Explaining the Human Microbiome Project

Site-specific distributions of bacterial phyla in healthy humans (provided by NIH Roadmap for Medical Research http://nihroadmap.nih.gov)

Consider your body as one of the most congested major traffic systems in the United States – complete with freeways (skin), bridges (nose), tunnels (mouth and gastrointestinal tract) and toll roads (vaginal tract) and it is rush hour.

Each vehicle in this traffic jam is a microbe, and there are as many types of microbes as there are vehicles. The drivers represent the microbial genomes, directing each microbe to its choice location in an effort to complete the desired task, whether that is to refuel, accept or deposit cargo or perhaps join a group of friends in an activity.

The good drivers are our commensal microbes, living in harmony with the rest of our body. (Commensal means living in a symbiosis that benefits one organism and does not affect the other.) Pathogens are those driving recklessly without a license, often causing traffic accidents.

Finding the microbes

Until recently, it's been relatively easy to tease out these pathogens because traffic accidents (or diseases) are often obvious, making them easy to study. Historically, the “good drivers” go unnoticed and are underrepresented in the scientific literature. However, this is all about to change, and scientists at Baylor College of Medicine are among those leading the way along a new path, using the Human Microbiome Project as a road map to study the microbial traffic that resides in and on the human body.

Among those involved in the BCM part of the project are Richard Gibbs, Ph.D., director of the Baylor Human Genome Sequencing Center; James Versalovic, M.D., Ph.D., associate professor of pathology, molecular and human genetics, pediatrics and molecular virology and microbiology; Wendy Keitel, M.D., associate professor of molecular virology and microbiology; and Sarah Highlander, Ph.D., associate professor in molecular virology and microbiology, and Joseph Petrosino, Ph.D., assistant professor in the same department.

The microbial traffic they will study has been defined as our microbiota. Our human cells are greatly outnumbered by microbial cells. In fact, there are 10 microbial cells for each human one. For every single human gene, there are 100 microbial genes! These overly abundant microbial genes are collectively referred to as our microbiome.

Where microbes live

While the majority of our microbes are housed within the gastrointestinal tract, it is quite clear that many organisms also reside on the skin, in the mouth, the upper respiratory tract and the vaginal tract.

Not only have pathogens been the stars in scientific literature, but most microbes have been studied in isolation with little attention to how they behave in their natural environments. Scientists have uniquely mapped the Human Microbiome Project to study natural microbial communities within each of these healthy human body sites.

There are four specific goals:

Determine if there are sets of microbes common to each human
Understand if changes in our microbiota result in different states of health or disease
Develop new technologies for studying complex microbial systems within their natural environments
Begin to deal with the legal, ethical and social complications that may arise with human microbiome research

First goal

To tackle the first goal of this project, scientists are using DNA sequencing to take inventory of the microbes present in the five regions of the body described above. Before we can learn how our microbiome affects our body, we must know who is living with us.

When collecting large amounts of sequence information for microbe identification, it is important to have a set of known sequences to which you can compare the information.

For example, imagine trying to identify a specific taste in a recipe without ever having tasted the individual ingredients. If you have the opportunity to taste a list of possible ingredients separately, the process of choosing one in a mixture becomes much easier.

Microbe genomes

The majority of microbial sequence data on the current list is dominated by pathogen genomes, while sequence data for our bodies are not. Therefore, an important part of this first phase is focused on sequencing the entire genomes of approximately 600 bacteria along with several non-bacterial microbes (like viruses, fungi, etc.). In doing this, scientists will create a known list of approximately 1,000 microbial genomes that will help ease the process of identifying those microbes found in communities throughout the human body.

Once scientists have cataloged the microbial communities present within the human body, they can begin to determine whether sets of microbes are common between individual humans.

To do this, they will sample from each of the five body sites of many different people. Then they will collectively analyze the microbial DNA sequence information from each site. The study of such large amounts of genomes in a community has been defined as metagenomics. By comparing such metagenomic information between many individuals, scientists will be able to identify the common (and uncommon) microbial traits present in the human microbiome.

