Julie Segre, Ph.D.

Chief and NIH Distinguished Investigator

Translational and Functional Genomics Branch

Head

Microbial Genomics Section

Education

B.A., Amherst College

Ph.D., Massachusetts Institute of Technology

Contact Info

BG 49 RM 4A26
49 CONVENT DR 4442
BETHESDA MD 20892-4442

Biography

Dr. Julie Segre received her B.A. summa cum laude in mathematics from Amherst College, where she now serves on the board of trustees. She received her Ph.D. from the Massachusetts Institute of Technology in the laboratory of Eric Lander, Ph.D., and the newly formed genome center. Dr. Segre then performed postdoctoral training with Elaine Fuchs, Ph.D., an expert in skin biology, at the University of Chicago.

Dr. Segre joined the National Human Genome Research Institute of NIH in 2000 and was promoted to a senior investigator with tenure in 2007. Dr. Segre's laboratory utilizes high-throughput sequencing and develops algorithms to study the microbial diversity of human skin in both health and disease states, with a focus on eczema and other microbial-associated infections. Dr. Segre published the first topographical maps of human skin bacterial and fungal diversity. Dr. Segre's laboratory also develops genomic tools to track hospital-acquired infections of multi-drug resistant organisms, including the NIH's recent Klebsiella pneumoniae outbreak.

Dr. Segre's research is based on active collaborations with the NIH Intramural Sequencing Center and the clinical departments of Infection Control, Microbiology and Dermatology. Dr. Segre is a leader in the NIH Roadmap Human Microbiome Project, communicating with multiple media sources to promote the concept of humans as ecological landscapes. Together with the NIH epidemiologist, Tara Palmore, M.D., Segre received the 2013 Service to America Medal, considered among the most prestigious for a federal employee, for their work to establish the clinical utility of microbial genomics.

Scientific Summary

The Microbial Genomics Section (MGS) explores the full genetic diversity of human-associated microbiota (bacteria, fungi, viruses) which contribute to both health and disease. We study and understand health with the perspective that humans coexist with billions of microbiota in our guts, on our skin and covering all epithelial surfaces. Pathogenic bacteria flourish and compete within a larger symbiotic microbial community, whose DNA is collectively referred to as the microbiome. The Microbial Genomics Section developed methods to characterize microbial communities with genomic sequencing and analysis, which offer significant advantages over traditional culture-based studies to capture microbial diversity.

MGS explores two major areas of clinical microbial genomics: foundational studies of the human skin microbiome and tracking hospital-associated bacterial pathogens. It performed the first skin bacterial survey, characterizing the diversity of microbes that live on normal volunteers, and determined that humans are ecosystems with niche-dependent bacterial populations (dry, moist or oily regions). Fungal diversity, by contrast, is more topographically driven with the greatest diversity observed on feet (toenails, toeweb, plantar heel).

clinical microbial genomics microscope view

Together with clinical collaborators, MGS extended these studies to patient populations with common atopic dermatitis (AD, eczema; OMIM 603165) and rare primary immune deficiencies. MGS focuses its studies on AD because these patients typically respond to various antimicrobial therapies, but there are no biomarkers to direct an individual patient's treatment. Our longitudinal study of pediatric AD patients shows a drop in skin microbial diversity and an increase in Staphylococcus aureus with disease flare. MGS's current efforts are directed at defining and assessing the role of specific strains of Staphylococcus aureus in the progression to disease flare. Mechanistically, they are assessing the function of skin-associated bacteria in priming the immune system and driving AD with animal models.

Future microbiome studies transition from survey-based studies of microbes to full metagenomic sequencing. To build the resources needed for skin microbiome analysis, they sequenced reference skin microbes, such as the commensal Staphylococcus epidermidis. MGS has determined that the S. epidermidis pan-genome is quite large with 80% core genes (~2,000 total) and the remaining 20% of genes selected from a large pool of ~5,000 genes. These sequenced reference genomes enabled us to fully harness the power of strain tracking across individuals and between skin body sites.

As a second area of focus, MGS developed pipelines to tracking hospital-associated bacterial pathogens with whole-genome sequencing. They retrospectively reconstructed a polymicrobial outbreak of multi-drug resistant Acinetobacter baumannii that swept through the NIH Clinical Center in 2007 to elucidate the role of recombination in diversification. The last line of antibiotic defense against A. baumannii is colistin, a polymixin peptide. MGS followed up the outbreak tracking with genomic sequence studies to identify molecular changes that conferred colistin resistance. Genomic studies are complemented by microbiological growth studies to assess variants' effects on the organism's overall fitness. MGS's long-term goal is to create a drug strategy that capitalizes on the bacterium's loss of fitness typically associated with acquisition of antibiotic resistance.

