Tuesday, September 18, 2012

What Does Infoscience Have To Do With Bioscience?

 These days, following the “genomic revolution” in life sciences, almost everything. If you are interested in being a biologist, it might be a good idea to get at least a masters in information technology before going on for your doctorate.

Okay, I may be exaggerating a bit…

But it is no exaggeration to say that a second revolution is currently going on in the life sciences that seems sure to cause radical transformation in the fields of human biology, medical science, and perhaps everything else that is biological, from molecular biology to ecology.

It’s bioinformatics – a new field of research where the rapidly evolving tools of information technology are married in an emerging partnership with the new genomic tools of the life sciences and together raise up the fruits of this union – an amazing and mystifying flood of information – by developing totally new skills through information theory. The children are going to be amazing.

UNC Charlotte saw this coming when a decade or so back it decided to strategically devote a considerable amount of its resources in developing a College of Computing and Informatics, and then in developing within that college a totally new – and world-class quality – multidisciplinary department, the Department of Bioinformatics and Genomics.

UNC Charlotte Bioinformatics Building
It was a very good gamble, and it’s already beginning to pay off.

Hard to see biology: microbes

Some of the first fruits of the bioinformatics revolution are in our emerging understanding of vast complexity of an unseen and still shockingly unknown microbial world – the “microbiome” – and how intricately it is connected to all other life on the planet.  Our new awareness of the scope and importance of microbes to all life in general is really a  recent result of rapid advances in genomic technology and bioinformatics, which together have given science a powerful new “telescope” into the amazing diversity, astounding complexity and profound impact that microbial communities have.

UNC Charlotte Associate Professor of Bioinformatics Anthony Fodor has been in the front lines of this new research, developing experimental techniques for probing vast, benign microbial ecologies inside the human body and understanding their dynamics and potential connection to human diseases, including those previously thought to be unconnected to pathogens, such as cancer.

A foundational finding…

Early this past summer, Fodor was part of a national announcement (see press release here) marking a major milestone in this work. In the culmination of a multi-year effort directed by the National Institutes of Health known as the Human Microbiome Project (HMP), some 200 hundred researchers nationwide joined to announce the first genomic compilation of the generalized biome of microbes in the human body that complement the human genome.

In a sprawling series of coordinated scientific reports published on June 14 in Nature and several journals in the Public Library of Science (PLoS), HMP researchers from nearly 80 multidisciplinary research institutions reported on five years of research and announced some fundamental, if preliminary findings.  Fodor was a co-author on three of these papers. The huge collaborative project’s work, including Fodor’s, had been funded by $153 million from the NIH Common Fund, a trans-NIH initiative that finances high-impact, large-scale research.

“Like 15th century explorers describing the outline of a new continent, HMP researchers employed a new technological strategy to comprehensively define, for the first time, the normal microbial makeup of the human body,” said NIH Director Francis S. Collins, M.D., Ph.D. “HMP created a remarkable reference database by using genome sequencing techniques to directly detect microbes in healthy volunteers. This lays the foundation for accelerating infectious disease research previously impossible without this community resource.”

When Collins at NIH and Craig Venter at Celera Inc. published the first complete draft sequences of the human genome in 2001, many people assumed that the genetic foundation for a new and complete understanding of the human body and its functions had been achieved. As it turned out this was far from the complete story, since we now know that our bodies are… not completely human. The human body contains trillions of microorganisms—outnumbering human cells by 10 to one. Because of their small size, however, microorganisms make up only about one to three percent of the body's mass, but play a vital role in human health.

The HMP team reported that this plethora of microbes contribute more genes responsible for human survival than humans themselves. Where the human genome carries some 22,000 protein-coding genes that carry out metabolic activities, researchers estimate that the microbiome contributes some 8 million unique protein-coding genes or 360-times more bacterial genes than human genes.

In addition, the bacterial genomic contribution is critical for human survival. Genes carried by bacteria in the gastro-intestinal track, for example, allow humans to digest foods and absorb nutrients that otherwise would be unavailable.

“Humans don’t have all the enzymes we need to digest our own diet,” said Lita Proctor, Ph.D., HMP program manager. “Microbes in the gut breakdown much of the proteins, lipids and carbohydrates in our diet into nutrients that we can then absorb. Moreover, the microbes produce beneficial compounds, like vitamins and anti-inflammatories (compounds that suppress inflammation in the gut) that our genome cannot produce.”

