The Reboot of Consumer Genomics? with Kian Sadeghi, Nucleus Genomics

Is this the reinvention of consumer genomics? Next on Mendel's Pod. Welcome to the program, everyone. I'm Tharel Thimpson. There's a new company out that is offering whole genome sequencing to the consumer for $399 in an attempt to revitalize consumer genomics. In 2022, Nucleus Genomics raised $18 million From Reddit founder Alexis Ohanian and Peter Thiel. I'm very excited to be joined by their founder and CEO, Kian Sadeghi. Hey, Kian, welcome to the program.

Hey, thanks so much for having me.

It's great to have you on. This, this is— this sounds to me like a real revitalization of the space. But it's also a bold move, given people who have tried it. So tell us why Nucleus? And, and what is your big vision here?

That's a great question. Thank you so much again for having me on. Very excited to be here. I think in the last 20 years or so, there's been 2 fundamental changes in genomics that have enabled a new nucleus. The first is the cost of actually sequencing or reading the entirety of someone's DNA. So when the first generation genetic testing companies like 23andMe, when they first got started in 2006, they're actually pretty old, almost 20 years old at this point. The cost of sequencing. Wow. Yeah. Can you believe that? 20 years?

I know. It's crazy. I remember I was just down the street starting another one.

Yeah.

Yeah. Anyway, yeah, so it's been a long time. Good.

Been a long time. And when 23andMe got started in 2006, the cost was around $10 million to sequence a genome. Obviously not economic. So instead they opted for much more naive, but at the time probably more innovative technology called microwave technology, which looks at a small snapshot of someone's DNA. Sure. The thing is, in the last, you know, 20 years or so, that cost has come down from $10 million to now on Nucleus's website, Right? That's an amazing, extraordinary decrease in cost driven, you know, by our collaborators over at Illumina primarily. So what ends up happening, the first thing is, no, now genomics is different. We can actually sequence DNA for a couple hundred bucks, right? The second thing that happened last 20 years is our ability to analyze this DNA. One thing is to read more DNA, another thing is to analyze it. Specifically, I'm referring to the rise of polygenic scores, which basically is a way of actually measuring common complex conditions, combining that with classical Mendelian genetic analysis, which looks at the presence or absence of rare DNA differences found in many genes throughout the genome. So if you think about Nucleus, we're combining the ability to read DNA much better with the ability to analyze it, both polygenic scores as well as rare variants genome-wide across hitting all, all genes.

Okay.

So those 2 innovations, yeah, have led to Nucleus's creation.

Well, congratulations. So what you're saying is timing actually. Yeah. I mean, maybe some who had done this before, you know, were, were actually early.

I think so. I mean, it was only literally in the last year, year and a half where we have a whole genome that you can sell to consumers, even economic positive for a couple hundred bucks. I mean, that's pretty crazy. So Nucleus is definitely pioneering that and it's a clinical grade test. It's physician ordered. So you can actually give out, you know, pathogenic, likely pathogenic variants, which is also unusual for a whole genome company. So all these factors, yeah, it's a very exciting time.

So do you feel like you're reinventing consumer genomics with this?

I think absolutely. I think one thing about the genetic industry is that it's sort of full of false dichotomies. So the first one is there's consumer genetics, which is kind of more generally viewed as a gimmick, right? does my pee smell like asparagus? A little bit, you know, where I'm from, some ancestry.

On the fun, entertaining side.

Yes, exactly.

Is a lot, is a lot how 23andMe started to market, but they, but they've gone all over the place. You're probably gonna get into that.

Yeah, yeah. And then eventually they, they evolved, but still people view it as almost as like a, a toy. Then there's other companies, clinical genetics companies, Myriad Genetics, Invitae at some point, Natera, and others where they provide very consequential kind of classical genetic analysis. You know, people always think BRCA1, BRCA2, right? They always think Angelina Jolie. These companies then are doing very serious tools in healthcare to basically stratify patients who are at much higher risk. I think that what needs to happen is you need to have the basically consumer reach of a 23andMe with the clinical consequence of a Myriad, right? Moreover, that's the first false dichotomy. So Nucleus is basically combining over, you could say, 70,000 genetic tests on the market today. into just one clinical-grade, high-coverage whole genome test. The second thing that we're doing is there tends to be a kind of tension between common DNA variants or polygenic scores and rare DNA variants, right? Mm-hmm. We're integrating both, right? We do polygenic scores and also rare variant analysis, and we can do that because we have someone's whole genome. And then we go one step further, which we also bring in non-genetic information, and integrating non-genetic information makes it so that we can get even more accurate assessment of someone's overall disease risk. So if you actually look closely, Nucleus is a healthcare company, not even a genetics company, but we can go more into that.

Okay. Yeah, no, I, I, I hear what you're saying. I mean, these more cl— the companies on the clinical side are very, you know, common guests for us on this program, right? And we've pursued all these various tests. So how are you, how are you marketing this or going to market this?

