When Science Fiction Becomes Reality (Josh Wolfe, Co-Founder of Lux Capital)

Josh Wolfe is a co-founder of Lux Capital, where he funds the kinds of ventures that change everything: think gene-edited pig organs and technology that lets you “record” smells. His approach? Relentless curiosity. He reads dozens of newspapers daily to identify patterns, always staying a few steps ahead. In this episode of The Generalist, Josh shares how his firm backs companies that don’t just predict the future, but create it. In our conversation, we explore: • The revolutionary development of genetically modified pig organs being transplanted into humans and what this means for the future of organ transplantation. • The recent achievement of "teleporting smell" across space and why computers that can replicate scents will open up entirely new industries. • Why Lux is investing in the search for real-life "X-Men" — genetic outliers in isolated populations whose DNA could lead to life-saving medical advancements. • How Josh evaluates macro trends to make smarter micro investment decisions and why ignoring the big picture is a mistake. • The three tech sectors that Josh believes will define the geopolitical balance in the decades ahead. • How Josh stays current on macroeconomic trends. • Much more — Thank you to the partners who make this possible Brex https://www.brex.com/mario: The banking solution for startups. WorkOS https://workos.com: The modern identity platform for B2B SaaS. Generalist+ https://thegeneralist.substack.com/: Essential intelligence for modern investors and technologists. — For a full transcript of the episode, please visit: https://thegeneralist.substack.com/p/shrinking-the-gap-between-sci-fi-and-sci-fact-josh-wolfe — Timestamps (00:00) Intro (04:38) A brief overview of Josh’s work at Lux Capital (05:57) The science fiction to science fact pipeline (09:11) Xenotransplantation (12:10) Proven transplantations with modified pig kidneys, and what’s next (15:38) Ethical questions around xenotransplantation (17:48) Lux Capital’s investment in eGenesis (19:34) The theory of persistent cellular memory (23:35) Why eGenesis began with kidneys (24:30) Digitizing smell (32:24) Commercializing digital olfaction technology (38:26) The potential applications for a “Shazam for smell” (43:16) Variant Bio’s work studying genetic outliers (52:00) Variant Bio's two primary clinical focuses (53:46) How Josh stays current on macroeconomic trends (59:44) Josh’s thoughts on the critical areas the U. S. should invest in (1:14:00) How to win the talent war (1:18:53) Final meditations — Follow Josh Wolfe X: https://x.com/wolfejosh LinkedIn: https://www.linkedin.com/in/josh-wolfe-7883/ — Follow Mario Gabriele Newsletter: https://thegeneralist.substack.com/ LinkedIn: https://www.linkedin.com/in/mariogabriele/ — Resources and episode mentions —Books— • 20,000 Leagues Under the Sea: https://www.amazon.com/000-Leagues-Under-Wordsworth-Classics/dp/1853260312 • War of the Worlds: https://www.amazon.com/War-Worlds-H-G-Wells/dp/8175992824/ • In Search of Lost Time: https://www.amazon.com/Search-Lost-Time-Library-Classics/dp/0812969642 • Perfume: The Story of a Murderer: https://www.amazon.com/Perfume-Story-Murderer-Patrick-Suskind/dp/0375725849/ • Poor Charlie's Almanack: The Wit and Wisdom of Charles T. Munger: https://www.amazon.com/Poor-Charlies-Almanack-Charles-Expanded/dp/1578645018 —Other Resources— • eGenesis: https://egenesisbio.com/ • Xenotransplantation: https://egenesisbio.com/xenotransplant/ • Surgeons Transplant Engineered Pig Kidney Into Fourth Patient: https://www.nytimes.com/2025/02/07/health/fourth-pig-kidney-transplant.html • CRISPR: https://www.genome.gov/genetics-glossary/CRISPR • Can an Organ Transplant Change Someone’s Personality? https://www.psychologytoday.com/us/blog/the-leading-edge/202402/do-organ-transplants-cause-personality-change-in-recipients# ... Episode resources continued at: https://thegeneralist.substack.com/p/shrinking-the-gap-between-sci-fi-and-sci-fact-josh-wolfe — Production and marketing by penname.co. For inquiries about sponsoring the podcast, email [email protected].

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Speaker 00

  What are the things that can go wrong? Because if you throw time and money and talent at those things that could go wrong, then you reduce risks, or you anticipate them and you kill them. And I think that's what great entrepreneurs do. I think it's what great investors do.

• 0:10Mario Gabriele?

  As you look ahead over the next five years, where do you see the most important technologies being? What are the most important places to own?

• 0:17Speaker 00

  Increasingly, the most important space to own is this information sphere, just information operations. Because the most dangerous weapon that I think exists today is the thing that can sort of influence and bend and shape and manipulate the will of the people. I do see a near future where robots will be performing science 24/7. The companies, the academic institutions, and ultimately, the countries that get this productivity gain in science are going to lead the next half century or more.

• 0:46Mario Gabriele?

  Hey, I'm Mario and this is the Generalist Podcast. You might have heard the saying, "The future is already here. It's just not evenly distributed." Every episode, I have a deep conversation with a founder, investor, or thinker living in that future to help you see it earlier, understand it better, and capitalize on it. Today, I'm speaking with Josh Wolfe, the co-founder of Lux Capital. Josh is one of the most fascinating futurists and technology investors of our time, with over $5 billion under management dedicated to shrinking what he calls "The Pipeline" from science fiction to science fact. In our conversation, Josh and I explore this pipeline, focusing on three extremely futuristic technologies. We discuss:

• 1:31Mario Gabriele?

  One, the remarkable breakthrough in xenotransplantation, where genetically modified pig organs are now being transplanted into humans. Two, the quest to digitize smell, with Josh sharing how one of his companies recently teleported the scent of a plum across space. And three, the hunt for real-life X-Men, looking for genetic outliers in isolated populations around the world to create promising new medical treatments. I learned so much from this conversation, both about how the technologies themselves work and how science fiction can become science fact. I hope you'll walk away with practical insights about how these innovations might reshape our world in the coming decades

• 2:16Mario Gabriele?

  and what you can do to scout the next breakthrough. This is a new podcast, so if you like it, I hope you'll consider subscribing and joining us for some of the incredible episodes we have coming up. Now, here's my conversation with Josh Wolfe. This episode is brought to you by Brex. Fred Adler, the influential venture capitalist of the 1970s, was known for displaying decorative pillows in his office that featured a signature business philosophy: corporate happiness is positive cash flow. In today's post-Serp environment, Adler's wisdom feels particularly relevant, as founders need to make every dollar work harder. That's exactly what Brex delivers. Their modern finance platform was built specifically

• 3:01Mario Gabriele?

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• 3:42Mario Gabriele?

  More than 30,000 companies, including one in three US venture-backed startups, trust Brex to help make every dollar count toward their mission. Join them at brex.com/maria. This episode is brought to you by WorkOS. What do companies like OpenAI, Cursor, Perplexity, Webflow, Plaid, and Vercel all have in common? They use WorkOS to power enterprise features like single sign-on, direct resync, and multi-factor authentication. WorkOS is set apart by its modern APIs and SDKs for seamless enterprise integrations. Plus, it's free to get started. Whether you're a scrappy startup or rapidly scaling, WorkOS has the solutions

• 4:26Mario Gabriele?

  you need to secure enterprise deals. Future-proof your authentication stack with the identity layer best suited to meet the evolving demands of enterprise environments. Find out how at workos.com. Josh, I'm so glad to have you here. Thanks so much for being with us.

• 4:42Speaker 00

  Good to be with you, man.

• 4:44Mario Gabriele?

  Today, we're going to be talking about some of the most futuristic technologies that are actually getting really close to true commercialization if they're not there already. And the way we, I know that you like to think about this, is sort of thinking through the pipeline from science fiction to science fact. Before we get into that concept, maybe you could give us a brief introduction on you and the investing you do with Lux.

• 5:12Speaker 00

  Co-founder of Lux, and it's great to see you and be with you today. We are a bit over 5 billion under management, firms about 20 years old. Peter A. Bear and I, the two co-founders, 40 people, New York and Menlo Park. About a third of what we do is cutting-edge biotech and med device and robotic surgery. And another third is aerospace and defense and autonomous systems. And then the final third is core technology, typically more defined by what we don't do. So very little on like internet, social media, mobile, video games, ad tech, that kind of stuff, a lot in edge inference and AI and compute infrastructure and brain machine interfaces that are non-invasive and all kinds of things that, as you note, are sort of shrinking the gap between sci-fi and sci-fi.

• 5:55Mario Gabriele?

  Yeah, you have set us up beautifully there. But one of the reasons I think you're such an interesting person and interesting thinker is that you're both an incredible storyteller, you're a great lover of stories, and of course, a great technologist and futurist. So when you talk about the pipeline from science fiction to science fact, what does that mean to you? And how do you start to think about when a technology might be ready to make that transition?

