Stanford Advisors

Contact

  • Academic
    jablum@stanford.edu
    University - Scholar Department: Genetics Position: Postdoctoral Scholar

All Publications

  • Accelerating scientific discovery with Co-Scientist. ArXiv Gottweis, J., Weng, W. H., Daryin, A., Tu, T., Sirkovic, P., Myaskovsky, A., Glowaty, G., Weissenberger, F., Orlandi, A., Popovici, D., Palepu, A., Rong, K., Tanno, R., Saab, K., Zhang, F., Blum, J., Carroll, A., Kulkarni, K., Tomašev, N., Zverinski, D., Rendulic, I., Vedadi, E., Hasler, F., Rimanic, L., Boia, M., Budiselic, I., Feinstein, B., Bellaiche, M., Sheffer, T., Freyberg, J., Ratcliff, J., Bertolli, O., Chou, K., Hassidim, A., Gokturk, B., Vahdat, A., Guan, Y., Dhillon, V., Vaishnav, E. D., Lee, B., Costa, T. R., Penadés, J. R., Peltz, G., Matias, Y., Manyika, J., Hassabis, D., Xu, Y., Kohli, P., Pawlosky, A., Karthikesalingam, A., Natarajan, V. 2026

    Abstract

    Scientific discovery is driven by scientists generating novel hypotheses for complex problems that undergo rigorous experimental validation. To augment this process, we introduce Co-Scientist, a multi-agent AI system built on Gemini for structured scientific thinking and hypothesis generation. Co-Scientist aims to help scientists discover new original knowledge. Conditioned on their research objectives and prior scientific evidence, it formulates demonstrably novel research hypotheses for experimental verification. The system's design involves agents continuously generating, critiquing and refining hypotheses accelerated by scaling test-time compute. Key contributions include: (1) a multi-agent architecture with an asynchronous task execution framework for flexible compute scaling; (2) a tournament evolution process for self-improving hypotheses generation. Automated evaluations show continued benefits of test-time compute scaling, improving hypothesis quality over time. While general purpose, we focus the validation in three biomedical applications: drug repurposing, novel target discovery 1, and explaining mechanisms of anti-microbial resistance 2. Specifically, Co-Scientist helped identify new drug repurposing candidates and synergistic combination therapies for acute myeloid leukemia, which were validated through in vitro experiments. These real-world validations demonstrate the potential of Co-Scientist to accelerate scientific discovery and usher in an era of AI empowered scientists.

    View details for DOI 10.1162/99608f92.4a42495c

    View details for PubMedID 42428019

    View details for PubMedCentralID PMC13345588

  • An emergent disease-associated motor neuron state precedes cell death in ALS. Cell Gautier, O., Blum, J. A., Nguyen, T. P., Cao, S., Klemm, S., Yamakawa, M., Huh, D., Hurt, J. A., Sinnott-Armstrong, N., Zeng, Y., Davis, C. O., Bombosch, J., Liu, C., Encarnacion, L. N., Guttenplan, K. A., Chen, D., Kathiria, A., Zhao, L., Moore, S., Meng, A., Ong, K., Cleveland, D. W., Ravits, J., Rexach, J. E., Greenleaf, W. J., Gitler, A. D. 2026

    Abstract

    To define molecular determinants of motor neuron degeneration in amyotrophic lateral sclerosis (ALS), we generated longitudinal single-nucleus transcriptomes and chromatin accessibility profiles of spinal motor neurons together with spatial transcriptomics from the SOD1-G93A mouse model. Vulnerable alpha motor neurons showed thousands of molecular changes, marking a transition into a distinct cell state we named "disease-associated motor neurons" (DMs). We identified transcription factor networks that govern how healthy cells transition into DMs and those associated with motor neuron subtype-selective vulnerability. Upregulation of DM-associated transcription factors in human motor neurons induced key features of DMs, demonstrating an active regulatory component. Human ALS spinal cord single-nucleus RNA sequencing data demonstrated conservation of the DM signature in alpha motor neurons, and human orthologs of regions differentially accessible in SOD1-G93A mouse motor neurons were enriched for ALS genetic risk variants. Together, these findings establish a conserved, genetically linked motor neuron signature in ALS.

