Advanced Organoid Studies

Personalized drug screening in patient-derived organoids of biliary tract cancer and its clinical application. https://lnkd.in/eRBpyMDC "Patients with biliary tract cancer (BTC) show different responses to chemotherapy, and there is no effective way to predict chemotherapeutic response. We have generated 61 BTC patient-derived organoids (PDOs) from 82 tumors (74.4%) that show similar histological and genetic characteristics to the corresponding primary BTC tissues. BTC tumor tissues with enhanced stemness- and proliferation-related gene expression by RNA sequencing can more easily form organoids. As expected, BTC PDOs show different responses to the chemotherapies of gemcitabine, cisplatin, 5-fluoruracil, oxaliplatin, etc. The drug screening results in PDOs are further validated in PDO-based xenografts and confirmed in 92.3% (12/13) of BTC patients with actual clinical response. Moreover, we have identified gene expression signatures of BTC PDOs with different drug responses and established gene expression panels to predict chemotherapy response in BTC patients. In conclusion, BTC PDO is a promising precision medicine tool for anti-cancer therapy in BTC patients." Interesting paper detailing the establishment of patient-derived organoids for in-vitro drug screening and subsequent development of gene expression signatures which can be used to predict therapy response in patients, by @Xiaoxue Ren and larger team

LAB-GROWN NERVE CIRCUIT RECREATES HUMAN PAIN PATHWAY Researchers have recreated the human ascending sensory pathway in a lab dish, using organoids that model the key brain and spinal cord regions responsible for transmitting pain. This breakthrough allows scientists to observe how pain signals travel from peripheral neurons to the brain for the first time outside the body. The model, called an assembloid, responds to pain-inducing stimuli and reflects the effects of genetic mutations known to alter pain perception. This innovation could revolutionize drug discovery for pain relief, particularly for conditions like chronic pain or hypersensitivity. 3 Key Facts: 1. Full Pain Pathway Recreated: Four connected brain and spinal organoids simulate human pain signal transmission. 2. Drug Discovery Platform: The assembloid enables testing of pain-inducing chemicals and potential pain-blocking drugs. 3. Gene-Specific Insights: Mutations in Nav1.7 sodium channels altered wave-like neural activity, mimicking pain disorders. Source: https://lnkd.in/g-sRD84B

I woke up to this news that: Scientists Just Solved Organoids' Biggest Problem! I’m happy to share highlights from a new Science paper by Dr. Oscar Abilez, Dr. Huaxiao 'Adam' Yang, Dr. Joseph C. Wu, and colleagues, a leap forward for organoid technology and regenerative medicine! What Did They Do? Stanford researchers have created the first heart and liver organoids with integrated, functional blood vessels. This solves a critical bottleneck: until now, organoids could only grow a few millimeters before their centers died from lack of oxygen and nutrients. With built-in vasculature, these mini-organs can grow larger, mature further, and better mimic real human tissues. How Did They Do It? *The team meticulously optimized a “recipe” of growth factors and signaling molecules, guiding pluripotent stem cells to differentiate into not just heart or liver cells, but also endothelial and smooth muscle cells that self-organize into branching blood vessels. *Their protocol mirrors early embryonic development, allowing the organoids to achieve a cellular complexity similar to a 6.5-week-old human embryonic heart, including beating function! Why Is This Important? *Better Disease Models: Vascularized organoids allow researchers to study early human development and test how drugs impact organ growth and blood vessel formation. *Personalized Medicine: These models can be tailored from patient-derived stem cells, paving the way for individualized drug testing and disease modeling. *Regenerative Therapies: In the future, vascularized cardiac organoids could be implanted to repair damaged heart tissue, offering a more complete cellular environment than current cell therapies Clinical Context As Dr Joseph C. Wu notes, ongoing clinical studies are already injecting lab-grown cardiomyocytes into patients with heart dysfunction. But real heart tissue is much more complex, containing blood vessels, pericytes, fibroblasts, and more. Vascularized organoids could one day provide all these cell types in a single, implantable tissue patch, dramatically improving integration and function. What’s Next? The team aims to: *Grow organoids longer to assess their maturation and size limits *Further refine the recipes to include immune and blood cells *Adapt this vascularization approach to other organs, moving closer to true “mini-organs” for research and therapy A huge CONGRATULATIONS to the entire Stanford team! References: https://lnkd.in/gmYc-cX9 https://lnkd.in/gbntyWgN https://lnkd.in/g-YT5wdU

