 And HLA is one of those rare parts where if you make the family tree of HLA copies, it doesn't go back a million years, or 1.2 or 2 million. It goes back 40 million years. So if you think of the tree, typically it would be like a million year tall Christmas tree. This is a 40 million year tall giant redwood. It goes way back in time for HLA. That's a mystery in itself. Why does it go back so deep in time? Where other parts of our chromosomes only go back a million years. Boom! What's up everyone? Welcome to Simulation. I'm your host, Alan Sockian. We are on site in Cambridge, Massachusetts. We are now going to be talking about magical genes. We have Dr. Nathaniel Pierce joining us on the show. Hello. Hello, sir. Thank you so much for coming on. Absolutely, pleasure. Very grateful for Alex K. Chen for introducing us. We're going to have an epic, yes? Yeah, I was just going to say, some people are crucial hubs, right? And connect with people in the world. That's right. That's right. AKC is such a crucial hub. We love you very much. Nathan is the founder of Root, which reads your most vital DNA for free, helping you roam your family roots, save patients via better matches, and spark science that you love. And you can check out Nathan's links below, his RootDeep.com link below, as well as his Twitter profile and his LinkedIn profile links below. So, magical genes. I'm really excited to talk about this. Nathan, let's start things off with your journey. Let's start things off with your story. You know, you have this profound story even right on your website about you when you were six. Teach us about this. Yeah, and so I was saying, you know, we're sitting on this couch. It feels Freudian and I will tell you about my mom. And my mom is one of the key sort of strands that wove together to become what Root is and the idea that burned and needed to make happen. And it's sort of like your shirt. So I love your shirt. This gets at the way that DNA really sort of traces into the past and our roots. So my story, what brought us here to this couch today is in part that as a young kid, as a young sort of proto-scientist in the world out exploring and, you know, getting dirty in streams and bringing home frogs and things like that, one really precious person in my life encouraging that, bringing out the young scientist in me was my mom. And in the short time that I got to spend with her, she taught me a lot about the world and really cultivated that spark of curiosity that would encourage somebody to become a scientist. Sadly, she died when she was very young. So she was 34 when she got to leukemia. So basically cells within her, as in any cancer, they mutinied. They had genetic changes that happened to them and that made them differ from the other cells in her body. They started to grow out of control and they overtook her body and they killed her. And she died in an early era of how we were treating blood cancers when we were just starting to think about how we might actually use transplant somebody else's cells to come to the rescue and stop that mutiny. Today we're trying to perfect that in the world. And so the mission of bone marrow transplant was planted as a seed in my understanding of the world very early on by her loss, by the flame that was snuffed out that was her. That memory lives on in me and every day I think of her, like many of us who have lost people think of that person every day. She still remains a big influence on me, but I think it was only as an adult that I realized later how that experience would entwine with my broader understanding of genetics to spark a new idea, an aha moment, about how we could help there. And the aha moment is the same genes that we screen to see if somebody would be a match for a transplant. To see if you could be the person who helps save that person who needs a transplant, be it a bone marrow or blood or a solid organ. Same genes that we screen for many kinds of transplant match are called HLA, five genes on our sixth chromosome, and those genes are in many ways the most magical and mysterious genes in our constellation of 20,000 genes. They are the ones that help our bodies sense what's going on within. I think of them as the hands of our cells. So they make these five proteins. So there's two copies, one from Mom and one from Dad. And they make these hands that each of our cells in our body use to sense what other little protein fragments are here in this body. And those could be proteins from a virus or a bacterium. So they're classically used to respond to bugs, to germs that might infect us and help the body decide what to do. But they also might be proteins from a tumor. They might be proteins from a fetus that's growing within us. And we need to know that we're pregnant in order to actually do good things to help that fetus grow. They may be from other proteins that our cells are making. They are the hands that help our cells sense what's going on within when they're blind otherwise. And they're exquisitely diverse. So just like human hands have fingerprints that are unique, these hand genes, these five genes, they come in so many varieties, there's a stunning diversity that we've kept around among our ancestors that it's really hard to find somebody who has exactly the same looking hands as you. And yet that becomes crucial for transplant. So this is where it becomes magic to me. And we talked a little bit, you know, just getting to know each other that transplant is a form of real magic. It's like, as we were saying, it's some Harry Potter shit. So, you know, that my bone marrow might save you is some kind of magical stuff and I might be the only person who could save you. So no one else could step up and save you. It's almost like that scene in Star Wars. It's like, help me Obi-Wan, you're our only hope. You may be the Obi-Wan for somebody out there in the world. And you may be the only person on the planet who could save that person. I couldn't. Whoever you are, viewer, you couldn't. Only you could. And likewise, you as the