Jack Dent

@srikosuri @rhomsany Congrats! 🍾

First in Human! When @rhomsany and I first started Octant, this was the dream. A platform that makes molecules that few others can go after… to get the chance to tackle severe diseases with poor to no standard of care. It's been a long journey but so incredibly proud of the team and thankful to the volunteers who make this attempt possible. We got to celebrate with these new sunhats! octant.bio/news/octant-an…

Memo: What If We're Right? We recently wrote a private letter to partners & friends of a common failure mode: the inability to consistently reason through the daisy chain of downstream consequence when non-consensus, low-probability, events actually occur pages: 1-3

Grateful to share the stage with @robzirk and @BenjamineYLiu at PhRMA Forum today. We are at a critical inflection point for the industry. AI deployment is taking off, and 2026 will be the year get a glimpse of how it will transform the future of medicine.

@dps Congrats @dps! Have been excited about this since I got the sneak preview

Jobs called computers "bicycles for the mind" -- tools we could shape to our will. But they never were. Until now. Every morning an agent preps me for my day -- calendar, news, last 24hrs of Slack -- in a personal podcast. I made it by asking. Same for hundreds of other things. Launching @dreamer in beta today. That 🧠 bicycle, finally. dreamer.com

@getCos @sidd @AccrualHQ Special people building a special company.

Ever since I met @sidd in our early days at Stripe, I hoped we’d one day find an idea big enough to start a company together. That day is finally here. After building quietly for the past year, I’m excited to officially launch @AccrualHQ, a new foundation for professional accounting 👇

Great opportunity to work with some of the best in the business

Great coverage from @xiaofei_lin on our deal with @EliLillyandCo and the start of the "year of deployment".

@AdvaitMaybhate Thanks Advait!

@jackdent Wooo, congrats!! 🎉

I’m proud to announce Chai Discovery’s partnership with Eli Lilly to accelerate the discovery of next-generation therapeutics. Through this collaboration, we'll deploy our frontier models, train custom models on Lilly's proprietary data, and create an entirely new toolchain for discovering life-changing medicines.

@ericjang11 Thanks @ericjang11! 🙏

@jackdent Congrats!

Congrats to @joshim5 @jackdent @chaidiscovery on their first major deal announcement with Eli Lilly! Always amazing to see their pace to adoption. 2026 looks like the tipping point in pharma adoption of AI tools up and down the stack! endpoints.news/eli-lilly-chai…

@mattkrisiloff Thanks @mattkrisiloff!

@jackdent So cool, congrats!!!

@jacobkimmel @newlimit More mice videos soon please

2025 @newlimit: - 0 -> 1 candidate medicine that restores multiple youthful functions in old livers - 2X discoveries/$ with our frontier AI system - >1000X more TF payloads tested vs. the field we built our 1st medicine & began development 2026: we move toward the clinic # discovery cadence @newlimit is built around a set of core technologies we call our Engine. our Engine discovers transcriptions factor (TF) payloads that make old cells look and act young. the Engine prioritizes payloads using: AI systems -> large-scale genomics screens -> functional assays -> animal models of aging & disease in 2025, we increased the scale & fidelity of the Engine many fold. key outputs: - >1000X more TF payloads tested than the field, combined - 16 payloads restore function in animal models - 36 payloads restore function in cells - 600+ make old cells look young based on gene expression - $/function hit down 17X, headcount only up 1.4X # entering early development therapeutic discovery transitions into development once an optimized prototype medicine known as a preclinical candidate is chosen for in-depth evaluation. we imagined at the founding of NewLimit that it would take 5+ years to create one. the science advanced faster than we thought, so we delivered ahead of schedule after just 3 years of operations. our first candidate is based on a payload with pleiotropic activity, making old hepatocytes both look young and act young across multiple dimensions. we discovered the candidate in a humanized liver screen, where it made old human hepatocytes look younger & regenerate like young cells too. one function in one assay isn't enough to say we truly reversed cell age, so we checked others. we found our candidate also restored regenerative function in mice after surgical injury and resilience to alcohol diet. the candidate was also safe -- the liver tolerated it well, and there were no signs of neoplasia (think, cancer). we ran our first lead optimization campaign and generated a candidate with 8X more specific expression and 1.6X the potency of our initial prototype. this became our preclinical candidate and we're moving it toward the clinic now. # AI systems accelerate therapeutic discovery there are >10^16 TF payloads we might test. no matter how many experiments we run, we'll never search the space completely. to discover an optimal reprogramming medicine, we need to effectively prioritize which hypotheses we test before ever entering the lab. only a few years ago, this problem was intractable. humans can't reason through a hypothesis space of this scale. AI systems by contrast can incorporate a plurality of prior knowledge to design experiments that maximize our rate of discovery. this year, we introduced Ambrosia, the 1st AI system that can accelerate the design of reprogramming payloads. Ambrosia builds atop knowledge captured in foundational models of molecular biology and natural language, initializing our system with a strong prior derived from both human languages and nature’s languages. our system first learns to predict the effect of arbitrary reprogramming payloads on both the state and function of old cells. given this discriminative model, Ambrosia can design reprogramming payloads that induce a target cell state or phenotype. the design process can even learn continually from sequential experiments. using Ambrosia to design our experiments, we can improve our discoveries/$ by >2X. we believe this is among the first AI systems that has been integrated effectively into a large scale target discovery process. the complexity of human pathology far exceeds the sophistication of most therapeutics. our medicines have been constrained by our intelligence. reprogramming medicines are only now entering the realm of the possible due to the advent of AI systems that remove this intelligence constraint. if successful, the design of reprogramming medicines that extend human health will represent one of the more dramatic impacts of AI on our world. # diversifying lineages @newlimit's ultimate ambition is to create reprogramming medicines to restore function across most cell types in the body. this year, our progress in hepatocytes & T cells convinced us it was time to add a 3rd type to the portfolio. in August, we launched a Vascular program focused on restoring function in endothelial cells, the cell type that lines blood vessels. endothelial cells are everywhere in the body, and their aging contributes to disease in the kidneys, heart, and even the brain. in just four months, our team - transferred our Engine tech with 0 modifications & executed discovery screens - built 2 functional assays for endothelial cell age - developed a lipid nanoparticle delivery method that delivers TFs to >60% of kidney endothelial cells we never expected this program to move so quickly. by next year, we imagine we'll be able to reprogram old endothelium back to a youthful state. # 2026 @newlimit's first 2 years were focused on a set of fundamental research and technology problems. We built a system to search for reprogramming medicines, discovered the first payloads that can reprogram cell age, and demonstrated that restoring youthful function in old cells was possible. in 2025, we created the first medicine we hope to bring to human trials and showed that it can rescue multiple youthful functions in old cells. 2026 will be the year that we transition from purely a research enterprise to an integrated research & development organization. effective execution in this next stage will allow us to bring reprogramming technology into human patients. if these medicines are successful, we believe they are among the most valuable products possible.