To define the normal human microbiome, HMP researchers sampled 242 healthy U.S. volunteers (129 male, 113 female), collecting tissues from 15 body sites in men and 18 body sites in women (including three vaginal sites). Researchers collected up to three samples from each volunteer at sites such as the mouth, nose, skin (two behind each ear and each inner elbow),and lower intestine (stool).
Where doctors had previously isolated only a few hundred bacterial species from the body, HMP researchers now calculate that more than 10,000 species occupy the human ecosystem. The researchers calculate that they have found between 81 and 99 percent of all the genuses of microorganisms in healthy adults.

Defining  “a”  human biome, however, can be difficult. Fodor and an HMP research group found immense variation in the bacterial communities, both in the diversity of bacterial groups from person to person, and in the relative abundance of  specific bacterial groups that many people shared. The variation in bacterial populations was extreme and nearly impossible to characterize, including population differences both between areas in the body and between similar areas  in different bodies.
As scientists explained in the major NIH announcement, “each body site can be inhabited by organisms as different as those in the Amazon Rainforest and the Sahara Desert”. Further, these sites on different individuals are populated with different assemblages of bacteria, or with some of the same bacteria, but in markedly different proportions.

In a paper Fodor co-authored, researchers asked the question of whether there were particular types of bacteria that were common, or “core”, across all the human subjects in the HMP.    Defining a core bacteria as one present in 95% of all subjects, an analysis found that the nine sample sites from the mouth had the highest numbers of shared “core” bacteria, with the number of “core” varieties shared between stool samples being somewhat lower and very few core bacteria found at the skin and vagina sample sites.

 Fodor noted that, while there is a small “core” of commonly shared bacteria at some body sites, the researchers also found that the abundances of “core” bacterial varieties could vary by several orders of magnitude between individual people. 

“Consider stool samples,” he said. “There’s one sample where a particular type of bacteria represents about 90% of the sequences that we saw. But then there are other samples where it represents not 90% but .01% -- and there’s everything in between.  And this kind of variation is not just true of this type of bacteria but of essentially every type of bacteria within the HMP.

 ”Since all of the volunteers within the HMP were healthy, this tells us that there do not appear to be particular bacteria that are required to be present in high numbers to maintain health,” Fodor noted.
Interestingly, this high level of variation in bacterial populations does not mean that the combined metabolic  functions those populations perform are similarly different.

“The microbiome doesn’t work that way,” Fodor said.  “You and I can both be perfectly healthy and one group of bacteria can represent 95% of my gut, and be .01% of your gut.  Maybe that is explained by the analysis in the Nature paper that shows that even though the types of bacteria are different, the function of genes within the genomes of these different bacteria appear to be very similar.”  From these data, it appears that very different communities composed of different bacteria can perform similar ecological functions in the body, according to Fodor.

Though the HMP announcement was a milestone in preliminarily defining the microbiome and introducing irrefutable evidence of it playing a major role in human body functions, Fodor notes that work has barely begun in understanding bacterial ecologies and how their interactions specifically relate to specific health issues.

 “It remains an open question how individual variation in the types of bacteria within healthy people influences disease development,” Fodor continued. “It will be really interesting to see how this question is resolved as the field continues to mature and we learn more about the contribution of the microbiome to specific diseases such as obesity, cancer, fatty liver and inflammatory bowel disease.”

… pointing to practical applications

And so even while the HMP announcement was breaking, Fodor was hard at work defining this next stage in the research. In a paper published about a year ago, Fodor and colleagues announced results from a clinical trial  that indicated linkages between various bacteria whose populations vary widely from human to human and a metabolic process that can be critical in causing liver disease. Shortly after the HMP announcement, Fodor published another finding that showed how major changes in bacterial diversity in the gut as well as the invasion of populations of bacteria not common in the intestines appears to have a strong relationship with developing colorectal cancer (see the press release here). Several other significant findings are in the works.

Central to all of Fodor’s work is this revolutionary thought: None of us are really individual organisms – we are biomes, cooperative assemblages of many organisms, whose purposes and genes dance with each other in maintaining the general human ecology that we call health.

This is really a totally transformational way of looking at ourselves and other organisms. Though ecologists have looked at the larger world around us using similar theories for quite some time, until the information became available and the information scientists found ways to examine it, we didn’t understand that this same complexity is going on at much smaller scales as well. As the popular saying goes, this changes everything.


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