337 - Endogenous Retroviruses and Disease, Dr. Arvinda Nath
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Kevin Folta: [00:00:00] Hello everybody. And welcome to today's podcast. A few weeks ago, we had on a guest that spoke about the new potential therapies for neurological disease issues like Ms. And ALS that promise not to just halt the disease or, or, or maybe limit the symptoms, but to actually reverse them because it interfered with the causative.

Kind of strange and elusive agent called an HGR veer, human endogenous retrovirus, that these viruses that were cataloged in the human genome that came back to life upon activation that lent to human disease. And this was a fascinating episode to me as a molecular biologist, that I started to drill down a little further into studying where else may these, these human endogenous retroviruses, where they may matter and what is their history?

Because we really glossed over that period. So today we're speaking with an expert at the national institutes of health we have on [00:01:00] the podcast today, Dr. Avenger Nath, he's the clinical director of the national Institute of neurological disorders and stroke at the national institutes of health. So welcome to the podcast, Dr.

Yeah, thank 

Arvinda Nath: you for having me on the podcast. 

Kevin Folta: I really appreciate you being with me because I've read a number of reviews and I've looked at some of the work that's out there, and I really appreciate the breadth of work that you've been associated with with respect to different versions of how this, how these HRV or Herve, how did they see that in the parlance of your discipline?

Arvinda Nath: So you know, I'm a neurologist and a got fascinated with these hers because they are really retroviruses and I'd been studying HIV. Decades when HIV was first discovered and we found that HIV can cause a dementia like illness and those infected with the virus. And then by happen chance, I saw a patient who had HIV infection and ALS, [00:02:00] and we treated that patient with antiretroviral drugs.

And the ALS actually got. So it turns out that there are several such rare cases published in the literature that seemed to have ALS like syndrome with HIV and they reversed with anti-retroviral drugs. So that send me looking to see, you know, what is it that is unusual about these patients? And when I started digging in there before.

A lot of people over many years had been reporting that they can find some kind of retroviral activity in ALS patients, but nobody's been able to figure out exactly what it really was. So we I had a fair bit of understanding. Retroviruses. And I thought that, okay, maybe we should look for in endogenous retrovirus.

So we made primers for various and dodginess retroviruses that were published in the literature and started looking and we found that one of them called the. Curve K [00:03:00] a was the one that was the most recently acquired in the human genome. And that was quite elevated in patients with ALS when we looked at the autopsy brain tissue.

So that set me into trying to understand the biology of these viruses, trying to understand how we acquired them and what happens to them. Under physiological conditions and under pathological. 

Kevin Folta: So this is really fascinating and I love the story. Maybe we can drill down on a little bit more about the HIV patient who received the antiretroviral therapy and cured the ALA.

We'll come back to that maybe, but can we even go back further? What is a retrovirus? And when we talk about hers, when you say this is one of the more recent ones. How, what our human endogenous retroviruses and how did they get there in when. 

Arvinda Nath: So it is, nobody knows how life actually started on this planet.

One you know, [00:04:00] hypothesis that it started as an RNA. Okay. If it started as an RNA, then you've got to figure out how did you get the DNA? And the only way you can get a DNA is if the RNA is, has to reverse translate. Into a DNA. So you need an enzyme called reverse transcriptase because normally we, you know, if you biology 1 0 1, people tell you you have the DNA and the DNA then forms the RNA and the RNA forms protein.

However, the reverse can happen too. So RNA can actually form DNA. So if the you have a situation where you have an RNA and a reverse transcriptase that can form DNA, then that becomes a retro virus of sorts. If it has. Proteins associated with it and other genes associated with it to make it into a viral particle.

In fact, most lifeforms evolve through retroviruses. Okay. So if you look at it you know, humans have not evolved for about a hundred thousand years or so we're exactly the same. We think that. We are very [00:05:00] different than our ancestors really are not. We just are more privileged than our ancestors.

If we took our ancestors out of the cave and gave them the Nintendo and the, and the fast cars and all that kind of stuff, they would probably do just as well as we are doing today. The the evolution occurred from Tim's to humans by the acquisition of retroviruses. So if you look at evolution, All species from non-human primers to humans, and the same way, if you could trace other species on the planet, what you will find is that every time they jump from one species to another, they acquire retroviral sequences and these retroviruses are all sexually transmitted.