    View details for DOI 10.1016/j.cell.2026.05.047

    View details for PubMedID 42335888

  • Accelerating scientific discovery with Co-Scientist. Nature Gottweis, J., Weng, W. H., Daryin, A., Tu, T., Sirkovic, P., Myaskovsky, A., Glowaty, G., Weissenberger, F., Orlandi, A., Popovici, D., Palepu, A., Rong, K., Tanno, R., Saab, K., Zhang, F., Blum, J., Carroll, A., Kulkarni, K., Tomašev, N., Zverinski, D., Rendulic, I., Vedadi, E., Hasler, F., Rimanic, L., Boia, M., Budiselic, I., Feinstein, B., Bellaiche, M., Sheffer, T., Freyberg, J., Ratcliff, J., Bertolli, O., Chou, K., Hassidim, A., Gokturk, B., Vahdat, A., Guan, Y., Dhillon, V., Vaishnav, E. D., Lee, B., Costa, T. R., Penadés, J. R., Peltz, G., Matias, Y., Manyika, J., Hassabis, D., Xu, Y., Kohli, P., Pawlosky, A., Karthikesalingam, A., Natarajan, V. 2026

    Abstract

    Scientific discovery is driven by scientists generating novel hypotheses for complex problems that undergo rigorous experimental validation. To augment this process, we introduce Co-Scientist, a multi-agent AI system built on Gemini for structured scientific thinking and hypothesis generation. Co-Scientist aims to help scientists discover new original knowledge. Conditioned on their research objectives and prior scientific evidence, it formulates demonstrably novel research hypotheses for experimental verification. The system's design involves agents continuously generating, critiquing and refining hypotheses accelerated by scaling test-time compute. Key contributions include: (1) a multi-agent architecture with an asynchronous task execution framework for flexible compute scaling; (2) a tournament evolution process for self-improving hypotheses generation. Automated evaluations show continued benefits of test-time compute scaling, improving hypothesis quality over time. While general purpose, we focus the validation in three biomedical applications: drug repurposing, novel target discovery 1, and explaining mechanisms of anti-microbial resistance 2. Specifically, Co-Scientist helped identify new drug repurposing candidates and synergistic combination therapies for acute myeloid leukemia, which were validated through in vitro experiments. These real-world validations demonstrate the potential of Co-Scientist to accelerate scientific discovery and usher in an era of AI empowered scientists.

    View details for DOI 10.1038/s41586-026-10644-y

    View details for PubMedID 42156544

  • A consensus spinal cord cell type atlas across mouse, macaque, and human. bioRxiv : the preprint server for biology Schmitz, M. T., Johansen, N. J., Kempynck, N., Kapen, I., Fu, Y., Hewitt, M., Seeman, S. C., Kussick, E., Gautier, O., Leone, M. J., Ding, S. L., Gao, Y., Bhandiwad, A., Ariza, J., Ayala, A., Barta, S., Blum, J. A., Cano-Gomez, L., Cardenas, T., Chakka, A. B., Cuevas, N. V., Donadio, N., Fancher, K. A., Thomas, E. D., Ferrer, R., Goldy, J., Hastings, S. D., Hirschstein, D., Ho, W., Huang, C., Juneau, Z. C., Kim, S. R., Lewis, Z. R., Liang, E., Martin, N. X., Nagra, J., Newman, D., Noh, M. C., Olsen, P., Oyama, A., Pena, N., Poldsam, H., Ray, P. L., Reding, M., Rimorin, C., Ruiz, A., Shapovalova, N. V., Shulga, L., Sobieski, C., Torkelson, A., Wirthlin, M., Yao, S., Lai, H., Pfenning, A., Pool, A. H., Seal, R., Tasic, B., Ting, J. T., Waters, J., Yao, Z., Gitler, A. D., McMillen, D., Ng, L., Zeng, H., van Velthoven, C. T., Daigle, T. L., Smith, K. A., Hodge, R. D., Lein, E. S., Bakken, T. E. 2026

