SIO524: Why We Haven't Cured Cancer Yet, Part 2 (with Dr. Eric Jaffe)

Transcript

This transcript was generated automatically and may contain errors — the audio is the record.

0:00:11 Thomas: Hello and welcome to Serious Inquiries Only. This is episode 524. I'm Thomas Smith and this is a part two. Part two alert. Make sure you listened to part one or you're not going to understand how we got here. And how we got here is Dr. Eric Jaffe. One of my favorite guests and people taught us about cancer in part one and it's so much weirder than I previously understood. Still don't 100 % get it, but in part two we're going to cure cancer. Guaranteed. 100%. Anyone with cancer who listens to this will be cured. I think that's what Eric said. Don't hold me to it, but hold him to it. But in seriousness, Eric is going to take us through how we treat cancer, why it's so hard. Are there cures? What's in the pipeline? Which different kinds can be cured? I mean, so many questions. I'm excited for you to hear this part too. So why don't we just get on over to it? We'll take that quick first break, which you can avoid at patreon.com/seriouspod. Hopefully you are hearing this early because you are on patreon.com/seriouspod. Thank you to those who support the the show. All right, after this break, we'll get to it.

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0:01:25 Thomas: Dr. Eric Jaffe, welcome back. How are you doing?

0:01:27 Eric: I'm doing pretty well. Just got a haircut, getting ready for a vacation in the Outer Banks, so, you know, summer break is going well and in full swing.

0:01:34 Thomas: Well, I'm just excited to cure cancer, personally. I think it's a long time. I'm glad we're doing it. Not sure why nobody else did. Seems like somebody should have done it by now, but I guess it's on us.

0:01:43 Eric: Yeah, although hopefully people have already listened to part one and recognize the challenges associated with that now. I should also, right, like, when talking about cures for cancer, I think I was a little glib in the last part where, I want to be clear, a lot of times when we're talking about cures, we're taking about instances of remission, right? Increasing survival curves over five to ten year horizons. A lot of times you're not able to fully get away all of the cancer permanently, but you are doing a lot of stuff that improves quality of life and extends that quality of Life through the next decade or so. Right. But unless you've surgically removed all the cells and there's no EMT, no spread, it can be very hard to fully remove the cancer as we'll talk about in this episode when we focus more on the therapies. These? Yeah.

0:02:29 Thomas: Yeah. Well, maybe we should do just a quick refresh of what we talked about last episode.

0:02:34 Eric: So what we talked about last episode is how we think of cancer as the disease itself, when really it's a kind of post hoc description of a broad class of conditions where cells start behaving like they're developmental again, instead of adult, right? They're in a more stem -like state. They lose a lot of their mature cellular identity, and then they start becoming rapidly what we call proliferative, right. They just go through the cell cycle over and over over again. And like cars piling up when there's nowhere to go, you end up with that three-dimensional structure that we call a tumor. And things get really bad once they lose that tight structure. And they undergo this process called EMT, where they then spread to other parts of the body. And that's when cancer progression really starts to take a more deadly turn a lot of times.

0:03:23 Thomas: That was summing a very complicated episode into a few seconds, but I I think we're good. I think we can move on to curing cancer now. So, I'm curious, I mean, I know you have a roadmap and a plan, but is there any cancer where you do just, like, cure it? It's like, I don't know what the cure would be. Is the cure always just removal of the cancerous cells, or is there some other form of cure? You know, is there a vaccine? Sure.

0:03:46 Eric: Yeah, and this is a kind of don't take medical advice from a podcast territory, especially from someone with a PhD instead of an MD. But what I would say is there are situations, and especially as we start talking about next generation treatments, and keep in mind when I say next generation, the other things we're talking about in the first part of this episode, radiation therapies, chemotherapies, it's not like they've stopped doing research on that stuff. But what we will talk about is ways to kind of like hijack the properties of virus or your own immune system to clear away all the cancer cells. And that's really our hope for like, really getting getting rid of stuff because, and we'll get into this in a little bit, but when you talk about radiation and chemo, a lot of times what happens because these cells are constantly dividing, constantly mutating, is you can end up with a situation where like you're your own petri dish for bacterial antibiotic resistance, right? The longer exposure that your cancer cells will have to chemotherapies and radiation, the more that they have the ability to develop resistance to those things, right? And so a lot of times what they can do is they can enter a senescent -like state, kind of like spores in bacteria or fungi, where they're no longer actually dividing anymore, but they're kind of biding their time until that selective pressure of the chemo is removed, and then they go back to being cancerous.

0:05:02 Eric: It's a really complicated Gordian knot of a disease. And again, it's made more complicated because, as we talked about in part one, even within an individual tumor, you're going to have cells with different identities, different genetic makeups, because of that rate of mutation in those constant divisions that happen. And so we really need to come up with ways to be adaptable to each individual tumor and each individual person as we start thinking about ways to really clear it. Now, when you're lucky, you get the cancer detected before you get that spread in that EMT, and you have surgical margins where you can completely remove the tumor, and then you can get something that's much more closely related to to true cure. Though again, this is oversimplified and overbroad. Every person's cancer story and treatment is going to be their own unique butterfly. It's that epithelial to mesenchymal transition, right? When you go from forming barriers.

