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Marsha Rosner: CBD (Cannabidiol), Antiviral Drugs, SARS-CoV-2 & Cancer Biology

Full episode transcript below. Beware of typos!

Nick Jikomes

Professor Marsha Rosner, thank you for joining me. Thank you. Can you start off by just telling everyone who you are and what your lab studies.

Marsha Rosner 3:33

So I am a cancer biologist and My lab studies, metastasis which is the process by which cells in solid tumors move from where the primary tumor starts to other parts of the body. And that is actually what kills you in cancer.

Nick Jikomes 3:59

Interesting. So you're a cancer biologist. But we're actually going to focus today on a recent study that you've published that's getting quite a bit of attention, which doesn't have anything directly to do with cancer and it's titled cannabidiol CBD inhibits SARS, cov to replication through induction of the host er stress and innate immune responses. So we're actually going to go through this paper in some detail with people and I'll be doing a screen share, but just to give people some background, let's walk through some of the the key terms in that in that title. And just give everyone a brief basic explanation of what we're talking about. So starting off with cannabidiol, what is CBD and what is it known for?

Marsha Rosner 4:44

So CBD is one of the compounds found in cannabis plants. And the two major cannabis plants that we think about our marijuana which we we all know and love and how up. And the two major compounds that we primarily focus on that we find in this cannabis plants are THC, which is the psychoactive ingredient. And that is what is in marijuana and CBD cannabidiol. They're very, very similar instruction. There's very subtle differences between them, but their actions are quite different. So CBD is primarily found in hemp plants at higher concentrations. And basically the definition of a hemp plant as opposed to a marijuana plant is that it has less than point 3% thc. So if you want something that's psychoactive, you go for THC, if you want something else, and that was the question, you asked me, What does that something else do? You would go for CBD. So what we know about CBD right now is that there is it is used as an FDA approved drug for one particular use, which is for epilepsy in pediatric patients. And that's basically technically the only really validated use of CBD that there is. That does not mean that people have not taken CBD for other purposes, often is taken for pain. And it's even been tempted for cancer, it's actually something that we're now interested in looking at. But probably it will be complicated. Because the other terms in that title.

Nick Jikomes 6:40

Yes, yes. So, you know, the title tells us here we're going to be talking about SARS, cov, two infection stuff. And you also mentioned the host er stress and innate immune immune responses. So what are those things? And why did you even think that there was something to study here to do with CBD in the first place? Yes.

Marsha Rosner 7:01

So you said what I did with the virus is completely unrelated to my work on cancer, but in truth, it's not. So when the pandemic started, a number of us kind of pivoted our research and said, What can we do to help with this pandemic. And so one of my colleagues who is a chemist said, Well, maybe I can come up with drugs that target the virus that blocked the virus. And that's actually most of the drugs that we know about today. And we thought, when there's a pathogen that hits our body, then we our cells actually mount a response, a protective response. And this happens whether the pathogen is a virus, or whether there's some kind of disease that happens such as cancer. And these are called Host stress responses. So, and these involve the immune system, just like we all know about vaccines that involves immune system, but the immune system is complicated. There's something called the innate immune system, which is really the part of the immune system that is immediately activated when a virus hits your body. And then there is another part of the immune system that is triggered later. And that's the part that gives us antibodies from B cells and other kinds of cellular responses. So, basically, in cancer, it turns out the immune system also plays an important role. Because, in fact, in metastasis, which is what I told you why I study, cells are driven to move because they're stressed. And so that stress response that you see in cells, cancer cells, often is very similar to the kind of stress response that you would see in ourselves normal cells responding to a pathogen like a virus.

Nick Jikomes 8:59

Interesting, so So the cancer cells metastasize when they feel stressed, because they're being attacked, basically. And it's very much like our own normal cells responding to something like a viral infection. So there's he's very, you're basically a cell biologist, you know a lot about the inner workings of cells and and what happens when different genes and different cellular programs turn on and off in the context of things like the stress responses.

Marsha Rosner 9:26

I'm actually a biochemist who does molecular biology and works with cells, but sure. Okay. Basically, we wear multiple hats.

Nick Jikomes 9:38

Interesting. So yeah, and there was a lot of different kinds of experiments and analysis done in the study, which was one of the things that was very interesting about it. So how did you get to CBD in particular, I'm not sure I understood that piece of it. So So you've got this background of cancer biology. You're pivoting to SARS, cov to stuff just to help with the general effort there and You've got a certain kind of expertise in conjunction with the expertise that some of your colleagues in drug development have, where does CBD in particular come into this whole mix?

Marsha Rosner 10:09

So, CBD came into the mix, because we were testing it in the context of a protein that we were studying as a turnout for cancer, but in fact, might potentially have a relationship to this post stress response I was talking about. And it was based on a paper that had recently come out. And so we tested it. And like many papers in this field, we discovered that it had the wrong target. It was not a protein. So there we were with CBD. And what the question was, what do we do with it. And what I had done at that time is organized a group of researchers to set up a screen at a facility near us Argonne National Labs, which was able to look at viruses, like SARS, cov, to under special conditions, so we physically couldn't go there. But we could hand them drugs. And so I in a group of my colleagues, were testing a number of drugs, not randomly, but drugs that we thought might influence the stress response. And we did try the target of CBD that we thought CBD might be targeting, or the target that CBD actually did target. And it turned out not to be involved. But we also knew that CBD was supposed to be a kind of anti inflammatory drug. And so when you step back for a minute, and think about what happens when you get COVID, when you get infected by SARS, cov, two, and it turns out, there's two phases with that infection, the first one comes from the virus, and so the virus is propagating in your cells, and you can get very sick from the virus. And that's really what we're targeting when we're using these vaccines and the antibodies that they generate. A second phase, however, is that our cells in trying to respond mount an immune attack by sending out factors that are called cytokines that pull in other cells. And sometimes they mount this in too strong away, it's called a cytokine storm. And we get to the cells coming in. And just like when when we have reactions to things that we're allergic to, they start attacking our own cells. And so that's that second phase. I thought that CBD might work in that second phase. So I sent it there. And I said, could you just try it in the cells that are being infected with the virus, we'll look at the soup that comes out of it and see whether these factors are there. But meanwhile, when they threw it into the cells, the virus was replicating. And so they just determine how much virus was made. And to their shock, and to my shock, it turned out the CBD block the ability of the virus to replicate itself. So why did we do this? Very simple word, serendipity. We had no clue. And it worked.

Nick Jikomes 13:22

Interesting. Interesting. So you mentioned that you obviously used CBD to do some of these experiments. One question that arises that you look at in the paper itself, but that other people might have is, where are you getting the CBD?