    Abstract

    The spinal cord contains evolutionarily conserved cell types critical for motor function, sensory processing, and autonomic regulation, many of which are implicated in diverse neurological diseases and injuries. Yet the field lacks a comprehensive molecular characterization of cellular diversity in human, macaque, and mouse spinal cord. Here, we present a unified, cross-species cell type atlas based on the integration of single-nucleus gene expression, chromatin accessibility, and spatial transcriptomic data from segments within cervical, thoracic, lumbar, and sacral regions, including motor neurons (MNs) sampled across the entire rostro-caudal axis of the macaque spinal cord. Leveraging the spatial distributions of our molecularly defined cell types, we generated a cell type-guided anatomical map of spinal cord laminae and nuclei. We identified both conserved and species-specific cellular features, including gene expression patterns across distinct MN subtypes in the primate spinal cord. Cross-species cis-regulatory analysis and deep learning sequence models dissected the enhancer logic underlying viral targeting, uncovering conserved transcription factor grammar encoding cellular identity. Together, these results establish a unifying molecular and anatomical taxonomy of spinal cord cell types across species.

    View details for DOI 10.64898/2026.02.04.703852

    View details for PubMedID 41676636

    View details for PubMedCentralID PMC12889617

  • An emergent disease-associated motor neuron state precedes cell death in a mouse model of ALS. bioRxiv : the preprint server for biology Gautier, O., Blum, J. A., Nguyen, T. P., Klemm, S., Yamakawa, M., Sinnott-Armstrong, N., Zeng, Y., Davis, C. O., Bombosch, J., Nakayama, L., Guttenplan, K. A., Chen, D., Kathira, A., Zhao, L., Rexach, J. E., Greenleaf, W. J., Gitler, A. D. 2025

    Abstract

    To uncover molecular determinants of motor neuron degeneration and selective vulnerability in amyotrophic lateral sclerosis (ALS), we generated longitudinal single-nucleus transcriptomes and chromatin accessibility profiles of spinal motor neurons from the SOD1-G93A ALS mouse model. Vulnerable alpha motor neurons showed thousands of molecular changes, marking a transition into a novel cell state we named 'disease-associated motor neurons' (DAMNs). We identified transcription factor regulatory networks that govern how healthy cells transition into DAMNs as well as those linked to vulnerable and resistant motor neuron subtypes. Using spatial transcriptomics, we found reactive glia located near motor neurons early in disease, suggesting early signaling events between motor neurons and glia. Finally, we found that the human orthologs of genomic regions with differential accessibility in SOD1-G93A alpha motor neurons are enriched for single nucleotide polymorphisms associated with human ALS, providing evidence that the genetic underpinnings of motor neuron vulnerability are conserved.

    View details for DOI 10.1101/2025.08.21.671404

    View details for PubMedID 40909710

    View details for PubMedCentralID PMC12407787

  • A molecular atlas of adult C. elegans motor neurons reveals ancient diversity delineated by conserved transcription factor codes. Cell reports Smith, J. J., Taylor, S. R., Blum, J. A., Feng, W., Collings, R., Gitler, A. D., Miller, D. M., Kratsios, P. 2024; 43 (3): 113857

    Abstract

    Motor neurons (MNs) constitute an ancient cell type targeted by multiple adult-onset diseases. It is therefore important to define the molecular makeup of adult MNs in animal models and extract organizing principles. Here, we generate a comprehensive molecular atlas of adult Caenorhabditis elegans MNs and a searchable database. Single-cell RNA sequencing of 13,200 cells reveals that ventral nerve cord MNs cluster into 29 molecularly distinct subclasses. Extending C. elegans Neuronal Gene Expression Map and Network (CeNGEN) findings, all MN subclasses are delineated by distinct expression codes of either neuropeptide or transcription factor gene families. Strikingly, combinatorial codes of homeodomain transcription factor genes succinctly delineate adult MN diversity in both C. elegans and mice. Further, molecularly defined MN subclasses in C. elegans display distinct patterns of connectivity. Hence, our study couples the connectivity map of the C. elegans motor circuit with a molecular atlas of its constituent MNs and uncovers organizing principles and conserved molecular codes of adult MN diversity.

