About

Mark A. Krasnow is the Paul and Mildred Berg Professor of Biochemistry and an Investigator at the Howard Hughes Medical Institute. He is based in Beckman B439 and can be contacted via Stanford University. The page lists him as a leading member of the Krasnow Lab, which focuses on various aspects of lung biology and development, including the mapping of output circuits of breathing and innate vocalization, the developmental trajectory of lung alveolar epithelial cell types, and the identification and characterization of human alveolar stem cells. The lab also investigates macrophage populations in lung adenocarcinoma, fibroblast stem cell dynamics, epithelial interactions in homeostasis and disease, and the development of alveolar organlet systems as disease and drug screening models. Krasnow's lab includes graduate students, postdoctoral fellows, instructors, research specialists, and research assistants working on these diverse projects. The lab's research environment fosters interdisciplinary studies and the development of new model organisms for biology and medicine.

Research topics

• Biology
• Genetics
• Computational biology
• Cell biology
• Immunology
• Pathology
• Medicine
• Virology
• Data Mining
• Internal medicine
• Artificial Intelligence
• Computer Science
• Database
• Evolutionary biology

Selected publications

• Rapid centromere turnover and the adaptive radiation of lemurs

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-05-19

  articleOpen access

  Centromeres represent essential chromosomal structures required for faithful chromosome segregation during cell division but are paradoxically hypermutable, leading to centromere drive and reproductive isolation in closely related species. Using long-read sequencing, we generate nearly complete genomes (2.1-2.5 Gbp) from eight lemur species and characterize the sequence, epigenetic and cytogenetic structure of 223 strepsirrhini centromeres providing an alternative primate perspective of centromere evolution. No lemur centromere consists of α-satellite DNA that typifies the haplorhine lineage; instead, each species evolved its own distinct higher-order centromeric repeat sequence, varying substantially in both monomer length (ranging from 41-548 bp) and primary sequence composition (GC percentages 28.7-67.9%) including centromere cooption of telomeric repeats in brown lemurs. Most centromeres show characteristic hypomethylation dip regions (110-300 kbp) as candidates for kinetochore attachment. The centromere sequence motif shows no apparent sequence homology among lemur genera, even for species separated by less than 15 million years (Lemur and Eulemur). We estimate a >6-fold increased rate in primary centromeric motif turnover in strepsirrhines when compared to haplorhines and this occurred in conjunction with positive selection of the CENP-B protein in lemur lineages. We propose that lemur radiation and centromere diversification are linked, whereby accelerated motif turnover provides a stasipatric barrier contributing to rapid chromosomal evolution.

  PublisherDOI

• Stem cell control in the lung by an autocrine injury-activated Igf complex

  Science · 2026-04-16 · 1 citations

  articleSenior author

  Stem cells proliferate after injury to repair damaged tissue, and chronic injury can promote cancer. However, the injury-activated signals and regulatory mechanisms, and their relationship to cancer, are poorly understood. Here, we identified insulin-like growth factor 2 (Igf2) as an injury-activated mitogen for lung neuroendocrine stem cells, which are facultative airway progenitors and a cell of origin of small-cell lung cancer in mice. Igf2 was constitutively produced by the stem cells but sequestered in the niche by coexpressed Igf binding proteins (Igfbps). Airway injury released Igf2 and induced proliferation by transiently activating Igf2 receptors and repressing retinoblastoma (Rb) tumor suppressor. Permanent pathway activation by Rb deletion initiated continuous stem cell division. Thus, beyond their classical hormonal roles in physiology, growth, and aging, Igf proteins operate locally and rapidly with Igfbp and Rb to control injury-induced stem cell proliferation and tumor initiation.

  PublisherDOI

• In vivo self-renewal and expansion of quiescent stem cells from a non-human primate

  Nature Communications · 2025-06-24 · 4 citations

  articleOpen access

  The development of non-human primate models is essential for the fields of developmental and regenerative biology because those models will more closely approximate human biology than do murine models. Based on single cell RNAseq and fluorescence-activated cell sorting, we report the identification and functional characterization of two quiescent stem cell populations (skeletal muscle stem cells (MuSCs) and mesenchymal stem cells termed fibro-adipogenic progenitors (FAPs)) in the non-human primate Microcebus murinus (the gray mouse lemur). We demonstrate in vivo proliferation, differentiation, and self-renewal of both MuSCs and FAPs. By combining cell phenotyping with cross-species molecular profiling and pharmacological interventions, we show that mouse lemur MuSCs and FAPs are more similar to human than to mouse counterparts. We identify unexpected gene targets involved in regulating primate MuSC proliferation and primate FAP adipogenic differentiation. Moreover, we find that the cellular composition of mouse lemur muscle better models human muscle than does macaque (Macaca fascicularis) muscle. Finally, we note that our approach presents as a generalizable pipeline for the identification, isolation, and characterization of stem cell populations in new animal models.

