"Don't romanticize it."

I was given that critical piece of advice by the Director of Design Engineering for McDonnell Douglas, at a pivotal point in my career and life.

An insight that was so stunning, penetrating, and timely that it's influenced even my faith; given the circumstances, twists and turns, and coincidences in my story, how could it NOT have been divine intervention?

And that insight has stuck with me, not just for how it's influenced my faith, but because of what it says about science.

And Innovation.

And life.

Though it took me a while, I came to see the same basic idea -- insight -- echoed in Thomas Kuhn's seminal work, The Structure of Scientific Revolutions. A book whose first and most important lesson, for me at least, is that science is, above all else, an entirely HUMAN endeavor.

Which means resistance to Innovation is NORMAL.

As is Groupthink.

And even shunning.

Even if it's no fun, any of it.

And though it costs time and, too often, lives.

That's just how it goes.

With people.

Both men and women.

That understanding has sustained me despite the frustrations that have resulted from the resistance to My Baseball Stuff; especially the fundamentally dishonest attacks Jeff Passan, now of ESPN, launched against me in his embarassing, rife with Confirmation Bias, book, "The Arm." A book that Straw Man-ned and ridiculed my insights about why, among other things, baseball pitchers can't stay healthy.

And are at a rapidly increasing risk of dying.

Because of Blood Clots and Thoracic Outlet Syndrome and Strokes.

A problem I've been unafraid to discuss, out in the open, and am being Shunned as a result.

But that's a story for another day.

The story for today -- the very PARALLEL story -- is the crisis, and complete and utter DISASTER, that is Alzheimer's Disease research.

Most people understand that the world of sports, and especially baseball, can be full of toxic, Stupid Macho B.S. In part, because things move so fast such that thinking is, too often, counterproductive.

As it was put so memorably in the movie Bull Durham...

Don't think. It can only hurt the ballclub.

The problem is that the world of science is too often idealized -- ROMANTICIZED -- as being DIFFERENT.

Populated by creatures of pure logic and reason.

Stripped of emotions and other human failings.

Vulcan on Earth.

UNLIKE the world of baseball.

However, the reality, and overwhelming likelihood, is that, in science as in baseball, if you figure out that something is wrong -- especially something important and PRECIOUS, to a field -- you're going to have a HECK of a time convincing people of that fact.

There's going to be HELL to pay.

And the slings and arrows that will INEVITABLY come will do so as much from those on the INSIDE as those on the OUTSIDE.

REGARDLESS -- or, sometimes, BECAUSE -- of the merits your insight.

The idea isn't to TRY to piss people off. However, it's important to understand that pissing people off -- and people getting pissed is NORMAL.

Even if it isn't particularly FUN.

The higher the stakes, and the rewards, the greater the volume and intensity of the attacks.

As Alzheimer's Disease researcher Dr. Ruth Itzhaki knows all too well.

However, she's also seen the fruits of her labor, and her persistence, start to pay off.

Over the past five years, the Infectious Hypothesis of Alzheimer's Disease, of which she is one of the champions, has seen increasing acceptance.

And the VERY recently discovered link between the Epstein-Barr Virus and Multiple Sclerosis -- a different, but related, Herpes virus than the one Dr. Itzhaki is studying -- I would suggest, makes it clear that she and her colleagues would seem to be on the right track.

Itzhaki on Alzheimer's & Crisis

In September 2021, I interviewed Alzheimer's Disease researcher Dr. Ruth Itzhaki. Topics we discussed included...

• Alzheimer's Disease
• The Infection Hypothesis
• Thomas Kuhn's work on Paradigms and Change and, in particular, his concept of "Crisis."

CHRIS O'LEARY: My guest today is Dr. Ruth Itzhaki. She's a research scientist, has a PhD in biophysics. One of the big names. In my opinion, one of the biggest names in Alzheimer's research is a fan of Thomas Kuhn who's known as the paradigm guy. I became interested in her story in part because her story tests and exemplifies his idea of Crisis, what science in Crisis looks like. Basically, I went looking for a field in Crisis, and I found it in Alzheimer's disease research, came across an article in STAT by the late Sharon Begley, who was just an absolute force. The article was entitled...