• 6:22Speaker 00

  Well, it starts with the inspiration, and the inspiration are often people who are imagining a future. And there's positive ways to do that and negative ways to do that. And I think both are constructive. I always say that failure comes from a failure to imagine failure. So on the one hand, I'm always thinking about in life and in businesses and in relationships, like what are the things that can go wrong? Because if you throw time and money and talent at those things that could go wrong, then you reduce risks, or you anticipate them and you kill them. And I think that's what great entrepreneurs do. I think it's what great investors do. I think it's what great leaders of countries do. I think it's what leaders and families do. And so constantly issue spotting and thinking, what can go wrong? And how do I prevent the bad thing from happening is a useful construct. It doesn't always make you the most pleasant person at a cocktail party, but I think

• 7:04Speaker 00

  it's a good mental model for life. But the flip side of that positively is thinking about the people that are imagining the future in a positive way. And oftentimes, those are entrepreneurs who say, this is the world that I want to live in, and this particular thing sucks, and I want to fix it. And so they're sort of pro socially motivated to go and do that. And then, of course, at the end of the rainbow is a pot of gold, and you know, they want to get it. But they're also just sci fi writers who sit around and imagine a world, sometimes dystopian, sometimes positive, sometimes take new technologies that are coming on to the scene, or ones that have been speculated about, or things that they might read in scientific literature. And then they make these sort of near term

• 7:46Speaker 00

  prognostications, or very far out ones. And that is the canon of literature that has existed for hundreds of years, really, but that have imagined, you know, everything from 20,000 leagues under the sea to War of the Worlds, to Star Wars and Star Trek, and Battlefield Galactica, and Total Recall. And these are the things that oftentimes provide a canon of inspiration for a scientist that says, that's pretty cool. Like, what if it actually could be made? What if it actually worked? And there you get everything from companies that are focused on real-life X-Men, you know, genetic mutants that actually could be the source of druggable targets for the rest of us, the sort of outlier people. You get people that have developed drones straight

• 8:31Speaker 00

  out of Star Wars, like the pod racing team. You got people that develop robotic surgery, like Oris Surgical Robotics, which we had sold to Johnson & Johnson for $6 billion that really came out of the scene from when Luke Skywalker's arm was cut off by Darth Vader and a robotic surgeon very acutely and with high precision repairs that arm. And so there's just endless archive of sci-fi authors who, one could argue, maybe became less creative, or our scientists have become more creative, compounding what they do and know through the application of technology. But it's a great source to look for new ideas and to find the entrepreneurs that are inspired by them.

• 9:12Mario Gabriele?

  Well, today, I'm, you know, super excited to dive into three of these extremely futuristic ideas that, if they weren't already happening, would absolutely feel, you know, potentially far-fetched or, you know, in the far frontier. And the three that, you know, we're going to talk about are xenotransplantation, which is a, you know, maybe a scary sounding word, but is actually a quite simple concept, computers that smell, which is just, you know, still blows my mind, and, you know, one that you mentioned just then, which is sort of these genetic mutants and how we leverage these different populations for, for, you know, basically these different populations to solve biological problems. And so, you know,

• 9:55Mario Gabriele?

  let's start with xenotransplantation. For those who maybe aren't as up to date on their ancient Greek, what does that really mean? And what is the sort of state of the art today in your involvement?

• 10:05Speaker 00

  Well, you know, the Xeno is a sort of foreign or alien, you know, or outside, so xenophobia, you're afraid of foreigners. Xenotransplantation is actually taking organs from another living organism and transplanting it. But instead of it being from a human to a human, it is from an animal to a human. And that was once a ridiculous idea, sounded like Frankenstein. But today, one of our companies called eGenesis has pioneered over many, many years, the capability to genetically engineer a pig. That produces organs, in this case kidney, to be able to transplant in a way that is immunocompatible with a human, so that they don't have to take as many or any drugs

• 10:49Speaker 00

  to suppress the immune system, which is naturally trying to reject this foreign body that is necessary to keep somebody alive. And so that is xenotransplantation. It is astounding to me, to put it in perspective, with eight billion people on Earth, and a billion five in India, and a billion four in China, and 375 million in the US, there's 10 people that are in outer space, which is pretty cool. But there's two people, only two, that are walking around with a genetically engineered kidney, grown in a pig, and then transplanted into a human to save their life. And it is the start, but it is one of these directional

• 11:30Speaker 00

  arrows of progress that's inevitable. And instead of having to wait for a loved one to be on a transplant list, and wait for somebody else to suffer and die in a car accident, so that their organs can be transplanted, this is the future. It starts with kidneys, and it'll go into liver, and heart, and other organs that are necessary. And it's one sci-fi, and now sci-fact. And, you know, we're talking here in second week of March, and it is just graced the front page of the New York Times, and reporting with crazy images of the pigs and the transplants, and we're really proud of that. So, yeah, sci-fi to sci-fact, and xenotransplantation.

• 12:11Mario Gabriele?

  Yeah, one of the orienting philosophies for launching this podcast is, you know, that famous phrase, "The future's here, it's just not evenly distributed." And this is, you know, such a tangible example. The future, you know, is here in this, in this idea that there are two people walking around with these modified kidneys. And, yeah, as you said, you can totally see how that is going to change over the coming decades, to be increasingly large numbers. One of the things that I was struck by when I was sort of researching this a little bit, was, you know, what a history there is in... Early xenotransplantation, you know, as far back as sort of the 1800s, I was reading about skin grafts where people were using frog skin on humans to try and,

• 12:56Mario Gabriele?

  you know, help with wounds and burns and things like that. And then in the 1960s, you know, there were sort of experiments with with chimp kidneys, I believe, that didn't, you know, ultimately work out, didn't really go anywhere. What was it about e genesis in particular that made you think, you know, this is the right time, this is the right team, the right technology that can really make a step forward here?

• 13:20Speaker 00

  A lot of this, the breakthroughs in genetic engineering, in particular in CRISPR. And so there's been a lot of hype about genetic engineering and very few actual tangible benefits. There have been some eye treatment for rare disease and blindness and some others that have been FDA approved. But by and large, this was just a very clever use of saying, how do we take the organs here that are rejected and make them compatible? And to do that, you have to change the genome of the organism, edit it, and ultimately be able to produce organs that are compatible. And so the team, a combination of Harvard and MIT and other brilliant academics and George Church, who's a very creative scientist, put in the hard work and it took a very long time. And we came in and I believe last year, year and

• 14:05Speaker 00

  a half ago, led a nearly $200 million financing and gave them the fuel for the fire that had now proven to be de-risked technologically and was about to go into the first live patients in Mass General Hospital, a very prestigious institution, performing the transplants. And this is now something that, from some of my international travels, there are people that are going to be competing to set up what may be very large farms of animals, taking into account everything from religious and ethics considerations and the morality of this, all in service of what I think is the great moral default undertone of much of what we do, which is how do you reduce human suffering?

• 14:48Speaker 00

  And I think it's a really noble endeavor and one that's going to save a lot of lives.

• 14:52Mario Gabriele?

  So to make sure I understood there, basically now that this is sort of, we see the early signs of it being proven and we're seeing, you know, people actually receive these kidneys, you're now seeing sort of this ecosystem emerge around it where you're getting farms for pigs to, you know, essentially, yeah, cultivate the organs that will then be used by humans. Is that, is that sort of, did I understand that right?

• 15:14Speaker 00

  It will. There aren't farms today, but, um, but there are groups that want to set these up. Um, and not just in the U. S. But in other parts of the, of other regions of the world, where there is, um, either a scarcity of organ donors or a culture that hasn't really, um, embraced transplantation and, and it's just a very interesting new capability that's going to be available to everybody on the planet.

• 15:39Mario Gabriele?

  Yeah. One of the things that, you know, is so interesting about it is that like there does feel like this sort of fundamental taboo of, you know, animal organs in humans, uh, you know, pigs are especially a loaded animal in many cultures. Did you have any sort of like visceral reactions to that idea? Have you sort of seen how others respond to it? And, and like how much education needs to happen for, for this to sort of really take off?

• 16:05Speaker 00

  No, I mean, we've always had sort of moral considerations in the stuff that we fund, but to me, um, you know, I eat pigs, right? I eat ham, I eat bacon, um, I eat cattle, um, I eat chicken. My co-founder, Peter, likes his food to be as distant from the animal as possible, you know, so he, he wouldn't eat like a live turkey, but sliced deli turkey is okay. Um, you know, like a Thanksgiving turkey is very, you know, discomforting. But the fact that we eat our animals and put them inside of our bodies is, you know, for some people, that's just absolutely, um,

• 16:38Speaker 00

  Immoral and disgraceful. But the vast majority of the world are omnivores and we eat plants and we eat animals. But instead of eating animals, if they are producing an organ and can themselves still survive with, you know, one kidney instead of two, and you can save somebody's life, it's a beautiful thing. So I think it's deeply moral. And I actually think that there are religious groups that, as you noted, you know, typically pork is not something that they ingest, but I think that you will see, even in some aspects of the Muslim world, that there will be fatwa's issue that say, not only is it consistent with something like Islam, but it's a moral imperative because to save one life is to save many.

• 17:23Speaker 00

  And yeah, I think, I think it's gonna for sure set up interesting conversations, but most importantly, it's, you know, reducing our ignorance into how do we produce more organs? And it would be great if we could grow them in vats and factories and labs, but today loved ones will suffer and die because they don't have a transplant. And if you can stop that human suffering, it's a great moral good.

• 17:49Mario Gabriele?

