RNA Viruses: Biology’s Dark Matter?

Call it the circle of life science: For generations, biology has moved outward from medically relevant discoveries to broader, big picture revelations on the nature and diversity of life—which in turn reveal new specific translational ideas in medicine. Advancing technologies like sequencing, imaging, or computation often drive the trend, as exemplified in a fascinating study published recently in the journal Science, which applied advanced computational methods to sequence data from various samples of plankton taken from the world’s oceans. 

The paper focused on the global presence of a broad class of biological agents notorious for their role in disease: the RNA viruses, which include some of the worst pathogens known to humankind—influenza, rabies, Zika, dengue, measles, hepatitis, West Nile, and of course SARS-CoV-2, the humble and horrible cause of our current pandemic. RNA viruses are infectious particles that use RNA to carry genetic information, rather than DNA, and they have been a big topic lately because of COVID-19, which is caused by an RNA virus. But most RNA viruses are not at all a threat to human health. In fact, as the new study reveals, they are literally all over the place, in every corner of the world, filling every ecological niche, likely for the entire history of life on Earth, especially in the oceans.

“After screening RNA sequences derived from plankton from literally the whole ocean, we have doubled the number of major taxonomic groups (known as phyla) of RNA viruses,” says Guillermo Dominguez Huerta, a postdoc at Ohio State University who was one of the lead authors on the new paper.

The new study is emblematic of the current data-heavy direction in biology because the researchers sequenced some 28 trillion bases of RNA from the world’s oceans. But it’s also a watershed conceptually because all that data reveals a stunning genetic diversity of RNA viruses in the sea, which is staggeringly larger than what we imagined and reveals that there is a wealth of organisms yet to be discovered. Before this study, scientists grouped known RNA viruses into just five broad taxonomic groups (technically known as “phyla”). 

“Now, we are suggesting that there are ten,” Dominguez Huerta says.

A new golden age?

The elucidation of the place in nature of RNA viruses follows the general storyline of other biological entities that has been unfolding over the past two centuries. Back in the “Golden Age of microbiology” in the late 19th and early 20th centuries, when germ theory was still new and scientists were first starting to connect particular bacteria to specific infectious diseases, they were generally limited to studying only bacteria that could be “cultured” or grown in the lab (we now know that many cannot), and the focus was squarely on disease-causing microbes, which are just a minuscule proportion of all microbial life. So biologists learned slowly about other microorganisms, and only in the late 20th century did they begin decoding their genomes. That led to some surprising rethinking of evolutionary relationships and the demise of the old five-kingdom model of biological classification that was based on traits rather than genes. Our new genetic understanding led to the emergence of the so-called domain model, categorizing life into three domains (archaea, bacteria, and eukarya), instead of the old model of five kingdoms (protists, fungi, plants, animals, and bacteria). 

Sequencing has become so cheap that instead of focusing on this virus or that one, researchers can cast a wide net and sequence everything they can suck up an oceanic straw.

The new study reflects a maturation in the technology as well. In the late 1990s, when scientists were rapidly sequencing the world’s viruses, they were focused on DNA viruses because the technology for sequencing RNA viruses was not yet mature. Now it is, and sequencing has become so cheap that instead of focusing on this virus or that one, researchers can cast a wide net and sequence everything they can suck up an oceanic straw.

“The new analytical road map developed in this study allows us to illuminate the RNA virus dark matter,” says James Wainaina, another Ohio State postdoc who authored the study. Dark matter is a concept from astrophysics used to describe nonluminous material within and between galaxies, which we know exists but can’t observe. The idea of dark matter in biology is that there are all these undiscovered RNA viruses out there shaping life in unknown and profound ways.

“The immense diversity of RNA viruses infecting plankton across the oceans confirms that more than 99 percent of [the] RNA virosphere is still biological dark matter,” Dominguez Huerta says. “It tells us that illuminating this unknown virus sequence space will bring many lessons about the evolution of viruses and life on Earth.”

At least one of the suggested new phylum classes of viruses, which the researchers propose calling Taraviricota, is revealing secrets about the very early evolution of RNA viruses, for instance, and may help us understand the very early stages of life on Earth, Dominguez Huerta says. In the circle of life science, such knowledge will also improve our understanding of new and emerging RNA viruses. 

“The study is a beautiful example of how new sequencing technologies and computational tools are allowing us to shift the focus from the medically-relevant sampling to a broader environmental exploration,” says Maia Larios Sanz, the chair of biology at the University of St. Thomas in Houston—an expert on microbiology with RNA research experience who was not involved in the study. “The more we learn about RNA viruses, which likely pre-date DNA genomes, the more we might be able to understand the origin and evolution of the genetic code, and how the flow of genetic information between biological entities—both cellular and acellular—came to be.”