Feature: From metagenomics to ecogenomics

Read part I: Metagenomics and beyond

Read part II: Metagenomics goes full circle

One of the major projects that Phil Hugenholtz has been involved in to date is part of the second research theme of host-associated microbiomes, and concerns the remarkable hindgut of the termite.

These eusocial insects are well known for their ability to consume difficult-to-digest lignocellulosic materials, which they break down with a lot of help from microbes in their hindgut.

This is not only a fascinating system to study in its own right, but understanding the manner in which termites digest their woody dinner could have practical applications as well.

“Degradation of lignocellulosic material is very topical at the moment because it is a bottleneck in the road to making cheap environmentally friendly biofuels from waste lignocellulosic streams,” says Hugenholtz. “There’s a lot of interest from the biofuels sector to come up with enzymes that can do that step efficiently.”

In research published in Nature in 2007, Hugenholtz, along with collaborators from the California Institute of Technology and Diversa (now Verenium) Corporation, used metagenomics to detail the process by which a dry wood feeding termite, a Nasutitermes species, breaks down cellulose.

They generated 62 million base pairs – a “drop in the ocean by today’s standards,” says Hugenholtz – and from that were able to reconstruct the major players in cellulose metabolism, including the roles played by the bacteria belonging to the treponeme spirochetes as well as fibrobacter, relatives of which are also found in the cows rumen.

This study put to rest a longstanding debate about whether it was microbes or enzymes intrinsic to the termite that were responsible for breaking down lignocellulosic material; it was clearly the microbes that do the heavy lifting.

Even though this study proved to be a great success, Hugenholtz believes the future is moving away from this ‘bulk’ metagenomics approach to become more precise in the way researchers investigate particular systems.

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“If you look at it from a macroscopic scale, this approach is like taking a rainforest, grinding it up, and getting the sequence back. In doing so, you miss all the spatially important information. You can’t distinguish the canopy species from the species inhabiting the forest floor.

“Where I see this centre going is to move away from bulk metagenomics, and move towards more spatially explicit genomics. What we’ve been doing with the termite is to use flow sorting to sort out single cells from the termite hindgut. There are methods now available where you can take a few femtograms of DNA and amplify that up with a viral polymerase into micrograms, and from that you can sequence it.”

This enables a much more fine-grained view of what’s going on. Hugenholtz has also returned to the microscope to figure out the spatial arrangement of cells “As people who normally look at sequence data – as ‘gene jockeys’ – you sometimes get removed from the system and you don’t actually look at it. But it’s good to actually stick the thing under the microscope and take a look at it occasionally.”

And in doing so, Hugenholtz and his collaborators have already discovered some interesting bugs, such as one particular spirochete that drills into plant cell walls like a corkscrew – one very droll student of his calls it the boring spirochete. They are now applying single cell genomics to the boring spirochete to recover its genome and identify the presumably potent cellulases therein.

The future of ecogenomics

It’s still early days for metagenomics, and even earlier days for ecogenomics, but they both promise to shed light on features of biology and biological systems that have hitherto been obscured from sight.

But ecogenomics doesn’t only have application for pure science. The approach is also being used to understand the role of microbial communities in disease processes that are overlooked by conventional culture-based methods

This is the benefit of working with in situ communities: you’re able to look at how a known pathogen interacts with other microorganisms in the host system, which may help keep the pathogen in check if it’s an antagonistic interaction.

Hugenholtz is currently working with clinical researchers to profile the broader microbial communities of diseases such as cystic fibrosis, where it is becoming increasing clear that many different microbial species are involved in the disease

“This is new for me,” he says. “The Joint Genome Institute, it being a Department of Energy facility, doesn’t do clinical research. But now I’m very much enjoying interacting with clinicians, who seem genuinely excited about these new techniques and are totally on board, and they’re proving to be great collaborators. I think in the next few years we’ll have some really nice results.”