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Sundar Pichai: Google’s Frontier Imperative, Compute Scarcity Dilemmas, Future AI Products and Businesses
Alphabet CEO Sundar Pichai has little patience for doubts about Google’s willingness or capacity to compete at the frontier of AI. His company’s latest Gemini 4 Argon model — long-promised and recently delivered — beats OpenAI and Anthropic’s latest public models on coding, math, science, and knowledge-work benchmarks and has placed Google’s AI back among the world’s best. Amid chatter that Google was fine with good-enough lightweight ‘Flash’ models, Pichai pushed back hard against any suggestion that company is limiting its research ambitions. “We won’t do it any other way,” he told me in a Big Technology Podcast interview recorded this week at Google’s Mountain View headquarters. Pursuing cutting-edge research is costly for Google, requiring compute and chips that otherwise could be sold at a high markup by its cloud business. But Pichai said allocating resources to frontier AI development is “ground zero” for Google. “Our cloud business is at any given moment in time forgoing short-term revenues because we are making compute trade-offs to support frontier AI development,” Pichai told me. In our conversation, we discussed Argon (which Pichai says processed three times as many tokens as Gemini 3 in the 72 hours after launch), AI’s role in developing better models, the AI interface of the future, competition with OpenAI, Google’s partnerships with Anthropic and Apple, data centers in space, and the nature of his optimism. You can read the full conversation, lightly edited for length and clarity, below, or listen to it on Apple Podcasts, Spotify, YouTube, or your podcast app of choice. Alex Kantrowitz: Google is back at the frontier with Gemini 4 Argon, which beats OpenAI’s and Anthropic’s public models on benchmarks spanning coding, math, science, and knowledge work. The conventional wisdom was that Google had given up on the frontier to focus on fast, good-enough models for its products. That was wrong? Sundar Pichai: Very wrong. Look, we are so committed to being at the frontier. It’s in our DNA. We won’t do it any other way. We’ve been thinking about the AI frontier for well over a decade now. The frontier is very dynamic. It’s very competitive. It’s very exciting. I couldn’t be more pleased with how Argon has come together. We took our time with it. We made sure we tested it safely and deployed it carefully. We took a bit longer than our other models, given its capabilities. Across the board, be it for agentic work, knowledge work, coding, creative tasks, Argon is one of the really good frontier models. The first 72 hours since we launched, it’s almost up to 25 trillion tokens used, which is about three times what Gemini 3.0 had in the first 72 hours. And we are capacity constrained as we are serving it. Excited, but there are always areas….. You know, the frontier is very dynamic, and you have to keep evolving the models. There are areas which we can see we need to improve as well. We’ll be at work on all of that as well. Which areas? On any given model, Argon would be across the board better at everything if you just look even two months back. But the space is so evolving. Even on coding, for example, there are pockets where we know we need to do better, and there’s clear feedback. We’ll make it better. The argument for standard models is that they’re already good enough to build great products, with the frontier valuable only for certain tasks. Meta built Muse with good models rather than the best, and Google could put standard models into Maps, Gmail, and Search. Why isn’t that sufficient? It’s definitely not how I have thought about it at all. We are deeply committed to driving the state of the art and actually pushing where this technology can go, all the way from transformers. That’s a journey we’ve been on. You will see us continue to do that. When you’re at the frontier, you get an earlier look into the emerging capabilities, earlier than others, which helps you better prepare for the future. We are fortunate to have a wide set of opportunities across consumer and enterprise. Some of our cloud customers, for sure, want the model at the frontier. The frontier models will be better at developing the next set of models in an era of recursive self-improvement. I would argue it matters there. Internally, we have definitely seen a steep point of inflection by deploying Argon to our developers. It definitely tackles problems which our previous models could not do. Being at the frontier puts you at the innovation frontier and helps you drive that as well. There is room for models of all sizes and capabilities. That’s why we did Flash, Flash-Lite, etc. I agree with you that you can develop very good product experiences with not necessarily the most frontier model, because they tend to be slower and more expensive too. But we care about the Pareto frontier, and we’re committed to doing all of that. You said developing frontier models gives you a look at what’s coming. What do you see on the horizon? What makes this moment so exciting is you build something which you think is a culmination of months of work, and you put it out. You already see clear headroom ahead. We’ve all been working on these agentic, long-horizon capabilities, but clearly the frontier is going to have multiple of these agents working together to do things. That’s an example of an exciting paradigm underway. It’s also clear to me that users, both in consumer and enterprise, will have access to some multi-agent framework for them, working all the time doing things. It feels like a moment of infinite possibilities. Sergey Brin said one of Argon’s core innovations was relying more on the model to help develop the model. Yet incidents involving OpenAI’s bots breaking containment and Google’s bots accessing a site they shouldn’t have suggest these systems still aren’t perfectly aligned. Isn’t there reasonable cause for concern about accelerating toward recursive self-improvement? There are three parts to your question. Let’s first talk about RSI itself. You’re right, Sergey mentioned RSI being a critical contributor as we are developing Argon. But to be very clear, today, in a continuum, we are pretty far from the end state of RSI or something like that. The right way to describe it is you have RSI loops along with AI researchers in various aspects of model development. You almost have agents helping AI researchers in some automated way work together to build these models. It’s good to at least understand where we are today, and it’s super exciting. I expect that continuum to keep making progress as we go into next year. The second question is around safety. Security comes from defense in depth. You’re talking about alignment, obviously. We all are doing a lot of work to make sure the models are as aligned as possible. But it’s an active area of research, and there are clear gaps. That’s not the only thing we rely on. You have the work you do on alignment, but beyond that, we put a lot of effort into real-time monitoring as these models are working. Making sure you have good telemetry into what’s happening so that you can intervene in real time if you see unexpected behaviors. How you do that, the architecture with which you do that, how you make sure it’s all sandboxed and isolated in a way that it can continue doing its job during real-time monitoring — these are all areas of investment. Obviously, when we deploy these models, giving customers, enterprises, control, both with real-time monitoring, but their ability to decide where they deploy, what type of data which models ever have access to, etc. All that work is very, very important, and we are doing a lot of that. As an industry, we need to constantly up our game and take the time to do all this stuff, including dedicating the compute required to make sure you can safely deploy these models. The third part is: Is it all enough? This is why there are a lot of conversations in the industry, and I think it’s reasonable to be worried. The right way to approach something you worry about is early on thinking about what more we can do. As an industry, you’re definitely seeing increased levels of work on alignment, testing for safety, etc., as we deploy these models. The next step would be developing better standards so there are cross-industry standards of how we do these things, including the ability to evaluate using independent evaluators. If you look at areas like financial controls, we have accounting standards, we have independent auditors. Those are all the next natural steps for us as an industry to work toward, and regulation will end up playing a role as we go through all of that as well. Google pursues both language models and world models, while some other AI companies like OpenAI have focused more heavily on LLMs as the path to AGI. Why is world-model research important to you? As humans, you obviously perceive the world around you, and you’re taking all those inputs. Making sure these models are able to understand the laws of physics, simulate the world in high fidelity. All that, I think, are key enabling blocks for intelligence. We are working across all possible applications of this. Take an area like robotics. It’s not an accident: If you look at embodied reasoning benchmarks, Argon is state of the art. That all comes from our experience building world models. Inherently, I would expect there will be architectures which will converge all of this in the future. But for us, we view this as, today, this jagged frontier that is intelligence. We want to be at the frontier of all the possible approaches, and that will help us both drive better research, better insights, and develop a much better AGI model, is how we think about it. Some people argue Google should focus on selling its computing resources rather than using them for AI research. Cloud wants to sell compute at a high markup, while researchers need a very big computer to build the best models. How do you balance those demands? Ground zero for us is making sure we are investing in the compute that’s needed to be at the AI frontier. In 2015, I set the company to be AI-first. AI is that key horizontal ingredient across everything we do, all the way from Search to Cloud to Waymo. That is ground zero for us, making sure both for research and developing the models that we have enough compute needed. Beyond that, we have these independent businesses which each have their own long-range plans. They’re using those long-range plans to project forward, and we plan for compute for all of them. The cloud team, they have a business and they have a projection and they have demand signals. They have committed contracts. With that help, we can plan on a long-term compute trajectory for them. We’re fortunate to have this wide set of opportunities. There’s no company in the world which isn’t making trade-offs at any given moment in time. But the first principles we operate on is making sure we have enough compute to invest in the frontier, and that’s non-negotiable, and everything else works on top. Remember, we are building our own compute, our own data centers. There are long lead times. The compute we have today is a function of decisions I made in 2024. Even if you think back to a year from today, last year the agentic coding takeoff hadn’t happened. Today, obviously, when you sit and look at anything, everyone is short—not just us, other companies—and everyone wishes you had two times what you had planned for. That comes with the territory. At any given moment in time, we are planning for what we would need two to three years out in the future. You’re going to find some decisions you make may look suboptimal two years out, depending on where the state of the art is. I don’t spend too much time thinking about it. The way I think about compute allocation is making sure Google DeepMind, both for research and frontier model development, is cutting edge in terms of compute access. After that, we plan for all our businesses. It’s great we can provide our compute to other people too, like we have done. It allows us to scale that up, get real tests for it in the widest application set possible, test it in the real world, and make sure we are at the cutting edge of technology at every layer of our AI stack as well. Ben Horowitz relayed on a podcast that Andy Jassy had said compute was sold out until 2028. Are you seeing the same thing? If today a customer is coming out and asking us for compute in ’27, that is incredibly difficult to do. Even last year we went out and leased some short-term compute to accommodate some customers and help them out. But yes, we are all dealing with similar timelines. Every major technology shift seems to involve overbuilding, from railroads to fiber. Do you think that’s happening here? It depends on the time frames you’re looking at. This level of build, if I take a long enough time frame, it makes complete sense to me. We are at early stages of the most consequential technology ever, and this is not like fiber. It’s not dark. We are using it. We are capacity constrained on a daily basis. The applications, the underlying technology is improving rapidly. But running a company, the way I work through the moment is you look at your demand signals. You look at your committed revenue opportunities that you’re getting in the form of contracts. You balance that with the underlying technical capability, or internally you balance how we are using it internally, the model trajectories. Based on all that, you take a disciplined approach—a confident, aggressive, but disciplined approach—to plan out compute. But when you talk about the broader economy as a whole, you’re having people operate with various levels of risk. I focus on what I can control as a company and plan through it. If your question is, can there be an overbuild? Yes, because you can have some constrained components. Remember, what matters is a set of everything you need to build out that compute. Memory, electricity, electricians…. Land. Like 2,000 components or more. You could get constrained at some point. There could be things which cause bottlenecks, and then you could have overbuilds. There could be external shocks to the economy. There are macro risks. All that is possible at any given