October 31, 2024 • 29 mins
Almost everyone on earth has Epstein-Barr virus. Usually it's pretty mild - you get sick, you get better. But the virus lives on in your body forever. Today, we talk with Dorothy Crawford (author of "Cancer Virus") about how one obsessive researcher uncovered a link between Epstein-Barr and cancer, and changed the way we think about viruses. Later in the show, we talk with Bill Robinson about his groundbreaking discovery of how Epstein-Barr can cause multiple sclerosis and other autoimmune diseases.
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Speaker 1 (00:00):
The epstein Bar virus infects almost everybody on Earth. For
the most part, it's relatively minor. Occasionally it causes mono.
You get sick, you get better. But it turns out
the epstein Bar virus EBV stays in our bodies forever,
and in some people, long after their initial infection, EBV
(00:21):
winds up causing cancer. In other people it causes multiple sclerosis,
which is not only scary, it's weird. When I think
of viral illness, I think you get infected with the virus,
maybe you get sick, your immune system responds, and most
of the time you get better. That's it. But EBV
(00:42):
isn't like that. And one lesson of EBV is maybe
we need to think differently about how viruses make us sick,
because sometimes they can hide out for decades and then
through a complicated and unlucky series of events, they can
do tremendous damage. I'm Jacob Goldstein, and this is Incubation,
(01:05):
a show about viruses. Today on the show epstein Bar,
let me just say a quick word about pronunciation. In
the US we say epstein bar. In the UK they
(01:26):
say epstein bar. You will hear both pronunciations in today's show.
The show as usual is in two parts. In the
second half of the show, we'll hear about this really
major breakthrough just from the last few years linking EBV
to multiple sclerosis and other autoimmune diseases. But first we're
(01:47):
going to go back to the nineteen sixties. At that time,
people knew that viruses could cause cancers in animals. In fact,
we talked about that last season in our episode about HPV.
In the sixties, no one had ever identified a virus
that caused cancer in people. There were some researchers who
(02:08):
thought such a thing might exist. One of those researchers
was a young British pathologist named Anthony Epstein.
Speaker 2 (02:15):
He was extraordinary, a one off, i would say.
Speaker 1 (02:18):
Dorothy Crawford was a grad student in Epstein's lab later
in the nineteen seventies, and she went on to co
write a book about him.
Speaker 2 (02:26):
He was supremely self confident. He was highly intelligent, he
was intuitive, he was persistent. He was somebody who's going
to find the bloody virus if he's.
Speaker 1 (02:35):
There, Dorothy says Epstein needed more than intelligence, confidence and
persistence to discover the link between viruses and cancer. She
says he needed some lucky breaks. Epstein's first big break,
according to Dorothy, was when a doctor named Dennis Burkett
just happened to give a lecture at the hospital where
Epstein worked.
Speaker 2 (02:55):
Dennis Burkett was a missionary doctor working in Uganda with children,
and he described these large tumors of the jaw that
was seemed to be very common among young children in
this particular area. He'd never seen anything like it before,
and neither had anybody else, and so he went on
(03:16):
a jeep ride around Africa to look at the epidemiology
of this tumor and tracking the geographical restriction of it.
The tumor only occurred where malaria was what we call
hyper endemic, so where malaria occurred all the year round
at the same level. And he thought, and many people thought,
(03:38):
that maybe it was caused by an infectious agent that
was transmitted by mosquitoes, because malaria is transmitted by mosquitoes.
Speaker 1 (03:47):
And Burkett gives a lecture at the hospital where Epstein
works talking about his work. That's right.
Speaker 2 (03:54):
It was the Middlesex hospital where Tony Epstein was working,
and Burkett came in nineteen sixty one to give a lecture,
and Tony Epstein just happened to see this notice on
a noticeboard and went along.
Speaker 1 (04:08):
You read in your book that Epstein hears this lecture
and he thinks, you know, this may be it, This
may be the tumor that is caused by a virus.
So what does he do next? What does he do
after he hears this lecture?
Speaker 2 (04:21):
That very day he approached Burkett and asked him if
he could send samples of the tumor to the Middlesex
Hospital for him to study. And I mean, it's all
very well to just say it like that, And they
started arriving. But you know, getting a fresh tumor biopsy
from Uganda to the Middlesex Hospital in time for it
(04:42):
not to have died, the cells to have died, it's
a mean feat on its own, despite everything else. In
the mid sixties, exactly in the mid sixties.
Speaker 1 (04:51):
Yes, So they start arriving every week, Yes, and Tony
Epstein starts looking at them, right, he wants to find
some path that is causing this tumor. Right, So what
does he start doing.
Speaker 2 (05:05):
Well, they were chunks of tumor and he straightway fixed
them for the electron microscope. So that he could look
at them under the electron microscope. And I just have
to add that, I mean, it was dead lucky that
the medal Sex had an electron microscope, but because at
that time, you know, those machines were like gold dust
and they're incredibly expensive. But pathology at the Middlesex Hospital
(05:28):
had one and Tony had access to it, and so
he started off preparing them and just looking at the
cells and seeing if he could see any viruses in them.
And the answer is he couldn't.
Speaker 1 (05:39):
He couldn't. Why not? What was going on?
Speaker 2 (05:43):
Because there weren't any no virus particles to see in
the cells. And so he also put them into tissue
culture to see if he could grow the cells, and
he couldn't.
Speaker 1 (05:56):
Just to be clear, is the idea that like, maybe
there were some very small number of virus particles in
the tumor cells, and if you could you grow a
bunch more cells, you could also get more virus particles
so they'd be easier to see.
Speaker 2 (06:08):
Yes, that they might increase the number of virus carrying cells,
but they didn't. He just basically spent three years getting
native results all the way through.
Speaker 1 (06:18):
So three years three years is a long time it
is to look and not see. I mean, it would
be reasonable to conclude, oh, my hypothesis was incorrect, this
tumor is not caused by a virus. Like, why doesn't
he come to that conclusion?
Speaker 2 (06:35):
He would never do that to Every time you asked
him why he did it, he said, because I just
knew it was right. That's what he always said. It
had to be right.
Speaker 1 (06:47):
So it's during this period, right that Yvonne Barr comes
to work with Tony Epstein, and she of course becomes
the other half of Epstein Bar. So tell me about her.