  PublisherOA PDFDOI

• A primate model organism for cardiac arrhythmias identifies a magnesium transporter in pacemaker function

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-06-01 · 2 citations

  preprintOpen accessSenior authorCorresponding

  ABSTRACT Cardiac arrhythmias afflict tens of millions of people, causing one-fifth of all deaths 1 . Although mouse models have aided understanding of some pacemaker genes and arrhythmias 2,3 , mice are not known to naturally acquire arrhythmias, and the substantial differences between mouse and human cardiac anatomy and physiology have limited their utility in preclinical studies and pharmacological testing 2,4 . To establish a primate genetic model organism for arrhythmias, we carried out an electrocardiographic (ECG) screen of over 350 lab and wild mouse lemurs ( Microcebus spp. ), an emerging model organism that is among the smallest, fastest-reproducing, and most abundant primates 5 . Twenty-two lemurs (6.2%) were identified with eight different naturally-occurring arrhythmias resembling human ECG pathologies (SSS, PACs, Afib, PVCs, NSVT, STD, iTWs, STE). Pedigree construction showed two were familial, premature atrial contractions (PACs)/atrial fibrillation (Afib) and sick sinus syndrome (SSS), an episodic bradycardia. Genome sequencing of the SSS pedigree mapped the disease locus to a 1.4 Mb interval on chromosome 7 and supported autosomal recessive Mendelian inheritance. The most appealing candidate gene in the interval was SLC41A2 , a little studied magnesium transporter 6,7 . SLC41A2 is expressed in human iPSC-derived sinoatrial node cells (iSANC) and localizes to the sarcoplasmic reticulum. Although mouse SLC41A2 knockouts do not show a cardiac pacemaker phenotype 8 , CRISPR-mediated SLC41A2 knockout altered human iSANC magnesium dynamics and slowed their calcium transient firing rate. The results suggest SLC41A2 functions cell autonomously and primate-specifically in cardiac pacemaker cells, and that intracellular magnesium dynamics have a crucial but previously unappreciated role in setting pacemaker rate. Thus, mouse lemur is a valuable model for discovering new genes, molecules, and mechanisms of the primate pacemaker, and for identifying novel candidate genes and therapeutic targets for human arrhythmias. The approach can be used to elucidate other primate diseases and traits.

  PublisherOA PDFDOI

• Chromatin and gene-regulatory dynamics of human pulmogenesis by single cell multiomic sequencing

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-09-25

  preprintOpen access

  Abstract Human lung development is governed by complex gene regulatory networks that orchestrate cellular differentiation and organogenesis. We present a single cell multiomic atlas of human pulmogenesis, simultaneously capturing both the chromatin accessibility profile and the transcriptome from each cell across fetal lungs spanning from post-conception weeks (PCW) 12 to 23. We identified 44 distinct developing cell clusters and mapped 581,745 candidate cis-regulatory elements and nominated 121,486 non-redundant peak-to-gene linkages. We identify highly regulated genes (HRGs) and the cognate highly regulating peaks (HRPs) that describe the most salient regulatory gene programs and developmental enhancer sites for each cell type. Trajectory analysis along with interpretable cell type specific convolutional neural network models were developed to delineate dynamic regulatory programs driving key developmental transitions, including aerocyte and arterial differentiation and alveolar formation. Furthermore, we identified distinct vascular smooth muscle subpopulations with unique spatial associations to either arterial or venous structures with reciprocal signaling within each niche. We also uncovered the regulatory modules of surfactant production in alveolar progenitors, implicating a direct role for the glucocorticoid receptor alongside novel transcription factors. Finally, using cell type specific models linking DNA sequence to chromatin accessibility we prioritize variants associated with impaired pulmonary function or disease and nominate mechanisms of motif disruption. Overall, our multiomic atlas deepens our understanding of the gene-regulatory architecture underlying human lung development and provides a valuable resource for the community to dissect the cellular and molecular programs of pulmonary physiology and disease at the cellular and nucleotide precision.