Now you would think that what is the advantage of a virus to be sexually transmitted? What they're trying to do is they're trying to get into the general. Okay. So if a retrovirus now gets into a germline, then what will happen is the next offspring acquires good 10 kilo basis of new genome that it never had before.

And it [00:06:00] will now the army on that virus will reverse transcribed, become a DNA. And that DNA gets integrated into the existing human chromosome. Right. And if it gets integrated at the time of fertilization, then the new. Offspring that is being formed that has this new DNA now in all organ 

Kevin Folta: systems.

Yeah. So when you say sexually transmitted, you mean that they are pushed forward through the germ germline that they are passed on from generation to generation and accumulate through generation. 

Arvinda Nath: That's absolutely correct. So because this is a retrovirus and it says an RNA and it has a R reverse transcriptase.

So when it reverse, transcribes into the DNA, it will get integrated into the chromosomal DNA. Once it gets integrated into the fertilized egg, there, then all cells that are going to get formed from there. We'll have a copy of that genome. Now, what can happen is that [00:07:00] copy can now multiply itself in do into the new offspring, so it can cut and paste itself in different areas of the human genome.

And and sometimes insists sometimes in training. And so it can influence nearby genes in many different ways and can form new proteins and and RNA that weren't there in the in the specie and hence it will lead to the evolution of a new species. 

Kevin Folta: Right. There's a lot of good evidence of this, that a lot of the traits that are really important that separate us from other organisms or even, you know, differentiate even, you know, one plant from another.

And I believe even the evolution of speech in, in primates has a retroviral component where this gene, which can move functionally or viruses that can be inserted into the genome, have the ability to reshape. Expression of the other genes genes in the genetic neighborhood. And you [00:08:00] get enough of these accumulating in a snowball effect, your generations, and then essentially you lead to speciation.

And this is one of the drivers of that process. So. Yeah, 

Arvinda Nath: you're absolutely right. You know Barbara McClintock did the classical experiment and corn, you know, you understand plants a lot better than I do, but that's the only thing I know about plants or the discovery of the transports. And what she showed was that these kernels that have different colors are because the genes will jump.

And at that time, nobody believed her. They thought that, you know, you're born with a DNA and that's basically it. And it never actually. But she showed that no, actually deans can jump them and they jumped. They can get inserted in a particular area and it can produce a different color carnal in the same corn.

And it took many years before people believe that. But the reason these jumping genes are really. Came from retroviruses. So are some elements of a retrovirus [00:09:00] and a, and that's happening to this day in species a and it happened to humans and how we acquired these retroviruses or the process of evolution.

Kevin Folta: And I've seen some maps of this, like more, more evolutionary trees that show when the major events occurred. And it seems that that virus. Retroviral integration. And in that some of the major human indogenous retroviral events that you can almost, whether you can trace them and really I'd understand exactly when they occurred in the lineage of primates.

And so, can you, do you have any ideas to one, many of the really influential or historical ones happened just to give the listener some texture as to when this. 

Arvinda Nath: So we share a number of endogenous retroviruses with non-human primates. So that means that they're probably occurred at a time when we had a common ancestor.

Right. But then there are others that are specific to humans and you [00:10:00] will not find them in terms. And then one of them is this curve cake. And there've been several insertions of RFK into the human genome over a million years. But the last one was around a hundred thousand years. So the current human species probably evolved around that time.

How people figure that out. It's a little bit beyond my expertise, but people who know how to date DNA, that's how they figured these things out. 

Kevin Folta: But it's really interesting because you think about. The nonhuman primates, accumulating. These changes in these changes, leading to other, leading to morphological and behavioral changes, brain development, whatever that ultimately would lead to our evolution as a species.

And now we see some unusual residues of this that have, that are pathological or have some associated pathology. When activated, and this is what was really elusive to me. When I spoke with our previous [00:11:00] guests, you know, there's like a funny black box here. We have these retroviruses that are in the genome.

How do they turn? 

Arvinda Nath: Yeah. So the retroviruses, as I said, are absolutely critical in organogenesis and in fetal development. So what they do is they'll different ones will get activated at different stages of development and they will form the various organs. Once the organ is formed and the cells don't need to divide any longer, you don't want them because if they're going to keep dividing is going to form cancer.