Speaker 2 (06:57):
Well, she joined a bit later, I mean as the
three years were coming to an end, so she was
virtually there when the breakthrough came. She was a scientist
from Ireland and her job was to set these cells
up in culture. So he looked at them under the
electron microscope and he also put them into culture, and
(07:19):
as I've already said, nothing grew. But that was her
job anyway.
Speaker 1 (07:23):
Huh So three years in nothing, nothing, nothing? Then what happened? Then?
Speaker 2 (07:29):
What happened was fog fog fog.
Speaker 1 (07:33):
A common occurrence in London.
Speaker 2 (07:35):
I'm told fog fog?
Speaker 1 (07:38):
Yes, why is fog? Why is fog important.
Speaker 2 (07:42):
Why, because it delayed the flight that the sample was
coming in on. And he throw is particularly low lying
and particularly prone to fog, and so they diverted the
plane to Manchester. Obviously, it arrived late. It was a
Friday afternoon. Everybody had gone home except on He waited
for it, and when he got it into the lab,
(08:04):
it came in a bottle of transport medium, as we
call it, and he held it up to the light
and it was all cloudy, and that means to everybody
that it was contaminated with bacteria. And because the temple
had been delayed, these bacteria had grown in the culture
and it would be useless.
Speaker 1 (08:23):
An urmal person would throw it out and wait for
the sample next week.
Speaker 2 (08:27):
Yes, but Tony didn't do that. He'd got some of
the sample out, looked at it under the microscope and
did not see any bacteria. He saw free floating tumor cells.
And so for the first time ever, he put the
free floating cells into a culture. Previously, he'd been putting
lumps of tumor into the culture, but there weren't any
(08:51):
lumps this time. They'd all shape, the cells had all
shaken free on the journey.
Speaker 1 (08:55):
So okay, so he finally now can see the cells,
he can culture the cells, which he's been on able
to do before.
Speaker 2 (09:01):
What happened, well, very soon he had enough cells to
look at them under the electron microscope, and he looked
down the microscope and in the very first grid that
he looked at, he saw viruses.
Speaker 1 (09:13):
He saw a virus, this thing that he's been looking
for and not seeing for three years. Yes, there it is.
Speaker 2 (09:19):
In the very first grid square he saw viruses. And
he knew immediately that they were herpes viruses by the
shape of the virus particles. And he says that he
was so excited. He was afraid, you know, he's going
to do something wrong, very unusual for Tony, I might say.
So he switched the microscope off, went for a walk
(09:40):
around the block in the snow, and then came back
and turned it on again and made sure that they
were still there, and they were.
Speaker 1 (09:47):
Wow. You imagine like his hands are shaking or something.
He's afraid he's going to knock it down or something.
Speaker 2 (09:52):
I suppose, yes, or that he's seeing things. And I
can tell you that we now know that only about
one percent at most of cells in those cell lines
contain virus particles.
Speaker 1 (10:04):
You're telling me there's a one in one hundred chants
that he would see it in the first grid.
Speaker 2 (10:08):
Yes, I am telling you that. Yes, I mean, you know,
it's ridiculous, but that's what happened.
Speaker 1 (10:14):
So, I mean, this is this is a big moment, right,
This is him seeming to find the link between a
virus and a tumor.
Speaker 2 (10:20):
Yes, but nobody believed it. I mean, I don't suppose
I would have believed it either, to be honest.
Speaker 1 (10:27):
Why not? Why wouldn't you have believed it?
Speaker 2 (10:30):
Because it's so ridiculous?
Speaker 1 (10:32):
Tell me more what I don't why why ridiculous?
Speaker 2 (10:35):
Well, because at that time, viruses were known to cause
things like flu and measles and mumps, you know, and
not tumors. I mean it just I can understand why
people just did not believe it.
Speaker 1 (10:48):
It does feel that way, right, And I guess also
the fact that there can be, certainly with some viruses
and tumors, a long latency period between infection and the
development of the tumor also, I guess makes it harder
to believe, right, I mean, harder to prove causality, Like
if you know, if you got spots all over your
(11:09):
body and then suddenly developed a tumor and be like, oh, okay,
I get it, that's the virus. But this doesn't work
that way.
Speaker 2 (11:15):
Right, Oh, no, it definitely doesn't. And I mean, okay,
in berkelnfoma, there's a long incubation period. And what that
means is that there must be other factors. The virus
is not the only thing needed to cause the tumor.
You need other things. And of course the obvious thing
in this case is malaria, which immuno suppresses the children
(11:39):
and causes them to be you know, more susceptible to
this virus.
Speaker 1 (11:43):
Aha. So that explains that original link between the tumor
and the geographic areas where malaria is especially prevalent. Yes,
So tell me about the rest of Tony Epstein's he
makes this big discovery, people don't believe him. Eventually they
(12:04):
do believe him. How does his career play out?
Speaker 2 (12:07):
Well, he was nothing if not single minded.
Speaker 1 (12:10):
You know, he was.
Speaker 2 (12:12):
Persistent in what he did. He never gave up. He
was highly self confident, and he was also an obsessional worker.
And so you know, as soon as he in his
own mind believed that this was a tumor virus. He
knew that what he had to do was make a
vaccine to stop the tumor.
Speaker 1 (12:33):
Right, it follows, right, Oh my god, we can prevent
cancer with the vaccine, yep.
Speaker 2 (12:38):
So it's a totally direct way of thinking, and he
just went for it. So you know, we're still on
a learning curve, frankly, and Tony was part of the
learning curve and had a huge, huge impact.
Speaker 1 (12:54):
I really appreciate your time of truly fascinating conversation. Thank
you so much, No problem. Dorothy Crawford is a retired
professor of medical microbiology and co author of the book
Cancer Virus, The Story of Epstein Barr Virus. Today, there
is still no vaccine for EBV, but people are working
on it. Since Epstein's original discovery, EBV has also been
(13:17):
linked to other forms of cancer, including Hodgkin's disease and
cancers of the nose, throat, and stomach. Epstein died earlier
this year at the age of one hundred and two.
As for Yvon Barr, she moved to Australia in nineteen
sixty six and became a high school math and science teacher.
