Harsh Thakkar (00:01)
Andrea, welcome to the show. For somebody who's scrolling through YouTube and landed on this video and they're looking at the title, know, worm derived therapeutics, Andrea, you know, autoimmune diseases. If they're considering watching the next 20, 30 minutes or, you know, considering maybe why they should watch the next 20 minutes, what do you have to say to them of what we're going to talk about today?

Andrea (00:30)
Well, first of all, thank you so much for having me. It's such a pleasure to be here. And I certainly understand the pause that somebody would take. I guess what I would say is, you know somebody with an allergic or autoimmune disease? And oftentimes the answer is, yes, we do.

And so just going into that and thinking about that, my question would be, did you know that we used to not have them? Did you know that at the turn of the century before the 1900s, that people rarely had allergic or autoimmune diseases and what could have changed that caused that? And also, do you know that areas of the world that have gut -dwelling roundworms are actually the areas of the world?

have the lowest incidence of allergic and autoimmune disease. I was not curious. Is there something there that could explain why we have allergic and autoimmune diseases? And is there something there that we can return back to mankind that could turn the tides? So if you're interested in exploring that possibility, then I would say stay tuned.

Harsh Thakkar (01:38)
Yeah, I have been researching your background. You've had careers of experience back from Caltech days when you were a postdoc, tons of research experience, then you went into entrepreneurship. You've also won some awards for emerging biotech, women in biotech and stuff like that. How did you get into this area? When you were at rewind back to your Caltech days,

Andrea (02:08)
You

Harsh Thakkar (02:08)
Was it something that you ended up accidentally doing a research on this topic or you always were fascinated and you wanted to do research on this topic?

Andrea (02:21)
I would say, I think in some ways I've always been interested in how animals communicate. in some ways, communication is so important. That how are animals communicating? And that's always been, I don't know, when you're a child, you think about that sort of thing. that's never, that's something that just continued. I never thought it would turn into a thesis project.

Harsh Thakkar (02:48)
Mm.

Andrea (02:48)
I actually went to a roundworm lab at Caltech because we had just been in the golden age of genetics. We had just finished human genome project. People were cloning in these genes into the simple roundworm to find ways of exploring what are all these awesome genes that we found in the human genome project? What could they mean for human health? That's what originally brought me into the laboratory, but I just got really...

pulled into this project studying how worms communicate and that that took over I would say. Also it happened to take over the summer that my PI left town so you know could have also just been that no one was watching over my shoulder as I just kept going down the rabbit hole of my own interest.

Harsh Thakkar (03:37)
And when this, at what point do you remember or how did this go from like a research and your thesis into you stepping into the world of entrepreneurship and forming the company Holoclara, which is specifically dedicated to this type of therapeutics.

Andrea (03:58)
Great question. I would say if I had to pinpoint a moment, it would probably be a couple of moments. One would be looking at the data set for the first time and seeing that we had found this Rosetta Stone of how worms have been communicating for millions of years. That was one moment paired with listening to a Radiolab podcast.

where we talked about a man that walked barefoot in Africa on purpose to get worms to treat his terrible illness and it working. And that, you know, despite this, people haven't yet found what it is that worms could be using, what molecules have been around for long enough to impart this effect. Then feeling that I had some of that in my hands. Then there's also the feeling of I was also in medical school and

Harsh Thakkar (04:50)
Hmm.

Andrea (04:52)
I don't know if you've ever, what was it that Maya Angelou said? Sometimes you don't remember something that someone said, but you'll remember how it made you feel. And I just think about a moment where if you really wanted to help someone and you could not, and I'll never forget that feeling of trying to help people with terrible allergic and autoimmune diseases, particularly a young girl with Crohn's disease and them walking, her and her family walking out feeling hopeless. That just was...

Harsh Thakkar (05:14)
Hmm.

Andrea (05:19)
a feeling that'll stay with me forever. I think feeling that I had something that could help that paired with seeing the need, I stepped up to the plate. I don't think I ever dreamed about being an entrepreneur. I will say I had my own plan to being a physician scientist going into clinic during the 80 20 dream of being a doctor, you know, seeing patients some percentage of the time and being in the lab some percentage of the time.