So they shut down and they've done their job. There's some low level, low expression of some of these endogenous retroviruses, and people think they may have some physiological function, but the vast majority of them. Now, what will happen is that at some point let's say they get reactivated. Let's say you have some breast cell or something like that.

And you activate these endogenous retroviruses. Their job was to make cells [00:12:00] divide. So what they're going to do is they're going to push that cell to my ptosis and they do so then you're going to get rescue. Right. And it's been shown that a lot of cancers have activation of various endogenous retroviruses.

For example, the curve K that I study, you will find that, teratomas I mean, sorry, testicular carcinomas have very, very high levels of them that are expressed there. And then you can find it in a, several other cancers as well. Now, if you do the same thing and now you express it in the. And particularly in neurons.

Okay. So if you take an uncle gene, you say, okay, now I'm going to push this neuron into my ptosis. What's going to happen is the neuron cannot divide, right? You have the cell body up in your brain and the process goes all the way down into your leg or whatever, and down your spinal cord. And you try to push it into my process is just going to die because it just cannot.

So it looks like it's [00:13:00] diagrammatically opposite things happening. You have the same ideological agent, which is this an argument of retroviruses in one cell, it causes cancer. And the other one, it causes degeneration. And but however, it's the same process. That's doing both in a different circumstance.

Kevin Folta: Okay. So I think I, I get this, but, but I guess the, the thing that. Intrigues me about this, is that, how do you know that it is the Herv K that is causing it to happen rather than a result of it happening? Yes, yes. Yes. 

Arvinda Nath: So you're absolutely right. So the only way to know that is to shut the hurricane down and see if your impact the course of the day.

Right now in cancer has been a little bit hard. People have known about these activation of endogenous retroviruses for a very long time. However, what happens is that if it initiates the process in cancer, once the cell starts dividing, it just [00:14:00] is a self perpetuating process. Now, if you even shut it down, you don't impact the course of the.

However in neurodegenerative diseases, what we hope will happen is we think that it is critical in the process of neurodegeneration so that if you were to shut it down, you would stop the downstream pathways. And if so, maybe you will call it. The rest of the disease or slow down the progression of the disease.

But unless we do that, we will never know for sure. 

Kevin Folta: That's really interesting to me because, so what w how many Herb's are the, you mentioned Herv. K. And so how many different ones are there and do they associate with specific diseases? 

Arvinda Nath: Okay. So there are lots of earth. The classification of hers is a little bit complicated and and it has evolved over a period of time as well.

So although I simplistically say her cave, actually 11 subfamilies amongst her. And they call [00:15:00] HTML one through HTML 11. And and amongst those, the HMO two is the one that we most recently acquired and then they are. And, and so her case is still the most recent and amongst the substance. The HTML too, is even, is the most recent of the hurricanes that we acquire now, besides her K there are whole host of other hers too, but there are a lot more primitive.

And so they are not within the human genome. They're all fragment. Okay. So you don't have them as complete viral genome setting in one place, but you have bits and pieces of them scattered around. So over a period of evolution, once you acquire them, they are these viruses. What happens is that. And and there'll be bits and pieces of them scattered around the human genome.

So there's her H that's been implicated and for example, renal cancer there's her L a lot of these things, the other hers don't form proteins that will form our neighbors. They [00:16:00] won't form. No. Okay. The herb key has the ability to form proteins 

Kevin Folta: R this is, this is even getting more and more intriguing.

So if you look at, so these are protein, these are, let me go backwards. These are DNAs that are in your genes. And they comprise, you know, 8% of the genome, as I recall. So substantial part of the genome and maybe little fragments, a little bits here and there that maybe are maybe expressed as RNA or proteins, but how do you turn them on, what is it that in, you mentioned that, you know, these associations with cell division.

Is this something that they're heterochromatin denies, meaning like they're locked up in DNA in a way that put away the way the cell kind of stashes its genetic information in ways that can't be expressed where something causes them to all of a sudden. 

Arvinda Nath: Yes, you're absolutely right. So there's chromatin remodeling around these things and also they're epigenetically [00:17:00] silenced.