• How an Alzheimer's cabal thwarted progress towards a cure

Obviously, the use of a term "cabal" evokes Crisis. So I wanted to talk to Dr. Itzhaki about her experiences, more about how she got here, then where she is, and the hell she's been put through. But we can talk about that if you'd like. But again, in my opinion, Dr. Itsuki, is Thomas Kuhn's book, The structure of scientific revolutions, brought to life so Dr. Itzhaki, thank you for the time, thank you, for everything you've done, is a son of an Alzheimer's survivor, I think you're awesome, and you're doing everything that you can. And I'm very grateful for all of your efforts. So thank you for the time.

DR. RUTH ITZHAKI: Thank you for saying all these nice things.

CHRIS O'LEARY: I mean it absolutely. So, the first question is kind of the big question. I'm going to talk about innovation. And as I said, I'm going to start off from a Kuhn's perspective, talking about Paradigms, talking about Crises, I can talk about a lot of that, based on stuff that you've published and things that have been published, but what I can't find out is how you got on to the trail of Herpes Simplex Virus 1, how you got from your graduate work, to your postgraduate work, to the 1988 paper to the 1991 paper to the 1997 paper, how'd you get from graduate school to 1997-1998, when you really started kind of making some really impressive publications.

DR. ITZHAKI: I decided, having graduated in physics, that I thought I would be more interested in finding out about living things, then about the roots of physics, although I enjoyed the physics very much. So I started off doing a course in biophysics, which there were only two at the time in the UK, and I was lucky enough to get a studentship to fund me for a couple of years. And that was quite interesting. We were supposed to convert to a knowledge of biology, which neither I nor the other person who got a scholarship had ever done any. So it was quite a hard path. Anyway, we managed. And then I went over to a course -- doing PhD research, and doing a PhD -- which was really chemical, I think, in nature, more or less. It was to do with polymers and radiation. So, rather different from what I've done before which the research I had done was to do with unbinding, and rat plasma. So quite a change.

I then moved to Cambridge and spent quite a number of years looking at the effects of radiation -- which was the interest of the department that was in -- effects of radiation, particularly on what's now called Chromatin; that's DNA protein complexes. Using a very difficult technique.

Anyway, to cut a long story short, after some years there, I moved to Manchester, where my husband got a job and I got a job, too, in Manchester, and worked -- and there's another theme -- which was chemical carcinogen effects on macromolecules.

So there's been a sort of a continuous theme, in a way, but none of them was at all close to each other, really.

CHRIS O'LEARY: I'm interested in the themes...

DR. ITZHAKI: Well, it's a sort of looking for changes that might be significant. But, usually there was a fairly good rationale for looking at these things. It didn't just pop out of the blue.

Eventually I ended up collaborating with somebody who was interested in viruses. Something I knew very little about. And I was fascinated by the work. And he really looked into one or two studies on this and drew my attention to some work which showed that in the case of a very serious viral illness in the brain, Herpes Simplex Encephalitis, which, years before had killed people, but gradually with various medications, they were able to survive, even though they were usually damaged in some way. They weren't as good as they were before.

And it was found, or it was noticed -- by an American actually, an American neuropathologist (named Dr. Melvyn J. Ball) -- that the regions of the brain that were most affected in this very serious disease, Herpes Simplex Encephalitis -- which I'll call HSE, in the future -- the regions affected the most were the same as those most affected in Alzheimer's Disease.

There were other factors that linked the two. In fact, if one postulates that some agent, infectious or otherwise, causes the disease, it must do so after a very long time; if it's in the body already, which herpes is known to be, because obviously, the disease becomes apparent in most cases and 99 or 95% of cases in old age. And so you have to postulate that whatever it is, is there for a long time and then starts, for some reason, becoming active. And the other requirement which really goes with this, with what I've just said, is that latency or dormancy is in a sense a prerequisite. Because, otherwise, if the agent in the body, in this case a virus, were active, it would cause HSE -- Herpes Simplex Encephalitis, an acute illness -- which it doesn't do. As far as I know, Alzheimer's Disease patients have never been shown to be particularly susceptible to HSE, Herpes Simplex Encephalitis, or particularly likely to suffer from it.

