About

Tom Maniatis, PhD, is the Isidore S. Edelman Professor of Biochemistry at Columbia University Irving Medical Center, affiliated with the Mortimer B. Zuckerman Mind Brain Behavior Institute. He is renowned for pioneering the development of gene cloning technology and its application to basic research and biotechnology, coauthoring the definitive laboratory manual on Molecular Cloning. His research has led to fundamental advances in understanding gene regulation, RNA splicing, innate immunity signaling pathways, single cell diversity in the nervous system, and neurodegenerative disease mechanisms. Dr. Maniatis received his B.A. and M.S. degrees from the University of Colorado in chemistry and biology, and his Ph.D. in molecular biology from Vanderbilt University. He completed postdoctoral studies at Harvard University and the Laboratory of Molecular Biology in Cambridge, England. His academic career includes positions at the California Institute of Technology and Harvard University. Currently, he serves as the Director of the Columbia University Precision Medicine Initiative, a member of the Executive Committee of the Zuckerman Mind Brain Behavior Institute, and the Principal Investigator of the Maniatis Lab. His research over the past decade has focused on disease mechanisms of ALS, utilizing human genetic, stem cell, and animal model approaches, as well as studying the structure and function of the clustered protocadherin genes, with investigations into motor and affective behaviors, and the role of autophagy in ALS progression. Dr. Maniatis's contributions have been recognized with numerous awards, including the Eli Lilly Award in Microbiology and Immunology, the Richard Lounsbery Award for Biology and Medicine, and the 2012 Lasker-Koshland Special Achievement Award in Medical Science. He is a member of the U.S. National Academy of Sciences, the U.S. Academy of Medicine, and a fellow of the U.S. Academy of Arts and Sciences.

Research topics

• Medicine
• Immunology
• Internal medicine
• Biology
• Virology
• Pathology
• Environmental health
• Genetics

Selected publications

• Genotype-specific interferon signatures in amyotrophic lateral sclerosis relate to disease severity

  Brain · 2025-09-03 · 2 citations

  articleOpen access

  Innate immune signalling pathways are hyperactivated in the CNS of patients with amyotrophic lateral sclerosis (ALS), as well as in preclinical models with diverse causative backgrounds including TDP-43, SOD1 and C9orf72 mutations. This raises an important question of whether these pathways are key pathogenic features of the disease, and whether therapeutic amelioration could be beneficial. Here, we systematically profile type-I interferon (IFN)-stimulated gene (ISG) expression signatures using a non-biased approach in CNS tissue from a cohort of 36 individuals with ALS, including sporadic ALS (sALS; n = 18), genetic ALS caused by: (i) a C9orf72 hexanucleotide repeat expansion (C9-ALS; n = 11); and (ii) a SOD1 mutation (SOD1-ALS; n = 5), alongside age- and sex-matched individuals who died of a non-neurological cause (n = 12). Using this deeply phenotyped cohort we have implemented targeted transcriptomic analysis and immunohistochemistry to interrogate the nature and extent of the activation of the type-I IFN response in patients. We determined disease- and genotype-specific IFN signatures that correlate with clinical phenotype. Correlation analysis linked six ISGs with aggressive disease progression, as indicated by negative correlation with age at death in ALS patients. Notably, significant upregulation of ISGs was observed in C9-ALS patients, with higher ISG expression correlating with shorter disease duration. Noting that our genotype- and disease-specific signatures correlated with metrics of disease progression, we explored the therapeutic potential of targeting this pathway in a mouse model of ALS. Treatment with an IFN pathway inhibitor reduced IFN response markers, delayed disease progression, including motor decline, and extended survival in ALS mice. We conclude that upregulation of gene expression in the type-I IFN pathway represents a key pathological feature of ALS and that inhibiting this pathway may provide a promising therapeutic approach for treating ALS.

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• Safeguarding the future of biomedical science in the United States

  Cell · 2025-02-28 · 1 citations

  article1st authorCorresponding
  PublisherDOI

• Enhancer Dynamics and Spatial Organization Drive Anatomically Restricted Cellular States in the Human Spinal Cord

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-01-11

  preprintOpen access

  Here, we report the spatial organization of RNA transcription and associated enhancer dynamics in the human spinal cord at single-cell and single-molecule resolution. We expand traditional multiomic measurements to reveal epigenetically poised and bivalent active transcriptional enhancer states that define cell type specification. Simultaneous detection of chromatin accessibility and histone modifications in spinal cord nuclei reveals previously unobserved cell-type specific cryptic enhancer activity, in which transcriptional activation is uncoupled from chromatin accessibility. Such cryptic enhancers define both stable cell type identity and transitions between cells undergoing differentiation. We also define glial cell gene regulatory networks that reorganize along the rostrocaudal axis, revealing anatomical differences in gene regulation. Finally, we identify the spatial organization of cells into distinct cellular organizations and address the functional significance of this observation in the context of paracrine signaling. We conclude that cellular diversity is best captured through the lens of enhancer state and intercellular interactions that drive transitions in cellular state. This study provides fundamental insights into the cellular organization of the healthy human spinal cord.