She died in twenty sixteen, at age eighty three. We'll
(13:39):
be back in a minute to discuss new research linking
EBV to multiple sclerosis. It's been clear for decades now
that EBV causes certain cancers, and there's been speculation that
(14:00):
the virus may also be linked to multiple sclerosis and
other autoimmune diseases, but until recently, that's all it was speculation.
Bill Robinson is a professor of medicine and chief of
the Division of Immunology and Rheumatology at Stanford. He specializes
in autoimmune diseases, and he says for a long time
(14:21):
he and his colleagues didn't really buy the idea that
EBV causes MS.
Speaker 3 (14:27):
We had dismissed it as epiphenomena, meaning ninety four percent
of all humans are infected with EBV, and how could
it actually be the cause of MASS given only about
one in nine hundred people developed mass.
Speaker 1 (14:42):
Was that your own view?
Speaker 3 (14:43):
That was definitely my view.
Speaker 1 (14:45):
Basically, almost everybody has EBV, almost nobody has MS. There's
no way there can be a cause of link. The
numbers just don't make sense exactly. So this idea is
out there for decades really, and only just in the
last couple of years, right in twenty twenty two, there
were two studies that really seemed compellingly to demonstrate a
(15:11):
link between epstein barvirus and multiple sclerosis. And I want
to talk about both studies. Of course, I want to
talk about the study you did, but before we get
to that, let's talk about the other study. Let's talk
about the epidemiological study. Tell me about that work.
Speaker 3 (15:27):
Yes, so, in the military, people are getting tested every
several years for HIV disease and other things, and the
military has banked samples from those collections. And Alberto Asherio
at Harvard School of Public Health, who's been a leader
in the field on the association of epstein bar virus
(15:50):
with multiple scrosis, completed a lot of paperwork and went
through a lot of regulatory requirements and with that received
blood samples that were did from individuals who developed multiple scrosis,
either in the military or following service, and basically use
these to show that essentially everybody who developed MS was
(16:14):
infected with EBV prior to developing MS. Huh More, specifically,
they had eight hundred one patients total, and eight hundred
out of the eight hundred and one, so ninety nine
point nine percent were infected with EBV before they developed
clinical multiple scrosis.
Speaker 1 (16:36):
So that study shows very elegantly and very compellingly that
EBV is basically necessary but not sufficient to get MS.
It doesn't tell us anything about why, about the mechanism,
about what's going on, and that's what your work tells us,
and I want to get to that, but before we do,
let's just talk briefly about multiple sclerosis as a disease,
(16:57):
both what happens to patients and also so well what
happens to patients sort of clinically and then what happens
at the cellular level tell me about multiple sclerosis.
Speaker 3 (17:06):
Yeah, so, in MS, the immune system attacks the milin sheath,
which is the insulating coating on neurons, and it's essential
for effective nerve conduction and thus sensation and you know,
muscle movement. I think of the milin sheath as you know,
(17:26):
the equivalent of the insulation around a wire. If you
cut the insulation on a wire, it's short circuits and
doesn't conduct. And likewise, if the immune system attacks and
damages the milin sheath on individual nerves, those nerves also
won't conduct. In us won't receive sensory signals or be
able to transmit signals to activate muscles in thus move.
Speaker 1 (17:50):
So okay, so this is what goes wrong in patients
who have multiple sclerosis. Their own immune system attacks the
milin sheath that's for their nerves. When you set out
to study the role of EBV and MS, what are
you what's your hypothesis?
Speaker 3 (18:11):
We were very focused on taking the B cells from
human multiple scrosis patients and then isolating the specific individual
antibodies produced by each B cell.
Speaker 1 (18:24):
A B cell is a cell that's part of the
immune system, right, So you're looking at the antibodies produced
by the B cells in a multiple sclerosis patient.
Speaker 3 (18:33):
Yes, And to our great surprise, many of the antibodies
were antibodies against viruses, of which EBV was a prominent virus.
Speaker 1 (18:44):
Huh. So, in a sense, these are immune cells doing
what immune cells are supposed to do. They're creating antibodies
to attack pathogens.
Speaker 3 (18:54):
And protect that individual against you know, viral pathogens such
as E as well as other herpes viruses.
Speaker 1 (19:02):
When you put it that way, seems good, right, Oh great,
there's a virus has infected my body. My immune cells
are creating antibodies to attack that virus. That's what's supposed
to happen. Where does it go wrong?
Speaker 3 (19:17):
So we discovered that some B cells made antibodies that
not only bound to EBV, but they cross bound to
human milin, meaning that.
Speaker 1 (19:28):
The same antibody could essentially attack both the epstein bar
virus and the patient's own the person's own milin.
Speaker 3 (19:38):
That's correct.
Speaker 1 (19:40):
So was there like a specific moment when you realize
that MS patients have these antibodies that attack both EBV
and their own milin.
Speaker 3 (19:50):
The lead author, Toby Lance on our Nature paper emailed
and called when he first found that these antibodies that
we had isolated from human MS patients spinal fluid B
cells when he found that they bound EBV. The email
may call me and they're like, Bill, they're reactive with EBV,
(20:11):
and I think we were both shocked.
Speaker 1 (20:13):
Yeah, what'd you say? What'd you think when you got
that call?
Speaker 3 (20:17):
I was floored. I couldn't believe it, and I was like, wow,
this is real. Because it's one thing to be statistically
or epidemiologically associated, and a second component is to have
a mechanistic basis, And our work provided the mechanistic basis
(20:39):
by which EBV was causing a subset of MS and
thus enables people to further believe the statistical finding that
it's strongly associated.
Speaker 1 (20:49):
So I know that your study applies to something like
a quarter of MS patients. And then, as I understand it,
there's other researchers that shows similar things, quite similar things
going on in other patients, essentially antibodies that bind you know,
both the EBV and tamiolin. Is that right?
Speaker 3 (21:10):
Yes, there's several groups studying other antigens that are mimicked
by EBV, including our own. And it turns out that
EBV infections also associated with other diseases such as systemic
loopus or SL and it's also associated with rheumatoid arthritis.
Speaker 1 (21:29):
So these are all autoimmune disease, these diseases where the
body's immune system is attacking itself. Basically, yes, I mean
is this like, are we right now? Are you right
now finding the answer to this question that people have
been asking for whatever fifty years, eighty years, like, are
you finding the virus that is causing autoimmune diseases?
