Learn. Share. Evolve…

0:00:06 [music]
0:00:06 Pushkin.
0:00:18 Hey, it’s Jacob. There’s another podcast that I host called Incubation. It’s a show about viruses.
0:00:23 And recently we did an episode that I thought would be particularly interesting to you,
0:00:29 to people who listen to What’s Your Problem? It’s about measles. Measles turns out to be
0:00:38 way more interesting and way more insidious than we thought. But also, measles may be a new way to
0:00:43 fight cancer. I hope you like the episode. I really found it interesting. One last thing,
0:00:48 we won’t be publishing episodes of What’s Your Problem? over the next few weeks. We’ll start
0:00:55 up again in January. I thought I knew what I needed to know about what happens when you get
0:01:03 measles. You get a fever and a rash. Maybe you get very sick. If you’re really unlucky, you die.
0:01:08 But chances are, you get measles, you get better, and that’s the end of it.
0:01:14 As it happens, I was wrong. I did not know what I needed to know about measles because
0:01:21 a recent discovery has blown open our whole idea of what the measles virus does to our bodies.
0:01:26 The world thought that measles was done being discovered. And then, boom, all of a sudden,
0:01:34 there’s this new idea of something that really had massive, massive consequences on humans that
0:01:40 we didn’t even realize. I’m Jacob Goldstein, and this is Incubation, a show about viruses.
0:01:47 Today on the show, how measles attacks your immune system and how researchers are trying to use
0:02:02 measles to cure cancer. My guest for the first half of today’s show is Michael Minna. He’s an
0:02:09 epidemiologist/immunologist/physician, and he’s kind of a measles superfan. He did a lot of work
0:02:15 we’ll talk about today while he was a professor at Harvard. He’s now chief scientific officer
0:02:20 at a company called eMed. We started by talking about a surprising thing that happened after
0:02:26 the measles vaccine was introduced in the 1960s. As more and more kids were vaccinated against
0:02:32 measles, the rate at which kids were dying of infectious disease went down way more than anybody
0:02:40 expected. It went down so much that it couldn’t be explained by measles alone. After the vaccine was
0:02:48 introduced, we saw market reductions in childhood mortality overall following the vaccine, which
0:02:56 drove a lot of questions. Why did that happen? Is it the vaccine actually acting directly
0:03:02 to somehow prevent other infections, or is there something else at play? Even if zero people died
0:03:07 of measles, even if zero children died of measles, you wouldn’t get that large of a reduction in
0:03:14 mortality. Some weird thing is going on. That’s exactly right. Weird good thing, unusually.
0:03:20 That’s right. A very weird good thing was going on. Now we have this interesting kind of happy
0:03:26 mystery in a way. Why are so few children dying of infectious disease after the rollout of the
0:03:33 measles vaccine? What do you do to try and figure out what’s going on? We said, well, maybe it’s
0:03:40 because measles had detrimental effects on somebody’s immune memory. That might be putting
0:03:45 them at risk for other stuff, other infections. What we did was we said, well, if that’s the case,
0:03:53 then if we look at a lot of data, could we map the numbers of cases of measles to the numbers of
0:04:00 deaths from other things besides measles from year to year? What we found was profoundly
0:04:08 predictive is if you asked, what were the number of measles cases in 1949 and what were the numbers
0:04:18 of deaths from non-measles infections from 1949, 1950, and 1951? When you accrued all three years,
0:04:25 it became extraordinarily predictive of how many children would die over the next three years of
0:04:31 non-measles infectious related deaths. Just to be clear, what you found is that when there’s a
0:04:37 measles outbreak in one year, the rate at which kids died from other infectious diseases went up
0:04:43 in the next few years. That’s exactly right. You used in your answer just there this phrase that I
0:04:50 just want to spend a moment on. Immune memory. What is immune memory? Immune memory is very
0:04:58 similar to our regular memory. All of our body’s memories, whether it be muscle memory, brain
0:05:06 memory, or immune memory, is stored in cells. The way that immune memory works is when you bump up
0:05:12 against a pathogen, let’s say a virus like measles or coronavirus, whatever it might be,
0:05:21 your body actually sees it, it recognizes that virus, it learns from it, and it actually remembers
0:05:28 it in B cells and T cells and plasma cells. That’s how our immune system works in terms
0:05:34 of developing immune memory and utilizing it to combat infections that we see in the future.
