Epstein-Barr Virus: Part 1 with Dr Mark Donohoe

Epstein-Barr Virus: Part 1 with Dr Mark Donohoe

Is Epstein-Barr virus (EBV) the ultimate Trojan horse?

Otherwise known as glandular fever, EBV has gained increasing notoriety over the past three decades as medicine has begun to unravel the role it plays in chronic fatigue disorders.

Dr Mark Donohoe describes EBV as his favourite pathogen and his intrigue with it delivers for us, an incredible podcast that dives into his 30 year history of following the evidence of this virus.

In today's episode, Dr Donohoe takes us through the history, evolution and virulence of EBV to round out part 1, with part 2 expected to be recorded at a later date.

Covered in this episode

[00:50] Welcoming back Dr Mark Donohoe
[01:13] Today's topic: Epstein-Barr Virus (EBV) Part 1
[01:44] The history of EBV and genetics
[09:04] Exposure and spread of EBV
[14:35] The role of tonsils
[16:52] Are all viruses pathogens?
[24:01] EBV's "homes" in the body
[28:32] The ultimate Trojan horse
[31:17] The interplay of the immune cells
[34:39] Viral transmission: hitching a ride
[36:00] Predisposing factors
[37:55] The importance of methylation
[38:48] Teasers of what to expect in Part 2
[40:10] Final summary and thanks

Andrew: This is FX Medicine. I'm Andrew Whitfield-Cook. Joining me in the studio again today is Dr. Mark Donohoe, a man who I have much respect for, who is an integrative practitioner of many years...

Mark: Not that many.

Andrew: ...and who is quite famous for taking on those really recalcitrant conditions. The people who've been everywhere, seen everyone, got no relief, and finally, they end up on at Mark's door.

Today, we're going to be discussing in part one of a two-part series, Epstein-Barr virus (EBV). Mark Donohoe, welcome to FX Medicine.

Mark: It's good to be back again. We're going to talk about my favourite pathogen.

Andrew: Now, this is really interesting because EBV, in my nursing knowledge, was just known as the “kissing disease” and something that you got in your teenage years. But I have since learned a heck of a lot more about this, indeed, in serious disease. Take us through, first, the history of Epstein-Barr virus.

Mark: Okay, well firstly, my history with it is: this was a big thing in 1988-89 when we were first kind of identifying the term of chronic fatigue syndrome. We kind of got to the case definition by around 1995.

But in the early days, people will remember that what now is called chronic fatigue syndrome, the Americans called chronic Epstein-Barr virus syndrome. And it went back to Paul Cheney's work, and the original work done on these oddly fatigued people showing high antibodies to Epstein-Barr.

So there was an early phase of chronic fatigue syndrome, where the American view was, "This is the all just chronic Epstein-Barr virus”, we will have a drug for that, and we will kill off that, and that will cure all the people's chronic fatigue syndrome.

Andrew: But how do you kill off a virus?

Mark: Yeah, so that...

Andrew: That is part two, isn't it?

Mark: That's right. This is like the war on cancer, the war on Epstein-Barr, the war on everything. It looks simple when you start it, and you think we can do this, and then you find the complexity. Like most bugs and most pathogens, they have tricks. Epstein-Barr has become a favourite of mine because the variety of tricks that it uses to maintain itself is spectacular.

Again, one thing that most people don't realise is we die with way more DNA in us than we are born with. It sounds crazy, doesn't it? You know, you think DNA is a constant thing, but the viruses are injecting DNA. We have Epstein-Barr, cytomegalovirus, all these others just insert themselves in our genome. So we actually die with about 5% more DNA than we were born with, and most of that is viral DNA. Some of it may come from other pathogens like microplasma. There are other methods of insertion into the DNA.

In the deep long history, we have this stuff in our DNA which came from the genome project, where we call it junk DNA. And how part of this turned out is 10% of our DNA, more than our own genetics - you know, the so-called “human genetics” - 10% of the total DNA was human endogenous retroviruses. These are herpes viruses, and most people don't know this, but glandular fever is a herpes virus. It's human herpes-4. So, most people with glandular fever have been part of the long tradition of these viruses getting in. Occasionally, they copy themselves into germ cells, and those germ cells then transfer across generations. We've always thought of those viruses, the junk DNA, as just “dead” DNA, you don't have to worry too much about it.

