Medical Research & Advancements, with Dr. Alessio Fasano

Longevity is mostly related to a state of inflammation when we start to have an increased destruction and not the capability to resupply. That's when we tilt the point in our return and we start that process of aging that will bring us down.

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Welcome to the Five Journeys podcast. Live like youe Matter. I am beyond psyched for our guest today because it's Dr. Alessio Fasano, Director of the center for Celiac Research and Treatment at Mass General Hospital for Children in Boston, Massachusetts. He's the author of Gluten Freedom, a book for general readers about celiac disease and gluten related disorders, and co author, with Susie Flaherty, of Gut Feelings, the Microbiome and Our health, published in March 2021 by MIT Press. Welcome, Dr. Fasano.

Thank you, Wendy.

Very welcome.

So I want to talk about Zonulins because literally when I read that paper, I was like, this is the root cause of autoimmune disease. This is why you get brain fog. This is why people get so sick. It's just fascinating to me, how did you get into Zonulins?

So long, long time ago, I was very much interested to how microorganisms interact with us, how they can cross talk and what is the outcome of this interaction. At that time, we were looking at one microorganism at a time, not as we do now with this whole ecosystem that we call the microbiome. My interest was on cholera, believe it or not, because when I went to medical school and I was trying to find a niche to save the world and I was thinking to got in research with cancer or something, my boss at that time that became my mentor, said, you don't want to do that. You want to focus on diarrheal diseases. I said, you're joking, right? Diarrhea, diseases, it's not glamorous.

Are you shitting me?

That's right. You shouldn't be. And he said, you know that every year, this was again a while ago, 5 million kids die because diarrhea. And that changed the prospect of the story. And the following few years I studied with him the physiology of the gastrointestinal tract. And again in my Naive kind of approach on life. I told them, I know everything about the host. Now I need to learn about the bug. Where should I go? And he said, well, I think that the best place is in United States, in Maryland, in Baltimore. The place is called center for Vaccine Development. They do this kind of stuff on enteric pathogens, including cholera. You go there and the following two years I was in Baltimore studying this bug and ultimately to develop a vaccine. So in other words, something that eventually can be given to kids that will not die of cholera. And the approach taken was to take the bug and take it out. The weapons that he used to make this purging diarrhea that make people dying with color because of dehydration. This was at the beginning that molecular biology allow us to cut and paste genes. So there was very cool stuff. And eventually I was put in charge in doing that on this bug. And after a fair amount of time and a lot of failures, I was able to develop this live attenuate vaccine that did not produce this huge purging of diarrhea in animal models. Because the bug did not have the weapon anymore. There was this very powerful toxins that is called cholera. To time was ready for prime time so that we had to give this to volunteers. Volunteers meaning medical students, obviously fair amount of money.

Wait, wait, wait, Alessio. Did you give them cholera and then test the vaccine on them? Or like how did you test that it worked?

Exactly. The way they went was they were paid a huge amount of money, $500 to be locked in. Because of course you don't want to spread cold around in a facility at University of Maryland. And you had three chances. One, placebo, so water. So you will take $500 for nothing. Two, my vaccine that will work because I showed in animals that they were not sick. Or three, the real deal, you shit your pants. But we would take care of you. Two out of the three though was in your favor. So that was the premise. And we did the trial, it did not work. I mean, you know, the placebo didn't get sick. The folks you know that you know, got the real deal end up to have up to 10 gallons of diarrhea. But we took care of them. The ones that they got the color of vaccine had much less diarrhea, but still enough a couple of gallons of diarrhea that made the vaccine not suitable. So bottom line, two years just flushed in the toilets. Literally. So I got drunk for a couple of days and didn't show up in the lab.

Phase years.