So those three or so criteria were ones which rather implicated virus in the disease, very indirectly. And we started with some funding; a small amount. We decided the first thing to know -- although it wouldn't be an essential requirement, but it would be very interesting -- was to find out whether the virus was present in the brain or not. Because if the infection was in the brain, it's likely that it will be there. Although not necessarily, because it might have been there and then gone and left a mark. But nonethless we decided to look for it. So we used what was the a very new technique, Polymerase Chain Reaction, which most people probably would have heard of now because of the tests; PCR tests for the SARS-COV-2 COVID-19 virus. So we use that way back in 1989. Yes, 1989. We started the work and had lots of problems with PCR at the time. Reproducibility and so on. It was notorious, then, for its difficulty. But things have been sorted out, now. It's much, much, much easier, after many years have gone by. Much easier and much more sensitive.

But, again, to cut a long story short, what we found was at first rather disappointing. We found the virus in brain, allright. And we were very excited about that. But we found it not only in Alzheimer's Disease patients but in elderly, control people; elderly people who didn't have the disease.

This was a bit off putting until I realized, after some time, actually, that this is not an unusual thing for an infection.

You can be INFECTED but not AFFECTED.

In other words, there's often, in case of many, perhaps all infectious agents, there are people who do not suffer from the disease, which is causing (problems) in others.

And the best known case of that probably is Tuberculosis. The bacterium that causes that infects about 10 times more people than the 1/10 in whom it causes the disease. So only about 1/10 of all those infected with the TB bacterium actually develop TB. And more relevantly, in Herpes infections of the periphery -- the non brain part of the body -- cold sores are apparent in some Herpes infected people. But there are an awful lot of people who are infected with the virus -- probably about 80% of us are infected by the age of about 60, although in previous years, they were infected at a much younger age -- but now there's about something like 25%, and maybe up to 40%, of people who do show cold sores, but the other 60 to 75% are not symptomatic.

So as I said, in short, you can be infected, but not affected.

That's quite important because people often ask me, "How can you think of a virus is involved when you found it in your elderly normal (controls)?"

And I have to explain this principle -- I've explained it over and over and over again -- and people still ask. I think, altough it's not a very DIFFICULT concept, it does seems to be one that a lot of people aren't willing to ACCEPT. But it's so obvious. But, in diseases like TB where the cause is known, it's very clear cut.

After that we did a series -- lots of experiments -- trying to link the virus with various happenings. And we also found, more importantly, we thought that what might be happening is a difference in genetic factors; in the genes carried by Alzheimer's disease patients, which differed from those carried by (elderly) normals. In other words, what's the difference between the Alzheimer's group and the normal group? A genetic factor?

At the time, there was a great deal of interest in a gene called Apolipoprotein E. Which is a mouthful, so I'll say APOE for short. And which does exist in somewhat different forms. Different what we call allelles; that means types of the same gene. And the type 4 allele was the one that was implicated as being a risk factor, or other susceptibility factor, for Alzheimer's. Susceptibility meaning that it isn't necessary or sufficient, but it presumably acts with something else to cause the disease.

So we looked at the APOE genes in the people whose postmortem brains we looked at and we found, some very, very nice results. Very clear cut. That those who had HSV1 in brain, AND an APOE4 allele, comprised a very high proportion of the Alzheimer's patients. Whereas those with APOE4 on its own, without the virus in brain, or those with virus in brain but without the APOE4, are much less likely to be in the Alzheimer disease group.

So just to summarize, what we showed was that it's a COMBINATION of HSV1 -- Herpes Simplex Virus type one -- in brain in people who carry the type 4 form of the APOE gene.

It's a bit of a mouthful. I'm not sure it that's clear.

CHRIS OLEARY: No, that's very good. It's basically you have to combine, you have to have infection, plus active disease, plus the APOE4 mutation. And the combination of those things, which kind of reduces 10% plus 10%, is why the number is relatively small. But in the people who have the combination of infection plus activation plus mutation, those are the ones who are going to be vulnerable to Alzheimer's disease.

DR. ITZHAKI: Well, that's more or less, right. It's not three factors. (It's two.)

It's not three factors...
Later on, Dr. Itzhaki makes the point that the virus must also be ACTIVE and not DORMANT, which is what I meant by a third factor.

1. Virus.
2. That is ACTIVE.
3. APOE4 Mutation.

But I didn't say it quite right, so she didn't get my point.

It's a virus in brain in people who have that particular type of the gene. Those two things are what confer the risk of Alzheimer's Disease.

