Can Your Gut Predict Alzheimer's?

Quinn: [00:00:00] Can your gut composition predict Alzheimer's? That's today's big question and my returning guest is Gautam Dantas. Gautam heads up the Dantas Lab at the Washington University School of Medicine at St. Louis. His lab works at the interface of microbiogenomics, ecology, synthetic biology, and systems biology to understand, harness, and engineer the biochemical processing potential of microbial communities.

Gautam's work on soil microbes helped explain how antibiotic resistance emerges and spreads. He also studies how the intestinal microbiome becomes established in childhood and showed that treating babies with antibiotics reduces the variety of healthy bacteria in their guts and promotes the growth of drug resistant species.

Since our last conversation feels like a hundred years ago, Gautam was named a fellow of the American Academy of Microbiology for his studies of microbial communities [00:01:00] and antibiotic resistance. I wanted to have him back on the show, not just selfishly, but I wanted to have this conversation, not just because Gautam is one of my favorite guests of all time, and not just because of this new study we're going to really dig into, but because you have probably been affected by Alzheimer's in some way.

I certainly have, my family certainly has, and Alzheimer's is growing more prevalent throughout the world every day as the U. S. and China and so many other countries get old. We've asked so many questions about dementia and Alzheimer's and other brain diseases and found so few answers, much less answers we can actually act on, that are repeatable and that can either prevent or just slow this disease in some way. And that's what makes me so excited about Gautam's new research, however preliminary it might be. We get to keep doing it. We get to keep asking these important questions that can help people. So [00:02:00] welcome to Important, not Important.

My name is Quinn Emmett, and this is science for people who give a shit. In these weekly conversations, I take a deep dive with an incredible human, like Gautam, who's working on the front lines of the future to build a radically better today and tomorrow for everyone. And along the way, we're going to discover not just information, but tips, strategies, and stories you can relate to and use to get involved yourself and become more effective for yourself and help unfuck the world around us.

So please enjoy my conversation with Gautam Dantas.

Gautam Dantas, welcome back to the show. Nothing has happened since we last talked.

Gautam Dantas: Yeah, nothing at all. Happy to be back.

Quinn: Very normal. Very normal. How is university life treating you? How is everything?

Gautam Dantas: Overall good. As we said right before this, things that I think I have some control over are great.

And then I guess you roll with the punches with the things that you don't have control over. So yeah, I, again, I don't quite remember when it was, it's been at [00:03:00] least five, I think, since we spoke.

Quinn: I, yeah. Who can know?

Gautam Dantas: Yeah. But yeah, lab is going really well. The best metric by how well a lab is doing, in some way at least, is a combination of the psyche of the current group, and then also where people have gone on to after they've left. And both of those, I'm very happy with. People are, our alumni are doing incredible things. Importantly in lots of diverse spheres, so they haven't specialized in one or the other, the people in biotech, there's people in education, there's people who've gone a similar route that I did, but it really is across the board. So that's really exciting to see. And then we've also fortunately been able to continue to attract diverse talent.

And yeah, by those two metrics, work life is good.

Quinn: That's about as good as it gets. There's something beautiful, my children are young now, but they think they're 10 years older than they are. And there's, I very reluctantly understand and I'm beginning to subscribe to the whole thing of eventually you [00:04:00] have to set them free to go do bigger, better things and try not to preload their therapy bills as much as you can before that. I imagine that's what running a lab feels like.

Gautam Dantas: It's funny because it's both that, but I also have young kids I guess not so young anymore, but 10 and 13. And so obviously, like a lot of kids in that age range, the pandemic was a huge deal in terms of how they found themselves, how they got out of it, how they supported themselves and their friends.

And yeah. Sometimes it's hard to distinguish between the methods you use as a parent and the methods you need to use as a mentor in the lab.

Quinn: Yeah, I know my friend who's the captain of a submarine wrestles with that as well. He definitely is a little frustrated that people at work listened to him far more than they do at home where he's definitely more impotent than he is there. It's interesting.

Gautam Dantas: The weird part of that also is, our kids, fortunately, are apparently angels at school. So every time we have a parent teacher conference, they're like, yeah, your kids are role models. They never speak [00:05:00] up or speak out. And it's a pleasure to have them in the classroom.

And it's this mixture of pride, obviously, and also like, who are you talking about?

Quinn: Right,are you ever, cause sometimes, we have our conferences next week and sometimes I feel mine are mostly similar. And sometimes I'm like, am I in the wrong conference? Because I've got some things I need to share. That's great.

Look, that's all you can hope for, right? It would be nice if it was similar tracks, but it's got to go awry in one way. That's fantastic. I'm glad to hear it. 13. Boy, that's a real human being. My 10 year old thinks he's that old, but he keeps saying things like, I, do you think I have a pimple yet?

Has my voice changed? I'm like, buddy, you're going to regret all of that stuff.

Gautam Dantas: Enjoy it while it lasts, but you don't have to worry about that.

Quinn: Yeah. Ah, just unbelievable. So anyways, a good host would have gone back and listened to our entire conversation and all these different things, life, I don't remember if I asked you this question, but I've definitely asked like a hundred plus guests since whenever, since time started, it's a little [00:06:00] ridiculous, but it also usually provokes something honest and proud.

So I will ask you either way. And then maybe we'll go back and compare. The question is, why are you vital to the survival of the species? And it's ridiculous, but let's have some fun with it. Be bold.

Gautam Dantas: First, I'll take the cop out. I don't think I am. And I don't say that with false humor, I think, it's, we have a buffer in humanity of having whatever, 8 billion people.

We have lots of brilliant people. Got lots of people who are cruising along and I think everyone has a vital contribution because most importantly, they impact the people around them. And so I think that's the, that's where I gain the most sort of happiness is those local interactions to see that hopefully you're making a difference.

But, you could probably delete me from that particular, any set of interactions and life, and certainly humanity would go on without a blip, but let's take that back a notch and say, okay, of course, let's assume that's true, right? Hopefully no one has actually directly answered [00:07:00] and said I'm absolutely vital to everything that happens.

I'm sure you've had a few, but...

Quinn: I need to do a super cut someday and dig those up, right?

Gautam Dantas: But what, I guess my answer to that would be what do I think is my value proposition? If you were to delete me what might we lose? And I think hopefully again the answer to that is essentially the same as the answer I gave earlier, that is I think my greatest value is the people that I get to interact with, the people hopefully through our interactions are inspired to go off and do cooler and better and more amazing things.

And that's both in the personal sphere, right? We talked about our kids and our families, right? So if we can by being a role model or just through the conversations we have, inspire people to do cool things despite you, I think that's where you've had the greatest impact. And I think, scientifically, I'll take a bit of a detour to answer your question.

One of the most impactful things that my postdoctoral advisor told me, George Church, was that, [00:08:00] and I'm paraphrasing here, but he said something along the lines of, he would decide that it was time to quit only when he could actually keep to a five-year plan. And what I took out of that was his plan to always be surprising himself, right?