Marsha Rosner 13:41

Okay, so one of the wonderful things about having this team is that you come to them with the result. And the first thing they do is question you. How do you really know that was CBD? After all, it comes from a plant. The plant has about 100 cannabinoids. How do you know that there's not some small contaminant and it's that contaminant that's actually causing the effect that you're seeing very valid question. In fact, I even got us asked, How do you know it's not the solvent that you put the powder in to dissolve it before you put it on the stylus that's causing the effect? So the question is, how do you do that? It's a very tricky question, right? Because we can only see what we see. So we did two things. The first thing was that I started looking at reviews can happen, because frankly, I knew nothing about them. And I lucked out and found a colleague who happened to be in Chicago where I am at a different institution, and happens to be a natural products chemist who is one of the world's experts on cannabinoids happens to be able to isolate them in a specific way to know what he's finding and also to analyze Then by a special technique that he developed quantitative NMR. And so his name is Guido Polly. And so I called him on. And I said, Hey, I'm working on this project. But I'm really worried that I'm not working with the right thing. So can you work with me and make sure that whatever I work with is pure. And so what we did is we said, well, it's probably not going to be good enough to just get it from one source, because we still won't know, you know, based on the level of purity, whether there's some other contaminants. So how about we get it from multiple sources. So the first thing we did was get it from chemical companies who synthesize it. So we know what goes in, and we know what the byproducts are. So we did that. And we knew that it was at least 98%, pure by this analysis. And then I thought, why don't we also go to commercial sources? Because we that's exactly the NMR that I'm talking about. Why don't we go to commercial sources? And see how good that is? Because we actually had no idea. And so I went to, I just went online, found a product that everyone said, Hey, I think this really works. And I thought, Okay, I'll order some and we'll try it. And it turned out, if you look at all of these different compounds, two of them were commercial. And two of them were from chemical companies, they look essentially identical.

Nick Jikomes 16:31

I see. Yeah. So you've got this picture here that we're looking at. And it basically just proves that these things are very, very, very, very similar. And you've got two you said that are basically from companies where it's more or less pure CBD and the other two from from product suppliers. Are those just like hemp extracts that contain tiny, tiny minute amounts of other things?

Marsha Rosner 16:51

Well, that's an interesting question. So if you go to your local dispensary, or to the stores, even online that sells CBD, they will tell you that these are natural products. But because we can do these NMR spectra, we can see that their signature, and we actually know that all of them have been synthesized chemically.

Nick Jikomes 17:14

Ah, so So the advertising has been misleading with some of those.

Marsha Rosner 17:18

Yes, but there are very interesting aspects of that that we have learned. For instance, once source that we looked at and did end up analyzing, we were told that it came from citrus plants instead of from hemp. That seems fairly odd drinking your orange juice, would you actually find CBD in it? Not usually. And so when we looked into it a little bit more detail, we realized that one of the paths to synthesizing CBD is using a byproduct of orange juice. And so that becomes your starting material so that you can then synthesize CBD. So by starting with orange juice that allows people who say, Well, this is a citrus by product. It's natural. But in fact, it's completely synthetic.

Nick Jikomes 18:09

Interesting. That's, that's an interesting little side note there, I had no idea about that. So anyways, you've got four different sources of CBD, they're all pretty much the same in terms of chemical composition, they are all having this effect at decreasing the number of Spike protein positive cells. Let's um, let's take this moment here to explain to people the nature of these experiments very generally. So these are in vitro studies, you've got cells growing in a petri dish, what's the basic setup there that people can imagine in their mind.

Marsha Rosner 18:40

So we have what's called a cell culture dish. And cells are layered in what's considered a monolayer, meaning there's just one cell going across the dish. So they're multiple cells, but they're not piling on top of each other, pretty much. They're just single cells sitting on the dishes. And we sometimes usually, what we did is we pre treated the cell with whatever drug we wanted to test, usually for a couple hours, and then we would drop some virus onto the cells, and the virus would enter the cells. In this case, there is a specific receptor for this virus. Most people have heard of Spike protein, which is the protein against which most of the vaccines have been made, and that sits on the surface of the virus. If I'd known you were doing this, I could have come up with a picture of the flyer. And the virus interacts with the receptor on the cell surface, and that's called the ACE two receptor. And once it interacts, it enables the virus to enter the cell. It's a process called receptor mediated endocytosis. So the cell kind of engulfs it, and it gets in and then the content have the virus are basically released. And the important contents here are some of the proteins and the the genomic material, which is an RNA. And those proteins start off kind of copying the RNA, and then they make more copies. And the virus reassembles itself and it's produced, I see. So this is the process that we're looking at.

Nick Jikomes 20:21

Yes, and we're gonna, we're gonna dissect that in some detail. So h2 receptor is a receptor on some of our cells, that allows the virus to get in. One thing I want to mention now, we'll circle back to this, but I'll just mention it for folks. Now, this anti SARS cov. Two effects that you initially observed with these four different CBD products, it seemed to work on multiple different vial viral variants that that you tested against, which is very interesting. And we'll come back to that. But a question I want to ask you now has to do with the fact that you sort of you sort of alluded to it earlier. You know, cannabis contains all of these other cannabinoid compounds, sometimes in just trace levels. But all these compounds are very, very similar. And so it looks like what you guys did is you tested not only CBD for this antiviral effect, but a variety of other cannabinoids. And so I've got that finger here for us. What were these other cannabinoids that you tested, and what was the general result you found with the other ones?

Marsha Rosner 21:21

So we just tested a few that are well known, some of which are precursors. So CBD is made from them, like CBD A. And what you see is even not knowing much about the chemistry, you can see that there's kind of these ring structures. And then this long chain, and those chains are the same kinds of chains that are in fatty acids. So you know, when we ingest fats, that's really basically what they look like. So CBD is a very fat like molecule, so it doesn't dissolve in water very well. So you can see CBD there sitting in the middle on the on the top. What's particularly interesting, and we use this is that CBD V is right next to it. And honestly, it's identical except for two carbons on that long chain. Just below in the middle on the left is THC. And if you look at it, the only difference is one of those ring structures is closed in THC and its open in CBD. So other than that, almost identical. But they act very differently in the cell. THC has specific receptors, CBD can potentially create the action of THC on those receptors, but by itself, it does not bind to them well at all very, very weakly. And in fact, no one does know what the real receptors for CBD are. That's something that we're looking into right now. And then we looked at some other ones, here is CBC and CBG. CBG is something that we ended up testing in animals unintentionally, because when we ordered CBD one day from a commercial source CBG showed up and we didn't notice. I personally would never take CBD after seeing what it does to animals. It made them break out in a rash and was completely ineffective. So wow, certainly wouldn't go there for COVID or other things related. I mean, we do inject them, of course, but certainly their skin did not like it at all.

Nick Jikomes 23:34

Interesting. So So what's the punchline for most other cannabinoids with respect to this antiviral effect,

Marsha Rosner 23:39

so the punch line is if you look at that upper graph, and you see that red curve on the bottom, that CBD, and what you're looking for is is a curve, and the concentration is on that x axis below and you're looking for that curve to go down in as low a dose as possible. And so what we call the easy 50, the the 50% dose is about one micromolar. So we talk about amounts in moles, and this is 10 to the minus x of a mole. If you look at the other curves, none of them go down very effectively, except for that green guy. So what is the green guy? So it turns out that one of the other ones is THC, we want to know whether potentially weed might be effective. And so what we did THC by itself clearly didn't do it. But what we did is combined THC with CBD. And what we found was that that was not only did that not work very well, but in fact, it blocked the ability of CBD to take it down normally. Or that that green guy is the seed Ah thc 121.