But I knew that I had to do it.

Harsh Thakkar (05:53)
Hmm, that's that's really powerful because you know a lot of people they get into entrepreneurship and they know from You know at very young age or at some point in their life that that's what they wanted to do But I always like hearing stories about you and tons of other guests that we've had on the podcast as well of how they are You know, I don't want to say accidentally stepped into entrepreneurship, but stepped into it with a deeper purpose and meaning which sounds like

you had found from your research. So at the start of the episode, you mentioned, you know, why should people stick around? Do they know somebody with an allergic or autoimmune disease? The answer probably is yes. So if you were to get a little bit more technical, like, what's, how does the worm derived therapeutics help for these kinds of diseases? Like if you were to simplify that for the audience.

Andrea (06:51)
Well, I would just first of all ask you to imagine that you're a worm. Pretend that you're a worm living in. Let's just go back in time to early human ancestors. OK, so you've been or you and your worm ancestors have actually been here longer than here are our human ancestors. So by the time that they're in our human ancestors, they've already had experience with living within other mammalian systems, whether it's been

Harsh Thakkar (06:57)
Mm.

Andrea (07:21)
you know, early mammals that roamed the earth. So if you were a worm living in a Lucy, do remember Lucy, the Australopithecus? Let's say you're a worm living in that individual. Over time, you wanna create things, tools, molecules, secrete things that are going to benefit both you and your host. That's your home.

It's not just a person. You're not there to feed off of them and that's it. You're living in that home. So quite simply, if there's a wound, you want to repair it. If there's inflammatory cells coming, the police force of the immune system is coming with their bazookas and they're shooting up the walls, you want them to stop. So you want to sort of harmonize the environment.

And then you want to lure in healing reparative cells to make your home happier and healthier. So the worms naturally evolved molecules to do that. And so now think about the power of trying to find those molecular tools and using them for ourselves to help with diseases where, by the way, the police force of the immune system for some reason has gone haywire. So that's the definition of allergic and autoimmune disease is

Harsh Thakkar (08:32)
Yeah.

Andrea (08:44)
If you're going haywire with eosinophils and whatnot, that's an allergic disease. If you're going haywire with neutrophils, that's an autoimmune disease. It's not as simple as that, but that's just one way of thinking classifying, right? TH1, TH2 diseases. And so when you have a disease where for some reason your cells are programmed to go a little more nuclear all the time and it's causing more damage than good,

Harsh Thakkar (08:56)
Mm -hmm.

Andrea (09:13)
then so imagine the power of those sorts of molecules to help calm down balance and restore the immune system and the host.

Harsh Thakkar (09:23)
Okay. And as I was reading through some of the stuff you've done and going through researching for this episode, I also saw that one of your main discoveries was this unique pheromone language that's shared by roundworms. So can you walk us through what that is and how does it tie into this worm -derived therapeutics?

Andrea (09:50)
Sure. I think in order to really appreciate how incredible the Worm language is, is let's just think about how long they've been here. So actually, let me ask you this. Can you name what is the oldest event in human history that you can think of?

Harsh Thakkar (10:12)
man, if since I'm from India, for me, it's probably like the Independence Day for India, which was like in 1940s. Yeah. Yeah.

Andrea (10:22)
1940s, okay. So I had a world history teacher in high school, Ms. Chrissy, and she said, if there's one thing you're gonna remember from this class, it's the Magna Carta was signed 1215, just like lunchtime 1215. So for me, that's that date. But we're not talking that long ago, right? 70 years.

Harsh Thakkar (10:39)
Mm.

Andrea (10:46)
or a couple hundred years. So let's just say, go back to, I don't know, middle ages. That's a, I don't know, let's round up to make it a thousand years. It's much sooner than that. But the scale of that is so little compared to how long animals have been on this earth. So if you imagine you could go back in time and you're in a time machine and you can go back,

Harsh Thakkar (11:08)
Hmm.