And there are a lot of consequences that you can deduce from that. But I won't go into that now.

It seemed to show a CAUSE and not just an ASSOCIATION.

Which is something that people often don't understand; that there's quite a difference between the two.

What was quite striking, although much less often noticed, was that we found that, in case of Cold Sores, which some people suffer from -- as I mentioned before, maybe 25 to 40 percent of those who are infected with Herpes -- only a percentage actually show Cold Sores. The others who were INFECTED were not AFFECTED.

We found that APOE4 was a strong risk factor for Cold Sores.

And in fact, it probably accounts for about 60% of people who are infected with the disease. (Versus the other 40%). In the case of Alzheimer's Disease, also, it's about 60% -- 50 to 60 percent -- of people with Alzheimer's Disease, we think have this, this combined factor of virus in brain and this genetic factor.

And it's a rather similar proportion in the case of Cold Sores. So we don't know -- (about) the other 40 percent -- why they get Alzheimer's Disease. It's almost certainly what they call a multifactorial disease. In other words, one with a number of different factors. What they are, we don't know. There could be other types of virus or they could be bacteria. And we're hoping to look into that if we get some money to do it.

So anyway, that was quite an exciting finding. And at first there was a great deal of interest, but then it sort of dwindled. And for all the years after that, which led to a paper in The Lancet, which was quite pleasing, we had to fight huge battles to get money and to get papers published. And, of course, one depends on the other. You can't get grants and funding if you haven't published papers. If you can't persuade people that what you're saying is factual, and likely correct, you don't get any funds. So it was a very, very difficult situation. I had to beg borrow, and almosy steal to get money. Or, more likely, I relied on small organizations. We're more willing to take the risk to do novel work, small funding bodies rather, rather than the large funding bodies, who just wouldn't look at it.

Anyway, we continue by looking for links between the disease -- Alzheimer's Disease and the (Herpes) virus -- and I won't go into those because it would take too long...

Until about five or so years ago, we were almost the only people working in that field. Other people told me they wanted to do some work in it, but they couldn't get money, which is exactly the trouble that we had. (But) about five years ago, people start getting a bit of money, and they haven't they found nearly everything. 99% of the papers, which have appeared since in the last five years -- say about 99% probably -- support what we've done. There are a few papers that don't. And I can think of one or two reasons why they don't, but I can't explain all of them.

So there's a bit of a mystery, here.

But overall, there are now several 100 papers, which, by very, very different methods from ones we use -- very diverse methods -- which is encouraging because the more diverse, the more likely they are, and they're consistent, to be correct. Because you wouldn't expect, if there's a mistake, or an error, in one method, you wouldn't expect the same mistake to be made in half a dozen other methods. Well, that was really very gratifying.

So that's the situation beyond now, there's still a huge... There are lots of people, and unfortunately, very influential people who control the moneybags, who object to the concept of a virus or any other infectious agent causing the disease.

But what is so annoying -- really and idiotic -- is that these people never voice any arguments against it.

I can't think of one solid, scientific argument that they can produce.

So, despite the fact the papers were repeatedly rejected, it wasn't because people said, "Oh, she's on this, and that's wrong. And there's this mistake. And that mistake." They didn't say that. They just gave various spurious reasons or claimed that I'd said something I didn't. However much one rebuts that, you know, the general impression was that this was a crazy idea and didn't belong to a respectable science.

But luckily, now, it is being taken much more seriously. And far more people are working in the field. But though, as I say that, there are still people who choose not to believe it. But the issue is that they are not looking to read the papers that have been published to support it. And so they really have no basis for that hostility.

CHRIS O'LEARY: You've got Galileo as company for that. While it may be apocryphal. But you know, people, evidently, refused to look through the telescope, because they believed that Satan could put any image that he wanted to in the telescope. And I've seen some of those comments, I'll sanitize one of them, but basically, a guy was rejected. And the comment was something to the effect of, "Well, he never mentions Amyloid, so we know that he doesn't know what he's talking about. So there's no point in even reading the paper."