While genomic studies of A. baumannii were performed retrospectively, MGS's carbapenem-resistant Klebsiella pneumonaie studies were carried out prospectively. In 2011, 17 patients were infected with a single K. pneumonaie isolate that is highly virulent and has now evolved resistance to all known antibiotics. For the first time, MGS's real-time genomic sequencing tracked exact patient-to-patient routes of transmission within the NIH Clinical Center and informed epidemiologists' actions to monitor and control this outbreak. MGS has now extended these studies to explore transfer between bacterial species of the plasmid that encodes carbapenemase. The section's mission is to use genomic information to model outbreaks, monitor evolution of antibiotic resistance and develop risk assessment strategies.

Publications

Johnson R, Deming C, Conlan S, Zellmer CJ, Michelin AV, Lee-Lin SQ, Thomas PJ, Park M, NISC Comparative Sequencing Program, Weingarten RA, Less J, Dekker JP, Frank KM, Musser KA, McQuiston JR, Henderson DK, Lau AF, Palmore TN, Segre JA. Investigation of cluster of Sphingomonas koreensis infections. New England Journal of Medicine, 379(26):2529-2539. doi: 10.1056/NEJMoa1803238. 2018. [PubMed]

Tirosh O, Conlan S, Deming C, Lee-Lin SQ, Huang X, NISC Comparative Sequencing Program, Su HC, Freeman AF, Segre JA, and Kong HH. Expanded skin virome in DOCK8-deficient patients. Nature Medicine, 24(12):1815-1821. doi: 10.1038/s41591-018-0211-7. 2018. [PubMed]

Weingarten, RA, Johnson, RC, Conlan S, Ramsburg, AM, Dekker JP, Lau AF, Khil, P, Odom, RT, Deming C, Park M, Thomas PJ, NISC Comparative Sequencing Program, Henderson, DK, Palmore TN, Segre, JA, Frank KM. Genomic Analysis of Hospital Plumbing Reveals Diverse Reservoir of Bacterial Plasmids Conferring Carbapenem Resistance. MBio, 9(1). pii: e02011-17. 2018. [PubMed]

Byrd AL, Deming C, Cassidy, SKB, Harrison, OJ, Ng W-I, Conlan S, NISC Comparative Sequence Program, Belkaid, Y, Segre, JA, Kong HH. Staphylococcus aureus and S. epidermidis strain diversity underlying human atopic dermatitis. Science Translational Medicine, 9(397). pii: eaal4651. 2017. [PubMed]

Oh J, Byrd AL, Park, M, NISC Comparative Sequence Program, Kong HH, Segre, JA. Temporal stability of the human skin microbiome. Cell, 165(4): 854-866. 2016. [PubMed]

Conlan S, Park M, Deming C, Thomas PJ, Young AC, Coleman H, Sison C; NISC Comparative Sequencing Program, Weingarten RA, Lau AF, Dekker JP, Palmore TN, Frank KM, Segre, JA. Plasmid Dynamics in KPC-Positive Klebsiella pneumoniae during Long-Term Patient Colonization. MBio, 7(3) pii: e00742-16. 2016. [PubMed]

Naik S, Bouladoux N, Linehan JL, Han SJ, Harrison OJ, Wilhelm C, Conlan S, Himmelfarb S, Byrd AL, Deming C, Quinones M, Brenchley JM, Kong HH, Tussiwand R, Murphy KM, Merad M, Segre JA, Belkaid Y. Commensal-dendritic cell dialogue specifies unique skin immune signature. Nature, 520 (7545):104-8. 2015. [PubMed]

Belkaid Y, Segre JA. Dialogue between Skin Microbiota and Immunity. Science, 346(6212):954-9. 2014. [PubMed]

Oh J, Byrd AL, Deming C, Conlan S, NISC Comparative Sequence Program, Kong HH, Segre JA. Biogeography and individuality shape the functional divergence of the human skin metagenome. Nature, 514(7520):59-64. 2014. [PubMed].

Conlan S, Thomas PJ, Deming C, Park M, Lau AF, Dekker JP, Snitkin ES, Clark TA, Luong K, Song Y, Tsai YC, Boitano M, Dayal J, Brooks SY, Schmidt B, Young AC, Thomas JW, Bouffard GG, Blakesley RW; NISC Comparative Sequencing Program, Mullikin JC, Korlach J, Henderson DK, Frank KM, Palmore TN, Segre JA. Single molecule sequencing to track plasmid diversity of hospital-associated carbapenemase-producing Enterobacteriaceae, Science Translational Medicine, 6(254):254ra126. 2014. [PubMed]

Oh J, Freeman AF; NISC Comparative Sequencing Program, Park M, Sokolic R, Candotti F, Holland SM, Segre JA, Kong HH. The altered landscape of the human skin microbiome in patients with primary immunodeficiencies, Genome Res, 23(12):2103-14. 2013. [PubMed]