The fact is that the viruses that get themselves successfully into us have been persistent viruses that worked over hundreds of thousands, sometimes millions of years, because they're also in primates, they're in other mammals as well. So they got in, they form a kind of backbone of our DNA and we thought it was just junk. Now, we're seeing that people with say, chronic fatigue syndrome were expressing antibodies against those so-called dead viruses. It's like the Titans, you know, the whole history of the Titans being put down underground by the gods, and the Titans are making their way out again. The viruses are starting to show their face again, and it looks very much like herpes viruses get themselves into us. We're carriers of them and eventually, they make their move again on us at a later time.

Andrew: Is this along the lines of junk RNA, junk DNA?

Mark: Junk DNA. So we were surprised - you remember the genome project? It was thought that we were we gonna have hundreds of thousands of genes. And to make a human, it looked like the minimum was going to be 150,000 to 200,000 genes and so, as Alessio Fasano said; “if wheat takes 180,000 genes, we’re more complex than wheat, surely?".

But 23,000, 24,000 genes just didn't seem enough to make a human. What was worse is along the way that we're looking for the genes that express proteins, and so these are the active genes that express a protein. And we understood, you know, from DNA to RNA to protein, we knew the mechanism. In the genome project, some smart guy came along and said, "Can I buy from you all the junk DNA, the stuff that doesn't do anything?" And the rights were sold to a single person, for everything that wasn't expressing a protein.

Andrew: What…..!?

Mark: … well people said, well, why would you wanna know? That's just the backbone, that's just the stuff that holds it together.

Within five years of reaching the end of it, it was clear that the guy had bought a goldmine because most of the non-expressing stuff is epigenetic, the whole change in that idea of it's a blueprint that you just are stuck with to; it's a menu that you select from, and the epigenetics are the process of which genes are expressed, which genes are non-expressed.

What was junk DNA is anything but junk. It's regulatory DNA, it's old viral DNA, it's some bacterial DNA. It's a gold mine of other modifying influences.

Andrew: Can I just ask a question around that? Are you saying that some guy bought the rights to use...this has gotta be a bank of DNA, from what is it… hundreds, thousands...?

Mark: It's basically when you do all of those base pairs, you get, you know, you read off 2 billion base pairs, only a tiny percentage of that has anything to do with expressing the protein. So it goes, you know, CGAT expresses under RNA and then it moves on to protein, and we thought that was what DNA was for. The rest of it was just like little bits of wire that held it all together so that it stayed there. And in fact, the discussion early on was, "Why would some idiot pay good money for something that's worthless?" And of course, like most things in biology, nothing is worthless. Biology is very efficient, and what holds together is methods and changes and ways of expressing genes which we had no idea about before we started it. But when we ended up with only one-tenth of the number of genes we expected, there had to be something else that was making a human as complicated and as complex as it was.

Andrew: Okay, but if somebody's now got the rights to investigate this junk DNA, could they if they compared, let's say, retrospectively with those people that might have developed certain diseases, could they be the ones who have "the answers" to teasing out if EBV is a causative agent?

Mark: Yeah, they can. And they can have the answers. I mean, this guy sold it off to other people. This is arbitrage, you know, "I get it for a few million, I sell it for a few hundred million to a few billion." And so it's not that this guy is doing all the work. This guy has the ownership of the rights to the use of it. And of course, in medicine, we've moved to epigenetics in a very, very big way.

Now, we're moving to understanding that, the retroviruses and the Herpes-like viruses that are able to cover themselves in the DNA are sitting there in large amounts. And when they start to express, when those things become active again, which we thought were dead, when those things become active again, people who have chronic fatigue syndrome develop antibodies. It's a tough call. Is this auto-immunity? Really, it's antibodies to fight a virus that the body sees, but the virus is built-in. So we're fighting ourselves without ever having realised that 10% of our DNA is not ourselves. It is from a viral or other background.

Andrew: So I've got to ask the question; Why is it that we tend to see EBV present itself symptomatically in the teenage sort of years, this kissing disease infectious mononucleosis? How does it spread?

Mark: Oh, it is a kissing disease. However, if you go around the world, Epstein-Barr, I think of as one of the champion pathogens of all time.... we'll just go through it on this occasion because the answer in part two to what do you do about it is going to rely on understanding in part one; How the hell does this thing make its living? Now, it's got a job to do, its job is to replicate itself. Humans have turned out to be a great host for doing that.