0:05:47 Thomas: So the EMT was the electromagnetic, no, what does EMT stand for? And it's where it spreads, right?

0:05:56 Thomas: Oh, the made -up word that But I swear to God, there's no chance it's real. That's a... Electromanimical Schmeichel. Is that... It's gonna be funny if I learn that you actually just can't say a real word and it's something totally different, but that's just a...

0:06:10 Eric: This isn't a dull and D -hole situation where I was mispronouncing dull for the K -9 episode as D -holes. This one's a real thing. I've heard it in actual science talks and have used it in my own science talks. I'm fairly confident it's epithelial and mesenchymal. But basically, epithelia cells are the ones like your skin, stomach lining, right? They form barriers because they're constantly connected through these junctional proteins. Whereas mesenchymal cells are more like your red and white blood cells, your macrophages, your hematopoietic system in general, where it's more free -floating and they don't form those cell contacts, which also means that they're free to travel around the body. And then once they get to a new spot, they undergo MET, mesenchymal to epithelial transitions, where they re-epithelialize and form a new tumor.

0:06:56 Thomas: So if you can get to it before that, you know, I think a lot of people are like loosely familiar with that based on cancer in either in their lives or families or TV or something, but getting to it before it spreads, basically. So I still am a little bit struggling with the difference between like cancer versus the process or the whatever state you're in that is making your cells do that. And so I guess if you totally remove a tumor, let's say you just have a tumor somewhere, it hasn't spread yet and you totally move it. And there's no, I guess, cancer anywhere else in your body, hypothetically, can you just be theoretically good to go? Like, is that just like you might just be totally fine? Or is there something still going on that would lead you to produce more cancer cells?

0:07:08 Eric: Exactly. Unfortunately, pretty much everyone has a frame of reference for dealing with these two episodes, which is part of why I wanted to talk about it, because it's something that touches everyone, but is also a great demonstration of how the basic principles of biology manifest in physiologic and medical ways. You're you're actually thinking about it right even though you're confused right if you completely remove the population of cells that have those suite of mutations that prime them to form tumors you will be good to go but most of the time what happens is you still have a pool of cells that has those mutations either because they spread or they're from a stem cell population that's still dividing and so you do have the ability for those to reform a tumor and mature in the same way those previous cells did so it depends on whether you still Have cells that have those genetic mutations that prime them to cancer. But you're right that we typically think of cancer as the phenotype, right? Once they actually start forming those masses, those tumors start switching to that Warburg metabolism where they're no longer using oxygen, when they start doing angiogenesis, right, those things that are the mature form of cancer is typically what we label it, but they all come from those genetic mutations in a population of cells at first. So hopefully that clears it up. It's really, you can have a roster capable of winning a title, but until they actually win a title they're not champions.

0:08:57 Eric: So I guess what I want to start with are the most traditional forms of treatment that probably most people are familiar with, chemotherapy and radiation.

0:09:05 Thomas: Yeah. How the hell is radiation, something that causes cancer, a treatment for cancer?

0:09:10 Eric: Yeah, that's a really, really good question, and I've spent a lot of time thinking about the right analogy, and it's not a perfect analogy, but I think it will work. The logic behind radiation is, as we mentioned, cancer cells are constantly dividing and they lose that ability to error check their DNA, right? They lose the ability to recognize DNA damage and halt the cell cycle. Whereas your normal cells aren't dividing nearly as often, and they have the ability apoptose, self -destruct, or halt division in the presence of damaged DNA. And so radiation is kind of like the equivalent of when you catch your kid smoking and you go, all right, bet. Now smoke the whole carton of cigarettes to learn your lesson.

0:09:52 Thomas: That's not good. I don't think that was an actual good treatment for

0:09:57 Eric: It's basically saying, okay, you want to pick up a bunch of mutations. Let's really give you the opportunity to pick up mutations and make you completely non -functional, right? Like really just the logic being that the cancer cells are going to divide more often and pick up more errors than your normal cells. So if you introduce an error generating mechanism, it will differentially affect the cancer cancer cells relative to your healthy cells. But that's partly why like if you get radiation in your scalp area, you'll lose hair follicles because you're damaging cells by definition that are dividing more often than you're damaged cells that don't divide more often.

0:09:59 Thomas: It oh my gosh this hair divide what do you

0:10:37 Eric: Yeah, your hair grows, right? Because of stem cells in the hair follicle constantly producing new cells. Right? Yeah. So that's more of a relevant thing for chemotherapy, as we'll talk about in a second. But where radiation really shines is when you have those nice epithelial tumors, right? When they haven't really spread yet and you can shine a laser quite literally and use that as your mechanism for clearance, right. Because then you can even target the laser beam onto the tumor to make sure that you're making as targeted as possible. And you're Making sure that you're targeting where the cancer is and you don't have to worry about it being spread to other areas that you're missing with that laser beam.