So they are methylated and acetylated so, but they're very tightly regulated. If they were easy to activate, then. Human genome or all lifeforms would be extinct. Right. So it's a, we try to see, okay. Let, why don't we take some deacetylation agents, put them on neurons and see if we can activate them.

We try. And nothing happened. Then we tried some D methylation agents. We said, let's activate it. Nothing happened is that, you know what maybe what we should do is make the neuron toxic, put some toxin on their neurons. Why don't we put hydrogen peroxide? So it'll make cause oxidative stress or we'll take an MDA and cause excited toxicity on it.

We try. And all of these mechanisms, none of them activated. And then we started doing combinations of things and we found that, okay, if you now DSM isolate and demodulate at the same time, you can activate the hurricane. Right? So these things are, [00:18:00] it taught us two things. Number one, that they're very tightly regulated.

The second thing is they're not activated through the process of neurodegeneration rather than activation causes neuro degeneration. 

Kevin Folta: Okay, so this is kind of interesting. So if, if just for the listeners out there, we talk about the methylation and deacetylation, these are essentially small chemical decorations that are added to DNA that affect its packaging.

And so frequently when we have genes that we want to silence epigenetically, as we say, this'll happen as a consequence of decoration of DNA with these aside or not the the decoration of DNA and with. The histones. So the proteins that package DNA, that these change in ways that maybe make the DNA difficult or inaccessible to be able to express.

And that's where a lot of these latent islands of information or, or maybe the ones that are. You know, as you're a fetus, but never again in your life, if you're lucky, that's where they put these. So, so what we're looking at in the [00:19:00] description here is that these are DNAs that are locked away with certain patterns of, of chemical modification that allow them to not be turned on and then they are, and this is some have also been linked to.

New viral infection. So what's the role of new viruses or new infections in the role of turning on these endogenous retrovirus? 

Arvinda Nath: Yeah, you explained that very well. So yes, it is quite possible that certain other viruses could activate them. So, and perfect. And a lot of retroviruses share the same transcription factors as well as the same regulatory factors within the.

And so the example I gave you a patient with HIV infection would well, they last, what we found was that in those patients, the RFK was activated. And when we shut [00:20:00] down the HIV, the LS got better because the Herv K got shut down. So is that okay? What is really activating her? K and I am HIV infected. So we knew that HIV has laboratory proteins, for example, rev and tat protein.

And that that is critical for transactivation of HIV and rev is important for nuclear export of the art. Horrific case or being a more primitive retrovirus does not have the tat protein there or the gene for the tat protein. And it also is missing a number of other regulatory proteins. So we took the hurricane DNA and the LTR, which is the regulatory region.

Of the the promoter region of the virus. And transfected the gene for tat on there, along with Reverend, we found that there was massive activation of heart. Okay, so dad alone can do it. And if you do tat and rev together, you get a synergistic response. So that told us that there is [00:21:00] crosstalk between these viruses.

One virus can activate the other. 

Kevin Folta: So this is in tissue culture, right? So you're you're so you're essentially you're. You're expressing these, these proteins and maybe even delivering these with viruses or transecting them, or how are you 

Arvinda Nath: delivering these plasma and then 

Kevin Folta: transfer. Okay. So, so just putting in the plasma it alone and creating this protein awakens, these endogenous retrovirus.

Yeah. So, you know, this is a fascinating part of biology that I, I, I just love, I'm so glad we're talking. This is Dr. A vendor NAF. He's the clinical director of the national Institute of neurological disorders and stroke. And we're talking about human endogenous retroviruses, and they're, they're very mysterious yet.

Probably very significant contribution to human disease. This is the talking biotech podcast and we'll be back in just.

And now we're back on the talking [00:22:00] biotech podcast. We're speaking with Dr. Avenger NAF. He's a clinical director at the national Institute of neurological disorders and stroke. And we're speaking about these human endogenous retroviruses, which are parts of all of our genomes in a way. I don't want to make a bad analogy, but in a way, almost like ticking time bombs, they're there to make us human yet at the same time.

Can also work against us if they become pathological and these latent genes, which can control many important facets of our development can become active upon new infection. And so when we're speaking with Dr. Nath, one of the ways you, you came on my radar was, was reading the story of treating an HIV patient, an HIV positive patient who also unfortunately had ALS.