If you take the world view, and from the human perspective, in Africa, you see Burkitt's Lymphoma is one of the outcomes. Why? Because kids at age two get their Epstein-Barr viruses when their tonsils are big, when their lymphatics are high, and when many of them have been undernourished. And so you have people in close living quarters, unwell mothers and unwell families, and high transmission of Epstein-Barr virus. So that in Africa, in certain parts of Africa, 95% of two-year-olds have already got exposure to Epstein-Barr virus. That's understandable, where living conditions, the closeness of that, the unhealthiness of people opens the gate for the virus to spread. And a whole different problem arises there. There's no chronic fatigue syndrome. Chronic fatigue syndrome is a luxury when the alternative is dying of starvation and survival. But Burkitt's Lymphoma, a kind of escalation of the lymphatics of the tonsils and the adenoids and the tissue in the upper respiratory tract, means that it's a very common outcome. And there is an upside to this….

Finally, the National Institute of Health in America, has paid attention and said, "Look, it's so strongly associated with that lymphoma" and in Asia, it's associated with nasopharyngeal carcinoma, it's now an oncovirus. And so once you discover something that's an oncovirus, the war on cancer, the funding for the war on cancer and the National Institute of Health means now there’s a big move to developing drugs and strategies for the prevention of Epstein-Barr and for the killing or the elimination of the virus once a person is infected.

Now, that's future work. That's just started in the last four years, but it does mean that when the Americans turn their attention to something and say, "How do we sabotage this virus?" they will develop techniques and ways that we just don't have today.

So they get it as two-year-olds, generally. In Asia, especially in the smoking population, they tend to get nasopharyngeal carcinoma. Now, both Burkitt's and nasopharyngeal carcinoma from Epstein-Barr are very rare in America, Australia, New Zealand, and in the countries that we think of, partly because we are not in poverty to begin with and we don't have such close living quarters and ill-health in the early years of life. Most of us are far from malnourished although you could argue the nutrition is not that great.

So what we can say is, in Australia about 10% of 12-year-olds have run into Epstein-Barr virus. 95% of people run into it by age 25. So in that roughly 12-13 year period, virtually all of us become infected. It is rare to find a 30-year-old who has not become infected. So we get it at a different time. Most practitioners will know this story, that when is the number one year that we see this happen? The high school certificate. In the end year of your schooling, when stresses are high, sleep is poor, you're going out and you may be kissing for the very first time, and that hits maybe up to 5%. One in out of every 20 students hits them in that year, sufficient to disrupt studies and often just turn them back to have to repeat an entire year.

Andrew: Okay, but what I don't understand is I've read...there's a couple of parts to this question. The first thing is that when you’re talking about impoverished nations, let's say developing nations, that one of the factors was malaria, that it was sort of co-morbid with malaria, so there is a mode of transmission. What interests me though, if it's a salivary thing and we call it “kissings disease”…. well, if it's kissing, your mum kisses you, and your mum very often kisses you on the lips, so certainly as a baby……

Mark: .....I have to stop you there…. Mothers rarely exchange the saliva that the teenager does with their girlfriend or boyfriend, right?

Andrew: Right.

Mark: So there is salivary expression of the virus and so, yeah, salivary-exchange or fluid-exchange seems to be an important thing. That's not true with babies that are very young. They've got breast milk. There are other potential methods by which babies are exposed that doesn't require saliva. But in Australia, you generally think, well, there are maybe half the people who have antibodies for Epstein-Barr virus do not even remember having been ill. But I remember a family member having been ill. What’s clear is you can get transmission of the virus if there's just enough to tickle the immune system but not enough to overwhelm it, then you get almost a trivial disease. People describe it as a cough or a cold...

Andrew: And they just become a carrier.

Mark: ...and they become immune to it, so they've effectively self-vaccinated.

Andrew: Not a carrier?

Mark: Well, no, they don't become a carrier. So I'll come to this in a second. The virus has a period of time where if sufficient numbers breed up, it expresses itself through the saliva. The home for Epstein-Barr virus is the nasopharynx. So 100% of people who get glandular fever have great big lymph nodes. The way we define glandular fever is a clinical disease, big lymph nodes, swollen tonsils, all that. When you look at those, the people initially present to doctors, and the doctor will look down and say, "It's either tonsillitis or glandular fever?" The typical story, the doctor says, "I'll give you a penicillin just in case it's the throat." What they don't realise is that if it's glandular fever, you knock off the other bugs around there, you actually increase the expression for the Epstein Barr virus. So, the worst cases of EBV is when the helpful doctor said, "Why don't we just try a course of antibiotics." So the passage onto the nasopharynx is very important.