He always wanted to be doing things that he couldn't have predicted five years ago that he'd be doing. And I was like, wow, that first of all, the confidence that takes is incredible. It's partly confidence and it's partly aspiration. And I've certainly tried to adopt some flavor of that in the kind of work that we do in the lab, at some clip, evaluate how much are we doing right now that we couldn't have put on paper five years ago.

And I think because the answer to that has always been more than 50 percent more than 50 percent of the work that we're doing in our lab right now did not exist in our minds. They did not exist as ideas here, at least, certainly by other people, 5 years ago. That in itself is[00:09:00] value, right? I think that's value that we as a group provide to say, let's be innovative enough.

Let's be committed enough to be doing new things that are not only the things that we had decided to do 5 years ago. We need to certainly fulfill our commitments, but also reserve a really important part of the lines of investigation to be at the point where we're asking new questions with new people.

So I know that's a very long way of answering your question, but yeah, I think that's the value proposition. It's the commitment to be doing things that are pushing the envelope.

Quinn: I love that. That's wonderful. And I love the way you see your sort of position in life and as the steward and leader of your lab.

Do you follow soccer at all or football?

Gautam Dantas: I do some, again, partly because of the 13 year old.

Quinn: What are you going to do? Unavoidable. The things I'm hit with on a daily brush, but there's a position, the number nine, where you basically, the offense flows through you. You're not the sexy goal scorer by default, though you certainly have them, [00:10:00] but you are the connector and you facilitate everything through that.

And it seems like you're very comfortable being that, not necessarily getting all of the glory, but at the same time, pushing the envelope and pushing it forward.

Gautam Dantas: Yeah, I think that's well put. I think it is really nice to be at the position where you have the privilege to do that, right?

Because I'm sure everyone would love to be able to do that. You're going to have to work towards it. And you're not always successful at it. I think that's also okay that, maybe your number nine needs to be subbed in every once in a while. But yeah, I think that well describes the aspects that I really enjoy about my job is to be the person who facilitates and mentors to enable people to take whatever risks they're willing to take, towards asking questions that honestly, I just don't have the ability to ask myself. I know that about myself, that the reason we have the diversity of questions in our group are partly just a self realization that if this group ran purely based on my ideas we'd stagnate. 100%. I'm not the idea generation engine that other people execute, right?

It's [00:11:00] more the, hopefully I'm the idea facilitator. And then, help get the resources to get things done.

Quinn: I find it's always telling not to just keep dragging it back to soccer, when one of those players retires or leaves or whatever it might be, and you can usually judge how valuable they actually were by how many of the teammates are like he was the most important player on the team and it's not even close and it might not be the highest selling jersey.

But if they're all saying that, then you know that's the deal, right? He's running the engine room. So listen, let's talk about some of your most recent work. And I'm going to do something questionable, intentionally questionable, and dangerous here. And it's actually for the second conversation in a row, now that I say this out loud, I'm going to attempt for about 10 seconds to simplify both the brain and the gut, which is just an enormous mistake. Here we go. So obviously a lot of news about Alzheimer's in the past year or so on the research front, we still don't really know the cause or causes well enough.

And that's probably because there's some[00:12:00] combination, depending on a person and in macro of genetic, environmental, and lifestyle factors, which I think is frustrating to a lot of people who have experienced this in their family or are genetically predisposed to it. I get it. I've seen plenty of it.

Your team conducted I believe an NIH funded human study that suggests that the gut microbiome composition in the earliest stage of Alzheimer's, so that's when brain change may have already started, but before cognitive symptoms become apparent. Is that right? Differs from healthy people. How much of that did I get wrong?

Gautam Dantas: You got a hundred percent of that, right. So, thank you.

Quinn: Maybe the first time a teacher's ever said that to me. So, thank you.

Gautam Dantas: Yeah, no, absolutely. No, you've got the most important part of that nicely and succinctly, but do you want me to embellish a little bit?

Quinn: I do. Before we go, though, I did read somewhere.

I can't remember, in my research that conducting the study came about beause was it you and your coauthor were, who studies all my Alzheimer's in particular, were [00:13:00] hanging out at your kid's soccer game, just shooting the shit. So start with that and then embellish for us about the study and the participants.

And we'll go from there.

Gautam Dantas: We're clearly on the same wavelength cause that's exactly where I was going to start. Yeah, this all starts with my friend and colleague. His name is Dr. Beau Ances, he’s a neurologist here at WashU. And exactly, as you said, we were at the sidelines of our respective kids soccer games.

They were not even playing in the same game. So, we were, you know, their field was next to each other.

Quinn: Wow, really stretching serendipity there.

Gautam Dantas: Yeah. And I think what had happened was we had actually bumped into each other several times over the years. But, these spheres really don't usually overlap, right?

People studying the gut microbiome and people studying the brain. And it was just very casually that Beau mentioned that it would be fun for us to work on something together, given this burgeoning interest in the gut-brain axis. And I said, yeah, sure. Obviously, we get along. So that's, we've checked one metric in terms of collaboration.

So it's almost weird that we start there, but it's, [00:14:00] oftentimes you find that you have a great scientific idea and then you need figure out all the negotiations about personalities. So, we'd got one box checked. So, he then proceeded to tell me about this really cool idea that you alluded to of so-called preclinical Alzheimer's disease.

WashU has been at the forefront of showing this concept where AD, Alzheimer's disease is a, it's a progressive neurodegenerative disorder, right? So, it's something where things get worse over time. Especially in old age, the manifestations that are the ones that we hear about that are sad and we have a lot of empathy for the people and their families who suffer from them, are the cognitive decline, right?

It's the dementia. And again, as you said, at the outset, unfortunately, we just don't understand clearly what the mechanism is. We don't know what causes this. We know what the symptoms are. But a lot of work has been done over decades to show that there are correlates, at least on the human side of things that are elevated, for instance, in the means of the blood of people who have clear Alzheimer's [00:15:00] disease symptoms that are different from people who don't, right? And that's how any good scientific clinical study starts. You look for correlates. You look for things that might be up or down in a significant way in the disease state versus the control state. And then you start asking is this a consequence of the disease?

Or is it the cause of the disease? And if it's potentially the cause of the disease, then you can use it for diagnostics, and you can also potentially use it for coming up with therapies. And that's essentially every disease that we try to do this with. So, what is preclinical AD? What was it that Beau told me about?

So, he said that there's been really this fascinating finding over the last decade or so, that when you start looking at patients who have a familial risk for AD and you're able to recruit them in, right? So, these people are highly motivated to understand what is going on with them based on a familial risk.

So, they're willing to be tracked, right, well before the age that usual AD would set up, and tracking those individuals means that some fraction of them because of their known familial risk will eventually [00:16:00] get to unfortunately, symptomatic AD and what has been done is all of those things that I told you that get elevated or get significantly different in the symptomatic individuals.