    View details for DOI 10.1016/j.celrep.2024.113857

    View details for PubMedID 38421866

  • Challenges of profiling motor neuron transcriptomes from human spinal cord. Neuron Gautier, O., Blum, J. A., Maksymetz, J., Chen, D., Schweingruber, C., Mei, I., Hermann, A., Hackos, D. H., Hedlund, E., Ravits, J., Gitler, A. D. 2023; 111 (23): 3739-3741

    View details for DOI 10.1016/j.neuron.2023.10.035

    View details for PubMedID 38061330

  • A molecular atlas of adult C. elegans motor neurons reveals ancient diversity delineated by conserved transcription factor codes. bioRxiv : the preprint server for biology Smith, J. J., Taylor, S. R., Blum, J. A., Gitler, A. D., Miller, D. M., Kratsios, P. 2023

    Abstract

    Motor neurons (MNs) constitute an ancient cell type targeted by multiple adult-onset diseases. It is therefore important to define the molecular makeup of adult MNs in animal models and extract organizing principles. Here, we generated a comprehensive molecular atlas of adult Caenorhabditis elegans MNs and a searchable database (http://celegans.spinalcordatlas.org). Single-cell RNA-sequencing of 13,200 cells revealed that ventral nerve cord MNs cluster into 29 molecularly distinct subclasses. All subclasses are delineated by unique expression codes of either neuropeptide or transcription factor gene families. Strikingly, we found that combinatorial codes of homeodomain transcription factor genes define adult MN diversity both in C. elegans and mice. Further, molecularly defined MN subclasses in C. elegans display distinct patterns of connectivity. Hence, our study couples the connectivity map of the C. elegans motor circuit with a molecular atlas of its constituent MNs, and uncovers organizing principles and conserved molecular codes of adult MN diversity.

    View details for DOI 10.1101/2023.08.04.552048

    View details for PubMedID 37577463

    View details for PubMedCentralID PMC10418256

  • Genome-wide CRISPR screen reveals v-ATPase as a drug target to lower levels of ALS protein ataxin-2. Cell reports Kim, G., Nakayama, L., Blum, J. A., Akiyama, T., Boeynaems, S., Chakraborty, M., Couthouis, J., Tassoni-Tsuchida, E., Rodriguez, C. M., Bassik, M. C., Gitler, A. D. 2022; 41 (4): 111508

    Abstract

    Mutations in the ataxin-2 gene (ATXN2) cause the neurodegenerative disorders amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2). A therapeutic strategy using antisense oligonucleotides targeting ATXN2 has entered clinical trial in humans. Additional ways to decrease ataxin-2 levels could lead to cheaper or less invasive therapies and elucidate how ataxin-2 is normally regulated. Here, we perform a genome-wide fluorescence-activated cell sorting (FACS)-based CRISPR-Cas9 screen in human cells and identify genes encoding components of the lysosomal vacuolar ATPase (v-ATPase) as modifiers of endogenous ataxin-2 protein levels. Multiple FDA-approved small molecule v-ATPase inhibitors lower ataxin-2 protein levels in mouse and human neurons, and oral administration of at least one of these drugs-etidronate-is sufficient to decrease ataxin-2 in the brains of mice. Together, we propose v-ATPase as a drug target for ALS and SCA2 and demonstrate the value of FACS-based screens in identifying genetic-and potentially druggable-modifiers of human disease proteins.

    View details for DOI 10.1016/j.celrep.2022.111508

    View details for PubMedID 36288714

  • Transcriptional dynamics of murine motor neuron maturation in vivo and in vitro. Nature communications Patel, T., Hammelman, J., Aziz, S., Jang, S., Closser, M., Michaels, T. L., Blum, J. A., Gifford, D. K., Wichterle, H. 2022; 13 (1): 5427

    Abstract

    Neurons born in the embryo can undergo a protracted period of maturation lasting well into postnatal life. How gene expression changes are regulated during maturation and whether they can be recapitulated in cultured neurons remains poorly understood. Here, we show that mouse motor neurons exhibit pervasive changes in gene expression and accessibility of associated regulatory regions from embryonic till juvenile age. While motifs of selector transcription factors, ISL1 and LHX3, are enriched in nascent regulatory regions, motifs of NFI factors, activity-dependent factors, and hormone receptors become more prominent in maturation-dependent enhancers. Notably, stem cell-derived motor neurons recapitulate ~40% of the maturation expression program in vitro, with neural activity playing only a modest role as a late-stage modulator. Thus, the genetic maturation program consists of a core hardwired subprogram that is correctly executed in vitro and an extrinsically-controlled subprogram that is dependent on the in vivo context of the maturing organism.