That's a good question. So to— I mentioned earlier how there's been kind of this fundamental change in the ability to read and analyze DNA. I would go even further than that, in that another thing that's changed in the last 20 years is actual consumer taste and demand. So you've seen this kind of rise of people a lot more cognizant of their health levels— Apple Watch, Oura, Eight Sleep, many other different kind of personal hardware devices that's tracking someone's, you know, heart rate, heart rate variability, calorie burn, etc. And you see the rise of people like Bryan Johnson, you know, Huberman, other influence in sort of the health, preventative health, um, kind of space. What I'm trying to get at here is there's been a quantified self-movement of sorts where health has become so much more part of lifestyle in a way that in the last, you know, when, you know, first-generation companies started, there was just no such precedent. So it's not just that the technology has changed, consumer taste has changed. And Nucleus is part of, I would say, the next generation's, um, next generation's tool to live a long, healthy, and ultimately preventative, preventative health lifestyle. So that, that is kind of what I think Nucleus is really tapping into.

Okay. So, so early adopters then will be these quantified self people, people who are already kind of monitoring themselves. They like all this data. They're actually pretty good at dealing with it at this point.

I think, yeah, I think that's to some extent true. 23andMe's average age customer is estimated to be like a 45-year-old female. Nucleus tends to skew a little bit younger than that. These people haven't necessarily done a genetic test before, right? They don't even know necessarily what a genetic test kind of entails and what it can encapsulate. So it's definitely, I think, a new paradigm shift for them, just the amount of data, especially in whole genome sequencing. We strive as a company to make it such that anyone can understand our results. You don't have to be technical, you don't have to be scientific. We give very clear, beautiful, clinical-grade results to everyone. But earlier adopters do seem to be people who are already kind of primed in that, you know, they, you know, one time we collected some data internally that showed disproportionately the people who do Nucleus or are interested in Nucleus own actually a wearable, which makes a lot of sense, right? It's part of like the kind of holistic package of someone who's trying to live a healthy and long life.

Okay. Yeah. So, so would you say marketing is the big part of what you're doing? I mean, so for instance, how does this differ from Illumina's whole genome sequencing, right? I mean, they've been offering clinical-grade whole genomes, or there's been a couple companies Um, there was Veritas. I think Nebula Genomics is still out there. Um, and so, uh, you know, how these companies have given this a try, um, are you saying that the price has come down since then and they're— and you're going to tap into a different kind of, uh, market or consumer sentiment?

Yeah, I think it's a multitude of factors. Um, I think, you know, Illumina is actually a collaborator. So we're complementary with Illumina. I like to say that the magic of Nucleus begins when the magic of Illumina ends, right? Off of Illumina's new X Plus machine in our partner laboratory in Boston comes out a raw DNA file, which is when Nucleus's laboratory, our informatics laboratory, begins. So Illumina is very complementary. Regarding other whole genome sequencing companies, I think the thing to remember is a lot of these companies actually were not physician ordered. They weren't clinical grade. They did not report out any rare variants. They're more research tools. Nebula, for example, is not actually physician-ordered. They don't report out pathogenic variants. It's not a laboratory. Hmm. It's more of a kind of a research tool actually. And more than that, they also don't usually calculate absolute scores or someone's overall risk of disease. They don't factor in non-genetic variants, excuse me, non-genetic information that you can use to further stratify someone's risk. So there's a multitude of reasons here. Nucleus actually does polygenic scores. Rare variants analysis combines in this non-genetic information. Then also I would say, you know, we sequence in the United States on US machines, et cetera. But the core value prop of combining kind of a clinical-grade Myriad with a 23andMe reach, I think is really unprecedented.

Oh, okay. So you're more clinical-grade then? That's—

Yeah, we give out rare variants. I mean, one of the most important things in genetics is actually, you know, do I have a BRCA variant, right? Do I have a BRCA2 variant? Right? Do I have a CHEK2 variant? Whatever gene it ends up being, you actually have to give patients these insights. And the way we've defined this, the way we designed the system is that if someone does have a pathogenic variant, they get that. If they don't, then they get a polygenic score. This way they get the entirety of the breadth of genomic insights that exist. It also goes well beyond just kind of human health. It also talks about preconception screening to see if someone's a carrier for a condition, which we can go more into, pharmacogenomics, right? How someone's DNA actually changes the way they metabolize drugs, even traits as well. So we do a kind of eclectic mix. a mix of different tests that today are in like tens of thousands of different tests. So it's very exciting.

It is very exciting. Yeah. I mean, you know, these are the variants that we talk about on this program all the time. And, and I'm personally in favor of whole genome sequencing at birth, right? Why not? I agree with that information. So it sounds like until we get there, Nucleus offers it.

Yes, we offer it.

You offer it. So, so let's walk through how the product works. So I've actually ordered it from you guys and I've already swabbed and sent it back. So what can I anticipate? What, how do you think this is gonna go for me?