Those features have been tracked in these individuals, right? Measures of amyloid, which a lot of people have heard that term at least associated with AD. And a few other markers, and this is done by imaging. It's done by looking at blood through spinal taps in the cerebrospinal fluid.

But in the end, those details don't matter. It's just a series of markers in the human that have been tracked. So, what preclinical AD has shown is that in individuals who've been tracked, who eventually go to develop AD, many of these markers start spiking in these individuals who go 10 or 15 years before they get symptomatic, which really puts a fine point on this idea that it is ASF disease.

That perhaps there are these sort of triggers that are setting this individual on this long course to eventually get the disease, it's happening so far in advance that perhaps at the [00:17:00] minimum, we would be able to diagnose these individuals. Decisions can be made by them and their family members about how they want to spend the next 10, 15 years of their life.

But more importantly, towards the future, hopefully that gives us an opportunity for therapeutic intervention, right? Maybe you can change those things around if those things are causative. So okay, that's all background that involves nothing about the gut microbiome.

Quinn: No, but it's really helpful because there's, it is an enormous problem affecting so many people and it's only going to grow.

Gautam Dantas: Exactly right. As we keep people older, longer. This is one of those things that's going to afflict a greater part of the population. So, we want to get a handle on it and hopefully come up with therapies. And so that's one piece of evidence. The other piece of evidence was work that was coming out from other groups to show that if you just look at the extremes, that is people with symptomatic AD versus appropriate healthy controls, age-matched and whatnot.

Their gut microbiomes are different, right? So someone else had just shown this. And interestingly this, the whole idea of the gut-brain axis, I think is partly seeded, the reason [00:18:00] people start looking at this is because of this observation that in almost any disease state, that we have in humans now, there's probably a difference in the gut microbiome, right?

Therein lies both an opportunity and a challenge, right? Because now, if you get to this point where the microbiome is always different, you want to be worried about red herring’s. Why is it different? Is it actually related to the disease or not? And I'll just say this up front, and I'll try to say this again later on, that we have to have this level of humility when we're looking for these correlations to be okay with something being not a cause but an effect, right?

In terms of the microbiome. And what do I mean by that? So, let's just take any neurodegenerative disorder. Let's take Parkinson's, or let's take AD as an example. When you are in dementia or severe dementia, everything about your life is going to change, including, for instance, your dietary habits, right?

And your ability to make decisions. And if that happens, 100 percent you're going to be impacting things like your microbiome. Because if you're eating completely different now, differently now than [00:19:00] you did 10 years ago, that's been shown to be a massive, interacting feature with your microbiome and could be different.

So the first thing that we should always ask ourselves, almost as the kind of null hypothesis, is that while it might be true that the microbiome is different and symptomatic, AD individuals versus healthy individuals, is the microbiome actually playing any role in the disease? Or is it simply a sort of another consequence of the disease?

Just making sure that we're thinking about that could be a possibility. But that still then motivated the study that you talked about which is to say because we fortunately through this amazing Alzheimer's disease research center that we have here at WashU, to have access to people with AD, as well as people with familiar risk of AD, this incredible cohort of people who have volunteered to be part of this tracking over long periods of time. And from that, we already knew we had a pretty large cohort of healthy individuals and preclinical AD individuals whose sort of their markers have begun to spike. But there was no evidence of any sort of neuro, of any cognitive [00:20:00] decline.

And through this NIH funded project, this is big program project around here, which is studying every aspect about these individuals, many different labs involved, in collaboration with the Ances lab, and then another lab, Phil Tarr's lab, who does a lot of sort of, gut inflammation work. The three of us proposed, and were fortunately selected to lead this effort looking at the gut-brain axis in this specific cohort, right?

So just the cohort already existed. We were leveraging that resource.

Quinn: Sorry to interrupt, but that in itself is huge. We've talked about quite a bit here over the past couple of years, just how difficult and expensive clinical trials remain, if not homogenous, because they're so expensive to travel to if you can travel to and recruiting them and all these different things.

And obviously yours is not one that can specifically be done via Apple Watch or things like that, which is helpful in, for some other ones, but not necessary, obviously for this. So to have that available to you is amazing. Can I ask one other question just to set the stage a little bit before we continue?

What is the current, and I had [00:21:00] quite a few grandparents with this. I've known other folks with it, today what is the current sort of standardized testing if it's out of a box testing for someone to find out if you have that risk? Essentially, way before symptoms, like talk to me about age and when it would be recommended and then again like off the shelf, what would that look like to say you're eligible for this because you have higher risk of it.

Gautam Dantas: Yeah, so first of all, let me be a very clear as a disclaimer.

I'm not a physician, right? I'm not a neurologist either. So I can't make any sense specific recommendations that anyone to do anything, even the research answer, at least and what I'm aware of. So first of all, let's distinguish between when you would be tested because you have AD symptoms versus when you would be tested or what you'd be eligible to do in terms of understanding risk.

If you have AD symptoms, so that you've got the sort of diagnosis of dementia which is probably through your primary care physician and then a specialist neurologist visit that would [00:22:00] trigger probably with the assistance of, as long as you have health insurance, coverage for a battery of tests, right?

That would occur, and that includes a combination of plasma markers, so things that would be taken from the blood. Looking at your cerebral spinal fluid, right? So this is by doing a spinal tap and looking at markers in the CSF and brain imaging. So those are the three sets of things that give you a variety of these biomarkers to confirm that you have elevated levels of the type of things that have been seen in prior patients who have had AD.

Again, that is all for people who've already have the symptoms, right? Who've gone that route. So, there's one more thing I mentioned, didn't mention that's important, and that is, there's also some amount of genetic risk. So, there are particular genes, particular alleles of genes or particular versions of genes.

If you happen to have that version then you're an elevated risk of developing AD. So that will also be checked. [00:23:00] While that's really important to understand what might be going in terms of your dementia, in many ways, sadly, that's a little bit too late.

Quinn: Sure, and that's not the people in your study.

Gautam Dantas: No, because that says you're confirming that something is at that sort of end stage of the disease. But usually, it's harder to intervene at that stage, right? So, you're really asking about, how do people assess their risk earlier on to know what trajectory they're on. And honestly, like almost every disease that's of this kind of, longer term, progressive nature.

One of the best predictors of your risk is past family history. It's the non sexy scientific stuff, right? It's the simple, intuitive, if you had two parents who had this disease, then you're likely to be at higher risk of that particular disease, right? So oftentimes, and in fact, the study that we are leveraging here is called the ACS study, which is the Adult Children's Study of people who had Alzheimer's disease, right? Sure. So these are people who already, that's the reason we think they're at risk. So those [00:24:00] people already will know to start looking for, maybe early symptoms. And then oftentimes the way they are able to get early information is right now, at least, through involvement in research and clinical trials.