Speaker 3 (21:54):
We believe we are, and we are performing experiments to
further bear out the mechanisms that would encompass one hundred
percent of MS and as well as of lupus and
other autoimmune diseases that are EBV associated.
Speaker 1 (22:10):
And just to be clear, in these other autoimmune diseases,
what are the immune cells? What are the antibodies attacking?
Speaker 3 (22:20):
In the other autoimmune diseases, They're not attacking myelin' They're
attacking their corresponding tissue anogens. So in loopus, the immune
system attacks the nucleus of cells and also the kidney.
In rheumatoid arthritis it attacks the joints.
Speaker 1 (22:38):
So I mean, why does this one virus, EBV, Why
does this one virus cause us to make antibodies that
attack so many different parts of the body, Like, what's
going on?
Speaker 3 (22:51):
You know? I think we don't know. We only you know,
hypothesize and speculate. My sense is that given EBV as
a herpes virus that's present in a person's B cells
as well as epithelial cells for life, and that it's
transiently reactivating on a periodic basis, that those properties make
(23:13):
it reimmunize the individual multiple times repeatedly over the courses
of their life.
Speaker 1 (23:20):
So basically, most people get this virus when they're a kid. Right,
So you have this virus not just in your body
for your whole life, but in your B cells, in
your immune cells, and it periodically sort of turns back
on basically and causes an immune response. And it's the
idea that it's happening again and again and again. That's
(23:41):
fundamentally the problem.
Speaker 3 (23:42):
I think that that's contributing to the problem.
Speaker 1 (23:46):
Almost everybody gets EBV, has EBV. Very few people get
autoimmune diseases, certainly relative to the share of people who
get EBV. What's going on there? Like, why do only
some people get autoimmune diseases if we all have EBV.
Speaker 3 (24:03):
Yeah, that's the big question, and that's why more than
five years ago we were skeptics that there was any
relationship between EBV and MS or these other autoimmune diseases
like lupus.
Speaker 1 (24:16):
Well, so presumably it's sort of necessary but not sufficient, right,
Like you need to have EBV and something else or
in some other set of phenomenon, characteristics, risk factors, whatever
to develop autoimmune disorders? Do you have a sense of
what the other things are.
Speaker 3 (24:37):
Recently, investigators in Germany Christian Muntz is showing that some
of these classic multiple sclerosis. Genetic risk factors are actually
risk factors for inability to mount a robust T cell
response to EBV. So they're basically preventing you from having
a T cell response that controls the EBV and that's
(25:00):
known to be associated with more rounds of reactivation.
Speaker 1 (25:04):
Huh. So, just to be clear, T cells are are
an immune cell. And so basically this finding is if
your body is bad at controlling EBV, if you're genetically
bad at controlling EBV, you are more likely to get MS.
And that makes sense because if you're bad at controlling EBV,
it's gonna you can have more sort of outbreaks within
(25:25):
your body of EBV and you're gonna have more rounds
of this kind of mutation of antibodies.
Speaker 3 (25:30):
Yes, let me give you another recent developments that's profound.
Speaker 1 (25:35):
Okay.
Speaker 3 (25:37):
A investigator in Germany, professor yorg Chet, gave human lupus
patients that had refractory disease that was refractory to all therapies.
Speaker 1 (25:49):
Refractory meaning treatment doesn't work.
Speaker 3 (25:50):
Treatment doesn't work. Yeah, he gave them a cancer drug
that completely depletes their B cells in a profound deep depletion.
So to get this drug, you have to be admitted
to the hospital for two weeks and receive chemotherapy for
a Boemero transplant, and then you receive this drug that
(26:11):
attacks all the B cells and removes them all from
the body.
Speaker 1 (26:14):
So this is like a hardcore, nasty cancer drug.
Speaker 3 (26:18):
Yes, okay, but he effectively cured these lupus patients.
Speaker 1 (26:24):
Huh.
Speaker 3 (26:25):
They're now three years out off all therapies, completely healthy.
Speaker 1 (26:31):
So is the basic idea that if you destroy all
of the B cells, these B cells that have evolved
essentially in a way that is causing them to attack
the body, get well, they're extinct. You basically make them
go extinct and you get to start again. Is that the.
Speaker 3 (26:49):
Idea there, exactly? And they term it an immune reset,
which I believe it is because after this Boemere transplant
type of B cell depletion merges our naive B cells
and then those repopulate the whole repertoire.
Speaker 1 (27:04):
Yeah, you're starting from scratch, you get to start over, Yes,
and the finding suggest that when you start from scratch,
you get better. Your new B cells are not creating
antibodies that attack your own body, if I understand.
Speaker 3 (27:17):
Correctly, that's correct. But you also have to rego through
all of your childhood infections and vaccines.
Speaker 1 (27:24):
Oh right, so it's just carpet bomb. You're just carpet
bombing the B cells. You're not immune to anything anymore.
Speaker 3 (27:32):
That's correct. You're starting from scratch, But compared to having
bad lupus or bad autoimmune disease, it's a huge win
for the individual patient.
Speaker 1 (27:42):
So what you want, presumably in the same way, we
have developed targeted cancer therapy, so you don't have to
carpet bomb whatever rapidly dividing cells. It seems like if
you could just target the B cells you don't like
and let all the other B cells be, that.
Speaker 3 (27:57):
Would be great, absolutely, and we're working hard to develop
therapeutic approaches that would do exactly that.
Speaker 1 (28:07):
Thank you so much for your time. I really appreciate
it great.
Speaker 3 (28:09):
Thanks for featuring EBV in our work.
Speaker 1 (28:14):
Bill Robinson is a professor of medicine and chief of
the Division of Immunology and Rheumatology at Stanford. Thanks to
my guest today, Dorothy Crawford and Bill Robinson next week
on incubation. Why did he jump on the boat or
train or boat and train or whatever and go to
this remote island in the North Sea.
Speaker 2 (28:36):
Why did he do that?
Speaker 1 (28:37):
A family doctor goes to great lengths to figure out
the relationship between chicken pox and shingles. Incubation is a
co production of Pushkin Industries and Ruby Studio at iHeartMedia.