Yeah, let's just like walk through kind of your listeners and how this actually works, right? So you go on the Nucleus website, you order a test, physician reviews the order, signs off on it. At that point, a DNA kit is actually behind me. It's sent to you, you open it up. Did you like the kit experience? Did you like the kit the way it felt?

Yeah. It was very nice.

Very nice. Oh, thank you. That's nice.

Yeah, it was sort of like the quality of Apple, right? Wow. Brought to genetic testing.

Wow. That's, that's a very high compliment. I'll let the team know that. You know, we really, we really want to build beautiful products, which honestly doesn't always happen in healthcare. Right. But also one that still has scientific rigor and is of clinical-grade quality. Right. We believe in both the kind of style and substance. It's very important to us. And I think that manifests in the kit. So I appreciate that. So yeah, you swab. Swab one cheek, right? Stick the tube in, swab the other cheek, stick the tube in, take the tube, put in a biohazard bag, you know, put in a prepaid envelope, goes into our partner laboratory in, that's a little bit outside Boston, takes your DNA, extracts the DNA, runs it on Illumina's newest X+, and then out comes a raw DNA file. That raw DNA file then goes into our pipelines, our analyses, which includes both, you know, polygenic scores and also rare variant analysis. And that, of course, those results will then go out to customers across many disease reports. Currently, we offer analysis on around 20 diseases. That's going to be scaling up pretty exponentially to hundreds. So— Oh, okay.

So in my report, I can expect to hear about 20 diseases?

Yes, 20 diseases for now, though, because it's whole genome, we can rapidly scale up the platform. So that's kind of the beauty of it, which is we've built out all the hardest parts now, and now we can just focus on providing value to the customer.

Okay, so not every, uh, genome analysis is, is equal, right?

No, no, no, definitely not.

I mean, there have been companies who have differentiated themselves in this space, for instance, like, uh, Fabric, right? And even when you're just looking for BRCA, I mean, Myriad has, has really perfected this. Uh, like, would you recommend if someone was a candidate for BRCA because of family history And age and so forth, that they get this test and it, it would be the same as a BRCA test from Myriad?

I mean, I would absolutely recommend that they, they can do Nucleus if they suspect maybe they're a carrier of BRCA or some other breast cancer-related gene. I would say that the founder of Myriad Genetics is actually on our scientific advisory board as well as the chief scientific officer. So we're very, very well acclimated to kind of Myriad's work and We have a lot of great discussions with our scientific advisory team on providing the best analyses to our customer. So absolutely. I also think that, you know, if someone doesn't have a pathogenic variant, which they may well not, right, even if they do have family history, it's the polygenic score we provide people can further stratify their risk. And in some cases, a high enough polygenic score can have risk equivalent to someone did have a BRCA variant, right? So the analysis really applies to both the person with a family history or even with a known pathogenic variant, and as well as people without. So I think that's what's so kind of powerful about the platform by integrating both these kinds of analyses, which is even if someone didn't have a BRCA variant traditionally, they wouldn't get any further risk stratification based off their genetics. Now though, through the power of polygenic scores, they actually can.

I see. So that's something you offer that Myriad doesn't.

Yeah. I mean, across different diseases, generally clinical genetics companies don't provide polygenic scores. Breast cancer might be the only exception, but across basically Alzheimer's, type 2 diabetes, age-related macular degeneration, many others, they usually don't know.

Now, how do you pick which pathogen— what is a pathogenic variant and whether you're going to report it back or not?

Yeah, that's a great question. We use a mix of kind of public and private databases. We run different in-house kind of studies to make sure that we're calling variants that are actually real. We also do have manual curation. So, you know, our software basically spit out a variant that currently someone will review and then make sure it's a legitimate call and then return it to the customer. So we basically multiple checks to ensure the kind of quality of the rare variant that's being handed out to the customer.

Uh-huh. Yeah. So, but what I'm thinking is, do you have sort of, do you list on your website all that you think are pathogenic variants? Do you follow any kind of guidelines?

ACMG guidelines. Yeah, we follow ACMG guidelines. You do? Yeah, we do. And then also what we do is, yeah, we do have that. So we have not only the genes, but upon request someone can actually ask for the list of variants we provide and we actually provide that to customers. So we're very transparent with what we do.

Okay. So how is this better than arrays or exomes? Okay. So I know you're giving more information. The exomes, you know, has a list of all, of all the, the genes. But there's also, there can be a risk of too much information. What, what, what do you say about that?

Yeah, so there's multiple questions in there. I'll first start with arrays. So if you look at like a traditional array, which is a traditional consumer-based genetic test, take breast cancer, we've been using breast cancer as an example. 23andMe's test, for example, looked at maybe 3 BRCA variants. Historically, now they're at 44. There's actually thousands though that are known to be pathogenic. They just simply don't look for them. If you look at Nucleus's task, instead of looking for 3 breast cancer-associated pathogenic variants or 44, we look at tens of thousands for a gene.

And you're picking those up off of like ClinVar?