Nick Jikomes 25:01

I see. So if you have the same amount of CBD in the presence of the same amount of THC, and it's in the same amount as just the the other experiment was just CBD, the CBD is not as effective so so the one to one is just not as good.

Marsha Rosner 25:17

Exactly. So what that says is, if you think you're going to smoke weed, you know it's going to help you with COVID. Not only would it not help you, but it will antagonize any CBD that happens to be

Nick Jikomes 25:31

there. Interesting, interesting. And so then we have this graph here where you're showing an antiviral effect from something called Seven hydroxy. CBD. And what is that molecule and why why is that interesting?

Marsha Rosner 25:44

So it turns out that our body metabolizes CBD, in large part because it's just as I said, not very soluble. So it comes it comes together kind of like a fat droplet. And if you don't break it up, it basically goes to the liver. And when it goes to the liver, it gets broken down into other byproducts. And one of them is this seven hydroxy CBD that shown there. And so that is one of the major byproducts. And there's another one, which is seven carboxy CBD, so we tested both of them. And in our hands, the seven carboxy did not work, but the seven hydroxy CBD do work and interestingly, not quite as well, but it did work. And interestingly, it also is works for epilepsy as well, whereas the seven carboxylase is not known to work for that. So there's a similarity in what we're seeing with the virus and and the kind of responses that one sees for epilepsy.

Nick Jikomes 26:50

I see So, so in your hands, this antiviral effect for SARS, cov. Two is impart it, you see it with CBD, you also see it to somewhat of a lesser extent with seven hydroxy CBD. And that would imply that if you were to swallow CBD, both the CBD and the seven hydroxy CBD that your body will turn it into are both going to have this kind of effect, potentially,

Marsha Rosner 27:13

in theory, in theory, here is a really, really important point. We can do these experiments and culture all we want. And you know, we could use doses. Ideally we'd want lower doses, you can use higher doses. But frankly, the only thing that matters is if you can get an effect at a dose that you would find in your body in your blood. And so what I told you is that most of the CBD gets broken down. And there is not that much in your blood. In fact, the majority of it is a seven hydroxy carboxy, not the seven hydroxy. So and there's actually more CBD than seven hydroxy in your blood. So in fact, the real question is Would you ever get these levels of low micromolar doses in your blood when you take CBD such that you can now potentially get this effect on your cells? And that's a really important question. We were lucky that because there is an FDA approved drug, those studies have been done with CBD. What's known is that you have to have a special formulation of CBD and a special high dose of CBD. But if you have that, so the formulation is to break up what are called micelles, these CBD molecules that want to stick together if you break them up. And also they would go into the liver but you know more of it would be able to get into the blood. And so that's the special formulation but also a relatively high dose much higher than most people would be taking. If you're taking for instance, you know, a tincture and you're just putting a few drops on your tongue. I'll also say that we did test flavored oils with CBD. And once we tested had point 3% CBD, which is basically nothing

Nick Jikomes 29:19

very, very bad. Yeah, very little. Now for Epidiolex, the FDA approved formulation of CBD used for epilepsy. What kind of doses are people taking per day?

Marsha Rosner 29:33

It's, I can tell you the concentration of it but the dose is which is it's it's given out at 100 milligrams per mil. The doses that people are taking depend on their weight. And I'm not going to tell you anything more because I don't want anyone to start trying to translate that into what they think they should take us Even though we will get to patient data of patients who have taken up a dial X, none of the data in our paper would say to this date at this stage, even though it's highly supportive, that CBD has the potential to work. It wouldn't say if you take it at this dose and you do this, then it will work.

Nick Jikomes 30:22

Yeah, yeah. I see. Okay, so you test these other cannabinoids. None of them work very well, except this metabolite of CBD. interesting parallels with the Epidiolex stuff for seizures there. Um, so figure three, CBD inhibits viral replication, after SARS cov two entry into the host cell. So this gets to the idea of like, where in that process of what the virus is doing is CBD actually acting. And we haven't I don't think we've quite said this yet. But you did mention the east to receptor so the virus has to touch this receptor to get inside of ourselves. And I guess one idea would be that you might think is that a drug like CBD or some other drug might interfere with that receptor interaction. But that doesn't appear to be what's going on. So So what stage of that process is CBD seem to be acting out here.

Marsha Rosner 31:11

So CBD is acting after the virus enters. And in fact, acting completely, at least six hours after the virus enters, and partially at even 15 hours after the virus enters. You can see that, yes, that's what you're circling. But I want to talk about why we bother to look at a stew. So when we first found our fact, we started reading in the literature and found papers that said, CBD is going to be effective against COVID. So we thought, Oh, that's interesting, wonder how it works. And so we looked at those papers. And pretty much all of them at that time said that the way CBD works is it causes the receptor for the virus to disappear, or to be reduced. So the first thing we were interested in doing is looking at that receptor and seeing whether the amounts have changed after we treated the cells with CBD,

Nick Jikomes 32:10

just to confirm the result that was reported elsewhere,

Marsha Rosner 32:13

just to show that it was incorrect.

Nick Jikomes 32:17

Okay, so you guys, you guys see something completely different here?

Marsha Rosner 32:19

That's right, and that that report is completely wrong? Yes. And we knew that it probably was wrong, because we were using cells that had hyped up receptor, we had put more receptor in the normal and put it in a different way. So it really didn't seem like that would be the mechanism. And we did this to confirm it.

Nick Jikomes 32:39

Yeah, I remember, I think I remember this paper was quite early in the whole COVID saga. And among other things, there was an interesting conflict of interest there. And some very bizarre things in that paper that I remember reviewing online. So it was very, it was very suspicious early on.

Marsha Rosner 32:59

Well, there were a few papers, some most of them. Actually, in the beginning, all, none of them actually involved using the virus to justice at all. They were all kind of speculation, they were just basically dropping it on cells. But sometimes they were using extracts, you know, that might be the one you remembering, which came from different plants. And so they had different amounts of CBD in them. And they said, Oh, well, it must be CBD. Because you know, there's more or less, and these guys with more CBD seem to be given, in fact, and these guys are giving less than an effect. But of course, when you have an extract, you have no idea what's in it. So it's very important to use pure compounds.

Nick Jikomes 33:39

So So anyways, what we have here from your results is you've got this antiviral effect that you've started to see in these petri dish experiments. But the expression of h2 is not affected here, what you what you've shown up to this point is the virus is still actually getting inside of ourselves. So something in something is changing inside of the cells after the virus actually physically gets inside that has to do with CBD here. So what, let's start to unpack that for people. This is where we get into things like

Marsha Rosner 34:09

just to finish what that figure was about. We also wanted to say that it was not going after other normal viral proteins. I mean, this this is about entry. Maybe we haven't gotten to that completely. Yeah, okay. You can keep going. We also blocked the spike protein with antibody just you know, to show that that was what it was doing.