time. But am I confident that the compute we are planning for, we will have uses for it given enough time? Absolutely, yes. I was in the room when you said AI would be as profound as fire and electricity. If you believe that, shouldn’t you give researchers the biggest possible computer, even at the expense of today’s cloud profits? We’re all doing some form of that. Our cloud business is at any given moment in time forgoing short-term revenues because we are making compute trade-offs to support frontier AI development. What you’re seeing is true already. But you want to be thoughtful. Even our AI researchers have some constraints, which are also good. That’s what inspires creativity. That’s what helps you come up with a more efficient algorithmic breakthrough, maybe to use less memory. What we are committed to is to invest what’s needed to stay at the frontier. OpenAI President Greg Brockman told me a few months ago that the ideal AI product might have no interface at all—just as natural as conversation. What do you think the interface looks like in the age of AI? Computing historically has been humans adapting to computing. With AI, it’ll be the other way around. The technology will adapt seamlessly to how humans live and go about their day-to-day life. You want to be able to speak to that AI when you want to. It has context. It can be persistently running somewhere, give you continuity. You’re not dealing with a lot of complexity. It’s natural. All that makes sense to me. That doesn’t mean it won’t have any interface, however. Nowadays, even on my phone, Gemini voice models are so good. I can just press the microphone button. I can just ramble. That’s why we call it Rambler. I can ramble. It intelligently corrects with my personal context. Even my friends’ names, weird names, it gets it right, even if it first guesses it wrong. It’s amazing. I’m not going in, backspacing, editing once I finish saying it. It’s remarkable how good it’s gotten. But there are going to be moments you will need an interface. You may want to entertain yourself. You may want to watch a video. You may ask your AI to create something, and you want to watch it, consume it. The way I think about it is, you want it to be as seamless and as natural as possible, and that you are not doing the hard work adapting to whatever the interface is. The technology is adapting to how you’re working at any given moment in time. When I asked Sam Altman about competition from Google, he argued that OpenAI was building AI-native products and implied Google was bolting AI onto existing ones. Do you accept that framing, and can a “bolt-on” compete with an AI-native product? First of all, it’s a very dynamic moment. We are all pushing each other. OpenAI has pushed us as a company too. This is not just we are doing something to them. Far from it. Yes, Google went into its own version of a code red too. In the AI moment, all of us have to respond with varying levels of urgency at any given moment in time. We are constantly building new products as well. Gemini was built from the ground up as a product—the Gemini app I’m talking about. Or tomorrow, as all of us are adapting to agents, are you bolting agents onto ChatGPT, or are they building it natively? How would you think about that? You can always put these questions back. I don’t think of it that way. I think of it as you want to build world-class product experiences that are AI-native and they are winning. Some of it is adapting products, some of it is rethinking new experiences. They will all be part of how you approach this moment. How do you expect to make money from these AI interfaces? If an agent recommends a product and I buy it, should it take a cut of the sale, even if that’s disclosed? I’m going to put enterprise aside. Consumers are going to increasingly value this technology. Take software developers today. Developers are willing to pay for these coding models because it really helps make them more productive. Nobody would want to code the way they were coding three years ago, or even the same time last year. When you’re delivering value, there’s value to be had. I’ve never seen examples where consumer products really scale to billions of users, where people are using it intensely, and haven’t had monetization to go along with it. If you’re providing value to people, there is inherent value to be had. The nature of it may change. You’re asking a scenario in which agents are doing stuff for you. At the end of the day, you will have commercial needs. The agents need to fulfill those commercial needs. The providers on the other side are going to see value in that. There’s going to be some mechanism by which it gets fleshed out. That’s what an efficient system does. But what matters is that you’re building those world-class consumer experiences. I promised myself one product feature request: Can you make Gemini-powered search in Gmail as good as searching Gmail through ChatGPT? What’s going on here? One of the exciting things we announced recently is the unified Gemini agent for enterprise, and we’re bringing that to consumers. These are persistent agents which run 24/7 in the cloud. We’re spinning up a micro VM effectively for every query, and from the runtime, the harness, the model—it’s all a headless service. It’ll work everywhere, and it has your context with you. You can address this agent whether you’re in Workspace, in Search, in Gemini. Agents are going to drive this unification from a customer experience, which people are looking for. When you have a broad product portfolio and you’re moving forward fast, there are always areas where you’re moving forward faster than some other areas. That’s valid feedback. But we are putting a lot of time and effort into making sure, as we build out our agentic experience, that unification and that capability works well across all these services. People have asked where Google’s equivalent of Muse or Dots is. Do you anticipate creating a new product to compete with them? Our goal with Gemini is to be a personal, proactive, and powerful assistant. That’s what we are working toward. You saw us describe the early versions of it at Google I/O this year with Spark. Effectively, already, if you open the Gemini app as a Pro or an Ultra user, you see Chat and Task, and they start giving you that agentic experience. With Argon now, that capability is dramatically accelerated. What we announced recently in our enterprise event, we are bringing that to consumers as well. Soon in Gemini, you will be able to ask something, and it’s a continuum. You don’t need to think about whether you’re asking a chat or an agentic task. It’ll just automatically do the right thing, and it can work persistently in the background securely and get things done for you. Already, empirically, when I look at what’s coming into Gemini in our app, last year you would have tagged them and most of them would have been chats. But a steadily growing percentage is already agentic tasks in Gemini. Yes, we are going to bring personal agents to our consumers. It’ll work in the Gemini app. It’ll work in Google Search. It’ll work in Gmail. You can address it, call it, etc. We want to make sure we’re getting it right. It’ll be powered by Argon, and we are very excited to bring it to our users. Google has invested and committed tens of billions of dollars to Anthropic. What do you see in Dario Amodei that makes you want such a deep investment and partnership? Very early on, when we looked at the founding team of Anthropic, it was very clear to us this was a world-class team which was involved in some of the earliest GPT models. We were quickly able to assess that they would be at the frontier. We’ve always tried to identify and partner with companies which would be at the cutting edge of technology. We’ve done that with SpaceX. We’ve done that with Anthropic. That’s what we saw, and we had a chance to partner. Is your partnership with Apple to license Gemini for Siri expanding, contracting, or standing still? For both us and Apple, that partnership was about translating the capabilities of AI into better experiences for users. I thought Apple has done a phenomenal job of incorporating—they customize these models and build it into Siri—and it’s been great to see the reception. We are committed to doing more. You’re going to do more with them? There’s nothing specific to comment, but it’s a partnership. It’s working well. What have you learned so far about the feasibility of data centers in space? It’s a very exciting project. Projects like this remind me—I still recall that moment in the desert for the DARPA Grand Challenge, watching the Stanley car compete in it, which ended up being the basis for Waymo. With all these technologies, you’re at a moment in time where it looks a bit like sci-fi, but 10 to 20 years down the line, it’s actually working in a meaningful way. I feel the same in space. We’ve always believed in betting big on these technologies. Quantum has been a great example of it. We’re probably 10 years into the journey. Waymo, we are almost 20 years into the journey. Space, we are two to three years into the journey. It’s clear to me that it’s an approach which will make a lot of sense in the future. Being in sub-synchronous orbits with 24/7 access to the most abundant form of energy we have access to will make a lot of sense for this exponential increase in compute that we are going to need. Having said that, this is a challenging project. The team has disciplined milestones. It was a super exciting milestone to send the TPUs up to space. Sometime, as we are speaking, we are expecting a “hello world” moment from them. I look forward to seeing that happen, and we’ll continue investing here too. You previously said 25% of the code written within Google was written by AI. What’s the number today? That number in our world today is meaningless in the sense that every part of what we now touch is influenced by AI deeply. What we are tracking with Argon, for example, it’s been a point of inflection. People are using Argon to really go tackle complex projects, including projects which affect millions of lines of code. In the four weeks since we have launched Argon, we have seen a 30% increase in CLs, and more importantly, almost a similar increase—a one-third decrease in rollbacks. People are writing code more productively and better code with it. We are tracking it with newer metrics now. How are you dealing with opposition to data centers? If you can’t build in the U.S. the way you want to, where else do you go? We’re very committed to building our data centers very responsibly. When I look at our largest data centers in some of the communities where we have been the longest, I visit them, I talk to people. There are people who come and tell us their kids have gone to college because of our investments in these communities, and we’ve grown in those communities. To me, this is about doing it right. Engaging with the communities early, doing it transparently. We are committed to making sure we are bringing incremental power, and we cover 100% of the cost of our power needs for these projects. It’s understanding the impact on neighborhoods and making sure you’re working thoroughly to address them. Done rightly, you can continue making progress. But we are constantly taking feedback into account. I do worry not everyone operates the same way. People have been surprised by data centers showing up in their backyard. Those are all important. As an industry, we should continue to do better. But part of the reason, in a 20-year time frame, we are thinking about things like data centers in space is making sure we are able to put these data centers where maybe the trade-offs will be different. What unproven area of AI is Google working hardest to crack? Is it continual learning—getting models to keep updating after release—or something else? There are multiple parallel paths. You saw with Argon we have a million output tokens. With our Gemini models early on, we had a one-million context window on the input side. These are all examples of breakthroughs we are constantly working on. How do you think about synthetic data? How do you think about continual learning? How do you think about more efficient architectures? We do dedicate a meaningful percentage of our compute to these research bets too. It always goes hand in hand, including our world models. Those are all bets we are placing. Sometimes, as part of these bets, there are ideas that emerge which just make their way into the mainline models. Maybe we don’t fully talk about it, but we have multiple steps in these areas. Working in technology requires optimism that building something will improve the world, but those bets can leave real consequences when they fail. I recently returned to a town in El Salvador where enthusiasm for Bitcoin had given way to unfinished construction and something resembling a ghost town. How do you maintain the optimism you spoke about in your Stanford commencement address while accounting for those risks? I genuinely have a deep conviction that improving technology and improving access to technology makes people’s lives better. It’s been my personal experience in my life, out of which comes that deep conviction, optimism. But with that, I’ve always felt humanity’s journey is always about working hard to harness that technology to make it work well for society. The optimism is not an optimism that you just build whatever you want, whenever. You work hard to make sure you’re building technology in the service of humanity, to make the human condition better. That’s got to be the defining goal as we are approaching it. With that framework, I’m very, very optimistic. We are in very early stages of the kind of progress that we are going to see on many areas. We’re all talking about areas like healthcare. A lot of the progress is ahead. The ability to make things in a fundamentally cheaper way on many things where things have been getting expensive for a long, long time, discovering new materials, etc., which really bend the curve—it’s tough to step today and understand the impact of all that, but they’re going to be very profound. I’m very optimistic, but we have to be rightfully concerned about all the ways this technology can go wrong. Sundar, I know you don’t do many of these. Thank you. Thanks, Alex. Appreciate it.