  You mentioned that, you know, this is a sort of team that's been working on this for a long time. I think, you know, eGenesis started in 2016, correct me if I'm wrong, and then Lux invested in 2024. Was there a specific moment you were looking for, a specific inflection that, you know, you were waiting to see before you invested? And I know that you also, I think, made it your largest first check ever. So that also strikes me as, you know, a sign of great conviction and perhaps that something had been unlocked?

• 18:18Speaker 00

  It was the fact that the surgeries themselves were happening. So, you know, there was a risk that the surgeries would not go well, but they did. And it was a company that also As part of our strategy, we do thesis-driven investments, we do people-driven investments, we do sort of special situations. Sometimes that's taking a team out of the big company, sometimes that's taking an existing company that's been around for six, seven, eight years and maybe was under-capitalized or maybe was overvalued and it wasn't sort of appropriately priced for the risk that people were taking. And so sometimes we can come in and treat the prior investors well, treat management well, but sort of recapitalize the business and that was the opportunity here. We've known the company, I want to say for probably five years, where we had looked at

• 19:03Speaker 00

  investing prior, but we just got more comfortable with the combination of the science being de-risk, you know, this being approved and being in the hands, literally, of some of the most capable surgeons in the world.

• 19:16Mario Gabriele?

  Yeah.

• 19:17Speaker 00

  Seeing the response from, you know, major key opinion leaders in the field and seeing a tremendous economic opportunity for the company. So yeah, it sort of all came together and we made a proposal and negotiated and it ended up working out really well.

• 19:34Mario Gabriele?

  Amazing. You mentioned that, you know, so much of it is about doing this sort of CRISPR editing to allow the human body not to reject this. At a, without being too nitty-gritty, like what are sort of the things that you have to start to edit or tweak to make a pig kidney palatable, for lack of a better word, to a human body?

• 19:57Speaker 00

  Well, you're ultimately trying to get the somatic cells to have genetic expression that will be consistent so that the human immune system doesn't reject it. And so you're doing germline genetic editing and, you know, that's a lot of trial and error over time, you know, which also took some time. But yeah, it was successfully done.

• 20:23Mario Gabriele?

  There's a sort of, I don't know if you'd call it a field or a... Subsect of interesting papers or studies around the idea of persistent cellular memories and how people who receive transplants sometimes take on the personality traits of the donors. And I remember when I first read a few of these stories, they really blew my mind. For listeners who haven't heard of this, it's on the order of guy works in a white collar job and the implication in some of these stories is that maybe he's a little bit xenophobic, so to speak. And then he gets a donor from someone from a totally different race who

• 21:03Mario Gabriele?

  happens to love jazz and plays the saxophone. And all of a sudden, this guy is hanging out with the totally other folks at the factory, is obsessed with jazz music, and has totally altered their personality. I suspect you've thought about this much more than I have. Do you think those phenomena are real? Do you think about that in response to something like e genesis?

• 21:27Speaker 00

  In that particular case, I don't know how much of it was something that integrated into the body's network or its nervous system versus somebody understanding that if, for example, they were racist before and now they have somebody, different cultural background, and they're alive because of it, they might have a profound sense of gratitude that could affect their preferences of their behavior. But yes, there are interesting studies about somatic cells that have their own form of memory that is outside of just our hippocampus and our brain and the patterns of neurons through experience and genetics. And there are some interesting studies there, but it's all quite early. I would here again probably turn to sci fi, because there are a whole bunch of thrillers that I remember in the

• 22:10Speaker 00

  90s of somebody that got a transplant, whether it was like eyes or a hand or a heart. And oftentimes, it was a serial killer that was being transplanted into this otherwise good person. And then the good person is like... So there's a whole trope of sci fi of like the hand that wants to do the bad thing, or the work that has turned evil, or vice versa, or the eyes that see things. But thankfully, that is fiction, but it is thought provoking. And for sure, we have...

• 22:47Speaker 00

  You know, sort of systemic stress and other things that affect epigenetics throughout our body. And so environment can, can, you know, sort of form its own physical instantiation of memory from events and traumas and, and great experiences and, but, but we know very little about that. So I would, I would say I'm excited about the scientists that are doing real work and speculating and coming up with hypotheses and then running them down. And then I would also just look towards the sci, the fictional sci-fi literature and, you know, and maybe find some inspiration and some good warnings there.

• 23:26Mario Gabriele?

  Yeah, let's hope in the, in the real world, it's more makes you love Miles Davis than becomes a serial killer.

• 23:32Speaker 00

  Yes.

• 23:33Mario Gabriele?

  But yeah, super, super interesting. Well, one sort of final thought on, on eugenicists. I'm curious why kidneys were the right place to start. Is that sort of a, a response to a need where those are just, you know, heavily sought after transplants? Is it something, you know, about the science that makes that the right place to begin?

• 23:51Speaker 00

  It's easier. They're primarily structural balloons. And so when you look at other things like liver and things that are maybe producing hormones or have much more chemical signaling pathways, it's more complicated. So I think that you will see those things next. I know that you will see those things next, but starting with kidney, which is effectively a structural, you know, thing, sort of like a bladder in, and, you know, it's a filtration device and it's just a lot easier. So kidneys and bladders are easier. And then, you know, as you move up, things that are more integrated with the nervous system and signaling pathways from, you know, liver, lung, heart, way more complicated. And brain, forget about.

• 24:32Mario Gabriele?

  Maybe we can move on to what I think has been quite a longstanding obsession of yours, which is the idea of digitizing smell, allowing computers to smell, recreating smell digitally. How did that obsession begin for you?

• 24:48Speaker 00

  It really was one of these things where I'm constantly looking at like what exists. And then in a very sort of, I don't know, David Deutsch or Carl Harper sense. It's like if you could imagine it and obeys the laws of physics, it can and will exist at some point. And we just have the ignorance and don't understand. So, you know, when I like look at my phone, you know, it's got eyes and ears. It's got camera that can see. And those cameras started out with pretty crappy quality and have gotten 4K or 8K quality. They could do still photos and now they could do high def video and cinematic distance. Um, audio started out sort of mono and not that great. And now it's very high quality stereo audio.

• 25:31Speaker 00

  And, you know, if you think about your five senses, um, you don't have computers really tasting. You don't have them really feeling physically. There are haptics that are being integrated into some robotic platforms. And then you can't smell. And it would be amazing just thinking about the evolutionary salience of our sense of smell. If you've ever read Proust in Search of Lost Time, the entire story unfolds. When he bites into a Madeline and the smell and the taste hearkens back to when he was nine or 10 or 11 years old. And the entire story sort of, you know, this flood of memories, you know, gives forth the flood of, of, of words in the story. We've all experienced that where you encounter a smell and it is a very personal, meaningful trigger.

• 26:15Speaker 00

  And it could be cotton candy. It could be the smell of the shampoo of your first kiss or your first boyfriend or girlfriend. It could be a sort of slight musky smell of a hat that your grandfather wore or shirt that your grandmother or perfume or a cologne. Um, the smell of a certain food or barbecue, the smell of a beach, the, you know, there's all these smells that are emotionally imprinted in, uh, in our body and our memory. Olfaction itself is the one sense that is not intermediated by any other sort of neural blocker. So you know, touch is intermediated and sight is intermediated, but smell and molecule binds directly to your olfactory bulb and goes right to your brain.

• 26:58Speaker 00

  And that's everything from, you know, the beauty of a rose to the stink of a fart. And that's little particles that bind. And so, so it's been something that I've been obsessed with and have watched as entertainment. People did like smell-a-vision and, you know, and then people have always been generating artificial smells, whether it's brands like Abercrombie and Fitch or, you know, the pretzel stores and malls and those kinds of things. And they're signature brands inside of hotels, you know, for a particular fragrance so that every time you walk in it invokes a particular feel, just like the retail experiences. And so we would spend a lot of time trying to find people that were developing the means to effectively record and playback smell in the same way that you could record a sound or record an image.

• 27:44Speaker 00

  And those things started out, again, crude and low resolution or black and white, and then became rich and 3D in full color. So we probably met with 20 groups over the years. None of them could really do it. People had small little, you know, sort of parlor trick type things.

• 28:03Speaker 00

  And then I'm on a biotech board, actually, for a CRISPR company where we backed Feng Zhang, who's one of the co-discoverers of CRISPR. And at Broad, and he's focused on targeted delivery of genetic medicine. And you've got an all-star board of John Maranor from Alnylam and Vicky Sato from Vertex and Bob Nelson from March and myself and, and Dave Shankin, who's at Google Ventures, GV. And Dave and I were talking about this particular interest of mine, and it was one of these serendipitous moments. And he said, you have to meet this guy, Alex Wilczko. And I'm like, who's he? And he's like, well, he spent some time with us at GV. You know, a day a week, sort of helping advise us on some life science stuff, but he's at Google Research, Google Brain.

