Pushkin. Hey, it's Jacob. There's another podcast that I host called Incubation. It's a show about viruses, and recently we did an episode that I thought would be particularly interesting to you, to people who listen to What's Your Problem, it's about measles. Measles turns out to be way more interesting and way more insidious than we thought, but also measles may be a new way to fight cancer. I hope you liked the episode. I really found it interesting.
One last thing, we won't be publishing episodes of What's Your Problem over the next few weeks. We'll start up again in January. I thought I knew what I needed to know about what happens when you get measles. You get a fever and a rash. Maybe you get very sick. If you're really unlucky, you die. But chances are you get measles, you get better, and that's the end of it as it happens. I was wrong. I did not
know what I needed to know about measles. Because a recent discovery has blown open our whole idea of what the measles virus does to our bodies.
The world thought that measles was done being discovered and then boom, all of a sudden, there's this new idea of something that really had massive, massive consequences on humans that we didn't even realize.
I'm Jacob Goldstein and this is Incubation, a show about viruses. Today on the show how measles attacks your immune system and how researchers are trying to use measles to cure cancer. My guest for the first half of today show is Michael Minna. He's an epidemiologist slash immunologist, slash physician, and he's kind of a measles superfan. He did a lot of work we'll talk about today while he was a professor at Harvard. He's now chief scientific officer at a
company called emed. We started by talking about a surprising thing that happened after the measles vaccine was introduced in the nineteen sixties. As more and more kids were vaccinated against measles, the rate at which kids were dying of infectious disease went down way more than anybody expected. It went down so much that it couldn't be explained by measles alone.
After the vaccine was introduced, we saw market reductions in childhood mortality overall following the vaccine, which drove a lot of questions, why did that happen? Is it the vaccine actually acting directly to somehow prevent other infections, or is there something else at play?
Even if zero people died of measles, even if zero children died of measles, you wouldn't get that large of a reduction immortality. Right, some weird thing is going.
On, that's exactly right.
Weird good thing, weird usually.
That's right, A very weird good thing was going on.
So now we have this interesting kind of happy mystery in a way. Why are so few children dying of infectious disease after the rollout of the measles vaccine? What do you do to try and figure out what's going on?
We said, well, maybe it's because measles had detrimental effects on somebody's immune memory that might be putting them at risk for other stuff, other infections. And so what we did was we said, well, if that's the case, then if we look at a lot of data, could we map the numbers of cases of measles to the numbers of deaths from other things besides measles from year to year?
And what we found was prof boundly predictive. Is if you asked what were the number of measles cases in nineteen forty nine and what were the numbers of deaths from non measles infections from nineteen forty nine, nineteen fifty and nineteen fifty one. When you accrued all three years, it became extraordinarily predictive of how many children would die over the next three years of non measles infectious related deaths.
So, just to be clear, what you found is that when there's a measle's outbreak in one year, the rate at which kids died from other infectious diseases went up in the next few years.
That's exactly right.
So you used in your answer just there this phrase that I just want to spend a moment on immune memory. What is immune memory?
Immune memory is very similar to our regular memory. All of our body's memories, whether it be muscle memory, brain memory, or immune memory, is stored in cells. The way that immune memory works is when you bump up against a pathogen as let's say, a virus like measles or coronavirus, whatever it might be, your body actually sees it, it recognizes that virus. It learns from it, and it actually remembers it in B cells and T cells and plasma cells.
And that's how our immune system works in terms of developing immune memory and utilizing it to combat infections that we see in the future.
Is what you're finding that in some way measles is attacking the kid's immune memory. Is that the hypothesis that follows.
That's exactly the hypothesis that follows. For example, if a six year old got measles, then maybe that measles infection could destroy some of the immune memory the defenses that that child gained over the last six years, and therefore when they are seven or eight years old, are actually more vulnerable than they otherwise would have been to those infections that they gained the immunity to when they were two or three.
So, okay, you have this hypothesis, how do you test it? How do you investigate what's really going on?
