The Human Microbiome Project: A Community Resource for the Healthy Human Microbiome The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Gevers, Dirk et al. “The Human Microbiome Project: A Community Resource for the Healthy Human Microbiome.” PLoS Biology 10.8 (2012): e1001377. CrossRef. Web. As Published http://dx.doi.org/10.1371/journal.pbio.1001377 Publisher Public Library of Science Version Final published version Citable link http://hdl.handle.net/1721.1/77220 Terms of Use Creative Commons Attribution Detailed Terms http://creativecommons.org/licenses/by/2.5/ Community Page The Human Microbiome Project: A Community Resource for the Healthy Human Microbiome Dirk Gevers1, Rob Knight2,3, Joseph F. Petrosino4,5,6, Katherine Huang1, Amy L. McGuire7, Bruce W. Birren1, Karen E. Nelson8, Owen White9, Barbara A. Methe´ 8*, Curtis Huttenhower1,10* 1 The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America, 2 Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado, United States of America, 3 Howard Hughes Medical Institute, Boulder, Colorado, United States of America, 4 Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States of America, 5 Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America, 6 Alkek Center for Metagenomics and Microbiome Research, Baylor College of Medicine, Houston, Texas, United States of America, 7 Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, Texas, United States of America, 8 J. Craig Venter Institute, Rockville, Maryland, United States of America, 9 Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, Maryland, United States of America, 10 Biostatistics, Harvard School of Public Health, Boston, Massachusetts, United States of America The Human Microbiome Project enabled sequencing of communities terizing the baseline state of the micro- (HMP) [1,2] is a concept that was long across the human body, and immunolo- biota is a critical first step in determining in the making. After the Human Ge- gists began exploring the fundamental how altered microbial states contribute nome Project, interest grew in sequenc- role of microorganisms in the maturation to disease (e.g., [13,20–23]). Previous ing the ‘‘other genome’’ of microbes oftheinnateandadaptiveimmune work showed wide inter- and intra- carried in and on the human body systems. Initial metagenomic studies of personal diversity of human-associated [3,4]. Microbial ecologists, realizing that human-associated microbial communi- microbes [24], necessitating analysis of a .99% of environmental microbes could ties were performed using the traditional large number of subjects and character- not be easily cultured, developed ap- Sanger platform [13,14]. Upon intro- ization of many reference bacterial proaches to study microorganisms in situ duction of pyrosequencing [15], the genomes [25] to assist in interpretation [5], primarily by sequencing the 16S number of 16S-based data sets increased of metagenomic data. The scope of the ribosomalRNAgene(16S)asaphylo- dramatically [16,17]. The time was right HMP thus required a particularly diverse genetic and taxonomic marker to identify to invest in a concerted study of the consortium (Figure 2A), and collabora- members of microbial communities [6]. microbial communities associated with tion among these teams ultimately stim- The need to develop corresponding new the human body and the metabolic ulated research growth throughout the methods for culture-independent studies capabilities they provide—the human field and produced a study including the [7,8] in turn precipitated a sea change in microbiome (Figure 1) [18]. first consistent sampling of many clini- the study of microbes and human health, To coordinate these efforts relating the cally relevant body habitats, within a inspiring the new term ‘‘metagenomics’’ microbiome to human health, the NIH large population, with paired 16S profil- [9] both to describe a technological Common Fund launched the HMP as a ing and deep metagenomic sequencing approach—sequencing and analysis of community resource program (http:// coverage for hundreds of microbial the genes from whole communities rath- commonfund.nih.gov/hmp/) [19]. One communities. er than from individual genomes—and of its main goals was to create a baseline The HMP required careful consider- to emphasize that microbes function view of the healthy human microbiome ation of ethical, legal, and social impli- within communities rather than as indi- in five major areas (airways, skin, oral cations (ELSI) unique to the study of the vidual