And when you treated. With antiretroviral drugs, HIV being human retrovirus, the ALS seemed to subside. [00:23:00] So can you tell me more about that particular story and were you really reversing ALS or just kind of arresting the simple. 

Arvinda Nath: So that is the thing that fascinated me the most. I couldn't believe my eyes.

The first patient I saw was this young guy. He was a hemophiliac and he had acquired HIV infections with blood transfusion and he was in his twenties at the time. And, you know, he'd take us pills. I wouldn't take his pills. You know, I was doing fine and, but the viral load was extremely high. So when I, when he developed symptoms of Alyssa was progressing really fast.

I mean, he it was around about Thanksgiving. He said he noticed that he couldn't lift the window really well. At Christmas, he was getting weakened, both his legs. And so when I suggested to him that he needs to take the anti-retroviral drugs on a regular basis, he says, doc, why should I bother now? I mean, I'm going to, I haven't died of HIV, all this.

Well, I'm going to die away. [00:24:00] Anyways, so as I know, there is a case report in the literature suggesting that anti-retroviral drugs can actually impact the course in patients who have both of these things. So. And I see him a month later and all his symptoms were gone. I said, this is absolutely bizarre.

I mean, the analyst never gets better. Right. And the neurons that are dead are not going to come back. So how did this guy go? So now over a period of time, we then saw several patients. Some got better. Some did not get better. Some actually their disease slowed down and they live for over a decade. And now that I followed these patients for a long time, So the difference is the critical period is the timing of starting of the anti-retroviral.

If you were to start it within six months of onset of the symptoms, you can actually reverse the course. If you start it after six months or a year later, you may be able to slow down the progression of the disease. If you started much more later and you don't impact it at all. [00:25:00] So that means. In the early part of the course of ALS the neurons are not dead yet, but their new rates may be retracting.

They are a dysfunctional, but not totally. And so there's an opportunity to reverse them that teaches us a lot about garden variety, ELs. And so if you're going to have something that you can impact it, you got to impact it early on. And after that there's a time comes when neurons start dying and now it's going to be hard to reverse the 

Kevin Folta: process, but this is really interesting.

How old was this patient? 

Arvinda Nath: He was in his 

Kevin Folta: twenties. Yeah. So, so that's like usually way out of the scope of when ALS was present for physical. 

Arvinda Nath: Yeah, absolutely. Right. That's the other fascinating thing. These patients are fairly young. No, 

Kevin Folta: but so at that point you still have some plasticity where perhaps a intervention that would allow you to reverse.

Neurological disease and I'm speaking well outside of my ballpark here, as as you know, [00:26:00] plant photo morphogenesis expert is it seems to me that, that those neurons have already made a decision. And they're going to continue this route of either either break down or is there really a neurological repair circuit that's realistic where you could actually reverse ALS in somebody who was young enough, if you caught it early.

That is 

Arvinda Nath: absolutely true. So now you can extrapolate from there, you can say, okay, what if they, what about patients who have ALS and do not have HIV? If we were to get them and director wild rice, would they get better or not? Right. So, so what happened is that we published a paper whereby we looked at all the anti-retroviral or.

In culture that is, and we treated her key with the enter various anti-retroviral drugs and compared to what happens with HIV. And we found that they do have some effect against her of K but not as well as they [00:27:00] were effective against HIV itself, except for one drug seem to be actually better against her if K, compared to HIV.

And that's called it. So when we publish that and we published our original paper showing that a hurricane can cause an ELs like syndrome because he made these transgenic mice with the envelope. And we showed that these transgenic mice develop an ALS like syndrome and the healthcare was activated in less patients.

There was an infectious disease doc that Julian gold in Australia, he wrote to me, he was in England at that time. And he says, I'm on my way back to Australia. And can I stop by and talk to you because of, and I said, well, it doesn't sound like Washington DC is on your way back Sydney. And I thought he must have some other business over here or whatever.

I said, sure, come on by. And then I thought I would never actually see him, but then I see he's waiting outside my [00:28:00] office and I was like, oh my God, you came all the way there. Talk to me about that. And so what he tried to convince me, he says, it's absolutely based on your findings. He says, it's absolutely unethical not to treat patients who have ALS with antiretroviral drugs and he's an infectious disease doc.