Findley K, Oh J, Yang J, Conlan S, Deming C, Meyer JA, Schoenfeld D, Nomicos E, Park M, NISC Comparative Sequencing Program, Kong HH, Segre JA (2013) Topographic diversity of fungal and bacterial communities in human skin. Nature, 498(7454):367-360. 2013. [PubMed]

Snitkin ES, Zelazny A, Gupta J, Palmore TN, Murray PR, Segre JA. Genomic insights into the fate of colistin resistance and Acinetobacter baumannii during patient treatment. Genome Res, 23(7):1155-62. 2013. [PubMed]

Yang JY, Brooks S, Meyer JA, Blakesley RR, Zelazny AM, Segre JA, Snitkin ES. Pan-PCR, a computational method for designing bacterial-typing assays based on whole genome sequence data. J Clin Microbiol, 51(3):752-8. 2013. [PubMed]

Oh J, Segre JA. Genomics: Resident risks. Nature, 490(7418):44-6. 2012. [PubMed]

Oh J, Conlan S, Polley E, Segre JA, Kong HH. Shifts in human skin and nares microbiota of healthy children and adults. Genome Med, 4(10):77. 2012. [PubMed]

Conlan S, Kong HH, Segre JA. Species-Level Analysis of DNA Sequence Data from the NIH Human Microbiome Project. PLoS One, 7(10):e47075. 2012. [PubMed]

Snitkin ES, Zelazny AM, Thomas PJ, Stock F; NISC Comparative Sequencing Program, Henderson DK, Palmore TN, Segre JA. Tracking a Hospital Outbreak of Carbapenem-Resistant Klebsiella pneumoniae with Whole-Genome Sequencing. Sci Transl Med, 4(148):148ra116. 2012. [PubMed]

Conlan S, Mijares LA, Comp Seq Program N, Becker J, Blakesley RR, Bouffard GG, Brooks S, Coleman HL, Gupta J, Gurson N, Park M, Schmidt B, Thomas PJ, Young A, Otto M, Kong HH, Murray PR, Segre JA. Staphylococcus epidermidis pan-genome sequence analysis reveals diversity of skin commensal and hospital infection-associated isolates. Genome Biol, 13(7):R64. 2012. [PubMed]

Naik S, Bouladoux N, Wilhelm C, Molloy MJ, Salcedo R, Kastenmuller W, Deming C, Quinones M, Koo L, Conlan S, Spencer S, Hall JA, Dzutsev A, Kong H, Campbell DJ, Trinchieri G, Segre JA, Belkaid Y. Compartmentalized Control of Skin Immunity by Resident Commensals. Science, 337(6098):1115-9. 2012. [PubMed]

Human Microbiome Project Consortium. Structure, function and diversity of the healthy human microbiome. Nature, 486(7402):207-14. 2012. [PubMed]

Grice EA, Segre JA. The Human Microbiome: Our Second Genome. Annu Rev Genomics Hum Genet, 13:151-70. 2012. [PubMed]

Kong HH, Oh J, Deming C, Conlan S, Grice EA, Beatson MA, Nomicos E, Polley EC, Komarow HD, NISC Comparative Sequence Program, Murray PR, Turner ML, Segre JA. Temporal shifts in the skin microbiome associated with disease flares and treatment in children with atopic dermatitis. Genome Res, 22(5):850-9. 2012. [PubMed]

Snitkin ES, Zelazny AM, Montero CI, Stock F, Mijares L; NISC Comparative Sequence Program, Murray PR, Segre JA. Proc Natl Acad Sci U S A, 108(33):13758-63. 2011. [PubMed]

Grice EA, Segre JA. The skin microbiome. Nat Rev Microbiol, 9(4):244-53. 2011. [PubMed]

Grice EA, Snitkin ES, Yockey LJ, Bermudez DM; NISC Comparative Sequencing Program, Liechty KW, Segre JA. Longitudinal shift in diabetic wound microbiota correlates with prolonged skin defense response. Proc Natl Acad Sci U S A, 107(33):14799-804. 2010. [PubMed]

Kong HH, Segre JA. Bridging the translational research gap: a successful partnership involving a physician and a basic scientist. J Invest Dermatol, 130(6):1478-80. 2010. [PubMed]

Grice EA, Kong HH, Conlan S, Deming CB, Davis J, Young AC; NISC Comparative Sequencing Program, Bouffard GG, Blakesley RW, Murray PR, Green ED, Turner ML, Segre JA. Topographical and temporal diversity of the human skin microbiome. Science, 324(5931):1190-2. 2009. [PubMed]

Grice EA, Kong HH, Renaud G, Young AC; NISC Comparative Sequencing Program, Bouffard GG, Blakesley RW, Wolfsberg TG, Turner ML, Segre JA. A diversity profile of the human skin microbiota. Genome Res, 18(7):1043-50. 2008. [PubMed]