viewer might be the Obi-Wan, the only person on the planet who could save somebody in need. And that is something that is just, it's almost mind-boggling that it's at once medieval and sci-fi. It's medieval in the sense that we still have to resort to that to save a cancer patient to, you know, a marrow transplant. That it's sci-fi and that it actually works sometimes. So thinking about my own experience with my mom and how many, many families are grieving from the loss of people like her who are big influences for kids and really important parts of our lives, I thought, how can we help more families find a good, well-matched, willing donor for every patient who needs one? Well, one way we could do that is by bringing those good donors, those volunteers, insight from that good deed about themselves. They're healthy volunteers. They've stood up to the world and said, if I'm needed to give bone marrow, to give platelets, to give, you know, any, as a transplant donor, call me if I'm needed in the one. And that, that good deed should be honored and they deserve to get their data back, to learn what it means for them, to learn how to weave it into their lives. And that's what we found a route to do. And your analogy with the hands was really powerful and I'm excited to unpack that in more detail. I want to take us to the steps that you took because you did Stanford, then you did University of Chicago Evolutionary Genetics PhD. Take us through those steps and then into your first industry work pre-route. Yeah. Okay, yeah. So, you know, I, so as a kid, you know, when I was splashing around in streams and stuff like that, my mom was encouraging me. I was always asking why questions. I realized that looking back, like we ask different questions in the world. I think people, engineers, for example, I think often ask maybe how questions. Very mechanistic. For me it was why. Why does, not just why is the sky blue, but, you know, why this, why that. And thinking about the history of things, it's the causal chain that leads from what was in the past to the present. How, how, how wise get us there? That is a, talking to peers in evolutionary biology and evolutionary genetics, it's a very common kind of way of thinking in evolutionary biology. You know, why, why are organisms, why are the critters that we love, people, birds, plants, the life form that, that, you know, the life forms that, that make the planet such a wonderful place to live. Why are they, why are they the way they are? Why are they so diverse? Why are they, in many cases, suited well to living in one way or one place, not another, et cetera. The questions that Darwin traveled with and really foundationally helped us understand. Well, many of us have followed in those footsteps. And at Stanford, you know, thinking about those why questions, I was interested in languages too, how they change and their parallels there with family trees and the trees of languages in their past. So that question of how do things diversify and why, that was sort of running through my thinking and I didn't really know where to put that thinking as an undergrad all the time. Like I worked, you know, with some really, I was lucky to work with some great peers and gurus on both of those fronts in biology and linguistics. Joe Greenberg on the languages side and Luca Cavalli-Sforza on biology and genetics. But eventually it crystallized and I started thinking about what Luca had really pioneered, which was understanding human diversity. How did we get so splendidly diverse on the planet in the way we look, the ways that we live our lives? What history does that reflect? And how can we look at our DNA and peer a little bit further back into that darkness from it? How does the DNA lead from the leaves on the tree today? Those are us, back in time towards the roots that are our ancestors. This is really good, yeah. And once you, you know, that was... We were each a leaf or a fruit and we're abundantly diverse in that and everybody's different. And you wanted to go back at the biological and archeological lineage of how we actually got to where we're at. And then twine. So one kind of evidence from DNA supplements what we can learn from digging through old, you know, trash heaps that old cultures had or now recovering the DNA from soil and trying to figure out what organisms lived there and what people were eating at the time or things like that. So that question came to captivate me. Human diversity. And I was really lucky at 25 to get to go on a long trip. Just before starting grad school, I went on a long trip across Southwest and Central Asia. So we basically drove from London to the Chinese border and back over five months. This was led by a guy named Spencer Wells who many of you may know. He's a prominent population geneticist. And Spencer sought fit to let me ride a long shotgun and help sort of, you know, speak languages to people along the way and process blood samples and things like that and start to document human genetic diversity in a part of the world that had been really not yet well studied yet and there remain other parts of the world especially outside of Europe that have just not been documented well. We've been very Eurocentric in our biases and this was an early effort to start to branch out beyond that a little bit and we learned a little bit scientifically from that trip from collecting blood from roughly a thousand people across that swath of the planet. It was a life for life. It was a mind warping experience to suddenly be exposed to the cultural diversity that you can get to with a jeep driving from London to China and the realization that this ocean of land has been open to people moving across it for many, not just millennia but dozens of millennia like the human rootedness of us in different parts of the planet started to dawn on me and it just was a real like mind opening experience to go on as a lucky young scientist. Then coming back that's how you, that's real population genetics. It's out there in the world and you going