It's produced by Kate Ferby and Brittany Cronin. The show
is edited by Lacy Roberts. It's mastered by Sarah Bruguier,
(28:58):
fact checking by Joseph Friedman. Our executive producers are Lacy
Roberts and Matt Roman. I'm Jacob Goldstein. Thanks for listening.
The epstein Bar virus infects almost everybody on Earth. For
the most part, it's relatively minor. Occasionally it causes mono.
You get sick, you get better. But it turns out
the epstein Bar virus EBV stays in our bodies forever,
and in some people, long after their initial infection, EBV
(00:21):
winds up causing cancer. In other people it causes multiple sclerosis,
which is not only scary, it's weird. When I think
of viral illness, I think you get infected with the virus,
maybe you get sick, your immune system responds, and most
of the time you get better. That's it. But EBV
(00:42):
isn't like that. And one lesson of EBV is maybe
we need to think differently about how viruses make us sick,
because sometimes they can hide out for decades and then
through a complicated and unlucky series of events, they can
do tremendous damage. I'm Jacob Goldstein, and this is Incubation,
(01:05):
a show about viruses. Today on the show epstein Bar,
let me just say a quick word about pronunciation. In
the US we say epstein bar. In the UK they
(01:26):
say epstein bar. You will hear both pronunciations in today's show.
The show as usual is in two parts. In the
second half of the show, we'll hear about this really
major breakthrough just from the last few years linking EBV
to multiple sclerosis and other autoimmune diseases. But first we're
(01:47):
going to go back to the nineteen sixties. At that time,
people knew that viruses could cause cancers in animals. In fact,
we talked about that last season in our episode about HPV.
In the sixties, no one had ever identified a virus
that caused cancer in people. There were some researchers who
(02:08):
thought such a thing might exist. One of those researchers
was a young British pathologist named Anthony Epstein.
Speaker 2 (02:15):
He was extraordinary, a one off, i would say.
Speaker 1 (02:18):
Dorothy Crawford was a grad student in Epstein's lab later
in the nineteen seventies, and she went on to co
write a book about him.
Speaker 2 (02:26):
He was supremely self confident. He was highly intelligent, he
was intuitive, he was persistent. He was somebody who's going
to find the bloody virus if he's.
Speaker 1 (02:35):
There, Dorothy says Epstein needed more than intelligence, confidence and
persistence to discover the link between viruses and cancer. She
says he needed some lucky breaks. Epstein's first big break,
according to Dorothy, was when a doctor named Dennis Burkett
just happened to give a lecture at the hospital where
Epstein worked.
Speaker 2 (02:55):
Dennis Burkett was a missionary doctor working in Uganda with children,
and he described these large tumors of the jaw that
was seemed to be very common among young children in
this particular area. He'd never seen anything like it before,
and neither had anybody else, and so he went on
(03:16):
a jeep ride around Africa to look at the epidemiology
of this tumor and tracking the geographical restriction of it.
The tumor only occurred where malaria was what we call
hyper endemic, so where malaria occurred all the year round
at the same level. And he thought, and many people thought,
(03:38):
that maybe it was caused by an infectious agent that
was transmitted by mosquitoes, because malaria is transmitted by mosquitoes.
Speaker 1 (03:47):
And Burkett gives a lecture at the hospital where Epstein
works talking about his work. That's right.
Speaker 2 (03:54):
It was the Middlesex hospital where Tony Epstein was working,
and Burkett came in nineteen sixty one to give a lecture,
and Tony Epstein just happened to see this notice on
a noticeboard and went along.
Speaker 1 (04:08):
You read in your book that Epstein hears this lecture
and he thinks, you know, this may be it, This
may be the tumor that is caused by a virus.
So what does he do next? What does he do
after he hears this lecture?
Speaker 2 (04:21):
That very day he approached Burkett and asked him if
he could send samples of the tumor to the Middlesex
Hospital for him to study. And I mean, it's all
very well to just say it like that, And they
started arriving. But you know, getting a fresh tumor biopsy
from Uganda to the Middlesex Hospital in time for it
(04:42):
not to have died, the cells to have died, it's
a mean feat on its own, despite everything else. In
the mid sixties, exactly in the mid sixties.
Speaker 1 (04:51):
Yes, So they start arriving every week, Yes, and Tony
Epstein starts looking at them, right, he wants to find
some path that is causing this tumor. Right, So what
does he start doing.
Speaker 2 (05:05):
Well, they were chunks of tumor and he straightway fixed
them for the electron microscope. So that he could look
at them under the electron microscope. And I just have
to add that, I mean, it was dead lucky that
the medal Sex had an electron microscope, but because at
that time, you know, those machines were like gold dust
and they're incredibly expensive. But pathology at the Middlesex Hospital
(05:28):
had one and Tony had access to it, and so
he started off preparing them and just looking at the
cells and seeing if he could see any viruses in them.
And the answer is he couldn't.
Speaker 1 (05:39):
He couldn't. Why not? What was going on?
Speaker 2 (05:43):
Because there weren't any no virus particles to see in
the cells. And so he also put them into tissue
culture to see if he could grow the cells, and
he couldn't.
Speaker 1 (05:56):
Just to be clear, is the idea that like, maybe
there were some very small number of virus particles in
the tumor cells, and if you could you grow a
bunch more cells, you could also get more virus particles
so they'd be easier to see.
Speaker 2 (06:08):
Yes, that they might increase the number of virus carrying cells,
but they didn't. He just basically spent three years getting
native results all the way through.
Speaker 1 (06:18):
So three years three years is a long time it
is to look and not see. I mean, it would
be reasonable to conclude, oh, my hypothesis was incorrect, this
tumor is not caused by a virus. Like, why doesn't
he come to that conclusion?
Speaker 2 (06:35):
He would never do that to Every time you asked
him why he did it, he said, because I just
knew it was right. That's what he always said. It
had to be right.
Speaker 1 (06:47):
So it's during this period, right that Yvonne Barr comes
to work with Tony Epstein, and she of course becomes
the other half of Epstein Bar. So tell me about her.
Speaker 2 (06:57):
Well, she joined a bit later, I mean as the
three years were coming to an end, so she was
virtually there when the breakthrough came. She was a scientist
from Ireland and her job was to set these cells
up in culture. So he looked at them under the
electron microscope and he also put them into culture, and
(07:19):
as I've already said, nothing grew. But that was her
job anyway.