• 28:44Speaker 00

  We had acquired one of his companies and he's here and he's, he got his PhD in Bob Dudd's lab and at Harvard, who was sort of like in the lineage of Richard Axel, who won the Nobel Prize for olfaction, who we had previously backed in another company based out of here in New York called Caliope, that was focused on decoding the gut-brain axis. I'm like, please introduce me to Alex. And we met, and I don't think he had met an investor that was as versed or interested in digital olfaction as me, and I had not met anybody that I thought was as credible and sophisticated in the space that could talk about the ultimately neural nets and AI and odor maps that he was creating on the software side, and the psychophysics of smell itself and how it's described and, you know, sort of

• 29:28Speaker 00

  language that sometimes sounds like wine, you know, it's robust and cedar and elegant and, you know, these things are sort of like qualitative, non-precise, and he was putting a mathematical precision to like smell of a rose or the smell of a plum. And that's the same sort of precision that you would see in Shazam, being able to detect a sound wave that if walked into a noisy cafe and you hear a Kendrick or a Drake song amongst the chatter, it's able to parse that sound wave and map it to a database and say, that is, you know, Kendrick song. And, um, and so that was pretty cool. And, uh, we ended up spinning out, which is a theme that we've been doing in a few companies, but for big tech, uh, spinning him and his team out.

• 30:10Speaker 00

  And, uh, GV and, uh, Amazon and a bunch of other people, uh, came in into a Lux led round. We did about 60 million to, uh, to finance him. And, uh, uh, he teleported the first smell about two months ago, which was actually a plum. They broke down the chemical essence of a plum and then used sensors and effectively, uh, chemical sniffers to decode it into a mathematical signal and then recreate that at the other end, using a combination of robotics and chemistry, uh, to transport, uh, smell of a plum from here to here, which was just wild. So, uh, yeah, this idea of giving machines a sense of smell is really profound and historic and important.

• 30:52Speaker 00

  And there's a few main markets there from Shazam for smell, odor generation, changing the economics of flavors and fragrances. And then even thinking about how In healthcare, diseases like COVID, cancer, Parkinson's, Alzheimer's, all have sort of a molecular signature that dogs can be trained to detect.

• 31:11Speaker 00

  We can't smell, but machines should be able to smell. And then there's some interesting adjacent markets in defense and intelligence use cases for being able to detect or tag certain actors in the world. So it's really a new capability. And yeah, we're super excited about that.

• 31:31Mario Gabriele?

  Truly a new capability. You're essentially giving computers, as you say, a new sense that they, you know, fundamentally did not have before. There's so many parts of Alex's story that I found really interesting and entertaining. One of them is he wrote a blog post, I think, about his obsession with smell and how, you know, he's an 11-year-old boy obsessed with cologne and perfume. And his parents are like, no, we're not going to be buying you a bunch of, you know, Davidoff Cool Water or whatever.

• 32:01Speaker 00

  By the way, he grew up in like College Station, Texas, you know, which is sort of like Friday Night Lights. You know, so imagine being a young tween teen who is into perfume and fragrances against the backdrop of a Friday night football. You know, I always like to say that chips on shoulders put chips in pockets. And, uh, you know, you're going to grow up with a pretty big chip on your shoulder in that kind of environment.

• 32:24Mario Gabriele?

  Yeah, as you said, straight out of science fiction, I think of, um, you know, Huxley, The Scent Origin. And then, uh, I couldn't help but think of a darker reference, which I wondered if you thought, if you've explored, which is, uh, the novel Perfume by Patrick Siskind.

• 32:40Speaker 00

  Yes.

• 32:40Mario Gabriele?

  I mean, it's a crazy idea, but it's basically a, I think, a perfumier from the sort of 1700s of France who becomes obsessed with a woman's scent and kills her to get it or something like that. But, um, it, you know, as you say, scent is just so emotionally loaded. You, you sort of referenced this first Plum 1.0, which I actually ordered a vial of, so I'll, I'm looking forward to smelling it soon. What are the sort of like nearest term tractable commercial opportunities that you see? Like, it feels like the Plum 1.0 is like an amazing, sort of almost proof of concept. But yeah, what comes next?

• 33:20Speaker 00

  Well, I think the low hanging fruit is the flavor and fragrance market. It's enormous. It's very analog in how things are done. There's a handful of perfumers and experts that smell things and it's very French and European in its style. And I think there's a level of precision of stripping some of the, you know, hand wavy qualitative things that people in the industry do when they're doing quote unquote briefs, which is basically saying like, this is what we want it to smell like and we want, you know, a little bit of cedar and a little bit of rose or we want it to sort of invoke this, you know, particular feeling.

• 34:03Speaker 00

  And then you have this perfumers that, you know, come in with a French accent and it's a little bit performative. And so there's a mathematical computational precision here, which can change the economics of that world for everybody from I F F, International Favors and Fragrance, to Givaudan or Furman Ish, where the major fragrance houses, to a long tail of small players in Pennsylvania and the U S and elsewhere that make these things. It's the ability for celebrities and influencers and all kinds of people that want to conjure their own scents.

• 34:38Mario Gabriele?

  Oh, wow.

• 34:39Speaker 00

  To be able to do that.

• 34:40Mario Gabriele?

  That is wild.

• 34:41Speaker 00

  So there's a long tail that if you wanted to create a generalist, you know, fragrance, then...

• 34:47Mario Gabriele?

  The Mario Spritz?

• 34:48Speaker 00

  Yeah. And so, you know, in some of this is... I don't personally wear cologne and I always find like the most offensive part of like the airport is going through duty three when they're like, you know, spraying you or almost stuff. It's like a barrage on my senses. But it is a huge market and people want to smell beautiful and people want to smell beautiful things. So I think, I think that that's the easy low hanging market. But to me, the bigger thing is continuing to miniaturize and have a moat around the capability to have a Shazam for smell. Because being able to record the moment when you're on the beach or you're in some weird factory and it smells bad

• 35:31Speaker 00

  or some amazing market in Thailand or India or Japan and just being able to record those experiences in this different dimension, which is a very rich one for us, is, I think, really powerful. And so that's the thing that I'm most excited about. And then they're already working with the Pentagon and certain groups on a variety of interesting things. In some cases, you might want to produce a smell that is really pungent and repelling people. And in other cases, you might want to be able to detect a group of people or certain people who have a particular odor. There's opportunities for more environmentally friendly insect repellents because that's a form of chemical creation that can repel or attract.

• 36:16Speaker 00

  So, yeah, all those kinds of things. And they've had inbounds from thousands of people. And some of these are not like great markets to go after. But one was for a very famous shoe company or reseller of like high-end shoes and sneakers that wants to be able to make sure that they have real ones or fake ones. And right now, they have human sniffers that are literally smelling the shoes because you can tell if something was made in a fake Chinese factory and it just smells sort of gross and rank versus something that originated from Nike or whatever. And so they developed the capability for that particular company that you can just do this super quickly.

• 36:59Mario Gabriele?

  I want to come back to the Shazam piece in a second. But before we do, you mentioned that it's sort of like fundamentally changes the cost structure in the fragrance market. Is that because it cuts out the sort of, you know, the French perfumier as a sort of middleman or tastemaker? Like, where does that piece get cut out?

• 37:20Speaker 00

  Some of it is in being able to simplify the concentrates and the key chemical components that go into these because they can very precisely say, you know, this is like to make Chanel number five or something like that. It's like these 17 different chemicals and these different processes. And they can deconstruct that and sort of recreate it and say, you only need these seven or eight things to produce that exact same effect on the human brain. But then there's all kinds of other things like...

• 37:48Mario Gabriele?

  You know, modifiers and things that sort of make the smell last or linger for longer, things that make certain notes more transient. So it's quite complicated and I have an appreciation for that. But yeah, being able to change the economics is being able to change the constituent components and and cut out things and make it faster and make it cheaper and then be able to generate things super fast instead of having to go through this very qualitative process. It's like, no, no, this is how you make this thing and this is how it will smell predictably every time. And here are the components for it. And the ingredients, here's the sort of like structural recipe of this and we have total control rather than, you know, this, this more intuitive sense. On the Shazam piece, what do you think happens

• 38:30Mario Gabriele?

  once we can do that? Like, do all of us start to have smell printers in our home that we, you know, are saying, ah, you know, this was the smell when I went to my son's Little League game or whatever it is, and we print those out to sort of remember? Or are they sort of incorporated on our devices somehow?

• 38:49Speaker 00

  It's gonna be a while until something is incorporated on a device because you basically still need a repository of chemicals that can be combined to, you know, produce that thing. Just like we don't have like, you know, printer. I mean, there are people that sort of make these small little printers that, you know, are portable. But so I think that that will take quite a while for something to be portable. But for sure, in home, the ability to conjure a smell that you recorded is something that I think is years away from people actually being able to possess and have. You know, I do that all the time. We host couples and families over our house and we go to people's homes and, you know, they show us photos or they share videos or like, you know, and that's a very human meaning-making, moment-sharing, timeless phenomenon. And to be able to say like, not

• 39:34Speaker 00

  only like, oh yeah, look at this time we were in Barbados or, you know, here's where we were in this market in Japan, but like, hold on, I want you to smell this.

• 39:42Mario Gabriele?

  Yeah, that's so intimate.

• 39:44Speaker 00

  It's just, and it's sharing. It's, so, yeah, that, that to me is an inevitability.

• 39:51Mario Gabriele?

  Yeah, for, for dishes, you can imagine that being so interesting if someone said, ah, this was the best place I went to in this Thai market. You should smell this curry I had.