There's a long, rich history of how to predict where measles is going to go next. It's actually famous for how predictive it is because it is so infectious that you just need to know how many people are vaccinated in a community, and if there's any measles anywhere in the region, you can expect that pretty soon at below certain levels, there's going to be an.
Outbreak below certain levels of vaccination.
That's right, and that's why measles is considered the canary and the coal mine for vaccine rates. It's literally the thing that pops up on the radar when you say who's what communities are having trouble vaccinating their population, and boom, if you see measles, you know they're having trouble vaccinating their populations. And so what we can do is we can leverage everything we know about measles epidemiology to help identify where might outbreaks happen. And that's exactly what Rick
de Swart and his team did. They are in the Netherlands. He's at Erasmus, which is in Rotterdam, and so he was able to say, hey, right in our backyard, there's a community that, for religious reasons, they chose not to vaccinate their children against measles. So they said, well, if you're not going to get a vaccine, would you be interested or willing to have us just draw a little sample of blood from your kids today and should measles
catch up to them in the future. Could we come back and draw another sample of blood.
You have the before measles blood samples, and you have from the same children the after measles blood samples. We have everything ready to go. What happens.
There was a big outbreak, and almost immediately we aren't seeing that we can measure all of these antibodies in the blood samples. And then when we actually look at the blood samples from right before the kids got measles to those same kids blood samples that they collected after, we saw marked reductions. Not just in a couple antibodies, but some kids lost eighty percent of all of the diversity of their antibodies that existed in that blood sample
before they got measles. And we compared it, we said, well, maybe that's normal. So we looked at kids who had gotten vaccinated for measles. We like the kids who just had no infections, And what we saw was the average person from any two time points, there'd be like five percent difference in their overall antibody repertoire. But the measles kids, the kids who got measles lost anywhere from twenty percent
to eighty percent of their whole immunological memory pool. This is the whole lifetime of immune memory that they've spent years building up and building up, just poof wiped away because of this measles infection and these kids. What that means is now, across millions and millions of kids who
were before the vaccines, almost every child got measles. And so at that scale, when you have so many people getting measles and this effect happening, which we call immunological amnesia, essentially they forgot their body, forgot because of the infection the immune memories that they formed before the infection. What that means is that you have all of these kids
that are more susceptible to other infectious diseases. So most most kids would survive, but it turned out that of those kids who did die from other things, about half of those deaths could be attributed to the immune amnesia associated with measles.
Is there something particularly insane if that happens at a population level. If you imagine a group of people in the absence of a vaccine entirely, where it's like, not only is each kid more vulnerable, but because all the other kids are more vulnerable, everybody is more vulnerable. Is there something like that that happens.
I am so happy you asked that question.
You're welcome.
So, yes, it is. It's a much much harder thing to measure.
I mean, it's sort of like the reverse of herd immunity in some weird broad spectrum way, right.
So what's so interesting that you bring that up? Because before my musle's work, I was working on influenza and its impacts on other bacterial infections. And during my PhD, I coined a term called generalized herd effects, and I explicitly didn't call it herd immunity because maybe it's not going to reduce things, but maybe you could exacerbate things.
Yeah, how about herd vulnerability. I want the opposite. What's the opposite of herd.
Immunity, that's herd vulnerability is a great term, and so the idea there as well. If you have a pathogen that's impacting your susceptibility to a lot of other pathogens, you could, you know, create a herd vulnerability because of infections of that initial pathogen. And on the contrary, if you figure out a vaccine against that initial pathogen, like the measles vaccine, you create massive benefits in getting rid of that herd vulnerability.
So what's going on on a cellular level.
As far as we know, measles is unique in its class. It's actually it's an amazing story. So if you give me forty seconds to describe it.
I will, oh go, you got a minute if you need it.
So, every virus has a receptor that it binds to and needs to latch onto on a cell. For measles, it's this molecule that's called CD one fifty or it's called SLAM. SLAM stands for a signaling of Lymphocyte Activation molecule, and it's when somebody gets a measles infection. The virus comes into somebody's lungs and we have these cool dendritic cells.