So they were, because we just don't know right now exactly what the predictors are. Your insurance company is not going to pay for you to do, frequent testing towards really any disease state. And there's a good reason for that. It's not just the sort of cynical game of they don't want to pay for things until they absolutely have to, that one of the reasons, they don't want to scare the shit out of everyone.

Based on telling you that, oh, here's your 20% risk of everything that can kill you.

Quinn: And that's what we're wrestling with BRCA and things like that. It's part of the reason they don't want you to do the full body MRIs and things like that. There's things that are in there that you might never even touch.

Gautam Dantas: 100%. A lot of these are combinatorial to say, yeah, there's a 20 percent risk of this, but you actually need to have all of these other things also have to happen, including for instance, trying to [00:25:00] show them. So that's a long way of saying that right now, if you're a 40-year-old and you're really interested in your risk of AD and you have no family risk of AD, there's virtually nothing your physician is going to recommend for you to do outside of tracking your health normally and doing your annual checkup or whatever it is, because at this stage, the information that you might get, that's probably too dangerous for you.

You're probably not going to be able to do anything with it. If, on the other hand, you are someone who has either, for whatever other reason, a known genetic risk factor. So one of these ApoE alleles, for instance, which is going to be correlated with AD, and you have a strong family history, then your best bet of getting information is to probably enroll in one of these, not trials, because they're not going to test any drugs on you, but one of these things that tracks you and helps you understand and get some amount of feedback.

And I, again, I would just say that our volunteer population here, that's part of this ADRCR are just incredible people, right? They're doing, obviously they're motivated, but they [00:26:00] go over and above to be, part of this enterprise that, at the back of their minds, they probably realize it's not really going to help them immediately.

They're making an investment for all of the other thousands of families and their kids and grandkids in terms of, you track me now, maybe I'll get some benefit out of it, but probably it's going to take another 10 years. And yet they're going to come in for these, annual testing and these extra things that they have to do.

And I cannot say how brave that is, and how altruistic that is for them to do this. So yeah, so it exists without those people and their commitment.

Quinn: I love it. Thank you. Thank you for sharing it again. I think that helps set the stage for people who might be thinking like, am I someone who might have this because of X and Y?

And what do I do? And what's the process? And again, you're not a physician, and very clearly neither am I. It helps to just set the stage for these things, because I think people hear about cancer blood tests, and find out all your stuff, and this and that, and then Theranos, and you go what? And is it too early?

And it's not. Anyways, that helps set the stage.

Gautam Dantas: I would, I'll give you the simple, oftentimes, I think what you should ask people [00:27:00] when they come up and talk about these things is what would you do, right? It's a version of whenever I try to contact a reference for someone who I'm trying to consider to hire.

The most important question I can ask that person is, would you hire this person? Would you rehire this person? So it's the same thing. And so I've never taken any of these tests. I haven't done any genetic testing not because I think there's anyone shouldn't do it. It's just that I at this point don't feel like I need that extra stressor.

I have none of the symptoms associated with these particular diseases. And so, I'll do what my general physician tells me in terms of whatever annual testing, I'm not going to ask for more information right now. I'm fully committed to the healthcare system and engaging with it if there's a reason to do but I'm not going to do it until then.

Quinn: Yeah, I got enough going on. I get it. Okay. So let's talk about these folks in the study. Now you had access to this cohort. How did this get off the ground here? You guys got approved for the grant, the three of you and you got to work.

Gautam Dantas: Exactly. So again, as I said it's one of these things called a program project grant.

So there's four or five different, interconnected [00:28:00] projects. Some of those were already ongoing. They're the ones who are collecting the plasma biomarkers and doing the metabolomics of the blood and doing the brain imaging and whatnot. Our project was a proposal to say, okay, let's go back to these individuals, re ask them whether they'd be willing to provide stool a particular frequency, we wanted to get at least a single stool pretty close to the rest of their measurements. And then over the course of this 5 year grant, we wanted to contact them, at least 3 more times so that we get some amount of, and there was 2 main things we wanted to ask or 2 main things we wanted to test for.

One was what happened statically. So this is what we call a cross-sectional study. And that's the study that we published on. But cross-sectional that in a second, but just to say what's next is, so right, the cross-sectional study is just to say, get as many individuals in these two groups as possible, the healthy group.

Versus the preclinical group and at single time points study their stool and look for correlations. And I'll get back to what we did with that. But what we're also hoping to do is say again that this is a progressive disease. And [00:29:00] we know based on previous statistics from this group, that sadly, some fraction of these individuals over time will switch groups as their disease progresses, right?

So, some fraction of the healthy people, because they're already in this familiar risk category, will actually become preclinical. And some fraction of the preclinicals will likely turn symptomatic over that five-year time point. And what's important about that recognition is that gives us an incredible test within our own cohort of whether any correlates we find are actually potentially predictive over time.

Because the hope would be that if we truly do find differences, let's say between preclinical and healthy and symptomatic and preclinical, then we should predict that people who switch states when they were in the preclinical stage, look more like preclinical individuals. And when they switch states to be symptomatic, they look more like symptomatic individuals.

So that's something that's down the line that's coming as the study progresses over sort of five years and then later type one. So what did we actually do in this case? The samples [00:30:00] that we published on came from about 150 individuals. About 50 of those were in the preclinical category, and about a hundred of those were in the healthy category.

Okay. The exact numbers are, I'm off by maybe five or so. That gives you a nice ballpark. It's about a two-to-one ratio. Okay. And what we did in terms of this study was we collected their stool samples and we sequenced all of the microbial DNA within the sample. The technical jargon is we did shotgun sequencing, right?

And it's called that because you literally just take all of the DNA that you extract out of the stool. Most of that is in the form of the microbes, and then you sequence all of it. And then you analyze it, right? And without getting into the gory details of all of the exactly what you analyze, let's talk about what you get out of it.

So what are you trying to infer? So largely by comparing that sequence information to databases, you can ask a couple of questions. One is you can ask which microbes are there, taking a census. Baseline. Exactly. Just saying, it [00:31:00] really is the census is actually the perfect word to use because it would be like saying, okay, I'm going to take a census of the people in Missouri and a census of the people in Virginia.

And then I'll ask, are there commonalities and differences in terms of, education and the ratio of people who have jobs versus not jobs, things like that, right? So we're doing something pretty similar where rather than two different, states of the country, we're talking about two different states of a disease, right?

You're just trying to understand upfront, which bacteria are there. And how many of them and then the 2nd thing you try to infer, because you're sequencing all of them is what functions might those bacteria have, right? Because all of our genomes have encoded things that give us the instructions of what to do.

Bacteria have the same thing. That's just the data that was collected. What did we find? Baseline, we found that there was in fact a difference in the microbiome on average of the people who are preclinical versus the people who are healthy. So that was the first check mark to [00:32:00] suggest that we were on the right track, that this is actually worth continuing to do.