Okay, but I digress. And then, you know, again, typically what distinguishes, you know, somebody that has the intellectual curiosity to do research. I went back to the blackboard and said, what went wrong? How come that, you know, this vaccine did not work and, you know, end up to discover another toxin besides, you know, the powerful one that I took out, you know, by genetic engineering, the vaccine that rather than purge water through the cell as the typical tox, they do, they loosen up the space in between cells. So these gates that keep the cells tied together, there was a black box at that time because we little knew that this space was dynamic. There was just the beginning understanding that you can even increase opening of the space in between cells. Therefore, this toxin was a brand new category autoxin with a very different and peculiar mechanism of action. I start to study the mechanism of action. I got more and more insider of what this key open this gate in between cells do to reach the point which, gee, this toxin goes after a very sophisticated machinery of these cells. I can't believe that this mach just to be the target of a bug that makes us sick, probably cholera, has been smart enough to understand and exploit something that we do for other purposes ourselves. So that led me to think there must be a counterpart molecule that does this job for us to open and close these gates in between cells. And that's how we discover the first member of the zoning family that was.

In the brain, right? It wasn't in the gut.

I think at the beginning we. Well, actually we discovered, you know, in the brain the receptor. And there was the brain first. But then, you know, we discovered these families. That is, they are everywhere. They are in the gut, they are in the heart, they are in the brain, the kidney, and so on and so forth. And of course, you know, after the discovery, we start to ask what this molecule does for a living, why we have it. And we realize that's important for some physiological reasons and as typically happen when you push physiology to the limits, you get into the disease, you know, territory and, you know, we start asking, you know, what kind of disease may have an issue in which you don't control the trafficking of the junk from the environment into your body that can eventually have consequences, of course, food allergies, chronic inflammation, they were on the list. But I was very much interested, for personal reason in our immunity. And that's how I focus mainly on autoimmune disease, because that's also an issue which we little knew that beside the genetic predisposition and disposure, something in the environment that makes you Sick. There is also the need that this instigator needs to come in our body. There was no port of entry that we're aware of. These are molecules, are very large. These are in general proteins that we instigate immune system to mount an immune response against their own body. And that cannot come through unless something goes wrong in these gates. And that's how the rest is history.

I want to go back to the work that you're doing. Are you allowed to talk about the medicine? Because I never want to eat gluten and it's gotten 95% better. But I, you know, I'll still get a headache, I'll still have some brain fog and my gut still reacts like.

Tiny, tiny amount of cross contamination.

Oh yeah, tiny cross contamination. So, so, so can you talk about the medicine you're developing and when's it going to come to market? No pressure, Alessio, but I've really been waiting for years.

The medicine that you are alluding to, this lorazozide, is an inhibitor of this zonolin. In other words, it binds to receptor and doesn't allow zoning to signal to the cell to open this gates, has been developed enough for a while. Is now in the phase three trial for celiac disease. We end up to have the possibility to use the same molecule because zoning is involved also in the pathogenesis. Some long Covid complications, particularly in kids. What we call the multi organ inflammatory system or MIS C syndrome. MIS C now is in phase two trial there. What this model does is stop this trafficking for CT disease of gluten, for mis C of this spike protein from COVID 19 from the gut into the bloodstream that caused the cytokine storm that makes this Fox 6 and so on and so forth. You know, drug development is a very long and inefficient route. You know, now we talk about phase three for CD disease. The phase three is still ongoing, May fail anytime or may be successful anytime. So when you say how long it takes, I don't know. The only thing that I know for the little that I've been involved. I work in academia. But you know, I helped to set up this company that's, you know, now it's non existent anymore, that it was in charge of this molecule is when you bring this molecule from the doorsteps of science to clinical applicability. The success of failure depends not on the science anymore, but business choice, study design, how you cut corners. So you do this right. Economic crisis like we had in 2008, so there was no money to do any trials, a pandemic that makes recruiting impossible. So there are so many things that can derail the process. So I cannot answer the question if and when this molecule will be on the market. But the idea is indeed, as your beloved husband was saying, a safety net. So that you know that all the time, particularly when you're outside of your household, because home you know what you're doing, there is a chance that somebody will not do the job right. Taking the pill that will allow you to have that peace of mind that you will be protected in case cross contamination makes a world of difference. Foresee the disease for which we know the trigger. Imagine all the autoimmune disease for which we don't know the trigger. So we don't have the option to take anything out that will protect eventually if it works also for these other immune diseases to have this trafficking of God knows what that makes these people sick.

