12.18.2020 08:00 AM

A New Field Guide for Earth’s Wild Microbes

The most massive database of microbial gene sequences so far shows that the tree of life is much larger than we knew.

Coxiella Burnetii — Photograph: NIAID/SCIENCE SOURCE

There are hardly any places on Earth that aren't inhabited by microbes. They live in lakes, streams, soil, and air; they colonize our bodies and even reside in extreme environments like scalding hydrothermal vents and acidic hot springs. And their numbers are staggering—there are as many microbes in a handful of soil as there are people living on Earth.

Yet scientists don’t know much about the majority of them. Only a small fraction have been grown in a lab where they can be studied. Getting a wild microbe to take root in a petri dish requires painstaking work, expert skills, and a lot of luck. It doesn't happen very often.

But in November, researchers from the Department of Energy’s Joint Genome Institute announced a significant advance: They have assembled the largest catalog of microbes to date, containing over 50,000 genomes from 18,000 different microbial species—12,000 of which have never been documented before. Their study, published in the journal Nature Biotechnology, expands the known tree of life by a whopping 45 percent.

“It’s a fucking incredible amount of data,” says Jonathan Eisen, evolutionary biologist from UC Davis and a founder of one of the first efforts to catalog microbes, the Genomic Encyclopedia of Bacteria and Archaea. “There are only about 10,000 species of microbes that have been cultured and described formally, and yet there might be a billion species. That is why this study is so important.”

In this new snapshot of life on Earth, scientists found many potentially useful things. Among them are thousands of new genes that encode enzymes with potential uses in medicine, scores of new strains of archaea, single-celled organisms that release carbon into the atmosphere, and a new species of the class B bioterrorism agent Coxiella burnetii—a highly contagious bacteria that can jump from farm animals to humans causing a disease called Q Fever. They also found 700,000 viruses and linked them to their bacterial and archeal hosts, further illuminating the vast interconnections in this unseen world.

“It's really meant to be this very large community resource for researchers across the world to be able to then use these data to try to answer questions that they're interested in,” says Emiley Eloe-Fadrosh, a bioinformatician at the Joint Genome Institute and senior author on the new study.

The study of microbes began in the 17th century, when the Dutch microscopist Antonie van Leeuwenhoek peered through his single-lens microscope and discovered a hidden world. But in the centuries that followed, scientists have only put a small dent in identifying the full biodiversity of microbes on Earth. According to Stephan Nayfatch, a bioinformatician at Lawrence Berkeley National Laboratory and lead author on the paper, the vast majority of microbes can't be grown under laboratory conditions, and that makes it “nearly impossible to study many organisms using traditional methods.”

One reason is that replicating the exact conditions of the biological soup needed for microbes to thrive is not easy. The quest to learn the secrets of one particular microbe buried in deep sea mud, for example, took a team of Japanese researchers 12 years. They had to find just the right combination of nutrients, gases and chemicals that allowed it to grow. The feat, which required adding a mixture of three different antibodies to kill contaminating strains, was a major accomplishment celebrated in the scientific community. Studying this microbe, which they named Prometheoarchaeum syntrophicum after the Greek god who created humans out of mud, answered longstanding questions about how complex life on Earth evolved. But this type of effort cannot be repeated for all of the trillions of microbes in the world, so scientists needed to find a more efficient way.

It was once thought you could only get high quality DNA directly from the animal or nicely preserved bones and specimens, but, starting in the 1990’s, microbiologists began sequencing DNA directly out of scoopfuls of soil, mud, and sea water. They were looking for genetic material called environmental DNA, or eDNA, that is shed by living things. Instead of having to grow microbes in the lab to obtain their genomes, they now use eENA and a technique called metagenomics to directly sequence the bits of discarded DNA. Nayfatch says this has “truly revolutionized how scientists study microbial diversity.”

Nayfatch is a research scientist at the Joint Genome Institute, which offers DNA sequencing services for scientists around the world. Over the past 15 years, the institute has sequenced eDNA from researchers studying deep sea thermal vents, Arctic permafrost, ocean mud, Greek lagoons, deep African gold mines, human and animal intestines, and more. This database, which is the culmination of research from all those groups, has allowed Eloe-Fadrosh and her colleagues to discover more branches of the tree of life.

Included in the new database, which will be made publicly available, are a treasure trove of new genes that encode useful compounds called “secondary metabolites.” These are small organic compounds found in nature that have therapeutic properties, such as opium produced by the poppy plant or penicillin from the Penicillium fungi. Soil bacteria are also a potent source of therapeutics. The soil bacterial strain Streptomyces, for example, has given rise to numerous antibiotics and even anti-cancer drugs. In fact, some of its compounds that were developed into drugs, like the antibiotics chloramphenicol and spectinomycin, are now considered essential medicines by the World Health Organization.

“I'm personally very interested in what diversity is out there and how we can catalog it,” says Eloe-Fadrosh. As a researcher for the Department of Energy, she is especially interested in the roles these microbes play in biogeochemical processes in the environment and carbon cycling. Microbes that reside in the soil break down organic matter and release carbon dioxide and methane, which contribute to greenhouse gases in the atmosphere.

A big question right now in microbial ecology is what will happen to the microbes in the Arctic permafrost when global temperatures warm and it starts to thaw. Will they unleash a flood of carbon into the atmosphere as they awaken and feast on the frozen plants and animals buried there? “People often want to know, how are the microbiota going to react to a changing climate? And we have a hard time answering those questions because we're still just understanding which of them live out there and what they do,” says Allison Murray, a microbial ecologist at the Desert Institute, who was not involved in the study.

This catalog is an important first step in understanding that, because it contains several new species of microbes with genes involved in methane production. Additionally, Eloe-Fadrosh says, she found many archaea that have genes that metabolize methane, taking it out of the atmosphere and using it as energy. She is excited about the future potential of somehow using these microbes to sequester atmospheric carbon.

Karen Lloyd, a microbiologist at the University of Tennessee Knoxville who was not involved in the project, says this source of new genetic sequences is “mind-boggling” in its potential to expand our options for useful biological molecules. For Lloyd, the study “lays out the full scope of the microbial world for us, and it shows us that the microbial landscape is vast and largely yet to be discovered.”

Eisen, an avid birder, likens this database to a first draft of a field guide for Earth’s undomesticated microbes. But he says that it is only the first step in understanding the function of these organisms and their importance in the ecosystem. The next step is to learn something about their biology.

Eloe-Fadrosh agrees. “By better cataloguing the diversity of microbes out there, we hope that we're better able to identify all the different metabolisms and unique functionalities that are encoded within the entire tree of life,” she says.