    View details for DOI 10.1038/s41467-022-33022-4

    View details for PubMedID 36109497

  • Heat-shock chaperone HSPB1 regulates cytoplasmic TDP-43 phase separation and liquid-to-gel transition. Nature cell biology Lu, S., Hu, J., Arogundade, O. A., Goginashvili, A., Vazquez-Sanchez, S., Diedrich, J. K., Gu, J., Blum, J., Oung, S., Ye, Q., Yu, H., Ravits, J., Liu, C., Yates, J. R., Cleveland, D. W. 2022

    Abstract

    While acetylated, RNA-binding-deficient TDP-43 reversibly phase separates within nuclei into complex droplets (anisosomes) comprised of TDP-43-containing liquid outer shells and liquid centres of HSP70-family chaperones, cytoplasmic aggregates of TDP-43 are hallmarks of multiple neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here we show that transient oxidative stress, proteasome inhibition or inhibition of the ATP-dependent chaperone activity of HSP70 provokes reversible cytoplasmic TDP-43 de-mixing and transition from liquid to gel/solid, independently of RNA binding or stress granules. Isotope labelling mass spectrometry was used to identify that phase-separated cytoplasmic TDP-43 is bound by the small heat-shock protein HSPB1. Binding is direct, mediated through TDP-43's RNA binding and low-complexity domains. HSPB1 partitions into TDP-43 droplets, inhibits TDP-43 assembly into fibrils, and is essential for disassembly of stress-induced TDP-43 droplets. A decrease in HSPB1 promotes cytoplasmic TDP-43 de-mixing and mislocalization. HSPB1 depletion was identified in spinal motor neurons of patients with ALS containing aggregated TDP-43. These findings identify HSPB1 to be a regulator of cytoplasmic TDP-43 phase separation and aggregation.

    View details for DOI 10.1038/s41556-022-00988-8

    View details for PubMedID 36075972

  • Singling out motor neurons in the age of single-cell transcriptomics. Trends in genetics : TIG Blum, J. A., Gitler, A. D. 2022

    Abstract

    Motor neurons are a remarkably powerful cell type in the central nervous system. They innervate and control the contraction of virtually every muscle in the body and their dysfunction underlies numerous neuromuscular diseases. Some motor neurons seem resistant to degeneration whereas others are vulnerable. The intrinsic heterogeneity of motor neurons in adult organisms has remained elusive. The development of high-throughput single-cell transcriptomics has changed the paradigm, empowering rapid isolation and profiling of motor neuron nuclei, revealing remarkable transcriptional diversity within the skeletal and autonomic nervous systems. Here, we discuss emerging technologies for defining motor neuron heterogeneity in the adult motor system as well as implications for disease and spinal cord injury. We establish a roadmap for future applications of emerging techniques - such as epigenetic profiling, spatial RNA sequencing, and single-cell somatic mutational profiling to adult motor neurons, which will revolutionize our understanding of the healthy and degenerating adult motor system.

    View details for DOI 10.1016/j.tig.2022.03.016

    View details for PubMedID 35487823

  • Neurotoxic reactive astrocytes induce cell death via saturated lipids. Nature Guttenplan, K. A., Weigel, M. K., Prakash, P., Wijewardhane, P. R., Hasel, P., Rufen-Blanchette, U., Munch, A. E., Blum, J. A., Fine, J., Neal, M. C., Bruce, K. D., Gitler, A. D., Chopra, G., Liddelow, S. A., Barres, B. A. 2021

    Abstract

    Astrocytes regulate the response of the central nervous system to disease and injury and have been hypothesized to actively kill neurons in neurodegenerative disease1-6. Here we report an approach to isolate one component of the long-sought astrocyte-derived toxic factor5,6. Notably, instead of a protein, saturated lipids contained in APOE and APOJ lipoparticles mediate astrocyte-induced toxicity. Eliminating the formation of long-chain saturated lipids by astrocyte-specific knockout of the saturated lipid synthesis enzyme ELOVL1 mitigates astrocyte-mediated toxicity in vitro as well as in a model of acute axonal injury in vivo. These results suggest a mechanism by which astrocytes kill cells in the central nervous system.

