Intuition will tell the thinking mind where to look next.

JONAS SALK


Everyone, or almost everyone, has heard about the Human genome project. It is probably the most talked about and the most ambitious of all recent projects in the discipline of genetics and human health. The project was a grand scale effort on the part of researchers to decipher the code of life by sequencing the genome of Homo sapiens. They used state –of- the – art technology and modern tools of bioinformatics to obtain and analyse the intricate pattern of genes in our genome. One of the key objectives of the HGP was to study variations in the patterns of genes in healthy and diseased individuals. The expected divergence in the genes of diseased individuals would then provide researchers with possible study areas and would guide them towards more accurate diagnostic and treatment methods. Therefore to put it in simple terms an attempt was made to study the sequence of our genes in order to correlate them to phenotypic effects such as diseases and hence to develop better drugs and improve the standard of human life.

A similar attempt is currently underway on a global scale, though this one is much more interesting. The project being referred to here is the Human Microbiome Project. Now, what exactly is meant by the term microbiome? A microbiome can be defined in the most simple terms as the sum total of all the Microbial flora that reside on or in the human body along with their genomes. The human microbiome project is an attempt to study the enormous diversity of microbes associated with the body, and to obtain sequence data of the same. The idea is to connect changes in the populations of the microbes with altered states of health. It is a mind boggling idea considering that the human body is home to trillions of different microbes. The very idea of obtaining such vast amounts of data and then deciphering it to obtain meaningful connections to specific diseases is awe inspiring. And yet, this is exactly what researchers in institutes across the world have decided to do, under the Aegis of the National Institutes of Health or the NIH. What is even more remarkable is that a few of the preliminary reports in the field have shown definitive connections between altered microbial populations in the body and the onset and development of diseases of various organ systems.

So, let’s get to know the microbiome project  a little better. Launched in December 2007, as a part of the NIH roadmap for research in Human Health, the Human Microbiome Project (HMP) is currently a $140 million effort, spaced over Five years, with the aim of providing a better insight into the millions of Microbes associated with Humans. The information gathered will be invaluable to researchers attempting to use this information for the betterment of Health and study of molecular underpinnings of disease.

Traditionally, Microbiologists have always underscored the role played by the microbiota of the human body. However, the study of microbes has always focused on obtaining pure cultures of individual microbes and studying them as discrete entities. This approach is severely limited by two factors, namely, information obtained is confined only to those species that can be cultured in the lab, and, further, no insights are gained into the possible inter-species or inter-community interactions that might possibly be occurring within microbial populations in the microenvironments within the body. Today, we recognize that a large number of microbes colonizing our bodies have not been studied due to our inability to culture them in the lab. This might be due to the inability of scientists to exactly replicate the complex microenvironments necessary for the growth of these species. Many of the populations of microbes form intricate association patterns in the body and may be dependent on each other in complex physiological ways for growth. Therefore, there is a lacuna in the quality of data that can be obtained by using traditional culture methods to study human microbiota. Further, those organisms that have been cultured have always been studied in isolation and there is a paucity of data with respect to interspecefic interactions and even Microbe-Host interactions.

Given the fact that in a normal, healthy human being, the microbial cells outnumber the host cells by a factor of 10: 1, understanding the intricate interactions of this microbiota and its contribution to human health and disease takes on substantial importance. Development of newer technologies in the field of genome sequencing has resulted in the field of Metagenomics. This allows researchers to sequence and study genomes of organisms that have not yet been cultured and to compare this sequence data with the existing data of known microbes. This is exactly what the HMP seeks to exploit. The metagenomic approach will allow analysis of genomes of entire populations of microbes harvested from natural environments, even if these microbes have not been cultured In Vitro. This, in combination with traditional methods will provide meaningful insights into the nature of interactions between the microbes and the host.

Thus, the HMP sets itself the following goals:

  • To determine whether humans share a common Microbiome
  • To try and examine the correlation between changes in microbiota and Human  health
  • To develop technology and tools of Bioinformatics to deal with the information being generated by the Study &
  • To deal with the ethical, legal and Social implications of the study.

The project is supporting several large scale DNA sequencing centres that are working in tandem to sequence at least 400 microbial genomes. Another 500 genomes are already sequenced or are in the pipeline and are being funded by the NIH or international funding agencies. Some of the centers along with the Principle investigators and the approximate funding levels are: Human Genome Sequencing Center, Baylor College of Medicine, Houston
Richard Gibbs, Ph.D.; $3.7 million ; Washington University Genome Sequencing Center, Washington University School of Medicine, Saint Louis, George Weinstock, Ph.D.; $16.1 million ; The J. Craig Venter Institute, Rockville, Md., Robert L. Strausberg, Ph.D.; $8.8 million. These studies are focusing on microbiota isolated from five sampling points in the body, namely, the digestive tract, the mouth, the skin, the nose and the vagina.