0:10:39 Thomas: Mean okay I don't know how hair works so wait is radiation treatment a laser beam gosh I know nothing about this oh so

0:11:22 Eric: Yes. So like basically you are shining a high, right? All radiation is electromagnetic emissions. And so when you're using rate, well, not all, right. You can take other forms of it, but in general, when you have those nice tight tumors. So when my dog had that bone cancer right on his skull, he wasn't a candidate for surgery because you'd have to cut into his brain to remove the tumor. And that's obviously not ideal. That's kind of throwing out the baby with the bathwater. So what they did was they used this technique called CyberKnife. And CyberKnife is a really high intensity concentrated laser that they shined right on that bulge on his skull. And you would watch over the next couple of days as it visibly shrunk as cells died in response to that laser. And this actually got him an extra year and a half to his life. So like it's a very useful and helpful thing in the right situations with the right types of highly organized cancer and tumors. The other side of that spectrum is is chemotherapy, right? And chemotherapy is kind of for the opposite spectrum. Here, it's already started to spread. So you can't really focus on one area. So you're going to take some type of oral medication that will help clear things systemically throughout the body. But again, the part that you're targeting is that proneness of cancer to cell division, right. So typically, with chemotherapy, what you're doing is you're trying to inhibit cell division. It's the opposite of, I caught my kids smoking, now they're going to smoke a whole carton of cigarettes. And instead it's, I cut my kids' smoking, they're grounded for the rest of their life because you're going get into more trouble when you go out. But you're also losing out on a lot of enriching things by going out because some of your cells are dividing for perfectly good reasons. And if you inhibit cell division globally, that will come with a suite of harmful effects, such as the hair loss, because you are targeting cells that are dividing. Well, with radiation, it's much more like you would only get the hair loss if you are targeting in that. Yeah, exactly. That's the benefit of radiation is

0:13:08 Thomas: Either way you're getting hair loss that's just how it is oh if you're targeting it yeah okay gotcha

0:13:19 Eric: You can make it more locally targeted, whereas chemo is more global. But chemo's more effective for cancer that's already started to spread. And so with chemotherapy, what they'll do is instead of trying to introduce mutations, they might inhibit the process or the proteins that govern DNA replication, replication, the, what we call polymerase or topoisomerase, which unwinds the DNA helix, right? Things that, well, not unwind, but relaxes the DNA Helix for DNA replication, but they target proteins that are involved with that cell replication process so that you can arrest it. And they're unable to do that anymore in

0:13:56 Thomas: So if someone says they're getting chemo versus someone says they'RE getting radiation you're more worried about the chemo person than the radiation person because they're like further

0:14:06 Eric: General. But again, this is starting to get a little bit more in the clinical area where I wouldn't be able to speak with confidence. But what I would say is, typically, there's a couple of other things that factor into that. There's this thing called the mitotic index, how rapidly the cells in your cancer subtype are dividing. And if they're dividing super quickly, you're a good candidate for chemo.

0:14:08 Thomas: Along in general yeah sure sure

0:14:27 Eric: But if they're not, you're not because there's nothing to inhibit if they're not dividing super quickly. So there's a bunch of other factors I would go into. But in general, I would say chemo is probably more taxing globally for the person and is indicative of a more global cancer burden, or it's that the type of cancer they have just isn't responsive to radiation. And again, these can also be yes and. Cancer therapy is often an improv approach to things where you're not doing one thing, you're doing a suite of things, right? You might combine chemotherapy with another type of targeted therapy that would block EMT. Maybe you have something that works on the protein TGF -beta, which is something that kind of tells cells, stop being epithelial, go into a mesenchymal program. And if you inhibit that protein, you lose the ability of the cancer to metastasize as readily. So they're often done in combination where you're both trying to stop the spread and you're trying to top the replication in general. These will also hopefully cause the cells to die because you're really messing up fundamental properties of cell culture or of cell propagation. The problem is that the only difference between your normal cells and your cancer cells are that the cancer cells you're dividing more often. So it's not like your other cells are completely immune to the negative effects of these two treatments.

0:14:27 Thomas: Sure gotcha

0:15:44 Eric: And so that's like our standard treatments. As I mentioned, there is more targeted therapies that you can do, whether it's attacking EMT or as that new breakthrough in pancreatic cancer research research that has, I think, doubled the time horizon for many of the patients in that clinical trial, they use what's called a RAS inhibitor, R -A -S. And what RAS is, is a particular protein that governs the cell cycle, tells cells it's time to keep going in the cell circle. And as you can imagine, in about 20 % of all cancers and 90 % of pancreatic cancer cells, depending on the a subtype, will express mutations in this RAS signaling pathway, that cosine for cell division. And so this new drug that has shown such success binds to a portion of that protein, right? Because all medicine, all drugs really, are about playing with the structure of biology. The fundamental principle of biology is form follows function. And the reason why your DNA matters is because it influences the structureof different proteins that will influence their function, kind of like we talked about in the eye color episode. And so what these new anti -RAS drugs do is they bind into a pocket of the protein RAS, and it forces it to be in an off state as opposed to an on state. Because many proteins, including many that are involved in cancer EMT and cell proliferation, are constantly expressed, but have a different structure based on whether they're active or they're inactive. And a lot of drugs try to trick these proteins into remaining in an inactive state, in an off state, by either competitively binding the site where another molecule would turn them on, or by binding a part of the protein that changes the structure so that the thing that turns them on can no longer bind them.