So he knows that these anti-retroviral drugs, you know, we have a lot of experience with them and HIV patients and the newer ones are fairly safe. And so he says it's absolutely unethical. And I said, that's an interesting approach. I tried to convince him it's absolutely unethical to treat patients with anti-retroviral.

So the argument I made to him was I said, All the, you can do all the things in culture. You can do all the things that animals you can do all the experiments. But when you do things in humans, many times you get surprised and I've practiced neurology for 40 years and I've participated in all kinds of clinical trials.[00:29:00] 

And I know that despite our best intentions, sometimes you can end up hurting people. For example, minus cycling, you would say that. And antibiotic people take it for acne. It's very safe. There were a lot of experimental data suggesting it could be actually helpful in ALS patients when a proper clinical trial was done, it actually made them worse, not better.

And I can give you multiple examples of these kinds of things, where we thought that. Agent retired that this will help multiple sclerosis patients. And there there's all kinds of animal models and data years and years of work. And then when we finally treated patients with it, they all develop relapses.

Same thing with Alzheimer's. We have all these inhibitors of base enzyme, and that if you prevent the formation of amyloid, patients will get better. They actually got through. Yeah. So and so I told him that, listen, if you're going to do this, you should do it in the context of a clinical trial. Okay.

And if you're going to do a clinical trial and you make sure you collect [00:30:00] blood and spinal fluid for me, because I want to analyze them to see what's happening with her case. So he went back to Australia, he called around some money. He actually treated 40 patients. And because it was done on a shoestring budget, he managed to collect some blood, but no spinal fluid.

So but he got us the the serum samples from these patients, we analyzed it and we found, yeah, they had, the hurricane levels could be detected in a subgroup of them. And over a period of 24 weeks, the levels of hurricane actually started coming down, but they never came down to zero. They did come down.

And when these patients went off the anti-retroviral drugs, their levels shot back up again within one week, the shot backup. So then before now I said open label study. So you one has to take it with a pinch of salt, you know? And it's a small sample size. So that's the caveat for board for whatever it's worth.

Then we look, we divided those 40 patients into groups of individuals and whom the hurricane levels came down and there were [00:31:00] some patients in whom the health care levels. And actually went up. So we said, okay, let's compare these two groups and see how they do clinically. So it looks like the ones in which the hurricane levels actually came down.

Their disease did not progress as rapidly as the ones in which the herb care levels never changed. Right. So now Julian gold are very interested. He tried to now convince all the neurologists there that we need to do a better, bigger, and better study, a double blind study and and treat patients with the same combination of anti-retroviral drugs and actually find out once.

And for sure whether it has any impact or not. So that's where he stands right now. I think he's managed to convince people he's managed to get some funding and he's in the process of starting another So we'll see what actually comes of it. 

Kevin Folta: Well, I have some thoughts on that. So first, and I'll mention this just because Mr.

Wooster was my teacher in health [00:32:00] class in eighth grade, and he still follows me on Twitter. And Mr. Wooster wrote something on the board one day and he said, there's no such thing as a free lunch. And he was speaking with regard to pharmacological effects of drugs. And so this is really what you're speaking about here.

That even though you can demonstrate this in tissue culture, it's physiological effect. If pharmacological effect, whether it's bioavailability, how can it get to the tissues? It needs all that stuff that remains to be seen. And that's, what's being tested now, but. There has been a cohort of people that since the mid 1990s, or even early 1990s, the magic Johnson's and folks like that, that have been receiving intensive antiretroviral therapies on a daily basis.

And do those folks in epidemiological profiles show less evidence of long-term neurological disease. 

Arvinda Nath: So that's a really good point. The problem is diseases like ALS. [00:33:00] They are not reportable diseases. So you don't have good data to be able to extrapolate that. Now, if there was a increase, you would have found that out pretty quickly.

People will start reporting. If there is a decrease, it's very hard to figure that out unless you had a reportable illness. Yeah. So I went to the CDC, the CDC has a database and we couldn't figure anything out from. Julian thinks that in Australia they should be able to collect data on it, but I don't think he's gotten it either.