We also had a tendency in Australia to remove tonsils. Tonsillectomies were not a great idea. If you want your immune system to be at the point where the virus gets in and you want it to develop good, strong response, having tonsils was a great idea. And the reason that tonsillectomies are so hard to come by these days is that doctors realised too late.… You know, what do we do? We remove tonsils trying to stop polio, we caused paralytic polio. It was a surgical procedure that if you had your tonsils out 30 days before or after exposure to the coxackie virus, you get paralytic disease.

So we stopped doing it based on; we thought the tonsils were the problem area that accumulated infections, and if we got rid of the tonsils, we'd be much the better for it. What we learned was if you remove the tonsils, you take away the primary defence, the early warning system, and you allow the bug to become far more established. It looks bad on the tonsils, but the tonsils are doing their job.

Andrew: Yeah, as long as the tonsils aren't overwhelmed by it because of poor nutrition.

Mark: That's right, or because of lots and lots of sugar and because they get strep growing, and staph growing, and all of that. So a lot of tonsils do have to be removed, not the decrying that. It's a little bit like, you know, cesareans - there’s a lot of good reasons for medical procedures. But the routine doing of it was thought to be helpful to the host, and what it did was remove frontline defenses that allow for good, balanced immune responses to develop. The same virus gets in the nasopharynx, and there's no lymphatic tissue around? That's a lot tougher for the person to get through.

Andrew: When you're talking about the viral component of DNA, are you saying that EBV is one of those viral components?

Mark: No, I'm saying, EBV...viruses, I think, these viruses, are correctly described as DNA wrapped up, you know, “bad news DNA wrapped up in a protein coat. What happens is that the little protein coat runs around the place, docks with a cell. When it docks with a cell, it injects its DNA in. That DNA wanders its way down into the nucleus. It even may be facilitated, and this is the tricky bit…. Do we consider all viruses pathogens? Is there something about viruses and us which is symbiotic? That the viruses may do something for us and that we shepherd DNA?

Raw DNA coming through the cytoplasm and making all its way to the nucleus, that sounds an odd thing. But there are docking mechanisms and transfer mechanisms which make it plausible, that we and viruses have a symbiotic reaction and that we've made the same mistake about viruses as we made about all bacteria. You know, that we keep on making these mistakes… that something wild and apparently sickening must be something to be avoided at all costs.

And so I think that we are starting to rethink the Pasteurian view. It's not just bad bugs everywhere just waiting to attack us, it's we have a great relationship with 99% of the bugs. We in-fact depend on them. Occasionally, one gets away from us, you know, a salmonella or a shigella or something like that, and all hell breaks loose, and our immune response to it goes berserk and does a lot of damage, and we spend a lot of our time attacking pathogens or finding ways to attack pathogens, but unfortunately take the goodies out along the way. I'm not suggesting yet that Epstein-Barr is a goody, but Epstein-Barr is an opportunistic virus that does some important jobs which we’ll come to later on. You know, it gets into you, it makes a home, and unlike all the other DNA viruses, it's little ringlets, it's little circles that sit in the nucleus but outside our normal DNA.

And so that gives it certain advantages. One of those advantages is all the drugs we've developed for shingles and for cytomegalovirus and for genital herpes and cold sores don't work very well with this one. So we inhibit a method of DNA transfer that requires the thing to be in linear DNA in a form that we're able to inhibit. The drugs that we’ve made for all the other herpes viruses, Epstein-Barr has escaped from largely and you’ve got to use huge doses, multiple drugs. It's a real bugger to get the Epstein-Barr under control with drug therapy.

Andrew: I've gotta say, this is smacking so much of the movie, "Prometheus."

Mark: Yes, it does, doesn't it?

Andrew: Yeah. Are you going to fly away in a spaceship soon Mark?

Mark: I know, I know. We can talk later about what's the obvious way of humans leaving Earth? We package our DNA up and we put that out on a meteor. That's right. You don't bother putting 20 people on a spaceship - although Hollywood loves that.