Nick Jikomes 34:35

So, so the virus gets into the cell. In some experiments there CBD present in some experiments there CBD absent and you're sort of comparing these two conditions. So what's actually going on in terms of what CB is doing inside of the cell here.

Marsha Rosner 34:52

So, this is an experiment to say what's happening with the RNA from the virus. So normally, so if you look at a, all those lines going across horizontally, show you RNA that's coding for different proteins in the virus. And so the first set of three because these are triplicate experiments, says, Well, when you don't have virus, whether or not you have CBD, you don't have any RNA. That's what blue means. Yep. So none of those proteins are made. The next one says, when you have virus, but you don't have CBD, all of a sudden, you make a message, which codes for all of these viral proteins, and it becomes a glaring red. If you just put in CBD, but you don't have virus, of course, you don't have viral proteins. But what was amazing was if you put them together, so as I said, You pretreat with CBD, then you put in the virus, you completely suppress the ability of the virus to make RNA for its proteins. And to make those proteins,

Nick Jikomes 36:05

it's nothing. So somehow the viruses getting inside of the cells, but if the CBD is already there at this concentration, it really can't do it can't do what it would normally do, which is make more viral proteins to be assembled into new virus particles. Correct? Wow. And so um,

Marsha Rosner 36:25

I don't think I want to go through the rest. Yeah,

Nick Jikomes 36:27

we don't need to go through this figure, because it's probably too complicated. But there's so what we just talked about is CVDs, inhibiting the ability of the viral RNA to then go on to make viral protein. But what's going on in terms of any other gene expression changes from the host genome?

Marsha Rosner 36:44

Yeah, so um, what's interesting, okay, so if we look at C, which is of funding kind of figure what it what it's really saying is, there are some components that are being affected by the virus in the host cell and some components that are being affected by CBD. And so we can ask about two components, for instance, and we don't even know what they are. But we just asked about them, where do they set? And so you can actually, so that's what each axis is. So on the x axis, the horizontal is one component on the y axis, which is vertical is the other component. And so you can say, Oh, well, we're on that map. It's just as though you're sitting on a map. Where would I be if I was just normal, and that's in that upper left hand corner? So that's what a normal cell would look like. And then you can ask, what happens when I infect it, and you see it zips over to the right to those triangles, and even moves down. So it's affecting both of those components on some level. And then you say, Well, what happens instead if I just put in CBD. And what you see, and that's a cross is that CBD by itself does have an effect. It's but only on in one of those components, not in the the one that affected the, you know, the virus so dramatically by the virus change. And if you put them both together, then you're very close to what CBD does by itself. So you're not normal, you're not the cells not back to normal, it has some changes. But those changes don't really reflect much from the virus itself. They're actually reflecting what CBD does to the cells.

Nick Jikomes 38:33

So in other words, correct me if I'm wrong, if you just expose cells to CBD all by itself, CBD will affect the expression of genes in the genome of those cells. Exactly. Interesting.

Marsha Rosner 38:46

And if you put them together, what you get back is not the normal cell, but the CBD. Treat itself.

Nick Jikomes 38:54

Interesting. So Iris, so somehow, someway, CBD gets gets to cells, in this case in a petri dish, and it can affect gene expression in very interesting ways. Let's just Let's just say that for now, you also did the same basic stuff with another very similar cannabinoids, CBD v. And what's the basic punch line there?

Marsha Rosner 39:14

So the basic punch line there is this other one, which I told you about before it had it was CBD V and very similar. It doesn't have the same effect. It cannot block the ability of the virus to replicate. And so even though it has a small effect on some of the RNAs, overall, the replication is fine. And so what that told us was that, but but if you look at this map, again, you're still getting some changes in the host cell, even even with this other ones cbdv. So we said, okay, maybe we can compare them. We know there's some changes in the host cell from CBD. And we know there's some changes in the host cell From CBD V, but CBD V isn't blocking replication. So what if we kind of subtracted? Changes from cbdv? From the changes we get with CBD what's left? And would that possibly explain how CBD is working?

Nick Jikomes 40:15

Interesting? So, um, so what did you find there? What are what are some of these gene expression changes? And what cellular processes do they start to tie in to?

Marsha Rosner 40:25

Right, so that's what this is showing us. And there were really two things that we saw that were really dramatically elevated activated in terms of processes by CBD, but not by cbdv. And one of them is called interferon signaling. So interferon is part of the innate immune responses, early immune response that our host cells have, when when they face these insults. And it's a factor that's secreted and it comes back and is can be secreted by other cells as well as part of the immune system, but also by our own cells, which is what's going on here, because we don't have immune cells here. And it can bind to receptors, just like the virus binds to a receptor on host cells. And it activates a series of events, which, in the end, basically fights the virus in many different ways. So one way that it does it is by activating enzymes that can cut up the RNA and other ways, it just makes all these other factors that make such genes that will fight the virus. So this is a very potent way that the cell has to fight viruses in general. And it's a very common response. But that response is depressed a bit by SARS, cov. Two by this particular virus, it's trying to stop our host cells from attacking it. So that's one of the responses that we saw. And what we saw was that CBD was much more effective at turning it on, turning on this response than CBD V was. The other thing we saw is something called, which is in the title, the endoplasmic reticulum stress response pathway. And also, an aspect of it is called the unfolded protein response. And what this really is, is when our cells are infected by something like a virus, and it's trying to make its own proteins, it sort of takes over our machinery that makes normal proteins. And so our cell gets stressed because it can't make the normal proteins because essentially, it's demoting all this machinery to this foreign agent that's taken over. So there's a particular type of response that's activated from this pathway. And it's a way of either breaking down misfolded proteins, because they're not normal. So we want to get rid of them. It's a way of getting rid of other kinds of agents. Because you have RNAs that shouldn't be there. And if you activate this sufficiently, it will attack those RNAs and break it down. And it's a way of actually generating interference. And so even though we didn't show that the interferon signaling that we saw came exactly from this unfolded protein response. there's pretty good evidence suggesting that that's at least one of the mechanisms by which CBD is activating interferon signaling.

Nick Jikomes 43:49

Interesting. So maybe very briefly, let's just unpack for people, the normal cell biology here. So this thing called the endoplasmic reticulum, what does it have to do with protein folding? And why does protein folding so important?

