Our lab studies molecular and cellular mechanisms underlying brain development and disease using human pluripotent stem cell models.

Lindy Barrett

 

Dysfunction in the human brain during development and aging contribute substantially to global health burdens. While scores of relatively modest genetic and environmental differences across individuals drive astonishing neurodiversity, larger deviations can have profound consequences for human health. Our laboratory aims to illuminate mechanisms driving inter- and intra- individual variation in the human brain, as well as the functional impacts of such variation on development, aging, and disease. To this end, we leverage tractable human induced pluripotent stem cell (iPSC) models, coupled with gene-editing, screening, and single-cell -omics approaches. Our long-term goal is to leverage molecular and cellular insights to better understand brain function, and ultimately to employ these insights to improve human health.

Example Projects:

Probing variation in the human brain

Many genetic diseases display significant inter-individual variation in phenotypic penetrance, severity, and treatment response. Within individuals, homogeneous cell types can also differ in the abundance or localization of molecules and in their response to perturbation. However, there is a critical gap in our understanding of mechanisms driving both inter- and intra-individual variation, particularly in the human brain. We hypothesize that some developmental and degenerative conditions drive increased variability in molecular expression, not just differential expression, which contributes to observed phenotypes. Using a combination of single-cell analyses, CRISPR screening approaches, and functional assays, we aim to dissect basic mechanisms of variation and deepen our understanding of how variation impacts brain health. 

Investigating epigenetic mechanisms

Proper epigenetic regulation is essential for normal brain development. We hypothesize that epigenetic re-wiring drives changes in cell fate and function across diverse neurodevelopmental disorders. We are therefore analyzing how a set of defined histone changes impacts brain cell types through genome-wide analyses. Ultimately, we aim to assess the molecular and phenotypic reversibility of epigenetic changes in developmental brain diseases.

 

 

Our work sits at the intersection of neuroscience, stem cell biology, and human genetics. Interested candidates are encouraged to contact lindy.barrett@sund.ku.dk.

 

 

EDUCATION AND EMPLOYMENT

2026-                    Associate Professor & Group Leader, Department of Neuroscience, University of Copenhagen, Copenhagen, Denmark

2016-2026 Senior Group Leader, Broad Institute of MIT and Harvard, Cambridge MA, USA

2014-2016 Group Leader, Broad Institute of MIT and Harvard, Cambridge MA, USA

2006-2014 Postdoctoral Fellow, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

2002-2006 PhD Student, University of Pennsylvania, Philadelphia, PA, USA

 

SCIENTIFIC GRANTS (LAST 10 YEARS)

2026-2033     Novo Nordisk Foundation, Ascending Investigator Award (PI)

2023-2026                          National Institutes of Health, Transformative R01 (PI)

2023-2025                          National Institutes of Health, Pilot Project (PI)

2022-2023                          National Institutes of Health, Supplement Award (PI)

2021-2023                          Jerome Lejeune Foundation, Research Project Award (PI)

2020-2025                          National Institutes of Health, R01 (PI)

2016-2019                          National Institutes of Health, R21 (PI)

2016-2019                          Broadnext10 Catalytic Steps Award (PI)

 

Upadhya S, Klein JA, Nathanson A, Holton KA, and Barrett LE (2025). Single-cell analyses reveal increased gene expression variability in human neurodevelopmental conditions. AJHG 112, doi: 10.1016/j.ajhg.2025.02.011.

Nehme R, Pietiläinen O, and Barrett LE (2024). Genomic, molecular, and cellular divergence of the human brain. Trends in Neurosciences 47(7), 491-505, doi: 10.1016/j.tins.2024.05.009. PubMed PMID: 38897852.

Pigoni M, Uzquiano A, Paulsen B, Kediagle A, Yang SM, Symvoulidis P, Adiconis X, Velasco S, Sartore R, Kim K, Tucewicz A, Tropp, SY, Tsafou K, Jin X, Barrett L, Chen F, Boyden E, Regev A, Levin JZ and Arlotta P (2023). Cell-type specific defects in PTEN-mutant cortical organoids converge on abnormal circuit activity. Human Molecular Genetics, ddad107, doi:10.1093/hmg/ddad107. PubMed PMID: 37384417.

Berryer MH, Tegtmeyer M, Binan L, Valakh V, Nathanson A, Trendafilova D, Crouse E, Klein JA, Meyer D, Pietilainen O, Rapino F, Farhi SL, Rubin LL, McCarroll SA, Nehme R and Barrett LE (2023).  Robust induction of functional astrocytes using NGN2 expression in human pluripotent stem cells. iScience 26, 106995, doi:10.1016/j.isci.2023.106995. PubMed PMID: 37534135.

Berryer MH, Rizki G, Nathanson A, Klein JA, Trendafilova D, Susco SG, Lam D, Messana A, Holton KM, Karhohs KW, Cimini BA, Pfaff K, Carpenter AE, Rubin LL and Barrett LE (2023). High-content synaptic phenotyping in human cellular models reveals a role for BET proteins in synapse assembly. eLife 12: e80168. doi: 10.7554/eLife.80168. PubMed PMID: 37083703.

Ghosh S, Nehme R and Barrett LE (2022). Greater genetic diversity is needed in human pluripotent stem cell models. Nature Communications 13: 7301. doi: 10.1038/s41467-022-34940-z. PubMed PMID: 36435871.