But if you come back to this perspective of what's the virus' job in life? The virus' job is to make more viruses. It's a pretty simple game, and the viruses that are most successful are the ones that routinely transfer and don't kill their hosts. And Epstein-Barr is a classic for one that very rarely kills its host, but it gets into 95% of people. And how do we know that? We measure antibodies in the general population. As I said, by the time you're 25, you've got a 95% chance of having Epstein-Barr IgG. This is one of the critical factors for doctors who do this testing; that if all you test for is immunoglobulin G, then you will find it in 95% of people, and I see this happening all the time. “You must have chronic fatigue syndrome because you got antibodies of the virus”. Wrong. If you’ve just got antibodies of the virus, the herpes virus keeps on niggling, you create antibodies lifelong, and that's what keeps it in jail. “In jail” meaning, it stops it expressing.

Andrews: Yeah. So you inhibit that by stress, the high arginine, peanuts, sunburn...

Mark: Yeah. There is a method of taking Epstein-Barr. If you lived with those huge lymph nodes under the chin and the raging inflammation at the back of the throat, you wouldn't live long. So we and the virus come to an agreed solution which is; you have a little bit of a real-estate, a little backyard here and there. You can play in those ones, and as long as you, as Epstein-Barr stay nice and quiet, we don't get upset about you. And the immunoglobulin G is just a marker of the police around the area though, they will be paying attention to you if you try and escape.

What then changes, as you eluded to, is the virus is there, you have the acute infection, whether you knew it or not, the virus is just sitting there, and then something, a stressor, in the broad, Hans Selye-type stressor, comes along, diminishes host defences, and suddenly, the efficiency of keeping that virus under control is lost.

Now, as I said, the high school certificate year is the typical year. You have the perfect storm of people kissing, lots of Epstein-Barr virus around, the transfer from person to person. Stressors of poor sleep, high demands, tendency towards having a bit of alcohol, drugs, or something to stay awake, sleep-loss while study is caught up on, and the virus, being a virus, just says “BINGO!”, you know.

This is party time, and it gets out, and once it gets away from the person, that person is sickened severely a second time. The fascinating thing for me is if it's a youngster and it's the first time, you get the classic glands coming up. If they've already had it, you don't get the classic appearance. You get extreme fatigue, you get the lymph nodes coming up all up and down the neck but not really huge ones, and you get the person just sleeping, you know, 14, 16, 18 hours-a-day.

Andrew: Hence, the chronic fatigue type theory.

Mark: Yeah. Now, here's the philosophical side, which I don't wanna get into is there are times when we overdo something and it's not good for us. The upside that my patients tell me and that I've learned over many, many years is that when you have Epstein-Barr virus, it's almost like a little switch that says, "Pushing too far, we're gonna flick a switch here, we're gonna turn you down. You will be forced to sleep. You can't study." All of these things happen.

Andrew: Yeah, That’s the sickness syndrome.

Mark: Yeah. Most other animals that become unwell rest because there's nothing else to do. Humans have a high school certificate. You've got to keep studying. And so we ignore that. We take coffee. We try and stay awake. We do things which counter the biology, which is saying, "You will now rest, there is no option," and we push it beyond that edge. And you do get the story of a person going downhill, downhill, downhill, and then one day, they wake up and they're falling off the cliff's edge. And that moment, most of the HSC people can put a date on it. They know the day that it happened and they say it happened on one day, but when you go back in the history, there was a three-month period before where little things were going wrong, where the nodes were up, where they'll say, "I wasn't feeling great."

And the Epstein-Barr has at least a degree of predictability to it. It has three homes in the body.

The first one, 100% of the time, is the nasopharynx. And if you look at the back of the throat, you do see the red arches on either side of people who’ve got tonsils there’s a bit of swelling around there. It's not rocket science because you see the IgG antibodies. They have had glandular fever. It's red again. Why would it be red? The second place, more than half of all the Epstein-Barr viruses in the initial infection get to the liver and they make their home in the liver. It's not such a great place for them. It's not as ideal for them, but they persist there in low numbers. And so you get...people go yellow and their liver function test change and they get Epstein-Barr hepatitis…

Andrew: So they actually show signs of jaundice?

Mark: In the first stage, they show that. What happens then is the virus goes quiet, and when it replicates, you find these mild transaminase, AST and ALT, these kind of enzymes which mark liver damage. That when they're sick, these start to become moderately abnormal, the liver's tender, the naturopath is saying, "You've got, a stressed liver." And so for that 50% of people, which is, you know, 45%, close to 50% of the population, there is a liver which is also virally-filled, capable of replicating, and capable of diminishing one secondary line of defence. Big organ filters everything from the gut. Now, you've got a liver that is compromised. What do teenagers also do? They did eat a lot of carbohydrates, they have a lot of junk food, and they get a lot of antibiotics from us doctors..