and doing it hands-on for five months and you said you sampled blood even and also were able to get behind the eyes of so many different humans and culture and talk with them about their experiences and their lives and admittedly often with halting a lingua franca that we could speak maybe I spoke a little bit of Russian or a little bit of Persian and they spoke maybe a little bit of English or Uyghur and you make do but you explain to each other they would take a loot down from the wall and play it and there are these human interactions that transcend the language barriers that are just as important as anything you're going to learn later in the lab from that person's DNA and it also teaches you what you can't yet learn, what you can't yet explain to them, it teaches you about some of the ethical challenges that we face in sort of swooping into a village and thank you very much sampling DNA from people and then how do you get back the insights to those people? How do you make sure that they understand well A why you're interested in their DNA that it's about human history in this case and not about helping them solve a family health issue and not about them maybe worrying about contamination in the soil you know from some making sure they understand you're not there because there's been an industrial accident or something like that ethics looms large and a lot of those questions are really challenging and they're suddenly in your face in the field so yes, field biology it's a great liberal education coming back from that it was lucky to go to grad school in the University of Chicago where suddenly you're in this very crystalline time in our field so evolutionary genetics in the 90s and the early 2000s was a very mathematically rigorizing field suddenly we didn't have DNA sequencers that can read a lot of DNA yet each letter we read was still pretty expensive so we had to learn as much as we could from the few that we could read and that meant thinking really carefully about how to understand the mathematics of what you learn so that was a good grounding in theoretical population genetics which teaches you a lot about all the things you can guess about the past I'm just looking at the way DNA varies today and that's when that's when the first inkling hit me of how much we can learn from this part of our genomes that we focus on in root which is called HLA and so these HLA genes think of a family tree and we've all got family trees for our own families where you go back in time and you branch to mom and dad and then there mom's mom and mom's dad and all the ancestors going back and eventually they entangle because some of them had the same ancestor so it's a complex web you want to learn about that just like we have family trees the copies of our chromosomes also have family trees so you could take your two copies of the sixth chromosome or the first chromosome and my two and your two and everybody in the planet's copies and you could make a family tree of how those copies go back to their own ancestors one generation back two generations back and then back into the sort of mist of deep time and we've unfortunately have not been able to do a good job at documenting the six million years of ancestral evolution you're talking about since our ancestors diverged from other great ancestors so we've started to patch it together and we're starting to get some amazing insights on the sort of it's a lot of soap opera insights about who stood up to back in time you know Denis Evans living in the Netherlands in Southeast Asia where there are islands now who may have intermingled with so-called modern humans who were suddenly traipsing through and they got it on and the story is the same everywhere when people get a chance they get it on and we are the wonderfully varied and wonderfully swirled together you know it's the 31 flavors and many more of humanity are the result of all that mixing so we can start to figure it out looking at our DNA now and we have a tendency to mix oh we do, you notice and all of us have probably noticed that so it's a good thing so the cool thing with HLA though so if you make this family treat of copies of a human chromosome typically they go back to one copy that all of those copies that are in us today all 14 billion or so copies of chromosome one at a given position would go back to one ancestral copy that ancestral copy was in somebody about typically a million years back so all of them go back to one copy and that was in an ancestor of ours about a million years ago to different ancestors you move along the chromosome for a complex little process called recombination where chromosomes get they get sort of cut and pasted back together in a quilt over time so this letter could be one ancestor a million years ago who lived in southeast Africa the letter over might go back to a different ancestor who lived 1.2 million years ago a thousand kilometers away they never knew each other different ancestors but more or less in the world southern or eastern Africa and more or less a million years ago okay for some parts of our genome the picture looks totally different and HLA is one of those rare parts where if you make the family tree of HLA copies it doesn't go back a million years or 1.2 or 2 million it goes back 40 million years so if you think of the tree typically it would be like a million year tall Christmas tree this is a 40 million year tall giant redwood it goes way back in time for HLA that's a mystery in itself why does it go back so deep in time where other parts of our chromosomes only go back a million years so HLA is found in the sixth chromosome our chromosomes have long and short arms they've got a long arm and they've got a short arm like this and HLA is on the short arm of the sixth chromosome and it's about a stretch of DNA that's about 4 million letters out of that much longer chromosome wow and it's all there together there's a bunch of little genes in there so there's five so-called classical genes in there and those are the ones that