December 19, 2024 • 30 mins
We thought we knew everything there was to know about measles. But in recent years, new research has revealed that the virus attacks the immune system and creates effects far more dramatic than a rash and fever. For this episode we’re joined by Michael Mina, a former Harvard epidemiologist now at eMed, who helped discover how measles was causing “immune amnesia.” Our second guest is Stephen Russell, a former Mayo Clinic researcher who co-founded a company called Vyriad. Russell is trying to use the measles virus to treat cancer. Enjoy this episode from Incubation, another Pushkin podcast.
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Speaker 1 (00:15):
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,
(00:36):
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
(00:57):
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
(01:21):
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.
Speaker 2 (01:30):
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.
Speaker 1 (01:45):
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.
(02:07):
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
(02:28):
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.
Speaker 2 (02:47):
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
(03:07):
there something else at play?
Speaker 1 (03:09):
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.
Speaker 2 (03:19):
On, that's exactly right.
Speaker 1 (03:21):
Weird good thing, weird usually.
Speaker 2 (03:23):
That's right, A very weird good thing was going on.
Speaker 1 (03:26):
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?
Speaker 2 (03:40):
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
(04:02):
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
(04:24):
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.
Speaker 1 (04:38):
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.
Speaker 2 (04:48):
That's exactly right.
Speaker 1 (04:49):
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?
Speaker 2 (04:58):
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,
(05:21):
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
(05:42):
we see in the future.
Speaker 1 (05:44):
Is what you're finding that in some way measles is
attacking the kid's immune memory. Is that the hypothesis that follows.
Speaker 2 (05:52):
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
(06:13):
more vulnerable than they otherwise would have been to those
infections that they gained the immunity to when they were
two or three.
Speaker 1 (06:21):
So, okay, you have this hypothesis, how do you test it?
How do you investigate what's really going on?
Speaker 2 (06:28):
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
(06:49):
certain levels, there's going to be an.
Speaker 1 (06:51):
Outbreak below certain levels of vaccination.
Speaker 2 (06:53):
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
(07:18):
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
(07:41):
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.
Speaker 1 (07:55):
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.
Speaker 2 (08:06):
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,
(08:28):
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
(08:48):
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
(09:10):
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,
(09:35):
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
(09:59):
of those deaths could be attributed to the immune amnesia
associated with measles.
Speaker 1 (10:07):
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.
Speaker 2 (10:25):
I am so happy you asked that question.
Speaker 1 (10:28):
You're welcome.
Speaker 2 (10:29):
So, yes, it is. It's a much much harder thing
to measure.
Speaker 1 (10:35):
I mean, it's sort of like the reverse of herd
immunity in some weird broad spectrum way, right.
Speaker 2 (10:41):
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.
Speaker 1 (11:03):
Yeah, how about herd vulnerability. I want the opposite. What's
the opposite of herd.
Speaker 2 (11:08):
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
(11:30):
the measles vaccine, you create massive benefits in getting rid
of that herd vulnerability.
Speaker 1 (11:38):
So what's going on on a cellular level.
Speaker 2 (11:42):
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.
Speaker 1 (11:52):
I will, oh go, you got a minute if you
need it.
Speaker 2 (11:56):
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
(12:18):
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,
(12:42):
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
(13:03):
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.
Speaker 1 (13:21):
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?
Speaker 2 (13:41):
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.
Speaker 1 (14:00):
That is very compelling. That it's like a viralogical horror
movie inside your body.
Speaker 2 (14:06):
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
(14:29):
destroying a huge, huge population of very important cells inside
of our body.
Speaker 1 (14:35):
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?
Speaker 2 (14:53):
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,
(15:19):
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
(15:41):
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.
Speaker 1 (15:55):
It was great to talk with you. Thank you so
much for your time.
Speaker 2 (15:58):
Well, thank you so much. It was a lot of fun.
Speaker 1 (16:01):
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,
(16:23):
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
(16:47):
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,
(17:09):
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
(17:31):
in using retroviruses as possible cancer treatments. Then he told
me he turned his attention to measles.
Speaker 3 (17:38):
Yeah, well, measles became the next love.
Speaker 1 (17:40):
You fell in love with measles? Yeah, of course, why
do you fall in love with measles? Well?
Speaker 3 (17:46):
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
(18:08):
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.
Speaker 1 (18:31):
Burko lymphoma also caused by a virus, right, the first
tumor we knew was caused by a virus.