Andrea (11:16)
I don't know, 100 years every hour, right? Within 30 minutes to an hour, you're gonna see the event that you just named in Indian history, right? And then within an hour and a half, we're gonna see Abe Lincoln, okay? So imagine you're traveling that fast backwards in time. To get to the time of T -Rex, you're gonna have to be in that time machine for 100 years. That's how long ago

Harsh Thakkar (11:25)
Hmm.

Yeah.

Andrea (11:46)
that animal roamed the earth and they're extinct. But imagine now the worms that have been there even before T -Rex are still here today. That's a long time for them to still be here. Think about that. Where have they been? How did they survive? They're in the host environment, able to secrete things that can confer benefit to themselves.

Harsh Thakkar (12:00)
Hmm.

Andrea (12:14)
but they've just been here for that long. So trying to understand what they're saying and how they're using those tools, it's just we can't afford to ignore those sorts of molecules. And I think that's where my project comes into this, which is I was super interested in knowing what the worms were saying. How are they communicating with each other? And when I looked at multiple species of worms, we found a unique signature.

Harsh Thakkar (12:34)
Hmm.

Andrea (12:43)
that was only made by worms that a lot of different species were using. And we tracked it back to worms that had evolved even 500 million years ago. That's, if T. rex was 100 million years ago, that's five times earlier. So I think that is what I'm calling our Rosetta Stone. It gave us a window of insight.

Harsh Thakkar (12:56)
Hmm.

Andrea (13:10)
into the types of molecules that worms are using to modify the environment around them, including the ones that can benefit human health. And so just thinking about the power of how long those have been around and then how long that molecular language has been around. And then imagine now you've suddenly taken it out of your system because you think worms are gross.

Harsh Thakkar (13:16)
Yeah.

Hmm.

Andrea (13:34)
So now pretend you're in early 1900s, you're living in an industrialized area, you're excited because now we have toilets that flush and we could take antibiotics and anti -helminthics. And now you're so clean and things are great, but suddenly you have a rash that won't go away or you have joint that won't go away, right? Or you have, you know, endless diarrhea. Wait a minute, I thought that I wouldn't have less diarrhea because...

Harsh Thakkar (13:53)
Mm -hmm.

Andrea (14:02)
I was flushed out everything in my gut. What you're finding is the opposite. I think that's the compelling piece that I would want to return back into the immune system to see if we could turn the tides on that.

Harsh Thakkar (14:07)
Right.

Yeah, and as you mentioned, you know, about studying the language of these worms and how they were communicating or the signals. Do you have any example of a signal that you found and how did you derive what that meant?

Andrea (14:30)
For sure. I think that one thing I'll say is we really looked at the metabolome. So if you think about the universe of biological molecules, you've got DNA, RNA, and you've got proteins, right? You got DNA is four letters of the alphabet.

RNA is four letters of the alphabet and amino acids, there's 500 of them in all animals. That's so amazing, by the way, if you think about that. If you go to a ladybug or some random animal you find, they're using the same DNA and RNA and amino acids, that library. That's kind of amazing. So if you now go to a whole other fourth category of metabolites.

Harsh Thakkar (15:05)
Hmm.

Andrea (15:15)
That means small molecules, large molecules, structures that there is no library. That is infinite space. That's what people have called the dark matter because it's like the side of the universe that we can't even see. But it's been under our nose this whole time. That's the area that we've been exploring with worms because we know that there's really important materials in there.

And so from there we sifted, from there we refined, and the metabolomics technologies have also improved drastically over the last specifically five to 10 years. So that also answers a little bit of why now. It's because the tools actually weren't there before. The tools for DNA, RNA, and proteins evolved much sooner than the tools for metabolomics. So from there, we were able to identify key molecules, make them from scratch, and test them in different

models of inflammation.

Harsh Thakkar (16:13)
Yeah, it's fascinating that all these species are so different, but yet when you talk at a level of the DNA, RNA, and the proteins, there's a lot of similarities. I remember this example of back from when I was in school and we're studying different...

species of monkeys or like different apes and how there's a lot of similarities between them and humans. Like when you look at the pictures, you can really see that, you know, how human beings evolved. And then like the example you gave also just, it's fascinating to, you know, see that from your perspective.

