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Nearly all microbes inside us unknown to science

A Stanford survey of DNA fragments circulating in the blood suggests the microbes living within us are vastly more diverse than previously known. In fact, 99 percent of that DNA has never been seen before.

- By Nathan Collins

Stephen Quake and his colleagues examined the bits and pieces of DNA floating freely in blood plasma and found that 99 percent of the nonhuman DNA fragments didn't match anything in existing genetic databases.
Norbert von der Groeben

A survey of DNA fragments circulating in human blood suggests that our bodies contain vastly more diverse microbes than anyone previously understood, according to Stanford researchers.

What’s more, the overwhelming majority of those microbes has never been seen before, let alone classified and named, the researchers report.

“We found the gamut,” said Stephen Quake, PhD, professor of bioengineering and of applied physics. “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.”

A paper describing the findings was published online Aug. 22 in the Proceedings of the National Academy of Sciences. Quake is the paper’s senior author. The lead author is graduate student Mark Kowarsky.

Searching for rejection

The survey was inspired by a curious observation Quake’s lab made while searching for noninvasive ways to predict whether an organ-transplant patient’s immune system would recognize the new organ as foreign and attack it, an event known as rejection. Ordinarily, it takes a tissue biopsy — meaning a large needle jabbed into one’s side and at least an afternoon in a hospital bed for observation — to detect rejection.

The lab members figured there was a better way. In theory, they might be able to detect rejection by taking blood samples and looking at the cell-free DNA — bits and pieces of DNA circulating freely in blood plasma — contained therein. Apart from fragments of a patient’s DNA, those samples would contain fragments of the organ donor’s DNA, as well as a comprehensive view of the collection of bacteria, viruses and other microbes that make up a person’s microbiome.

Over the course of several studies, the first of which was published in 2013, Quake and his colleagues collected samples from 156 heart, lung and bone marrow transplant recipients, as well as from 32 pregnant women. (Pregnancy, like immunosuppressant drugs taken by transplant patients, also changes the immune system, albeit in ways both more complicated and less well understood.)

The results of these earlier studies suggested there were identifiable changes to the microbiomes of people with compromised immune systems and that positive tests for the organ donor’s DNA were a good sign of rejection.

Something weirder

But there was something else, too — something weirder. Of all the nonhuman DNA fragments the team gathered, 99 percent of them failed to match anything in existing genetic databases the researchers examined.

With that in mind, Kowarsky set about characterizing all of that mystery DNA.

The vast majority of it belonged to a phylum called proteobacteria, which includes pathogens such as E. coli and Salmonella. Previously unidentified viruses in the torque teno family, which is generally not associated with disease but often found in immunocompromised patients, made up the largest group of viruses. “We’ve doubled the number of known viruses in that family through this work,” said Quake, who also holds the Lee Otterson Professorship in the School of Engineering.

Perhaps more important, they identified an entirely new group of torque teno viruses. Among the known torque teno viruses, one group infects humans and another infects animals, but many of the ones the researchers found didn’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,” he said.

An unsurprising surprise?

“I’d say it’s not that baffling in some respects because the lens that people examined the microbial universe with was one that was very biased,” Quake said, in the sense that narrow studies often miss the bigger picture. For one thing, researchers tend to go deep in the microbiome in only one part of the body, such as the gut or skin, at a time. Blood samples, in contrast, “go deeply everywhere at the same time.”

For another, researchers often focus their attention on just a few interesting microbes, “and people just don’t look at what the remaining things are,” Kowarsky said. “There probably are some interesting, novel things there, but it’s not relevant to the experiment people want to do at that time.”

It arms infectious disease doctors with a whole set of new bugs to track and see if they’re associated with disease.

It was looking at blood samples in an unbiased way, Quake said, that led to the new results and a new appreciation of just how diverse the human microbiome is.

Going forward, Quake said, the lab hopes to study the microbiomes of other organisms to see what’s there. “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.” Understanding what those viruses are could help doctors manage and track outbreaks, he said.

“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 disease,” Quake said. “That’s going to be a whole other chapter of work for people to do.”

Quake is a member of Stanford Bio-X, the Stanford Cardiovascular Institute, the Stanford Cancer Institute and the Stanford Neurosciences Institute, as well as a faculty fellow of Stanford ChEM-H.

Other Stanford co-authors are Yasser El-Sayed, MD, professor of obstetrics and gynecology; Yair Blumenfeld, MD, associate professor of obstetrics and gynecology; David Stevenson, MD, professor of pediatrics; Gary Shaw, DrPH, professor of pediatrics; postdoctoral scholar Joan Camunas-Soler, PhD; graduate students Michael Kertesz, Winston Koh, Wenying Pan and Lance Martin; senior research scientists Norma Neff, PhD, and Ronald Wong; and research assistant Jennifer Okamoto.

The work was supported by the Bill and Melinda Gates Foundation, the March of Dimes Prematurity Research Center at Stanford, the Stanford Child Health Research Institute, the John Templeton Foundation and the United States Agency for International Development.

Stanford’s Department of Bioengineering, which is jointly managed by the schools of Engineering and of Medicine, also supported the work.

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