Speaker 1 (07:23):
Huh So three years in nothing, nothing, nothing? Then what happened? Then?
Speaker 2 (07:29):
What happened was fog fog fog.
Speaker 1 (07:33):
A common occurrence in London.
Speaker 2 (07:35):
I'm told fog fog?
Speaker 1 (07:38):
Yes, why is fog? Why is fog important.
Speaker 2 (07:42):
Why, because it delayed the flight that the sample was
coming in on. And he throw is particularly low lying
and particularly prone to fog, and so they diverted the
plane to Manchester. Obviously, it arrived late. It was a
Friday afternoon. Everybody had gone home except on He waited
for it, and when he got it into the lab,
(08:04):
it came in a bottle of transport medium, as we
call it, and he held it up to the light
and it was all cloudy, and that means to everybody
that it was contaminated with bacteria. And because the temple
had been delayed, these bacteria had grown in the culture
and it would be useless.
Speaker 1 (08:23):
An urmal person would throw it out and wait for
the sample next week.
Speaker 2 (08:27):
Yes, but Tony didn't do that. He'd got some of
the sample out, looked at it under the microscope and
did not see any bacteria. He saw free floating tumor cells.
And so for the first time ever, he put the
free floating cells into a culture. Previously, he'd been putting
lumps of tumor into the culture, but there weren't any
(08:51):
lumps this time. They'd all shape, the cells had all
shaken free on the journey.
Speaker 1 (08:55):
So okay, so he finally now can see the cells,
he can culture the cells, which he's been on able
to do before.
Speaker 2 (09:01):
What happened, well, very soon he had enough cells to
look at them under the electron microscope, and he looked
down the microscope and in the very first grid that
he looked at, he saw viruses.
Speaker 1 (09:13):
He saw a virus, this thing that he's been looking
for and not seeing for three years. Yes, there it is.
Speaker 2 (09:19):
In the very first grid square he saw viruses. And
he knew immediately that they were herpes viruses by the
shape of the virus particles. And he says that he
was so excited. He was afraid, you know, he's going
to do something wrong, very unusual for Tony, I might say.
So he switched the microscope off, went for a walk
(09:40):
around the block in the snow, and then came back
and turned it on again and made sure that they
were still there, and they were.
Speaker 1 (09:47):
Wow. You imagine like his hands are shaking or something.
He's afraid he's going to knock it down or something.
Speaker 2 (09:52):
I suppose, yes, or that he's seeing things. And I
can tell you that we now know that only about
one percent at most of cells in those cell lines
contain virus particles.
Speaker 1 (10:04):
You're telling me there's a one in one hundred chants
that he would see it in the first grid.
Speaker 2 (10:08):
Yes, I am telling you that. Yes, I mean, you know,
it's ridiculous, but that's what happened.
Speaker 1 (10:14):
So, I mean, this is this is a big moment, right,
This is him seeming to find the link between a
virus and a tumor.
Speaker 2 (10:20):
Yes, but nobody believed it. I mean, I don't suppose
I would have believed it either, to be honest.
Speaker 1 (10:27):
Why not? Why wouldn't you have believed it?
Speaker 2 (10:30):
Because it's so ridiculous?
Speaker 1 (10:32):
Tell me more what I don't why why ridiculous?
Speaker 2 (10:35):
Well, because at that time, viruses were known to cause
things like flu and measles and mumps, you know, and
not tumors. I mean it just I can understand why
people just did not believe it.
Speaker 1 (10:48):
It does feel that way, right, And I guess also
the fact that there can be, certainly with some viruses
and tumors, a long latency period between infection and the
development of the tumor also, I guess makes it harder
to believe, right, I mean, harder to prove causality, Like
if you know, if you got spots all over your
(11:09):
body and then suddenly developed a tumor and be like, oh, okay,
I get it, that's the virus. But this doesn't work
that way.
Speaker 2 (11:15):
Right, Oh, no, it definitely doesn't. And I mean, okay,
in berkelnfoma, there's a long incubation period. And what that
means is that there must be other factors. The virus
is not the only thing needed to cause the tumor.
You need other things. And of course the obvious thing
in this case is malaria, which immuno suppresses the children
(11:39):
and causes them to be you know, more susceptible to
this virus.
Speaker 1 (11:43):
Aha. So that explains that original link between the tumor
and the geographic areas where malaria is especially prevalent. Yes,
So tell me about the rest of Tony Epstein's he
makes this big discovery, people don't believe him. Eventually they
(12:04):
do believe him. How does his career play out?
Speaker 2 (12:07):
Well, he was nothing if not single minded.
Speaker 1 (12:10):
You know, he was.
Speaker 2 (12:12):
Persistent in what he did. He never gave up. He
was highly self confident, and he was also an obsessional worker.
And so you know, as soon as he in his
own mind believed that this was a tumor virus. He
knew that what he had to do was make a
vaccine to stop the tumor.
Speaker 1 (12:33):
Right, it follows, right, Oh my god, we can prevent
cancer with the vaccine, yep.
Speaker 2 (12:38):
So it's a totally direct way of thinking, and he
just went for it. So you know, we're still on
a learning curve, frankly, and Tony was part of the
learning curve and had a huge, huge impact.
Speaker 1 (12:54):
I really appreciate your time of truly fascinating conversation. Thank
you so much, No problem. Dorothy Crawford is a retired
professor of medical microbiology and co author of the book
Cancer Virus, The Story of Epstein Barr Virus. Today, there
is still no vaccine for EBV, but people are working
on it. Since Epstein's original discovery, EBV has also been
(13:17):
linked to other forms of cancer, including Hodgkin's disease and
cancers of the nose, throat, and stomach. Epstein died earlier
this year at the age of one hundred and two.
As for Yvon Barr, she moved to Australia in nineteen
sixty six and became a high school math and science teacher.
She died in twenty sixteen, at age eighty three. We'll
(13:39):
be back in a minute to discuss new research linking
EBV to multiple sclerosis. It's been clear for decades now
that EBV causes certain cancers, and there's been speculation that
(14:00):
the virus may also be linked to multiple sclerosis and
other autoimmune diseases, but until recently, that's all it was speculation.