Andrew: Hormonal surges?

Mark: That's right. The liver compromised is the secondary effect of the Epstein-Barr virus. And so we say, "Why would your liver be bad? You're not drinking that much." But the virus is capable of replicating there. In rare cases, you even see overt hepatitis. The bilirubin goes high, they start to look yellow if it's bad enough. But that mild liver function abnormality, I used to disparage, and I've seen naturopaths go, "Your liver needs help." These things look okay to me in the testing, but then something happens. They go out. You think, “Gee, the liver was on edge”. We just never noticed it. It was getting close, didn't fall over, and now it did.

Andrew: Would you also be getting the more classical signs of a viral infection? You know, when the virus invades the hypothalamus and upsets the temperature set point, so you start to get the night sweats, the chills, do you see that or not?

Mark: I think the evidence is Epstein-Barr does not get into the brain. So the viruses have their own ways of acting. It doesn't get into the gut. It's not in the enterocytes as well. There are effects on the brain from the cytokines from the immunology. And so I think a lot of what we say is, "That must be a viral infection. That may be encephalitis." If you had a viral encephalitis with something as capable as Epstein-Barr, you'd be dead. So I can be reasonably confident that we're seeing the body's immune response to where the virus is replicating, sabotaging brain function, and causing a lot of the neurological effects.

There are surprises here. I mean, Martin Lerner is a researcher in America and he worked with Paul Cheney and others and has done a lot of studies to show Epstein-Barr virus is also seen in cardiac cells. And so the heart; the compromise that was seen in chronic fatigue syndrome of a low cardiac output and maybe the hypotensive response is this kind of POTS: "postural orthostatic tachycardia". There is a bit of an argument because he biopsied hearts and showed that the heart cells were infected with Epstein-Barr virus.

Andrew: But if 95% of people are infected with EBV, it would be reasonable that you'd find it if you are looking at damaged hearts?.

Mark: It's not always there. So there's the thing. So the common areas are the nasopharynx, the liver, and I’ll come to the last one which I think is where the magic of this virus is. And occasionally, it gets to other organs, which is not its natural hiding place. So you have microplasma can get to the lungs and the gut, but occasionally gets to other cavities in the body. So, all of these bugs have their preferred living environments. They generally have a relationship with the host as the host never get so sick that they can't manage, that they don't die. Occasionally, they get to organs which they shouldn't get to. Martin Lerner's thing was here’s the Epstein-Barr affected cardiac-people. They have had abnormalities of cardiac function which contributes to their fatigue syndrome. And I don't have any doubt that he's right because he's actually done the work of biopsy confirming it.

The third place, though, that they hang out, and this is, I think, the big story that we're learning about Epstein-Barr. Is about 20 years ago, or 15 years ago, we knew that some of these viruses get into a group of lymphocytes called naïve B cells or naïve B lymphocytes. Naïve doesn't mean they’re just doping around the place not knowing about about life. It means they haven't been committed to fight anything. So when we start life, nearly all of our B cells, B lymphocytes are naïve, and as we go on through life, more and more of them get committed to do a particular job. Once they are committed, they tighten up their DNA. They produce a particular antibody. Each B cell produces only one, and we know how they clone themselves. So they'll fight the flu, they'll fight candida, they'll fight something and they're committed. The younger you're infected, the more naïve B lymphocytes you've got.

Now, we thought only 5% were infected. Now, the current researchers know that 95% of people have infection of the naïve B lymphocytes. These are lymphocytes that are waiting to be given a job, but the virus gets them before they've got that job. It sits quietly in their DNA, inside the nucleus, and then when that lymphocyte, in the future gets called on to do something, what does it do? It clones itself massively and it clones the virus massively when it does that.

So this is almost like the classic Trojan horse. You put your virus inside a cell that’s just sitting there doing nothing. It seems innocuous. Nothing goes on. And then say, 6 weeks, 6 months, or 10 years later, that cell gets the message from our immune system saying, "Hang on. We've got this thing called candida here. We've never seen it before, but your job will be to do something to produce antibodies about this." And the little immune cell goes, “Right Captain. I'm gonna make billions of myself in order to do that job." And every time that cell divides, the Epstein-Barr goes on the back of it. It just divides along with it and sits there. And then while the body's immune system is busy fighting that other thing, the Epstein-Barr virus replicates itself and start shedding again.

