Steven McCarroll, 2011


    Ling E, Nemesh J, Goldman M, Kamitaki N, Reed N, Handsaker RE, Genovese G, Vogelgsang JS, Gerges S, Kashin S, Ghosh S, Esposito JM, Morris K, Meyer D, Lutservitz A, Mullally CD, Wysoker A, Spina L, Neumann A, Hogan M, Ichihara K, Berretta S, McCarroll SA. A concerted neuron-astrocyte program declines in ageing and schizophrenia. Nature. 2024 Mar;627(8004):604-611. doi: 10.1038/s41586-024-07109-5. Epub 2024 Mar 6. PMID: 38448582; PMCID: PMC10954558.

    Del Rosario RCH, Krienen FM, Zhang Q, Goldman M, Mello C, Lutservitz A, Ichihara K, Wysoker A, Nemesh J, Feng G, McCarroll SA. Sibling chimerism among microglia in marmosets. bioRxiv [Preprint]. 2023 Oct 17:2023.10.16.562516. doi: 10.1101/2023.10.16.562516. PMID: 37904944; PMCID: PMC10614798.

    Krienen FM, Goldman M, Zhang Q, C H Del Rosario R, Florio M, Machold R, Saunders A, Levandowski K, Zaniewski H, Schuman B, Wu C, Lutservitz A, Mullally CD, Reed N, Bien E, Bortolin L, Fernandez-Otero M, Lin JD, Wysoker A, Nemesh J, Kulp D, Burns M, Tkachev V, Smith R, Walsh CA, Dimidschstein J, Rudy B, S Kean L, Berretta S, Fishell G, Feng G, McCarroll SA. Innovations present in the primate interneuron repertoire. Nature. 2020 Oct;586(7828):262-269. doi: 10.1038/s41586-020-2781-z. Epub 2020 Sep 30.. PMID: 32999462; PMCID: PMC7957574.

    Kamitaki N, Sekar A, Handsaker RE, de Rivera H, Tooley K, Morris DL, Taylor KE, Whelan CW, Tombleson P, Loohuis LMO; Schizophrenia Working Group of the Psychiatric Genomics Consortium; Boehnke M, Kimberly RP, Kaufman KM, Harley JB, Langefeld CD, Seidman CE, Pato MT, Pato CN, Ophoff RA, Graham RR, Criswell LA, Vyse TJ, McCarroll SA. Complement genes contribute sex-biased vulnerability in diverse disorders. Nature. 2020 Jun;582(7813):577-581. doi: 10.1038/s41586-020-2277-x. Epub 2020 May 11. PMID: 32499649; PMCID: PMC7319891.

    Macosko EZ, Basu A, Satija R, Nemesh J, Shekhar K, Goldman M, Tirosh I, Bialas AR, Kamitaki N, Martersteck EM, Trombetta JJ, Weitz DA, Sanes JR, Shalek AK, Regev A, McCarroll SA. Highly Parallel Genome-wide Expression Profiling of Individual Cells Using Nanoliter Droplets. Cell. 2015 May 21;161(5):1202-1214. doi: 10.1016/j.cell.2015.05.002. PMID: 26000488; PMCID: PMC4481139.


    2019     Broad Institute Award for Mentoring

    2016     National Alliance on Mental Illness (NAMI) Scientific Research Award for 2016

    2014     Mentoring Award, Harvard Medical School Graduate Program in Biological and Biomedical Sciences (BBS)

    2011     Armenise Harvard Junior Faculty Grant, Department of Genetics: “Active Alu Retrotransposition in the Human Genome.”

Who he is

Steve McCarroll is the Dorothy and Milton Flier Professor of Biomedical Science and Genetics, Harvard Medical School and the Director of Genomic Neurobiology, Stanley Center, Broad Institute of MIT and Harvard.

What he does 

The scientific teams in our lab are working to recognize the biology that underlies human brain health and illness, and the ways in which human genes, inherited genetic variation, and somatic mutations conspire to shape this biology. The biological basis for most brain disorders is unknown today: most are understood mainly in terms of collections of symptoms, neuropathological observations – such as cortical thinning, protein aggregates, or death of a specific kind of cell – and human-genetic associations. We need to deeply understand these disorders as biological entities so that we can develop new and innovative ways to monitor and treat them.

Our lab is especially excited about (i) DNA-repeat disorders and (ii) the disruptions of mental health commonly known as “psychiatric disorders”, especially schizophrenia.

Our research team brings together people with experiences, approaches and insights from biology, human genetics, statistics, and computer science.

News from the Lab

We discovered a large constellation of gene-expression changes that are implemented together by neurons and astrocytes in a coordinated manner; that vary in magnitude among individual persons; and that are compromised in schizophrenia and in brain aging (Ling et al., Nature 2024).

Huntington Disease (HD) is a fatal genetic disease in which most of a person’s striatal projection neurons (SPNs) degenerate and die.  The central biological question about HD has involved how the disease-causing inherited DNA repeat (CAGn) in the huntingtin (HTT) gene leads to neurodegeneration after a long latent period. The length of the HTT CAG repeat varies within the brain (somatic mosaicism), and many common human-genetic modifiers of HD age-at-onset are in genes that affect DNA-repeat stability. To understand how the HTT CAG repeat might underlie pathological changes in HD, we developed a method to sequence and measure the CAG repeat together with genome-wide RNA expression in the same cells. We found that the CAG repeat routinely expands from 40-45 CAGs (germline) to 100-500+ CAGs in SPNs but not in other striatal cell types, with these long expansions acquired asynchronously by individual SPNs.  Surprisingly, somatic expansion from 40 to 150 CAGs had no apparent direct effect upon SPN gene expression. In contrast, sparse SPNs with 150-500+ CAGs had profound gene-expression changes – affecting hundreds of genes, escalating with further repeat expansion, eroding positive and then negative features of SPN identity, and culminating in expression of senescence/apoptosis genes. Across stages of HD, these “SLEAT” SPNs (with somatic long expansions and asynchronous toxicity) appeared in proportion to rates of SPN loss. Our experiments, analyses and simulations suggest that individual SPNs undergo decades of biologically quiet DNA-repeat expansion to a high threshold length, then asynchronously pass through a brief toxicity phase before dying. We conclude that, at any moment in the course of HD, most SPNs have an innocuous (but unstable) huntingtin gene, and that HD pathogenesis is a DNA process for almost all of a neuron’s life.  (Handsaker, Kashin et al., manuscript in preparation.)