The Human Microbiome Project is also funding new pilot demonstration projects  which will aim to study differences in Microbiomes between healthy and diseased volunteers  by researchers that will sample the microbiomes of healthy volunteers and volunteers with specific diseases over the next year. These studies will use samples collected from seven areas of the body: the digestive tract, the mouth, the skin, the nose, the vagina, the blood and the male urethra. These pilot studies are distributed among a large number of institutes focusing on specific regions of the body and on specific diseases for example on vaginitis, sexually transmitted diseases autoimmune disorders, Crohn’s Disease, ulcerative colitis and many others.

The Huge amount of data that has been generated by these research efforts now poses a new problem; one of managing, classifying and systematising this data so that it can be useful to other workers.  As a part of the problem solving effort, grantees of the National Institute of Dental and Craniofacial Research (NIDCR), part of the National Institutes of Health, have launched the first comprehensive database of the oral microbiome, or the approximately 600 distinct microorganisms currently known to live in the mouth. Known as the Human oral Microbiome Database, HOMD, it provides detailed information about each individual species, along with a catalogue of all of the genes expressed by these organisms. What is more, it will provide a systematic nomenclature system for all those organisms that were hitherto unnamed or uncultured in the lab. The database is expected to be a rich source of all kinds of data on the organisms of the oral cavity. Further, 16S rRNa sequence data, as well as protein expression data for those organisms whose DNA has already been sequenced will also be made available. This will allow for phylogenetic classification of the organisms. One can begin to appreciate the enormous power of this kind of data in the hands of dedicated researchers.

Similar efforts are on to determine core microbiome of the Skin. Under the guidance of Julie Segre,  the National Human Genome Research Institute has generated a diversity profile of human skin microbiota by sequencing 16S rRNA. The results were encouraging. They found that in healthy volunteers the inner elbow microbiota was predominantly composed of Proteobacteria (predominantly Pseudomonas and Janthinobacterium). The study also indicated that individuals share a common core microbiota and this fact may be critical for studying disease. Scientists hope to use this data for arriving at cures for Acne and atopic dermatitis (eczema). Another important spin off is the discovery that many of the microbes are similar to those of rat skins, suggesting that rats can be used as model animals to study skin microbiota.

Results of other studies are even more surprising. In the first-ever global study comparing diversity of microbiota, Dr. Mark Stoneking with his team of researchers from the  Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, has analyzed variations in the 16 S rRNA sequences of oral flora of 120 healthy volunteers spanning 6 different geographical locations.They compared this information with already existing databases of 16S rRNA sequences. They found that while a large number of different species do exist in the mouths of individuals, the species don’t vary substantially across geographical locations. This is astonishing considering that there is a tremendous diversity of eating and other cultural habits across the world, again adding weight to the theory of a shared microbiome. This data has tremendous implications for studying disease and health as well as the implications of dietary and social aspects on the oral microbiome.

However, the most definitive results linking alteration in gene expression patterns of Microbiota to a diseased state of health is the research on Gut microflora carried out by Washington University School of Medicine in St. Louis. They studied the microflora of the gut using fraternal twins and their mothers with respect to microbial diversity. They found that most individuals had different species of organisms in their gut, though there were substantial similarities between species carried by individuals of the same family. However, they also found that though the species were different they all expressed some genes that were common. These genes performed functions that complemented our own genes. Further, it was found that when healthy and obese fraternal twins were compared, there was an increased representation of around 300 genes in the flora of the obese individuals and these genes were linked to functions of extracting calories from food and nutrient processing.

These results provide renewed hope to researchers grappling with the problems of dealing with an ever-increasing set of diseases. The prospect of a shared microbiota among healthy individuals brings with it the potential of linking altered states of health with changes in the shared microbiome that can be monitored and used to diagnose onsets of disease. Similarly, if we can link specific microbes to specific positive functions, we can create formulations of these microbes in order to replenish falling levels or to combat increased levels of non- beneficial microbes through competition. This will provide a boost to the study of Probiotics and we will probably be able to maintain good health by “culturing” just the right microbial flora within our bodies. That is indeed a comforting thought !

Reference:

1) Nasidze I., Quinque D., Li J., Li M., Tang K., and Stoneking M. (2009) Comparative analysis of human saliva microbiome diversity by barcoded pyrosequencing and cloning approaches. Analytical Biochemistry. 391: 64–68.

2) Nasidze I., Li J., Quinque D., Tang K., and Stoneking M. (2009) Global Diversity in the Human Salivary Microbiome. Genome Research. 19:636-643.