So it's the opportunistic virus. It's riding on the back of an immune system fighting something else. While that immune system is distracted fighting that ‘something else’, the Epstein-Barr virus is being cloned by our own body's response and appears again. It doesn't give the classic signs of any infection. What it does is it replicates and induces those antibodies that have been grumbling there, saying, "Hey, come on, you've gotta get back in your shell again. Go back to where you were." And that low-grade immune response to try and push the virus back to behave itself and not to replicate too far seems to be where the fatigue comes from.

Andrew: But you're getting B-cells, which sort of originate in bone, and then you've got things like T-cell initiation or responses, indeed, you've got a rare cancer thymoma, a cancer of the thymus gland, attributed to EBV. So talk to us about this?

Mark: We had a division of cell-mediated versus humeral immunity. And so in the old-days, everyone was, "Well, these are T cells derived from the thymus and these are B cells and they're derived from the bone marrow,"

Andrew: And never the twain shall meet!

Mark: Yeah. And life got far more complicated. T regulatory cells and T-cells turn on and turn off B-cells. There is an ability of these various cells to express themself. They're all moderated in the early days through the thymus so the thymus does a lot of the selecting. If the thymus is busily selecting those cells, then the T-cells certainly play a part in it, and the potential for the virus to enter T-cells is certainly present.

So the virus is not, as I said, it's not absolutely committed to nasopharynx, the liver, and the naïve B cells. You give it enough of a playground to play in, it'll find its way into other areas, and it's nearly always a worse outcome. Why doesn't it happen all the time? Because if the virus killed its hosts all the time, we may not get to the point where we're kissing and passing it on. So there is a natural evolutionary pressure for viruses to have an investment in their host staying alive.

Andrew: Now, I have to interject here because this is something that confuses the hell out of me. And I know that it's off-topic. Ebola virus, I don't understand why, if it's so pathogenic, if it's so devastating, how does it survive in the wild? Has it got a carrier, like, what is it, the bush meat?

Mark: Ahh, that is a whole other story, but there is this combination of infectivity. Ebola is highly transmissible. So it doesn't have quite the same investment in the host staying alive, but it is self-limiting. As you saw, you know, there was a lot of effort put into controlling Ebola virus, but it was controllable. You try and control Epstein-Barr virus, you will not succeed. And so Ebola virus is one of those pathogens where everyone is sitting looking at it and saying, "Is it as fatal as we thought?" The common problem that we have as first-world people is not understanding that if you put war, poverty, starvation anywhere, you open the gate for anything to become potentially fatally pathogenic. And so we keep on saying, "Measles will kill everybody." Measles will kill a naive population but it also will come back when war and devastation and problems arise. Bluntly, pathogens are there to mop up the mess that happens after we've damaged things in so many other ways. And so I don't think you can make a comparison there.

But still, just let's get to the end of this. You've got a virus now that lives happily in the throat, but we don't know anything that kills it, and it sits there in sufficient numbers just to keep itself ticking over. A really healthy person, that's all that goes on. And they die with a little bit more DNA, and the Epstein-Barr says, "So-long, thanks for the fish, we're done here," and off they go. But the virus that's going to be successful is one that's learned, What does this host do? You know, How does it fight other things? Where's my next, car ride to the city? How am I going to get breeding again? And many of the cytomegalovirus and human herpes, well let's say, herpes-2, have found ways. Sexual transmission, they found cold sores through kissing. So you get ways of transmission. Hepatitis is transmitted through blood contact. They're relatively rare.

So everything has its trick, but the Epstein-Barr has got two tricks. One is it doesn't tie itself into single strands of DNA. It's circular DNA. So it's protected from a lot of the repair mechanisms that our DNA otherwise has in place, and it has three preferred homes; the nasopharynx, the liver if it could get there, and then the naïve immune cells. And the naïve immune cells are the beauties because they're self-replicating and they will go off like firecrackers every time you see it. From the virus’ perspective, the best time possible is a naïve immune cell that's going to fight something very common in the future. And for the person who gets recurrent strep throats, the person that gets recurrent eye infections…. something, the bad luck of having Epstein-Barr occupying your immune cells, that they're going to pick that fight, means that it's gonna catch a free ride every single time you do the job that your immune system is meant to do.