As prior auth becomes an AI ‘arms race,’ Otter Health raises $8M for a different approach
Prior authorization has long been a source of friction between payers and providers, and now, with algorithmic tools for claims reviews and LLMs for appeals, it's evolved into an AI "arms race" as | The company built an AI-powered real-time clinical quality platform to better manage healthcare utilization by influencing care decisions rather than requiring clinicians to get permission for them.
This era’s public health threat is digital (Opinion)
We addressed car safety through design standards, such as airbags. Policymakers could treat infinite scroll, autoplay, streaks, algorithmic recommendations as design choices potentially subject to similar public policies.
Cyborg Politics 3.0: AI and the Algorithms of Unpeace
How AI is transforming politics, warfare, and peacemaking, creating a new era of cyborg power and algorithmic "unpeace."
Is Fury v Joshua about meritocratic sporting excellence or just algorithmic celebrity power?
This long-awaited fight is happening exactly as intended: at the sweet spot where commercial potential meets a genuine absence of jeopardy
September Monthly Review: Health MCP Guy?
For all the time I spend talking about APIs and data exchange, this newsletter has had embarrassingly little interoperability of its own. It’s old-school SaaS, baby - UI or bust. Not all of that is my fault! Substack, for all its popularity, is (as mentioned before) really frustrating as my system of record. The primary user it optimizes towards is the reader, whose attention feeds the app, the Notes feed, and the recommendation network that Substack is actually selling. Health API Guy is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber. Subscribe They’re falling into the same trap that Medium once sprinted into, albeit at a much more glacial speed. Younger generations may not remember (or never knew) it, but Medium once lured publications like The Ringer and Signal v. Noise onto its platform, only to lose them as it rebuilt itself around a paywall and an algorithmic feed. Substack’s original pitch circa 2020 was the antidote (you own your list), but every new feed feature chips away at it. I get it: writers are generic supply in the eyes of the Substack product team. Generic supply follows demand, so the consistent pressure on the PMs is to generate demand, which leads to every product cycle going toward discovery (Notes, recommendations, the app, live video). The end result lackluster author tools (laggy and broken analytics are truly crippling) all despite the premium price point. The archive is where it crosses from authorial gripes to actual reader impact, though. Across Substack and LinkedIn, I’ve published 1,218 posts and nearly 900,000 words since 2018. Substack’s native search can see only the 464 posts that live on Substack, and even there it’s woefully inadequate at surfacing relevant content (even for the guy who wrote it)! Readers have the same problem, writ large. Ask the Archive Fixing search (for both my readers and my own use) turned out to be extremely non-trivial, unfortunately: There’s no public API for readers to access content RSS exists for new content notification, but it only carries the 20 most recent posts and cuts paid ones off at the preview The only Substack MCP is an admin tool for analytics The export exists for authors, but it’s painfully awkward and slow. So I built something to work around that: the Health API Guy MCP. It’s a private MCP server holding the full text of everything I’ve written across Substack and LinkedIn. Add it to Claude or ChatGPT as a connector and you can ask things like: It pairs keyword search (for acronyms and case names, of which we have many) with semantic search. Every post is also labeled by topic, form, and court case, so you can pull a lawsuit’s (or multiple cases’) entire docket across Substack and LinkedIn in one query: Hail, Healthapiguyhydra This is also a bit of me eating my own cooking. I’ve spent the year arguing that headless healthcare is arriving and that developers want primitives over abstractions. Last week in Hail, Benihydra, I watched Salesforce plug its platform into Claude and bet that the records underneath outlive whatever interface sits on top: Salesforce must believe that the Hydra’s immortal head is the records, permissions, and business logic (in that they will survive whatever happens to the interface). It felt a bit hypocritical to keep my own archive behind a Substack search bar. The archive is the body. Substack is one head, and now whatever tool you might use is another. Will the EHRs follow my lead? Probably not imminently, but one can hope! Why Founding Members Only The MCP is available to Founding Member subscribers. A few reasons: It costs money and time to run. Hosting, the database, Clerk usage and AI compute for search and labeling are significant operational costs (that increase with usage). Substack gives me no way to automate access. There’s no API to check whether someone is a paid subscriber, so every user is manual operations for now. It’s a beta. We’ll need to improve things and parts will break. I’d rather they break for a small group of dedicated readers who will tell me about it. The Founding tier deserved a real benefit. Until now it was mostly a generous tip. Now it comes with something. If you’re already a Founding Member, reply to this email with the address you’d like provisioned. If you’re not and want in, upgrade here. Larger teams (such as companies) can get access too: group subscriptions at the Founding tier come with the group discount. The admin for the subscription can reply with the list of addresses to provision. Get 20% off a group subscription Pricing Founding membership is now a flat $200 a year, replacing the old suggested $150 that readers could adjust. Existing Founding Members will have access grandfathered in at their previous rate. Month in Review Articles Published Make Networks Dumb Again (Sep 11): AI is making old analog networks cheaper to use and flooding them with machine traffic in the process. A plea for agent-native rails with the intelligence at the endpoints, and for Washington to drag them to ubiquity. Interoperability, Unbuttoned (Sep 29): Interoperability is a series of workflows in a trenchcoat, and this post finally takes the trenchcoat off. A color-coded map shows which provider workflows went digital, which are fragmented, and which still run on fax. Video Content Antitrust’s System of Record Problem (Sep 3): The FTC’s investigation into Epic prompted a ninety-minute webinar, now posted with chapters and a smoothed transcript. We get into why market definition, missing B2B share data, and the SSNIP test leave antitrust poorly suited to systems of record, plus why information blocking may be doing more than any pending lawsuit. The Information Exchange: Cerner Milking Edition (Sep 18): This was so fucking fun. Ryan Tucker, Ryan Brickner, Brad Thorson, and I try an Around the Horn format, complete with points, penalties, and a mute button. We debate whether Oracle Health is dead, who would actually buy Cerner (IBM enters the chat), p(Doom), and why the front desk still hands you a clipboard. Regulatory Ask Not What Your Network Can Do (Sep 23): CDC’s RFI on public health data intermediaries lists use cases already served, unevenly, by eCR, lab reporting, IZ Gateway, and syndromic surveillance. The real opportunity sits in one question about AI: a network that can handle the next emergency without another interface project. Court cases Particle v. Epic: The Naughty Schoolteacher (Sep 4): After a summer-long vigil, the answer on Epic’s early summary judgment bid is two paragraphs and a remedial assignment. Particle advances to the next grade, and market definition gets another year of discovery. The Epic Discovery Files (Sep 8): Texas’s motions to compel arrive with a 251-page appendix of requests, objections, and meet-and-confer letters with Cravath. Inside: Epic using generative AI for document review, denied interoperability requests in scope, and Noerr-Pennington raised against lobbying discovery. Epic v. Health Gorilla: “Working as Designed” (Sep 9): Epic wants nothing to do with the data breach MDL, and explaining why puts fresh discovery on the public docket. The spiciest allegation: Health Gorilla told GuardDog to scrub its law firm business from its website instead of cutting off access. Veeva v. Epic: Legal Bypass Surgery (Sep 15): Veeva asks the Wisconsin Supreme Court to skip the Court of Appeals, while law professors and three policy groups line up as amici. Meanwhile, Epic’s lawyers apologize for another round of citation errors, including a quote that never existed. Texas v. Epic: Behind the Black Bars (Sep 17): The court portal served up Epic’s unredacted filings, revealing a $5 million document review budget and the AI workflow behind it. Also inside: the 200-plus company names Texas wants searched, and one very expensive Zoom invitation. OpenEvidence v. Doximity: Consequences Will Follow (Sep 25): OpenEvidence tells the court it will not comply with a discovery order, and its own lawyers at Quinn Emanuel say they won’t defend the choice. Add years of Slack reported unrecoverable, and Rule 37 sanctions come into view. Health Tech Keeps Choosing Violence (Sep 28): Doximity moves to end OpenEvidence’s case, Epic asks Texas to show its work, and a sleepy Audacious Inquiry patent fight sprouts antitrust and information blocking counterclaims. The main event is a long-sealed Cognizant v. Infosys ruling that hints where system of record antitrust claims can survive. EHRs One Verb for Oracle Health (Sep 14): Oracle’s earnings call quantifies every data center to the decimal point, while Oracle Health gets a single verb: “accelerate.” Panning the few healthcare mentions turns up an agentic care management system, a research-to-care ledger play, and the question of whether healthcare gets Larry’s patience. Epic’s Forretress Under Siege (Sep 30): Judy Faulkner tells a panel Epic paused hundreds of projects to harden its software and calls it a “shame,” while a spokesperson insists the roadmap hasn’t changed. Project Glasswing, a Pokémon-branded QAN sprint, and a trove of Jodel grievances reconcile the two Epics and preview the Jevons paradox coming for all software. Industry Analysis Scanning for a Network (Sep 1): Scan.com raises $220M to build the imaging network labs never got, speedrunning Zocdoc’s consumer-to-B2B pivot. Its wedge to network density may be the most American one available: personal injury litigation. The Front Desk Wants the Damn Whole Building (Sep 16): Hello Patient buys Converse Health, pushing its AI front desk into referrals, chart work, and prior auth. The copilot categories keep blurring, and your distribution partner is still your final boss. Cross-industry Comparisons A Different Patchwork Quilt (Sep 10): Healthcare loves to envy open banking, but the US version has no mandate, a toll booth at Chase, and data quality problems of its own. The grass isn’t greener; it’s another American patchwork quilt, and perhaps a worse one. Hail, Benihydra (Sep 21): Salesforce brings its platform into Claude, Slack, and its own agent, inviting the interfaces that might replace it. Cut off one head and more grow back, so long as the records underneath stay put. Living on A Trade Secret Prayer (Sep 22): Six credit unions are suing Fiserv, the Epic of core banking, by claiming their own member records as trade secrets. Banking has