• 40:03Speaker 00

  And, and you know, look, again, people do like aromatherapy, but if there's a happy place, you know, some people take photos or videos of a beach, they're feeling stressed, they might watch it, but if there's a particular moment that you want to go back and sort of like, it really does provide that very personal like, and it just brings you back, just like, you know, in search of lost time by Proust, and it's very real, and it's, and it's universal to people. The, the great irony, by the way, is when I struck the deal with Alex to spin this group out of Google, I had evaded COVID.

• 40:38Mario Gabriele?

  Hmm.

• 40:38Speaker 00

  Two and a half years, so this was late 22. Um, and I finally got COVID, but I didn't know it. I had come from San Francisco from another board meeting of a high-tech biotech instrumentation company. I landed in New York, I go home, I go to the gym, I work out, I go upstairs, my wife is like, get in the shower, you stink. And I'm like, no, I don't. And, and I go in the shower and I use that shampoo and the soap and I couldn't smell anything. And I was like, oh crap, I, I totally have COVID and I test positive. And that was my only symptom was, um, uh, lost in my sense of smell. And I guess my second symptom was the anxiety of when I would get it back, which turned out to be three weeks. There's not much you could do. Then there's some people that have reported a loss of smell.

• 41:21Speaker 00

  But the irony was that was when I was striking the deal with Alex.

• 41:24Mario Gabriele?

  Yeah, totally.

• 41:25Speaker 00

  When you strike the deal, I had lost my sense of smell. And then I remember a few weeks later, I was in LA and I was taking a walk with a friend down in, um, the Marina Del Rey area and, uh, I smell suddenly again, wafting burger in the air. And I like screamed out, you know, the guys, what is going on? I'm like, you smell that burger? He's like, yeah, like, what's the big deal?

• 41:46Mario Gabriele?

  I can smell.

• 41:47Speaker 00

  Exactly. So.

• 41:49Mario Gabriele?

  Oh, that's amazing. You would have recorded that if you'd had the chance.

• 41:51Speaker 00

  Exactly.

• 41:52Mario Gabriele?

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• 42:37Mario Gabriele?

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• 43:16Mario Gabriele?

  The third topic is really, maybe not sci-fi, but certainly comic books, which is sort of mutants, variant bio, which I think you told me about maybe a couple of years ago at this point. And I remember when you first mentioned it, it was like one of those moments where I was like, wow, I just, I understand so little of what the future will look like and what people are trying and experimenting with. So yeah, tell us about variant bio and what they're trying to do.

• 43:48Speaker 00

  Well, it starts with that guy. I don't know if you can see, Professor X.

• 43:54Mario Gabriele?

  Oh, yes, there we go.

• 43:55Speaker 00

  So, you know, I read the comic books growing up. I watched the movies. I watched movies with my kids. And the basic idea was like, eight billion people on earth, a one in a billion chance of some crazy phenotype, so some actual trait. There should be eight people that are walking around that instead of conjuring fire from their fingers or shooting lasers out of their eyes, or levitating, or going invisible, or shape shifting, or whatever's ridiculous and not real, that they, in reality, only need two hours of sleep a night, or have some crazy metabolism, can eat fatty foods and not gain weight, or can drink alcohol and have a protective variant against liver disease, or smoke and don't get lung cancer, or can ascend the heights of the Himalayas

• 44:39Speaker 00

  or the depths of the ocean and be able to hold their breath for long periods of time. And so that was the founding thesis. And usually when we have these crazy theses and we're creating a new company or trying to find one that exists, we share with everybody. We're never worried about somebody stealing our idea. And just like the thing with smell. One of my other founders of a neuro company had two colleagues that he had gotten his PhD with at Cold Spring Harbor. And he said, you gotta meet these two. And I did in a coffee shop in Tribeca. And I told him the vision that I had. And they said, this is literally all we ever wanted to do with our lives. And so it's just sort of a perfect, you know,

• 45:20Speaker 00

  match. We founded it, yeah, it was probably four years ago, or there about. And I spent about six months recruiting a CEO. And we were able to get an incredible guy who was like this mensch on a mission, this guy Andrew Farnham, who is molecular bio undergrad, and then worked for Chris Hohn at TCI, which is like a big hedge fund, but focused on a lot of his global philanthropy. Then went to the Gates Foundation where he became the investor for them, putting out about $2 billion a year. And so he was like me, a venture capitalist. And, and he's like, this is incredible. And he wanted to join as CEO. And it was just again, another match made in heaven. So yeah, that was the founding

• 46:00Speaker 00

  thesis. You had one member of the team that was extraordinarily compassionate, great moral compass, really thinking about indigenous populations around the world and how you set up benefit sharing programs so that these people could benefit, not just from the science of the technology, but financially, or equity, or healthcare that, you know, might come to them. We had somebody else that was a combination of population genetics and computational bio. And so you had this great setup of people that were saying, look, most of the people that were sequenced in genetics, 23 and me, or Genentech Roche, were pale, male, stale, white European, or white, but most of the really interesting genetics and the

• 46:42Speaker 00

  diversity is in all other parts of the world, in some places, places that are too poor for farmer biotech, or even US academia that sometimes care about. And so you also have co-sanguineous populations, co-sanguineous means blood related. So people that might be intermarrying through cousins or distant cousins, they're generally called genetic island populations, not because they physically are on an island, although in some cases they are, but because they're very closely interrelated. And in those populations, you have a higher Probability of a monogenic condition, so a single gene makes a protein which might be the trait that is expressed in the phenotype that gives you this sort of, you know, superpower

• 47:24Speaker 00

  protective variant or and and so that became the founding thesis for the company and we financed them and I think we did $15 million seed or series A and then they would go on and we would continue to invest about 150 million in the first two years and now they've got partnerships all over the world with the Maoris in New Zealand and Pakistan and Faroe Islands and Ethiopia and Uganda and and it's it's it's it's wild and they have two main hits that are now progressing to the clinic interestingly focused on on liver and kidney and they keep scouting really interesting outlier

• 48:05Speaker 00

  people in outlier parts of the world with outlier traits and the small populations are going to be the source of evolved natural phenotypes embedded in their genes that become druggable targets for the rest of us. Sci fi to sci fact, it started with this crazy thesis and in X-Men and Professor X finding mutants in in fiction and and it ended with us finding real life mutants although they don't like when I call them that in the real world and and helping to sort of flip the idea of genetics on its head instead of doing large population finding the variant, you're going to these really unique populations and and finding the variants.

• 48:48Mario Gabriele?

  I mean, it's such a such a wild and fascinating idea. Tangibly is the way that it works like, hey, we go to Vanuatu, Uganda, Ecuador, wherever it is, and we're taking cheek swabs, taking hair samples, taking blood, like what are the the sort of right inputs to to get these, you know, this genetic information in surface, I can't remember what you called it, mono genetic?

• 49:13Speaker 00

  Monogenic.

• 49:15Mario Gabriele?

  Monogenic.

• 49:16Speaker 00

  Yeah, because sometimes you might have a trait, but it's a confluence of, you know. Epigenetics and five different, you know, pathways, but you're really trying to find like one thing that's a drugable target. But yes, they do set up in these partnerships. In some cases, it's with local tribal leaders. In some cases, it's with academic institutions that are local that, you know, sort of help take care of and study their local populations. In some cases, it's nonprofits. But yeah, it is sample collection, which could be blood or cheek swabs or other means of genetic collection. And all of these people benefit in some way through these benefit sharing programs that they probably spent six months

• 49:57Speaker 00

  from the company's inception to really, you know, pun intended, to have in their DNA this moral compass that so many of these indigenous populations through history were basically exploited. And instead, they should benefit and they should share in those benefits. And so some of it is information, some of it is healthcare, some of it is diagnostic, some of it is financial. But all of these groups are going to have positive experiences that could be transformative for their communities.

• 50:24Mario Gabriele?

  Is there ever a version of it that makes sense where you almost do index on these, the individual more where you say, hey, actually, we know very well that, you know, for instance, Michael Phelps is a genetic anomaly when it comes to swimming. We should actually just be like trying to get as much deep data on him and, you know, see if we can find others like him. Like, is that a viable approach? Or does it really require on more of that sort of population level to get interesting insights?

• 50:54Speaker 00

  You can. You need to disambiguate, you know, whether it really is like singular genetics, but things like cholesterol drugs, you know, really came from PCSK9 genetic condition where, you know, people had these levels of high LDL or low LDL. And that became sort of the origin of our modern statins as targets. But it's really finding these outliers. But Mayo Clinic, I believe, was doing some of these like hyper athletes and, you know, like, I don't know if they did Michael Phelps, but looking at like Usain Bolt and some of these other like star performers. There's another group that was looking at Leonardo da Vinci and

• 51:37Speaker 00

  They had exclusive access to some of the physical manuscripts and artwork and whatever. And there was like DNA on that. So they were trying to see like, is there some correlation of hyper creativity? But those have been sort of punctuated, you know, point off things. And this team decided, let's really focus on the outliers in these outlier places. But for sure, you know, there's, as somebody said, you know, the cure and the code, there's a lot of interesting genetics out there.

• 52:04Mario Gabriele?

  You mentioned that they have these two hits sort of around liver and kidney. When you say they have these hits, like, what is the sort of impact that might come from, from these first two?