Through the power of whole genome sequencing, yes. ClinVar, HGMD, other databases where we actually look at far more genes and actually the entirety of the gene, right? Not like a small snippet like a microarray is. So now you can apply that model to every single every single disease, where instead of looking at a very small fraction of the variants, which risk a lot of false negatives, suddenly you can give people, you know, even millions of people, like what's something that's really interesting is studies estimate millions of people walk around with a variant for breast cancer, colorectal cancer, or familial hypercholesterolemia. Millions in the United States, more than 90% don't know. Can you, can you believe that? I mean, I, I still kind of tremble on that, knowing that all those things are actionable. Yeah. And you can materially reduce your risk for those conditions. They don't know it though. And that's kind of the power of Nucleus and the power of our technology, which is we can pick up on these variants that, you know, more than 10 million people may have missed out on. So that's the first thing. On whole exome, you can't run polygenic scores. So it's true you can get, you know, the presence or absence of, you know, more high-effect rare DNA differences, but you can't then stratify someone's risk further through polygenic scores, which is obviously a key part especially of, you know, type 2 diabetes, AMD, CAD, and many other diseases to stratify someone's disease risk. So that's why you have to do kind of a whole genome test. And for $399, I mean, it's kind of a no-brainer. It's probably the single most kind of consequential lab test that you could possibly do that can give you so much insights into your genetic risk for disease, as well as amongst, you know, other things as well. To your point on the kind of too much information, well, I think that's our job at Nucleus. Our job at Nucleus is to very intelligently and thoughtfully present the huge amount of insights that exist in someone's DNA to the customer. And, you know, I can't wait for you to actually see your results because I think we did that pretty successfully. Historically, genetics companies have a very bad rap for UI and UX. It's not necessarily their forte, right? Especially clinical genetics companies. It's not exactly— they're not exactly paying attention to that. But to us, that's true.

And, but a lot of their reporting to doctors, so, uh, yeah, they are reporting doctors, they can be more technical. And, and having said that, I do think 23andMe Really pioneered basically, you know, UX design for genomics. They did pretty good.

Yeah, no, I think we, we're very grateful at the foundation that the first generation genetic testing companies have built, right? If you look across industries, there's always usually a first, you know, kind of bounce of the ball and then a second player that goes much, much further. So I think they did a great job of kind of popularizing consumer genetics and it being even a thing. But now, you know, the world is different, the technology is different, the kind of data foundation that you know, companies are built on is just, is dramatically changed. And so then to your point on doctors, like, I think it's true, like, you know, the report they give is also for patients. I mean, if you do Invitae or, you know, when it existed or Myriad, you do get a report and then you also can bring that report to your physician. Nucleus does the same thing. We have a consumer-facing report and we also have a physician report.

Hmm.

So we also build our software with physicians in mind, knowing that if someone, especially if they have a pathogenic variant might want to go to their doctor and talk about it. We also have genetic counselors on hand. People can actually talk to genetic counselors after finding what we call high-effect variant, what you may know as a pathogenic variant. So we view ourselves as building for both the kind of healthcare ecosystem, primarily for the customer, right? Because the customer ultimately is the result it's affecting, but also physicians and genetic counselors definitely fit in there.

With the genetic counselor, let's say you reported back a pathogenic variant to me. You will provide a genetic counselor, you will list some genetic counselors that I can reach out to. How will that work?

Yeah, it's a great question. So we, we partner with StudyMD, which is an independent physician network, and we work with their genetic counselors. So through our software, you can basically just go, you know, to a calendar, select a time, and then, you know, au revoir, you'll book with the genetic counselor. It is an add-on feature, but it's available for anyone that would like to, especially if you have a pathogenic variance. We encourage it for customers.

Ah, nice, nice. Now there are some pathogenic variants like APOE. I remember when I got my 23andMe report, I chose not to see that. I might have, I might have changed my mind a bit on that.

Do you have a family history of Alzheimer's? Did you, did you?

Yes.

Do you have any? Oh, you do? Okay.

Yes. I do. And that gene is, is so important, right? It's like 85% increase in risk. Um, so do you just report everything, um, or are you going to have some things, um, locked up?

So that's a great question. We believe in liberty for the customer. It's not our job as a company to decide what people should or shouldn't get. It's the customer's job to decide what they want. So every customer during the signup flow can actually decide to opt out of certain diseases or traits too, if they don't want analysis for that. So that way we can never accidentally report something to someone when they don't want that insight.

I wondered if I was doing that. So that's in the signup process?

Yeah. Yeah. Did you, if you missed that then—

And you asked me, I guess it asked me, you know, is there any, is there anything you don't want to know or something like that? Exactly. Is that right?

Exactly. Yeah. Did you, did you block out Alzheimer's? If not, I can make sure we can, you know, handle that after and make sure you don't get it.

I think I, I didn't. I just wanted, I wanted to see what happened if, you know, everything came.

Okay. So are you gonna check your Alzheimer's result? I'm just curious.

I think I will. I think I will.

Oh wow. Okay. Well, I would say that our Alzheimer's result also factors in other genetic variants as well beyond just APOE. So the analysis can actually further stratify your risk, which is really powerful for people. So that's just something to note.