no Cures Act, so its lawyers reach for legal alchemy that healthcare has already tried. Other News None this month External Media Nabla Accelerate NYC: I kicked off fall conference season at Nabla’s Accelerate event in New York, where Delphine Groll opened by asking the room to picture the company it wants to become and the one it doesn’t. I liked her framework of bureaucracy, fear, and ego as the blockers. I also love vendor conferences/events in general - different vibe than industry biggies. Healthcare 101 with Nikhil Krishnan: I briefly guest lectured Out-Of-Pocket’s Healthcare 101 class. Appreciated Nikhil’s takeaways cover whether AI doctors can query HIEs, why healthcare’s data-liberation rules beat most industries’, and the hi-res graphic is in the comments. HCN: Epic Probed by the FTC: I joined the HCN guys to talk through the FTC’s investigation into Epic. Cedric’s new hairdo was an unexpected plot twist. The episode also covers MFN drug pricing, healthcare M&A and Eli Lilly’s acquisition streak. Fall Conferences: At eHealth Exchange’s Annual Meeting in Austin on Oct 27, I’ll moderate a panel on the tensions between AI, HIEs, and timely patient access with Jean Ross (Primary Record), Therasa Bell (Kno2), Byron Crowe (Doctronic), and Michael Marchant (Freenome). Here’s the rest of my schedule if you want to meet up: CommonWell (Redwood Shores, CA): Oct 13-14 Will be participating in a fun Jeopardy event Open@Epic (Madison, WI): Oct 20-23 Will be enjoying Verona, Willy Street, and other local adventures eHealth Exchange and Sequoia Project (Austin, TX): Oct 27-29 Yeehaw HLTH (Vegas): Nov 15-18 Groundhog Day, Venetian Edition RSNA (Chicago): Nov 30-Dec 2 See me at “Governing AI in Breast Imaging: What Health Systems Are Actually Doing” Digital Health Counsel 2026 AI Summit (Seattle): December 2-3 Will likely be speaking to a bunch of lawyers about information blocking Posts I Liked ChatGPT’s Epic integration: game changer or nothing burger?: Joshua Liu, MD offers five thoughts on OpenAI’s Epic launch, starting from the point that it rides the same open APIs available to anyone. He argues read-only access leaves ordering to Art and the ambient startups, and asks why HCA is piloting it alongside Commure. He’s sorta a must-follow at this point - consistently excellent, thought-provoking takes. Epic, Lilly, and the Discovery pass: Seth Chaney reads Epic’s first major Discovery deal (with Eli Lilly), as well as its revised developer terms on commercial displays, as the pipe finally opening between EHRs and pharma. Life sciences and health continue to collide. Scott Rossignol on EHR payer platforms and ePA fees: Scott argues the top ambulatory EHR vendors are turning the prior auth mandate into a per-member-per-year toll on payers, for an API whose operating cost has nothing to do with covered lives. His fix is two lines of regulatory text: put the CRD/DTR/PAS certification criteria in the Base EHR definition, and bring payer-facing ePA connectivity under § 170.404’s cost-based fee rules. It’s a good solution. Health API Guy is a reader-supported publication. To receive new posts and support my work, consider becoming a free or paid subscriber. Subscribe
Robots and AI find a hidden reaction inside 135-year-old chemistry
Chemical reactions are often written as simple equations: starting materials go in, and a product comes out. In reality, the samesubstrates can follow many different pathways depending on their concentrations, temperature, catalysts, and other conditions. Exploring all of these possibilities by hand is practically impossible. Now, advances in laboratory automation and chemical artificial intelligence are allowing researchers to systematically map this vast “reaction hyperspace”—and uncover chemistry that may have remained hidden even in reactions studied for more than a century. To address this question, scientists led by Prof. Bartosz A. GRZYBOWSKI, Director of the Center for Algorithmic and Robotized Synthesis within the Institute for Basic Science (IBS) used an automated robotic platform to explore 960 different sets of conditions for the Biginelli reaction, a classic multicomponent reaction first reported in 1891.
Mental Health Workers Say Algorithmic Triage Is Hurting Patients
Workers and policymakers are pushing for safeguards around AI’s use in health care through collective bargaining and legislation.
Mental health workers say algorithmic triage is hurting patients
Therapists, clinicians, academic experts and advocates say hasty integration of AI is eroding patients’ access to timely mental health care.
Cornish-Adebiyi v. Caesars Entertainment: The Third Circuit Deals Algorithmic-Pricing, Hub-and-Spoke Theory Another Hand
Antitrust scrutiny of information exchanges and algorithmic pricing tools has intensified recently—from public enforcers and private plaintiffs alike—as companies across industries increasingly...
The Science Behind the AI Panic Is Shakier Than You Think
A column by Sascha Lobo Is AI making us dumb? So asked DER SPIEGEL on its cover a while ago. After a few weeks of recovery and a therapeutic intervention with the help of my AI, I feel able to respond. That’s a bit unfair, of course; the article itself is more nuanced than the loud cover, the image of a schoolkid with dull prompt questions, or the subtitle: “AI is conquering the schools, and educators fear a disaster.” The short answer to “Is AI making us dumb?” is: no. The long answer is more interesting, and even carries a preliminary glimmer of the spectacular. Unfortunately, it requires a detour into the sphere of artificial intelligence, into the mogul-field terrain of technology assessment, the attention economy, and the destructive virus of cultural pessimism. Along with narrowing the scope to AI’s effects on education and work rather than on intelligence. Because the honest version of the question would be: Does AI help us learn and work, or not? Generative AI, which set off the still-ongoing hype with ChatGPT, has only existed in relevant distribution since late 2022, early 2023. For a technology-driven transformation of people and society, that is extremely short. For that reason alone, research is still in its infancy. And technology assessment is not a fast discipline anyway. Prominent voices from Elizabeth Eisenstein to RAND to Tom Wheeler say we still cannot conclusively judge the consequences of the printing press. Its invention is a mere 580 years back, and some scholars would rather not circulate assessments that might have to be retracted in two or three hundred years. We’re Going Through Growing Pains A phenomenon that already caused upheaval in social media research makes serious assessment of AI’s consequences even harder: the “moving target” problem of LLM-ology, as the linguist Sean Trott called it in 2025. AI develops so quickly and so unpredictably that researchers often end up studying snapshots of the past. There are concepts, from morphological analysis to anticipatory governance, for keeping research, planning, and regulation halfway meaningful anyway. But even with those, universally valid statements are rare. DER SPIEGEL - The German View is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber. Subscribe We should therefore treat findings about the interplay between humans and AI as far more procedural and situational. Unfortunately, this challenge comes at the worst possible time. We are going through growing pains: AI’s everyday impact has grown very large very fast, and with it the longing for guidance. Annoyingly, the body of solid knowledge has not exploded along with it. Experts cannot be moved to broad consensus on even banal statements about AI. Sascha Lobo, born in 1975, is an author and strategy consultant focusing on the internet and digital technologies. Together with Jule Lobo, he explores the debates of the day in the podcast “Feel the News – Was Deutschland bewegt” (”What Moves Germany”). Nvidia CEO Jensen Huang says software developers are dying out. Bill Gates considers coders one of only three professions that will survive the AI tsunami. Top tech economists find virtually irrefutable arguments both for and against an AI bubble. The same naturally applies to the structurally youth-hostile debate over whether AI is good or bad for young people. The gap between the demand for insight and the supply of solid knowledge creates an orientation vacuum. This vacuum of AI cluelessness is filled, as the attention economy described by Georg Franck in 1998 would have it, with half-knowledge (funnily enough, often AI-generated), marketing, and self-marketing. After all, infinite money is at stake, along with academia’s best current shot at global fame. But this iridescent froth of interpretation operates more by the algorithmic principles of the digital public sphere than by seriously earned insight. That is why dramatized, fear-feeding claims about AI are so promising. It tempts parts of academia into distorted drivel, and parts of the media then sensationalize the published drivel once more. Was the Research Aimed at a Desired Result? How badly this can influence academia and public perception is demonstrated by one of the most-discussed studies on AI’s effects: “Your Brain on ChatGPT.” The MIT study by Nataliya Kosmyna also gets plenty of space in the SPIEGEL cover story. What was measured and interpreted: lower brain activity in people who write with AI assistance, compared to people who only google or write without any tools. As is common with preprints, the study has not yet been peer-reviewed, and it contains substantial weaknesses that experts have sharply criticized. The first round had 54 participants in three groups, the second only 18, who reportedly also came from MIT’s own orbit. There was no preregistration (committing in advance to what you want to find out with which data). In their analysis, Stanković et al. even discovered an opposite effect that the study does not further explain. Some measurement data has not (yet) been published. And the EEG analysis method used is considered too imprecise to support such far-reaching conclusions. The biggest criticism, though, is the suspicion of an activism-driven study. In an interview with Time, lead author Kosmyna said she published the study immediately, rather than after full peer review, because she feared politicians might otherwise decide to put ChatGPT in kindergartens. She considers that absolutely harmful. It is legitimate to hold such a view. It just seems unscientific to approach a study with it, and then to design the setup so that the chance of a fitting desired result remains as high as possible. Ideologies Collide It is not easy to separate genuine AI insights from studies that trivialize and weaken well-founded AI criticism. The same goes for the opposing, AI-enthusiastic narratives, because the pro-AI side works against it with billions in resources. Ideologies collide, fed by egos, PR strategies, moral posturing, and once-in-a-lifetime opportunities. Doomsday marketing makes the search even harder: AI companies can profit from warnings about the dangers of AI, whether through the notoriety of apocalypse narratives or because, in some target groups, danger translates into power. Some seemingly negative findings are therefore quite welcome in the AI industry. If you try to get at the findings presumably less influenced by interest groups, the picture in education seems relatively clear: AI can improve educational outcomes when the right AI is used the right way, namely pedagogically. Simply