Andrea (16:56)
yeah. I mean, it's remarkable how similar we are to the animals around us. Just absolutely remarkable. I was in a research lab, neuroscience research lab, where we were studying peptides that controlled aggression in both flies, mice and humans. And so, I mean, it's just it's just remarkable to think about how many how much we have in similar that we have in common with

the world around us.

Harsh Thakkar (17:27)
Right, for anyone who's a patient or listening to this episode and they're like, okay, great, you're talking about worms and you're talking about all this cool stuff, how does it help my condition? Do you have a pill? Do you have an injection? Do I take something? Can you walk us through how did all this research, all these years of effort that you put into studying how worms are communicating?

How did all that translate to real world solutions at HoloClara at your company?

Andrea (18:04)
Yes, so I, there's something that drew me to worms that I can't put my finger on. It's almost like my hand on my shoulder that said, look at this. The same thing happened when I wanted to look at a type of molecule. I was really lured to small molecules. So there's proteins and then there's small molecules. Proteins are things where it's like, you imagine an egg and you put, you apply it to heat, it turns white and it never goes backwards. You can never get that egg to go from white.

Harsh Thakkar (18:09)
Hmm.

Andrea (18:34)
to clear again. You can stick it in the fridge, it's not going to help, right? So proteins can get denatured in that way. That's why when you take a protein technology, like insulin, for example, you can't ingest it because your stomach acid and the heat will change it before it can get into your body and help you. That's why a lot of protein technologies are injectable. Small molecules, on the other hand, can be ingested.

Harsh Thakkar (18:55)
Mm.

Andrea (19:00)
for the most part, if they have the right properties that can withstand heat and are stable enough. So I've always been fascinated with small molecules and that's where we went again with the metabolomic technology. And so this will be a orally available pill that one could take, let's say every day.

Harsh Thakkar (19:25)
Okay. And, and a of the audience, a lot of the people in the audience, are thinking around, you know, regulatory challenges or clinical trial challenges and all the other kinds of hurdles that come in from, you know, getting a molecule or compound that you research in the lab out to, you know, the patients. And there's, you know, sometimes it can take 10, 15 years and billions of dollars until everything's said and done. So.

from your perspective as a founder, as a CEO of the company, you're probably involved in every little thing that's going on around these challenges. So what are some of the hurdles that you've had to cross up to this point or maybe something that you might cross in the coming few years? Can you share some of those?

Andrea (20:17)
Interestingly, it's just being a human being, a baby, working with people. Without people, we can't do anything. The technical challenges, I've never felt like that was going to stop us or regulatory challenges or finding money. Those things I've never felt intimidated by. I don't know. It's not that people intimidate me either, but I care deeply about how we work with people because people are everything.

Harsh Thakkar (20:21)
Hmm.

Right.

Andrea (20:46)
So imagine now you have a team of people and I mean, it's very challenging to have, I'm telling my team, hey, we're going to a football game. You're playing in the game, start running. You've never seen this field before. I'm going to throw the ball to you. I'm going to tell you the rules of the game while you're running and you catch the ball. The rules of the game are going to change during the game as the same way that market change, regulatory guidelines change, geopolitical topics change that impact.

the company, the rules of the game are always changing. so imagine now you have a team of people where you're telling them that. And then while you're telling them that you're also saying, and don't stop running. It's really hard. It's really, it's a really hard challenge to have so many people running at that speed and understand understanding that we're all doing this for this mission, but it's challenging. It's,

Harsh Thakkar (21:29)
Hmm.

Andrea (21:45)
It's something that everyone, every company deals with.

Harsh Thakkar (21:50)
Yeah, you're in a very unique space. That's why I asked you this question at the top of the episode. For somebody who's clicked on this, they're probably thinking like, what the heck is this? Like, is this real? Like, I need to listen to at least 10 minutes of this to figure out what this episode is all about. But, you know, as you're keeping up with all the developments that are going on in this space,

Andrea (22:02)
Hahaha

Harsh Thakkar (22:16)
in terms of other companies or other entrepreneurs or maybe researchers. What do you think are other applications of worm -derived therapeutics? Are you noticing any innovative products or innovative research that maybe in the next five or 10 years will apply this, what you've studied, to other areas?