0:17:31 Thomas: How does that target the cancer and not just stop all your

0:17:35 Eric: Again, the key here is that because cancer cells are dividing much more often, you're going to target them way more than other cells. But these are somewhat nonspecific, and there is what we call cytotoxic effects to pretty pretty much all of these type of therapies. And cytotoxic just means, cyto always means cell, toxic is toxic. So cytotxic means they kill cells as side effects.

0:18:00 Eric: So right, that's part of why you get nausea and fatigue and all of These other side effects that come with chemo radiation, and these anti cancer therapies.

0:18:00 Thomas: Cells so I get so with the radiation I got that it was like all right because theyre multiplying more often theyre gonna pick up more mutations and youre trying to like make them smoke the whole pack. With this one, I guess I don't get how the multiplying more makes them. Is it that it only picks up the thing that stops them from multiplying forever when they multiply? How does the differential...

0:18:32 Eric: It's more I would say, like, I would see this one is much more of a time buyer, right? This one buys you more time, you usually do chemo a lot of times in conjunction with radiation or other anti -cancer therapies that are more targeted. But I would say a lot of times with chemo, what you're really trying to do is buy as much time as possible, or you're combining chemo with another thing that will both stop the growth and kill the cancer cell.

0:18:56 Thomas: So I was asking about the protein thing.

0:18:59 Eric: Oh, for the anti-RAS signaling,

0:19:00 Thomas: Yeah. How does that differentially affect cancer just because cancer reproduces more? But then you eventually have to stop doing that, right doesn't it just go right back on

0:19:05 Eric: Because these RAS proteins are involved in the proliferation, they're the thing that's telling cancer to keep dividing, dividing, dividing, dividing, dividing. And so if you shut off that signal, even though the gene is still mutated, you've blocked the ability of that constant on to be constant on. Because typically the mutation you get in RAS is something that keeps it in the on state. And So what you're trying to do is turn it off forcefully after the fact.

0:19:37 Eric: So this is partly why a lot of these therapies are more about increasing the five and 10 year survival curve, right? Because a lot lot of times you're right, it is kind of just putting it off and slowing the spread. That's partly also why early detection is so key. Because the earlier you detect things, the more you can slow the spread, the More time you have, especially because a lot of these cancers, you know, show up in your middle age. And if I'm being honest, let's say I get pancreatic cancer at 40. And something tells me I can get 20 years. By the time I get to be 6570, I'm starting to be in a different phase mentally in terms of what I'm willing to do, how I feel about the life I've lived, things like that. These are imperfect solutions though.

0:20:20 Eric: And that's why these are also kind of the prior generation of cancer treatments. We're going to talk about three of kind of The Next Gen, even the protein one. It's still working at a more targeted therapy. The reason why it's so useful and why it'S considered new is because this was a protein that was very, very hard to find that that pocket, that area that you can bind a molecule to that would inhibit it. So this protein was called undruggable for a long time because there was very hard to get them to disassociate from the molecule that turns it on. It was very harder to get it to change its shape because we're talking about a very small protein in the grand scheme of things. These new drugs found a very minor groove on the opposite side of the protein that subtly changes its structure to make it unable to bind the molecule. That turns it off. So it's a really important breakthrough through, but it's not really a cure. It's more of an extender. Now, the three things we're going to talk about is like our next generation of drugs. I call them next generation, not because we're not doing research on improved ways of radiation, chemo and targeted therapies, but because these ones have the ability to be broadly adaptive and do generally deal with trying to clear and destroy the cells as opposed to just limiting their ability to reproduce and things like that. And so the first one we're gonna talk about uses our good friend CRISPR. Well, Well, it doesn't have to use CRISPR, but CRISPR has really been a supercharger of this process, right? It's been really helpful in making this process easier and more efficient. And what you basically do, it's called CAR -T therapy, chimeric antigen receptor, which is basically I'm making a new recognition thing. Antigen is the part of a virus, bacteria, cancer cell that your immune cell recognizes to then clear away from the body, right. It's the, you're the bad cell. I need to get rid of these, Parker. And so what chimeric antigen receptor therapy does is takes out your own white blood cells, your own T cells, and reprograms them genetically using things like CRISPR to recognize proteins that are mutated just in your cancer cells and just expressed in your canter cells, right? So these will actually leave your own cells, your own healthy cells alone, and will only work as an immune system towards the cancer cells.

0:20:27 Thomas: Even that protein one finally

0:22:41 Eric: As a form of immunotherapy. And the reason why this is so exciting is because, as we mentioned, cancer is its own individual snowflake for each individual person. So now what you can do is you can take samples of the cancer cells, genetically sequence them, or do assays that recognize the proteins on the cell membrane of these cells, and then develop T cells with genetic modifications that specifically target the proteins on that cellular membrane. So now they're going to recognize those as bad foreign cells. The cancer cells are no longer able to evade the immune system because they're not looking for the old things anymore. They're looking for The Thing specific to your specific cancer cells. It's a way to prime the night watch on who are the actual people running amok in town. And so this is really exciting because Because theoretically, with CRISPR getting cheaper and more efficient each time, it gets easier and easier to target and tailor each therapy for each individual person.