dumping an AI chatbot into a classroom, by contrast, accomplishes little. Huge surprise. But something else is also obvious: whether they are allowed to or not, kids use AI for school, which is why the controlled integration of AI tools into education is, in the medium term, entirely without alternative. In the world of work, the landscape of findings is more complex and requires more differentiation. A series of serious studies points to an AI effect that suits neither the alarmists, regulation fetishists, and AI opponents, nor the trillion-dollar corporations with their armada of paid scientists, PR professionals, and ecosystems: working with AI helps the inexperienced (at least for now) considerably more than it helps the pros, in certain fields of work, and provided they know how to use it correctly. Missing Domain Knowledge Among the experienced, the professionals, and the high flyers, by contrast, despite frequent time savings, partially negative effects and new problems are emerging. Take the jagged frontier problem: AI solves task A brilliantly and fails completely at task B, even though both look similar even to professionals. Or the verification-cost problem, in which AI’s greater productivity gets eaten up by the enormous effort of checking its output. Or the illusion of competence, because AI makes new domains seem easily penetrable, until you painfully discover that deep domain knowledge is missing. Taken as a whole, the effects of working with AI do lean positive. But the promise that AI works as a turbocharger for everyone and boosts practically everything simply refuses to materialize. The AI magic the world has been feeling since ChatGPT arrived in late 2022 has so far barely shown up in most companies’ numbers. The consulting firm McKinsey has coined a term for this, the “gen AI paradox,” and believes that work processes and corporate structures would have to be rebuilt quite fundamentally to realize AI’s benefits at scale. Reuters just reported that only 3.3 percent of Microsoft’s customers have subscribed to the AI package Copilot. That may be down to the product; in other areas we continue to see soaring successes and new AI triumphs. But after the first quarter of 2026, disillusionment is the word for all too many AI projects at traditional companies: because the promised revolution of AI agents has so far failed to arrive or been postponed, and because of the leveling effect that many of the studies cited here suggest. Against Inequality The societal effects, on the other hand, appear rather encouraging. Many previous technologies operated on the Matthew principle, named for the Gospel verse about giving to those who already have: they tended to reward the more competent and more privileged. AI, however, seems more often to have an equalizing effect once a threshold of access and education is crossed. Some anecdotal insights point in this direction, for example, how an unemployed man in Leipzig successfully defended himself in court in 2025 against fraud accusations from Germany’s federal employment agency — without a lawyer, armed only with ChatGPT. The AI made mistakes and cited invented court rulings, but in the end the man walked away unpunished. And a key capability of artificial intelligence is its capacity to learn: set up correctly and fed with data, it can keep getting better. It is a question of time, or more precisely of AI innovations and training data, until even free AI chatbots write better legal briefs than law graduates with perfect exam scores. Whether that will make anyone dumb is something the world’s press will surely inform us of in due time. Subscribe Leave a comment
New York finalizes social media restrictions for kids
The regulations, which take effect in January, limit the use of algorithmic feeds and nighttime notifications.
Case-led working group proposes gerrymandering solutions
The proposal advocates the use of independent commissions, national standards and algorithmic mapping to prevent partisan interference
Long Reads for the Long Weekend
(Welcome to the Entertainment Strategy Guy, a newsletter on the entertainment industry and business strategy. I write a weekly Streaming Ratings Report and a bi-weekly strategy column, along with occasional deep dives into other topics, like today’s article. Please subscribe.) Happy Fourth of July weekend! As has been a tradition of mine going back to the beginning of the EntStrategyGuy website, I’m sharing my favorite long reads of the last year, like I did in 2019, 2020, 2021, 2024, and 2025. Let’s dive right in! Subscribe “Different Prices for the Same Ride: How Uber and Lyft Use AI to Get More Money Out of You“ by Derek Kravitz in Consumer Reports I don’t think surveillance pricing, like the kind described in this brilliant Consumer Reports article, is long for the world—it’s toxically unpopular—but we’ll see if either party takes on this issue. If I ran a political party focused on affordability, I would focus on a few pro-consumer and pro-market policies: Banning non-compete agreements. Ending surveillance pricing Eliminating junk fees (read more here...) Ensuring “right to repair” for consumer (and military!) products Capping excessive app store fees Stopping digital/algorithmic price-fixing tools. Preventing automatic subscription price increases. And more. If you want to fight inflation, there are a lot of great ways to do it quickly. Speaking of higher prices... “Secret Documents Show Pepsi and Walmart Colluded to Raise Food Prices Across the Economy“ by Matt Stoller in BIG Again, I think a political party should focus on lowering prices for consumers. And deals like this—Walmart making a deal/forcing Pepsi to offer the lowest prices at its stores and nowhere else—hypothetically lower prices at Walmart...but raise them everywhere else. “15 DUIs, still driving: California’s failure to take repeat drunk drivers off the road“ by Robert Lewis and Lauren Hepler in CalMatters CalMatters does terrific reporting in California, something the Golden State desperately needs more of, and this article is a great example of that. “PugLips: The next insanely popular thing you’ve never heard of…” by Simon Carless in Game Discover Co I thought that this parody article (and yes, it’s a parody, but I was definitely unsure at first) was hilarious and totally nailed how much tech/business journalism feels these days. Actually, three of my favorite articles this year were on hype in the video game industry, including Georg Zoller’s “The Video Game Industries Very Dark Night”—which I linked to recently and wrote a follow-up here—and Owen Mahoney’s “Derek Zoolander, Videogame Exec”. In particular, I like Mahoney’s focus on user experience as a guide to what trends will actually grab hold of customers. “The Matrix Lies“ by Evan Shapiro in Media War & Peace Evan Shapiro’s first person account of his experience with AI was hilarious. I think LLMs capabilities have significantly grown from last summer, and yet...my editor/researcher just had an abysmal experience using an LLM to do a quite basic task (which our LLM normally does each week) and the LLM made a mistake on every single data entry...along with seven different mistakes affecting twelve of the twenty or so entries, including mistakes that are explicitly spelled out in the prompt. That’s a brutal failure rate. Again, if you use AI/LLM for data collection, you need to take a lot of extra steps to verify and check the data. “Ghosts in the Balcony: A Cross-Country Trip to 58 Theaters Fighting to Survive“ by Matthew Frank in The Ankler I thought Matthew Frank’s pitch to head across America to visit theaters sounded insane aggressive at the time—at least it felt that way to someone a decade older than him; man, to be in your twenties again, am I right?—but I knew the result would be great. And it was, a terrific feature by a great young writer. Also, I loved Matthew’s recent article on who’s getting the precious few entry level jobs in Hollywood. (Hint: nepotism.) “Disney erased FiveThirtyEight“ and “Did Las Vegas get too greedy?” by Nate Silver in Silver Bulletin I love media history and analysis, and there’s no one better to get the history of FiveThirtyEight than from Nate Silver, who wrote about his personal experience in one of my favorite pieces from this year. I also loved Nate’s breakdown of what’s causing Vegas’ woes, but I’ll offer one criticism, summarized as “Might I suggest antitrust?” Many centrists/center-right/libertarian thinkers (Nate is self-described as the latter) often don’t consider consolidation or antitrust as factors in policy issues like housing, America’s military readiness, or, in this case, Las Vegas. Even if libertarians want to debunk antitrust/consolidation concerns, I’d love to read that debunking. In this case, Vegas is incredibly consolidated (though it also has been for a long time) and I’d have loved to read Nate at least contending with this factor, since he addresses almost every other potential factor for Vegas’ decline. “Why Microsoft’s Carbon Removal Pullback Is Such a Big Deal“ by Robinson Meyer in Heatmap News I’m a big supporter of carbon removal efforts, but this nascent industry faces a lot of headwinds, including this big move most recently. I think it’s clear that solar panels and batteries should be able to get the world to its carbon footprint goals, but effective carbon renewal remains necessary to prevent the worst impacts of global warming. “AI is killing the cheap smartphone“ by David Oks LLMs and AI will impact the world in ways we’re not ready for, and already, third world countries are seeing the prices of cheap cellphones skyrocket due to the cost of chips skyrocketing. This article by David Oks is a terrific breakdown. “100 Days of Madness: Netflix, Paramount, Warner and the Future of Hollywood“ by Wade Major at Hollywood Heretic Wade Major dove deep into Hollywood/streaming’s financials in this must read piece. Not that I agree with everything in this article (read my take on Warner Bros./Paramount here) but the analysis is top notch. I think many people discount how quality thinking, regardless of the argument/conclusion, will make you a better thinker. “Erased by the UFC: Frank Shamrock, The MMA GOAT of the 20th Century“ by Nate Wilcox in The MMA Draw Newsletter Growing up playing the UFC fighting game on the Dreamcast, Frank Shamrock was my favorite MMA fighter, and this history/tribute to him was great. Other Fun Reads “The Hardest Part Of History To Tell Is How It Felt“ by Craig Fehrman at Defector “Unmasking the Sea Star Killer“ by Craig Welch at bioGraphic “What Could Save the Industry? Fin-Syn“ by Richard Rushfield in The Ankler Alex Rollins Berg in Underexposed on movie bumpers, pillow shots, Disney trash cinema, cult films, and Casablanca. David H. Montgomery in YouGov’s The Surveyor on punctuation marks, condiments, dinosaurs, and comic strips and kids media. “How Medium finally pivoted its way to profitability“ and “Why the best journalists on YouTube are all former Vox employees“ by Simon Owens in Simon Owens’s Media Newsletter “It’s Not Just You, Netflix Shows Have Gotten Slightly Shorter: Here’s What the Data Says“ by Kasey Moore at What’s on Netflix “Numlock Awards: How Diane Warren became the biggest loser in Oscar history“ by Nathaniel Rakich and “Numlock Awards: The Oscar Bait era is over. The Oscar Chum era is here.” by Walt Hickey & Michael Domanico at Numlock Awards
We’re still writing p3ri0d
What algorithmic suppression of women’s health content is actually costing us.