Speaker 3 (18:37):
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
(19:01):
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.
Speaker 1 (19:20):
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
(19:42):
infect non tumor.
Speaker 3 (19:43):
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.
Speaker 1 (19:54):
And is that just because those are easy cells to
grow because they liked to propagate.
Speaker 4 (19:58):
Yeah.
Speaker 3 (19:58):
Yeah, It's very, very difficult to grow non cancerous sects.
Speaker 1 (20:02):
Yeah, it's like the problem with cancer, right, it just
loves to divide.
Speaker 3 (20:06):
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
(20:27):
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.
Speaker 1 (20:54):
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
(21:15):
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.
Speaker 3 (21:26):
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
(21:48):
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.
(22:10):
I mean, there was nothing.
Speaker 1 (22:11):
She was going to die soon.
Speaker 3 (22:13):
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.
Speaker 1 (22:36):
Like, how much did she get compared to how much
somebody gets when they get the measles vaxing.
Speaker 3 (22:40):
It's about ten million doses of vaccine, okay.
Speaker 1 (22:43):
For this one person, So she's getting quite a lot.
And what happens.
Speaker 3 (22:48):
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
(23:10):
it had settled down.
Speaker 1 (23:11):
And is that essentially like a response to a massive infection.
She's essentially has this massive infection.
Speaker 3 (23:17):
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
(23:40):
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
(24:02):
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
(24:26):
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
(24:50):
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,
(25:14):
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.
Speaker 1 (25:26):
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.
Speaker 3 (25:34):
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.
Speaker 1 (25:50):
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
(26:12):
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.
Speaker 3 (26:26):
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.
Speaker 1 (26:45):
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?
Speaker 3 (26:59):
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.
(27:23):
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
(27:44):
to attack by these t cells that exist in people
who've been measles immunized.
Speaker 1 (27:51):
Well, does it work in mice? Okay, it's a start.
Speaker 3 (27:56):
We haven't taken that one into human clinical tests yet.
Speaker 1 (28:00):
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?
Speaker 3 (28:15):
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
(28:36):
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.
Speaker 1 (28:56):
I appreciate your time so much. It was great to
talk with you.
Speaker 3 (28:59):
Great talking with you too. Thank you very much.
Speaker 1 (29:02):
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.
Speaker 3 (29:23):
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.
Speaker 1 (29:38):
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.
Speaker 4 (29:51):
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.
Speaker 1 (30:07):
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.
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,
(00:36):
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
(00:57):
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
(01:21):
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.
Speaker 2 (01:30):
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.
Speaker 1 (01:45):
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.
(02:07):
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
(02:28):
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.
Speaker 2 (02:47):
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
(03:07):
there something else at play?
Speaker 1 (03:09):
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.
Speaker 2 (03:19):
On, that's exactly right.
Speaker 1 (03:21):
Weird good thing, weird usually.
Speaker 2 (03:23):
That's right, A very weird good thing was going on.
Speaker 1 (03:26):
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?
Speaker 2 (03:40):
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
(04:02):
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
(04:24):
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.
Speaker 1 (04:38):
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.
Speaker 2 (04:48):
That's exactly right.
Speaker 1 (04:49):
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?
Speaker 2 (04:58):
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,
(05:21):
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
(05:42):
we see in the future.
Speaker 1 (05:44):
Is what you're finding that in some way measles is
attacking the kid's immune memory. Is that the hypothesis that follows.
Speaker 2 (05:52):
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
(06:13):
more vulnerable than they otherwise would have been to those
infections that they gained the immunity to when they were
two or three.
Speaker 1 (06:21):
So, okay, you have this hypothesis, how do you test it?
How do you investigate what's really going on?
Speaker 2 (06:28):
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
(06:49):
certain levels, there's going to be an.
Speaker 1 (06:51):
Outbreak below certain levels of vaccination.
Speaker 2 (06:53):
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
(07:18):
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
(07:41):
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.
Speaker 1 (07:55):
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.
Speaker 2 (08:06):
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,
(08:28):
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
(08:48):
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
(09:10):
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,
(09:35):
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
(09:59):
of those deaths could be attributed to the immune amnesia
associated with measles.
Speaker 1 (10:07):
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.
Speaker 2 (10:25):
I am so happy you asked that question.
Speaker 1 (10:28):
You're welcome.
