cancer won't like it. SALMAN KHAN: Wow. Fascinating. Fascinating. And then we have pictures of what some of these things look like. So what is this right over here? DAVID AGUS: So this is a liver that's taken out of a patient. And the white spots there are colon cancer that's metathesizes, again spread to the liver. SALMAN KHAN: Right. So it's a cancer that grew up in the colon. And at some point, it was able to spread and kind of liberate itself and then attach on to the liver. And it's metastasized to the liver. And now, it's kind of growing in this-- it looks, at least from this picture, kind of a cauliflower-like shape. DAVID AGUS: Exactly. Exactly. And then if I showed this to a surgeon, or someone who normally operates on livers, they would know right away, hey, that looks like colon cancer gone to liver. SALMAN KHAN: Right. Right. SALMAN KHAN: And if you look at the next picture on the right, that's colon cancer inside of a lymph node under a microscope. SALMAN KHAN: And these are the lymph? DAVID AGUS: Those are the normal lymphs. SALMAN KHAN: Lymphs. And this right here is the colon cancer? DAVID AGUS: Exactly. SALMAN KHAN: OK. DAVID AGUS: And so any pathologist would look under a microscope and they would make a diagnosis and say, hey, this looks like colon cancer gone to the lymph. And in the bottom is a different way of looking at cancer, which is a CAT scan. So this is basically a three-dimensional X-ray. I took a slice right in the middle that person's body and those translucent areas in the middle there are colon cancer metastasis. SALMAN KHAN: This? DAVID AGUS: Those darker areas, yes. SALMAN KHAN: OK. DAVID AGUS: And so what's amazing is-- SALMAN KHAN: That's in their liver. DAVID AGUS: Colon cancer looks a certain way, in a lymph node, in the liver, on a CAT scan. And it always looks that way. The body doesn't care what the underlying genetics are because the genetics are dramatically different patient, to patient, to patient. But it always looks the same. SALMAN KHAN: I see. DAVID AGUS: So somehow, evolution is selecting out for phenotype, which is what things look like, not necessarily for genotype. SALMAN KHAN: Which is their actual-- the DNA that makes up what they are. DAVID AGUS: Exactly. And so we're focusing on genotype. And genotype is very important and it's going to give us some understanding over time. But we have to also take that step back and look at the phenotype, and look at what it looks like, and try to change those interactions. Remember, if a patient has early cancer, we've learned a lot in the last 10 years. So if you have early cancer, and I cure you with surgery, the day before surgery I can always find cancer cells in the blood,-- SALMAN KHAN: Wow. DAVID AGUS: --even though you were cured. So the old days, we thought, well, you have to wait till it goes out through our bloodstream and gets out there. That's wrong. It's can it live outside that original organ? SALMAN KHAN: I see. So there's someone who's cured or they're not cancering right now. And there is actually cancer in their blood. But because they're healthy now, or healthier, or they're healhing, or I guess however you want to call it, that cancer isn't able to take hold. DAVID AGUS: And those cells, they can't live anywhere but the colon. SALMAN KHAN: Fascinating. DAVID AGUS: So listen to this experiment. This is the wildest experiment. They took a mouse. And they took breast cancer and they put it in the left breast and the right breast. And they colored them red and green, the cells. They waited a day, they went back, and the cells were half red, half green; half red, half green. Because we always thought if cancer is something in one local spot, it really is a disease that keep going through the bloodstream. And it likes those breasts. That's why it keeps going back there. SALMAN KHAN: So interesting. And when I always think of metastases, and I can never say is the word, I always imagine it, OK, that's the cancer that's finally gotten to the lymph network. It's finally gotten to the blood vessels and now it's spreading But you're saying that there's actually often cancer that has gotten to the transportation networks of the body. But it has still not metastasized because it's not able to take hold yet. DAVID AGUS: Exactly. SALMAN KHAN: That's fascinating. DAVID AGUS: Exactly. And over time, we're going to get the technology to interrogate those cells to say, hey, this one can take hold here. Therefore, I have to change where it would take hold. We're just at the beginning of that technology that's going to change everything. SALMAN KHAN: And the reason why we're looking at these, the fact that colon cancer starts in the colon and this is how it looks when it spreads to different parts of the body, what you're saying is that we shouldn't maybe be so fixated on just the DNA of colon cancer because it can be very different from one patient to the next. But maybe on kind of its macrobehavior, it's phenotype, how it looks, and how behaves. And that way, it'll give us clues maybe on how we can change it. DAVID AGUS: Exactly. SALMAN KHAN: Fascinating. Thanks a bunch. This is very interesting. DAVID AGUS: It's great.