DR. ITZHAKI: That's very likely. I'm not surprised you found that. I think that what the Amyloid people don't realize is that we don't REJECT the idea of Amyloid being important. It almost certainly IS important. But what we're saying is it almost certainly does not CAUSE the disease. It's a FEATURE of the disease. And that's a very different factor. We can't even say that herpes causes it. Because we haven't got very, very definite proof. We have proof of associations rather than actual causal ones. And that might be solved with the present -- unique really -- trial that is going on in New York. I must say I was very, very pleased that there was a trial going on. But rather sad that it wasn't in this country. Because I tried for five years to get funding for a trial, along with a number of clinicians. And we were just repeatedly refused. So I had a mixture of pleasure and, in a way, sadness, not being involved in the New York one. But if that shows that treatment with antiviral agents works, that will be a huge step forward. I think people will have to more or less accept that a virus is A cause. But I have to say that the trial might not succeed, for all varieties of reasons. The sort of reasons that have been put forward to explain why Amyloid doesn't. Because one could say it is used too late; when the damage is already done. Or, the alternative is, that the antiviral agents don't work as well as we thought, they would. I've got an idea of using a combination of viral agents, which work by completely different methods. They stop the virus from dividing and replicating. But I haven't, so far, got any funding for that one. I haven't given up trying, but I haven't got enough clinicians around to. We're willing to support it. They're very busy with other things. And the ones who applied before, I think, got fed up with applying for several years and not really getting anywhere. I'm hoping very much that the New York trial will work.

CHRIS O'LEARY: Can you explain the overlap between your ideas and the Amyloid Hypothesis? And I've seen Amyloid described as an anti microbial peptide, does that mean that there's an anti viral peptide? And maybe that's why the relationship isn't one to one. Can you go a little bit into that?

DR. ITZHAKI: Yes, I will try. Well, a few years ago, at least two groups showed that Amyloid has got action. Initially, against microbes. And that means bacteria AND viruses. I have to say -- and I hope I didn't seem too conceited -- we showed in 2009, that in cells, in living tissue, we used a technique called in situ PCR, which means PCR used on tissue sections, rather than on extracted DNA, which is what they mostly do. It's a very, very difficult technique, and it took us several years to set it up. So we were lucky. We just about managed to get enough money to do it. And what we found was -- you've heard of Amyloid plaques, which is the deposits of Amyloid in the brain -- we looked at plaques... Well, we looked at tissue, which contains plaques, from both Alzheimer patients and elderly normals. Because elderly NORMALS often DO contain a lot of Amyloid, which is one of the strong arguments against (Amyloid) being a cause. What we found was that the Amyloid in most of the plaques -- nearly all, meaning in 70 plus percent of the plaques in Alzheimer's brains -- the DNA of the virus was surrounded by Amyloid in a sort of capsule. And in elderly normals, it was the same thing, but a much lower proportion of the virus -- viral DNA, 20 something percent -- was included in these. We don't know why; what the difference means. But it was just a very interesting finding. And I think that's what led -- I'm quite sure -- at least one of the people to look for antimicrobial action. We actually DID look for antimicrobial action in 2007. And we mentioned it in a paper that we wrote then. But the experiments weren't successful; trying to find out whether it was. Because the Amyloid we used was commercial, and probably not very good. And it killed the cells. So, even though it DID show antiviral activity, we couldn't really make anything of that, because it killed the cells, eventually. So I'm not saying this to claim priority, but it's a bit galling, because the person -- one of the main names in the field, who actually discovered the antimicrobial properties -- I'm pretty sure based it on OUR work. And based on the work of a completely different person, an Australian, who published a paper in 2002, suggesting that Amyloid encages the virus -- viral DNA or virus -- in other words, keeps it in a prison. And he is never mentioned, except by me in my reviews. And our work is hardly mentioned (when it comes to) antimicrobial peptides. So it's a little bit annoying, but it's an interesting finding. And certainly quite consistent with what we've shown. And what it seems -- though the authors have never actually said this -- is that the initial action of Amyloid, probably, in cells, is to operate against the virus or against bacteria. But, later on, PROBABLY -- we don't actually say this, but probably -- as the concentration increases and increases, (Amyloid) then becomes toxic and blocks various things. Synapses and the brain and so on. And becomes really damaging. So it will be interesting if one... I think it's this change of state, of aggregation of Amyloid, that causes problems. But then nothing is very definitely known about this. Not really quite understood.

CHRIS O'LEARY: No, that's good. That's very good. So, on science Friday, the NPR science program with Ira Flatow, someone came on two weeks ago and was talking about Inflammation, and now everything is Inflammation.