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• Mapping and characterization of structural variation in 17,795 human genomes

  UNC Libraries · 2024-03-07

  articleOpen access

  A key goal of whole-genome sequencing for studies of human genetics is to interrogate all forms of variation, including single-nucleotide variants, small insertion or deletion (indel) variants and structural variants. However, tools and resources for the study of structural variants have lagged behind those for smaller variants. Here we used a scalable pipeline1 to map and characterize structural variants in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest, to our knowledge, whole-genome-sequencing-based structural variant resource so far. On average, individuals carry 2.9 rare structural variants that alter coding regions; these variants affect the dosage or structure of 4.2 genes and account for 4.0–11.2% of rare high-impact coding alleles. Using a computational model, we estimate that structural variants account for 17.2% of rare alleles genome-wide, with predicted deleterious effects that are equivalent to loss-of-function coding alleles; approximately 90% of such structural variants are noncoding deletions (mean 19.1 per genome). We report 158,991 ultra-rare structural variants and show that 2% of individuals carry ultra-rare megabase-scale structural variants, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and noncoding elements, and reveal trends that relate to element class and conservation. This work will help to guide the analysis and interpretation of structural variants in the era of whole-genome sequencing.

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• From bacterial operons to gene therapy: 50 years of the journal Cell

  Cell · 2024-11-01 · 1 citations

  article1st authorCorresponding
  PublisherDOI

• Correction: Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

  Genome Medicine · 2024-01-06 · 1 citations

  erratumOpen access

  International audience

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• Lack of association between classical HLA genes and asymptomatic SARS-CoV-2 infection

  Human Genetics and Genomics Advances · 2024-04-26 · 6 citations

  articleOpen access

  Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

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• Abstract C037: Polyethnic-1000: A New York-based initiative to advance cancer genomics through recruitment of diverse racial & ethnic populations

  Cancer Epidemiology Biomarkers & Prevention · 2023-01-01

  article

  Abstract Recent advances in DNA sequencing technologies have revolutionized approaches to the prevention, early detection, diagnosis, and treatment of cancers. However, our current knowledge about tumor biology, cancer risk, and response to treatment is limited due to significant underrepresentation of non-European populations in genomic cancer research, including clinical trials. The vast majority of samples in publicly available genomic databases have been derived from patients of European descent. These inequities limit our understanding of cancer and the impact of ancestry on the various manifestations of this disease. Moreover, exclusion of minoritized populations may exacerbate health disparities and stymie their ability to equally benefit from participation in trials or the innovations that result from such studies. Through the Polyethnic-1000 (P1000) initiative, we sought to leverage the racial and ethnic diversity within New York City to conduct initial investigations that address the existing disparities in cancer genomics studies. We recruited healthcare facilities to join the P1000 Consortium with a particular focus on hospitals outside Manhattan that served a diverse racial and ethnic population. In Phase 1, clinical and scientific protocols were implemented to collect and process 176 archival tumor samples representing 39 cancer types from individuals who self-identified as “non-white.” This pilot study confirmed our ability to procure and analyze tissues using whole-exome and RNA sequencing. Importantly, we estimated each participant’s percentage of ancestry at the continental and subregional levels by applying ADMIXTURE software to our tumor samples using the reference populations from the 1000 Genomes Project. We observed that genetic information nearly always correlates at least partially with self-identified origins, but genetic classifications are more specific and allow the identification of mixed ancestry. We entered Phase 2 of the P1000 Initiative by launching a research program. The awards allowed investigators in the Consortium to compete for support of new or recently initiated projects designed to identify ancestry-associated genomic determinants in specific cancer types. We funded seven of the competing groups; the projects span eight primary cancers. All but one of the studies are focused on individuals of African ancestry; one addresses lung cancer in East Asian patients. With support from Illumina, we plan to perform tumor/normal whole genome sequencing and tumor RNASeq on 1000 cases. The resulting data set would be among the largest and most diverse collection of full-genome pairs available in oncology. It will be housed at the NYGC with initial access for all members of the P-1000 Consortium then for the entire research community after an embargo period. P1000 has established a framework to enhance interactions among our region’s academic and health centers to advance cancer genomics. These efforts should improve and widen the use of genomics for all, especially currently underserved racial and ethnic populations. Citation Format: Onyinye Balogun, Melissa Davis, Michelle Mehallow, Nicolas Robine, Lara Winterkorn, Dayna Oschwald, Michael Zody, Samuel Aparicio, Tom Maniatis, Harold Varmus, Charles Sawyers, David Tuveson. Polyethnic-1000: A New York-based initiative to advance cancer genomics through recruitment of diverse racial & ethnic populations [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C037.