Quinn: That could go two different ways.

Gautam Dantas: Sure, absolutely. We could have easily found that even though the earlier studies were correct that the extremes healthy versus symptomatic were different. Maybe there was no difference in the microbiome in between. And we were willing to accept that. But that's not what we found.

We did find that in fact, the preclinical individuals had a significant difference in the type of bugs that they had in their guts. And so let's again stop now in terms of interpretation. What does that mean? What can we take away from this? And what we find and what our interpretation is that, Oh, I should say, we also want to know not only what it is, but what it may not be.

So this goes back to the thing that I said at the very beginning of explaining the study is that it's okay to find differences in any of these particular studies without them necessarily being related to cause, right? And what do I mean by that? Why do I say that? Because again, this goes back to the point I said that your microbiome might be [00:33:00] different because you changed your eating habits.

Your microbiome might be different in a particular group because the disease itself caused some problem which caused the microbes to change. It wasn't the microbes that were causing anything to do with the disease, right? But we were okay with that, not only because, of course, you need to be okay with whatever data shows, but because there's still clinical value with the finding where purely a difference in the microbiome being an effect rather than a cause, because it could be diagnostic, right?

So because we're now able to show that the microbes are different in these preclinical individuals versus healthy individuals, you could envision a future where, as long as we can show this reproducibly, that you could design a very simple stool test, right? Which looks for the presence or absence of these discriminatory bacteria, right?

The ones that are higher or lower in the healthy versus a preclinical state. And it's a very quick and very cheap compared to all of the other testing we talked about, screen that could basically tell someone, [00:34:00] should I go and get further AD testing or not?

Quinn: Which might influence insurance, et cetera, et cetera.

And by the way, if you are, if you've never done a stool test and you might feel like you're disgusted by it, compared to a spinal tap, it's not even close. It's over so quick.

Gautam Dantas: Exactly. 100%. So again, I will be clear. That's not what we're seeing we can show right now.

We haven't designed a stool test. We're not saying anyone should go out and do this. We're saying that we're providing the evidence base that this is something that we could consider as one part of AD diagnosis in the future. So that's one part. But there's a tantalizing, separate or additional prospect in terms of what we showed.

And that is one of these microbes are part of the disease progressions process, right? Maybe they're not just markers to tell you something's wrong in the gut. Maybe these bugs are doing things, either bugs that are enriched in the healthy individuals are somehow potentially keeping the disease process in check, right?

Or [00:35:00] a group of other microbes because they're either up or down in the people who have preclinical symptoms sorry, preclinical markers. Maybe they're allowing the disease to move a little bit faster. Not the only reason but part of the disease process. For that reason, you can't only look at the bugs.

You have to look at their functions, right? So that's why I said, that's the other thing that we can look at. And short answer is the jury's out a little bit as to what the exact connections might be, but we did find a few functions that also seemed to discriminate between those two groups, right? Between the preclinical and healthy.

And what we're doing now is going a little bit deeper into that. So, this is work that's not published, but that's ongoing. It's the next phase is, as I said, we're collecting more samples from the same individuals, and we've also continued to recruit new individuals, test and strengthen our prediction so far, but then to apply a slightly different set of methods or complimentary methods, we'd start looking for things on the host side.

So look at, for instance, markers in the gut of the individuals, so that from the human side to say, what is one [00:36:00] mechanism that bugs could be doing bad things in terms of the gut-brain axis? Maybe they're elevating inflammation in the gut. We know a lot of this diseases where that's one of the important steps, right?

IBD, and even other kinds of infectious disorders, usually they trigger things and the immune system kind of starts reacting and that can cause a lot of problems on the host side. And that's one of the primary kind of mechanisms that's been put forth in terms of how the gut and the brain could be connected.

It could be inflammation in the gut that is transmitted over as signals over to the brain. Or actually, you can even imagine the other direction. Something in the brain triggers, signals to increased inflammation in the gut, and that could cause, dysbiosis in terms of the bugs going haywire.

Quinn: It seems like the, and please excuse my complete lack of nuance, but just to illustrate it, it seems like the easy question, the tantalizing question, is the chicken and egg one, right? Okay. We know that there's this here, is the gut driving the changes in the brain, which might become cognitive symptoms [00:37:00] or are the brain changes driving something in the gut, in which case, like you said, maybe then it's a diagnostic, but obviously again, going back to the very beginning of my introduction, there's just an enormous amount of gray area and things we just don't know between both of those, much less combined, add in inflammation, environmental, et cetera, et cetera.

But you did get to take the next step, which is the exciting part. That first question said, there are differences.

Gautam Dantas: Yep. That's exactly right. That's exactly right. If there were no differences, we wouldn't be able to answer any of the, or ask any of these other questions. So in the time we have remaining, I want to talk about two things, right?

One is what, where are we going towards testing that chicken and egg, right? Also, if let's say we do find that the direction of the chicken and egg is, the brain is causing the dysbiosis and it's entirely the host causing the microbes to be different. How can we still use that? And how can we test that from a diagnostic perspective?

And in fact, I'll talk about the second part first. And that is the ability to very quantitatively use some of this information in terms of how, what do you actually do with that stool test, right? [00:38:00] How can it help with the diagnostic part? And that actually turns towards this, this particular field that's getting a lot of press, obviously, even in a lot of attention certainly in the popular imagination.

And this is so called artificial intelligence or machine learning approaches, right? Which I'll just be pretty blunt that much of that is packaging. Really what we're talking about instead of, boring old school speak is doing pattern recognition, right? Doing statistical analysis, looking for things that are up or down in one particular case versus another, right?

And then what we, what all of this machine learning stuff is basically saying, let computers figure out those patterns and use those patterns to make predictions, right? So that is, if I find differences in group A versus group B, I can then train an algorithm to look for those differences in group C and then classify group C to be more like A or B.

That's really sort of machine learning 101.

Quinn: And the more stool samples you have. The more data you get.

Gautam Dantas: 100% right. And so what we did, and so [00:39:00] this is, I should have mentioned at the outset, most importantly, the study was run by a really incredibly talented, led by really incredibly talented graduate student at the time, Aura Ferreiro.

So what Aura did in this particular paper was after all of those correlations that I told you about, she trained a machine learning model, but she did a really clever thing. Where she said, okay, we have all of these host markers, right? Everything I just told you about that study, the spinal tap measures and the plasma measures and the brain imaging measures.

They're what's used to classify these people as preclinical versus healthy. I could design, in fact we do that, right? We take the combination of each of those measures to say if they're above or below these thresholds, they are in one group or the other. And so you could build a machine learning model based purely on that, right?

