ERIC BAPTESTE is on a hunt for life, but not as we know it. He doesn’t think we have to sift through Martian soils or trawl lunar oceans to find these entities. His hunting ground is far closer to home: the human body.
“Biology is full of surprises,” says Bapteste, an evolutionary biologist at the Pierre and Marie Curie University in Paris. “Since we have not yet exhaustively sampled all the DNA in the world, there is still room for finding rare, strange creatures.”
Advertisement
A realist might say that Bapteste’s mission is doomed to fail. After all, we are in the 2010s, not the 1710s. It is unthinkable that biologists can unearth new divisions of life on Earth – let alone make those discoveries in the intimately familiar environment of the human body.
They would be wrong. Recent research shows that our bodies are home to microbes unlike anything science has encountered before – some so alien that they are rewriting the tree of life. What’s more, this microbial “dark matter” could be having a profound effect on our health, for better and worse.
The body is home to some , which outnumber our 30 trillion human cells. Our skin has 10 million bacteria per square centimetre. Earlier this year, a study found that as many as – although a smaller subset of these live in or on any one individual. For years we assumed these microbes were harmful, but we now know that many of them are actually our allies, closely linked with our health and well-being (see “The human zoo”). Thanks to new technology, we can now study them in unprecedented detail.
Until a few decades ago, microbiologists had to grow microbes in the lab before they could identify and study them. However, the vast majority of microbes can’t be cultured this way, seriously limiting the scope of our understanding. Today, we can get around this problem using metagenomic sequencing, a technique used to identify microbes from their DNA – in a sample of human faeces, for instance – even if the microbes won’t grow in culture. Once snippets of DNA have been identified, we can use software to reconstruct whole genomes from those fragments. Thanks to this approach, every month seems to bring a new discovery of previously unknown microbes living or on us.
Occasionally, these are truly unexpected. In 2013, for example, a team led by Jillian Banfield at the University of California, Berkeley, and Ruth Ley at Cornell University in New York discovered evidence that our guts are home to to the evolution of complex life. The team named these newly found microbes Melainabacteria, after the nymph of dark waters from Greek mythology.
The facilitators of life
The connection of Melainabacteria to cyanobacteria was intriguing: the latter are, as far as we know, the only organisms ever to develop a form of photosynthesis that generates oxygen as a by-product (plants have this ability only because they incorporated cyanobacteria into their cells). This innovation transformed the planet’s atmosphere and paved the way for complex life. But how cyanobacteria have evolved has been a bit of a mystery, largely because we have struggled to find related microbes.
Melainabacteria plug that gap. They have already helped microbiologists and geologists to argue that .
What’s more, they may play an important role in human health too. A 2018 study revealed that than those without the condition. The microbes might protect us by outcompeting cyanobacteria, which generate neurotoxins, for nutrients and preventing them from gaining a toehold.
This finding hints at something important about human microbiomes: they are complex ecosystems containing a range of microbes interacting with one another (see “The ecosystem inside”). This diversity is plucked from all three of the major branches, or domains, of the tree of life.
The cyanobacteria, for instance, belong to the bacterial domain. Our bodies are also home to microbes that look superficially like bacteria but actually belong to a distinct domain called the archaea, commonly found in extreme environments such as hot springs. The body was once thought to be an unlikely habitat for these simple organisms, but last year a team reported that archaea are as abundant as bacteria in the human appendix and nasal passages. Our bodies also play host to a huge number of microbes – including fungi – from the domain of complex, eukaryotic life that also contains animals and plants.
But is it possible that within us lie completely new life forms, microbes that don’t fit within these three known domains?
Bapteste has reason to believe so. In 2015, he and his colleagues sifted through gene sequences from faecal samples and found DNA that was so unusual it hinted at the existence of a mysterious fourth domain of life. The work is some way from solid proof that our bodies are home to such weird organisms, but one recent discovery suggests the idea isn’t as far-fetched as it might sound.
Back in 2010, a team exploring the life forms living in our mouths – the – found genetic material belonging to two rare groups of bacteria, known simply as TM7 and SR1. These had first been found a few years earlier in a peat bog and in river sediment, respectively.
By 2013, a group had pieced together essentially complete from a wastewater treatment plant. Another team, led by Banfield, had done the same for microbes living in groundwater. They discovered that all of the genomes were curiously small – roughly a quarter of the size of the genome of Escherichia coli bacteria, which are commonly found in the gut and the wider environment. As a consequence of being so small, the genomes seemed to lack some genes thought to be essential for independent life. This could mean they belonged to bacteria that survive only in intimate symbiosis with other cells that give them what they can’t make themselves.
Since then, we have learned a lot more about these odd bacteria. In 2015, to show that some are so small that they are on the cusp of being impossible. Individual cells tend to be no more than a few hundred nanometres in length, which is about as small as biologists have calculated .
The same year brought even more unexpected news. Banfield and her colleagues studied almost 800 bacteria with small genomes (including TM7 and SR1). They realised that the bacteria belonged on a single evolutionary branch, which was given the working name of the Candidate Phyla Radiation (CPR). What’s more, the CPR branch was a staggeringly stout one: Banfield and her colleagues suspect that the CPR account for as much as .
The upshot is that we really do seem to have a newly recognised set of very unusual microbes in our bodies. “We think it’s a new player … these ultra-small bacteria with tiny genomes that we’re just learning about,” says Jeffrey McLean at the University of Washington in Seattle. They may not be distinct enough to qualify as a fourth domain, but the CPR “subdomain” has revolutionised our picture of the tree of life (see diagram, below) and profoundly affected our thinking about human microbiomes.