Speaker 2 (10:29):
So, yes, it is. It's a much much harder thing
to measure.
Speaker 1 (10:35):
I mean, it's sort of like the reverse of herd
immunity in some weird broad spectrum way, right.
Speaker 2 (10:41):
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.
Speaker 1 (11:03):
Yeah, how about herd vulnerability. I want the opposite. What's
the opposite of herd.
Speaker 2 (11:08):
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
(11:30):
the measles vaccine, you create massive benefits in getting rid
of that herd vulnerability.
Speaker 1 (11:38):
So what's going on on a cellular level.
Speaker 2 (11:42):
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.
Speaker 1 (11:52):
I will, oh go, you got a minute if you
need it.
Speaker 2 (11:56):
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
(12:18):
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,
(12:42):
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
(13:03):
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.
Speaker 1 (13:21):
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?
Speaker 2 (13:41):
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.
Speaker 1 (14:00):
That is very compelling. That it's like a viralogical horror
movie inside your body.
Speaker 2 (14:06):
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
(14:29):
destroying a huge, huge population of very important cells inside
of our body.
Speaker 1 (14:35):
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?
Speaker 2 (14:53):
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,
(15:19):
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
(15:41):
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.
Speaker 1 (15:55):
It was great to talk with you. Thank you so
much for your time.
Speaker 2 (15:58):
Well, thank you so much. It was a lot of fun.
Speaker 1 (16:01):
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,
(16:23):
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
(16:47):
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,
(17:09):
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
(17:31):
in using retroviruses as possible cancer treatments. Then he told
me he turned his attention to measles.
Speaker 3 (17:38):
Yeah, well, measles became the next love.
Speaker 1 (17:40):
You fell in love with measles? Yeah, of course, why
do you fall in love with measles? Well?
Speaker 3 (17:46):
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
(18:08):
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.
Speaker 1 (18:31):
Burko lymphoma also caused by a virus, right, the first
tumor we knew was caused by a virus.
Speaker 3 (18:37):
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
(19:01):
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.
Speaker 1 (19:20):
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
(19:42):
infect non tumor.
Speaker 3 (19:43):
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.
Speaker 1 (19:54):
And is that just because those are easy cells to
grow because they liked to propagate.
Speaker 4 (19:58):
Yeah.
Speaker 3 (19:58):
Yeah, It's very, very difficult to grow non cancerous sects.
Speaker 1 (20:02):
Yeah, it's like the problem with cancer, right, it just
loves to divide.
Speaker 3 (20:06):
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
(20:27):
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.
Speaker 1 (20:54):
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
(21:15):
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.
Speaker 3 (21:26):
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
(21:48):
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.
(22:10):
I mean, there was nothing.
Speaker 1 (22:11):
She was going to die soon.
Speaker 3 (22:13):
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.
Speaker 1 (22:36):
Like, how much did she get compared to how much
somebody gets when they get the measles vaxing.
Speaker 3 (22:40):
It's about ten million doses of vaccine, okay.
Speaker 1 (22:43):
For this one person, So she's getting quite a lot.
And what happens.
Speaker 3 (22:48):
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
(23:10):
it had settled down.
Speaker 1 (23:11):
And is that essentially like a response to a massive infection.
She's essentially has this massive infection.
Speaker 3 (23:17):
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
(23:40):
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
(24:02):
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
(24:26):
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
(24:50):
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,
(25:14):
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.
Speaker 1 (25:26):
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.
Speaker 3 (25:34):
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.
Speaker 1 (25:50):
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
(26:12):
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.
Speaker 3 (26:26):
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.
Speaker 1 (26:45):
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?
Speaker 3 (26:59):
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.
(27:23):
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
(27:44):
to attack by these t cells that exist in people
who've been measles immunized.
Speaker 1 (27:51):
Well, does it work in mice? Okay, it's a start.
Speaker 3 (27:56):
We haven't taken that one into human clinical tests yet.
Speaker 1 (28:00):
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?
Speaker 3 (28:15):
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
(28:36):
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.
Speaker 1 (28:56):
I appreciate your time so much. It was great to
talk with you.
Speaker 3 (28:59):
Great talking with you too. Thank you very much.
Speaker 1 (29:02):
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.
Speaker 3 (29:23):
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.
Speaker 1 (29:38):
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.
Speaker 4 (29:51):
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.
Speaker 1 (30:07):
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.
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