The
only time you’re completely human is before you’re born. For the rest
of your life, microbes from the environment colonize ecosystems around
your body, outnumbering your
37 trillion human cells by
about 10 to one.
Over the past decade, scientists have been exploring how the microbes
living on and inside the body influence our health. Why do some make us
sick while others protect against pathogens?
Rather than trying to grow each species in a lab and reading its
sequence of DNA letters to make a single genome, researchers are using a
more economical approach: collect samples from one location (such as
the gut), chop-up all the DNA, then read the short fragments. The result
is a ‘metagenome’, the collected genetic material from an entire
microbial community.
Metagenomes generate a huge amount of data at relatively low cost. For $170m, the first phase of the
Human Microbiome Project
catalogued the microbes at five sites – mouth, nose, skin, urogenital
and gastrointestinal tracts – in 242 American adults. As well as
revealing the secrets of known species, information in the depths of
metagenomes can also be mined to uncover microbes that we never knew we
had, such as a newly-discovered virus called crAssphage.
A bacteriophage virus (CC BY-NC-SA 2.0 / original by origamiwolf: https://flic.kr/p/oDCK1)
The crAssphage virus is a bacteriophage, or ‘eater of bacteria’. It infects species of
Bacteroides, a group that makes up
50% of gut bacteria on average and behaves as
both good and bad bacteria.
Most of the time the relationship is mutually beneficial: we provide a
home, they help digest our food. But they can also be harmful, being
associated with health issues such as diabetes and obesity. The strain
enterotoxigenic
Bacteroides fragilis is
linked to colorectal cancer. By preying on
Bacteroides, crAssphage probably helps keep us healthy.
The virus was discovered by Dr Bas Dutilh, a bioinformatician at
Radboud University Medical Centre in the Netherlands, who rebuilt its
genome from DNA fragments in faeces. In programming, it’s normal to
combine words and capitalize the first letter, and the computer tool
that Dutilh developed to assemble the viral genome is called crAss (for
‘cross Assembly’). He tells Forbes that the virus’s name wasn’t inspired
by where it came from.
“Initially we didn’t give it any name, it was just called ‘the new
virus’,” says Dutilh, adding that one of the scientists reviewing his
research paper
suggested giving the virus a name. “Then I was like, Oh okay, maybe I
can use this opportunity to advertise my computer tool. And basically
that’s how it got the name crAssphage.”
Reconstructing crAssphage’s genome was no mean feat, as each
metagenome includes DNA fragments from an entire community of microbes.
Imagine a metagenome as a box full of pieces from hundreds of different
puzzles. The genome of a known organism can be assembled using a related
species as a guide, like looking at the picture on the front of the
box, but how do you find something that you don’t even know exists?
Dutilh’s computer tool pieces a genome together by detecting DNA
fragments that are equally abundant within the same metagenome. Say you
find puzzle pieces with the same distinctive shape in different boxes,
except that box A contains 10 copies of each piece while box B has 100
copies. Because the distinctive pieces are ‘co-abundant’ within a box,
they’re probably parts of the same puzzle.
Working with collaborators at San Diego State University, Dutilh used
his crAss software to analyze faecal metagenomes from 12 individuals.
This revealed a set of distinctive DNA fragments that could be assembled
into a genome. DNA tests on one of the 12 stool samples confirmed that
crAssphage was there.
The researchers then searched public DNA databases and detected the
virus in 73% of 466 faecal metagenomes from the US, Europe and South
Korea. This wide distribution implies that crAssphage occurs in up to
three-quarters of people around the world, and means trillions of
viruses are probably living in your gut right now.
Not much is known about crAssphage. It’s too small to be seen under a
light microscope, but will no doubt have the angular head, tail and
‘legs’ typical of bacteriophages. Its genome is 97,000 letters long, and
patterns in its DNA indicate the virus has 80 genes, only half of which
are similar to known genetic sequences. Some encode structural proteins
and molecules that manipulate its host’s DNA-making machinery, and
several genes are predicted to encode proteins that attach to
Bacteroides.
Bacteroides fragilis (source: http://phil.cdc.gov)
Dutilh and his collaborators have several lines of evidence to indicate that crAssphage infects
Bacteroides.
Parasites need hosts, so you would expect a relationship between
numbers of bacteriophages and bacteria. Indeed, when the abundance of
crAssphage DNA was compared against the bacterial strains in 151
metagenomes from the Human Microbiome Project, there was a clear
correlation between the amount of crAssphage and
Bacteroides
DNA. When the virus was used to search a database of 3000 bacterial
genomes for CRISPR sequences – patterns in a bacterium’s immune system
that record encounters with viral DNA, like antibodies matching antigens
–
Bacteroides was the top search result.
As well as controlling gut bacteria in healthy people, crAssphage
might one day be used to fight disease. For example, you could isolate a
virus that specifically targets pathogenic strains of
Bacteroides fragilis. A genetically-engineered crAssphage could also serve as a therapeutic ‘phage vector’ for delivering drugs or vitamins.
So far, metagenome research has focused on bacteria. Viruses have
been neglected, partly because it’s assumed their DNA evolves too
quickly to detect. But as crAssphage shows, viruses can be extremely
abundant and therefore play a large role in a microbial community.
“Our intestinal bacteria are one huge ecosystem,” says Dutilh. “But
to understand that ecosystem, you need to understand the viruses as
well.”