Marsha Rosner 44:02

So the endoplasmic reticulum is a place where proteins are made. They can be made in what's called the cytoplasm of the cell, but there are certain kinds of proteins that get put in particular places like in the membrane, and so on. And they are made in the endoplasmic reticulum, which has membranes, which is kind of think of it like skin around cells or around little vesicles. And what excuse me, why is protein folding important? Well, proteins have to have a particular structure. And to get that structure, they have to fold in a proper way. And if they don't fold in that way, they don't do their job. It's kind of like a factory worker who has arms or legs, they're damaged, and so they can't really effectively do what they're supposed to be doing. As they would have if they were completely healthy. And so sales pretty brutal. So it says I'm going to get rid of them. But first it does try to fix them and so has something called a chaperon that can bind to it and try to refold it back into the right way. So kind of like a person's damaged factory worker or they go to the hospital, they either get fixed, or you know, they can't do their job and they get fired.

Nick Jikomes 45:18

I see. So with this, basically say that what's likely going on here at the cellular level is, you know, the cell gets infected with a bunch of virus, this is going to cause the cell to become stress and proteins are not going to fold properly. But in the presence of CBD, there's this counteracting effect, where it's going to help that stress response, ensure that the cells normal proteins get folded properly, at least more often,

Marsha Rosner 45:41

it's going to try but it's also going to activate a process to get rid of these foreign guys, interlopers. And what you're seeing in that diagram is, is that a number of viruses actually do use that normally, right? Because you can imagine maybe some of their proteins get mis folded to, but SARS cov. Two does not it actually suppresses that pathway, and overrides it, and turns it back on.

Nick Jikomes 46:06

Ah, so the viruses are doing this trick where it's not only hijacking the machinery to actually manufacture more pieces of virus, but it's actually suppressing these other things that would normally engage in these these other mechanisms for the cell actually. Interesting. Interesting. So I'm at this point. So this is figure six, and figure seven is about this host cell interferon response. And so what do you think and in this induction of cytokines, so I think this is going to be an important place to talk about things like cytokines and cytokine storms, which you mentioned earlier, but what's the what's the basic result here? And why is this so important? Beyond this just initial sort of antiviral effect.

Marsha Rosner 46:53

So what this is asking is, what what kinds of things are happening and what we we noticed, and we kind of skipped over, you know, what are the consequences to host cell proteins or host the way the host cell functions when you when you have virus infection, and then when you have CBD, but basically, what we noticed was when you add CBD, some of the normal functions, or proteins activated by the virus, are completely suppressed, they're actually completely reversed when you treat with CBD. And we're just assuming it's because they, they, in fact, never get made, you're blocking the replication, you're not making enough virus, and they don't get made. So it turns out that I mentioned the cytokine storm, and some of the cytokines that are released are released as a consequence of the virus actually infecting the cell. And so this is something that you would see, we'd see a lot of these cytokines. And in fact, some of our early attempts to treat the virus involved trying to block some of these cytokines. And what you see here is that you are inducing genes that are related to interferons, I F ns, but you're, you're not inducing genes that are related to cytokines. So you're completely suppressing the cytokine storm that would be activated by our cells are initially infected by the virus. And so we don't know whether you could try this trick later. Whether it would have an effect, because at that point, other cells are engaged. And we, you know, and it's complicated, which cells actually are producing these, these cytokines leader, but certainly, as an early response, this is a good thing, because it's turning on the good guys, which are the interferons, but getting rid of our blocking the bad guys, which are the cytokines

Nick Jikomes 48:57

I see. And why is this this concept of cytokine? Storm? So relevant here for COVID? So in cases of severe COVID, is this actually a common component of what is?

Marsha Rosner 49:09

Yes, that's what I was saying initially. So there are two phases of COVID. One involves the virus The second phase is when the virus is gone. Right. You might ask why am I still sick even though, you know, the virus should be gone by about seven days. And why are people even saying, you know, we should quarantine for longer and why are symptoms sticking around? And a lot of that comes from essentially later effects. Many of them are caused by our immune system overreacting. And that's what we mean by that cytokine storm. And our unfortunate response to that, which as I said, is similar sometimes to an allergic reaction where we're talking our own cells. What this figure in D shows though, is that we Know that interference are important. And the way we know that is not just that we're we're making them. But when they're made, we can ask, Well, what happens if CBD induces the interferons and makes them and then we get rid of them is CBD effective still. And that's what that figure is saying. And what it's saying is that maybe interference aren't the entire story because we don't recover all the potency all the virus, then, you know, we would have had, so CBD is still doing something. But this is a log scale, you see, really, I'm getting rid of the interferons, really, in a sense, rescues the virus effect.

Nick Jikomes 50:50

And it's a big effect. Yeah,

Marsha Rosner 50:52

it's a very big effect.

Nick Jikomes 50:53

Right? Interesting. And then you know, at this point in the paper, this is where you always say, for a paper like this, this is all very exciting, but it's all in a petri dish, how do we know that any of this stuff is actually going to work inside the body of a living animal. And that brings us to the next set of experiments where you do some work in mice. So So what kind of mice were these and what exactly was going on here.

Marsha Rosner 51:16

So before I explain this, I have to tell you that this is something like the fifth or sixth attempt. I'm trying to see whether CBD would work in mice. So these are special mice. Mice don't get infected by SARS cov. Two, and they don't get COVID. So but we do need some kind of an animal. Because we cannot experiment, clean people to see whether this might be effective. And so a mouse was developed, where it expresses the human h2 receptor to enable SARS cov to to get into the minds. And this is pretty much throughout the body of the mouse. So it's not just lung cells, it's pretty much every cell in the body of the mouse. What that effectively means is that SARS cov, two can infect the mice, but it's like a major infection, we in our bodies don't have as much human ace to receptor as this mouse does. So it's it's a very potent infection. So it's not a perfect model. But it does allow us to ask the question whether if you treat the mice, and in this case, it was preventative, we pretreated with CBD, whether we could decrease the amount of virus that is made in the lungs, which is thought to be the primary place where the virus propagates, and also in the nasal passages, which is the first place that we think the virus goes. And we see effects in both. And what's important here is we see what's called a dose response, meaning this is really related to CBD, then if you use less CBD, you'll get less of an effect. And if you use more CBD, you'll get more of an effect. And you can see that most dramatically for the lungs, the fluid from the lungs and the virus in the lungs. And so that gives you confidence that this really is related to the drug and not to something else.

Nick Jikomes 53:18

Interesting. Okay, so you've got all of these interesting results in vitro, you've now got this interesting in vivo result in these mice, which are, you know, special mice made to express this h2 receptor. And of course, mice aren't humans. So we still don't know would this actually work in humans? But you had another another analysis that you did that was quite clever, you made use of the best sort of information to do with humans that you could get your hands on. And and you saw something interesting here. So So walk us through the human data that you were actually able to analyze?