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• Molecular and Clinical Epidemiology of SARS-CoV-2 Infection Among Vaccinated and Unvaccinated Individuals in a Large Healthcare Organization from New Jersey

  Preprints.org · 2023-07-21 · 4 citations

  preprintOpen access

  New Jersey was among the first states impacted by the COVID-19 pandemic, with one of the highest overall death rates in the nation. Nevertheless, relatively few reports have been published focusing specifically on New Jersey. Here we report on molecular, clinical, and epidemiologic observations from the largest healthcare network in the state, in a cohort of vaccinated and unvaccinated individuals with laboratory-confirmed SARS-CoV-2 infection. We conducted molecular surveillance of SARS-CoV-2-positive nasopharyngeal swabs collected in nine hospitals from December 2020 through June 2022, using both whole genome sequencing (WGS) and a real-time RT-PCR screening assay targeting spike protein mutations found in variants of concern (VOC) within our region. De-identified clinical data were obtained retrospectively, including demographics, COVID-19 vaccination status, ICU admission, ventilator support, mortality, and medical history. Statistical analyses were performed to identify associations between SARS-CoV-2 variants, vaccination status, clinical outcomes, and medical risk factors. A total of 5,007 SARS-CoV-2-positive nasopharyngeal swabs were successfully screened and/or sequenced. Variant screening identified three predominant VOC, including Alpha (n =714), Delta (n =1,877), and Omicron (n =1,802). Omicron isolates were further sub-typed as BA.1 (n =899), BA.2 (n =853), and BA.4/BA.5 (n =50); the remaining 614 isolates were classified as “Other”. Approximately 31.5% (1,577/5,007) of the samples were associated with vaccine breakthrough infections, which increased in frequency following the emergence of Delta and Omicron. Severe clinical outcomes included ICU admission (336/5007 = 6.7%), ventilator support (236/5007 = 4.7%), and mortality (430/5007 = 8.6%), with increasing age being the most significant contributor to each (p <0.001). Unvaccinated individuals accounted for 79.7% (268/336) of ICU admissions, 78.3% (185/236) of ventilator cases, and 74.4% (320/430) of deaths. Highly significant (p <0.001) increases in mortality were observed in individuals with cardiovascular disease, hypertension, cancer, diabetes, and hyperlipidemia, but not with obesity, thyroid disease, or respiratory disease. Significant differences (p <0.001) in clinical outcomes were also noted between SARS-CoV-2 variants, including Delta, Omicron BA.1, and Omicron BA.2. Vaccination was associated with significantly improved clinical outcomes in our study, despite an increase in breakthrough infections associated with waning immunity, greater antigenic variability, or both. Underlying comorbidities contributed significantly to mortality in both vaccinated and unvaccinated individuals, with increasing risk based on the total number of comorbidities. Real-time RT-PCR-based screening facilitated timely identification of predominant variants using a minimal number of spike protein mutations, with faster turnaround time and reduced cost compared to WGS. Continued evolution of SARS-CoV-2 variants will likely require ongoing surveillance for new VOCs, with real-time assessment of clinical impact.

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• Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

  Genome Medicine · 2023-04-05 · 77 citations

  articleOpen access

  Abstract Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7 , with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10 −4 ) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10 −4 ). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10 −3 ), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10 −8 ). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10 −5 ). Conclusions Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.

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Recent grants

• NIH Grant R56NS043915

  NIH · $553k · 2013

• NIH Grant R01NS043915

  NIH · $6.5M · 2012

• Single Cell Studies of Lineage Specific Expression of the Protocadherin Gene Clus

  NIH · $440k · 2014–2016

• The Role of Clustered Protocadherins in Neurite Self-avoidance

  NIH · $1.5M · 2015–2019

• NIH Grant P01GM029301

  NIH · $7.7M · 1995

Frequent coauthors

• Yu Zhang

  207 shared

• Jean‐Laurent Casanova

  Université Paris Cité

  150 shared

• Qian Zhang

  Inserm

  137 shared

• Laurent Abel

  Université Paris Cité

  124 shared

• YL Lau

  University of Hong Kong

  104 shared

• Peng Zhang

  Zhejiang Hospital

  92 shared

• Emmanuelle Jouanguy

  Hospital for Sick Children

  74 shared

• Laurent Rénia

  Agency for Science, Technology and Research

  73 shared

Education

• B.A., Chemistry

  University of Colorado

• M.S., Biology

  University of Colorado

• Ph.D., Molecular Biology

  Vanderbilt University

Awards & honors

• Eli Lilly Award in Microbiology and Immunology
• The Richard Lounsbery Award for Biology and Medicine
• 2012 Lasker-Koshland Special Achievement Award in Medical Sc…