0:05:41 Is what you’re finding that in some way measles is attacking the kids immune memory? Is that the
0:05:46 hypothesis that follows? That’s exactly the hypothesis that follows. For example, if a
0:05:55 six-year-old got measles, then maybe that measles infection could destroy some of the immune memory,
0:06:02 the defenses that that child gained over the last six years. Therefore, when they are seven or eight
0:06:09 years old, they are actually more vulnerable than they otherwise would have been to those infections
0:06:15 that they gained the immunity to when they were two or three. You have this hypothesis. How do you
0:06:23 test it? How do you investigate what’s really going on? There’s a long rich history of how to
0:06:29 predict where measles is going to go next. It’s actually famous for how predictive it is because
0:06:35 it is so infectious that you just need to know how many people are vaccinated in a community,
0:06:39 and if there’s any measles anywhere in the region, you can expect that pretty soon
0:06:44 at below certain levels, there’s going to be an outbreak. Below certain levels of vaccination.
0:06:49 That’s right. That’s why measles is considered the canary in the coal mine for vaccine rates. It’s
0:06:55 literally the thing that pops up on the radar when you say, “What communities are having trouble
0:06:59 vaccinating their population?” And boom, if you see measles, you know they’re having trouble
0:07:05 vaccinating their populations. And so what we can do is we can leverage everything we know
0:07:13 about measles epidemiology to help identify where might outbreaks happen. And that’s exactly what
0:07:20 Rick Deswaart and his team did. They are in the Netherlands. He’s at Erasmus, which is in Rotterdam,
0:07:26 and so he was able to say, “Hey, right in our backyard, there’s a community that for religious
0:07:31 reasons they chose not to vaccinate their children against measles.” So they said, “Well,
0:07:36 if you’re not going to get a vaccine, would you be interested or willing to have us just
0:07:42 draw a little sample of blood from your kids today, and should measles catch up to them in the
0:07:48 future, could we come back and draw another sample of blood?” You have the before measles
0:07:54 blood samples, and you have from the same children the after measles blood samples. We have everything
0:08:00 ready to go. What happens? There was a big outbreak, and almost immediately we start seeing that we
0:08:07 can measure all of these antibodies in the blood samples. And then when we actually look at the
0:08:12 blood samples from right before the kids got measles to those same kids blood samples that they
0:08:20 collected after, we saw market reductions, not just in a couple antibodies, but some kids lost
0:08:27 80% of all of the diversity of their antibodies that existed in that blood sample before they
0:08:33 got measles. And we compared it. We said, “Well, maybe that’s normal.” So we looked at kids who had
0:08:38 gotten vaccinated for measles. We looked at kids who just had no infections, and what we saw was the
0:08:44 average person would, from any two time points, there’d be like 5% difference in their overall
0:08:52 antibody repertoire. But the measles kids, the kids who got measles lost anywhere from 20% to 80%
0:09:00 of their whole immunological memory pool. This is the whole lifetime of immune memory protection
0:09:07 that they’ve spent years building up and building up just poof, wiped away because of this measles
0:09:12 infection. And these kids, what that means is now across millions and millions of kids who were,
0:09:19 you know, before the vaccines, almost every child got measles. And so, at that scale, when you have
0:09:25 so many people getting measles, and this effect happening, which we call immunological amnesia,
0:09:32 essentially they forgot, their body forgot because of the infection, the immune memories
0:09:37 that they formed before the infection, what that means is that you have all of these kids that are
0:09:43 more susceptible to other infectious diseases. So most, most kids would survive, but it turned out
0:09:53 that of those kids who did die from other things, about half of those deaths could be attributed
0:10:00 to the immune amnesia associated with measles. Is there something particularly insidious if
0:10:05 that happens at a population level, if you imagine a group of people in the absence of a vaccine
0:10:11 entirely where it’s like, not only is each kid more vulnerable, but because all the other kids
0:10:15 are more vulnerable, everybody is more vulnerable? Is there something like that that happens?