Marsha Rosner 53:54

Right? So what we could do is what's called a retrospective study, meaning we use medical records for patients. And we thought, initially, our first thought was to go to marijuana or CBD dispensaries and you know, check patients and kind of survey them, see if they got COVID, and so on. And then we realized that was a very formidable task. And then we thought, well, because we were very fortunate that some patients, some fraction of the population is taking this FDA approved clinician prescribed drug, CBD Epidiolex. Maybe we can focus on those patients and ask whether we can see a trend toward protection. This is not a clinical trial. It's not controlled from the outset. So we kind of had to do it backwards. We had to go through medical records. Look at patients try to find patients who suffered from epilepsy because we want it to be as close on record as possible and make sure that the CBD was CBD that we understood, we knew the dose, we knew the formulation, we knew it was Epidiolex. So in order to do that, we started with over 5 million patients. And we had to work with a national consortium to get the data for these patients. So this was all across the country. And then we said, Okay, we really want to be, as I said, on label as much as possible. So let's look at the patients who have some kind of seizure type condition. And that got us down to 300. About 300,000. If you see what's, what we actually were asking then is these patients weren't random patients, they were patients who had shown up to get tested for COVID. And so what you see in the blue is, so all the patients the circle, but in the red are the fraction of those patients who are positive for COVID. So this is actually a very high level 25% for the 5 million. And I think that's because these were patients who were showing up to get tested. This is not from a random population. And then you see that that goes down a bit for the fraction of patients who have seizures 14%. So that says that something about their lifestyle, whatever, you know, likely protects them a bit more. But what we wanted to do, as I said, is find patients who are actually taking cannabinoids and the best data we had were people who had been on Epidiolex, before they got tested, you know, it didn't just take it or what hadn't just taken in the past and then stopped taking it, we really wanted patients who had taken it all along. So that's that last one. And that took us down to just a bit over 1000 patients, of which we then looked at half as taking Epidiolex, taking CBD, and half that were not all of them had Caesar type conditions. And then these were patients, the control patients that we matched as much as we could, for every parameter that that we could think of, which would be

age, sex, calm comorbidities, even when they might be in pain, even to the level of what might be in your blood. And so it's important to understand that all we could come up with is a correlation. Right? It's not a cause and effect. It's just a correlation. If you're taking CBD, what is the incidence of you having a positive test? And how does that compare to someone not taking CBD. And we can't rule out, you know, some confounding factor that we haven't thought of. But we and I won't take credit for this. This was colleagues Tom best and David Meltzer. And if you looked at this paper, there's basically a paper in this paper, which is all about the analyses that were done. They're extremely rigorous. And essentially, the bottom line is about a two fold difference that about 9% of the patients tested positive for COVID in the control group, and 4.9%, in the group that had been taking Epidiolex, or CBD. So that was really significant, which is what that P value tells you. And it's kind of not a random thing, we did a few more analyses. So basically, this is a very, very solid statistical evidence that there is a difference in the incidence of COVID. If you've been on Epidiolex, again, there are caveats to that. But as far as I know, we're the only group that put all of these parameters together, they experimental, in a cell and in animals with patient data.

Nick Jikomes 59:10

And all of this collectively says that, you know, it's quite likely that at the right dose taken in the right way, a compound, CBD this compound might have this antiviral effect in humans. This is what's being indicated, even though not it's not 100 people, I don't

Marsha Rosner 59:25

want to say quite likely, but it says there there's good reason to do a trial, like to do a trial because it suggests that there's a potential end goal and the evidence is quite supportive.

Nick Jikomes 59:38

Yes. And so when you get to thinking about the type of trial design that you or someone else might do, to follow up on this, what do you start to think about there? Do you think about using Epidiolex? itself? Would you think about using people that are at risk for severe COVID? What would you imagine a good trial design would be for something like that?

Marsha Rosner 59:58

Well, we're currently in engineered because we're just about to do a clinical trial. So we so there are two kinds of trials you could do, the one that was done for vaccines is a preventative trial, right. And so you're just looking at a broad scope of people, you don't know whether they're exposed to COVID, non exposed to COVID. And so this requires a huge, huge number of patients. And that's why these trials have been so expensive, conducted by companies who were given special support, you'd be interested to know we've gotten no support from NIH for this. Talk to them about a trial. And they basically told us show it works, show us it works. And then we'll give you money, which means that we have to do a pilot of much smaller numbers of patients, and we have to be pretty sure that they have COVID. So instead of doing a prevention trial, we want to do an early response trial. So we told you that we think that CBD would work even after we, the virus has entered ourselves. So that's what we're going to test. And we're going to be looking at patients who probably show up to be tested have early symptoms, and so as close as possible to knowing that they have the virus in an early response type of way. These are the patients that we want to treat with CBD, and then we'll be monitoring the amount of virus that they have compared to patients who are not taking CBD

Nick Jikomes 1:01:34

I see. So the the result you'll be hoping for there is that those taking CBD in the form of Epidiolex will have less virus than those that are not and they'll be less likely to progress to a severe case.

Marsha Rosner 1:01:48

Yes, except that it won't be Epidiolex Oh, okay, what are you using? So, we have found a different company with a formulation that is as effective as diet Epidiolex, they've already done a phase one trial. So we know how much gets in the blood, or, or more effective, actually more one more soluble in water. We have tried to approach the company that makes Epidiolex used to be GW pharmaceutical, and we've actually had a lot of conversations with them. But somewhere in the middle of our study, they got taken over by jazz pharmaceutical, and they have not seemed to have had any interest in pursuing this.

Nick Jikomes 1:02:30

Interesting I wonder why

Marsha Rosner 1:02:34

we can all speculate

Nick Jikomes 1:02:35

interesting. So you're using a another version of CBD, it will still be orally is still orally consumed, how what is the trailers really

Marsha Rosner 1:02:44

consumed. It's not another version of CBD, all of these will have pure, you know, it's pure as possible CBD. But there is a formulation, you put it into something so that the patient can take it in a form that will make it more soluble in water.

Nick Jikomes 1:02:59

I see I see. And, you know, thinking about the fact that, you know, these are oral routes of administration. You know, part of the reason that these doses for things like Epidiolex are so high is because of the low oral bioavailability of CBD. How do you think about routes of transmission and the ideal route when you're thinking about CBD in general.

Marsha Rosner 1:03:20

So we have thought about other kinds of formulations that might be useful, for instance, when we think about the virus coming through our nasal passages, so maybe an aerosol spray, right, something like that could be effective. But what we know most about for CBD in terms of its efficacy and people is an oral preparation, like Epidiolex. So it makes sense to start there and say, Is there something here? Can it be effective? If it can be that's when one should start trying other kinds of formulations and other types of delivery?

Nick Jikomes 1:03:59

And just to say it explicitly for people. So given sort of the mechanisms that seem to be at play here that you've looked at in the study, and how all of this seems to be working in vitro? What is what is potentially exciting hear about CBD with respect to different bio viral variants, would you expect it to work against different variants or not?

Marsha Rosner 1:04:21

So we touched on that in the beginning a little bit, we had tried three viral variants, and that was alpha, beta and gamma. We are currently trying delta and omachron. We'll know the results on Monday. But we expect that it should work because it's not about blocking the virus from entering, which is why the vaccines are less effective with these other variants. But it's about how the host cell response and pretty much it's responding the same to all these different variants.

