Laura 🌲 ⛰️

Builders is back with episode 3. Hosts @josh_coyne and @LM_Braswell are joined by @LauraDeming, @untillabs and @jacobkimmel, @newlimit to discuss two of the most ambitious goals in biotech: preserving organs long-term and resetting the biology of aging. They discuss how cryo could ease the transplant shortage, why cellular reprogramming is moving from concept to clinic, and how AI is speeding up discovery. Full episode link in the comments.

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.