    View details for DOI 10.1038/s41586-021-03960-y

    View details for PubMedID 34616039

  • Single-cell transcriptomic analysis of the adult mouse spinal cord reveals molecular diversity of autonomic and skeletal motor neurons. Nature neuroscience Blum, J. A., Klemm, S., Shadrach, J. L., Guttenplan, K. A., Nakayama, L., Kathiria, A., Hoang, P. T., Gautier, O., Kaltschmidt, J. A., Greenleaf, W. J., Gitler, A. D. 2021

    Abstract

    The spinal cord is a fascinating structure that is responsible for coordinating movement in vertebrates. Spinal motor neurons control muscle activity by transmitting signals from the spinal cord to diverse peripheral targets. In this study, we profiled 43,890 single-nucleus transcriptomes from the adult mouse spinal cord using fluorescence-activated nuclei sorting to enrich for motor neuron nuclei. We identified 16 sympathetic motor neuron clusters, which are distinguishable by spatial localization and expression of neuromodulatory signaling genes. We found surprising skeletal motor neuron heterogeneity in the adult spinal cord, including transcriptional differences that correlate with electrophysiologically and spatially distinct motor pools. We also provide evidence for a novel transcriptional subpopulation of skeletal motor neuron (gamma*). Collectively, these data provide a single-cell transcriptional atlas ( http://spinalcordatlas.org ) for investigating the organizing molecular logic of adult motor neuron diversity, as well as the cellular and molecular basis of motor neuron function in health and disease.

    View details for DOI 10.1038/s41593-020-00795-0

    View details for PubMedID 33589834

  • p53 is a central regulator driving neurodegeneration caused by C9orf72 poly(PR). Cell Maor-Nof, M. n., Shipony, Z. n., Lopez-Gonzalez, R. n., Nakayama, L. n., Zhang, Y. J., Couthouis, J. n., Blum, J. A., Castruita, P. A., Linares, G. R., Ruan, K. n., Ramaswami, G. n., Simon, D. J., Nof, A. n., Santana, M. n., Han, K. n., Sinnott-Armstrong, N. n., Bassik, M. C., Geschwind, D. H., Tessier-Lavigne, M. n., Attardi, L. D., Lloyd, T. E., Ichida, J. K., Gao, F. B., Greenleaf, W. J., Yokoyama, J. S., Petrucelli, L. n., Gitler, A. D. 2021

    Abstract

    The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a GGGGCC repeat expansion in the C9orf72 gene. We developed a platform to interrogate the chromatin accessibility landscape and transcriptional program within neurons during degeneration. We provide evidence that neurons expressing the dipeptide repeat protein poly(proline-arginine), translated from the C9orf72 repeat expansion, activate a highly specific transcriptional program, exemplified by a single transcription factor, p53. Ablating p53 in mice completely rescued neurons from degeneration and markedly increased survival in a C9orf72 mouse model. p53 reduction also rescued axonal degeneration caused by poly(glycine-arginine), increased survival of C9orf72 ALS/FTD-patient-induced pluripotent stem cell (iPSC)-derived motor neurons, and mitigated neurodegeneration in a C9orf72 fly model. We show that p53 activates a downstream transcriptional program, including Puma, which drives neurodegeneration. These data demonstrate a neurodegenerative mechanism dynamically regulated through transcription-factor-binding events and provide a framework to apply chromatin accessibility and transcription program profiles to neurodegeneration.

    View details for DOI 10.1016/j.cell.2020.12.025

    View details for PubMedID 33482083

  • A Role for Microglia in Retinal Development. The Journal of neuroscience : the official journal of the Society for Neuroscience Guttenplan, K., Blum, J., Bennett, M. 2018; 38 (43): 9126–28

    View details for PubMedID 30355623

  • A Role for Microglia in Retinal Development JOURNAL OF NEUROSCIENCE Guttenplan, K., Blum, J., Bennett, M. 2018; 38 (43): 9126-9128

    View details for DOI 10.1523/JNEUROSCI.1813-18.2018

    View details for Web of Science ID 000448145700002