Yeah. I mean, I think it's great that you're putting this out to you know, the average person, it does take some education. Absolutely. To kind of know how to use this product. Is that right? I mean, using it could be educational itself, but the more education you have, the better.

Yeah. And I think if you go on the Nucleus website, we take great care and very thoughtful in all the education we try to provide customers. So if you go to our deep dives, for example, we very thoroughly explain the difference between microarray and sequencing. We talk about, you know, we have a blog post about what to know before you get your results, right? We have information on what we call common genetic scores, what you might know as polygenic scores. So we're very deliberate in that regard. Also, I think our reports are extremely thoughtfully designed. We both have kind of different abstractions to the information we provide customers. So sometimes it can be kind of more direct and more simple. And if someone wants to dive in deeper and to see what we actually did, they can then go to our more detailed report to do that. Obviously though, we always are taking in customer feedback and trying to improve because nothing's more important than someone understanding what the result means, right? That's very important. I mean, nothing's more important than

that. Polygenic risk scores, you've mentioned them a few times. What disease areas are you reporting those?

For basically every, basically every common complex disease of the 20 diseases we provide, we provide polygenic scores. Yeah.

So, okay. So I know there's pretty good scores for, for cardio.

Yes.

And neuro, some in cancer, neuro, Alzheimer's.

Exactly. The way we designed the platform is we want to focus on the diseases that have the highest powered polygenic scores. So if you look at our platform, you see things like breast cancer, you see type 2 diabetes, Alzheimer's, you see things like, you know, there's other various other cancers in there. So we really are mindful of providing customers insights that are at the kind of frontier of medicine and science. And then also by leading with overall risk, it makes the polygenic scores more understandable. Because one problem with polygenic scores is it gives out a relative risk assessment, you know, oh, you're in this percentile or you're one standard deviation above the mean. But what does that actually mean for the customer? It means your risk goes from, you know, 10 to 15%, for example. So that is the most important communications we do, which I think is a further value add of Nucleus beyond just our technical prowess. It's also, the communications of the results and doing all the best practices for some more complex genetic analysis.

Okay, so for those who are getting a, the product from you and a report, there's going to be some pathogenic variants which they could do something with. Could be long QT, it could be FH, it could be BRCA. I mean, I think those are the 3 big ones, and, and we should probably have population screening for those. This is a kind of population screening. It's a self-initiated screening. So, so you might get one of those, and that could be very helpful because you could take a drug, for instance, or—

More aggressive screening, earlier screening as well.

Earlier screening, yes. Now, with the polygenic risk score and just kind of general risk, let's say your risk is at 15%. What does someone do with that?

There's actually cases where studies have found that polygenic scores stratify risk equivalent to those found in classical Mendelian analysis. So by that logic, the guidelines should be the same, but I would defer to the genetic counselor or to the physician on giving the patient the next steps. I think though that's really powerful because all of a sudden, you know, if you're 3 standard deviations above the mean for your breast cancer polygenic score, You may maybe need to get the same guidelines recommendations as if you had like a check two variants because if you remember across breast cancer associated genes, there's different levels of penetrance, right? Basically how bad in quotes we think the the gene is, right? How much does it actually increase your risk by? And you can see that not just across you know breast cancer. You can see it type two diabetes. You can see it across CAD and others. So I think that's sort of the power of polygenic scores. I also think that. Even if there is not a risk equivalent to classical monogenic analysis, you can still take specific guidelines and measures that you wouldn't otherwise have. Right. I think one thing is that, you know, sometimes people say it's like, oh, you know, exercise and eat more and eat healthier.

Exercise and eat better.

Yeah, eat better. It's a little bit mocked. I think part of the mission at Nucleus is to actually bring in the entirety of someone's health data onto the platform, right? Such that it says, hey, Kian, as a 24-year-old male in Brooklyn, wow, you had super high LDL levels in your last blood test. That's actually no surprise because you're in the 95th percentile for familial hypercholesterolemia. We found people with similar genetic sex, age as you saw a 10% reduction when they ate these things and did this specific workout over the course of 4 months. And then you kind of keep track of the patient in that regard. That is the future of genomics and really healthcare. I think building a consumer-centric, quantified, real-time health platform that closes the loop where even if you are higher risk for something, right, you can start actually measuring What happens if I lose weight? Once my cholesterol comes down, how does that affect my risk for these different conditions? Connecting those 2 pieces, I think it's gonna be very important and it's gonna be one of the goals of, of Nucleus.

Cool. Wow, you're 24 and you've founded this new whole genome sequencing company. That's, that's amazing. Thank you. How did, how did, how did you get into this? Why you?