• 52:14Speaker 00

  Uh, one has to do with something related to fibrosis, but there, there's sort of conditions that afflict large numbers of people in the Western world and in Europe. And these populations have a protective genetic variant for a variety of reasons. And, and you want to sort of understand, like, why did they evolve that capability? What was it in their ancestral environment or in that particular region that, that lent itself to that? So, yeah, it's, I mean, there's another one, which has not become part of the clinical programs, but in South America, in part because of the precipitous temperature drops in this one particular region, there's like a family of like 19 people and they

• 52:59Speaker 00

  all have this like heat shock protein that raises their basal metabolic rate when they're sleeping all night to sort of warm them. And that's something that just evolved over generations in this particular region. But what one could imagine is that that could be a druggable target that is sort of like, instead of a GLP-1 that's reducing your desire for food, that, and it's sort of an agonist, it, it would raise your metabolism and your temperature and while you're sleeping, burn fat, you know, which would.

• 53:30Speaker 00

  Also seem like it's out of sci fi. So yeah, it's super cool, but you know, it's got to be rooted in real science and paired with good ethics and good leadership. And we've been very grateful to assemble a team at Variant Bio that is doing all those things and really proud.

• 53:46Mario Gabriele?

  Fascinating. Well, in addition to being sort of a interpreter of of science fiction, I always think you are such an interesting and gifted reader of, you know, the macro environment. You published quarterly letters for Lux and they're always like both extremely entertaining and well written. And I always find cause me to think of things that I might not have otherwise come across. How have you started to build or how have you trained your ability to understand macro? And what are the inputs into your view of the world?

• 54:23Speaker 00

  The inputs start with in whether innate or learned, but very competitive, you know, sort of intellectual framework. So I want to understand what other people who I think are super smart understand. And when I don't know something, I'm highly motivated to reduce my ignorance and learn. You know, on the macro piece, in venture capital, everybody thinks we think we're all super smart. And we're backing really intelligent people who want to be around intelligent people. And so, you know, I say like the average intellect of like really high performing VCs is is pretty high and they're very intellectually competitive.

• 55:04Speaker 00

  But we're not as smart as people think. And oftentimes it's just the cost of capital. And so when the cost capital is low and rates are low, everybody thinks and feels like they're geniuses when you have an upmarket. And oh, my theses are playing out really well. And then, you know, nobody's stupid as everybody thinks when suddenly your companies aren't working or you're losing money because interest rates have risen and the cost of capital is up and your company valuations are down and you've destroyed capital. And so I've always said that ignorance of the macro is no virtue. And I've used the analogy that if you think about what we do, we're trying to find the entrepreneur who started a company is commercializing a technology, ideally a breakthrough technology, and they're going to build a team. And we're trying to pick the best entrepreneur in the best sector

• 55:50Speaker 00

  and the best technology. And we like to do it in areas where there are 50 competitors, but five. The analogy is like trying to pick the best dish on a menu in the best restaurant, having picked the best neighborhood in the best city and you've done all this sort of micro-selection. And then you're about to take a bite of this delicious morsel of food and then Godzilla comes and just steps on you. So ignorance of the virtue, ignorance of the macro is no virtue. And being aware of these big exogenous forces, whether it's, you know, global flows of capital, interest rates, indebtedness, low probability, high magnitude, prospects of war, um, trade

• 56:35Speaker 00

  agreements, there's all these giant forces that people don't appreciate. And I am a voracious reader of 30 to 40 plus newspapers every day around the world. I'm flipping through, when I say reading, I'm like reading headlines and.

• 56:51Mario Gabriele?

  You're doing osmendius, sort of scanning, scanning the global culture?

• 56:55Speaker 00

  Yes, yeah. And, and, and really looking for what are the things on like C22 or D7 that people are not looking at as front page news? And, and the anticipation, which is no different, honestly, no different from what we do on a daily basis, trying to find the thing that other people haven't found. It would be no different if I was in A and R rep in the music world, the kind of music I've always been personally drawn to are things that are just like not mainstream music. I happen to like it because they're more discordant and tonal and emotionally resonant with my own childhood background and whatnot, whereas my wife loves pop music and, you know, Pink and Sia and Gaga and Madonna and all that kind of stuff.

• 57:39Speaker 00

  And I like weird stuff, but part of the reason that I liked weird stuff growing up was I had an ear for this stuff, but there's social currency that you get by discovering the band before everybody else has. And so I'm not reading, you know, When I was younger, like I actually would read like Rolling Stone and Spin and all the Music Macs, but I was looking in the back page of the Village Voice in New York and seeing who was playing at CBGB's and Arcade and Academy and Coney Island High and La Moore's and like, you know, and then you find like this band that's, nobody's paying attention to, and then, you know, 10 years later, they're like headlining arenas, you know, and then you're bemoaning that they sold out or whatever, but it's the same thing

• 58:24Speaker 00

  in, if you were in real estate trying to find the neighborhood, and there might be early signals about where the artists are going, or where the coffee shops are going, or, you know, that's not yet mainstream, and there's no Starbucks, but it's like it's gonna be the hot new neighborhood, or in fashion, or in movies, sort of what 824 does in finding the cool, cutting-edge, cerebral, unique, not, you know, the Michael Bay explosive blockbuster action movie. And it's the epitome of what we do at Lux. We're trying to find the scientist, the engineer, the entrepreneur that other people haven't yet discovered in a sector that people don't yet appreciate. And so, it's the same thing for macro of

• 59:04Speaker 00

  trying to find these low probability, high magnitude events, trying to find weak signals that eventually are gonna be front page news. And it's led us to a lot of theses that are speculative, because we don't know, but I would say there's a five-year psychological bias and everybody wants to be invested today where they should have been five years ago. And so, my job is to anticipate in three, four, five years, what are the things that people are gonna wanna be invested in and to be invested in them today. So yeah, I find like, being curious and attuned into macro forces can lead you to better micro decisions.

• 59:44Mario Gabriele?

  Well, one of the macro themes and topics from some recent quarterly letters has been sort of great power conflict, US versus China. As you look ahead over the next five years, where do you see the most important technologies being? I know that you've, I think it was in your most recent letter, or maybe the one before, you mentioned that China is leading in sort of 37 of the 44 key fields. If we were to condense it down even further, or perhaps sort of pick super themes within those fields, like what are the most important places to own?

• 1:00:21Speaker 00

  Increasingly, the most important space to own, which is not a deeply technical one, is this sort of just information sphere, just information operations. Because the most dangerous weapon that I think exists today is the thing that can sort of influence and bend and shape and manipulate the will of the people. And the will of the people to fight with each other, create divisive civil society, the will of the people to want to support allies or military action, cultural institutions. And we see that playing out, and some of it is organic.

• 1:00:57Speaker 00

  But if I was a foreign adversary and I had a democracy that I was concerned was thwarting my ambitions or interfering with my personal interests, then I would use that democracy and freedom of speech and the vectors, and I would attack it from within. And I think that Russia did this quite well, and some of those tactics have been revealed in the 80s with their propaganda. And we do it too, but I would argue for more benevolent purposes of trying to promote human rights and freedom and democracy. And not everybody wants that, and many cultures can't actually handle that. And they shouldn't have the kind of freedom and democracy that we have. It weirdly would not be good for the world.

• 1:01:42Speaker 00

  But here it is. And I'm a patriotic American, and I think that foreign forces that would foment dissent and use our digital tools and other things to divide us and basically identify the seams where they can rip us apart, whether it's black versus white, racial relations, whether it's male versus female and gender relations, whether it's rich versus poor, left versus right, political, Republican versus Democrat.

• 1:02:12Speaker 00

  You know, any, any area where I could, as a foreign adversary, spot an opportunity for civil war between people would be something that I would try to, you know, really amplify. And we see that. So, so that to me is actually the, the vector. And it may be that there are technological tools that help, um, you know, community notes is a small little one in Twitter, but I think it's being adopted by other tech companies. And I think it's a great virtuous thing that Elon, you know, sort of pioneered and the team at Twitter has pioneered and Meta will adopt. But you need more. Some of that is just basic education, um, so that people can be sort of immunized from foreign information operations. So, so that's a less technical,

• 1:02:57Speaker 00

  sci-fi, sci-tech, you know, kind of.

• 1:02:59Mario Gabriele?

  Yeah, but the soft power and the social networks.

• 1:03:02Speaker 00

  It's a big one. So that, to me, is the vector where, um, even if people were just educated to understand, there are forces that want you to hate thy neighbor. Um, and we need to be a United States. I think that's an important thing. So, um, I will say the two areas that I don't think are important are, um, you know, quantum computing and 5G, which is in most government, you know, reports is like, we need to be China.

• 1:03:27Mario Gabriele?

  Need to be ahead on quantum.

• 1:03:29Speaker 00

  Yeah. Yeah. It's quantum because nobody really understands it. And people project onto it, these crazy capabilities of unbreakable cryptographic messages and the ability to do molecular modeling and discover drugs. And, and it just feels like, you know, this futuristic thing, but I'm super skeptical about almost everything in quantum. Not to say that there won't eventually be some breakthrough that is meaningful, but many of those things that people prophesied, you know, like exist, but not because of quantum computing, but because of GPUs and cutting edge algorithms and AI. And, and nobody that was promoting quantum, you know, played a role in that or really saw it coming. So, uh, I do think space is a contested area. I think that's really important geopolitically,

• 1:04:12Speaker 00

  the ability to launch, the ability to deny launch, the ability to sabotage or thwart the, um,

• 1:04:21Speaker 00

  Uh, orbit of certain assets that are in low Earth orbit or geostationary orbit, Leo or Geo is going to be important. And that's everything from comms to imagery, to communication, to experiments that are being done up in space. When China blew up a weather satellite to de-orbit it, they weren't really de-orbiting weather satellite. They were demonstrating capability and flex. And so I think that that's important. I think people that are able to develop the automation for scientific experimentation and its advance are going to be really advantaged. And so this is a combination of robotics, automation, chemistry, material science and AI.

