Manolis Kellis

Kellis Lab is hiring! New grants in #Alzheimers #Schizophrenia #Cancer #EHR #SingleCell #Genome #Epigenome #Transcription #Disease integration. Computational & experimental positions, profiling and circuitry dissection. Join us! @MIT_CSAIL @BroadInstitute compbio.mit.edu/positions.html

Excited to share our Cross-Species Single-cell Atlas of the Human Brain's Striatum, the brain region that integrates action planning, reward, motivation, decision-making, movement, learning, and reinforcement, implicated in schizophrenia, depression, addiction, and Huntington's Disease: authors.elsevier.com/c/1niW9L7PXy43t

Our map spans 109 samples, 69 donors, and 670,000 nuclei. We identify 31 neuronal subpopulations, including 9 types of medium spiny neurons, and rare D1 interface MSNs forming island-like structures. Patch-clamp recordings show outlier MSNs have smaller somata and stronger hyperpolarization-activated currents than their neighbors.

We show that the dorsolateral-ventromedial gradient shapes: receptor repertoires, disease gene expression, vulnerability.

Across 124 GWAS, we show genetic risk for neuropsychiatric, cognitive and addiction traits concentrates in MSNs and is depleted in glia and vascular cells. Schizophrenia, bipolar and ADHD risk genes are dorsally enriched, and so, unexpectedly, are opioid use disorder risk genes — even though opioid signaling itself is ventrally biased, suggesting heritable risk and acute drug action may engage different parts of the striatum.

Only a quarter of the human gradient genes are similarly zonated in mice. Several drug targets sit in different cells across species, including the mu-opioid receptor, the M5 muscarinic receptor, and the GLP-1 receptor, with important implications for preclinical screening. Profiling chronic antipsychotic exposure in mice, we find the transcriptional response strongly biased toward ventral MSNs.

Finally, we connect genotype to phenotype at single-cell resolution. Our new method, scMOSAIC, reads HTT CAG repeat length and gene expression from the same nucleus — and finds that repeat length varies along that same dorsolateral-ventromedial axis.

Huge congrats to Raleigh Linville @LinvilleRaleigh , Benjamin James @__ben_james__ , who carried this from start to finish, and to co-senior authors #MyriamHeiman and #DanaGabuzda, and Kiki Galani, Li-Lun Ho, Stu Fass, James Cameron, Brent Fitzwalter, Erica Engelberg-Cook, Sebastian Pineda, Dennis Dickson, Deborah Mash, Gustavo Turecki, Vanessa Wheeler, and Veronica Alvarez, across Massachusetts Institute of Technology, The Picower Institute for Learning and Memory, MIT Computer Science and Artificial Intelligence Laboratory (CSAIL), Broad Institute of MIT and Harvard, Dana-Farber Cancer Institute, The National Institutes of Health, Mass General Brigham, Mayo Clinic, McLean Hospital, McGill University, and beyond.

Huge thanks to the #SCORCH consortium and the brain banks in the US and Canada, and a huge thanks to the donors and their families. Every cell in this atlas came from someone who decided their brain should go on being useful. The data are public, and we hope other labs take them further than we can.

So proud of #RileyMangan and #NikithaThoduguli presenting platform talks at #ASHG25 today on #SingleCell phenotypes for #Alzheimers, and #DeepLearning #Evolution of human cis-regulatory elements. Spread the word! @MIT @BroadInstitute @HarvardMed

MIT Course announcement: Machine Learning for Computational Biology #MLCB25
Fall'24 Lecture Videos: tinyurl.com/MLCBlectures
Fall'24 Lecture Notes: tinyurl.com/MLCB24notes
(a) Genomes: Statistical genomics, gene regulation, genome language models, chromatin structure, 3D genome topology, epigenomics, regulatory networks.
(b) Proteins: Protein language models, structure and folding, protein design, cryo-EM, AlphaFold2, transformers, multimodal joint representation learning.
(c) Therapeutics: Chemical landscapes, small-molecule representation, docking, structure-function embeddings, agentic drug discovery, disease circuitry, and target identification.
(d) Patients: Electronic health records, medical genomics, genetic variation, comparative genomics, evolutionary evidence, patient latent representation, AI-driven systems biology.
Foundations and frontiers of computational biology, combining theory with practice. Generative AI, foundation models, machine learning, algorithm design, influential problems and techniques, analysis of large-scale biological datasets, applications to human disease and drug discovery. 
First Lecture: Thu Sept 4 at 1pm in 32-144
With: Prof. Manolis Kellis @manoliskellis, Prof. Eric Alm @ejalm, TAs: Ananth Shyamal, Shitong Luo @luost26
Course website: compbio.mit.edu/mlcb
@MIT @MITEECS @MITdeptofBE @MITCSBPhD @MIT_CSAIL @Harvard @HarvardMed @BroadInstitute

Greek friends, join us next Sunday July 6 in @Athens, as we hack the Future of #AI in the Cradle of Western Civilization, at the #EugenidesFoundation. After the success of our last hack at MIT, we're partnering with SundAI Club again to bring cutting-edge technologies to the Hacker and Builder communities of the world.
Register here: lu.ma/hwxuxliq
(1) WhatIsMantis: Imagine peeking into the mind of an AI like ChatGPT, and #visualizing how it organizes ideas, thoughts, documents, proteins, drugs. Imagine watching them come to life as you speak with the AI, revealing meaningful #constellations of relevant information in a cognitive landscape of information. Now, imagine a full cognitive #workbench that allows you to manipulate these clusters directly, powered by visual tools, next-gen search, auto-macros, agentic workflows, and real-world actions. Lastly, imagine working with your team and #collaborators on shared workbench, with multiple interlinked cognitive floors, co-browsing, taking joint actions, partitioning tasks, visualizing trends, detecting outliers, and sharing discovery journeys in a predictive, learning, adapting system, fully integrated within your daily workflows.
See Mantis Demos: tinyurl.com/MantisDemos
(2) On July 6, you can bring this vision to reality, by using our Mantis AI platform to create your own applications and solutions in any vertical, and turn unstructured data into structured insights, semantic graphs, hierarchical ontological views, custom vertical-tuned tools, and agentic workflows bringing data to life and revealing systematic insights. We'll start with breakfast and intros, brainstorming and team formation, dataset gathering and project refinement, and tool creation across agents, journeys, workflows, and interactive coding notebooks, all in one day in Sundai Club fashion!
See our last hacks here: sundai.club/projects (search: Mantis)
(3) We’ll have applications in education, law, government, startups, investment, cultural heritage, tourism, news, politics, media, jobs, policy, customers, reddit, YouTube, shopping, Linkeode, healthcare, drug discovery, or anything that you are passionate about. You can work alone or in groups, bring your own team or make new friends, bring your own data, work with our sample datasets, or scrape away, with many members of our team supporting in person and remotely.
(4) Links:
- Create a Mantis account here: home.withmantis.com/inquire
- Use Mantis here: alpha.withmantis.com
- Join the Mantis team here: tinyurl.com/MantisOnboardi…
With Serge Vasylechko, Konstantina Yaneva, Christina Koutsoumpa, PhD, Vassilis Papakonstantinou, Alexios Ntavlouros, Nicolas Pigadas, Minas Megalokonomos, Pascal Passigan, Jophy Ye, and many members of the Sundai and Mantis AI teams joining remotely!
All participants to the Hackathon will get a free ticket to the #UniversalAI launch event on Tuesday July 8, with Dimitris Bertsimas, Theodoros Evgeniou, and more. uaisummit.mit.edu