@ashleevance @chaidiscovery Thank you @ashleevance for having us on, and for the wide-ranging conversation. We were honoured to join you.

The folks @chaidiscovery have been producing potential drug designs at an incredible clip. We get into the latest (and hopefully more real) era of AI-aided drug discovery on this week's pod corememory.com/p/is-the-era-o…

I'm very excited that we now have results from an almost two-year randomized controlled trial that we ran across thousands of businesses on Stripe: those that accepted a loan from @Stripe Capital grew annual revenue around 27% faster. (Two years isn't that long in the scheme of things, but it is when you're waiting for the results of an experiment you're interested in.) We had two kinds of controls: businesses to whom we offered loans but didn't accept them, and a holdout group of businesses to whom we randomly did not offer loans but which were otherwise identical to those to which we did. As such, we feel confident in the causal nature of this conclusion. While this might not sound like news ("capital increases growth"), I think the finding is a good reminder that many businesses are still quite capital-starved (this effect is on top of all of the other sources of capital that businesses have access to), and it is consistent with what we hear directly from businesses in surveys. Beyond Stripe, inefficient capital allocation at economy-wide scale is likely a major bottleneck to growth around the world. We have an ambitious roadmap planned and we're very much looking forward to expanding worldwide access to growth capital.

@ArdaGoreci @chaidiscovery Thanks Arda!

@jackdent @chaidiscovery Congrats Jack!

The team is @chaidiscovery is truly exceptional... it's a joy to go to work every day with my polymathic group of colleagues.

The @chaidiscovery team is at NeurIPS this week and co-hosting an event Friday night. Ping me if you're interested in AI that transforms drug discovery into an engineering discipline.

autumn @newlimit -- we've advanced our 1st reprogramming medicine through optimization highlights - 8X specificity, 1.6X potency for our lead prototype medicine - +2 TF sets that restore liver function, +20 that restore phenotype - 0 -> 1 preclinical models of endothelial age # engineering therapeutic molecules in september, we selected our first prototype medicine for liver aging to advance toward the clinic. this initiated our first lead optimization campaign to improve the potency & specificity of our prototype. our RNA medicines allow for engineering at the sequence level. RNAs are not translated into proteins equally across cell types, and we can design sequences to maximize activity in our target cells (hepatocytes) and minimize activity elsewhere. our campaign achieved an 8X increase in the specificity of our prototype & a 1.6X increase in the potency within hepatocytes. we believe these optimizations will yield a safer, more effective medicine. # restoring youthful resilience alongside progressing our first asset, we've continued to discover reprogramming payloads that restore youthful function. in october, we discovered +2 payloads that restore youthful resilience to alcohol damage in old livers. these payloads emerged from our discovery screens & validated as prototype RNA medicines. each month, more of these payloads emerge from Discovery Engine, giving us confidence that the well of potential reprogramming medicines is deep. # in vivo T cell reprogramming hepatic reprogramming is only one of several therapeutic applications we’re pursuing. we’ve previously discovered reprogramming payloads that restore youthful cytotoxic capacity and stem-like states to old human T cells. the next stage in the development of these payloads is to test whether they can rescue function in a more complex animal model. before we can test their effects directly, we need to build molecular tools to deliver reprogramming payloads to T cells in vivo. after a series of engineering iterations, we've developed a lipid chemistry that can carry our RNA medicines into T cells in animals. our chemistry is now nearly matching the current state-of-the-art. # measuring endothelial cell age our most recent therapeutic program is focused on restoring function in endothelial cells of the vasculature. we believe improving endothelial function could create renal, cardiovascular, and cognitive health. endothelial cell aging is dramatic enough that we’ve been able to discover functional impairments in just our first few experiments. human endothelial cells are less regenerative in simple in vitro systems, and endothelial injury leads to more dramatic renal damage in old animals. even these early tools allow us to start testing the effect of reprogramming on aged endothelial function, in addition to phenotypes. # join our team we're recruiting talented scientists & engineers across our therapeutic programs and technology teams. reach out if you're excited to create a new class of medicines that add healthy, happy years for ~everyone.

@apartovi Thanks for sharing these stories Ali

As a young founder, I learned a $50 million lesson about the sanctity of a handshake. I’m ashamed to say that I played a morally questionable role in this story. Fortunately, the experience changed my path.... 🧵