Nick Jikomes 1:04:54

Interesting, interesting and, and, you know, we will reiterate some of the things we've already talked about. But why are these results so exciting in your view when you think about something like CBD in comparison with other antiviral drugs that that people have been using.

Marsha Rosner 1:05:11

So, as I mentioned, most of the antivirals, right now are focused on targeting the virus itself. And that is effective. And that's good. And maybe the most effective ones are the ones that blocked the virus from entering. For instance, you can get treated with antibodies, although now we know that with the new variants, sometimes they can even bypass some of these antibodies. So that's the problem with antibodies is the mutations that occur, that change the virus so that they're not as effective. And we see that with breakthrough infections as well. There are other other types of drugs that target for instance, proteases, which are enzymes that break down the proteins. For the virus to use, they actually start out making a very long protein, and they need to be chopped into smaller pieces so they can be assembled. And so there are new drugs that are targeting these proteases. And they are quite effective. But usually they have to be given. You know, they're given after you know that you have the infection. And they're given usually in hospital circumstances. So why is CBD potentially attractive? First of all, it's out there, it's fairly easy to make or to extract, it's not quite as cheap as aspirin. But in theory, it should be a lot cheaper than a lot of these other drugs that are being made. And if we can figure out how to take it with the right controls, meaning don't go to a random place, I can tell you that some of the CBD that look good when we first went to the same place, and then went back, completely broke down and actually killed ourselves same stuff.

Nick Jikomes 1:07:06

So the same product

Marsha Rosner 1:07:10

from the same place worked in the beginning. And we even analyzed it very pure. And when we went back later, it killed ourselves. So you have to be extremely careful about quality control, when you go to just a commercial entity. Some of it can be very good. And some of it can be very bad. And you don't know. So I think that CBD has a potential, if dispensed by reputable company where we know there's quality control. And we know it has the right formulation that for I think relatively cheaply. It can be widely distributed. For us in the US, you can imagine that you can use it as preventative, if you're traveling and you want to be sure you're safe to go into a hotspot and so on. But perhaps even more important for the rest of the world that doesn't have access to vaccines. It could be hugely important.

Nick Jikomes 1:08:10

Interesting. Interesting. So I mean, this is this is very interesting research. I know that there's been some other studies sort of related to this general idea of CBD and some of these potential other plant cannabinoids potentially having some kind of antiviral effect. I also know that just given what the result is here, and was for some of those other studies and what their claims were, there's been a lot of media attention around this. So is there anything you want to say about not just this research, but some of the other studies that have been coming out and any sort of misconceptions that you've seen in the media?

Marsha Rosner 1:08:53

Yes. In fact, mostly, what I've seen are misconceptions in the media, and I've been spending a lot of time recently trying to counteract those. Before I go there, I just want to stress a couple things that I've just said. And then I will talk about these other studies. So we are not suggesting that CBD should we place vaccines or vaccination, I told you that, you know, vaccines are not perfect. We all know this, we get breakthrough infections. But at the moment, vaccines are really the best way we have a protecting ourselves. Usually, I also say that people should stay masked and you know, follow CDC guidelines, although I realized that this game is going away in some places and CBD guidelines are changing as we speak. But again, this is CBD I would think of as a tool in the toolbox. You know, another tool that we have, but not a replacement for what exists. And then again, I want to start And this relates to the response to some of these other papers and some of the media storm, there were a lot of jokes about smoking weed and using it again to to counteract COVID. And as I said before, weed will not do it, in fact, might even be counteract, though I know this won't stop people from smoking it, but certainly don't smoke it for the purpose of protecting yourself against COVID.

Nick Jikomes 1:10:26

Yeah, I mean, just to reiterate, I mean, we discussed this earlier, but your result was that actually, just to say it again, THC was basically getting in the way of what positive effects CBD was having on its own.

Marsha Rosner 1:10:39

Absolutely. So and the last thing is that, and I've never done this in a paper before. But in this paper in our abstract at the end, we wrote two sentences that we never would have done before. One is do not go to your local dispensary, and get CBD and try this yourself. You know, we really are advising, quality controlled, medically dispensed CBD for something like this, even if we carry it through. And the second is to say as we discussed before, that all of this evidence together does not say that CBD will work. But it's very good support for saying we really should find out let's do a clinical trial. So now let me speak to one other study in particular, which is really what triggered this recent at least media storm and excitement about cannabinoids. And that was a study came out of Oregon. And that was a study that tested some of the same compounds that we tested, some are different, but some are the same. And their conclusion was that these cannabinoids blocked the virus from entering the cell. So your first reaction is oh my gosh, you guys are contradicting each other. We just told you that. That's not even the way CBD works. And that these other cannabinoids that we tested are not even effective. And here's a paper saying that it blocks entry of the virus, and therefore should be considered as an agent that can fight COVID. And that just went viral. So why the difference? So I think the evidence that they showed is valid, what they did is valid, the difference is the conditions. So I told you that we use CBD at a level and we knew what that level was. That is the same or comparable to a level you would find in the blood of patients taking CBD. That's super important. If you can't get close to that level, doesn't matter what your drug does, because you won't have enough of it to be effective.

Nick Jikomes 1:12:58

So you guys designed it this way on purpose, you were using concentrations that you knew from the the literature on Epidiolex is going to be at least in the in the basic ballpark of what is actually in the blood of those patients.

Marsha Rosner 1:13:10

Absolutely not. We went did our study, and then said, Oh my gosh, do you think this would work? And people we better go and look up whatever. I would love to say we thought about all this first, but no, we first found out the dose that was effective. And then we went back to see whether that meant that this was reasonable. And part of that were my colleagues here, team science is great. I have some clinical colleagues, and they're saying to me don't even think about a clinical trial unless it's realistic. So what's different between what we did and this other group was, the other group use doses that were approximately there was a range of six to 20 micromolar, which is approximately 10 times more than the dose that we used. But they used it for compounds that are much more unstable than CBD when we ingest them in the body. So that says that you've got to have 10 times more CBD in the blood for these compounds to work. But the likelihood of getting that is very low because they get broken down in the body very quickly. So why didn't they pick this up? Because these studies were done with cells in culture. And if you're blocking the ability of the virus to enter, you just need to put the compound their coat whenever, you know, you need to go to block. In this case, I think spike protein and then see what happens. So it turns out that there are a number of compounds that have passed this barrier, which is they work in cell culture. One of them is Chloroquine, which we all have heard a lot about from our former press But Chloroquine never worked in animals. And there are a number of compounds like Chloroquine that work in cells, but don't work in animals. And that's why showing this in an animal model, in a mammalian model, is considered the gold standard for showing that a drug has the potential to work and people with those two things, you need the right dose that's realistic, and people, but often with some of these drugs, we don't know what that is. And then too, so what you start out doing is saying, okay, it doesn't just work in cells, it works in animals. So this other study stopped itself did not do animals, and, of course, did not do patients. So if you check the boxes that I mentioned, that we just went through in our paper, they get through box one, which is yes, it worked in cells, but they don't check any of the other boxes. What about concentration, the dose? What about animal models, etc?

