The Machine That Goes Ping

USC’s 454 Life Sciences DNA sequencer is rather humble for a half-million dollar marvel on the frontier of science.

“It’s the machine that goes ping — sounds really impressive but looks really plain,” said John Heidelberg, a marine microbiologist based at the USC Wrigley Marine Science Center.

As one of the fastest sequencers in the world, acquired by USC after the 2006 “cluster hire” of seven top marine biologists, its power is mind-boggling.

“Let me put this in perspective,” said Eric Webb, one of those seven. “When I was in grad school, I spent six months sequencing a gene that was a thousand base-pairs long. Now, on Catalina, they’re sequencing an entire genome in a week — it’s crazy!”

Webb recently worked with Heidelberg to sequence the genome of a key marine microbe called Trichodesmium erythraeum.

Considering that “Trick-o,” as they call it, boasts a genome that is 7.5 million base-pairs long, this speedy delivery of genetic code is remarkable.

The technology has led to what many call the “metagenomics revolution.”

According to Webb, “In terms of marine microbiology, things have really just blown wide open, especially since 2000.”

It was in that year when, thanks in part to the “shotgun sequencing” method, the human genome was largely decoded.

The three Catalina-based scientists who work most closely with the sequencer — Karla Heidelberg, John Heidelberg and Bill Nelson — all worked at some point with institutions affiliated with J. Craig Venter, one of the two scientists credited by former President Bill Clinton with mapping the human genome.

Since then, these same techniques have been applied to marine microbiology. With the 454 up and running on Catalina, USC is at the forefront of astonishing advances.

The Rise of the Omics

At its simplest level, a gene is a string of four chemical “bases” abbreviated by A, T, C and G. Sequencing a gene is figuring out the order of those bases and sequencing a genome is figuring out the order of every base of every gene in a particular organism.

Having this code allows scientists to determine the “molecular machinery” of an organism, such as a gene that codes for the ability to fix nitrogen. In the past, this has been done for single organisms painstakingly grown in the lab and sequenced over weeks, months or years.

With shotgun sequencing, DNA is broken into pieces and sequenced and then the genome is reconstructed using a computer. The DNA can come from a single organism, or in the case of metagenomics, from a community of microorganisms.

A metagenome offers scientists a picture of who’s there (based on key genes of certain families of organisms), what they have the potential to do (for example, a gene that allows a microbe to fix carbon dioxide) and what they are actually doing in the environment.

So far, one paper after another has revealed a shocking diversity of microbes in some strange places.

“At one point it became a joke to me: the highly expected unexpected diversity of microbes,” Nelson said.

Heidelberg is currently involved in a metagenomic study of the hypersaline Lake Tyrrell in Australia.

With water 300 times saltier than the sea, it may seem inhospitable, but is actually full of life. Heidelberg and colleagues are using metagenomic samples to build the most comprehensive genomic picture of any environment to date.

The study is important because groundwater the world over, including Southern California, is becoming saltier due to over-exploitation. And since microbes make the difference between fertile soil and a toxic soup, understanding how they function in salty places is critical.

In addition, Heidelberg is looking at bugs that might be able to produce biofuels such as glycerol. Scientists interested in bioenergy often focus on extreme environments because it’s easier to concentrate large amounts of microbes in places with few other competing species.

“Lake Tyrrell is a really good example of how metagenomics is helping us understand an entire community of organisms,” Heidelberg said. “When this is done, it will be the most-described system in the world that I know about.”

And all this is made possible by a machine the size of an office printer, whose soft hums — let alone pings — are no match for Catalina’s squawking seagulls.

The New Frontier

The potential uses for this technology are only limited by time, money and imagination. Across USC, there are potential collaborations involving the 454 DNA sequencer that range from finding the biofuel of the future to studying the “metagenome” of the bacteria in the mouth or gut.

“I think it’s a great opportunity to bring together questions that have never been asked before,” Heidelberg said. “That’s the power of this particular instrument.”

For the time being, metagenomic research is so new that it’s still about basic exploration of little understood but crucial systems.

“It brings up more questions than answers at this point,” she said. “Getting a baseline understanding on what’s out there and how it operates is going to be critical to designing future experiments to test specifically how it works.”

But it’s this sense of the unknown, coupled with knowing the field’s far-reaching potential for critical environmental and health issues, which makes the complex and tedious work worth it.

“For a lot of what’s going on in the metagenomics revolution, it’s really going back to this exploratory frontier-like feeling,” Nelson said. “It’s like hitting the coast of Africa for the first time and seeing a giraffe.”

“It’s exciting,” Heidelberg said. “We still have room for Charles Darwin-type discoveries.”