Feature: Metagenomics goes full circle

Read part I: Metagenomics and beyond

Establishing the Australian Centre for Ecogenomics actually brings Phil Hugenholtz back to his home turf; he held a faculty position at the University of Queensland in the maths department doing bioinformatics back in 2000.

The following year he was lured over to the United States by geomicrobiologist and geochemist – and metagenomics pioneer – Jill Banfield, also an expat Aussie, originally from Armidale.

While Banfield was visiting UQ, she got chatting to Hugenholtz about a community of microorganisms she was studying in an abandoned mine in northern California. It looked like it could be an ideal test bed for metagenomics techniques, mainly because it was relatively simple, consisting of only a handful of species.

This was attractive because, at this stage, metagenomics was still unproven as an approach, and there was some question over whether it would be possible to make any sense of the panoply of genomic data returned from sequencing an entire environment.

“Jill said she wanted to apply shotgun sequencing to this simple community, and if it didn’t work for that, then we’d know the method wouldn’t work for more complex communities,” says Hugenholtz.

Thankfully the study turned out to be a tremendous success. It revealed an intriguing interdependence between a range of species, both bacteria and archaea, working together to metabolise the iron oxide in acid mine drainage.

Thus metagenomics gained a tremendous boost, demonstrating that the approach can yield useful data, and giving Hugenholtz an insight into how metagenomics compares to the traditional approach.

“These studies are always somewhat of a fishing expedition,” he says. “You may have some hypotheses you want to check, but essentially you’re getting a snapshot of the whole genetic potential of the community, and you’ve got to go in with an open mind.

“You’ve got to be open to seeing things you may not have been looking for. That’s a little uncomfortable if you’re used to hypothesis-driven science, but you get the hang of it.”

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After this venture, Hugenholtz stayed on in the US, shifting to the Department of Energy’s Joint Genome Institute. This is where he stayed for several years, until UQ Vice Chancellor, Paul Greenfield, caught wind of this new field of metagenomics, and made the executive decision that this is just the type of thing UQ should be investing in.

And who better to turn to than UQ alumni, Hugenholtz and Tyson, who had recently returned to UQ after a successful PhD and postdoc in the US. Greenfield lured Hugenholtz back home with the prospect of establishing a new centre together with Tyson to advance the discipline, and they both embraced the opportunity.

The approach the two will be taking is to use a mix of tools to explore the workings of biological communities, all under the moniker of ecogenomics. “We’ve chosen to define ecogenomics as comprising metagenomics, single-cell genomics, metatranscriptomics and metaproteomics,” says Hugenholtz.

“Metagenomics is a great baseline technique, and we’ll do that for most of the ecosystems we look at, but it’s only one tool in the toolkit. You want to apply these other techniques to get a better handle on what’s going on in the community.”

The centre has three main research themes, the first being environmental, championed by Tyson. This involves looking at biogeochemical cycling, particularly in marine ecosystems, and doing similar studies to the pioneering acid mine drainage one.

The second area of focus is host-associated microbiomes, which is Hugenholtz’s speciality. One aspect of this includes looking at human systems, particularly disease states, using metagenomic techniques.

“Traditionally people just study the pathogen and don’t consider the ecological context,” says Hugenholtz. “But that organism doesn’t work in a vacuum. Even areas of the body that you think are sterile have communities rather than a single organism.”

The third research theme is on the tree of life, specifically the microbial tree of life, including viruses. Culture-independent studies have repeatedly highlighted the huge gaps in our knowledge of the tree of life, and this tree – i.e. evolution – underpins all ecogenomic analyses. Indeed, evolution and ecology are two faces of the same coin.

“For example, we’ve been looking at viral communities in activated sludge systems, seven months apart,” says Hugenholtz. “You can see how the virus has evolved over time, where the changes in genome have occurred and what were the evolutionary drivers, because they’re in an arms race with their host.

“By doing this, we’ll start to get a handle on real-time evolutionary dynamics, which I think has been largely missing from microbial ecology studies so far. There’s been a lot of speculation about evolutionary rates, and now we can actually, at least on the microevolutionary scale, get hard data on what’s happening, how fast it’s happening and why it’s happening. I think that’ll be very exciting.”

Read part III: From metagenomics to ecogenomics