Yeah, that's a good, that's a good question. You know, you mentioned Long QT earlier. Unfortunately, my cousin actually suddenly died in her sleep around, you know, 14 or so. Oh wow. She went to sleep one night and did not wake up the next day. And doctors attributed it to, you know, bad genetics, possibly to Long QT. And at the time I kept asking my parents, you know, how's this happen? How's this happen? How's this happen? They just kept saying, you know, bad genetics. Didn't understand what that meant. Eventually I started studying genetics. I started realizing that, you know, diseases can be caused by like a single kind of mutation in someone's gene. Um, so I picked up gene editing. Uh, so in high school I did a lot of work with actually CRISPR. I engineered yeast to make them illuminate, edited bacteria to make them resistant to antibiotics. And I started thinking about like, what if you combine this kind of beauty and depth of biology with the iterability of programming? Because one thing about the wet lab is the life cycles could be so long. On the computer it felt so much more malleable. So I like that. So I went to Penn where I studied computational biology for like a year and a half, and then I decided, you know what, um, COVID hit, I was like, you know, I actually have this vision. I was in Bio 221, which is actually a genetics class. I had this vision where the professor, the chairman of the department at the time, showed the decreasing cost of human sequencing. At the time, it was like probably, you know, a couple thousand bucks. I remember thinking to myself, what is the world going to look like as that cost approaches zero? Someone probably has to build the kind of application layer for, for this. So I figured, well, you know, I'm in my bedroom, you know, I was outta school at this point. Let, let me do it myself. You know, quite, quite a naive retrospectively, but, you know, bold. And so I began doing research into understanding the underlying analysis and models of how do you analyze whole genome data. And then I realized I could provide myself much more on more disease and more traits and much better by combining polygenic scores and classical genetic analysis results to customers. And that's how Nucleus got started. So it got started with curiosity. And I think The thing is, what's so powerful to me is, you know, and, and kind of sad too, but as powerful as, you know, like my grandmother recently passed away, you know, several weeks ago. Mm-hmm. Uh, she had, you know, lung cancer.

Sorry.

Thank you. Uh, and I think to myself, you know, at no point was, you know, genetics used. Um, and it wasn't, it wasn't even lung cancer actually linked to smoking either. So, and, you know, she had breast cancer historically as well. My mother, grand— my other grandmother died of, um, pancreatic cancer. And so when I think about these stories, I think about how the stats I give of 1 million people, 2 million people, 3 million people with a pathogenic variant, it sounds kind of abstracted. It's kind of higher level. It's a number, but these are people with families. Then when you think about the work we're doing at Nucleus, to know that maybe we can give someone some insight that could potentially help save their life, I think that's so powerful. So that's why I'm so grateful for the team and the work that we do, and I'm excited to bring genomics much more to a broader audience than it's ever been. Because even you look at like these, you know, 23andMe, these other companies, we're talking about 14, 15 million people. Honestly, the United States is 300 million people, right? There's hundreds of millions of people have never even done a genetic test. And to think that a genetic test, a swab could save their life, it's so powerful. Or even their children's lives. If you look at like infant mortality, actually the number one cause is still genetics, which is unbelievable. If people could, you know, literally swab and we can do mass preconception screening. Every single person, hundreds of millions of people in the United States are a carrier for a DNA variant that they don't know. Hundreds of millions. I mean, that's, I mean, like, it, it's pretty crazy to me. Like, in a way there's this narrative that like genetics is tried and true in consumer genetics, but it's simply not the case. And so I'm excited to say that again.

Yes. To everyone. A narrative though.

The, the one, there's a, there's a narrative that, you know, like consumer genetics, it's kind of like, you know, dying right now. Oh, that's interesting. There's 23andMe, it kind of came, but to me it's like dying, you know? You know, less than, you know, 0.001% of the population's done a whole genome test. I mean, like, what are we talking about? Like, you know, 100 million people never got— yeah, I mean, ever. I mean, if you, if you don't even look at whole genome, if you look at microarray, microarray, they, they, you know, only 15 million people have done it. And that itself is an extremely, extremely limited test, uh, with millions of false negatives. So I just think there's so much to build and I, and that's why I'm so excited.

Cool. Very cool. You know, it's great hearing you. The access problem, um, you know, you mentioned your grandmother, um, who had lung cancer. Why didn't she have some kind of, of genetic testing, um, looking for what kind of cancer it is? Um, there's a lot that's, that's available now. And we ask this question all the time on this program. Um, yeah. And we often hear that it's, you know, doctors are not educated. Uh, they didn't train in this because genetics is so new and they don't have time. Yeah. to pick it up, right? And, um, so I can see how this is one approach to the access problem, and I, I believe in it more and more. Um, you know, I have a friend who is the director for precision medicine at University of Colorado, and they have probably the, the biggest, um, research facility, uh, for giving out genetic results. Um, they're actually using arrays still. Really? But yeah, he's told me, he said he'll run into people and they'll say, hey, I want to find out about my genetics. I want to, you know, I want to learn if I'm this, this, or this, or this. And so he believes, even though they're doing it through the University of Colorado medical system, he believes that it will ultimately be consumers that drive this.