DR. ITZHAKI: Yeah, that's that's funny, because 20 years ago, the world was anathema. If it was mentioned, people were thought to be crazy. Nothing to do with me. I can't claim any credit for anything to do with that. But it is ironic.

CHRIS O'LEARY: Does it at least make sense? Is the Inflammation a response to some of what you're observing?

DR. ITZHAKI: Yes. Yes and no. It's very interesting. We've explained our results, quite a lot, by saying that it is known that Inflammation reactivates latent but dormant virus.

Inflammation reactivates latent but dormant virus...
Above, I commented that THREE things were needed for Alzheimer's Disease, besides the presence of the HSV1 virus and the APOE4 gene. That third thing was that the virus was ACTIVE and not DORMANT.

That's well known. So yes, it makes perfect sense.

And it explains the fact that infections, generally, are known to affect cognitive ability. And also, now, are known to be a risk factor for Alzheimer's. And what we think is happening is infection in the periphery -- which means outside the brain -- cause Inflammation there. The Inflammation there somehow also causes it in the brain, where it's called Neuro Inflammation. And that Neuro Inflammation reactivates, what was previously dormant, virus, which then starts it replicating and then does its damage.

And what is, in a way, very intriguing, we're suggesting, is the fact is that Herpes virus damage is caused not only by DIRECT viral damage, but also by itself causing Inflammation.

So it's sort of a vicious circle.

And we've got some results, which are very interesting, which suggest that -- at least in cell culture experiments -- which suggest that this really is likely to be the case. We're hoping to write up that work in a paper, soon.

So I think (Inflammation) ties in very well.

I'm sure the Neuro Inflammation is very important, and I think it's important through reactivation of the Herpes virus.

CHRIS O'LEARY: So, assuming some of the attacks are in good faith, and getting back to the point of Kuhn, is it possible that the Blood Brain Barrier is serving as a paradigm that's making certain things unthinkable?

Blood Brain Barrier...
My point, and question, which I think Dr. Itzahki got and took, was whether the idea of the Blood Brain Barrier, which IS an issue when it comes to getting certain DRUGS into the brain was keeping people from being able to consider whether a VIRUS could get into the brain. The assumption being that, if it's hard for a DRUG to get into a brain, it's going to be hard for a VIRUS to get into the brain. But that's at least a significant assumption.

I see lots of mention of the Blood Brain Barrier, it seems like a lot of people just stop thinking, as soon as they throw that term out. I'm curious what your thoughts are on the validity of the Blood Brain Barrier?

DR. ITZHAKI: Well, I'm sure it's there. And I didn't know that much in detail about it. But I think it's very important. Because amongst other things, I'm particularly relevant to what I've been talking about is the fact that at least some antiviral agents do go through the Blood Brain Barrier, which is like, literally a barrier, and prevents large organisms or large molecules getting through under some conditions. So obviously, if we want to treat people with an agent, you've got to make sure it gets into the brain. If it's in the blood, you can't know if it's going to get into the actual brain. And it won't work unless it's in the brain, not just in the blood vessels.

There was an interesting paper recently -- which I haven't had time to read yet, because I've found too many papers, appearing everywhere -- which talks about APOE affecting the permeability (of the Blood Brain Barrier). I haven't read it, I don't know if it's relevant, but it just struck me as being interesting.

But, from the point of view of a virus (and the brain), the virus DOESN'T get through (to the brain) from the blood. It doesn't TRAVEL in the blood.

It's not IN the blood.

It's not IN the blood...
This feels like a VERY important point. I wonder if people are assuming, as I did, that the virus is just floating around in the blood, which is how it gets into the brain, or does not; if it's blocked by the Blood Brain Barrier. But that's NOT how the Herpes virus at least -- and the COVID-19 virus, too, it seems -- gets into the brain.

It's in the nervous tissue; in the periphery and what's called the Trigeminal Ganglia, which are collections of cells in the periphery. And it's actually reactivation of virus, from there -- from the periphery -- that causes Cold Sores. And we think, if it gets in, it will not leave. And it has been thought and we didn't do the work was done quite some time ago, it's thought that the virus gets into the brain either through the nose was full, the olfactory nerves go into the brain, and they can travel -- the virus -- even though it's very large can travel along these nerves. That's one possibility. The other possibility they go directly from the Nervous System in the Trigeminal Ganglia. So it's not really... I don't know how relevant the Blood Brain Barrier is. Except in respect to treatment, right? There, it might be much more relevant. There might be something that we've just never thought of or dealt with, but I can't immediately see it is directly relevant.