Andrea (22:40)
think that the possibilities are endless. This should be able to impact all corners of human health, especially with the idea that worms are really interested for their own benefit in wound healing. So there are many, many different, can't even bracket wound healing into a specific class of indications because it touches almost every disease in that way. And then to think about where we could go from there.

It's just how do we do it all at the same time? You can't, right? Even Leonardo, when she said, how do we do so much? It's one at a time. And so I think that's the challenge is trying to figure out how to strategically wedge our foot in the door so that we can truly explore the opportunity.

Harsh Thakkar (23:31)
And when you are I also meant to ask you this earlier but when you you studied these types of worms and the communication and the signals was there a specific You know type of worm that is part of your technology or Will your your company's technology and research would work with maybe different types of forms. Would it exclude certain types? Can you share some details there?

Andrea (23:59)
I think we are looking at all kinds of different worms for sure. But within those, I think the ones that have stood the test of time, and it's so interesting because I never talked about time so much as I have on this podcast. don't know why it keeps coming back to me. But what are the ones that have stood the test of time? What are the ones that have had the chance to evolve this sort of technology and they have a reason to?

Harsh Thakkar (24:12)
Yeah.

Hmm.

Andrea (24:26)
Because if you're a worm that's just in and out, why would you even bother, right? You've got to be a worm that cares truly about the long -term investment of your host, the health of your host. And so that's where we're looking. And that captures our lead molecule as well.

Harsh Thakkar (24:32)
Right.

Interesting when when you're not doing thinking about this research or thinking about you know growth and other strategies at your company What do you what do you like to do in your past time? Do you have any hobbies? Do you read books? What's what's some of the things you do to disconnect from all of this?

Andrea (25:10)
my life is bustling because first of all, I have a four year old child, right? So it's life is always exciting. also my husband, Miguel Atwood Ferguson has is an incredible musician whose work I've been following for a decade. had Guardians number one album of the year last year. So, I mean, it's it's nonstop. You know, he's he's working on his mission. I'm working on my mission.

Harsh Thakkar (25:26)
Hmm.

Wow.

Andrea (25:39)
Our sun is somewhere in between and there's Legos on the floor at all times. So it's nonstop. also I just moved to a neighborhood where we have a black bear living in our backyard. So let's just say the spice of life is always there.

Harsh Thakkar (25:42)
Yeah.

Mmm.

Right. Yeah, I can relate with the the Legos on the floor because my son is turning four in November. So I have plenty of those in my living room. And also when you were mentioning about going back in time and, you know, maybe you would see T -Rex. I first split second was thinking about how excited my son would be because he's also extremely fascinated by dinosaurs.

Andrea (26:28)
That's awesome. I need to make some Holoclara merch where it's a T -Rex with a worm inside of it. That would be the present that we give to everyone and your son will be the first to get it, let's say.

Harsh Thakkar (26:34)
Yeah, I, yeah.

All right, that sounds great. Listen, this has been a very interesting topic and a very interesting conversation for anybody that's listening to this episode. If they want to learn more about you or more about your company, what's the best way for them to find you?

Andrea (26:59)
that would that yeah, that's a great question. Holoclara .com is where our website is. And we're also we also have socials on LinkedIn and X. So look for us there. You just have to have to learn how to spell the name Holoclara. H O L O Clara C L A R A.

Harsh Thakkar (27:10)
All right.

All right, we'll link that in the show notes. And before we drop off, is there one thing that you want people to take away from this episode if they've made it this far?

Andrea (27:34)
I think it would be, anyone, you know, anyone can do it. It's like Virgil Abloh said, anyone can make art, but you really have to be able to take a hard look at yourself and hear feedback and look for the opportunity and feedback rather than the immediate no. If you can do that, then you can do anything.

Harsh Thakkar (27:39)
Yeah.

All right, we'll leave it at that. Thank you so much and wish you and your team tons of success. Thank you.

Andrea (28:01)
Thank you. It's such a pleasure to talk to you. That was a lot of fun chatting with you.

Harsh Thakkar (28:06)
Likewise, thanks.