Bill Robinson is a professor of medicine and chief of
the Division of Immunology and Rheumatology at Stanford. He specializes
in autoimmune diseases, and he says for a long time
(14:21):
he and his colleagues didn't really buy the idea that
EBV causes MS.
Speaker 3 (14:27):
We had dismissed it as epiphenomena, meaning ninety four percent
of all humans are infected with EBV, and how could
it actually be the cause of MASS given only about
one in nine hundred people developed mass.
Speaker 1 (14:42):
Was that your own view?
Speaker 3 (14:43):
That was definitely my view.
Speaker 1 (14:45):
Basically, almost everybody has EBV, almost nobody has MS. There's
no way there can be a cause of link. The
numbers just don't make sense exactly. So this idea is
out there for decades really, and only just in the
last couple of years, right in twenty twenty two, there
were two studies that really seemed compellingly to demonstrate a
(15:11):
link between epstein barvirus and multiple sclerosis. And I want
to talk about both studies. Of course, I want to
talk about the study you did, but before we get
to that, let's talk about the other study. Let's talk
about the epidemiological study. Tell me about that work.
Speaker 3 (15:27):
Yes, so, in the military, people are getting tested every
several years for HIV disease and other things, and the
military has banked samples from those collections. And Alberto Asherio
at Harvard School of Public Health, who's been a leader
in the field on the association of epstein bar virus
(15:50):
with multiple scrosis, completed a lot of paperwork and went
through a lot of regulatory requirements and with that received
blood samples that were did from individuals who developed multiple scrosis,
either in the military or following service, and basically use
these to show that essentially everybody who developed MS was
(16:14):
infected with EBV prior to developing MS. Huh More, specifically,
they had eight hundred one patients total, and eight hundred
out of the eight hundred and one, so ninety nine
point nine percent were infected with EBV before they developed
clinical multiple scrosis.
Speaker 1 (16:36):
So that study shows very elegantly and very compellingly that
EBV is basically necessary but not sufficient to get MS.
It doesn't tell us anything about why, about the mechanism,
about what's going on, and that's what your work tells us,
and I want to get to that, but before we do,
let's just talk briefly about multiple sclerosis as a disease,
(16:57):
both what happens to patients and also so well what
happens to patients sort of clinically and then what happens
at the cellular level tell me about multiple sclerosis.
Speaker 3 (17:06):
Yeah, so, in MS, the immune system attacks the milin sheath,
which is the insulating coating on neurons, and it's essential
for effective nerve conduction and thus sensation and you know,
muscle movement. I think of the milin sheath as you know,
(17:26):
the equivalent of the insulation around a wire. If you
cut the insulation on a wire, it's short circuits and
doesn't conduct. And likewise, if the immune system attacks and
damages the milin sheath on individual nerves, those nerves also
won't conduct. In us won't receive sensory signals or be
able to transmit signals to activate muscles in thus move.
Speaker 1 (17:50):
So okay, so this is what goes wrong in patients
who have multiple sclerosis. Their own immune system attacks the
milin sheath that's for their nerves. When you set out
to study the role of EBV and MS, what are
you what's your hypothesis?
Speaker 3 (18:11):
We were very focused on taking the B cells from
human multiple scrosis patients and then isolating the specific individual
antibodies produced by each B cell.
Speaker 1 (18:24):
A B cell is a cell that's part of the
immune system, right, So you're looking at the antibodies produced
by the B cells in a multiple sclerosis patient.
Speaker 3 (18:33):
Yes, And to our great surprise, many of the antibodies
were antibodies against viruses, of which EBV was a prominent virus.
Speaker 1 (18:44):
Huh. So, in a sense, these are immune cells doing
what immune cells are supposed to do. They're creating antibodies
to attack pathogens.
Speaker 3 (18:54):
And protect that individual against you know, viral pathogens such
as E as well as other herpes viruses.
Speaker 1 (19:02):
When you put it that way, seems good, right, Oh great,
there's a virus has infected my body. My immune cells
are creating antibodies to attack that virus. That's what's supposed
to happen. Where does it go wrong?
Speaker 3 (19:17):
So we discovered that some B cells made antibodies that
not only bound to EBV, but they cross bound to
human milin, meaning that.
Speaker 1 (19:28):
The same antibody could essentially attack both the epstein bar
virus and the patient's own the person's own milin.
Speaker 3 (19:38):
That's correct.
Speaker 1 (19:40):
So was there like a specific moment when you realize
that MS patients have these antibodies that attack both EBV
and their own milin.
Speaker 3 (19:50):
The lead author, Toby Lance on our Nature paper emailed
and called when he first found that these antibodies that
we had isolated from human MS patients spinal fluid B
cells when he found that they bound EBV. The email
may call me and they're like, Bill, they're reactive with EBV,
(20:11):
and I think we were both shocked.
Speaker 1 (20:13):
Yeah, what'd you say? What'd you think when you got
that call?
Speaker 3 (20:17):
I was floored. I couldn't believe it, and I was like, wow,
this is real. Because it's one thing to be statistically
or epidemiologically associated, and a second component is to have
a mechanistic basis, And our work provided the mechanistic basis
(20:39):
by which EBV was causing a subset of MS and
thus enables people to further believe the statistical finding that
it's strongly associated.
Speaker 1 (20:49):
So I know that your study applies to something like
a quarter of MS patients. And then, as I understand it,
there's other researchers that shows similar things, quite similar things
going on in other patients, essentially antibodies that bind you know,
both the EBV and tamiolin. Is that right?
Speaker 3 (21:10):
Yes, there's several groups studying other antigens that are mimicked
by EBV, including our own. And it turns out that
EBV infections also associated with other diseases such as systemic
loopus or SL and it's also associated with rheumatoid arthritis.
Speaker 1 (21:29):
So these are all autoimmune disease, these diseases where the
body's immune system is attacking itself. Basically, yes, I mean
is this like, are we right now? Are you right
now finding the answer to this question that people have
been asking for whatever fifty years, eighty years, like, are
you finding the virus that is causing autoimmune diseases?
Speaker 3 (21:54):
We believe we are, and we are performing experiments to
further bear out the mechanisms that would encompass one hundred
percent of MS and as well as of lupus and
other autoimmune diseases that are EBV associated.