Nick Jikomes 1:16:02

Yeah. And just to hammer this home, in case it's not already crystal clear, would you say it's common for a drug to look really interesting and promising in an in vitro study, and then failed to show that interesting effect in an animal model?

Marsha Rosner 1:16:16

Absolutely. And it's happened a lot with with drugs that people have tried to use for SARS, cov. Two fact there was a whole paper looking at a complete class of drugs, explaining why they look like they work in in in in cell culture model, but in fact, aren't really working against the virus in the way that's needed in an animal interest. And the problem with an animal, by the way, is that it's not you're not just asking the question, can it work in a cell, because a lot of things will legitimately work against the virus in a cell. But when that cell is in your body, now you have the immune system, now you have a lot of other things that can break it down, moving away, trap it, do all kinds of things. So you need that translation from a cell system, which is fairly pure, almost like a test to, to what happens when you really, you know, hit the physiology that we live with.

Nick Jikomes 1:17:10

So you mentioned that, that you guys are gonna be doing these clinical trials. And of course, it'll be interesting, see what the results are there? Do you have a sense for approximately how long that will take?

Marsha Rosner 1:17:19

So we're just setting it up. Now, the hardest part was raising funding. And what we think is, it'll probably take us about three months to get that started. Once we get that started, we think that we'll get the results fairly quickly. Because this is not a long trial, you're going finding patients, we hope to have some who have been vaccinated, and some have not been vaccinated. So we can even do that comparison. And you're trying to find patients who are showing up for COVID testing. I have to say, if we've done this during the omachron wave, it might have been easier. Now that we're coming off of it, it might be a little more challenging, but this is what we anticipate.

Nick Jikomes 1:18:01

Interesting. So you're a cancer biologist, and and you are presumably studying, you have probably a number of other research projects going on. Do you mind sharing with us some of the other cancer biology work that you have going on that might be particularly interesting to you right now?

Marsha Rosner 1:18:18

Sure. So as I said, our focus is on trying to figure out why our cells move and metastasize. So they move to other places. So I'm very interested in mechanism understanding on a molecular level, why this occurs? That's why we kind of walked through this er stress response and unfolded response and interference. So we look for those same kinds of things. But in the context of cancer, what is driving those cells to move there? And then given what is driving those cells? Can we make them reverse? Can we move them back? Why would we care about doing that? One way of thinking about the problem is we do have the ability to treat cancer cells, and we do have the ability to kill cancer cells. But our problem is that what makes a cancer cell different from a normal cell is very subtle. It's often the same genes and same proteins, but maybe they're activated longer, or they sit in another place. So there's nothing really alien about cancer. It's just a normal cell that's gone a bit haywire. And so we normally have cells that respond to drugs, and then we have some cells that are resistant. And it turns out the ones that tend to move to these other places tend to be more drug resistant, and the ones that are sensitive. And so there's actually some studies going on that even are playing with the idea that maybe if you have a Drugs sensitive and a drug resistant cells since the one that's drug resistant, maybe needs a few more bells and whistles to be able to be resistant than one that's sensitive to drug, but just just focus on growing, that when you're, they're in an environment that is very permissive for them to grow, there's no drugs around and so on. Maybe the sensitive cells can even outcompete the resistant cells, so they can keep them down. But when you get rid of all those sensitive cells, there's nothing, there's no competition, and the resistance cells just take off. And so that's what we see, we treat cancers. A classic example is melanoma, we actually know a lot of the mutations that drive it, we can even find drugs that go after those mutations in those proteins. And sometimes people look cured for about four to seven months, and then bam, it comes right back because resistance cells take over. So what we're playing with this idea of can we turn these resistant cells into non metastatic, maybe more drug sensitive cells, and then if we can do that, maybe we can do better?

Nick Jikomes 1:21:04

I see some small response when we were getting drugs with the drug general strategy there be to first think about, you know, if you can find a drug that doesn't kill the cells, but changes them changes their sensitivity, you would use something like that, and then and then take the approach that actually destroys

Marsha Rosner 1:21:23

them. You are exactly right. It's a two hit idea, move them into that space, and then catch, you know, hit them with something that's going to destroy them. It's exactly that idea.

Nick Jikomes 1:21:34

And so where are you in the discovery process there? Are you searching for a good candidate? Or do you already have some good candidates there.

Marsha Rosner 1:21:41

So we have some candidates, we have some genes, some proteins that we know drive metastasis. And when I told you we were looking for we got into CBD, because we're looking at its effect on one of those proteins. That's exactly what we were doing. We were trying to see whether CBD might be that guy that could block its ability to metastasize. As it turns out, it wasn't in this particular case, but we do have some potential drugs that can do that. And we're also working with some chemists to develop new drugs that maybe can do that. And we're also wondering whether drug combinations might be more effective at doing that. So again, what we tend to do is use a sledge hammer, when we use drugs, we try to hit whatever we're targeting as hard as possible. But what if you didn't do that, but instead, hit a number of targets. So collectively, the amount that you're kind of taking them down is the same, but it's distributed among a number of targets. We've found that we've done some analyses and they would suggest that you're less likely to get further mutations that cause the cancer to come back, when you kind of have multiple targets. But you don't dose each one is high. So that's another angle that we're going after.

Nick Jikomes 1:23:09

Interesting, interesting. Well, Marsh, I want to thank you for your time. You've walked us through a lot today in this research is, is quite exciting. Are there any final thoughts you want to leave people with or anything you want to reiterate? Before we go?

Marsha Rosner 1:23:22

I think what I'd like to do is think and mention my co team members who were involved in that study that we talked about. There were 33 of us in the end on this paper, and it represented approximately 10 different laboratories. And we all know that COVID has been really difficult for everyone, it's been hard to find silver linings. But for the scientific community, I would say one silver lining is that COVID brought many, many investigators from many different disciplines together to work on a problem and use their own area of expertise. And in some kind of allowed us to get to the end a lot faster. And what was wonderful about the way that was done is usually everyone wants to get credit for themselves. So I am the spokesperson for the study. But it is not my study. This is a study that all of us contributed to. And it's important to realize that but also what was truly amazing. And you would know this because you know when our first preprint came out, we did the study very quickly, actually, in three months. We had all the data except, you know, proof of the mechanism in the animal studies. We had that in three months. And it took us suppressed of a year to get all the rest of the data to repeat it and so on and then to get through journals to get peer reviewed because we did not want to put this out there. As you know, I wouldn't even talk to you until it was peer reviewed and published. In a form that could be taken seriously. So I just want to suggest that this is maybe the way science should be done in the future. We shouldn't have teams. And what was so amazing about this period is everyone left their egos at the door. Okay? It's not my work. I'm not the terrific person who did this. We're all just interested in getting good science done, and doing something that would benefit the public. And I think this was not just our group, but there were many groups that did this.

Nick Jikomes 1:25:30

Excellent. Well, Dr. Marshall Rosner, thank you for your time. Thank you.


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