make the five fingers that our cells use to sort of sense the proteins that part was so profound too so so HLA genes give cells the ability to sense what's going on in the body and make the adjustments that are needed is this everything from like digestion? absolutely and we often caricature them we think of them as the epicenter of the immune system so we think that they help respond to bacteria, viruses, protozoa other germs that we eat or that we get from somebody sneezing or however or from sex and they help our bodies respond to those and know that there's an alarm set off the alarm, call the immune system call the T cells in and they come and then it's almost like the classic Victorian murder mystery what they're doing is these hands are taking a little scrap of protein from that germ like the bloodhound with the handkerchief from the killer and they're saying here immune system smell this your bloodhound, smell this what does this little protein smell like now go get them any cell that has this little fragment of a protein kill the cell that's the classic way we think about HLA is like prompting the immune system to rally and kill off an invader it's much more nuanced than that and you asked about digestion we teach us what HLA stands for yeah sure so it's human leukocyte so human like people like us leukocyte is white blood cells antigen so antibodies they're these proteins that swarm in on like a germ and help the immune system say hey over here we're holding it down for you take care of this one so antigens are what prompt those antibodies to come and swarm they wouldn't fit so human leukocyte antigen and so it's sort of how we make the helping hold out the little fragment of proteins so that the immune system can respond to it in broader other mammals it's called the major histocompatibility complex MHC same genes just different fancy jargon same genes so those genes they're really important to how can I make a potential rookie fresh perspective is it could be that the reason why it is a redwood compared to just a Christmas tree is because of its use case in the body it's such a profound value in the body so you have a hunch a great hunch and that hunch is very well intuited we think and it's not proven but we think that one reason at least why HLA remains so diverse basically we've kept around diversity in our population of ancestors since 40 million years ago we think that just for as your question guesses that's because it's been useful to keep that diversity around and the simple way of thinking about that why would it be useful to have diversity in immune response system so to make sure that our kids can respond to a diverse array of potential threats you know germs so you want to have a healthy brood of kids you want to make sure that they can respond to this virus that bacterium that protozoan and so you we think that our ancestors have maybe chosen mates to have HLA that differs from their own to have kids that are more diverse with an HLA than they would be at random so it's almost the opposite like in transplant we're trying to find that rare match for somebody who needs we need to find that OB1 who happens to match exactly your HLA with mate choice we think it's almost the opposite we think people may have been trying to find somebody who smelled a little different and they didn't know why it's not like there's nobody reading HLA out but just felt sexier there is more of that spark there and we think that that might have to do with HLA so how does that happen we don't know yet we don't even know if it happens something I'm curious about but you could one way it could happen we know about microbiomes now so microbiomes are the mix of germs that lives in say our gut or in our mouth our microbiomes include skin microbiomes so what grows our armpits or on our skin generally and the different mix of germs on there is going to smell different so it could be that folks are you're used to your own smell from that mix of microbes that are living on your skin and that's in part because of which germs your HLA prompts your body to rally against and which ones it kind of welcomes it's a distinctive mix to you and in finding somebody who smells sexy to you maybe you're just looking for somebody who smells a little bit different and that's one idea of how it could happen. It's profoundly fascinating and it's cool how HLA both gives you the rare match as well as the desire for swirl and it swirls up and there's a lot of complexity and so I've caricatured it here like in a just so story way in a really simple fable and reality is a lot messier and we still have a lot to learn but let me get back to your question about digestion because that's a great one so HLA epicenter of our immune system along with some other genes that help as well like interleukins and these kinds of genes but also crucial in just about every big auto-immune disease type 1 diabetes lupus rheumatoid arthritis all the biggies there celiac disease so how some people can't eat wheat without getting sick I'm talking about real celiac not where people are just sort of avoiding gluten because it's trendy not to caricature that but where people their hair falls out you know they get severe symptoms if they have wheat that is prompted mainly through HLA so if I know that you have true celiac disease I know that you very likely like 95% chance have one of two different HLA types that predispose to that disease likewise everything we know about peanut allergy so where the body is again responding to a little protein fragment of what we eat traces first to HLA and a couple other genes much of our bodies sort of like blind figuring out what's here has to do with that HLA sensing the protein be it a peanut protein a wheat protein a viral protein or in the cases the good stuff again when we're pregnant when we need to make sure that that newly conceived fetus implants well you know and gets a good placenta to supply it with nutrients over the course of pregnancy that process is mediated in part through HLA