  PublisherOA PDFDOI

• Neuronal activity-dependent mechanisms of small cell lung cancer pathogenesis

  Nature · 2025-09-10 · 41 citations

  articleOpen access

  Neural activity is increasingly recognized as a crucial regulator of cancer growth. In the brain, neuronal activity robustly influences glioma growth through paracrine mechanisms1 and by electrochemical integration of malignant cells into neural circuitry via neuron-to-glioma synapses2,3. Outside of the central nervous system, innervation of tumours such as prostate, head and neck, breast, pancreatic, and gastrointestinal cancers by peripheral nerves similarly regulates cancer progression4–12. However, the extent to which the nervous system regulates small cell lung cancer (SCLC) progression, either in the lung or when growing within the brain, is less well understood. SCLC is a lethal high-grade neuroendocrine tumour that exhibits a strong propensity to metastasize to the brain. Here we demonstrate that in the lung, vagus nerve transection markedly inhibits primary lung tumour development and progression, highlighting a critical role for innervation in SCLC growth. In the brain, SCLC cells co-opt neuronal activity-regulated mechanisms to stimulate growth and progression. Glutamatergic and GABAergic (γ-aminobutyric acid-producing) cortical neuronal activity each drive proliferation of SCLC in the brain through paracrine and synaptic neuron–cancer interactions. SCLC cells form bona fide neuron-to-SCLC synapses and exhibit depolarizing currents with consequent calcium transients in response to neuronal activity; such SCLC cell membrane depolarization is sufficient to promote the growth of intracranial tumours. Together, these findings illustrate that neuronal activity has a crucial role in dictating SCLC pathogenesis. Glutamatergic and GABAergic (γ-aminobutyric acid-producing) cortical neuronal activity drives proliferation of small lung cell cancer via paracrine interactions and through synapses formed with tumour cells.

  PublisherOA PDFDOI

• In vivo self-renewal and expansion of quiescent stem cells from a non-human primate

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-03-28

  preprintOpen access

  Abstract The development of non-human primate models is essential for the fields of developmental and regenerative biology because those models will more closely approximate human biology than do murine models. Based on single cell RNAseq and fluorescence-activated cell sorting, we report the identification and functional characterization of two quiescent stem cell populations (skeletal muscle stem cells (MuSCs) and mesenchymal stem cells termed fibro-adipogenic progenitors (FAPs)) in the non-human primate Microcebus murinus (the gray mouse lemur). We demonstrate in vivo proliferation, differentiation, and self-renewal of both MuSCs and FAPs. By combining cell phenotyping with cross-species molecular profiling and pharmacological interventions, we show that mouse lemur MuSCs and FAPs are more similar to human than to mouse counterparts. We identify unexpected gene targets involved in regulating primate MuSC proliferation and primate FAP adipogenic differentiation. Moreover, we find that the cellular composition of mouse lemur muscle better models human muscle than does macaque ( Macaca fascicularis ) muscle. Finally, we note that our approach presents as a generalizable pipeline for the identification, isolation, and characterization of stem cell populations in new animal models.

  PublisherOA PDFDOI

• Benchmarking cell type and gene set annotation by large language models with AnnDictionary

  Nature Communications · 2025-10-28 · 4 citations

  articleOpen access

  We develop an open-source package called AnnDictionary to facilitate the parallel, independent analysis of multiple anndata. AnnDictionary is built on top of LangChain and AnnData and supports all common large language model (LLM) providers. AnnDictionary only requires 1 line of code to configure or switch the LLM backend and it contains numerous multithreading optimizations to support the analysis of many anndata and large anndata. We use AnnDictionary to perform the first benchmarking study of all major LLMs at de novo cell-type annotation. LLMs vary greatly in absolute agreement with manual annotation based on model size. Inter-LLM agreement also varies with model size. We find that LLM annotation of most major cell types to be more than 80-90% accurate, and will maintain a leaderboard of LLM cell type annotation. Furthermore, we benchmark these LLMs at functional annotation of gene sets, and find that Claude 3.5 Sonnet recovers close matches of functional gene set annotations in over 80% of test sets. Cell type labelling in single-cell datasets remains a major bottleneck. Here, the authors present AnnDictionary, an open-source toolkit that enables atlas-scale analysis and provides the first benchmark of LLMs for de novo cell type annotation from marker genes, showing high accuracy at low cost.