0:10:24 I am so happy you asked that question. You’re welcome. So yes, it is, it’s a much,
0:10:30 much harder thing to measure. I mean, it’s sort of like the reverse of herd immunity in some weird
0:10:36 broad-spectrum way, right? So what’s so interesting that you bring that up, because before my measles
0:10:41 work, I was working on influenza and its impacts on other bacterial infections, and during my PhD,
0:10:49 I coined a term called generalized herd effects. And I explicitly didn’t call it herd immunity,
0:10:54 because maybe it’s not going to reduce things, but maybe it could exacerbate things.
0:10:59 Yeah, how about herd vulnerability? I want the opposite. What’s the opposite of herd immunity?
0:11:03 That’s exact herd vulnerability is a great term. And so the idea there was, well,
0:11:09 if you have a pathogen that’s impacting your susceptibility to a lot of other pathogens,
0:11:17 you could create a herd vulnerability because of infections of that initial pathogen. And on the
0:11:22 contrary, if you figure out a vaccine against that initial pathogen, like the measles vaccine,
0:11:28 you create massive benefits in getting rid of that herd vulnerability.
0:11:38 So what’s going on on a cellular level? As far as we know, measles is unique in its class.
0:11:44 It’s actually an amazing story. So if you give me 40 seconds to describe it, I will.
0:11:50 Oh, go. You got a minute if you need it. So every virus has a receptor that it binds to
0:11:56 and needs to latch onto on a cell. For measles, it’s this molecule that’s called CD150,
0:12:04 or it’s called SLAM. SLAM stands for signaling of lymphocyte activation molecule. And it’s when
0:12:10 somebody gets a measles infection. The virus comes into somebody’s lungs, and we have these cool
0:12:14 dendritic cells. And dendritic cells are like these cells with big arms, and they go out and
0:12:19 reach pathogens that they know shouldn’t be there. And they capture them and bring them in.
0:12:25 And then they shuttle them into the lymphoid system, which is where all of our immune cells are.
0:12:30 And so normally what would happen is the dendritic cells would say, hey, immune system,
0:12:37 here’s a pathogen, take it and develop immune memory against it. And so it literally hands it
0:12:45 off to B cells and T cells. In this case, when the dendritic cell does exactly that same process,
0:12:50 it hands off measles virus to B cells and T cells. And this is a big mistake, because now you have
0:12:55 a virus that instead of being handed off to a B and T cell and having that B and T cell,
0:13:01 you know, ingest it and learn from it, the measles flips on its receptor utilization and
0:13:08 grabs CD150 or SLAM, these molecules on the outside of the B cells and the T cells,
0:13:16 and it actually invades them like a Trojan horse. So it’s like a trick, right? Like,
0:13:22 measles is there acting like a normal virus until it gets to the B cells in the T cells
0:13:26 in the immune system. And normally, the B cells in the T cells would destroy measles,
0:13:32 would destroy the virus. But in that case, this doesn’t happen, right? So what does happen?
0:13:37 Now it’s in the cushy lymphoid system. And it’s just full of food. And it just
0:13:46 replicates like crazy inside the immune system all the while, cell by cell, destroying the valuable
0:13:50 immune memory is stored inside each of those cells that it’s destroying.
0:13:57 That is very compelling. That’s like a virological horror movie inside your body.
0:14:04 It absolutely is. And what we see when we see the prototypic measles rash, which is like dots
0:14:11 all over a child’s body, red dots, it is truly the tip of the iceberg in terms of where the
0:14:18 damage is being done. The real damage inside a child is much, much deeper and much, much more
0:14:25 profound in terms of destroying a huge, huge population of very important cells inside of
0:14:33 our body. So if you sort of step back and think about this idea that measles not only gives you
0:14:39 measles, but makes you vulnerable to lots of other infectious diseases, does it make you think
0:14:43 differently about viruses, about the immune system? Like what, where do you land?
0:14:53 Measles brings together for me, mathematics, biology, ecology and evolution, and vaccinology.
