Blast Past the Bottleneck - Brute Force or Irresistible Attraction?

(May 4th 2007) Metagenomics is the tantalising shortcut for microbiology. Skip pure culture, skip describing species and go straight to the genomic diversity of bacterial life out there. Craig Venter is one of the many modern adventurers responding to this call. He is certainly the individual with the broadest approach and the fattest purse in the game. However, public research funding and chemical companies are also hot on his heels in the race to spend an obscene amount of money on metagenomics, reports Brynja Adam-Radmanic.

Current estimates reckon that as much as 99% of all microbes are still missing from our census of bacterial life. While scientific hunters, armed with botanist's container and butterfly nets, filled the ever-increasing collections throughout the last centuries, microbiology's quest to find and name all the bacteria in the world still hasn't even scratched the surface.

In contrast to zoologists and botanists microbiologists can't rely on morphology, as the more characteristic traits of microbes are biochemical and genetic features. Unfortunately, most microbes still cannot be kept in pure culture, a prerequisite for studying their physiology and genetics and, subsequently, for describing new species. Is metagenomics the ultimate answer to this problem?

Well, apparently it finally allows microbiologists and genome chasers to experience the same excitement that zoologists and botanists tasted during historic 18th and 19th century expeditions, where every trek was a step towards an unknown diversity of new species. Venter especially celebrates this aspect of metagenomics in his Sorcerer II expedition.

Whilst other metagenomic researchers were extracting bacterial DNA from hot springs or residents in the human gut, Venter set sail over the oceans, pressing surface seawater through ever-finer filters every 250 miles. A first study in 2004 in the Sargasso Sea had already brought an incredibly surprising number of new genes and species to light.

The data of the recently published Global Ocean Sampling (GOS) expedition primarily shows just what an incredible amount of bacterial diversity is yet to be discovered. The expedition almost doubled the number of known genes in public databases and discovery is still in its linear phase with no saturation in sight. Every haul of water reveals not only new proteins but new protein families, too.

However astounding Venter's expedition may be, this is paradoxically its major drawback. Shotgun sequencing of bacterial diversity is good for discovering genes but rather crude when it comes to discovering species. Especially given the vast number of microbes (and viruses) in sea water there's no chance of assembling the DNA sequences as whole genomes.

So bacteria can finally be collected and sequenced without culturing them but the resulting loss of information on the species is a high price to pay. Genome snippets are lumped together with no clue as to where or what they belong. All that remains is a relative number of species that can be inferred from 16S rRNA variants. Therefore, grand scale approaches, such as this, will continue to be very dissatisfying for many microbiologists.

Nevertheless, even without species info, metagenomics data like Venter's will be a rich source for discoveries in the ensuing years. The first papers based on the Sorcerer II data published in PloS already demonstrate this. Plenty of questions concerning whole protein families can now be tackled on a much broader basis. Hence Kannon et al. have been able to compare all 45,000 known kinases, including the 16,000 newly identified prokaryotic ones, providing new insights and explanations for their expansion in eukaryotes.

A new report on metagenomics by the National Academies in the US, published in March, recommends the establishment of a Global Metagenomics Initiative in analogy to the Human Genome Project. The brief report promises, "Virtually all biologists - whether they work on evolution, development, ecology or cancer and whether they study yeast, plants, corals, or mammals - will find that greater understanding of microbial communities has something to contribute to their research."

Furthermore, metagenomics also holds advances for applied research and development. Chemical companies are constantly looking for new enzymes to be used in laundry detergents or for the biotechnical production of chemicals. It's much easier to screen pre-annotated metagenomic libraries for appropriate candidates than starting from scratch with a gene already known to be inappropriate and trying to mutate it in the lab to show some sought-after features.

Diversa in the US was a pioneer company specialising in such metagenomic services for academic and industrial partners; and the market is still emerging with European companies like BRAIN in Germany or LibraGen in France supplying those growing needs.

So metagenomics seems to be more than a hip, new branch of microbiology. Although not the ultimate answer to microbiology's problem with diversity, it still expands our knowledge beyond many borders. Some might abhor metagenomics as applying brute-force to research whilst others hoping for great breakthroughs and money simply cannot resist the attraction.

PloS collection of Sorcerer II expedition: original papers and posters based on Venter's data, plus editorial, essay and synopsis. http://collections.plos.org/plosbiology/gos-2007.php

Report in Brief of the US-National Academies (March 2007): The New Science of Metagenomics - Revealing the Secrets of Our Microbial Planet http://dels.nas.edu/dels/rpt_briefs/ metagenomics_brief_final.pdf

Diversa http://www.diversa.com/

BRAIN AG http://www.brain-biotech.de/en/home.php

LibraGen, Toulouse, France http://www.libragen.com/