And there's nothing, there's no learning to do. That's almost definitional, right? To say, if I have all of these markers and you give me a new individual and you give me, all of those other things, it could tell you preclinical or not. So what she started doing is she said, okay, can I systematically go in and start removing some of those almost [00:40:00] definitional features.

And instead put in some of my microbiome data. Can I start substituting out officially in this model, right? Microbiome features. So which is basically presence-absence of particular bacterial functions. And could they act as surrogate markers compared to these much harder to get much more invasive things to collect.

And that was I think one of the real great strengths towards the future of this particular study that Aura did, that the answer was yes. That there was some of these markers, essentially, let's take a very practical term, which means is, there are a certain number of human tests that you may not have to do.

And instead, you could sequence someone's stool sample. Now, again, I have to be very careful to say that we can't do that yet.

Quinn: Yep. Nope. Nope. Nope. Nope. Just asking questions.

Gautam Dantas: Exactly. This has the possibility in the future, because of what we did here, to say, look, this really becomes a way in which to say, maybe you'll eventually still need to do that spinal tap.

But you don't need to do that now [00:41:00] because, this is a screen tool. So I think that's a huge value proposition because every new study that someone does, whether it's us or another group on the microbiome, they can be used to refine and improve these models. Once the model exists, right?

You can just keep adding to that. So I think that was a really, I think, important deliverable from the study is to say, not only we find these correlations, but we can train these predictive models that can be improved with more data. So that's independent of chicken or egg.

And then the exactly what we're doing now to answer what came first is, as I mentioned, we're now trying to collect more information from the stool sample, honestly, looking for the kind of markers that we know are correlated with inflammation on the host side.

So we're looking into the stool at greater depth. And then also asking, what are the microbes making? Everything we did in terms of the analysis we described was sequencing of the DNA. And really, if you stop back, almost step back and philosophically, what does [00:42:00] DNA sequence tell you?

It tells you about potential, right? It tells you about what could happen, but it's not telling you actually what's happening, right? Because all DNA is, is the blueprint, right? It needs to be read, however, right? And I think blueprint is a good idea. It's before you go to a city and figure out, what kind of stuff you can do, the DNA would just tell you about the kind of like map of where things are, but you wouldn't get any of the Yelp ratings of like, how good the restaurant is, right?

How quickly you can get to places, to have all of that extra flavor, you need to look at other things, right? And you need to look at RNA. This is the stuff that's actually being expressed, right? So that's telling you that here's what the traffic signals are like, and you know that this neighborhood is more accessible than the other neighborhood.

And then you also want to understand, what the language is that's spoken, right? How are you communicating in this particular study? And those are the metabolites. Those are the small molecules that the bugs are sending to each other. They're the signals that they use to talk to the immune system and the host.

And so it's this idea, it's this [00:43:00] particular field called metabolomics, much like genomics. And so essentially we're taking the same stool samples and adding a few more layers of asking for these more details, right? Not only who's there and what they could do, but what are they doing? And how are they talking to each other as a way to answer that chicken and egg question, because if we can find different metabolites and we can find different expression of genes from both the bug and the host side, that'll begin to tell us, yeah, I think, this might be going in the direction of the bugs telling the host to do some bad stuff.

Or is it, the bugs are more responding to stuff that the host is doing. So that's the next phase of what's going on with this particular study.

Quinn: Either way, again, you get to keep asking questions, right? You get to advance to the next boss as it were, to D& D your game thought.

It seems like there's already and again, very early, still asking questions, all preclinical, et cetera, et cetera, but there are really interesting implications with this in a world where, again, as we've seen in the past year and a [00:44:00] half or so with the news about the past couple of decades of Alzheimer's research, leaving aside the microbiome, we have relied on a sort of a set of facts and assumptions that may not have necessarily held up and put billions of dollars behind them.

And now we get to ask new questions about a whole new field that we're trying to understand. And you're leading as it is just these questions of again, here, someone's doctor says, take these probiotics and do this and this, but at the same time, understanding, forget if the consumer or the patient understands what they are like, baseline DNA what are these things? Much less, what do they do? What do they produce? What do they influence, the different systems in the body? Knowing that like you said, on the immunology side or the inflammation side, what that might be. But it seems like so far the implications are, we could by just adding more stool and asking more questions on what we have, we can hopefully improve the accuracy of those machine learning models, right? For further strengthening the study and again, maybe running into things that make us go, Oh, that's interesting. And what about that? Possibly [00:45:00] a precursor, again, possibly a precursor test to your spinal taps, your brain scans, things like that, to establish if you have any risk, much less an increased risk of developing dementia.

And again, it's a gross oversimplification, but I think of how you know, you might use an Xray or an MRI or something to discover some sort of tumor, and then you're going to find out if it's benign or malignant, things like that, right?

Gautam Dantas: 100%. Yep. Yep.

Quinn: But also possibly making diagnostics that are just easier and hopefully more affordable in a world where so many people don't even have Medicaid of any sort.

And that's obviously our health system is, and again, I know you're obviously not a physician here, but so much of it is predicated on reaction and surgery versus wellness and prevention. So, what in your mind on the microbiome part is, what if this is new to you? So, when you guys go back to that soccer practice and you think, how can I get my discipline involved in this?

What [00:46:00] of this has been surprising and new to you and made these next five years exciting to ask questions that you didn't get to ask last year that maybe you get to ask five years from now?

Gautam Dantas: That's a wonderful question because that's not just on our gut-brain axis stuff, but it's really everything else our lab does, right?

Our lab is very much a kind of, let's look at the microbiome and everything kind of lab, right? We're trying to understand, which parts of it tell us something about health, which parts can be manipulated, which ones should we left alone. And what do we know now that we didn't know back then and what would we like to learn?

And I think, one thing that we've learned that I think we didn't know back then is this power of including other aspects of human measurements is essentially part of our microbiome analyses in an integrative fashion, being able to do so much more than if we were just reading the microbiome on its own.

And so this is a concept that it's actually been around for a really long time, but I think it's coming back into, in vogue, if you will. And that's this concept of the human being a [00:47:00] holo-biome or a holo-organism that especially from the microbiome centric point is to say that the microbiome shouldn't be thought of as accessory anything, right?

It's just another organ. But it's a really unique organ because unlike our eyes and our hands and our guts, for instance, right? We can't willy nilly change those in a very, like we can do transplants, but that's a huge deal, right? But we're effectively born with those because of the DNA blueprints that are in our genomes.

The microbiome is unique, however. Not only does it have all of those features of a critical organ that it talks to every other organ, but it's fundamentally malleable, right? You can change the components of it, whether you like it or not, right? So you can change it inadvertently by taking huge doses of antibiotics or, changing your diet, but you can also potentially figure out if there's something wrong, there are opportunities to change it in ways that you cannot do with any other organ.

And I think, did we not fundamentally understand that five years ago? Of course not, right? Of course, we [00:48:00] had that idea, but I think five years on, we are beginning to appreciate not only how important that is conceptually, that there are so many aspects about human health and disease that we might be able to diagnose and intervene on because of the fundamental malleability of the microbiome, right?