It's possible that maybe the national health service in the UK, maybe a place to go ALS is again, a clinical diagnosis. And you have to make sure the accuracy is correct. It's not like you can do a blood test and figure it out that this is what the patient had. So it's a bit complicated in our group, but your idea is absolutely correct.

Eh, 

Kevin Folta: cause it's all it's diagnosed post-mortem typically, or is it, how, what are [00:34:00] the markers that are used to say yes, this is a confirmed case available. 

Arvinda Nath: Basically your neurologist says you have ALS you have 

Kevin Folta: so, so could, could ALS have several different layers of different types of neurological pathologies that are related or present the same yet?

Have very different etiology. 

Arvinda Nath: Yes, I think you're absolutely right. Let's drew up most neurological syndromes. Yeah. And. Yeah, same through a Parkinson's disease. And Alzheimer's you think that these diseases are iron and stone and exactly a neurologist knows what is what, and that's not really true. I think there there's a fair bit of heterogeneity to these diseases and and unless we understand the genetic basis of these.

Our dwell biomarkers, that's going to be very hard to be absolutely certain, but yes, there are a number of familial forms of ALS where genes have been identified, but are still about 90% of [00:35:00] individuals who are sporadic, ALS that don't have a family history. And amongst them, if you look for genes, you'll find another 10%.

You could probably find a genetic cause for it. But the 80% of them, you don't find any genetic causes. 

Kevin Folta: Oh, this is really fascinating. And one of the papers that's come out in the last year or so that's been really on my radar is that you induce. Proteins in response to COVID infection. And that turns out to be a very predictable biomarker for COVID-19 infection.

Severity is elevation of her proteins. And have you seen any of these data and do you have any thoughts on how these may be contributing to long COVID symptoms? Symptoms? 

Arvinda Nath: Okay. Yeah, we wrote an editorial on that paper. So they showed her w being activated in macrophages. Patients who are severely ill with with COVID.

So the next stage is to see if it's also activated in individuals who have long COVID. [00:36:00] And if that's the case, then yes. One can dampen that down. It would be worthwhile seeing if it impacts the course of the disease, but again, all of these things have to be done in the context of clinical. 

Kevin Folta: I understand that.

And it's kind of frustrating because we talk about the vaccine for instance, and also these you know antibody treatments, the monoclonal antibodies, but there may be an argument out there that we use these. Antiretroviral cocktails for HIV. That seemed to be extremely safe at this point. And should that be part of a COVID therapy?

And when you talk about, is it ethical or unethical? It really raises some important questions. 

Arvinda Nath: Okay. So now there's a little bit of a difference between her w and her, the COVID patients that show her w activation not hurricane her. W it's only the sensitive, which is the envelope that is activated. It's not the [00:37:00] reverse transcriptase.

So the antiretroviral drugs would not be expected to impact the expression of her. W. 

Kevin Folta: I see that. Okay. So, so it's a different part of the retrovirus that's being expressed. And not 

Arvinda Nath: only that part of it, I can form protein. 

Kevin Folta: I see. So, so there is a possibility of causing other pathologies, but the retroviral therapy ha would have no effect on that.

Okay. You know, this has all been really fascinating and really help drill down on this. You mentioned earlier things like testicular cancer. Renal cancers that are, can be ascribed to specific curves. Are there, is there increasing evidence that specific Herb's may be playing roles in cancers? And are there specific targets that you're aware of that may be, you know, ultimately, maybe retroviral therapies may play a role.

And addressing those kinds of cancers. 

Arvinda Nath: So I don't know about anti-retroviral therapy [00:38:00] in cancer, but what is what the cancer guys are doing it. So for example, with the renal cancer is a. Ecologist here, Richard towels and at NIH. And he showed that her E is and is activated and in renal cancer, three or cell carcinoma of the kidney and what he used that he said, okay, if it's being expressed, and this is only expressed in the cancer, what you can do is now do T cells that are directed against that retro while.

Right. So now you are to score car T cell therapies is the big thing these days and cancer. And so now if you can do up these T-cells that are going to now precisely go and attack that retroviral antigen it'll attack, only those cells that are those cancer cells that are expressing it. And maybe that way you can treat that cancer, it becomes a tumor antigen.

