ӳ����ý

Samples for the Human Microbiome Project will be collected from five sites of the human body.
Image courtesy of Nadav Kupiec and Bang Wong, ӳ����ý Communications

In a paper published in the May 21 issue of Science, authors representing the consortium of genomics centers involved in the Human Microbiome Project (HMP) announced the sequencing of 178 microorganisms found in the human body. “None of these bacterial strains had been seen before,” explains Bruce Birren, Co-Director of the Genome Sequencing and Analysis Program at the ӳ����ý of MIT and Harvard, which played a major role in the study. As an example of the novel microbial diversity revealed in this work, a total of nearly 30,000 new proteins were discovered.

“This paper represents an enormous amount of brand new biology,” says Birren. “These organisms are walking around in us, affecting the way we live, the way we get our nutrients, and our daily health,” says Birren. The genomes presented in this paper derive mostly from the gastrointestinal (GI) tract, just one of several body sites, including the mouth, airways, skin and vagina, to be studied in the HMP. All of the genome sequences from these organisms are now in public databases as part of the HMP’s mission of quickly disseminating information from the project.

Launched in 2007 as part of the National Institutes of Health’s (NIH) Common Fund’s Roadmap for Medical Research, the HMP is a $140 million, five-year effort to define the human microbiome and establish its role in health and disease. The ӳ����ý is one of four sequencing centers funded through the HMP.

The HMP continues the collaborative practices of the Human Genome Project to generate rich, comprehensive and publicly available data for the scientific community to understand and ultimately improve human health. The Science paper represents the initial explorations of the largely unknown microbiome and sets the stage for understanding the vast ecology of the human body and the microorganisms that inhabit it

“The human microbiome — that collection of microorganisms that live in us and on us — is complex and we know very little about it,” explains Doyle Ward, a research scientist within the ӳ����ý’s Genome Sequencing and Analysis Program and a co-author of the study. Bacteria outnumber the human body cell count by 10-fold and it is estimated that the number of genes encoded in the microbiome exceed that of the human genome by 100-fold. “We are basically describing terra incognita in this paper,” says Ward. “This is a first step toward revealing the unknown microbial landscape that is part of our bodies and profoundly contributes to our wellbeing in ways we don’t yet understand.”

Before the HMP, the vast majority of sequenced bacteria were disease-causing pathogens; organisms like Staphlococcus aureus and pathogenic E. coli. “But it is becoming clear that the overwhelming majority of the species comprising the human microbiome are not pathogens, yet they impact our health in very complex ways,” explains Ward. The human microbiome is thought to influence a whole range of health conditions including obesity, inflammatory bowel diseases, dermatitis, vaginal infections and even pre-term birth.

The collection of bacterial reference genomes generated will provide a framework for understanding the microbiome — its constituents, their functions and their impact on human health. “If you look at a community of organisms, is it who is in the community or what they are doing in the community that is important?” asks Ward. “Right now the jury is out on that, but these genomes enable us to get at function so that we can address this fundamental question.”

Determining what the microbiome is doing is not a simple task. The genome of an organism represents a significant advance toward understanding its functional potential but it is not the final word. Illustrating the point, ӳ����ý researchers investigated multiple species of Lactobacillus and other bacteria common to the human microbiome.

“What we have learned from sequencing several strains of the same species is that members of a species can actually be highly evolutionarily and functionally divergent,” explains co-author Michael Feldgarden, also a member of the ӳ����ý’s Genome Sequencing and Analysis Program team.

“Moreover, members of a species can vary widely in gene content,” explains co-author Dirk Gevers, a computational biologist at the ӳ����ý. He and his colleagues determined that within different isolates of the same Lactobacillus species, the genes they carry can differ by as much as 30%. “Evolutionarily they are all the same species but it could not be more clear that the functional potential of their genomes is very different,” says Gevers.

This kind of genomic analysis highlights the true diversity among isolates in terms of evolutionary relatedness. “You need the genomes to get at this information,” adds Feldgarden. “You won’t get it from the old-time taxonomy.”

ӳ����ý researchers reached out to an international community of microbiologists to obtain novel organisms for this project; many of these organisms had never been cultured until recently. Thus, these genomes provide a first look into their biology.

ӳ����ý research scientist Ashlee Earl used 16S rDNA surveys of the human microbiome to identify some of these previously unrepresented species for the HMP. “The 16S rDNA gene serves as a species ‘barcode” we can use to identify bacteria,” explains Earl, who worked closely with numerous collaborating microbiologists to obtain many of the unique bacterial genomes presented in this analysis. 16S sequences provide a species-specific signature useful for bacterial identification, particularly for species that are difficult to classify otherwise.

“Many of the organisms we have been able to collect, for example in the genera Veillonella, are so unique we do not know what species they are; sometimes we cannot determine the genus,” explains Earl. “The information we are unlocking from these genomes is what makes this project especially exciting.”

Having a more robust set of reference genomes is critical for the second phase of the HMP when complex microbial communities will be sequenced. “Then, it will be like having a puzzle with billions of pieces,” says Ward. Having reference genomes will provide a map that will enable researchers to figure out what these pieces are and where they fit. As an example, the Science paper reports that researchers can now identify about 40% of the sequenced pieces of DNA from the GI tract thanks to the availability of this set of bacterial genomes.

“The implications of this early work on the Human Microbiome Project are that we are realizing the bacteria within and on us are far more complex than we realized and that the work we are doing is going to really impact our knowledge and understanding,” explains Ward. Over the next year, the HMP expects to publish additional reference genomes and to begin to describe the interactions between the microbiome and human health.