0:15:03 And I love bringing those pieces together. And it gives you a very deep appreciation for the
0:15:09 delicate balance we have between infectious diseases, immunity, cancer and autoimmune disease,
0:15:16 and how those all interplay with each other. The world thought that measles was done being
0:15:24 discovered. And then, boom, all of a sudden, there’s this new idea of something that really
0:15:30 had massive, massive consequences on humans that we didn’t even realize. And so it drives
0:15:35 this renewed excitement around measles vaccination and the importance of it.
0:15:39 It’s not just a cool finding. It hopefully helps us move
0:15:43 further and further towards eradication of the virus altogether.
0:15:49 It was great to talk with you. Thank you so much for your time.
0:15:50 Well, thank you so much. It was a lot of fun.
0:15:56 Michael Minna is Chief Science Officer at eMed Digital Healthcare.
0:15:59 He was previously a professor at the Harvard School of Public Health.
0:16:03 When we come back, using measles to fight cancer.
0:16:20 Going back all the way to the 1800s, which was before anybody even knew what a virus really was,
0:16:27 there have been occasional reports of cancer patients who get some kind of viral infection
0:16:32 and then go into remission from cancer. And at a certain level, this makes sense.
0:16:39 Viruses are highly evolved to enter and destroy cells. Normally, we think of this as a bad thing,
0:16:45 but if a virus is entering and destroying cancer cells, this enter a cell and destroy it property
0:16:52 might be a very good thing. By the 1950s, researchers were actively trying to figure out
0:16:58 how to use viruses to treat cancer. But then new kinds of cancer drugs were discovered,
0:17:04 basically chemotherapy, and researchers got less interested in that virus cancer link.
0:17:10 My guest for this half of the show is Stephen Russell. Stephen has spent his career trying to
0:17:16 use viruses to cure cancer. And as you’ll hear, he and other researchers in the field
0:17:21 have made real progress. When Stephen was starting his career in the 1980s,
0:17:25 he was interested in using retroviruses as possible cancer treatments.
0:17:29 Then he told me he turned his attention to measles.
0:17:31 Yeah, well, measles became the next love.
0:17:33 You fell in love with measles.
0:17:34 Yeah, of course.
0:17:36 Why’d you fall in love with measles?
0:17:43 Well, all viruses are quite beautiful, I have to say. And the life cycles are extraordinarily
0:17:51 elegant. But measles, I could do things with. I knew that there was a very remarkable case of a boy
0:17:58 with a retroorbital burkit lymphoma, a very aggressive lymphoma that was sort of bulging his
0:18:03 eye out. And he went to a clinic and was told, well, come back in a couple of weeks and we’ll
0:18:10 start the therapy. And he came back in a couple of weeks and the tumor had just resolved.
0:18:14 But in the meantime, he’d had a severe measles infection.
0:18:20 And so it looked like it was pretty certain that the measles infection had driven this
0:18:21 response that he had.
0:18:28 Burkit lymphoma also caused by a virus, right? The first tumor we knew was caused by a virus.
0:18:30 Epstein bar, yeah.
0:18:31 So go on, I apologize.
0:18:38 So anyway, looking at measles, it seemed to tick a lot of boxes. But there was this whole
0:18:44 history of the development of a vaccine strain of measles. And measles had been, the vaccine had
0:18:53 been created by taking a virus from the throat of a patient with measles. He was an 11-year-old boy
0:19:00 at the time, David Edmundston in 1954, and then growing that virus on cancer cells in tissue
0:19:08 culture. And the virus had acquired the ability to propagate efficiently in cancer cells, but it
0:19:10 lost the ability to cause measles.
0:19:16 And wait, just to be clear, this was just, they weren’t trying when they were doing this to
0:19:22 fight cancer. They were just trying to develop a measles vaccine. They were just saying we’re
0:19:28 going to grow this measles in culture over time and make it be a tenuator, make it be weaker.
0:19:34 And it adapted in such a way that it preferred to infect tumor cells and not to infect non-tumor
0:19:40 cells. Because of the way they adapted it. Because remember that the cells that they were growing
0:19:45 in the lab that they could put the measles virus on were basically cancer cells.
0:19:48 And is that just because those are easy cells to grow because they like to propagate?
0:19:52 Yeah, it’s very, very difficult to grow non-cancerous cells.