Since it's not in blood.

Since it's not in blood.
Again, I have to wonder if this is a (problematic) assumption. Do the people who are rejecting the Infectious Hypothesis, out of hand, at least, know that the virua isn NOT in the blood? Rather, than it gets into the brain via some other route.

CHRIS O'LEARY: Speaking of tissue death, how tightly does HSV1 bind to the neurons? Is there? Is there any chance that tissue death and volume reduction in Alzheimer's Disease is essentially an auto immune response where the immune system is trying to kill the HSV1 but ends up killing neurons which may not have been healthy or were infected? I'm just kind of curious where if there are any theories about where the volume loss comes from neurons.

DR. ITZHAKI: Yes, I think neuronal death is because, in general, herpes viruses -- HSV1, in particular -- does kill cells. It either kills the cells or, in some cases, to preserve itself. I mean, if a virus kills a person then you might as well say the virus itself has lost its ability to replicate. Was it has it has to replicate in in cells you can't replicate it on its own so it's to its advantage not always to kill cells but rather to remain latent in them. In which state it is thought to do probably very little to them. Not much is known about latency. It is quite mysterious.

I'm sorry. What was your question, again? Oh, it was, "Why do I think (brain) volume changes (in Alzheimer's Disease)?

I think, generally, the damage, when (HSV1) reactivates,it will kill the cells. It will definitely kill the cells. So that's why, presumably, there's a loss of volume; as a number of cells are killed.

Well, there's an interesting case, having to do with football, and also boxing, which is thought to be another cause, both of which do lead to dementia. It is known that head injury -- serious head injury -- damages the nerve fibers. And nerve fiber damage is thought to be another thing that reactivates dormant Herpes. So, obviously, there might be other things that happen. But we're saying that one possible explanation is that blows to the head damage nerve fibers, and that cause reactivation of herpes. Which then causes damage. And then, if it's damaged, then the virus replicates, and some cells simply die. Some must be left in a latent state, otherwise, it wouldn't go on for years. In this seamless, continuous cycle of replication. Then some stay latent or go latent. And then, later on, they react to it and so on. It's complicated.

CHRIS O'LEARY: It's the brain. So yes, I was wondering if you had any comments on Aducanumab (Aduhelm). My mom theoretically is eligible, I'm not going to do it, because it doesn't seem to make sense. It's ridiculously expensive for at best a small benefit. But also I mean, if there is a positive role for Amyloid, then it seems that keeping Amyloid from being able to perform that positive function could be a really terrible thing to do; could be a really bad mistake. I'm just curious if you have any thoughts on Aducanumad, Amyloid, and that kind of thing.

DR. ITZHAKI: I'm not a clinician. So the details are not clear. But, from what I gather, the one trial, it seemed to be partially successful, but in another trial it didn't. And so the fact that the FDA sanctioned (Aduhelm) is extraordinary. I agree with all the people, as much as I'm able to agree with them -- being rather ignorant -- that they think it should not have been allowed. And because, as you say, the price is ridiculous.

As far as Amyloid being possibly useful, I agree. There's another series of papers, which you wouldn't probably have come across, by -- the main person is named Karim Ezzat -- the sounds very interesting.

• High cerebrospinal amyloid-β 42 is associated with normal cognition in individuals with brain amyloidosis

He's done some very interesting work, that's aroused a huge amount of controversy -- although it hasn't yet been widely discussed -- but he reckons that Amyloid has nothing to do, necessarily, with the antimicrobial action, but it is a necessary a molecule that you NEED to have it.

And so again, getting rid of it, whatever its use, doesn't seem like a good idea at all.

If you are going to get rid of it you have to do it in a very careful way; get rid of it where there's a lot of it perhaps.

But, by then, it's probably too late.

I can't answer that very clearly, because I don't know whether Kareem Ezzat is correct or not. But I think his arguments are good. But I'm not a specialist in Amyloid. So I'm waiting to see what the reaction will be when it becomes a bit more public.

And as for the treatment that you mentioned -- the unpronounceable word, Aducanumab (Aduhelm) -- I think it's very, very risky.