But that also that now that becomes a novel way to really think about human health holistically, right? That we think of ourselves as, and I think this is where we have, we always have this balance between gen versus specialist, right? So you go to a doctor, right? That's the reason why when you talk to a physician, ideally you first talk to a general practitioner.

Because they're going to ask you the big picture question, how are you doing? Not, is your eye twitching, right? They want to understand generally, are you in a good space, right? Including your mental health and your physical health. And it's only if there's something that's arrived, might they send you down the route of that specialist.

And I think what, that thinking has really influenced us in terms of our day to day [00:49:00] aspects of the microbiome to say, much like we don't want the people on the host side to forget the microbiome or ignore the microbiome in terms of its role in human health. We also ourselves must have that humility to not only think of the microbiome in a host agnostic way.

I think we were guilty of it, certainly I was guilty of it. I've been known to, even though it's facetious and flippant to say, for a lot of our studies, the human is a really exciting Petri dish, because we care about the microbes, and of course we don't think that, fundamentally, we're doing this because we care about human health, but I think the practical nature of it, what we can do now and I think what we need to do in five years is to collect that correlate to data, right? When you're running a microbiome study, collect as much about the host as you can find out what they're eating, find out about their demographic features and their socioeconomic features, because so much of that is going to influence what's going on with the microbiome such that you can control for those features.

You can [00:50:00] customize those for diverse populations and then look for those particular needles in the haystack that might be either the diagnostic or the thing that you can therapeutically intervene on.

Quinn: I'm not scared to take this back to our soccer metaphor here, Gautam, which is the sense that this is, you are the microbiome, the microbiome's you, right?

It is this thing that is so malleable, but is also very, from my very limited basic perspective, a facilitator for so many other parts of the body in this holobiome, or you want to call it a closed system or a bag of meat, whatever we might be, right? 70 percent water. It is, so clearly is influenced by and can influence so many other systems.

Like you said, it cannot just be an accessory. It's the beauty of, again, asking questions about the brain, right? Which is you pull the string and you don't just get the rest of the sweater. There's different sweaters and they're different shapes and sizes. And you go, Oh my God, what have I done? And the microbiome is the same thing.

You don't just go, okay, do the, is there this genetic influence on what it might be? There's also just as saying environmental is so many different things from [00:51:00] food and drink and the air and the water and all of these different things, you might put microplastics, whatever it might be, like there's so many different factors, but in the end, it's beautiful because again, the more of this is very simplistic too, the more data we have about these things, the more we can find out what it can do and what it cannot do.

And what don't we know yet. That's one of my favorite questions here. It's just what don't we know yet? What are the known unknowns or the unknown unknowns about this, which you said five, 10 years ago for the microbiome was everything basically.

Gautam Dantas: Yeah. And I think that's why this field is so exciting, just as exciting and more exciting now than it was, when I started working in this, whatever, 15, 20 years ago, when I first heard about the work in the microbiome is that while I think the field, and I think we have played a small part in it, has advanced, right? We know a lot more. There is this entire new universe of things that we're discovering that we realize that there is so much more to learn about those both known unknowns and unknown unknowns that are going to be fundamentally [00:52:00] important for making the microbiome and a sort of critical part of maintaining human health, not just treating it, but maintaining it. And 1 aspect that because it was not involved in the study, I didn't allude to, but, hopefully at least planted the seed, but by calling the microbiome malleable, right? It does let us know that, or at least it tells us that becomes a super unique root of novel therapeutic intervention in the future. So you talked about probiotics and most people think of probiotics right now is the kind of supplements you can get, a good bug associated with something and that is one version of it. But the way we think about probiotics is one step further to say, they're engineerable vehicles, right?

They are the ways in which that these are living, breathing, drug delivery vehicles. If we can safely engineer a microbe to produce a particular drug at a particular part of the body, have so much more exquisite control in principle, as opposed to popping a single pill of some type.

And there's a whole arm of our lab [00:53:00] who's working on that. To say, in so many of the at least gut-relevant pathologies, you pop a pill and it needs to go through the stomach and all of the low pH digestive juices and that kills a lot of our drugs.

You know what if instead we could get a bug that's already adapted to pass all the way through and then you engineer it to produce that drug where it needs to go. So again, there's a ways to go with that. I think that's another huge part of synthesizing all of this basic science and clinical sort of observational research to say good bugs, bad bugs, benign bugs, correlated with health and disease, but now the way we can intervene doesn't have to only go back to old school medicines, right? It doesn't have to go back to say, okay, this is bad and this is good. And we can give diet or drugs. We can actually engineer the next round of bugs to be the ones that actually deliver the next round of this thing, either health-promoting or disease mitigating medicines of the future.

Quinn: I love it. If there are more of these altruistic people out there listening, who are [00:54:00] either on the healthy side or on the preclinical side, because they know their markers or they don't, is there a way to get involved there or are there other studies you would send people, folks towards again, just in the sense that there's people out who are like, yeah, sure.

Take my blood, take my poop for 10 years. I don't care. If it helps, great.

Gautam Dantas: Yeah certainly, I think that probably the simplest thing for you as an individual is to look geographically close to you as to where your closest medical center is. And there's clinical trials and there's observational trials always running.

Alzheimer's disease is one of the grandest medical challenges of our time. There are many such studies. And WashU just happens to have a really excellent medical center here. So if you're in the region or even if not in the region, if you go to, it's called the A. D. R. C, the Knight ADRC and see what volunteer opportunities exist there, again just for helping the families for convenience they tend to recruit people who are local so that there's not a huge travel burden but yeah, we're not the only ones. There's great centers over, I [00:55:00] think Duke might have a really excellent center. And I think there's some down in California. I think the Mayo Clinic does themselves. So really honestly, any really large medical center is likely to have Alzheimer's disease studies ongoing.

And then you can decide by looking at what those options are. And then probably through those, find other sort of patient as well as family networks of deciding, do you want to be in an interventional study or do you want to be in something that's observational?

Quinn: Sure. I'll let our second light change there be our indicator to ask you my last couple of questions and get you out of here so you can go back to examining poop.

Last few, first of all, this has been tremendous. Thank you so much. I truly love learning about this. It matters so much. I think it's going to impact so many people. And we obviously, if we get to do, as I say to my children, we don't have to do, we get to do so many more years of incredible research and the more greater variety of folks and environments we can pull in the better.

You got started in this a long time ago, back when the microbiome was in black and white, obviously, in general, what would you say [00:56:00] was the first time in your life where you felt like you had the power to you need to make some sort of change, whether yourself or with a group. Could have been as a child, a teen, student, grad student, adult, running your lab, whatever it might be where you looked up and said, Oh, that's interesting.

Look what I can do.