Nehme R, Pietilainen O, Artomov M, Tegtmeyer M, Valakh, V, Lehtonen L, Bell C, Singh T, Trehan A, Sherwood J, Manning D, Peirent E, Malik R, Guss EJ, Hawes D, Beccard A, Bara AM, Hazelbaker DZ, Zuccaro E, Genovese G, Loboda AA, Neumann A, Lilliehook C, Kuismin O, Hamalainen E, Kurki M, Hultman CM, Kahler A, Paulo JA, Ganna A, Madison J, Cohen B, McPhie D, Adolfsson R, Perlis R, Dolmetsch R, Farhi S, McCarroll S, Hyman S, Neale B, Barrett LE, Harper W, Palotie A, Daly M and Eggan K (2022). The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia. Nature Communications 13: 3690. doi: 10.1038/s41467-022-31436-8. PubMed PMID: 35760976.

Susco SG, Ghosh S, Mazzucato P, Angelini G, Beccard A, Barrera V, Berryer M, Messana A, Lam D, Hazelbaker DZ and Barrett LE (2022). Molecular convergence between Down syndrome and fragile X syndrome identified using human pluripotent stem cell models. Cell Reports 40, 111312. doi: 10.1016/j.celrep.2022.111312. PubMed PMID: 36070702.

Paulsen B, Velasco S, Kedaigle AJ, Pigoni M, Quadrato G, Deo AJ, Adiconis X, Uzquiano, A, Sartore R, Yang SM, Simmons SK, Symvoulidis P, Kim K, Tsafou K, Podury A, Abbate C, Tucewicz A, Smith SN, Albanese A, Barrett L, Sanjana NE, Shi X, Chung K, Lage K, Boyden ES, Regev A, Levin JZ, Arlotta P (2022). Autism genes converge on asynchronous development of shared neuron classes. Nature 602:268-273. doi: 10.1038/s41586-021-04358-6. Epub 2022 Feb 2. PubMed PMID: 35110736.

Fukuda A, Hazelbaker DZ, Motosugi N, Hao J, Limone F, Beccard A, Mazzucato P, Messana A, Okada C, San Juan IG, Qian M, Umezawa A, Akutsu H, Barrett LE and Eggan K (2021). De novo DNA methyltransferases DNMT3A and DNMT3B are essential for XIST silencing for erosion of dosage compensation in pluripotent stem cells. Stem Cell Reports 16(9): 2138-2148.  doi: 10.1016/j.stemcr.2021.07.015. Epub 2021 Aug 19. PubMed PMID: 34416176.

Susco SG, Arias-Garcia MA, Huerta VL, Beccard A, Bara AM, Moffitt J, Korn J, Fu Z and Barrett LE (2020). FMR1 loss in a human stem cell model reveals early changes to intrinsic membrane excitability. Developmental Biology 468(1-2): 93-100. doi: 10.1016/j.ydbio.2020.09.012. Epub 2020 Sep 22. PubMed PMID: 32976839.

Nehme R and Barrett LE (2020). Using human pluripotent stem cell models to study autism in the era of big data. Molecular Autism 11(1) :21.  doi: 10.1186/s13229-020-00322-9. Review. PubMed PMID: 32293529.

Hazelbaker DZ, Beccard A, Angelini G, Mazzucato P, Messana A, Lam D, Eggan K and Barrett LE (2020). A multiplexed gRNA piggyBac transposon system facilitates efficient induction of CRISPRi and CRISPRa in human pluripotent stem cells. Scientific Reports 10(1): 635. doi: 10.1038/s41598-020-57500-1. PubMed PMID: 31959800.

Nehme R, Zuccaro E, Ghosh SD, Li C, Sherwood JL, Pietilainen O, Barrett LE, Limone F, Worringer KA, Kommineni S, Zang Y, Cacchiarelli D, Meissner A, Adolfsson R, Haggarty S, Madison J, Muller M, Arlotta P, Fu Z, Feng G and Eggan K (2018).  Combining NGN2 programming with developmental patterning generates human excitatory neurons with NMDAR-mediated synaptic transmission. Cell Reports 23(8): 2509-2523.  doi: 10.1016/j.celrep.2018.04.066. PubMed PMID: 29791859.

Hazelbaker DZ, Beccard A, Bara AM, Dabkowski N, Messana A, Mazzucato P, Lam D, Manning D, Eggan K and Barrett LE (2017). A Scaled Framework for CRISPR Editing of Human Pluripotent Stem Cells to Study Psychiatric Disease. Stem Cell Reports 9(4): 1315-1327. doi: 10.1016/j.stemcr.2017.09.006. PubMed PMID: 29020615.

 

 

 

 

  • Human pluripotent stem cells
  • In vitro differentiation (e.g., glutamatergic neurons, astrocytes, neural progenitor cells)
  • CRISPR-mediated genome engineering and screening
  • -omics level analyses (bulk and single-cell RNA-seq, ATAC-seq, CUT&Tag)
  • Python and R programming
  • Western blotting, immunocytochemistry, flow cytometry, etc.

 

 

Lab members

Name Title Job responsibilities
Lindy Barrett Associate Professor Billede af Lindy Barrett