Speaker 1 (22:10):
And just to be clear, in these other autoimmune diseases,
what are the immune cells? What are the antibodies attacking?
Speaker 3 (22:20):
In the other autoimmune diseases, They're not attacking myelin' They're
attacking their corresponding tissue anogens. So in loopus, the immune
system attacks the nucleus of cells and also the kidney.
In rheumatoid arthritis it attacks the joints.
Speaker 1 (22:38):
So I mean, why does this one virus, EBV, Why
does this one virus cause us to make antibodies that
attack so many different parts of the body, Like, what's
going on?
Speaker 3 (22:51):
You know? I think we don't know. We only you know,
hypothesize and speculate. My sense is that given EBV as
a herpes virus that's present in a person's B cells
as well as epithelial cells for life, and that it's
transiently reactivating on a periodic basis, that those properties make
(23:13):
it reimmunize the individual multiple times repeatedly over the courses
of their life.
Speaker 1 (23:20):
So basically, most people get this virus when they're a kid. Right,
So you have this virus not just in your body
for your whole life, but in your B cells, in
your immune cells, and it periodically sort of turns back
on basically and causes an immune response. And it's the
idea that it's happening again and again and again. That's
(23:41):
fundamentally the problem.
Speaker 3 (23:42):
I think that that's contributing to the problem.
Speaker 1 (23:46):
Almost everybody gets EBV, has EBV. Very few people get
autoimmune diseases, certainly relative to the share of people who
get EBV. What's going on there? Like, why do only
some people get autoimmune diseases if we all have EBV.
Speaker 3 (24:03):
Yeah, that's the big question, and that's why more than
five years ago we were skeptics that there was any
relationship between EBV and MS or these other autoimmune diseases
like lupus.
Speaker 1 (24:16):
Well, so presumably it's sort of necessary but not sufficient, right,
Like you need to have EBV and something else or
in some other set of phenomenon, characteristics, risk factors, whatever
to develop autoimmune disorders? Do you have a sense of
what the other things are.
Speaker 3 (24:37):
Recently, investigators in Germany Christian Muntz is showing that some
of these classic multiple sclerosis. Genetic risk factors are actually
risk factors for inability to mount a robust T cell
response to EBV. So they're basically preventing you from having
a T cell response that controls the EBV and that's
(25:00):
known to be associated with more rounds of reactivation.
Speaker 1 (25:04):
Huh. So, just to be clear, T cells are are
an immune cell. And so basically this finding is if
your body is bad at controlling EBV, if you're genetically
bad at controlling EBV, you are more likely to get MS.
And that makes sense because if you're bad at controlling EBV,
it's gonna you can have more sort of outbreaks within
(25:25):
your body of EBV and you're gonna have more rounds
of this kind of mutation of antibodies.
Speaker 3 (25:30):
Yes, let me give you another recent developments that's profound.
Speaker 1 (25:35):
Okay.
Speaker 3 (25:37):
A investigator in Germany, professor yorg Chet, gave human lupus
patients that had refractory disease that was refractory to all therapies.
Speaker 1 (25:49):
Refractory meaning treatment doesn't work.
Speaker 3 (25:50):
Treatment doesn't work. Yeah, he gave them a cancer drug
that completely depletes their B cells in a profound deep depletion.
So to get this drug, you have to be admitted
to the hospital for two weeks and receive chemotherapy for
a Boemero transplant, and then you receive this drug that
(26:11):
attacks all the B cells and removes them all from
the body.
Speaker 1 (26:14):
So this is like a hardcore, nasty cancer drug.
Speaker 3 (26:18):
Yes, okay, but he effectively cured these lupus patients.
Speaker 1 (26:24):
Huh.
Speaker 3 (26:25):
They're now three years out off all therapies, completely healthy.
Speaker 1 (26:31):
So is the basic idea that if you destroy all
of the B cells, these B cells that have evolved
essentially in a way that is causing them to attack
the body, get well, they're extinct. You basically make them
go extinct and you get to start again. Is that the.
Speaker 3 (26:49):
Idea there, exactly? And they term it an immune reset,
which I believe it is because after this Boemere transplant
type of B cell depletion merges our naive B cells
and then those repopulate the whole repertoire.
Speaker 1 (27:04):
Yeah, you're starting from scratch, you get to start over, Yes,
and the finding suggest that when you start from scratch,
you get better. Your new B cells are not creating
antibodies that attack your own body, if I understand.
Speaker 3 (27:17):
Correctly, that's correct. But you also have to rego through
all of your childhood infections and vaccines.
Speaker 1 (27:24):
Oh right, so it's just carpet bomb. You're just carpet
bombing the B cells. You're not immune to anything anymore.
Speaker 3 (27:32):
That's correct. You're starting from scratch, But compared to having
bad lupus or bad autoimmune disease, it's a huge win
for the individual patient.
Speaker 1 (27:42):
So what you want, presumably in the same way, we
have developed targeted cancer therapy, so you don't have to
carpet bomb whatever rapidly dividing cells. It seems like if
you could just target the B cells you don't like
and let all the other B cells be, that.
Speaker 3 (27:57):
Would be great, absolutely, and we're working hard to develop
therapeutic approaches that would do exactly that.
Speaker 1 (28:07):
Thank you so much for your time. I really appreciate
it great.
Speaker 3 (28:09):
Thanks for featuring EBV in our work.
Speaker 1 (28:14):
Bill Robinson is a professor of medicine and chief of
the Division of Immunology and Rheumatology at Stanford. Thanks to
my guest today, Dorothy Crawford and Bill Robinson next week
on incubation. Why did he jump on the boat or
train or boat and train or whatever and go to
this remote island in the North Sea.
Speaker 2 (28:36):
Why did he do that?
Speaker 1 (28:37):
A family doctor goes to great lengths to figure out
the relationship between chicken pox and shingles. Incubation is a
co production of Pushkin Industries and Ruby Studio at iHeartMedia.
It's produced by Kate Ferby and Brittany Cronin. The show
is edited by Lacy Roberts. It's mastered by Sarah Bruguier,
(28:58):
fact checking by Joseph Friedman. Our executive producers are Lacy
Roberts and Matt Roman. I'm Jacob Goldstein. Thanks for listening.
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