0:23:42 Thomas: Yeah so what's stopping this this feels like oh we found it we found the cure why isn't this the cure

0:23:48 Eric: So this is, yeah, this is as we talked about, I forget if it was the Direwolf episode or one of the other episodes, but right, you still have to do the work of finding the right proteins, figuring out how to develop an antigen that the T cells will respond to, making sure that you have a system that you can adapt and making sure that it covers all of the cells in the tumor. Because if your cells are going to have different genetic mutations, even within a single tumor, it can be tricky to find the thing that's common to all of them to help clear that tumor away. This would be even better if we could actually just go into the cancer cells and use CRISPR to genetically engineer them. But as you can probably imagine, when they're clustered in a tight tumor, It can be hard to even deliver that CRISPR therapy into the cells. So it's much easier to take the immune cells out, get them to recognize the cancer cells, and then implant them back into the body. So that's our first kind of real next generation treatment is using immunotherapy combined with genetic engineering to make your own cells kind of the cancer watch of your body.

0:24:53 Thomas: Yeah I feel like I heard that about that a long time ago it just feels like it's like oh yeah okay that then that that does it. Shouldn't that be it? We won.

0:25:02 Eric: We want ethical research is another big thing, right? And so you can't just move on to clinical trials before you validated it in in vivo and in vitro models, right? And so typically there's a lot of time and effort because you have to humanize your mice with the specific cancer subtype that you're trying to study so that you know that your therapy is targeted for that cancer subtype. You have to then get either primary cells from the mouse or patient samples, culture them in the cell and validate that it works on human cells, right. So then you combine the in vivo, the animal studies with the cell studies. And you go, I know it works both in the 3D architecture of multiple tissues of the complex mammal organism. And I know what works on human cells specifically. And that process can take a lot of time just because we're doing it ethically. And that's before you even get into stage one, stage two, and stage three clinical trials. And those have to be done on a far enough time horizon that you know that what you're seeing is actually real and kind of holding, right? If you're trying to improve five to 10 year survival curves, Almost by definition, your study has to last five to 10 years if you're doing a truly longitudinal study. But that is coming on the horizon, and it's already in kind of clinical stages in real patients right now where if you have the right cancer subtype with the right conditions where they don't think you're responsive to chemo, radiation, or targeted therapies, you're already eligible to start getting those type of immunotherapies.

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0:26:42 Eric: Another big one, and this one's kind of the opposite, is instead of using the immune system to target cells, we already know of molecules that target our cells, viruses. And the way viruses recognize enter and exit cells is by binding to surface proteins. The reason why the spike protein was so famous in coronavirus is because it's the spike protein that binds to the cell receptors in our respiratory cells and uses that as kind of the lock and key to enter into our our cells. With flu, the reason why HN is always like the H5N1, what those are referring to are the hemagglutinin and neuraminidase proteins that both govern entering the cell by recognizing sialic acid and exiting the cell with neuraminides, right? And these entry and exit things are both, we'll get into this if we ever talk about vaccines, what vaccines and T -cells are targeting, right, but for our purposes for fighting cancer, they're going to be tailored to recognize, again, the proteins that are specific to your cancer subtype. So now you're going to have a virus go in, ignore your normal healthy cells because they don't have the right protein on their cell membrane, and they're going to recognize the cancer cell, enter there, do what viruses do, trigger an immune response, cause it to lyse just by overloading them, take over the host cellular machinery, and they are going to target and kill or set up the immune system to kill your own cancer cells.

0:28:07 Thomas: We got it. It's all done.

0:28:09 Eric: Yeah, it's basically act three of Jurassic World Dominion, right? Just instead of targeting mosquitoes, you're targeting the cancer cells.

0:28:16 Thomas: There's no chance I could remember that. Forgettable movie. Yeah.

0:28:18 Eric: It's a real throwback. But yeah, it was a really bad movie. But the basic principle still kind of stays, right.

0:28:23 Thomas: But it had dinosaurs. So for you, it's an 11 out of 10.

0:28:27 Eric: Yeah, no, that's really the benefit of the viral one is again, these are both both the viral and the amino ones are super, super targeted to the specific cells that you want. And they're actually going to kill and clear those cells away. So the ideal world for these is you won't have, you know, remission and then reoccurrence, you will actually be able to get rid of all the cells in your body, because they're going to sweep through and recognize all of the cells with those particular proteins. Now, obviously, these again, have the same challenges where the cancer cells aren't going to stop dividing, they're going to keep picking up more and more mutations. And there's always a chance that they pick up what we call an escape mutation that changes the structure of those surface proteins that the virus or the immune system no longer recognizes, right? That's why you have to get a new flu shot every year is the hemagglutinin protein will change its shape ever so subtly. And now your vaccine developed antibodies no longer recognize that viral protein. So my guess is that would be something that you would probably be in constant concert with your physician with over time, where you're constantly surveilling to make sure there's no reoccurrence. Resampling, if you ever get reoccurrences, those cells to develop new and better, more updated for your body, T cells or viruses that recognize the new version of those proteins.

0:29:44 Thomas: Are people getting this yet?