Making Our Own Luck
We are cross-posting a piece that former NIH official Kris Willis wrote for Macroscience. Kris is now the President and Founder of the Woodley Park Institute, for which I’m a board member. Picking winners or hedging bets? Federal science agencies have long wrestled with the question of how to ensure their billions of dollars of grants and contracts result in maximum benefits for Americans. On the surface, it might seem that a goal-oriented, interventionist style of management would be the best policy: prioritize our most pressing problems and distribute funding accordingly.This top-down strategy creates a unique hazard, though: bad choices can send resources in the wrong direction, resulting in slow progress that impedes the delivery of tangible benefits to citizens. Moreover, if decision makers pursue an applied advance when the underlying scientific principles remain poorly understood, they risk costly failures and a loss of support for the research enterprise at large. Examples include Nixon’s 1971 War on Cancer, undertaken on the premise that a cure could be achieved in less than a decade, the drive to build an operational commercial fusion plant by the mid-1990s, and the National Plan to Address Alzheimer’s Disease, which failed to produce the effective treatments and prevention strategies promised by 2025. The contrasting laissez-faire approach is to hedge your bets. If the path to an advance is impossible to predict, then the wisest choice might be to distribute funding to as widely as possible. The main risk of this strategy is that spreading funding thinly may limit the resources available to the most promising research, resulting in the same negative outcomes as the interventionist approach: limited support for the most promising topics, slow progress, and delayed returns. In reality, at science agencies like the National Science Foundation and National Institutes of Health, program managers navigate between these two extremes, setting some funds aside to target high-priority areas and using the rest to cover the widest possible range of meritorious proposals. This middle path seems like the most rational way to proceed, but it still requires making choices. How much should be set aside for high priority topics? What should those topics be? How should we define merit? Expert opinion can provide a helpful guide, but leading experts can have remarkably different opinions about what matters and what should be prioritized. Moreover, experts and administrators alike can be risk averse, giving an edge to high-profile, well-established concepts. What’s really needed is a data-driven framework to help guide decision-making, one that doesn’t simply repackage prestige or incumbency. Recognizing breakthroughs years in advance Many breakthroughs fail to attract funding or recognition at the earliest stages of development. Katalin Karikó, for example, spent years struggling to win grants for work on mRNA that would eventually win her and Drew Weissman a Nobel Prize. Similar stories can be told about Jim Allison’s groundbreaking studies leading to the development of cancer immunotherapy, Stan Pruisner’s demonstration that prions can self-replicate without DNA, or Robin Warren and Barry Marshall’s proof that Helicobacter pylori, not stress, causes ulcers. Yet at some point, the scientific community recognizes and responds to transformative breakthroughs like these. How does that change happen? And what if science funders could identify the areas that are on the cusp of a breakthrough? Those questions led my collaborators and me to study how scientists responded to past breakthroughs. Based on patterns in that data, we developed a means of predicting future breakthroughs, using biomedicine as a proof of concept. It’s worth taking a moment to describe how our approach works. Briefly, our prediction process begins by grouping the 18 million or so peer-reviewed papers in PubMed, the authoritative database of biomedical research, into roughly 50,000 unique topics. A small subset of these topics are so widely acclaimed as breakthroughs that they have been recognized with a major prize like a Nobel or a Lasker Award. We theorized that studying the development of these outliers over time, especially before they gained acclaim, was the key to identifying future instances of them. After defining topics, we chose 21 representative breakthroughs and asked what they looked like before they won prestigious prizes. To answer that question, we re-ran our topic-mapping algorithm repeatedly, winding back the clock one year each time, stringing together the years to follow the progress of each field as it grew and advanced. We found that in each case, the years leading up to a discovery followed a pattern: a burst of papers on a new, rapidly evolving topic, many of which quickly became influential. These characteristics—the percent of papers that are new, the percentage of papers that are brought in from other topics, and the influence of each individual paper—can all be measured separately for any given topic. Together, they act as a predictive signal that is detectable an average of five years before a transformative discovery is made, and up to thirty years before the discovery receives a major prize. Scanning the current research landscape for topics that display this signal allows us to predict what work will likely produce a future breakthrough. Each year we analyzed includes four or five signals, a number that appears to have remained constant across a twenty year time frame. In their classic work on the sociology of science, Bruno Latour and Steve Woolgar established that the desire to participate in a major discovery is an important motivator for scientists as they consider whether they should take up (or abandon) a research problem. Although further work is needed, the simplest explanation for our results is that this behavior is widespread enough to detect at scale. A foundational advance, or something like it, draws the attention of scientists and causes them to change the direction of their research. They vote with their feet, staking their own reputation and careers by publishing on and citing the new idea. That upswell of interest is the foundation of our breakthrough signal. What kind of research does our model identify as a breakthrough? After building a model based on the patterns in our 21 preselected breakthroughs, we tested it by identifying all early signals of discovery from 1994 through 1997. Of the 18 signals we found in that time period, 17 can be traced forward in time to a breakthrough. Examples include super-resolution fluorescence microscopy (see the image above), the directed evolution of proteins and enzymes (Chemistry Nobel, 2018), and sequencing the human genome (National Medal of Science, 2008). The discovery of the role of leptin signaling in obesity is a particularly interesting case study. Around 1950, scientists noticed the existence of a type of lab mouse that suffered from a unique inherited form of obesity. When given the freedom to choose their own diet, these mice ate more than normal and preferred food that was high in fat. Researchers had few clues as to why the animals overate; early experiments pointed to the existence of a soluble ob factor found circulating in the bloodstream that regulated appetite, but its identity was unknown. In 1994, Jeffrey Friedman and colleagues identified and sequenced the ob gene, noting that the protein it encoded appeared to fit the profile of a circulating factor. A year later, a trio of high-profile publications demonstrated that ob was a hormone that regulated body weight and fat deposition by regulating appetite. One of these was co-authored by Friedman, who christened it leptin from the ancient Greek word for thin. Using our model, the data from 1996 make it clear this advance would become a breakthrough. Scientists had flocked to study the biology of the new hormone, generating the flurry of new papers and citations required to produce a signal. One of these demonstrated that serum leptin concentrations reflected the amount of adipose tissue in the human body, providing clinical validation of the earlier mouse studies. Before the identification of leptin, scientists were unable to point to a specific molecule that controlled appetite and adiposity, so that it was impossible to rule out non-physiological causes of obesity; its characterization fundamentally changed our concept of weight gain. In 2010, Friedman and fellow pioneer Douglas Coleman were awarded a Lasker for the discovery. Our work also identifies breakthroughs in clinical practice and behavioral and social sciences, even though these areas are less likely to draw the attention of major prize committees. One example that falls into this category is the introduction of endovascular aneurysm repair, a minimally invasive surgical procedure for the treatment of abdominal aortic aneurysm, a leading cause of death among Americans over the age of 65. Relative to the previous standard of care, it reduces in-hospital mortality by almost four-fold. In 2017, Timothy Chuter received the American College of Surgeons’ prestigious Jacobsen Innovation award for his multiple refinements to the technique. Another under-recognized breakthrough identified by our model is the development of standardized survey instruments to assess the quality of life for HIV+ patients. The antiretroviral cocktails introduced in the mid-1990s reduced AIDS mortality, but treatment came with serious side effects. The new evaluations showed that patients whose disease progressed had worse physical functioning than Americans with other chronic diseases, while those who were asymptomatic maintained a health-related quality of life on par with the overall US population. This evidence made it possible for patients and activists to argue that even in the absence of a total cure, and in spite of the side effects, alleviation of symptoms was a worthwhile priority for clinicians. My colleagues and I have failed to identify any significant recognition for the physicians and health policy experts who pioneered this advance, although in 2016, researchers called for the World Health Organization to set targets for good health-related quality of life as part of its framework to end the AIDS pandemic. From forecasting to funding How should science funders use our predictions? Any serious discussion of what we should do with this new capability needs to begin with an understanding of its limitations. We can’t (and shouldn’t) invest all of our resources in the small number of topics predicted to produce breakthroughs. Innovative new fields are born from existing ones; they rarely arise de novo. If funders don’t maintain a diverse portfolio, the breakthroughs of tomorrow will have no antecedents. Think of this as eating the seed corn, or killing the goose that lays the golden egg. There are also multiple goals of funding beyond basic scientific discovery, including translating discoveries into clinical practice, developing new technologies, supporting economic development, and training new scientists. The investments needed to accomplish these goals are likely different from those required to support emerging breakthroughs. Finally, we must be aware that we may not capture every instance of a breakthrough. The concept is fuzzy, and not every significant discovery is recognized with a major award. Further, breakthroughs are rare, meaning that our dataset is, by necessity, small. This makes formal estimates of accuracy challenging. Although our overall success rate appears to be high, any one signal may turn out to be a false positive. We found one apparent example: the development of the third generation COX-2 inhibitors, Vioxx and Celebrex, which were much celebrated in the early 2000s as effective but non-addictive pain relievers, meets all the algorithmic criteria of a breakthrough. Five years after it received FDA approval, researchers demonstrated that Vioxx was associated with serious cardiovascular complications, and the manufacturer voluntarily pulled the drug from the market. Celebrex remains available, although like other NSAIDs, it carries an FDA warning for increased cardiovascular risk. Decision makers who were overly focused on the breakthrough potential of this research might have wasted substantial resources nurturing an area that ultimately proved to be a failure—but so would those who relied on expert opinion at the time. That said, the potential benefits of funding the next mRNA vaccine or cancer immunotherapy years earlier than we might have are large. When we can’t assume the outcome of an action, it’s worth conducting an experiment. Can targeted support for areas that are poised to produce a breakthrough increase the return on scientific investment without cannibalizing future advances? With the necessary administrative infrastructure in place, conducting this experiment would be straightforward. First, identify all the breakthrough signals between 2018 and 2023, select half at random, and commit to a decade of investment. For biomedicine, a six year window should yield about 30 topics with the potential to produce a breakthrough. Providing strong support to half of these might be accomplished for $300 million a year. That’s roughly half of the recent annual budget of the NIH Common Fund or around 20% of the fiscal year 2025 budget for ARPA-H. After five years, then again at ten, compare to see which group — the one that was actively managed, or the control — produced more breakthroughs, and on what timescale. Although we used biomedicine as an example, the same experiment could just as well be run for physics, materials science, or any other discipline. Any attempt to undertake such an experiment should keep three points top of mind. First, we can predict the topic of future breakthroughs, but the people and vision for how to move the work forward are still important. In practice, this means success requires active program managers with the expertise to develop the science and the authority to do so, including by recruiting investigators. Second, we would be wise to learn from the failures of past attempts to fund transformative research. High among these are funding modestly repackaged work, confusing the genuinely novel with the merely unfamiliar, and relying too much on incumbent investigators. All of these risks can be mitigated by thoroughly and intelligently integrating high quality data into portfolio management. Finally, we need to have patience. Even with strong funding support, producing a breakthrough takes time. If supporting breakthroughs is the best way to nurture the birth of new fields, we also need to accurately describe and properly manage the other two stages, so that we invest wisely throughout the productive lifetime of ideas and divest once they reach the point of diminishing returns. We would benefit from more study of all of these phases, especially the transition from one to another. More research could answer questions like: When does a breakthrough become an established field? How do the availability of funding, the size and characteristics of the available workforce, and the accumulation of evidence that disagrees with prevailing models affect a field’s decline? Exactly how do old ideas give birth to new ones, and can we speed up the process? The more we understand about the dynamics of scientific progress, the better we can maximize the odds that our curiosity leads to results. I’d call that finding a way to make our own luck.