Gautam Dantas: Yeah, that's a great question. Honestly, I think it is well before I heard about anything new with microbiome, but just to answer that question, when did I, when did I look up and wonder and think about things that I could have a role in? And it was actually in boarding school.

So I grew up in India. I grew up in then called Bombay, now Mumbai. And in ninth grade, surprisingly, I was jazzed about the idea of going to boarding school. So it's not like my parents sent me away, but I went to a small American-run boarding school in South India. And it was an eye-opening experience just because of the incredible opportunities that, again, I had the privilege of accessing because my parents decided to fund this.

And there, one of the things you got to do is run an independent research study, if you wanted to. And I did [00:57:00] this in my senior year under the tutelage of my biology professor. And he had me team up with a local biochemistry student who was running, doing his PhD. And I played a tiny role.

Inconsequential role to the research project, but it was there that I was introduced to this idea of use local to think global, if you will. And what I mean by that is this person was really interested in understanding sort of local exposure to seasonal pollen, right? Because this is an area that was very lush and thinking about how that might impact allergic reactions on the host site.

And so, he was collecting pollen from a variety of different plants in different seasons and the sort of hills that we lived around. And then he was studying particular immune responses in the blood to that particular pollen. And all of that, I probably appreciated more many years later.

At that point, as a high school student, I appreciated a small amount of it, but really, the aspect of it was to say, Hey, this [00:58:00] guy is spending, a dedicated part of his life looking at the tiniest details, which you can't even really visualize, but his motivation for it is to hopefully understand how allergies work.

And so that's what I mean by start local. He was looking at the plants around him, and he was looking at it at this exquisite level of detail, but he was trying to ask and answer bigger questions. And I found that exceptionally motivational. And I never, I didn't go into pollen or plants or anything like that, but I was just inspired by that, I think now somewhat perhaps see obvious or simple point of how biology and other kinds of science works, where you want to think about what the big picture motivation is, even if you're not the person who's going to necessarily solve it, but use that as a way in which to then think, what can I locally do to advance this at least a little bit?

So I think that's probably the first time that I can crystallize where, that little bit of spark came in to say, this is the type of thing that I want.

Quinn: I love that. Thank you for sharing that. One last one before we get you out of here. What is a book that you've read this [00:59:00] year in all of your free time that's either opened your mind to a topic or an idea you hadn't considered before entirely, or has actually changed your thinking in some way on something else?

And we've got a whole sort of list.

Gautam Dantas: Yeah, that's great. Honestly, I'm in a better place to answer this question than I think when we spoke last because that's one nice thing that the, silver lining, the pandemic did is it gave me a lot more time to read. And then it also gave me a fair amount of time because I really got into bike riding like on my bicycle of listening to books like audio books.

Quinn: Game changer.

Gautam Dantas: Yeah, absolutely. It's been really wonderful. And so one of the most sort of influential books that, for me, at least, and I would say most of my reading has been fiction, not nonfiction, is a series that many of your readers are probably going to be familiar with called the Three Body Problem, right?

So this is a thing that came out several years ago, the first book, I'm going to butcher the author's name, I think it's Cixin Liu. A Chinese author. And it's interesting. What was most influential for me about that book was not actually the details [01:00:00] of the story. But it was realizing with almost some amount of guilt of how Western centric we've been in appreciating the place that we might have in the future.

Every other science fiction book that I really read centers around a sort of either Eurocentric or America centric future. And this book, because it's written by a Chinese author just didn't have that perspective, right? And a different group of people were centered in it.

And so while it was still, it's a fascinating story. And I've gone and actually watched the, whatever the Chinese version, the TV series based on the first book. So I've enjoyed the story tremendously. But in terms of true impact, what that book really did for me was open my eyes to the bias that I had to say that, of course, we center ourselves in our stories, and it's really neat when these art forms get more global because we get to see perspectives from people and from very rich cultural traditions that we've lost out on by only [01:01:00] having this thin slice of how this has been presented to us.

So that's why, and I've tried to seek out more of those type of books. And it's what's been really good is again with my kind of my bent towards science fiction, I feel like the people who vote for the Hugo and the Nebula awards, right? The big sci fi awards have been really championing diverse voices.

And this is just one example of it, but I think the last few years, it's been really cool to see, gender representation used across many different facets, challenging the way we even use, all of the controversy about pronouns to see that just thrown away and used in such a creative way with books.

And but anyway, this book, I think for me was eye-opening to think about, even in fiction, how bias is important to address and then actually uses a way in which to improve the way we tell our stories.

Quinn: I love that thoroughly. Three things. I'm going to say them before I forget them. I assume you've read some Ted Chiang.

I haven't actually, no. Oh man, it's fantastic. Just go down the rabbit hole. I'm a big fan of short stories, which brings me to my second one. [01:02:00] There's a collection, they're not sci fi, of South Korean short stories I read years ago called Once the Shore. And same thing, where I was just like I need to get outside this bubble of this, which is all wonderful, but there's so much more out there.

And there's a, oh, third one. There was a short, I don't know if you call it a novella novel. I don't, it's won a bunch of awards. This is How You Lose the Time War, came out a couple of years ago. Don't read anything about it. It's one story. It's incredible. It's one of those ones you put down and just go, how does this come to be, and I'm not going to give you no other background, but I appreciate that.

Thank you for sharing your expanded perspective on that. Where can our listeners follow the work that you all are doing and keep track of everything magical you're bringing into the world here?

Gautam Dantas: We try to keep our website pretty up to date in terms of most importantly, the people who are part of the group, but also all our publications, we put links to where they can find the papers if they want to get into it, links to when people in our lab are engaging with others.

So yeah, that's, it's just dantaslab. [01:03:00] org and I am like many other people, but I've got a little bit burnt at the intensity of dialogue on social media. So I'm no longer on any actual social media platforms. That was entirely a personal mental health decision. Some of the people in my lab are still on in different ways but there's no engagement out there outside of that.

But yeah we try to keep our website very up to date. And encourage people if they have questions to reach out to me, or more importantly, the other people in the lab, all of their email information is there too.

Quinn: Fantastic. I cannot thank you enough for coming back. It is I have always looked fondly on our conversation, even if I was a young whippersnapper who had no idea what I was doing, like you said, a lot has happened, including this incredible study, which you get to continue and build on and expand and connect with all these other programs, which is just so exciting, even if it turns into nothing. And that's great because then we'll have found out. And that's wonderful.

Gautam Dantas: Disproving hypotheses is just as critical as supporting them, right? Because it helps other [01:04:00] people decide what to put their energies to. But I've also really enjoyed this conversation. Thank you. This is, it's really nice to talk to someone who has done their homework and is able to present some of the stuff that we've done in a simple and easy digest way.

And to make this a fun conversation. So I thank you for that.

Quinn: I appreciate it. Sometimes morons can make a dent in the universe. I appreciate you.