0:29:46 Eric: I believe these are also in clinical trials, right? So like if you have the right cancer subtype, the right situation, you're not responding well to normal therapies, you're probably a candidate for these type of treatments as well.

0:29:57 Thomas: What's the right cancer type for that?

0:29:59 Eric: Well, it would be, are you able to develop an antigen that's easily recognizable, right? Do they have a surface protein that you can attack with these viruses or with the T cells, right, so you would do tests to see, can I make an antibody develop the right thing to actually neutralize these proteins or to recognize these proteins, because it can be tricky to just make an anti body that recognized it. This is the rub on making a universal flu vaccine is there is a way to make a universal fluid vaccine that I used to do research on, where you would target the more conserved area of that hemagglutinin protein instead of the part that is actually interacting with the protein. Because theoretically, it's conserved because you can't mutate that part of the protein without fundamentally making it ineffective. But if you can change other parts of the routine that are more recognized by either the T cell or the virus without it harming its function, then the cancer cell is able to escape or you're not able to develop an effective antibody. You can also develop one for that conserved region, but just because it recognizes and binds the protein doesn't necessarily mean that you're neutralizing the protein, right? If I am trying to block myself from holding onto a bottle of water and I place something on the back of my hand, that doesn't really block me from holding the bottle of Water. But if I find a ball and place it in my hand now, I'm blocked from from picking up a bottle of water.

0:31:27 Thomas: Mutate another few fingers or something.

0:31:30 Eric: Exactly. Or until I develop a bigger groove in my hand and now the ball doesn't fit into the palm of my hand anymore and my hand is back to being free to picking up water. Sorry, there's just a bottle of water in front of me.

0:31:42 Thomas: Just a way to drop the water. I didn't even think about that

0:31:44 Eric: Right, exactly. But if the protein needs to mutate so much to be able to drop the ball that it can no longer pick up the water, then I've found an area that is conserved, right? If it can't mutate around the ball in a a way that will make it still able to pick up the water, then it won't select for that mutation that makes it unable to pickup the ball because it's lost its main function of picking up the water. And that's what a lot of these targeted and new age, really all medicine is trying to do is how can I develop the right ball to interrupt the disease's hand from picking up the water? Or how can I help the water change its shape so that the disease can no longer pick it up.

0:31:45 Thomas: Or a way to sorry a way to drop the ball so that you're yeah here let's use something more Americans will understand it's a gun you need them to not pick up a gun so you gotta put something else in their hand or pass universal background check but no no that's probably too hard we'll do the

0:32:33 Eric: Right. How can I find the right banana that I can trick the hand into thinking it's a gun?

0:32:42 Eric: Well, that one right is more like the universal background check would be how can I make it so that the disease never enters the body to begin with?

0:32:45 Thomas: So like there's no

0:32:52 Eric: It's more like a vaccine with red flag laws, right? Like I've already figured out what are the type that are going to cause problems with guns? How can I prevent them? Right? How Can I prime my immune system to do a background check to get rid of these viruses, these bacteria before they can actually do it. Similar to, I've now done a universal background check. I know what my cancer cells are. How can I prevent these cells from forming again from my immune system? Now, here's going to be a really fun one because just like the mRNA vaccines were an improvement on traditional vaccines because of the ease of production, the simplicity of them, the cost in developing them, we're doing the same principles of that immunotherapy, or even that oncolytic virus, right? We're priming the immune system to recognize cancer cells, only we can now do them with those targeted mRNAs, right, where we just take the mRNA that's being expressed to build those proteins on the outside of the cancer cells and just start feeding them directly into our immune system going, hey, these are really not great. I want you to be on high alert for this particular protein. And now they're going to clear the cancer cells in the same way. We show them a copy of the spike protein, go, hey, the spike routine is really not cool. You need to clear those cells that have that spike protein. And so those are our next generation because they both work to get rid of the cells fully, right? They're not just arresting their growth. They're not just passively altering their biology. They are really trying to get rid of them. And there is really really much, much more specificity, right? The cytotoxicity is much lower in these advanced therapies because they're really not harming your healthy cells at all in the same way. Yes, you'll have general inflammation from the immune response the same way I get a sore throat when my immune system is killing viral cells or cells infected with virus, but they're not targeting those cells anymore, right. It's not like radiation where harmless cells will be harmed in this process.

0:32:55 Thomas: Guns well why don't we have that is there only a certain type of cancers is it even with stuff like this hypothetically is a matter of time and getting it to adapt to all cancers or would there be ones that it couldn't attack or

0:35:03 Eric: There probably would always be some that are just hard to attack either because they're undetectable until it really is already too late, right? I actually struggled this a lot with my graduate school research project where we were developing ways to detect and cure spina bifida, neural tube closure defects. The problem is most people's neural tube closes, everyone's neural tube closes before most people even know they're pregnant. It happens in week three to four of of pregnancy. And so there was a little bit of that, like we can get all the good therapies we want, but oftentimes the process has already gone wrong by the time we even know there's something to ameliorate.