  PublisherOA PDFDOI

• CNSC-61. NEURONAL-ACTIVITY DEPENDENT MECHANISMS OF SMALL CELL LUNG CANCER PATHOGENESIS

  Neuro-Oncology · 2024-11-01

  articleOpen access

  Abstract Neural activity is increasingly recognized as a crucial regulator of cancer growth. In the brain, neuronal activity robustly influences glioma growth both through paracrine mechanisms and through electrochemical integration of malignant cells into neural circuitry via neuron-to-glioma synapses. Outside of the CNS, innervation of tumors such as prostate, breast, pancreatic, and gastrointestinal cancers by peripheral nerves similarly regulates cancer progression. However, the extent to which the nervous system regulates lung cancer progression, either in the lung or when metastatic to the brain, is less well understood. Small cell lung cancer (SCLC) is a lethal high-grade neuroendocrine tumor that exhibits a strong propensity to metastasize to the brain. Here we demonstrate that SCLC cells in the brain co-opt neuronal activity-regulated mechanisms to stimulate growth and progression. With in vivo optogenetic stimulation, we show that glutamatergic and GABAergic cortical neuronal activity each drive proliferation of SCLC through both paracrine and synaptic neuron-cancer interactions. In the brain, SCLC cells form bona fide neuron-to-SCLC synapses evident on immunoelectron microscopy for the first time for non-brain derived malignancy. Using electrophysiology and two-photon calcium imaging, we find that SCLC cells exhibit depolarizing currents with consequent calcium transients in response to neuronal activity. SCLC cell membrane depolarization is sufficient to promote the growth of intracranial tumors. We also demonstrate reciprocal effects of SCLC on neurons, manifesting as increased neuronal synaptogenesis and elevated field potentials in regions of the tumor. Finally, in the lung, vagus nerve transection markedly inhibits primary lung tumor formation and development and awards survival benefit in spontaneous genetic SCLC model, highlighting a critical role for innervation in overall SCLC growth. Taken together, these studies illustrate that neuronal activity plays a crucial role in dictating SCLC pathogenesis in both the lung and the brain.

  PublisherOA PDFDOI

• Interstitial macrophages are a focus of viral takeover and inflammation in COVID-19 initiation in human lung

  The Journal of Experimental Medicine · 2024-04-10 · 43 citations

  articleOpen accessSenior authorCorresponding

  Early stages of deadly respiratory diseases including COVID-19 are challenging to elucidate in humans. Here, we define cellular tropism and transcriptomic effects of SARS-CoV-2 virus by productively infecting healthy human lung tissue and using scRNA-seq to reconstruct the transcriptional program in "infection pseudotime" for individual lung cell types. SARS-CoV-2 predominantly infected activated interstitial macrophages (IMs), which can accumulate thousands of viral RNA molecules, taking over 60% of the cell transcriptome and forming dense viral RNA bodies while inducing host profibrotic (TGFB1, SPP1) and inflammatory (early interferon response, CCL2/7/8/13, CXCL10, and IL6/10) programs and destroying host cell architecture. Infected alveolar macrophages (AMs) showed none of these extreme responses. Spike-dependent viral entry into AMs used ACE2 and Sialoadhesin/CD169, whereas IM entry used DC-SIGN/CD209. These results identify activated IMs as a prominent site of viral takeover, the focus of inflammation and fibrosis, and suggest targeting CD209 to prevent early pathology in COVID-19 pneumonia. This approach can be generalized to any human lung infection and to evaluate therapeutics.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R01HL075769

  NIH · $1.4M · 2009

• Molecular mechanisms of SCLC initiation and detection in mice and humans

  NIH · $2.3M · 2018–2024

• NIH Grant K12HL089989

  NIH · $1.6M · 2014

• Interrogation of individual cells to identify progenitor cells and their niches

  NIH · $7.0M · 2009–2017

• Medical Scientist Training Program

  NIH · $49.7M · 1976–2022

Frequent coauthors

• Stephen R. Quake

  Stanford University

  58 shared

• Astrid Gillich

  Howard Hughes Medical Institute

  39 shared

• Christin S. Kuo

  Stanford University

  38 shared

• Douglas Brownfield

  Howard Hughes Medical Institute

  33 shared

• F. Hernán Espinoza

  Howard Hughes Medical Institute

  30 shared

• Kyle J. Travaglini

  Allen Institute

  29 shared

• Laure‐Emmanuelle Zaragosi

  Institut de Pharmacologie Moléculaire et Cellulaire

  29 shared

• José Ordovás-Montañés

  Broad Institute

  26 shared

Labs

• Krasnow LabPI

Education

• M.D.

  University of Chicago

  1985

• Ph.D., Biochemistry

  University of Chicago

  1983

• B.S., Biology and Chemistry

  University of Illinois at Urbana

  1978

Awards & honors

• Paul and Mildred Berg Professor
• Beckman Center Director (effective September 1, 2025)