recognizing somebody different in the cell in the blood here I'm sensing proteins that don't look like they're from us body looks like from another body and so HLA figures crucially in pregnancy health so a lot of what we want to do with root is start with helping people who volunteer as a transplant volunteer and say I'm available if I'm ever needed very few people will ever get the call to give marrow so maybe 1 in 400 will ever get to give marrow the other 399 all want to do something good in the world with their cells their data they want to help the health of others and humanity there is so much science that is mediated centrally through HLA first understanding peanut allergy who gets type 1 diabetes understanding who gets lupus understanding who gets pregnancy complications how people respond to immunotherapies and other drugs all of that science goes right through HLA people deserve to get their data back their HLA data for free to take charge of it and own it so that they know it's that they decide how it's used in the world not somebody else and ideally they can get some steak in how it's used so if there's a discovery made I would like to see routers get credited for that discovery intellectually and ideally also when there's lucre when there's profit made on that discovery I'd like to see people see part of that profit they've contributed to it and they deserve that so we'd like to do this in a public benefit corporation kind of way that we can make happen for those 399 people who never get to get bone marrow but would still love to help out with science there's so much starts with HLA and I say that it's funny I think really broadly about our genomes I think about almost 7 billion letters in your genome and mine and how all of those can matter but I would go to science conference after conference year after year and HLA always photobombs the picture when there's a big study of where in our genomes varies with who gets sick and who doesn't with this particular disease and again it could be lupus, it could be narcolepsy, it could be MS, multiple sclerosis it could be any number it could be ankylosing spondylitis or how do people get alopecia when their hair falls out in health questions HLA would always be there there'd be a huge peak on chromosome 6P on the short arm and the researcher will always say well of course we saw a strong association with HLA but let's look at the next slide where we can see a different peak that we can understand better because that diversity of HLA I wonk out on it because it's so deep it goes so far back in time and it's time to dig in and time to say hey with crowd data, with your help, with all of our help pooling our data we can actually advance science with HLA your story is what I think many people can relate to because we usually find our greatest treasures on the other side of our greatest traumas and thought of our greatest fears and you experienced what you did with your mother potentially so that you could be this biology and anthropology pioneer and that HLA gene pioneer this may be and it's a huge potentially moment of a-ha for other young people that are like why are these walls up well maybe the walls are up to challenge you to get through the walls so that you can find your greatest treasures on the other side of the walls and that's where we find the most meaning in our life but then you take us all the way to you've been doing root now for three years and so when someone signs up for root they're usually getting saliva is that the so HLA typing is typically done today through spit you give a spit kit either at a marrow drive or we're going to have ways to arrange to get a kit to you and then that DNA gets typed and we want to bring people back their HLA type and I should mention also we will likely branch out soon to blood donation as well because we can do something very similar and helpful there and when you look at blood donation it's a low side jargon sorry other genes in our genome that really matter for blood donation as well for blood match and we know of course you know ABO so the ABO blood group a similarly mysterious one where the diversity goes way back in time by the way 40 million years back way predates the divergence of people in chimpanzee ancestors so we're talking about diversity that's actually shared with other great apes which is remarkable with blood donation we'll bring people back insights about ABO and the other parts of our genomes that are screened for that process as well and HLA matters a lot in platelet donation so the little thin layer when blood gets spun down there's a thin layer of platelets which will help stop the bleeding basically when somebody's got a car accident or they need chronic transfusions because they have a blood cancer and they're bleeding a lot platelet donation works much better when it's HLA matched the same way that marrow would be so HLA matters in the blood world too and we love the idea of being able to help encourage that here in Boston and in most cities today on a Saturday a typical day roughly two thirds of blood banks have less than three days worth of blood on hand so that's dire right so it's a constant a constant search for new blood and platelets in particular go bad after a week they have to be kept at room temperature so we really hope that we can help there as well I loved your insight that often traumas it's trite but you could think of them as the stuff that doesn't kill us that makes us stronger the grit in the oyster that then the pearl forms around sometimes these tough the tough experiences that everybody goes through in life and they're going to vary from person to person you've got yours, you've got yours I know some of mine those do indeed prompt the deep thinking the soul searching the gut wrenching soul searching that can go on for years until it it marries itself to an idea aptitude acumen what else you've got and other lucky resources you have in your family and your world to then say aha this is a direction that I could go in to help better