0:35:06 Thomas: What

0:35:45 Eric: But to answer your really good question, the way this would look is you develop the process that's then adaptable to each individual person. Because again, the whole point is that every person's cancer is really going to be their cancer. Andso the key is to to get a process that you can then adapt using samples from the patient to then prime their own cells or their own immune system to then attack those specific cells. So the holdup is one, especially with the mRNA, these are relatively new technologies and they have to go through the research process. Two, there's never going to be a moment where we go, we've got every cancer cured because you have to make sure you're able to develop those antibodies, those viruses that that are able to target each person's individual cancer. And it will never be guaranteed because every person's protein will be mutated in slightly different ways. And sometimes you just don't have a good place to develop the antibody that will recognize and neutralize those proteins. And so that would be one example of someone that's insensitive. If their cell membrane protein that's specific to cancer is hard to develop a good antibody response to, it will still be able to avoid immune detection. So you have to find the right proteins to target in each cancer subtype, and then personalize it for each individual person's mutation. The third thing is we just cut, like I think it was a billion dollars of mRNA research. Those mRNA research was going into exactly this type of therapy.

0:37:11 Eric: It's not great. It's Not What You Want. It's just about the COVID vaccines. It's about these personalized cancer therapies that are being harmed in a lot of our research cuts. Not to mention there will always be fear -mongering about new technologies, right? I'm sure Brett Weinstein will talk about how the mRNA technology for treating cancer is actually bad and it's unnatural and we need to develop natural immunity to our cancer or something like that.

0:37:10 Thomas: And that's not

0:37:34 Eric: So that's really where we're at now is that we have these three kind of vectors or these processes that can be infinitely adaptable to each individual person for personalized medicine. They just have to go through the proper ethical clearances, get the proper research funding support and all that to become actionable at it up to scale. Because there are people already signing up for these, and the reports, I believe, are pretty promising, but they just need to be built up to a scale and make sure that they're applicable to each cancer. Just because it's applicable to pancreatic cancer doesn't mean that lung cancer will respond the same way. It doesn't means that leukemia will respond the sameway. So developing them as specific targets of action using those general principles will be an ongoing thing. No biologist is going to be going out of business, which again, cuts into the conspiracy theory, right? They're not holding back on cure for cancers because because of profit motives, because cancer is always going to change. So you're always going to need to do active research to develop the next wave of this process. In the same way, once you have a road developed, it's not like you stop charging a toll for that road, because that road is constant maintenance, upkeep, and construction that's being done to keep it applicable to new age and to respond to new challenges.

0:37:33 Thomas: Good yeah plus if someone cures cancer they can have money and I'm fine with that go for

0:38:52 Eric: But what I'm saying is the profit motive doesn't really go away, even if you come up with a cure because right exactly

0:38:54 Thomas: It oh for the theory that like they're not curing it because then the profit goes well yeah well that's

0:39:02 Eric: Right because even if you find the cure what you're really finding the what finding the cure means is you're finding a repeatable and adaptable process

0:39:05 Thomas: Stupid yeah plus there's always more people like I don't you

0:39:14 Eric: Exactly right and there will probably also be new cancers that develop because

0:39:15 Thomas: Know hopefully no I'm just kidding sure I'm just imagining us consoling a saddened big pharma executive hey there's their buddy there'll be more cancers there's more people born all the time they constantly have cancer people go in the sun too much you know don't worry you can always get people to smoke more

0:39:20 Eric: Again but right all cancer is is genetic mutations that cause these adverse effects on cell behavior and those can develop in so many myriad of different ways at at different times in life, in different cellular micro environments, that you're always going to have these novel situations, which is why my big caveat here is everything I've just talked about is overbroad and oversimplified because I'd have to be talking about and doing the research and frankly, medical degree training to really talk about the individual mechanisms of each individual cancer subtype.

0:40:09 Eric: Luckily, most of the pharma executives, I would guess, know about what's called the red queen hypothesis which is basically like as we develop new medicines as our immune system gets better and better the things that they're targeting are also undergoing evolutionary selective pressures so they're going to change and adapt as well similar to um I don't know why it's called the Red Queen hypothesis because I don't know Alice in Wonderland well enough I always think of Batman right where like in the Dark Knight they talk about how the more Batman escalates things the more you get the propensity for jokers and two faces and escalation on the criminal side and really what is cancer but a joker inside the body that's just trying to cause as much chaos as possible

0:40:29 Thomas: Again yeah I was waiting for that that propensity for jokers so many jokers yeah that's this just yeah it's true

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0:41:06 Eric: So that's where we're at I know it's a little bit of an unsatisfying conclusion because there isn't really a cure for cancer yet but that was kind of the whole point of these

0:41:07 Thomas: Yeah so I guess maybe I want to make sure I understand when you say like okay is it still conceivably possible that you could find a cure for all cancers it just like is it is it a matter of like or is it like some cancers are just too different or or it sounds like it might be the case like you talked about a second ago where some you just can't discover early enough so that's what makes it all different or because fundamentally it's it still is it sounds like if you had a way just hypothetical for for just so I can understand let's say we invent some sort of medicine that just we know it's able to like go turn off any cell in your body target in a targeted way that that would cure cancer, right? Okay. So it's, oh, right. So it's not just about the cure in the sense of the thing you're using on it. It's also the targeting system, like knowing where it is.