And disgracefully expensive.

That is really shocking.

Chesterton's Fence
This part of the conversation brings to mind the idea of Chesterton's Fence, which is the idea that, if you don't know what something is FOR, don't go about CHANGING it.

CHRIS O'LEARY: All right, one last question. So going back to Kuhn's concept of "Crisis." You've endured shunning. There's a lot of Groupthink going on. I was just wondering if you could talk a little bit about the evidence for Crisis; that the field is in Crisis. Some of what you've endured, that you may not have talked about before. It may... I know... I'm sure it's traumatic and difficult, but I'm just kind of curious if you can give people an understanding of what a field in Crisis looks like and what it's like to endure that.

DR. ITZHAKI: Well, I think it's in crisis because there's evidence now that the numbers of people who are going to have the disease, but that people are living longer is going to be very, very large. And it's not only emotionally ghastly for people when they're at the stage when they know that -- if they know -- if they're told they're likely to have it or develop it. And there are obviously, sometimes people are told or sometimes not. I mean, that is dreadful for their carers. Extremely emotionally. Incredibly upsetting. And, of course, economically, it's terrible. So there's a crisis in that respect.

I suffered because as you say, I was rebutted and people were making sort of snide remarks about this and that and the other. Just really in the absence of any adequate arguments. And I think this might be true of other ideas that crop up or other results that have cropped up.

But I don't see how one's going to get over this is probably true in all scientific fields.

You've got to be skeptical of a new idea.

I accept that; that's very, very important.

Because, otherwise, you can get some really totally nonsensical ones.

And the there are ones that obviously -- you know, like, staring at the moon will kill you have this after the other or something like that -- you've got to be skeptical about that.

And you've got to make sure that it's repeated.

(Repeatable) by the same method or other methods which give the same conclusion.

But, after a certain time, and there's enough evidence, you've really got to take it seriously. Which is what a lot of Amyloid people, and people in the Alzheimer's Disease field, have not done.

Crisis? Yes, from the point of view of numbers. Crisis? Yes, people like me have had difficulty in the past. Maybe less difficulty now, because there are some people who support our work. And I think even NIH and NIA are starting to think there's something in it. It's just that the various reasons for why the opponents are opponents, one being that they've worked for so long lists them in the Amyloid field, they can't -- it's hard for them to accept -- that it might not have the importance they attached to it.

And the other is, a lot of them don't know anything -- quite understandably -- about viruses. Don't realized the particular characteristics of herpes viruses. Of being latent. Staying in the body indefinitely. In the present, one can't eliminate them. This will probably come in the future, but in the present one can't certainly can't get rid of them.

That, I suppose, is a crisis that the right work isn't being funded adequately. But maybe that will change and new ideas are being suppressed. But as I said, it happens in every scientific field. I think, I'm sure it was happening in cancer research with so many people doing it. Well, do an adequate amount.

CHRIS O'LEARY: No that's, that's... You're being honest and you're being forthright about it, which is exactly what it requires. I wish there was more of that. And less of the, "Pay no attention to that man behind the curtain," kind of arguments that I've been hearing. I appreciate your time. I appreciate your effort. I want to thank you for everything that you've done today. And in the past. It's very much appreciated. You're, a hero, a rock star to me. Thank you for the time. Thank you for all the effort. I think you've definitely advanced the world and made the world a better place. And I think a great thing.

DR. ITZHAKI: Thank you. Bye.

*   *   *

Chris O'Leary here with a quick postscript.

After I stopped recording, Dr. Itzhaki and I chatted for a few more minutes.

She made a point of reiterating a point she touched on in our interview. Something I think is both important and disturbing; that she — still — has NO idea why people object to her core theory. Because her detractors won't talk to her. Not even through the scientific journals, where scientists sometimes write letters.

She's been COMPLETELY shut out of things.

Because she's a woman?

Because they don't like her hair?

Because she's a City fan, and not a United fan?

I don't know.

Because she doesn't know.

Because people won't talk to her.

Which, yes, I get. In some ways. Science, among other things, is above all else, a HUMAN enterprise. Movies and romance notwithstanding, a VERY human enterprise. Maybe the MOST human enterprise. Give the rewards available. And thus subject to the limitations of humans.

But how many lives will that cost us?