things happen in the world and absolutely so many people when we talk and you may experience this as well with folks you talk with and their career paths or especially many of my colleagues likewise were drawn to be scientists or caregivers or funders of healthcare and research because of personal experiences with loss because they lost a sibling they lost a spouse they many kinds of loss and those make one acutely feel they hurt they make one think and understand hurt makes you want to take a burden on your back to go and research and learn and be a part of contributing to the edge of that field so that you can help other people going through the experience a couple thoughts here one of the thoughts is when you explain to people that go through deep you get the saliva kit, you ship it back in and then you actually provide you gave a couple examples here one of the examples is you give them an understanding of their roots an understanding of their ancestry you also mentioned that they're contributing to the spark of science actually there's three ways that we bring people three views on your data because it can be wonky stuff, right? there's a bunch of letters in your DNA what does it mean? think of them almost as past you could think of them roughly as past present and future so looking back into the past what does your DNA say about the past the human past and the past in particular in your ancestry so you mentioned around a globe and we want people to feel that connection to the planet we live on and to other people on it and so where on the planet does your DNA your HLA in particular tie you to other leaves on that tree on that family tree of HLA where you have cousins you haven't met yet who maybe ticklishly far apart from you in ways you never would have foreseen a real surprise on the other side of the planet and people who don't necessarily look anything like you in the mirror but are nonetheless your close cousins in HLA and we should emphasize that HLA because it goes so deep it can take you way across the planet other parts of our genome tell you about other ancestors that you may share with people so part of our interface is that we need to connect you and I are cousins we don't know exactly where in our genome there's the evidence of that most clearly like most recently could be HLA, could be elsewhere but we're cousins and every pair of people is we want to bring people closer together with that understanding of where their cousins are on the planet today and in turn to be able to contemplate what does that mean for the past who migrated to those different parts of the planet so that's what the globe interface is about that's looking back in history to the roots of people of your own roots in Alex Haley's memorable phrase on the science side that's looking ahead to the future and there's a wide open set of questions really a rainbow of questions that HLA sort of shines light onto it is the first thing we know genetically about everything we've said from lupus to preeclampsia and preterm birth to narcolepsy and peanut allergy and celiac disease and all these other amazingly diverse frontiers of health knowledge nonetheless we still know too little about each of those so what we want in root is to be able to let people decide what kinds of research turns them on so let's say a question like why do some germs make some people sick and not other people we want people to be able to like a dating app swipe right hey that's a cool question boring take me to the next question what else you got and decide what kinds of questions they would like to put their data toward and they don't have to they can decide to keep their data fully to themselves they don't have to share your data in root at all it belongs to you you decide how and if it gets shared at all and again we want you to benefit and know how that's happening and it's in a national registry in the case that somebody does in the 1 in 400 case need a marrow that's where it starts so when you join the national marrow donor program registry you're agreeing to take that phone call if you're needed yes if you're needed and then you're also sparking all of this additional science but this is open frontiers of science and why I say that is like your choice with these valves for data control right so let me give an example let's take the peanut allergy example so most of what we know genetically about who gets peanut allergy traces to HLA and a couple of other genes but we know far too little yet to say Kevin Toddler is going to get you know anaphylactic shock if she eats peanuts we can't predict yet that we can't predict from your DNA if you're going to be allergic to peanuts that's a sobering realization that we don't expect your DNA to tell you too much yet it's almost like Kennedy ask not what your DNA can do for you ask what our DNA together could do for a future generation to help understand for a future Toddler to make her genome more informative of whether or not her parents should feed her peanuts before weaning after weaning at any point in her life we need to do more research and pool together what we know and what we don't know and follow it over at the speed of life how allergies unfold not light but life and in doing so like drive research that makes it clearer in five years or in ten years who is going to be allergic to peanuts from birth and maybe intervene then there may be emerging ways to intervene and make sure somebody doesn't get sick if they're given peanuts at a restaurant accidentally beyond just having an api-pen but to sort of like more systemically kind of do that and so to let people flex their data like muscles on behalf of the science questions that excite them that's the forward-looking part of what Root wants to do and then there's the now what does my DNA say about me now and that's the health report so Root will we want to deliver to people a very narrow and well-grounded health report that does not try to stretch what we can say so one of the problems in human genetics is that because