A new paper looking at the DNA fragments floating around in human blood reports that there are way more microbes living inside us than we thought — and we’ve never seen most of them before.

Image credits Colin Behrens.

The idea behind this paper started taking shape as a team led by Stephen Quake, a professor of bioengineering and applied physics, a member of Stanford Bio-X and the paper’s senior author, were looking for a new non-invasive method to determine the risk of rejection in transplant patients. This is traditionally done using a biopsy, which involves a very large needle and quite a bit of ‘ow’.

Needless to say, nobody was very big on the procedure. So Quake’s lab wanted to see if they can work around the issue by looking at the bits of DNA floating around in patients’ blood — what’s known as cell-free DNA. The team expected to find the patient’s DNA, the donor’s DNA, and genetic material from all the bacteria, viruses, and all the other critters that make up our personal microbiome. A spike of donor DNA would, in theory, be one of the first signs of organ rejection.

But what the team didn’t expect to find was the sheer quantity and diversity of microbiome-derived DNA in the blood samples they used.

Bugs galore

“We found the gamut,” says professor Quake. “We found things that are related to things people have seen before, we found things that are divergent, and we found things that are completely novel.”

Throughout their project (which spanned several studies), the team gathered samples from 156 heart, lung, and bone marrow transplant recipients, and 32 from pregnant woman — pregnancy also has a huge effect on the immune system, similar to immunosuppressants, although we don’t really know how.

Of all the non-human DNA bits found in these samples, a whopping 99% couldn’t be matched to anything in existing genetic databases. In other words, they came from strains we didn’t even know existed. So the team went to work on characterizing all that genetic material. According to them, the “vast majority” falls into the phylum proteobacteria. The largest single group of viruses identified in this study belong to the torque teno family (TTVs). In fact, Quake says their work has “doubled the number of known viruses in that family” in one fell swoop.

Known torque teno viruses infect either animals or humans, but many of the TTVs the team identified don’t fit in either group.

“We’ve now found a whole new class of human-infecting ones that are closer to the animal class than to the previously known human ones, so quite divergent on the evolutionary scale,” Quake adds.

The team believes that we’ve missed all these microbes up to now because narrow studies, by their very nature, miss the bigger picture. Researchers often focus their attention on a few interesting microbes and glance over everything else. Blood samples, by contrast, allowed them to look at everything swimming around inside of us, instead of looking at a few individual pieces. It was this net-cast-wide approach — which the team humorously refer to as a “massive shotgun sequencing” of cell-free DNA — that allowed the team to discover how hugely diverse human microbiomes are.

In the future, the team plans to take a similar look at other animals to see what species their microbiomes harbor.

“There’s all kinds of viruses that jump from other species into humans, a sort of spillover effect, and one of the dreams here is to discover new viruses that might ultimately become human pandemics,” Quake says.

“What this does is it arms infectious disease doctors with a whole set of new bugs to track and see if they’re associated with diseases. That’s going to be a whole other chapter of work for people to do.”

The paper “Numerous uncharacterized and highly divergent microbes which colonize humans are revealed by circulating cell-free DNA” has been published in the journal Proceedings of the National Academy of Sciences.