Core microbes or core genes?

Some people think there will be a core set of microbes present in all humans, while others think it more likely there will be a core set of microbial genes present within a diverse range of microbes. As the Human Microbiome Project continues, the answers to those questions will become apparent.

While most research has focused on how pathogens cause disease in humans, scientists are moving toward studying how our commensal microbes (or the lack thereof) may be responsible for health or disease. Humans have evolved to live with commensal microbes, each microbe being specifically chosen for symbiotic cohabitation.

Microbial benefits

Some microbes provide nutritional benefits by producing vitamins that humans cannot produce themselves. Other microbes provide protection from pathogenic organisms, and others still are capable of communicating with our immune, endocrine and nervous systems.

Once scientists have profiled the commensal microbe population of the healthy human body, they can begin to compare these profiles with those of people in disease states. Some diseases of interest to scientists studying this project are allergies, antibiotic-associated diarrhea, bacterial vaginosis (associated with an imbalance in the microbes normally found in a woman's vagina), chronic periodontal (or gum) disease, inflammatory bowel disease and obesity to name a few. Characterization of microbiomes in diseased states may allow scientists to identify key microbial players responsible for specific diseases. If specific microbes are missing, present or out of balance in one disease when compared to a healthy microbiome, it may be possible to treat such diseases by adding, removing or balancing the key microbiota.

Better technology

Until recently, the task of the Human Microbiome Project was just too daunting to tackle. How on earth could so many microorganisms within the human body be identified?

Microbial culturing techniques are laborious and time consuming. Approaching the problem this way would take decades and miss many microbes that cannot yet be cultured in a laboratory setting.

Identifying organisms based on DNA sequences unique to each microbe provides a better way to tackle the problem.

Current advances in sequencing technology have finally made this possible. For example, the first human genome sequence was completed in 2003, taking a period of 13 years and costing $2.7 billion. Just four years later in 2007, Dr. James Watson's genome was completed in a collaboration between the BCM Human Genome Sequencing Center and a company called 454 Life Sciences. The work took two months and cost $1 million.

Developing and refining technology

Because the Human Microbiome Project involves identifying so many microbes and sequencing their genes, it requires this kind of leap in technology and beyond. One goal of this project is technology development. As scientists begin to approach the challenges of the Human Microbiome Project, they must develop new technologies, from DNA isolation and sequencing to bioinformatic analysis, to increase the speed and accuracy while decreasing the cost of the experimental processes involved.

Doing it ethically

The fourth goal of the Human Microbiome Project includes predicting and understanding the legal, ethical and social implications this kind of information may bring. Scientists must understand what is important for volunteers to know when they become involved in human microbiome research. Are there privacy concerns that relate to each person, his or her family or other groups? Other issues may arise when considering changing a person's microbiome, especially very early on in life. The potential applications of human microbiome research to medicine (i.e. probiotics, microbiome transplants or diagnostics) must also be examined and considered carefully. Effective strategies for educating the public about human microbiome research and how the results may impact health, medicine and society are also important.

Eventually, the hope is that microbiome research will not only tell us more about how humans evolved amidst all of the microbial traffic, but also that the results will lead to groundbreaking medical treatments for many complicated diseases.

For more information visit these web sites:

http://nihroadmap.nih.gov/hmp/index.asp

http://nihroadmap.nih.gov/hmp/initiatives.asp

Jennifer Spinler, Ph.D., is a post-doctoral associate in the laboratory of James Versalovic, M.D., Ph.D., associate professor of pathology at Baylor College of Medicine and a leader in the BCM portion of the Human Microbiome Project. Spinler will be contributing occasional articles to From the Laboratories at Baylor College of Medicine about some of the basic science activities ongoing at the College. Spinler received her undergraduate degree from Texas State University in San Marcos and her doctorate in microbiology from the University of Colorado Denver Health Sciences Center.