everybody's striving for venture capital funding and people want to get a big lead here and there they're always kind of pushing the envelope of what the data mean and kind of towing the boundary of bullshit and we don't want that we want to inoculate people against bullshit we want people to understand what their data don't yet say so what can HLA say about your health today there's a very narrow set of drug response outlook findings so we know and the FDA has already validated that we know that people with particular HLA types are more much more at risk of say severe liver damage if they take a tumor drug called Lopatinib or of a full body blistering a very like a horrific skin blistering that happens called Stevens-Johnson syndrome if they take a couple of nerve disease drugs say for epilepsy or other nerve diseases we know that HLA strongly predicts those risks and the FDA has validated those insights scientifically and those are the kind of insights that we would feel comfortable bringing back to people personally about their own health outlook today that's a narrow sliver so just like in Nabokov Nabokov has this beautiful passage I think in speak memory talking about life as this brief like flash of light between two dark voids that's the narrow now the moment we're living in and there's something to say from HLA and from other parts of our genomes for people there but we want them to know how limited that is but we also want to cast that light into the two other directions so looking back into the past where does it shine light on our common roots on a particular part of the planet way back in a million years back even 40 million years back when I go to the zoo I can know if I know the HLA type my HLA type and I know a particular western lowland gorillas type and a different one I know which of those gorillas is my closest cousin not just that they're we all know now that other great apes are our cousins but I know that one of them is actually a closer cousin to me than you are I'm closer in HLA maybe to that gorilla than to you and that gorilla is closer to me than to its own sibling or cage made that's remarkable depth of understanding of the past and evolution and the future and then looking into the future again how can we take our data pull it together as we will with autonomy safeguarding our rights and our privacy and making sure that we have a stake in outcomes but how can we come together and make a baby's genome much more informative for her health outlook 10 years hence that's the vision that everybody aspires to in our field and everybody's kind of on board and there are different boats but Root wants to be one of those boats and we want to be the one that focuses on these five genes that have really gone unsung outside of the transplant world but that means so much and I'll add one more thing here and I'm a member of 23andMe in advanced history DNA and I do every I wear a fit but I'm a data geek and maybe you are too and all that is I love it but 23andMe's test can't they get only a very blurry look at HLA HLA is far too diverse it's like they don't have a light powerful enough to shine 40 million years back in the past their light shines about a million years back but across multiple they're looking at sites scattered across our genomes that's really well put it's like Christmas tree lights there's like a million sites strung out all over chromosomes at each of those in 23andMe there are two spellings typically and each copy of a chromosome has one of those two spellings and both of them are common common spellings are informative they help us distinguish what the copies look like and where the continents and where yours might have come from but the harmful stuff and the really rare, functionally distinctive stuff and intriguing stuff in our genomes never gets common it remains the rare variation the rare letters that are hardly ever seen but are sometimes vitally needed sometimes they're harmful but sometimes they're vitally needed to find a match and HLA is one of those spots DNA there is way too intricate and rare to guess from the kind of like Wheel of Fortune letters that 23andMe opens they open like every tenth letter and you have to guess what the phrase is if the phrase is a really rare piece of text you can't guess it and that's HLA HLA is this really rare little gem of a poem about you in very, very distinctive words and somewhere out there there might be somebody with like a matching locket that has the rest of that the same poem written in it and that may be also true not only for the donor on the match side but also for your swirl for your mating absolutely and again so you've got two copies of that poem and think of them as love sonnets in this case but you're looking for somebody out there who has a different sonnet and you can swirl yours together and there's we could go crazier with analogies it's like a mash-up it's like you're making this great mash-up musically between two really great two really great songs that you never thought might go together or like the Jane Austen Zombies that's HLA Jane Austen meets the Zombies and you mash them up and you get something utterly new utterly textually distinctive in DNA text and riveting and so all this is to say 23 Me is great Root is bringing you a different look a much deeper look at a part of your genome that you can't get through 23 Me 40 million years back so do both if you can afford 99 bucks pay 23 Me and get that broad look of the Christmas trees across your chromosomes if you would be willing to help other people with your cells someday join Root get that insight back for free because we want to be different that way too you're doing something really good as a potential transplant volunteer blood donor whatever it might be you deserve that for free you should not have to pay for that so do it do Root 2 get both of those insights back and then decide in the world A how you want to have fun with your data and understand what it means about your family past and your cousins today and