And dendritic cells are like these cells of big arms, and they go out and reach pathogens that they that they know shouldn't be there, and they capture them and bring them in and then they shuttle them into the lymphoid system, which is where all of our immune cells are. And so normally what would happen is the dendritic cells would say, hey, immune system, you know here's a pathogen, take it and develop immune memory against it. And so it literally hands it off to B cells and T cells.
In this case, when the dendritic cell does exactly that same process, it hands off Measles virus to B cells and T cells. And this is a big mistake because now you have a virus that, instead of being handed off to a B and T cell and having that B and T cell you know ingest it and learn from it. The Measles flips on it receptor utilization and grabs city one point fifty or slam these molecules on the outside of the B cells and the T cells and it actually invades them like a trojan horse.
Aha. So it's like a like a trick, right, Like Measles is there acting like a normal virus until it gets to the B cells in the T cells in the immune system. And normally the B cells in the T cells would destroy Measles, would destroy the virus. But in that case this doesn't happen, right, So what does happen?
Now It's in the cushy lymphoid system and it's just full of food and it just replicates like crazy inside the immune system all the while cell by cell destroying the valuable immune memory is stored inside each of those cells that it's destroying.
That is very compelling. That it's like a viralogical horror movie inside your body.
It absolutely is. And what we see when we see the prototypic measles rash, which is like dots all over a child's body, red dots, it is truly the tip of the iceberg in terms of where the damage is being done. The real damage inside a child is much much deeper and much much more profound in terms of destroying a huge, huge population of very important cells inside of our body.
So if you sort of step back and think about this idea that measles not only gives you measles but makes you vulnerable to lots of other infectious diseases, does it make you think differently about viruses, about the immune system, Like where do you land?
Measles brings together for me mathematics, biology, ecology and evolution and vaccinology, And I love bringing those pieces together. It gives you a very deep appreciation for the delicate balance we have between infectious diseases, immunity, cancer, and autoimmune disease,
and how those all interplay with each other. You know, the world thought that measles was done being discovered and then boom, all of a sudden, there's this new idea of something that really had massive, massive consequences on humans that we didn't even realize, and so it drives this renewed excitement around measles vaccination and the importance of it. It's not just a cool finding. It hopefully helps us move further and further towards eradication of the virus altogether.
It was great to talk with you. Thank you so much for your time.
Well, thank you so much. It was a lot of fun.
Michael Minna is Chief science Officer at EMED Digital Healthcare. He was previously a professor at the Harvard School of Public Health. When we come back using measles to fight cancer, going back all the way to the eighteen hundreds, which was before anybody even knew what a virus really was, there have been occasional reports of cancer patients who get some kind of viral infection and then go into remission from cancer. And at a certain level, this makes sense.
Viruses are highly evolved to enter and destroy cells. Normally we think of this as a bad thing, but if a virus is entering and destroying cancer cells, this ter a cell and destroy it property might be a very good thing. By the nineteen fifties, researchers were actively trying to figure out how to use viruses to treat cancer. But then new kinds of cancer drugs were discovered, basically chemotherapy, and researchers got less interested in that virus cancer link.
My guest for this half of the show is Stephen Russell. Stephen has spent his career trying to use viruses to cure cancer, and as you'll hear, he and other researchers in the field have made real progress. When Stephen was starting his career in the nineteen eighties, he was interested in using retroviruses as possible cancer treatments. Then he told me he turned his attention to measles.
Yeah, well, measles became the next love.
You fell in love with measles? Yeah, of course, why do you fall in love with measles? Well?
All viruses are quite beautiful, I have to say, and the life cycles are extraordinarily elegant. But measles I could do things with. I knew that there was a very remarkable case of a boy with a retro orbital Burkitt lymphoma, a very aggressive lymphoma that was sort of bulging his eye out, and he went to a clinic and was told, well, come back in a couple of weeks and we'll start the therapy. And he came back in a couple of weeks and the tumor had just resolved. But in the
meantime he'd had a severe measles infection. Huh, And so it looked like it was pretty certain that the measles infection had driven this response that he had.