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Bari Weiss: Think For Yourself, Not By Yourself
When we launched The Free Press, the plan was simple: Tell the truth plainly, and let readers come to their own conclusions. I thought there would be a sizable enough group of people who would pay the cost of one coffee a month to read high-quality news and opinion journalism. But what happened next surprised even me. Yes, you came for the stories—for the investigations, essays, debates, interviews, podcasts, and arguments. But over the past few years, you also found one another. I’ve watched strangers become friends in the lobby before our debates. I’ve seen people trade numbers after live recordings of Honestly, launch businesses after Free Press dinners, fall in love after our meetups—even get married (!?), and say some version of the same sentence over and over again: I thought I was the only one. We live in the most connected age in history, and yet, millions of people feel isolated, alienated, politically homeless, and starved for real conversation. We have followers and no neighbors. Algorithms instead of interlocutors. Our social media feeds are like troughs, but what we really need is a table to gather around. The Free Press is a publication, yes, but it is also a gathering place for independent minds. So today, I’m thrilled to share our new investment in you. We are launching a new world of community experiences for our paid subscribers, designed to bring _Free Press_ers together online and in real life. Introducing Our Community Launch The Free Press Forum Our new digital home for paid subscribers, the Forum, is now live. This is where _Free Press_ers can meet, debate, recommend, organize, joke, argue, and converse like civilized people. Imagine that. This is not social media as you know it. No bots. No algorithmic rage bait. No performative nonsense. Just smart people talking to one another. Inside the Forum, you’ll find conversations on the things our readers already care about most: the issues of the day, recommendations (books, music, travel), work and networking, parenting, dating, and where to find your people—online and in real life. Jump in! Introduce yourself and join the first conversations in the Free Press Forum here. You’ll also find announcements from us (paid subscribers are first to hear!) and our writers, hosting regular Ask Me Anythings (AMAs)—live conversations where subscribers can ask questions, push back, and continue the discussion beyond the page. This Thursday, subscribers can chat with our brilliant reporter, culture vulture, and co-founder Suzy Weiss. Friday, I’ll be lending you Nellie Bowles, queen of TGIF, to answer subscriber questions live. Read more about The Forum directly from Nellie here. The Free Press Supper Club The best part of being a _Free Press_er is meeting other _Free Press_ers. So we’re inviting you all to dinner to do just that. It’s part salon, part blind date, part old-fashioned dinner party. Here’s how it works: You answer a short questionnaire. We match you with a small group of _Free Press_ers in your city. We send you to a great restaurant. You show up for supper. The rest is up to you. Your next best friend, co-founder, or future spouse may already be waiting at the table. Learn more and sign up here for our first Supper Club in 12 cities in three countries taking place on June 18. Don’t see your city? Raise your hand if you’d like a Free Press Supper Club near you. Yes, St. Louis—we hear you. The Free Press Retreats and Excursions We’re also building something new for 2027: immersive experiences for Free Press readers who want to continue the conversation trailside, poolside, or around a fire long after dessert. The Free Press Retreat will be an intimate long weekend built around big ideas, outdoor adventure, great meals, and the kinds of discussions that happen when curious people spend meaningful time together. Bring your spouse, your parents, your children—or come on your own. Free Press Excursions will take us farther afield: curated trips with Free Press writers and contributors exploring places that help explain the world we live in, from the battlefields of Gettysburg and Normandy to the Vatican in Rome. We’ll share more details this summer. If you’d like an early look when these experiences open for registration, show your interest here.**A Note to Our Subscribers** These new offerings exist because of our paying subscribers. If you’re already one: Thank you. You built this. And you keep us going. If you’ve been reading us for free and wondering whether to join, this is a very good time. For a short while only, we’re offering a rare 20 percent discount for you to join our community as a paid subscriber. You’ll unlock everything we publish, plus exclusive access to our members-only Forum, Supper Clubs, and more insider perks. Thinking for yourself shouldn’t mean thinking by yourself. See you there. —Bari
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Your Thymus and Your Healthspan
Our thymus gland plays a central role in the development or our immune system, specifically for supporting T cell development (how these cells got their name, maturation and differentiation in the thymus) and discriminating between self and foreign, non-self antigen proteins with production of dendritic cells. As we age, our thymus gland shrinks—the process known as involution—with progressive change from spongy to fatty tissue, with loss of functionality. But this process, with respect to timeline and extent, markedly varies from one person to the next. And to make things even more complicated, our thymus gland anatomy and precise location in the chest also is highly variable. So the famous Frank Netter diagrams from the 1960s (such as at left below) don’t capture the remarkable heterogeneity that a random set of 12 chest CT scans (below at right). What I consider as 2 landmark papers in Nature this week (here and here) used AI to quantify health of the thymus in 2 large cohorts, and then correlate the metric to a broad array of health outcomes. In this edition of Ground Truths, I’m going to cover three questions: (1) How was thymus health determined by AI?; (2) How is thymus health linked to key clinical outcomes? and (3) Are there ways we can promote a healthy (aka rejuvenate) thymus gland in our later years? Subscribe 1. How was thymus health determined by AI? This was accomplished by extensive work developing and validating an AI pipeline for 2 stages, the first for localization and segmentation of the thymus bed, and the second to quantify a digital marker, termed the thymic health score. There’s a lot to this algorithmic development, so I won’t go into all the details, but just provide a rudimentary outline of what was done. The 1st stage used supervised learning with 2 radiologists reviewing 2,461 chest CT scans. That work trained a 3D U-Net model to automatically identify the thymic bed’s 3D cropped region using center of mass coordinates, which reached 99.8% accuracy. The 2nd stage used a foundation model that was pre-trained with SwAV (which stands for Swapping Assignment between multiple Views), a self-supervised model, that generated a high-dimensional thymus representation of 4,096 features. That compares to the radiology reductionist and subjective scoring of 0 to 3 where 0 means the thymus is fully degenerated and fatty, and 3 is considered dense, intact glandular soft tissue. Notably, the self-supervised learning (SSL) performance was superior to supervised (AUC ~0.75 vs 0.55, respectively) reflecting the shallowness of the 0-3 classifier vs SSL’s holistic, self-taught AI. The thymic health score ranged from 0 to 100, with the highest number indexed to fully preserved thymic health. The algorithmic work extended to explainability with both Shapely value distribution, meaning the model was holistic not relying on any “magic” pixel, and occlusion sensitivity, demonstrating the model’s performance was not affected by ribs, sternum, lung tissue, but rather focused on the thymic bed directly. Below are a few saliency maps from the occlusion sensitivity that indicate the thymic bed focus, not affected by neighboring structures, using the jet color scale. Now the AI was ready for processing ~25,000 CT scans, each over 30 MB files, from the 2 large participant cohorts to provide a thymic health score, it did so in less than 14 hours, which is less than 2 seconds per scan! Share 2. How is thymus health linked to key clinical outcomes? The two cohorts were the National Lung Screening Trial, NLST (N=25,031) and the Framingham Heart Study, FHS (N=2,581) each with baseline demographics and long term follow up of >12 years for health outcomes. From the NSLT, you can see below that increased age and body-mass index were correlated to reduced thymic health. And, overall, men had reduced thymic health scores compared with women. There are a lot of graphs in the paper for outcomes, for both the NLST and FHS cohorts. To simplify the major outcomes, below is a composite Figure with striking reduction of all-cause mortality and for the different causes of death. The results were consistent between the 2 cohorts. For example, the cardiovascular mortality hazard ratio average was 0.57 in NLST and 0.38 in FHS (weighted to be 0.53 for the aggregate). The reduction of mortality also extended to digestive diseases and pulmonary disease (data not shown below). Lung cancer incidence was reduced by 36% for high vs low thymic health (Figure below, with a panel -incidence and b panel-mortality, adjusted for age, sex, BMI, smoking status). Notably, there was a smoker’s paradox: lower incidence and improved survival for lung cancer in smokers who had a high thymus health score. Smoking was associated with lower thymic scores whereas alcohol was not. Higher thymic health was linked to higher HDL cholesterol, lower triglycerides, lower fasting blood glucose, and lower systolic and diastolic blood pressure. Inflammation biomarkers, such as C-reactive protein and interleukin-6, were elevated in the people with lower thymic health scores. In their second paper, the same team looked at the relationship between thymic score and outcomes for 3,476 patients receiving cancer immunotherapy. The non-small cell lung cancer progression-free survival was reduced in patients with low thymic health score. A parallel relationship for survival was seen for other types of cancer including melanoma, breast, and kidney with a 44% lower risk among high thymic scores (Figure). A similar pattern was seen with different immune checkpoint inhibitors. The thymus health score outperformed programmed death ligand-1 (PD-L1)and tumor mutation burden (TMB) assay of the tumor and was an independent prognostic marker of progression-free survival. In this dataset, a direct connect with thymus score and adaptive immune function was noted with a correlation before cancer treatment for both T-cell diversity and thymus T-cell production (a metric known as T cell receptor excision circles). Thymus Removal Study There is a highly relevant citation about thymus function before moving onto ways to rejuvenate it. In 2023, a very important study of thymus removal during cardiothoracic surgery was published, with 1146 patients undergoing thymus removal vs 1146 matched controls (mean age 55 years). The adverse outcomes for thymus removal were striking, with a 2.9 higher risk of all-cause mortality and doubling of cancer incidence, 1.5 fold increase in cancer mortality, and 1.5-fold increase in autoimmune diseases. The immune function showed marked compromise after thymus