then think about what kinds of science questions would I like to help answer yeah this is such a good conversation if any of us had such a blast talking to you about the magical genes that are HLA I love that you let people you let them geek out and what obsesses them and hopefully that spark of what obsesses somebody else and has been driving them for a long time hopefully it catches in a few brains that are watching when I watch shows like yours I love that you're stretching eclectic minds to never knew topics that might excite them and might clue them into something that not just interests them but that they can do something about in the world it might be start their own startup based on an idea that a tragic loss brought them in their own experience it might also be thinking about the science questions that excite them the ones that why do some germs make some people sick well how could I help answer that well now you know you know and there's lots of ways that you're inspiring people to do good things I love that thank you so much fist bump again to the Sistine fist bump again the Sistine I love it alright two quick questions on the way out that we like asking our guests on the show are we in a simulation I'm gonna dissimulate on that my hunch is yes and no my hunch is that the simulation my hunch is that that experience is real that the squishy pockets of the universe in your brain and mine that are little squishy pockets of the cosmos there they are synthesizing information that's coming in from around them streaming together and swirling around and they are then conjuring up this consciousness right this is the great hard problem right the consciousness problem so the universe is self aware and it's self aware through at least one I'm gonna grant you this it's your solipsism at least one and two simulations why I feel like there's simulations as well of course everything is distorted of course I'm only seeing colors you know artificially projected onto my visual field that represent part a little sliver the spectrum of photons of frequencies that I could be seeing so I've distilled down my squishy bit of the cosmos distilled down all that information to a very very simplistic representation of it that to me feels like a model maybe a simulation in some ways plus I know that I can probably not by free will I'm gonna say but my little squishy pocket does imagine rift off and daydream and those are simulations so my answer is yes number one and then the other question is what is the most beautiful thing in the world I don't know I know the I know the one singular breath taking beauty epiphany that sticks in my craw and I think about it is I'm not sure if it was Michael light or another astronaut but the big blue marble image oh the pale blue dot not that was later that was really cool too but this is earlier this is the first blue marble the boom marble was when one of the lunar astronauts they were they were orbiting the moon and they did one orbit around the you know the dark side and came up over again and and saw the overview fact and they saw earth rising and amid this you know stark sterile moonscape yeah suddenly there is this this marble baskin robbins swirl rising up in front of them yeah and the reason that came to mind when you asked the question is like you said the most beautiful thing well it's really hard to pick one little fragment of earth which is where my experience in yours is confined to and say that's the most beautiful like the face of somebody you know the face of love or or you know Shakespeare's sonnet or whatever it might be or a piece of music there's so much beauty we're seething in it but all of it is confined to this to this big blue marble yeah I love that image and it I don't know just stuck with me in memory agreed yeah the overview fact is one of the most profound ways for us to gain stewardship for earth and the one the oneness that we need to prosper most effectively this was such a stellar interview I'm very excited for when you come back to San Francisco or for when we come back to Cambridge we got to talk more HLA genes we got to talk more about all this this was just so enlightening there's a lot that we could go into the roots the leaves there's so many places that will rock that will rock and let's say I hope when that happens that more folks will have joined route and there'll be more to talk about from and with each other as part of the conversation that you're just stoking yes through the show here yes well more boom I love it I love it everyone thank you so so much for tuning in we greatly appreciate it we would love to hear your thoughts in the comments below let us know what you're thinking about the episode go and share these conversations about HLA genes go start talking other people in your communities your family online your co-workers let's get the conversations rolling also check out the link in the bio to rootdeep rootdeep.com go and check them out and go in go and maybe potentially enter in enter in and see what this process is like go and try 23 and me to see what the process like start wearing Fitbits get these quantified self or rings get your get yourself moving in the quantified self world and just feel that out see how it is and also follow Nathan below as well as Twitter also his LinkedIn profile go and follow him and also support the artists and entrepreneurs that you believe in around the world support the organizations around the world that are making great impact simulations links are below help us grow and scale help us continue being able to come on site like place like Cambridge to conduct these interviews and go and build the future everyone manifest your dreams into the world thank you so much for tuning in we love you very much we'll see you soon peace not rocked amen that's him a brother really well put thank you very much yeah that's how we do that's really eloquent I love what do you say manifest your manifest your dreams your destiny into the world yeah just make it real yeah just make it real