Burko lymphoma also caused by a virus, right, the first tumor we knew was caused by a virus.
Epstein By Yeah, so go on, I apologize. So anyway, I looking at measles, it seemed to tick a lot of boxes. But there was this whole history of the development of a vaccine strain of measles, and measles had been the vaccine had been created by taking a virus
from the throat of a patient with measles. He was an eleven year old boy at the time, David Edmonstone in nineteen fifty four, and then growing that virus on cancer cells in tissue culture, and the virus had required the ability to propagate efficiently in cancer cells, but it lost the ability to cause measles.
And wait, I just just to be clear, this was just they weren't trying when they were doing this to fight cancer. They were just trying to develop a measles vaccine. They were just saying, we're going to grow this measles in culture over time and make it be attenuator, make it be weaker. And it adapted in such a way that it preferred to infect tumor cells and not to infect non tumor.
Cells because of the way they adapted it. Because remember that the cells that they were growing in the lab that they could put the measles virus on were basically cancer cells.
And is that just because those are easy cells to grow because they liked to propagate.
Yeah.
Yeah, It's very, very difficult to grow non cancerous sects.
Yeah, it's like the problem with cancer, right, it just loves to divide.
Yeah. Yeah. So they put this virus on on the cells in culture, and the virus had actually adapted and it had learned to use a receptor that is more abundant on cancer cells than on normal cells, and it was losing all sorts of things that it needed in order to cause disease because it didn't need them to be able to propagate the cancer cells. So it spontaneously attenuated through a lot of mutations that arose in the
viral genome. And so there it was and had been given to billions of people, and it looked like it was fairly well adapted to test in human studies against cancer.
The measles virus used in the vaccine didn't make people sick, and it tended to attack cancer cells. So Stephen started using that form of the virus in studies to see if measles could treat cancer. Eventually he landed on a kind of cancer called multiple myeloma that can take hold in the bone marrow and suppress the immune system. And there was one multiple myeloma patient in particular who had a huge effect on how Stephen thought about using measles
to fight cancer. The patient's name was Stacy.
Erholtz, so Stacy. She had multiple myeloma. She had been on treatment for ten years, on and off, but probably more on than off treatment for the first ten years of her diagnosis, because every time she stopped the treatment, or even if she continued on it, the disease would come back and then she needs switch to something else. She had a large tumor on her forehead that was
destroying the underlying bone and compressing her brain. She had four other solid tumors, and then her bone marrow was diffusely infiltrated with myeloma and it was moving fast, and she was out of treatment and options at the time. I mean, there was nothing.
She was going to die soon.
She was going to die, yeah, and she had three children still at school and everything to play for. She was fifty years old at the time. We'd moved up through every dose level that FDA had negotiated with us. Based on a starting dose level of a million, we'd gone up to just tenfold short of a billion.
Like, how much did she get compared to how much somebody gets when they get the measles vaxing.
It's about ten million doses of vaccine, okay.
For this one person, So she's getting quite a lot. And what happens.
Well as with other patients, she had a reaction to the infusion of virus. So she got the virus infused. She felt fine for a couple of hours, and then she started shivering and shaking, and her temperature rose and she felt pretty unwell overnight, but by the following morning it had settled down.
And is that essentially like a response to a massive infection. She's essentially has this massive infection.