I agree. I mean, the largest genetic databases in the world today, if you look at microarray, they belong to consumer companies, right? It's not government projects. Today, the largest whole genome database is 500,000 people approximately from the UK Biobank. Right. That's not a lot of people. 500,000. I mean, we have billions of people to sequence. We have billions of people to help. So I agree. I strongly agree.

Okay. So the FDA recently announced they're gonna regulate tests like this. You know, the whole story with 23andMe was a kind of back and forth with the FDA, right? What are you anticipating? How do you think that'll impact you?

Well, I'll just say a couple things. One is we're obviously not direct-to-consumer. We're physician-ordered. We're an LDT. We're CLIA and CAP accredited.

Okay.

So we're currently compliant with all regulations. If those regulations change, then we'll adapt to make sure we're always regulatory compliant.

So. What do you think is your biggest challenge going forward? Well, I think we just talked about the vision here, right? And, and really it needs to go out to billions of people.

It does.

What do you think is your biggest challenge?

I think people— there's some definitely education to your point of people don't understand if they did 23andMe, for example, they don't really understand the difference between their, the technology they did and the new technology. Right. It's almost like, you know, you know, a horse carriage versus like a self-driving car. It's like, what is this? Like, but there's horses, like it's, it's okay. And I'm like, no, no, no. Like, you don't understand. These are like dramatically different orders of magnitude, different technology capabilities. And so part of, I think our job at, at Nucleus is educating, showing people all the insights that they are missing out from a whole genome test. And then moreover, Bringing in new constituents, people who've never done genetic testing before, and educating them about the power and consequence. There's many narratives in, in genetics. It's actually, if you actually really think about it, it's interesting. There's narratives about, you know, Golden Gate Killer and, you know, using it to, you know, make you go to jail. There's narratives that it will save, you know, a newborn's life. Then there's narratives about how you should do it for BRCA testing. Then there's yet more narratives about how, you know, consumer genetics is like kind of for traits and like genealogy, that whole application, right? There's so many.

Yeah. Ancestry. It really boomed with the ancestry testing.

It really boomed. Yeah. Right. Like, so there's so many of these, these different narratives and, and I think people still don't fully get exactly the, the, the just how important the, I mean, the whole genome is the foundation of your health, right? I think people still don't get that and take some education. So over time though, I think people, once they start seeing their friends getting these kind of very powerful results, I definitely think it's gonna spread. Um, and I think everyone's gonna get their genome sequenced. And as I think, as you said, a baby's gonna be born and their DNA's gonna be sequenced. Moreover, the baby's probably have a wearable too that's going to track, you know, their heart rate, et cetera. You already start seeing that with kind of new parents today. There's probably going to be a software that kind of tracks and monitors all this. So part of our job today is very much kind of marketing education and giving people insights that, that can, you know, potentially save their life.

The Golden State Killer story came out just during that ancestry boom, you know, ancestry testing boom. I mean, it just looked like that was going to grow. You know, exponentially. And then I wondered if that story made just your average person a little bit more careful because they started to think about the privacy issues. And so that's a big, you know, that's a big topic when we get into genomics. What thinking have you done on that to help them, reassure them? Yeah, I have. Of the privacy.

100%. There's 2 things here. Um, one is that what a lot of people miss out on is that like even Golden Gate Killer, nothing to do with a private genetic database, right? They actually use a public genealogy database. Also, the FBI has their own genetic database. Like they don't need private companies, unfortunately.

Oh, okay.

Uh, it doesn't actually touch private genetic companies. It never has. If you look at 23andMe in the last 15 years, they actually publish how many law enforcement requests they get. In 15 years, they got around 15 requests. My understanding is no data was ever handed over, right? 23andMe is a database of 15 million people. Google, Amazon, these other companies, they get 20,000 subpoenas, you know, a quarter. They get, you know, like they get insane number of requests for access to data and they comply with the vast majority of them. I think Google is like more than 90%. So that's a narrative violation. People don't realize that actually it's not the private genetics. Like this isn't, just isn't happening. That said, of course we still understand the concern. I mean, I was— when starting Nucleus, one of the foundational things I wanted to do was have a safe platform, right? Because I mean, my DNA is on it, my family's DNA. I mean, of course, right? So then we did a couple of things foundationally from the beginning differently. One is we're HIPAA compliant. So unlike 23andMe, which is actually not HIPAA compliant. So that means we, we much, much more judicious about both your genetic data as well, your protected health information. It's similar to kind of a hospital or a doctor's offices, the procedures and practices we follow, because we're actually a laboratory. That's one. 2 is we sequence all samples in the United States on US machines. What makes me very sad is that the kind of other sequencing companies, they tend to use— actually, either they tend to not sequence in the United States, or if they do sequence in the United States, they use, unfortunately, like Chinese machines. They use BGI, right? Which I think just defies kind of safety. We're proud to sequence in the United States on US machines. Okay. Thanks for our collab with— thanks with our collaboration with Illumina. Moreover, by default, we don't share any genetic or PHI with any third party except if it's a service provider like our physician network, for example. And that's powerful because it's very simple. People should have agency over the results. Sometimes people want to share the results for research and they should have the right to do that. We're all about liberty.