What are the downsides? Out of curiosity for the drug?

The downsides is that you have to take this every single time that you eat. Because there can be a good thing or bad thing because its action, it's like for two, three hours. And therefore you have to take this often. But on the other hand, the fact that the short lived avoids complication and blocking the system that must be there because we need it and acts in the gut, so it doesn't go systemically. So in general, side effects are due to the presence of something that doesn't belong to your body in your bloodstream. And this doesn't go there. These are the features you have to take that for life because there is not a cure the treatment. So that's the other downside is so.

When are we getting the CRISPR change gene change to fix all the Celiacs?

You know, I don't know if genetic editing would be the solution. Actually, you know, personally, you know, if you're born with the genes and we talk about CT disease, but we can talk about again anything else, Alzheimer's, breast cancer and so on and so forth, the gene editing. It's such difficult path to follow. But I believe that learning what kind of mistakes that made us to accelerate the incidence of this stuff will allow us to do what I believe will be much easier prevention, primary prevention. Try to intercept that rather than fix one is already broken. So my dream is to be the Jeff Lub of the situation. So that you come to me to change your oil rather than the mechanic of the situation that you. Because I am the mechanic now you come when your engine is broken and I Have to fix your engine. It's much more complicated, it's much more costly to do that. And in that sense we have two big projects ongoing. One is on CD disease and the other one is on autism. To try to understand on a specific genetic background of risk, because these are neonates that they have somebody in the family with either disease. How come that some of these kids will eventually derail and develop serious disease or autism and others stay put and would not. We do what we call now this multiomics. We look at the genes, we look at the microbiome, we look at their zolins, we look at their proteomics, the metabolomic profiling and trying to see any sign that will suggest me that they are making that turn that will lead to that final destination. That's wrong one. And now we start to see that there are particularly derailment in the microbiome that epigenetically will make motion some genes that will influence gut permeability or permeability because its biosis will increase zoning. Then eventually we start the march from genetic predisposition to clinical outcome. And this require huge amount of data that needs to be modeled to artificial intelligence to do prediction model. So that if I know that when they shift the microbiome in a certain way, and the model is telling me that because of that in 10 years her chance to develop Alzheimer's is 75% I have a way to bring her back and say I changed the microbiome so I epigenetically turn off what has been turned on and this is not going to happen. Prevention again is much cheaper than treatment. And by the way, because the goal is quality of life and containing the health care expenses, it's a win win situation for everybody, for the patients, for the health insurance, for who cares about our population in terms of political, social issues and so on. So I see this as a future. Your office, for example, somebody goes to Wendy's office and that will be me. I give her my genomic chip that I have on my chain here. She looks into the computer with 23,000 genes and she will eventually receive also the stool samples that I brought with me because she told me to do so. And she's going to put in the back of her office in the machine that would analyze the microbiome while we talk. And we'll also do some epigenetic analysis. And by the time that she finished her physical exam on me, she has all this data in the computer that is now comparing this data to gaddillions of similar Data, that model, what will be the outcome when all these pieces, they come together? She would tell me, yeah, Alicia, you are fine. You will live healthy until age 72.5, after which you have 92% chance to develop Parkinson's. And we need to change this by manipulating what I can. That is your microbiome and this is what you need to do. Come back in six months and let's see if we made this happening. I come back in six months, we go through the same routine. She do the modeling and say, oh, that risk for 92% now is 5%. I think that that's stay put there. And she can give me probiotics, symbiotics, prebiotics, a diet. Because I'm pretty sure that the future is. Most of the diseases can be handled with the diet because of what I'm telling you that the microbiome is so influential for so many reasons, why we develop diseases, that as we derail by changing the microbiome, we can bring this back. And when I say microbiome, I intend the zone and the antigen traffic and all night yards because they all influence each other. It would be much better to do that way.