Yes, it's similar to that, although it wasn't causing measles in her so it was it was more the body reacting to the foreign stuff in the blood and a very kind of rapid reaction. That settled down, and then she left hospital, went home and after a few days she started noticing that the tumor on her forehead she and her family had named it Evan, and this tumor Evan,
started to shrink and actually melted away. And you know, we conducted thorough evaluations on her intervals thereafter, and we were staggered to see that she went into a complete disease remission. She felt fantastic. You know. We thought at the time, Okay, we've got it. This is the way to cure multiple myeloma, and so we gave it to a lot of other multiple myeloma patients and it didn't work nearly so well. There was some partial responses, but
there was really nothing as dramatic as Stacy. So we studied Stacy pretty intensively. To try and understand what was special about her, because that would be the key to the success of virotherapy. I mean, what we knew from Stacy as wow, this can actually happen. You can give a virus systemically nothing else, and you can get a dramatic resolution of tumor at all sites. So the studies that we did on Stacy showed that number one, she
had no anti measles antibody detectable. She had, however, been vaccinated as a child, and then she had lost her immune and she'd been revaccinated after her first stem cell transplant, the immunity had come back, and she'd lost it again after the second stem cell transplant. Huh, So she had no antibodies to block the virus from getting to the target.
So basically, her immune system was the same as the immune system of a person who has never had measles and not been vaccinated for measles.
Not quite, because we looked at her T cells, the cells that come into the tumor and attack the virus infected cells, and she had a very high level of anti measles T cells.
As it turned out, this was a perfect combination. Stacy didn't have any antibodies, so the measles virus was free to go into her body and infect her tumor cells. But she did have anti measles T cells, so once the measles infected the tumor cells, those T cells could attack hack her tumor cells. So now she had both the measles virus and her own T cells attacking and
destroying the tumor. Stephen told me he learned a lot from Stacy's case and it helped him figure out how to move forward with his research.
Yeah, so there are two pathways that we took. One was to switch to a different virus that people do not have prior exposure to, and so we started working with the sicular stomatitis virus VSV, which causes naturally a blistering illness in cattle.
Uh huh. So that's that's one way to get around the immunity to measles problem. Right, You're you're using a virus that most people don't get and are therefore not immune to. How is that going?
It's going. It's going well. Where you know, it's not in every cancer that we see anything, but the results that we have at the moment are looking very promising in certain indications. The other approach we took was to stealth measles virus so that it would still be measles virus.
It would still be that vaccine strain, but it would have a new coat, huh, that was no longer recognizable by circulating antibodies, And so we would in that situation, we would have a virus we could give systemically that would penetrate the tumor, and that would then be subject to attack by these t cells that exist in people who've been measles immunized.
Well, does it work in mice? Okay, it's a start.
We haven't taken that one into human clinical tests yet.
Let's talk for a minute about using viruses to treat cancer more broadly. Right, people have been trying other viruses to treat other cancers. What's the state of the field more generally?
There has been incremental progress, and there are viruses that are looking very promising in brain cancer injected into the brain tumor, in bladder cancer instilled into the bladder, and I think many ongoing programs which show great promise. So I'm still a complete believer in the capability of viruses to really bring a transformation in the approach to cancer therapy. I feel like it's coming soon, but not everybody agrees with me.
I appreciate your time so much. It was great to talk with you.
Great talking with you too. Thank you very much.
Stephen Russell founded the Department of Molecular Medicine at the Mayo Clinic. He is currently the CEO of Viria, a company that is trying to use viruses to treat cancer. One last thing, Stephen told me that he's still in touch with Stacy Airholtz, the patient who had multiple myeloma and went into complete remission after being treated with measles.
Stacy Holtz is, you know, a guiding light for me. I'm friends with her, I'm in contact with her on a regular basis, and she's got grandkids. She's having a happy life. She's a very positive woman.
Thanks to both of our guests today, Michael Minna and Stephen Russell. Next week on the show, I talked to a scientist who discovered an entirely new kind of virus, and it turns out this virus is everywhere.
Boiling Springs Lake, deep Sea Sediment's Korean air sample, monkey feces, dragonfly guts, soil just outside the lab at Portland State University. Basically anywhere that we have looked, we found these cruci viruses.
Incubation is a co production of Pushkin Industries and Ruby Studio at iHeartMedia. It's produced by Kate Furby and Brittany Cronin. The show is edited by Lacey Roberts. It's mastered by Sarah Bruguer, fact checking by Joseph Friedman. Our executive producers are Lacey Roberts and Matt Romano. I'm Jacob Goldstein. Thanks for listening.