removal, as reflected by CD4+ and CD8+ T cells (Figure below) Share Ground Truths 3. Are there ways we can promote a healthy (aka rejuvenate) thymus gland in our later years? In recent months we’ve learned a lot about the process of thymus involution and the pathways by which this may be modulated. Thymus involution is primarily due to loss to thymus epithelial cells (TECs) and there are 2 subtypes with different functions: the cortical, responsible for positive selection of T cells, and the medullary, for negative selection. When adipose tissue infiltrates the thymus, thymic adipocytes are pro-inflammatory, knocking out T-cell output. Likewise, systemic inflammation, or “inflammaging,” from smoking, obesity, and chronic stress promote thymic adipocytes. Now, from preclinical studies, we know about key pathways that account for these processes. Historically, back in 2014, FOXN1 was recognized as a single master transcription factor essential for TEC function, with studies in mice with forced FOXN1 upregulation leading to thymus regeneration. That laid the foundation for potential regrowth of quiescent thymus cells. It took awhile to find pathways to accomplish this goal and to even refute its role as the master regulator. The Liver-Thymus Axis Feng Zhang and his team recently showed that injection of an mRNA vaccine to the liver encoding DLL1, IL-7 and FLT3-L in combination, factors known to support thymopoiesis (Figure), successfully enhanced immune function in aged mice. However, the effect was transient. The FGF21 Story Two reports in 2025 addressed the thymus gland’s production of FGF21, a growth factor (fibroblast growth factor 21) and its control of thymus involution. This growth factor is also produced by the liver, but it doesn’t have impact on the thymus in aged rodent models. In contrast, The liver’s hepatocyte growth factor (HGF) has been shown to reverse senescent TEC structural changes. Growth hormone stimulates production of insulin growth factor-1 (IGF-1) in the liver and the thymus. Two small studies in human participants (TRIIM, for Thymus Regeneration, Immunorestoration, and Insulin Mitigation) of 6 and 50 people, respectively, treated with combined human growth hormone, metformin and DHEA, suggested the potential of slowing epigenetic aging and improving thymus mass and function. But the combination of drugs, small sample, and lack of controls make conclusions murky. Increased thymus FGF21 led to increased CD8 T cells in old mice and extended healthspan and improved physical performance. Building on the previous FOXN1 data, ablation of β-klotho, the obligatory co-receptor for FOXN1, accelerated thymic aging. The benefit to FGF21 was confirmed in a companion paper using an FGF21 knock-in mouse model showing thymus enlargement and increased TECs throughout the lifespan. (schematic Figure below). The accompanying editorial for these 2 papers speculated: “The proposed link between age-associated thymus involution and organismal aging is intriguing, and suggests we might seek to achieve systemic rejuvenation by counteracting thymic involution.” Other Factors Lessons from the Axolotl (Mexican Salamander) In an elegant set of experiments of the axolotl (Figure), known for its complete thymus regeneration after total surgical removal, mediators were identified. Surprisingly FOXN1 was dispensable. But midkine, a growth factor, appeared to be the driver, the initiator of thymus cell growth, survival, and repair. Other components that contributed were Postn+ (periostin-expressing mesenchymal niches) and Ccl19, a chemokine protein from the bloodstream. RANK and RANKL RANK (receptor activator of nuclear factor κB its ligand (RANKL) have been considered key regulators of medullary TECs. In a study of both aged mice and human thymus cell cultures, their key role was confirmed, with multiple benefits of resorting TEC function, recruitment of progenitor cells, and T cell development. Subscribe Summing Up This body of work strongly supports the health of the thymus gland as a critical regulator of human healthspan, not just a correlate or link. The new landmark studies are reinforced by the regenerative biology experimental models that have shown, via an array of mediators, that healthspan of aged mice is at least in part dependent on thymus gland function and its critical role for maintaining adaptive immunity. It sure seems that we’d be better off having an immune reservoir of naive T cells instead of a profile in older adults of exhausted, low quality, memory T cells, with a senescent phenotype. It is striking that we ignored the importance of the thymus gland for many decades. A wake-up call was the results of the thymectomy matched control study reviewed here, with the opposite of high thymic health score improved health outcomes. The convergence of AI and healthspan here is notable. The exceptional and laborious work for developing and validating (no less explaining) the AI to quantify thymus health set the foundation for probing the connect the major health outcomes in two cohorts with extensive follow-up. We’ve never had a way to meaningfully quantify the thymus gland before, so this represents important leverage of supervised, self-supervised, and transformer models. The study wouldn’t have been possible without AI. And it begs the question as to whether there are ways we can maintain our thymus at a high health score. But it’s not so simple to rejuvenate our thymus. There are multiple risks including the induction of autoimmunity, increasing the risk of cancer, and inducing a pro-inflammatory state. For example, factors that increase TEC proliferation could compromise the medulllary negative selection process and leak out auto-reactive (self-attacking) T cells. Thymic cells could be induced to proliferate, but we know, for example, that growth hormone and IGF-1 are associated with an increase risk of cancer. If thymus rejuvenation doesn’t clear out the accumulated senescent cells in older adults, then inflammation within the gland could block the production of TECs. Keeping these risks in mind, we now have identified many ways to keep our thymus healthy as we age that undoubtedly will be tested in clinical trials going forward. Ultimately, the benefit-to-risk tradeoffs will be defined. In the meantime, we have desperately needed an immunome. As I’ve stressed in multiple prior Ground Truths, we have no test in the clinic to assess a patient’s immune status! It was very encouraging for me to get an email from Hugo Aerts, the senior author of the landmark papers in the days after they were published: “I also wanted to say that your Substack on “Why We Need an Immunome” was inspiring for this work. We found it a very compelling perspective and greatly enjoyed reading it.” Just having an assessment of a person’s immune status via a chest CT scan, with millions of these performed per year, might help in guiding the right immunotherapy for cancer (e.g. more intensive, combinations for those with low thymic health scores) and help define people who are increased risk for age-related diseases of cancer, cardiovascular, and neurodegenerative. The main theme of Super Agers is that we now have many layers of data (genetics, proteins, biomarkers, organ clocks that can be integrated via multimodal AI) for us to define a person’s specific risk decades before one of these age-related diseases leads to symptoms, enabling prevention. From the new studies this week, we can add thymus health score as yet another way to understand a person’s risk, a window into their adaptive immune system and healthspan. And perhaps someday we will be able to safely rejuvenate the thymus, or maintain its health through one’s life, and use the thymus health score to monitor. NB: I wrote this post (No A.I.) A Quick Poll Loading... ********************************************************************* Thanks to Ground Truths subscribers (now > 200,000) from every US state and 212 countries. Your subscription to these free essays and podcasts makes my work in putting them together worthwhile. Please join! If you found this interesting PLEASE share it! Share Ground Truths Paid subscriptions are voluntary and all proceeds from them go to support Scripps Research. They do allow for posting comments and questions, which I do my best to respond to. Please don’t hesitate to post comments and give me feedback. Let me know topics that you would like to see covered. Leave a comment Many thanks to those who have contributed—they have greatly helped fund our summer internship programs for the past two years. It enabled us to accept and support 47 summer interns in 2025! We aim to accept even more of the several thousand who will apply for summer 2026.
Markiplier to Microdramas: The Ankler x NAB Show’s Future of Entertainment
Share Subscribe Vegas, baby! The Ankler is heading back to NAB Show for a second year in a row — and doubling down on conversations with the smartest people in the industry. From April 18–22, we’re partnering again with the industry’s biggest media and tech gathering to break down the Business of Media and Entertainment as it’s actually evolving: faster, riskier and increasingly driven by new formats, new audiences and new power players. This curated series will bring together top creators, executives and innovators to tackle the forces reshaping the industry — from the AI disruption of Hollywood’s creative ecosystem to the rise of the creator economy, shifting audience behavior and the changing economics of production. We’ll be rolling out more programming in the coming weeks — including top speakers from leading AI studios, prediction markets and beyond — so keep an eye on the Business of Media and Entertainment hub. But first up, we’re announcing two panels about what’s actually working in Hollywood: The Scary-Smart Business of Horror A good scare has become one of the entertainment economy’s most reliable engines. With disciplined budgets, built-in fandoms and global box office upside, horror consistently outperforms. From theatrical releases to streaming-first originals and creator-driven IP, the genre is artistically flexible and financially durable — and one of the last truly communal experiences for Gen Z and Gen Alpha audiences. Join YouTube creator Mark Fischbach, aka Markiplier, whose independent feature Iron Lung earned more than $50 million at the global box office, Atomic Monster president Michael Clear and screenwriter Akela Cooper (M3GAN, Malignant) for a conversation moderated by Like & Subscribe’s Natalie Jarvey about why horror travels so effectively across platforms and borders, how studios and independents are building sustainable genre pipelines and why the next wave of breakout franchises may emerge from unexpected sources. Inside the Microdrama Boom Short-form serialized storytelling is having a major moment. Microdramas, social-native series and creator-led narratives are capturing massive audiences with low-cost, rapid production cycles and direct-to-fan distribution. What was once dismissed as niche or experimental is now attracting major platform investment. Moderated by Jarvey, this panel of microdrama creators and executives — including one of the format’s top stars and producers, Kasey Esser, and Dhar Mann Studios’ head of vertical content, Erin McFarlane — examines how format innovation, fandom dynamics and algorithmic discovery are reshaping the economics of scripted storytelling and what traditional studios can learn from these agile models. For sponsorship opportunities, contact Lynne@theankler.com Share
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