0:19:57 Yeah, it’s like the problem with cancer, right? It just loves to divide.
0:20:06 So they put this virus on the cells in culture and the virus had actually adapted and it had
0:20:14 learned to use a receptor that is more abundant on cancer cells and on normal cells. And it was
0:20:21 losing all sorts of things that it needed in order to cause disease because it didn’t need them to be
0:20:28 able to propagate in the cancer cells. So it spontaneously attenuated through a lot of mutations
0:20:34 that arose in the viral genome. And so there it was and had been given to billions of people.
0:20:44 And it looked like it was fairly well adapted to test in human studies against cancer.
0:20:51 The measles virus used in the vaccine didn’t make people sick and it tended to attack cancer cells.
0:20:57 So Stephen started using that form of the virus in studies to see if measles could treat cancer.
0:21:03 Eventually, he landed on a kind of cancer called multiple myeloma that can take hold in the bone
0:21:10 marrow and suppress the immune system. And there was one multiple myeloma patient in particular
0:21:16 who had a huge effect on how Stephen thought about using measles to fight cancer. The patient’s name
0:21:25 was Stacey Earholz. So Stacey, she had multiple myeloma. She had been on treatment for 10 years,
0:21:33 on and off, but probably more on and off treatment for the first 10 years of her diagnosis. Because
0:21:39 every time she stopped the treatment or even if she continued on it, the disease would come back
0:21:45 and then she’d need to switch to something else. She had a large tumor on her forehead that was
0:21:53 destroying the underlying bone and compressing her brain. She had four other solid tumors and then
0:21:59 her bone marrow was diffusely infiltrated with myeloma and it was moving fast. And she was
0:22:04 out of treatment options at the time. I mean, there was nothing… She was going to die soon.
0:22:11 She was going to die. Yeah. And she had three children still at school and everything to play
0:22:18 for. She was 50 years old at the time. We’d moved up through every dose level that FDA had
0:22:24 negotiated with us based on a starting dose level of a million. We’d gone up to just 10
0:22:29 fold short of a billion. How much did she get compared to how much somebody gets when they
0:22:35 get the measles vaccine? It’s about 10 million doses of vaccine. Okay. For this one person,
0:22:43 so she’s getting quite a lot and what happens? Well, as with other patients, she had a reaction
0:22:52 to the infusion of virus. So, she got the virus infused. She felt fine for a couple of hours and
0:22:59 then she started shivering and shaking and her temperature rose and she felt pretty unwell
0:23:04 overnight. But by the following morning, it had settled down. And is that essentially like a
0:23:10 response to a massive infection? She’s essentially has this massive infection? Yes, it’s similar to
0:23:18 that. Although it wasn’t causing measles in her. So, it was more the body reacting to the foreign
0:23:26 stuff in the blood and a very kind of rapid reaction that settled down. And then she left
0:23:34 hospital, went home and after a few days, she started noticing that the tumor on her forehead,
0:23:42 she and her family had named it Evan. And this tumor Evan started to shrink
0:23:51 and actually melted away. And we conducted thorough evaluations on her intervals thereafter.
0:23:57 And we were staggered to see that she went into a complete disease remission.
0:24:05 She felt fantastic. We thought at the time, okay, we’ve got it. This is the way to cure multiple
0:24:13 myeloma. And so we gave it to a lot of other multiple myeloma patients and it didn’t work
0:24:19 nearly so well. There were some partial responses, but there was really nothing as dramatic as Stacey.
0:24:27 So, we studied Stacey pretty intensively to try and understand what was special about her.
0:24:33 Because that would be the key to the success of vire therapy. I mean, what we knew from Stacey is,
0:24:40 wow, this can actually happen. You can give a virus systemically, nothing else, and you can
0:24:48 get a dramatic resolution of tumor at all sites. So, the studies that we did on Stacey
0:24:55 showed that number one, she had no anti measles antibody detectable. She had, however, been
0:25:02 vaccinated as a child. And then she had lost her immunity and she’d been revaccinated after her
0:25:10 first stem cell transplant. The immunity had come back and she’d lost it again after the
0:25:16 second stem cell transplant. So, she had no antibodies to block the virus from getting
0:25:22 to the target. So, basically, her immune system was the same as the immune system of a person who
0:25:28 has never had measles and not been vaccinated for measles. Not quite, because we looked at her T cells,
0:25:34 the cells that come into the tumor and attack the virus infected cells.
