The Human Microbiome Project (HMP) , is a concept that was long in the making. After the Human Genome Project, interest grew in sequencing the “other genome" of microbes carried in and on the human body ,. Microbial ecologists, realizing that >99% of environmental microbes could not be easily cultured, developed approaches to study microorganisms in situ , primarily by sequencing the 16S ribosomal RNA gene (16S) as a phylogenetic and taxonomic marker to identify members of microbial communities . The need to develop corresponding new methods for culture-independent studies , in turn precipitated a sea change in the study of microbes and human health, inspiring the new term “metagenomics"  both to describe a technological approach—sequencing and analysis of the genes from whole communities rather than from individual genomes—and to emphasize that microbes function within communities rather than as individual species. This shift from a focus on individual organisms to microbial interactions  culminated in a National Academy of Science report , which outlined challenges and promises for metagenomics as a way of understanding the foundational role of microbial communities both in the environment and in human health.
Pioneering medical microbiologists applied these approaches, finding far more microbial diversity than expected even in well-studied body site habitats . Technological advances further enabled sequencing of communities across the human body, and immunologists began exploring the fundamental role of microorganisms in the maturation of the innate and adaptive immune systems. Initial metagenomic studies of human-associated microbial communities were performed using the traditional Sanger platform ,. Upon introduction of pyrosequencing , the number of 16S-based data sets increased dramatically ,. The time was right to invest in a concerted study of the microbial communities associated with the human body and the metabolic capabilities they provide—the human microbiome (Figure 1) .
To coordinate these efforts relating the microbiome to human health, the NIH Common Fund launched the HMP as a community resource program (http://commonfund.nih.gov/hmp/) . One of its main goals was to create a baseline view of the healthy human microbiome in five major areas (airways, skin, oral cavity, gastrointestinal tract, and vagina) and to make this resource available to the broad scientific community. Characterizing the baseline state of the microbiota is a critical first step in determining how altered microbial states contribute to disease (e.g., ,–). Previous work showed wide inter- and intra-personal diversity of human-associated microbes , necessitating analysis of a large number of subjects and characterization of many reference bacterial genomes  to assist in interpretation of metagenomic data. The scope of the HMP thus required a particularly diverse consortium (Figure 2A), and collaboration among these teams ultimately stimulated research growth throughout the field and produced a study including the first consistent sampling of many clinically relevant body habitats, within a large population, with paired 16S profiling and deep metagenomic sequencing coverage for hundreds of microbial communities.
The HMP required careful consideration of ethical, legal, and social implications (ELSI) unique to the study of the microbiome . Such research raises questions regarding traditional distinctions between self and non-self, human and non-human, genetics and environment, and health and disease. The prospect of manipulating the microbiota in ways that could permanently alter an individual's biological identity requires the development of new ethical paradigms analogous to, but not identical to, those already considered for gene therapy. Likewise, just as gene patents have proven controversial, defining who “owns" a microbiome raises difficult questions of intellectual property. The ELSI team helped to develop an appropriate sample collection protocol, to draft a template for informed consent, and consulted on ethical issues arising during the study, such as the possibility that unique human microbiome “signatures"  might compromise participant privacy. A portion of the HMP's dedicated research budget continues to be committed to integrating multidisciplinary approaches (including philosophical, social science, and legal methods) to study these issues and involve stakeholders including study participants, scientists, policy makers, patients, and indigenous populations.