0:42:01 Eric: Episodes yes but you would have to do the work for each individual cancer to know what to turn off because there's not going to be one off switch for every cancer that's what I mean by always always a work in progress. What it would look like once you get one of these, or probably a combination of these with things like chemo and radiation, right? Again, improv rules, it's yes and. But what it would Look like in this next generation is, you would find out you have cancer, you would then go to an oncologist, and they would take a sample of your cancer. And they would then develop a process, a cure that's specific to you. But until they're able to validate that they're able to generate antibodies, I wouldn't say it's safe to say that you have a cure for your cancer.

0:42:52 Thomas: Gotcha.

0:42:52 Eric: There's the promise of a cure or the hope of a cure. But you'd have to validate in the lab that your particular proteins are responsive to antibody production or a virus that you can make that targets those cell types, right. And that can be tricky, especially if you have like a rare subtype with a particular structure in their membrane proteins that makes it very hard to interact with other things for the detection part. There's actually a lot of really interesting things that are being developed on that way one of them very close to my heart, dogs are really really good at yep at picking up the kind of subtle changes that under that your body undergoes metabolically that

0:43:26 Thomas: Oh yeah. The smelling. How is that possible? What the hell are they smelling?

0:43:38 Eric: I don't know enough about dogs to tell you. What I will say is it's one of those things, and not to get too trippy right at the end, but just always remember that the reality that humans see isn't objective reality, right? It's the things that our brains are geared to sense. And dogs have a very different suite of reality that they're sensing, and their noses are just much more sensitive. They're able to pick up on metabolites that we breathe out in our breath that we're just insensitive to.

0:44:03 Thomas: And when you have cancer, do we know like what the thing is that's different that that causes that?

0:44:09 Eric: We do know certain things that are different, right?

0:44:12 Thomas: Oh.

0:44:12 Eric: The types of sugars and byproducts of metabolism that you produce are going to subtly change. You're going to have more lactic acid because you have that Warburg metabolism. Actually, a big thing besides just the dogs that we're doing is metabolic screening now, where you can actually look at your byproduct of mitochondrial processes and actually look if there's any warning signs for cancer based on the metabolites that's being produced there, right. So that actually is something that we're doing research on for early detection. We're trying to see before it gets to be a real thing and there's visible tumors, can we pick up on that subtle shift in your own body's metabolism to really detect it early before there's a physical phenotype that we can see? That's another area of next generation that we'd be doing in conjunction with all the other things.

0:44:59 Thomas: Super interesting. I think we should, maybe we should put funding into this. Are we doing that? How are we doing funding-wise?

0:45:05 Eric: It's why my Patreon username is support basic science research. It is the single biggest return on investment, both societally and economically. That we can do.

0:45:14 Thomas: Yeah, and I don't think the Republicans are doing that.

0:45:18 Eric: And again, just to really bookend this from the start of episode one, most of this research at this level is being done in academic research labs, right? Until it starts getting to more clinical trials or specific drug development, a lot of the mechanisms and underpinnings that underlie all of this research is being done in research labs. When I was a rotation student, I was doing the effects of a transcription factor mutation that causes breast cancer on angiogenesis, on the development of blood cells. And I would look at healthy cells and cancer cells and see where the angiogenesis is happening and what proteins are being upregulated, what genes are being expressed to cause that angiogenesis as a therapeutic target. As I mentioned, my best friend, also named Eric, was doing research on how to invade a podiaform and that will help develop drugs for anti-EMT, anti-invasion and anti-metastasis. But all of this is using the products of that very basic biological research being done in academic institutions, which need funding.

0:46:21 Thomas: Yeah, which need funding? Yeah. Well, this was super interesting. Let's see. Anything else to leave the audience with?

0:46:28 Eric: No. And again, I recognize that, especially on this part, the clinical aspects are not my thing. Please, I promise you, I don't have an ego about corrections. I would much rather the correct information get out there. So if there's anything you quibble with, please feel free to write in to either me or Thomas.

0:46:42 Thomas: We've got quibblers. We've got quibbler. We've got quibblers.

0:46:46 Eric: It's one of the things I appreciate about your community is there's a lot of highly educated people in it.

0:46:46 Thomas: That's, uh, it's our community. You're part of it. You're a quibbler.

0:46:53 Eric: Fair. I have become somewhat regular enough that I think we can call it our community.

0:46:57 Thomas: Awesome, well, Dr. Eric Chaffee thanks so much really learned a ton and uh stay cancer free out there everybody don't give yourselves a gun or something I don't know I don't remember yeah the sun does cause it smoking the sun what about like the eating meats and all that

0:47:07 Eric: Packed a lot of sunscreen for that Outer Banks trip.

0:47:14 Eric: Eating meat, I would say is probably less about the kind of genetic mutations and more about both the micro environment, whether it develops more inflammation, whether it changes your metabolism that can help select for cancer cells, right? That's more where it's coming from, as opposed to like actually mutating your DNA, unless you eat a GMO, because obviously everyone knows GMOs mutate your DNA. Always

0:47:28 Thomas: Stuff hmm yeah They're designed to give you cancer that's the point all right thanks so much

0:47:39 Eric: A pleasure.