Kevin Folta: No, that that makes a lot of sense. We've we've talked a lot about car T cell therapies on the [00:39:00] podcast over the years. And this is, you know, seems like another really excellent application because those would be antigens that would be expressed strictly in those rapidly proliferating cells. Yeah. Well, all of this has been really fascinating.

Are you ever looking for someone to come up there on sabbatical? Like a good molecular biologist who really likes to work hard and maybe do podcasts now, and then

I'll tell you, I am. I am. It just to me as a scientist, this seems like just, just like like w like, like scientists like you and some others have hit the pinata and there's candy on the floor here to pick up with so many interesting interventions into what are some of the most insidious human diseases.

And here's an opportunity for us to maybe to get to the basis of those. So, if you had to get out your crystal ball and look at what are the therapeutic targets [00:40:00] of Herb's. So the things that may be realistically may be resolved through some sort of either a antiretroviral or antibody therapy. Are there some low-hanging fruit that you believe may be diseases or pathologies that might.

Be addressed in the next decade by focusing on the Herb's. 

Arvinda Nath: So my passion really is to try and understand the role of these retroviruses or retroviral genes and neurodegenerative diseases. You know, if you look at the total burden of neurodegenerative diseases for humans on this planet right now, that's the one that's increasing as lifespan is increasing.

So are all the. Everything we've done so far has failed to treat everything. And I think the reason is that we're fighting against just a very small part of the human genome. That's the protein coding region, which is only 3% of the humans here. While you have all [00:41:00] this other part of the human genome that has these retroviral sequences and nobody's ever studied, though.

I think if one were to study them, you have a whole host of new therapeutic targets that would open. And so I really think that it would be very wise for us to invest resources into understanding these viral genes in the context of neurodegenerative diseases and manipulate them. And you can manipulate them, not just when direct a while, but you have genetic therapies.

For example, antisense molecules, Atmos associated viral electors. Now there are many different ways in metal plating. These genes, sir. And so and, and see if you can actually impact these diseases. I think that to me would be the new frontier. 

Kevin Folta: Well, this makes me really happy because I feel the same way you do, as people are not dying of pneumonia and heart attacks and the old school things that killed us at 45 or 50 [00:42:00] people are living longer.

Nerd generative disease is not just a toll. Individuals, but also on families and on society. And then on national health care, it's extremely expensive to D to deal with and treat the long-term degenerative care of people who have healthy hearts and healthy everything else. So this is the next big frontier.

So Dr. thank you so much for joining me on this. It makes me so happy to talk to you and understand this process better. So. 

Arvinda Nath: Well, if there's such a player, so let me leave you with one last thought, govern. Okay. 

Kevin Folta: One last 

Arvinda Nath: I love it. So, you know, we make nature re complicated. The rules of nature are very simple.

Okay. So if you look at it, the very genes that are important in our existence, which are, for example, these retrovirals, you know, you need them for development of all your organs, all that kind of stuff. Right. You need them, but then it is the same, very things that. Take us out in the end, they cause cancer [00:43:00] neurodegeneration.

They suppress our immune system and and the like, and so the is this such a simplistic way of thinking about it that we, we don't need to think about re complicated mechanisms as to how these diseases are occurring and then we never make any kind of headway. But I think if you think in these simplistic terms, we can really understand.

W the existence of human life and what really it's, how it occurs and how it ends. Does that make sense? That makes 

Kevin Folta: perfect sense to me. I think it's a really profound statement that maybe we're overthinking this a little bit and that we have to get back to the roots of how does change and development really occur and what are the roots of it.

And not just what are the major markers that are easy to find, but maybe what are these little more hidden and latent things that we've never considered. And, you know, we, we, we might join back on the podcast in 10 more years and see the huge role that. Human endogenous [00:44:00] retroviruses play. So I don't know.

We'll see how it goes. So well, let's stop there and let me thank all the listeners for being loyal listeners. This weekly podcast, our numbers have never been better. And I hope that intriguing guests like doc Dr. Neff really do continue to stoke your ability to be hopeful about the future that biotechnology can bring and your assistance in sharing this podcast with others that may benefit from understanding the whole.

That previous problems that maybe thought to be hopeless, maybe can be solved. So this is the talking biotech podcast, and we'll talk to you again next week.