Our latest paper is out in Nature today! Zonation is a design principle of the human liver. For decades, scientists have known that liver function varies by zone — with diseases like DILI (Drug-Induced Liver Injury) and MASLD often striking specific areas near the central vein. Yet, no human stem cell-derived model has been able to reproduce this complexity — until now. In this study, we report the first human iPSC-derived liver organoids that exhibit controlled zonation, capturing real metabolic gradients across the lobule. 👉 Read the full paper: https://rdcu.be/eh3nX • We restored a functional Gulo gene (defective in humans) to induce an endogenous ascorbate gradient, layered with bilirubin to simulate natural zonation cues. • Zonally primed organoid can fuse to self-assemble and reconstruct all three zones. • Zone-specific functions and toxicities revealed: several drugs target only zone 1 or zone 3 hepatocytes. • Elastic epigenetic regulation uncovered — driven by TET1 (ascorbate) and HIF1A (bilirubin). • Multi-zonal organoid transplantation reduces total liver dysfunction as a promising strategy for regeneration. This project was led by my first US based PhD student, Hasan Al Reza, PhD, who immigrated from Bangladesh to pursue science with passion and resilience. Deep gratitude to the team at Cincinnati Children's for pushing the boundary of human organoid models. #Organoids #LiverZonation #StemCells #GuloGene #AscorbateGradient #RegenerativeMedicine #iPSC #DrugDiscovery #PrecisionMedicine #DiversityInSTEM #NaturePaper #DILI

Sharing today the latest from our lab, just published in 𝙉𝙖𝙩𝙪𝙧𝙚 𝘽𝙞𝙤𝙢𝙚𝙙𝙞𝙘𝙖𝙡 𝙀𝙣𝙜𝙞𝙣𝙚𝙚𝙧𝙞𝙣𝙜. As stem cell–based neural models gain traction for disease modeling and drug testing, one of the major bottlenecks has been scaling up production. In work led by Yuki Miura and Genta Narazaki, we present a simple and cost-effective way to prevent neural organoid fusion that allows scalable generation of cortical organoids without compromising quality. In brief, this is done by simply adding the cheap food additive xantham gum! This enabled a single experimenter to screen all FDA-approved drugs for neuropsychiatric disorders across 2,400 organoids, identifying compounds that impair human cortical development. Hoping that will be one more step toward scalable human models for brain development and drug discovery. Link to the article here: https://lnkd.in/gBUqNHpb and a short video made by Yuki to show how to dissolve the xantham gum: https://lnkd.in/gX5wipSe #Organoids #StemCells #DrugScreening #Neurodevelopment #TranslationalResearch

Dual CAR-T: Brain tumor organoids accurately model patient response to CAR T cell therapy - Penn Medicine, University of Pennsylvania Health System PHILADELPHIA— For the first time, researchers used lab-grown organoids created from tumors of individuals with glioblastoma (GBM) to accurately model a patient’s response to CAR T cell therapy in real time. The organoid’s response to therapy mirrored the response of the actual tumor in the patient’s brain. That is, if the tumor-derived organoid shrunk after treatment, so did the patient’s actual tumor, according to new research from the Perelman School of Medicine at the University of Pennsylvania, published today in Cell Stem Cell. “It’s hard to measure how a patient with GBM responds to treatment because we can’t regularly biopsy the brain, and it can be difficult to discern tumor growth from treatment-related inflammation on MRI imaging,” said Hongjun Song, PhD, the Perelman Professor of Neuroscience and co-senior author of the research. “These organoids reflect what is happening in an individual’s brain with great accuracy, and we hope that they can be used in the future to ‘get to know’ each patient’s distinctly complicated tumor and quickly determine which therapies would be most effective for them for personalized medicine.” Patient-derived glioblastoma organoids as real-time avatars for assessing responses to clinical CAR-T cell therapy Highlights •Rapid GBO generation in a phase 1 clinical trial for real-time treatment assessment •A unique trial design with parallel treatments of patients and patient-derived GBOs •Cell cytolysis and target antigen reduction in GBOs treated with patient CAR-T cells •Cytokine release and the degree of cytolysis in GBOs correlated with patient metrics Summary Patient-derived tumor organoids have been leveraged for disease modeling and preclinical studies but rarely applied in real time to aid with interpretation of patient treatment responses in clinics. We recently demonstrated early efficacy signals in a first-in-human, phase 1 study of dual-targeting chimeric antigen receptor (CAR)-T cells (EGFR-IL13Rα2 CAR-T cells) in patients with recurrent glioblastoma. Here, we analyzed six sets of patient-derived glioblastoma organoids (GBOs) treated concurrently with the same autologous CAR-T cell products as patients in our phase 1 study. We found that CAR-T cell treatment led to target antigen reduction and cytolysis of tumor cells in GBOs, the degree of which correlated with CAR-T cell engraftment detected in patients’ cerebrospinal fluid (CSF). Furthermore, cytokine release patterns in GBOs mirrored those in patient CSF samples over time. https://lnkd.in/eusyxeba https://lnkd.in/es-s4MSt