You can check a button for that.

Exactly. You can check a button for that.

Okay.

So that's another thing. Moreover, if you look at the recent 23andMe hack, It was very unfortunate. They didn't even have 2FA enabled. It was kind of table stakes these days. 2FA? To log in. Yeah, 2FA. It's like after you put in your email and there's, you know, make sure it's actually your email, they send you a code, right? It's kind of table stakes for a technology company, really. So we make sure, you know, all the data is encrypted, both genetic and PHI information. The genetic data is also stored separately. It's stored separately from your other PHI. So we do a variety of things up and down the stack to make sure that customers have not only the peace of mind of security, but also of agency. It's both, right? Because people don't just want to obviously have security, they actually want to be able to control how it's used. And that should be the full jurisdiction of the customer.

Right. Well, and I guess, you know, there is not used here that you may change your mind at some point, right? Because I, in watching 23andMe over the years, And, you know, I, I've been a big advocate of 23andMe and so fascinated by what they're doing. And we've had Anne Wojcicki on the program several times, um, over the course of their life. Um, so, but what happened there was they ended up selling the data to GSK. And, you know, they were always kind of an early adopter. It was kind of a citizen science feel. There was a kind of trust and a bond, you know, 23andMe and people felt like they were pioneering something. And I think a lot of people felt like when their data was sold off to a drug developer, that, that trust was breached. I didn't particularly feel that way. You know, I'm glad there's drug developers out there able to do that. But so are you saying you would never sell your data?

One thing I want to say about 23andMe here is that, and maybe this was after the whole GSK fiasco, I actually don't know. But, you know, 80% of their customers do opt in to have their data shared and they don't share it otherwise. So I don't know exactly when they implemented that. And I imagine, 'cause I'm not, 2013 is a while ago. You were just a kid.

I don't know.

Yeah, I was a kid. Exactly. But I think they actually do report out that 80% of their customers choose to opt in and maybe it's not clear enough in the communication and they should probably improve that. I think it's good for

the

entire genetics industry. Also, I would add in that people sometimes do want their data shared. Especially if someone has some sort of serious later onset condition where there's no cure. I mean, Alzheimer's is a great example of this. Parkinson's. People actually ask sometimes to have their data shared. To me, the question is a matter of liberty. I don't think I'm ever going to change on my perspective, which is people have the right to decide. I mean, it's that simple. I mean, I don't think it's more complicated than that. And if people want to share their data, they should also understand where it's going and how it's going to be used. And it will be used to advance research in medicine, which is notable and worthwhile. But if someone's not comfortable with that, of course, then they should just not share the data and Nucleus won't.

You tweeted earlier this month that what, the first results had just gone out?

A couple weeks ago. Yeah. Yeah. A couple weeks ago.

Yeah. Yeah. Well, congratulations. What are you hearing? Early responses?

People seem to really like it. I mean, I'm very grateful for the early feedback from our customers, many of which have never done genetic tests before. And so, and some of which actually have done 23andMe and have learned something dramatically new from their Nucleus Insights. So it's very exciting to see people engage with their DNA and see kind of this new era, especially with like, you know, kind of polygenic scores of ability to stratify risk. And then moreover is to see their excitement about what's to come on the platform, right? We're adding carrier screening over the next couple months where we add, you know, analysis on 800 more genes, you know, and people are going to discover that there are carrier-fairest conditions and they can actually take action today in being cognizant and making sure that, you know, their offspring eventually, if they want to have children, obviously don't have a very kind of very serious condition so they can get their partner potentially screened as well. Pharmacogenomics and various other, you know, analyses as well. So I think it's been very great. I think obviously we always have room to improve as a company and make results more clear. And that's, that's part of the job. We're very excited for that.

Oh, okay. So you do offer the partner Screening around reproductive health already, or you're going?

Not yet. So we will. We will.

You will.

Okay.

That's cool.

You know, I just yeah. Yeah.

I was just talking to my nephew, and you know he knows I have this podcast, and he said, "Hey, I just got a genetic test," and I said, "Seriously? What? Are you okay?" And he's like, "Yeah, we wanted to have a second kid, and you know I was somewhat related to my wife, and so we wanted to." Uh, get screened. And it turned out everything was fine. Great. But, um, he, he found the test, you know, he's living in Boulder, Colorado. He, he found a place to do it and, and came up with all this, I guess, just because, um, you know, he, uh, reads the news.

Right. I hope there's an expanded carrier screening panel. Um, because obviously Nucleus is whole genome. So if he wants another genetic test, feel free to— I,

I'll tell him about it.

Tell him.

And I, hey, I just wanna say I wish you the best on this. Um, we want to have you guys on again soon to maybe talk more narrow angles about this, and, and I'll be, you know, avidly following, uh, following this with you. Kian Sadeghi is the founder and CEO of Nucleus Genomics. Thanks so much for coming on.

Thank you for having me.