• 1:05:06Speaker 00

  Um, I do see a near future where robots will be performing science 24/7. They might not look like humanoid robots, but it'll be with handlers and cell sorting and all of the scientific instrumentation today that requires a person in a white lab coat and a wet bench to take a beaker and put it into a test tube and uh, put it into a centrifuge and then uh, run some assay and pipette things and uh, increasingly all of those things are going to become automated. And what's interesting is in the same way that you can imagine a musician like 20 years ago, if they wanted to make a song or write an album, they would go with their colleagues and their instruments,

• 1:05:48Speaker 00

  their physical instruments, and they would go to a recording studio and um, and and then put it down on a track or ultimately digital and whatever. But over time, all those instruments became virtualized. On your laptop, you can use Logic or Pro Tools or GarageBand or any other number of um, uh, software to basically write music and you can do it collaboratively. And you don't have to go into the studio. You don't even have to play an instrument. And so I think that the same thing is going to happen in science. You don't need to know how to operate the centrifuge or the um, the physical scientific instruments. You can effectively on an iPad on the beach in the Bahamas. Dial up an experiment, then it will run in cloud labs and those cloud labs will be

• 1:06:30Speaker 00

  run by robots with high fidelity, which presents two interesting things. One, you will help to solve the reproducibility crisis in science. That's the upside. The downside is so many great breakthroughs in science often happen because somebody was like, huh, that's funny. You know, there was Mr. You know, the Petri dish left on the window, penicillin, you know, the discovery of galvanizing rubber and all these things were sort of like happy accidents. You want to introduce probably some stochastic random processes that allow for some screw ups in scientific process. So that's not perfectly precise because you need happy errors. But when those experiments run, and maybe it's an eight hour experiments, you go to sleep and you run it and you wake up and it says, hey, here's the results. They're

• 1:07:13Speaker 00

  quantified. We can write a paper for you and explain, you know, materials and methods and hypothesis and observations and conclusion. But we also noticed that the conclusion that we just came up with, the robots, the system, the AI, there's some interesting paper from 1972 and one from 1996. These might be spear's correlations, but would you like to rerun the experiment changing these two variables? And then all you do is click yes, and then it goes and runs it. Now, I say this because to your question of like, what are the technologies that matter? The, the companies, the academic institutions, and ultimately the countries that get this productivity gain in science are going to lead the next half century or more, because it's going to be truly like a secret weapon to generating knowledge and

• 1:07:56Speaker 00

  knowledge being power and that kind of power being weaponized for defense applications or for, you know, company advantage. But that's the kind of thing where it is in the US interest to see those kinds of companies here so that the market cap and the flow of capital here, which further reduces the cost of capital and attracts talent and money globally, which allows us to have the world's largest tax base for military, like all of that is really important. So, so that's a vector of like automation of science coupled with AI and generating 24/7 productivity and in knowledge production through, through scientific experimentation, I think is going to be really profound. Aerospace and defense is huge.

• 1:08:39Speaker 00

  You know, we've had a relatively slow sclerotic bureaucratic defense base that has shrunk from 50 primes to five. And now we have funded from day one companies like Anduril, Saldron, Hadrian, Varda, Impulse Space, Nominal, that are becoming like the next gen leaders and are coveted. And you will see neo-primes, next-gen defense primes that are not only giving the US advantage. And it is a pendulum swing away from the military-industrial complex, which was, you

• 1:09:19Speaker 00

  know, pejoratively spoken of and we were warned about by Eisenhower. And you have, in contrast, China's military-civil fusion, where every company works with the government and the military and the Chinese Communist Party. And so their coordination, you know, is something short of a democracy, is really powerful and we have to compete for that. So I'm really proud of these young women and men who not only serve our country but are motivated in the calling to work on defense tech. And so I think that's a really important area, too. And then the last note I'd say is just compute infrastructure. It's great that Nvidia is a US company. You know, probably the smartest thing for China to avoid kinetic war, which I believe

• 1:10:04Speaker 00

  is a low probability, if the US over TSMC and Taiwan, is what you're seeing with TSMC saying, hey, we're going to build, you know, $100 billion in the US. And that will take time, but the smartest strategy for China is to allow the US and the world's industrial base to hedge against Taiwan, just so it loses relative import in the national interest of Americans. Because imagine Trump saying, you know, we're going to go to war for Taiwan, but we actually have redundancy in our semiconductors and we don't really need to do this, but we're doing it for fighting democracy. You're going to have a whole, you know, slew of people who may already be influenced by fomented foreign information operations to say like, why is that in our strategic interest?

• 1:10:49Speaker 00

  Why do we care so much? Why are we going to spill blood and treasure, you know, for Taiwan? If I was China, that's what I would do.

• 1:10:58Mario Gabriele?

  It sounds like you think that some of these information agendas or initiatives might be like much larger than we're currently appreciating. Is that a fair appraisal?

• 1:11:10Speaker 00

  Well, much larger than many people appreciate, but there are many that are fighting these. And so, you know, the easy vector, which a former KGB guy was on a talk show, I don't know, 15, 20 years ago or something, you can find it on Twitter. It's a probably 18 minute segment or something, but he's like, here's how we attack you. Like, he gives the playbook. And we start with the universities, because you have young people who are already rebelling against both their parents and authority. And they're also open and they're very social. And, you know, so if you can get like the attractive women, you know, then men want to be around the attractive women. And if the women are like, I really care about this issue. And the men are like, me, I too, too.

• 1:11:53Mario Gabriele?

  I love this issue.

• 1:11:54Speaker 00

  No, and it's really a very, honestly admirable, understanding of human nature and how to manipulate it. But there are useful idiots that were used during the Cold War. There are useful idiots that are used now in a variety of conflicts, you know, whether it's Russia, Ukraine, Israel, Gaza. And there's like very clear moral line, I think, in these issues between like what is right and wrong and who the aggressor is, who's the victim. And, and these things can very easily get conflated. And a combination of, in some of these facets being outnumbered and just being really well organized on the vectors of attack. But yes, I believe that

• 1:12:35Speaker 00

  many US academic institutions have become vectors for this, number one, many nonprofits, number two, many industrial associations, number three. But they're all sort of, again, if you put yourself in the shoes of an adversary of any of crink, China, Russia, Iran, North Korea, easy to infiltrate. And you're not doing it with like, you know, locals from Russia or China. You know, you're finding the ways to appeal to the interests of 17, 18, 19, 20 year olds and, and create movements. And so, yeah, I, I think that that's a pretty

• 1:13:17Speaker 00

  salient attack vector. And then also, in some cases, people have overtly talked about.

• 1:13:24Speaker 00

  You know, sort of what Leo Leonard did for an issue that our family and my wife deeply cares about, which is women's rights in overturning Roe v. Wade. You know, he was able to not go on Twitter and Fox News and write op-eds and just quietly and insidiously figured out the law schools and how to get them clerkships and the judges and like, and just basically before anybody felt what was going on, like it just, you were like, oh, my God, like, this has been a 15-year

• 1:13:56Speaker 00

  trust game. And so, yeah.

• 1:13:58Mario Gabriele?

  We, we mentioned briefly in sort of how to build maybe this, uh, this innovation machine of AI and chemistry and, you know, cloud labs, the importance of, of talent. And I know that's something that, uh, you know, is, is top of your mind these days. And just how close the talent sort of war is with China around, you know, key topics like AI researchers, for example. If you were sort of dropped into the White House today, or, you know, whatever position would give you the most power to enact a useful initiative, what would you be doing to try and make sure America, you know, does win the talent war for these key fields?

• 1:14:37Speaker 00

  Well, first of all, you're right. And just to put some numbers behind the comment, like, I think 38% of researchers in the US that are focused on AI are from China, outnumbering our own domestic native researchers with, you know, that are 37%. We used to account for about 22, 23, 25% of the share of foreign PhD researchers. And I think that's now down to like 13 to 15%.

• 1:15:10Speaker 00

  And so, uh, China has orchestrated a slew of very smart programs to attract not only, you know, Chinese foreign, you know, meaning like Chinese Americans to come back to China.

• 1:15:24Speaker 00

  But You know, just to attract global talent, it's something that benefited the US immensely. You know, anybody that has seen Hamilton or read American history understands the power of immigrants and how important they are. So we should be effortlessly seeking to have a global brain drain. And obviously you want the best and the brightest and you want them working on really smart stuff. And that's going to be more of the hard sciences than on the soft sciences. In fact, most of the university problems that people are seeing now that are creating dissent are not coming from the chemistry or biology or physics or math or computer science departments. They're coming from like the sociology and, you know, gender studies and these kinds of things that don't really, I think, may help to promote and advance human rights in some cases.