A human embryo was grown without sperm, egg, or womb — and it's real For the first time in scientific history, researchers at the Weizmann Institute of Science in Israel have successfully grown a complete synthetic human embryo — not from a sperm and egg, but entirely from reprogrammed stem cells. No uterus, no fertilization, and no implantation required. The embryo model, grown in a special rotating bottle incubator, developed a brain-like structure, heart precursor, yolk sac, and even early signs of organ formation — all within 14 days. No synthetic embryo has ever made it this far before. Scientists used only human stem cells, chemically coaxed into forming all major embryonic tissues — without any DNA editing or cloning. This new method mimics natural development far more accurately than previous organoids or partial structures. It recreates how a real embryo forms, down to the symmetry, cell communication, and spontaneous compartment formation that gives rise to organs and limbs. What this means is staggering. Scientists now have a way to observe the first two weeks of human development in precise detail — a stage that’s normally invisible inside the womb. This could reveal the causes behind early miscarriages, implantation failure, and congenital disease, potentially saving millions of lives through earlier intervention. But it also forces us to face profound questions. These aren’t real embryos that could grow into babies — yet. But they aren’t entirely artificial either. They resemble nature too closely to ignore. Where is the boundary between life and model? Between ethics and necessity? Whether humanity uses this breakthrough to heal — or to control life — will define the century ahead.

I’m so excited to announce the publication of this important paper by Lorenzo Ferri at McGill University and Elee Shimshoni from my team showing the value of Organ Chips for personalized medicine and clinical care.   Esophageal adenocarcinoma (EAC) is the sixth-deadliest cancer in the world. In this study, we leveraged Organ Chips, organoids derived from treatment-naïve patient tumors or adjacent normal tissues, and patient-matched cancer-associated or normal fibroblasts, respectively, to develop a novel, physiologically relevant, high-fidelity preclinical esophagus-on-a-chip model.   These models faithfully recreated the tumor-stroma interface and accurately predicted the response to neoadjuvant chemotherapy within a clinically useful timeframe more accurately than patient-derived organoid cultures. The Organ Chips effectively complement high-throughput organoid-based drug testing and provide improved insights into drug efficacy before human studies.   https://lnkd.in/eXHQVvEB

Liver fibrosis is a complex, progressive liver scarring condition affecting millions globally with very few treatment options. Driven by this unmet need, we have been collaborating with Dr Gary Peltz at Stanford University School of Medicine to explore how our Google DeepMind Google Research AI co-scientist might assist in uncovering novel therapeutic avenues for this challenging disease. Really excited to share comprehensive experimental validation results, led by Yuan Guan, Jakkapong Inchai, Zhuoqing Fang from Dr. Peltz’s lab, demonstrating our co-scientist's efficacy in uncovering promising targets and drug repurposing candidates for this disease. We specifically tasked the AI co-scientist with the challenge: "Propose novel hypotheses about specific epigenetic changes contributing to myofibroblast formation in liver fibrosis and indicate what drugs should we test as new treatments... Novel experiments performed in hepatic organoids are preferred". The AI co-scientist proposed that epigenetic alterations, particularly histone deacetylation and changes in DNA methylation, are crucial in driving fibrosis. It then suggested specific drug classes to test this, including HDAC inhibitors (like Vorinostat), DNMT inhibitors, and Bromodomain (BRD4) inhibitors. In subsequent experiments using a high-throughput micro-human hepatic organoid (microHO) platform pioneered by Dr Peltz’s lab, we found that: 1. Vorinostat (an FDA-approved HDAC inhibitor) and BRD4 inhibitors indeed showed potent anti-fibrotic effects in our human liver organoid models, without causing toxicity at effective concentrations. 2. Further supporting the co-scientist's line of reasoning, Vorinostat was observed to significantly reduce TGFβ-induced chromatin structural changes (by 91%) and also promoted the regeneration of liver parenchymal cells. While the DNMT1 inhibitor suggested by the system did not prove effective, the success with HDAC and BRD4 inhibitors highlights the AI co-scientist's potential to act as a valuable partner for scientists tackling complex diseases. By helping formulate detailed, testable hypotheses rooted in scientific literature, the co-scientist can meaningfully assist in navigating the complexities of disease and rapidly accelerate the path towards new cures. Notably, this work was done with an older version of the system.  We have made considerable progress building on the latest Gemini 2.5 models and look forward to sharing more progress soon. Huge thanks to our incredible collaborators at Stanford and with amazing teammates at Google Research Google DeepMind Google Cloud: Tao Tu, Juro Gottweis Yunhan Xu Keran Rong Artiom Myaskovsky Alexander Daryin Annalisa Pawlosky Kavita Kulkarni Anil Palepu Wei-Hung Weng Alan Karthikesalingam MD PhD Preprint link - https://lnkd.in/eADZ8tJd AI co-scientist blog - https://lnkd.in/gEDeaRfu