Andrew: So I'm thinking about, not just infections, but other a stressors to the immune system like allergies, chronic rhino-sinusitis.

Mark: Yeah, absolutely true. We do know that this thing expresses itself far, far more aggressively in people who've got recurrent irritation or inflammation of the upper respiratory tract.

Andrew: Right. So therefore, just thinking about, if you like, the sequelae of symptomatology (sorry, big words) but how people present and the timeline of that, do people get chronic fatigue, and one of the presentations of that is allergies, or do people have allergies and they just then present the chronic fatigue because some other stressor threw them down the chasm?

Mark: Allergy is, in my mind, very definitely, a predisposing factor. So what I do in my practice is; we line up what were the previous positions?

If you look at allergy, allergy is present in around about maybe 30% of the population. So it's a big slab of the population. When I ask my patients, probably 60% tend to have allergy, and it's one method of irritation that opens up the nasopharynx to infection.

There are plenty of other stressors in life, and what we become is a kind of monoculture of how we eat, and especially in our first world where we do see Epstein-Barr related to chronic fatigue syndrome. What we've done is we've created a culture where the person who can manage sugar, manage a supermarket, eat their diet like that, and manage sleeplessness and heavily stressful jobs, they can be relatively immune to it. They can be doing everything wrong and still, that virus doesn’t get a chance. And for the small percentage where it never gets to the immune cells, where the initial infection fails, there’s no method of replication, it just sits in the throat and you'll get a bit of a sore throat each time, but you don't get fatigue syndromes or other problems.

So, yes, what's the art of medicine? The art of medicine is: Where are all the predisposing factors? There is one that everyone knows about, who has ever listened to us, and that's the methylation. What does the body do to stop a herpes virus from replicating? It methylates its DNA. You have poor methylators who get by fine when the stresses are not high, when they don't have 100,000 jobs requiring rapid methylation. There is certainly something to the high rates of the MTHFR homozygous group that keeps on making these people turn up. The obvious thing is since you require methylation, acetylation, histone formation, that's the trick the body has to stop the virus. Just replicating and doing that job over and over, give those methylators something… I’m kind of getting into our next one, but give methylation a chance, and you do something to inhibit viral replication, viral progression, and you can bring it to an end a lot quicker. So, really good methylators have a big advantage when it comes to stopping herpes viruses from replicating themselves.

We'll go into others on the next occasion, but that is just one little gem along the way, that since we know certain predispositions, allergy is one, poor methylation is one, immune activation. What we do know about from Alessio Fasano again? What happens when you get people with certain genetics exposed to gluten and the prolamines? It triggers their immune activation.

Andrew: I can see that the next podcast is gonna be a rather long and detailed one. We're gonna go into all sorts of rooms with this sort of thing.

Mark: I agree.

Andrew: It's not just gonna be a simple little, "Here you go. Here, you manage this." I think there's gonna be several parts to this one.

Mark: I'm not gonna give the magic name of that one antiviral antibiotic, although there are people in America, you know, they are proposing, "Oh, we've used antivirals and we can diminish chronic fatigue syndrome by 50%." But that's not what we're about to talk about. We're about to talk about; We know the lifecycle of this little fella, what can we do to make it safe for teenagers to enter their HSC, and what can we do to minimise the risk of that viral replication? And in the extreme, what do we know about how to turn this little bugger down so that it and us get together and we have a happy life together and a good and healthy life rather than the one that is stuck with these rocks on which we smash our health.

Andrew: Dr. Mark Donohoe, you're an absolute genius. I learn so much, everytime.

Mark: I love to hear that! This only took me 30 … years. I nearly said the bad word.

Andrew: But you always teach me, indeed us, so much, and it's your clinical experience, those decades of experience, of seeing patients and trialling new things, seeing where the research is going and where it's passed, where it's failed, where we needed to tweak it… That's what I love about talking with you is that you bring these really salient things, that we now have a much clearer picture of, to the table to help our practitioner listeners. So thank you so much for joining us again.

Mark: It’s been my pleasure. I feel half-finished at the moment, I am busting to get onto our next one.

Andrew: Yes, thank you so much for half-finishing, and we'll see you again soon.

Mark: Yes, you will.

Other Podcasts with Mark include:

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