• 1:16:05Speaker 00

  But they're not advancing the canon of human knowledge in the same kind of way that people can compound and create wealth and reduce human suffering by developing technologies and companies and distributing those widely to the masses. So that's the thing that matters. You know, you have a very weird moment right now where the Trump administration is punishing many colleges for failing to act and protect their students, particularly Jewish students. And the result is hundreds of millions of dollars of federal funding that say Columbia, the NIH and researchers who are recipients of those grants are going to shut down or lose their jobs. And so it's going to have a very weird ripple effect. And I can sort of agree with both things in that I think that these universities have had failed leadership.

• 1:16:49Speaker 00

  And I think that there was almost an onus of responsibility and anticipation for some of these other departments in physics, chemistry, et cetera, to say like, guys, what are you doing? Like, you know, this is a research institution, stop allowing this to be politicized. And people like Vanderbilt did a really good job where they said, free speech, yes, but intimidation and violence and fomenting this kind of stuff, no. And no, we're not going to divest, you know, from Israel or oil or anything. We are here to grow the endowment so that we can provide scholarships and research institutions. And we're not going to take political stances on issues. So I think. Universities have failed, but my message would be we need to double down or triple down in many of these like hard, basic sciences, and we should be attracting foreigners to

• 1:17:30Speaker 00

  come here so that, just like we saw in World War II, we want Einstein here, not in Germany. You know, you weren't the best and the brightest that are going to develop future capabilities that give the country an advantage to be on these shores and staying here. So, you know, you come here, you get a PhD, and you can adequately show that you're not anti-American as some of these, you know, people who have been given student visas are. You should get a visa, and your family should be free to come too. So that, you know, they're not held hostage as China does in some cases where there might be a Chinese researcher who comes here, but you know, there's a lot of leverage held over them because their parents are back there. Same thing with Iran. You know, there are brilliant Iranians who would be the greatest peace dividend that the world has seen to see a free, you

• 1:18:14Speaker 00

  know, Iran, but they come here and they might have parents that are professors in universities and other things that have nothing to do with the regime, but they have to be very careful. So, being able to give people the, the sort of, you know, amnesty and safe cover here that are our elite people, and this was a debate, you know, that happened right when Trump was elected with Elon and Shri Ram, and it's wild to see like the far right, you know, explode over this, but I think it's really important. We should have a really robust immigration program around the most technical, cutting-edge areas and attracting people to stay here.

• 1:18:50Mario Gabriele?

  Well, we're in hearty agreement on that point. In our final few minutes, we always like to, to wrap up with a few sort of more abstract philosophical questions. So, maybe just a couple here. What experiment would you run if you had unlimited resources and no operational constraints?

• 1:19:12Speaker 00

  I'll give you two sort of geopolitical ones here. Like if I was SecDef or Secretary of State for the day and I had unlimited budget, I would very quickly shore up the Western Hemisphere, like specifically, you know, the sort of pan-pax Americana. We treat so much of Central and South America like places we import coffee and bananas and go on vacation to, but again, China CCP has infiltrated a lot of these places from Nicaragua to Honduras and even elements of Mexico and Brazil and, you know... World War III came pretty close when Russia and Cuba and Cuban Missile Crisis and this is gonna happen again. And so I think that there's an opportunity here to shore up. You've got a billion people.

• 1:19:57Speaker 00

  You have power projection as the US does in both the Atlantic and the Pacific. You have rich natural resources. Almost everybody speaks, you know, English and Spanish as they for Portuguese in Brazil. But I would really make that a proactive initiative and figure out new trade agreements and resource and humanitarian support and reintegrate the hemisphere into the US sphere of interest. So that would be a big initiative and I would put a lot of money and a lot of resource and talent into that because it's our backyard and I think there's a lot of future threats that we'll face for that. And then the second area geopolitically that I would also put a lot of money into because I think it's going to be the next major disaster.

• 1:20:39Speaker 00

  And it's interesting because I've documented this on Twitter going back six plus years. Is this a hail in Maghreb? And so the sort of region latitudinally in north and central North Africa, you have a mix of violent extremists, religious extremists and Islamists who are coming from Syria, Iraq, Afghanistan. You have a lot of young men without purpose that are being recruited to the equivalents of ISIS and Al Qaeda on the continent. You have Russian mercenaries who are, you know, extracting resources and or getting paid to help, you know, overthrow Western colonial interests that were once there in Mali and Chad and Niger and Sudan and elsewhere.

• 1:21:23Speaker 00

  And then you have China infrastructure that's coming up as well. Africom, I think, is an important military command for us. It's, you know, historically been based out of Stuttgart, Germany. But France was kicked out of Mali, you know, US forces have been kicked out of some of those countries. And we need to do partner and alliance building and training and win hearts and minds of people because you are one terror event away, being projected into Europe. And then suddenly that entire region becomes like our next Afghanistan. And again, if you're China, Russia, Iran, North Korea, nothing more that you would love than to see forces and money and weapon systems diverted.

• 1:22:05Speaker 00

  You know, from anything that might thwart your own ambitions and are suddenly like ensconced on the quote unquote dark continent. And that's against the backdrop where you have brilliant young generation of entrepreneurs who went to HBS and Stanford and MIT that come from Kenya and Ghana and South Africa and Nigeria and I hope that due attention is there. But those are two areas that if I had unlimited funds, not so much an experiment, but like a hardcore five, 10 year initiative of sustained commitment, I think is important for stabilizing the world because there are actors that want those regions in the US in our interest to be destabilized.

• 1:22:50Speaker 00

  So.

• 1:22:51Mario Gabriele?

  Fascinating. Uh, final question. If you were to come up with a brief curriculum for someone to read a few books that you think would prepare someone well for the future of these technologies, of these conflicts, could be fiction, could be comics, could be nonfiction, what would make the sort of shortlist for you?

• 1:23:11Speaker 00

  It's interesting because in my day job, the one through line is human nature. Because the players and the stages and the costumes change, but there's like 20 narrative stories of humans and conflict and from Shakespeare till modernity, they're pretty constant. And so I would say that technologies change and businesses change and markets change and the cost of capital changes and the company names changes and conventions and culture changes, but human nature is a constant. Greed, fear, avarice, petty jealousies, alliances, revenge, chips on your shoulder, all of that is just a constant.

• 1:23:52Speaker 00

  So, so I think being really well versed in these timeless human stories is really important. So I would, I would read Shakespeare, I would read the Victorian literature, you know, that sort of details and dense, beautiful prose, human nature, because these stories just keep repeating, you know, with different styles. So that would be one. I think. You know, Poor Charlie's Almanack, from Seeking Wisdom, from Darwin to Munger. I think that he, Charlie Munger, Warren Buffett's partner, was just a great erudite, lifelong learner, that really tried to reach into other people's fields and take some of the best ideas.

• 1:24:33Speaker 00

  And I think the most interesting people that I know, you know, do that. So, reading the speeches and mental models and those books, I think, are sort of the next thing, because they touch on physics and chemistry and beyond just human psychology. For technology itself, I do think science fiction is the best thing to sort of serve as our present speculations about what the near future will or could or should look like. And then it often inspires people to say, oh, no, no, I don't want it to look like that, I want to go this way. Yes, like, I want that to be real, and they dedicate their life to it. And so, you know, even now, for example, I'm on the side that robots are going to be

• 1:25:17Speaker 00

  a huge field, but I'm sort of more bearish on humanoid robots, and I'm very booked on broad robots. And why? Because from Darwin, like, endless forms most beautiful, and, you know, sort of the cantina scene in Star Wars, even though the droids weren't really allowed in the cantina, just like the diversity of these weird creatures, to me, is what robots should look like. They shouldn't be two arms and two legs, like, you know, Elon is doing with Optimus or other people are doing. They should have like six arms and, and, and they should come into a room and do something, and people are like, holy crap, how did you do that? Yes. So, yeah, I would, I would read sci-fi, I would watch sci-fi. And, and, you know, like, Star Trek is timeless, because it has great moral lessons and, and,

• 1:26:02Speaker 00

  and great sort of technological prognostications. Asimov, you know, he's been sort of canceled because of behavior, but Neil Gaiman, you know, sort of at the cusp of both sci-fi and fantasy.

• 1:26:18Speaker 00

  Terry Pritchard, Neil Stephenson, which is just a beautiful mix of both history and future. I think all those things can be sort of super inspiring. So, yeah.

• 1:26:30Mario Gabriele?

  Amazing. Well, there are a few things I enjoyed chatting about more than fiction and technology, and this was such an amazing blend of that with a nice dash of global politics. And yeah, I can't thank you enough for your time. I really, really enjoyed it.

• 1:26:45Speaker 00

  Great to be with you. Love all that you put out into the world. So thanks for having me.

• 1:26:49Mario Gabriele?

  Thanks so much, Josh.

• 1:26:52Mario Gabriele?

  That's it. Thank you for listening to this episode of The Generalist Podcast. Please subscribe on Apple Podcasts, Spotify, or your preferred podcast app. Ratings and reviews help others discover these discussions. So if you enjoyed the conversation, I'd be grateful if you could take a moment to leave one. For all past episodes and more, visit us at thegeneralist.substack.com. See you next time as we continue to explore the future.