species. This shift from a focus on cavity, gastrointestinal tract, and vagina) microbiome [26]. Such research raises individual organisms to microbial inter- and to make this resource available to questions regarding traditional distinc- actions [10] culminated in a National the broad scientific community. Charac- tions between self and non-self, human Academy of Science report [11], which outlined challenges and promises for Citation: Gevers D, Knight R, Petrosino JF, Huang K, McGuire AL, et al. (2012) The Human Microbiome Project: metagenomics as a way of understanding A Community Resource for the Healthy Human Microbiome. PLoS Biol 10(8): e1001377. doi:10.1371/ the foundational role of microbial com- journal.pbio.1001377 munities both in the environment and in Published August 14, 2012 human health. Copyright: ß 2012 Gevers et al. This is an open-access article distributed under the terms of the Creative Pioneering medical microbiologists Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, applied these approaches, finding far provided the original author and source are credited. more microbial diversity than expected Funding: This research was supported in part by National Institutes of Health grants U54HG004969 to B.W.B., D.G. and K.H.; U54HG004973 to J.F.P.; U54AI084844 to B.A.M and K.E.N.; U01HG004866 to O.R.W.; R01HG005969 even in well-studied body site habitats to C.H.; R01HG004872 to R.K.; Army Research Office grant W911NF-11-1-0473 and National Science Foundation [12]. Technological advances further grants NSF DBI-1053486 to C.H.; R.K. is an HHMI Early Career Scientist. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. The Community Page is a forum for organizations and societies to highlight their efforts to enhance Abbreviations: 16S, 16S ribosomal RNA gene; DACC, HMP Data Analysis Coordination Center; ELSI, Ethical the dissemination and value of scientific knowledge. Legal and Social Implications; HMP, Human Microbiome Project * E-mail: [email protected] (CH); [email protected] (BAM) PLOS Biology | www.plosbiology.org 1 August 2012 | Volume 10 | Issue 8 | e1001377 Figure 1. Timeline of microbial community studies using high-throughput sequencing. Each circle represents a high-throughput sequence-based 16S or shotgun metagenomic bioproject in NCBI (May 2012), indicating the amount of sequence data produced for each project (circle area and y-coordinate) at the time of publication/registration (x-coordinate). Projects are grouped by human-associated (red), other animal (black), or environmental (green) communities, and shotgun metagenomic projects are marked with a grey band. Selected representative projects are labeled: open ocean [68], deep sea [69], lean mouse [70], diarrheal illness [71], costal ocean [72], lean/obese gut [53], human microbiome [56], MetaHIT (gut) [58], cow rumen [73], soil (NCBI BioProject PRJNA50473), and human gut [74]. Note that HMP has deposited a total of 7.44 terabases of shotgun data in SRA, of which 49% is host DNA derived data that was filtered and only available through protected access in dbGaP project phs000228. doi:10.1371/journal.pbio.1001377.g001 and non-human, genetics and environ- Planning for Human Finally, quality data generation from ment, and health and disease. The Microbiome Studies: Tools, appropriately designed microbiome stud- prospect of manipulating the microbiota Techniques, and Design ies enables a variety of subsequent com- in ways that could permanently alter an putational analyses (Figure 2B). While we individual’s biological identity requires Any study of human populations must refer the reader to existing broader reviews the development of new ethical para- put both subject protection and study of human microbiome bioinformatics [35– digms analogous to, but not identical to, design first, and the HMP was no excep- 37], here we highlight numerous recent those already considered for gene thera- tion. Power calculations for microbiome approaches specifically developed during py. Likewise, just as gene patents have studies in human cohorts are particularly the HMP. Several of these focused on proven controversial, defining who challenging, as they must simultaneously microbial interactions, such as ecological ‘‘owns’’ a microbiome raises difficult address assay types (e.g., 16S versus shot- network reconstruction [38,39]. Other questions of intellectual property. The gun), depth of sequencing, taxon detection, computational methods dealt with meta- ELSI team helped to develop an appro- and fold abundance changes in