Yeah, I mean that requires quantum computing. My guess.

Well, Genova Diagnostics is doing that now on the stool samples. It's a report that drives me nuts. And we said to them, this report drives us nuts. It drives the patients nuts. Put it towards the end because people would get stuck on. People with your similar microbiome often have these different things. It's still there where they go the up and the down.

The Genoa principle, it's, it's, it's correct. It's not mature though for prime time use because we don't have all this data, we don't have that mathematical modeling that's been building. That's what we're doing now. But we have to, we're running. You need to learn walking and before walking you need to learn crowing. We are barely sitting and not standing yet.

I don't even think we're pushing up. You know, we're flat, we're flat. Just try to turn your head exactly right.

But we will be able to at some point. So. But you know, again, of course there are some, it's not, I'm not saying this is Genova's case, but there are some companies that are trying to really exploit the potentials running what we don't know how to run yet. And we made take misstep, so to speak, you know, and again, because I know what kind of healthcare business, you guys involved. Ultimately, our goal as healthcare professional is to improve the quality of life for people. That's what it is. No more, no less, no matter what it takes. And you know, for me, you know, when I got a pushback and said, geez, you know, you're saying that we're, you know, doing some, some anything wrong right now, but you know, life expectancy now is eight years. It's now 14 years like was, you know, 2 million years ago. And that's, that's true. But how we achieve their goals, major milestones. You know, we were spending 95% for procurement, the 5% appropriation. That's what we're doing 2 million years ago, you know, when we, with the event of agriculture, domesticated food and crops, There was a major milestone 10,000 years ago. Now we free up time to build Eiffel Tower, the Colosseum, because now we can unleash the creativity. We have more time. But when we reach the point in which you ask yourself, it's better to live up to 60 but self sufficient, healthy, or up to 80 but on a wheelchair with the tube of your nose and, and you know, pull ups because you should do your pants.

Quality over quantity.

Well, it's health.

Healthspan versus lifespan.

That's right. I believe that both can be achieved if we made the right choices that are not that hard to, you know, put on a piece of paper, but extremely hard to implement. We go back to the dominance. For example, longevity. Longevity is mostly related to a state of inflammation. Matter of fact, it's called inflammation. All our cells in our body, they are destroyed and resupplied with new cells. With a few exceptions. When we start to have an increased destruction and not the capability to resupply, that's when we tilt the point in our return and we start that process of aging that will bring us down to a point of no return and we die. Unless again, intervening disease will speed up the process. If you look at ultracentenaria, their level of zoneline is extremely low compared to people in the 40s on the 50s with cardiovascular diseases.

It all ties in, unfortunately.

We got to actually I could legit.

Chat with you all day. So Alyssa, where we'll put everything in the show notes. Is there something in particular you want people to follow you on or find you or like which? Both books. Like what do you want to tell people as we sort of close down?

I think that again most of the stuff that we discuss is in the book that Susan I put together. There was a work of love and sweat and pain. Because we're writing on the microbiome when you write it chapter and then you move to the next and the previous chapter already obsolete because you know the literature there's. I've never seen anything like this. It's still hot. 700 papers a day comes out. I don't have any comparison any other field in the past. And that yeah I. You know again we. We try to really put some fundamental pillars that would not change in the discussion there so that the book will not become obsolete. A matter of fact we finished the book wrap it up given to the editor that Covid came so we had to write that part. I mean that was so.

Okay, so go read the book. Go get the book. Gut Feelings the Microbiome and our Health.

I think the resource to rationalize why you need to do some changes or lifestyle choices to be capable to make full use of your potential of whatever mother nature gave you genetically and play your genetic cards well so that you can win the game no matter what.

Awesome. Dr. Fasano, thank you for joining us for another episode of the Five Journeys podcast. Live like you matter. If this made a difference for you, pay it forward. Write a five star review so other people can discover it and tell your friends. Have a great day. Don't go it alone.

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