0:25:43 And she had a very high level of anti measles T cells. As it turned out, this was a perfect
0:25:50 combination. Stacey didn’t have any antibodies. So, the measles virus was free to go into her body
0:25:57 and infect her tumor cells. But she did have anti measles T cells. So, once the measles infected
0:26:04 the tumor cells, those T cells could attack her tumor cells. So, now, she had both the measles
0:26:12 virus and her own T cells attacking and destroying the tumor. Stephen told me he learned a lot from
0:26:16 Stacey’s case and it helped him figure out how to move forward with his research.
0:26:23 Yeah. So, there are two pathways that we took. One was to switch to a different virus that people
0:26:31 do not have prior exposure to. And so, we started working with vesicular stomatitis virus, VSV,
0:26:36 which causes naturally a blistering illness in cattle.
0:26:44 So, that’s one way to get around the immunity to measles problem, right? You’re using a virus
0:26:50 that most people don’t get and are therefore not immune to. How is that going?
0:26:58 It’s going well. You know, it’s not in every cancer that we see anything, but the results that we
0:27:06 have at the moment are looking very promising in certain indications. The other approach we took
0:27:15 was to stealth measles virus so that it would still be measles virus. It would still be that
0:27:23 vaccine strain, but it would have a new coat that was no longer recognizable by circulating
0:27:31 antibodies. And so, in that situation, we would have a virus we could give systemically that would
0:27:38 penetrate the tumor and that would then be subject to attack by these T cells that exist
0:27:47 in people who’ve been measles immunized. Well, does it work? In mice. Okay, it’s a start. We
0:27:54 haven’t taken that one into human clinical tests yet. Let’s talk for a minute about using viruses
0:28:02 to treat cancer more broadly, right? People have been trying other viruses to treat other cancers.
0:28:08 What’s the state of the field more generally? There has been incremental progress and there
0:28:15 are viruses that are looking very promising in brain cancer injected into the brain tumor,
0:28:22 in bladder cancer instilled into the bladder, and I think many ongoing programs which
0:28:32 show great promise. So, I’m still a complete believer in the capability of viruses to really
0:28:39 bring a transformation in the approach to cancer therapy. I feel like it’s coming soon,
0:28:50 but not everybody agrees with me. I appreciate your time so much. It was great to talk with you.
0:28:55 Great talking with you too. Thank you very much. Stephen Russell founded the Department
0:29:01 of Molecular Medicine at the Mayo Clinic. He is currently the CEO of Viriad, a company that is
0:29:07 trying to use viruses to treat cancer. One last thing, Stephen told me that he’s still in touch
0:29:12 with Stacey Earholz, the patient who had multiple myeloma and went into complete remission after
0:29:20 being treated with measles. Stacey Earholz is a guiding light for me. I’m friends with her,
0:29:26 I’m in contact with her on a regular basis, and she’s got grandkids, she’s having a happy life,
0:29:32 she’s a very positive woman. Thanks to both of our guests today, Michael Mina and Stephen Russell.
0:29:38 Next week on the show, I talk to a scientist who discovered an entirely new kind of virus,
0:29:44 and it turns out this virus is everywhere. Boiling Springs Lake, deep sea sediments,
0:29:50 Korean air samples, monkey feces, dragonfly guts, soil just outside the lab at Portland
0:29:56 State University. Basically, anywhere that we have looked, we’ve found these cruci viruses.
0:30:03 Incubation is a co-production of Pushkin Industries and Ruby Studio at iHeart Media.
0:30:08 It’s produced by Kate Furby and Brittany Cronin. The show is edited by Lacey Roberts.
0:30:13 It’s mastered by Sarah Bruguere. Fact-checking by Joseph Friedman.
0:30:18 Our executive producers are Lacey Roberts and Matt Romano. I’m Jacob Goldstein, thanks for listening.
0:30:19 you
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