There are, in fact, three different types of CPR bacteria that we know of in the human body – TM7, SR1 and a third called GN02. So far, they have been found in the human mouth, gut and vagina and on the skin. Now we know they existed in Neanderthals too. Studies of mineral deposits taken from 48,000-year-old Neanderthal teeth found several strains of CPR bacteria, including one called TM7x.
What exactly are these bacteria doing? An answer is beginning to emerge, and it isn’t good news. CPR bacteria usually comprise no more than 1 per cent of microbiome populations, but can be far more abundant in people with certain illnesses, including inflammatory bowel disease. In people with severe gum disease, 20 per cent of the oral microbiome may be composed of CPR bacteria.
But are these mystery microbes actually causing these health woes? To answer that, McLean and Xuesong He, now at the Forsyth Institute in Cambridge, Massachusetts, decided to take a closer look. In 2015, they led a team that managed to taken from the human mouth, making it possible to study the microbes’ biology and behaviour under the microscope. This strain – TM7x – remains the only CPR bacterium that has been successfully cultured to date.
A cloak of parasites
It wasn’t easy. McLean and He’s team found they could only grow TM7x in a co-culture that also included a strain of another oral bacterium called Actinomyces odontolyticus, which can itself cause inflammatory disease if it becomes overabundant in our microbiomes. Studying the cultures under the microscope revealed why the two must be grown together: the tiny TM7x cells are parasites that bind themselves to the surface of the larger A. odontolyticus bacteria.
This kind of microbe-on-microbe parasitism has been seen elsewhere in nature, but never before within us. “Having a bacterium parasitise another bacterium in our bodies is a new finding,” says McLean.
“The bacteria are so small that they are on the cusp of being impossible”
But even though McLean and He have evidence that TM7x can kill A. odontolyticus cells, the parasitic relationship is a strange and complex one. Intriguingly, when A. odontolyticus are parasitised by TM7x, they gain the ability to dodge detection by our immune system.
This might help explain the link between CPR bacteria and conditions including gingivitis and inflammatory bowel disease. These are caused by bacteria that are standard components of the healthy human microbiome, but that overwhelm our immune system if they become too abundant. Perhaps being parasitised by CPR microbes gives certain bacteria the ability to avoid detection by our immune system and helps them become abundant enough to increase inflammation – although that is an idea that hasn’t yet been tested, says McLean.
“The discovery of the CPR bacteria was a big surprise,” says Bapteste – and it is one with big possible implications. After all, if we have only just realised that our microbiomes are home to a previously unknown subdomain of life, who knows what additional life forms may be lurking within us.
Bapteste is realistic, and recognises that identifying them will take time and won’t be easy. “Finding novelty is always far more difficult than finding more of the creatures we already know,” he says. “It’s going to be a long quest.”
The ecosystem inside
It’s a jungle in there. There is a surprising diversity of microbes living in and on our bodies. And like jungle species, they interact to form intricate ecosystems.
The interactions stretch across the three known domains of life – eukaryotes, bacteria and archaea. In our guts, for instance, suggested that eukaryotic Candida yeast degrade starches in our diet, freeing up simpler sugars that Ruminococcus bacteria ferment. Methanobrevibacter archaea then thrive on the waste products released by the bacterial fermenters.
“By-products and waste products become resources for other organisms, and the system functions only through those interdependencies,” says Jillian Banfield at the University of California, Berkeley.
Sometimes this interaction can trigger disease, such as when oral bacteria are parasitised by strange, tiny bacteria and together seem to dodge the immune system. But it can keep us healthy too.
In your mouth, Candida albicans yeast can trigger nasty infections, but through interaction with a bacterial species called Fusobacterium nucleatum, the . This means it is less able to kill cells of the immune system and become dangerously overabundant in the oral microbiome.
As we learn more about such interactions, it might even be possible to find new ways to treat diseases that result from microbial pathogens. Antibiotics have had a hugely beneficial impact on human health, but they are blunt tools. “They are generally not specific, so they kill most bugs and not just the ones you want to kill,” says Xuesong He, a microbiologist at the Forsyth Institute in Cambridge, Massachusetts.
We may be able to target specific pathogens by disrupting their vital ecological interactions with other species in the microbiome. “The idea is to use the power of the microbes that live with the pathogens,” says He. “Using the microbiome to do the treatment.”
The human zoo
Our bodies are home to an astonishing variety of species, which can influence our health and even our minds. Here is a snapshot:
Eyelash mites
Shaped like a slug with eight legs, Demodex mites are a relative of spiders and grow up to 0.4 millimetres long. Two species live on the human face, and can cause skin problems such as rosacea.
Obesity bacteria
The average human gut contains about 160 species of bacteria, weighing about 1.5 kilograms in total. In Western populations, bacteria from the Firmicutes and the Bacteroidetes groups dominate. They break down carbohydrates and make essential nutrients like B vitamins. People with obesity seem to have – and lower than normal levels of Bacteroidetes.
Death microbiome
Bacteria including Clostridium difficile (which can cause diarrhoea) and Clostridium botulinum (which can trigger botulism) become abundant in the human “death microbiome”, the army of microbes that take over after you die.
Mind-altering microbes
The content of your gut might influence your mental health: people with depression have gut microbiomes containing lower than average .
Alzheimer’s bacteria
One of the key bacteria involved in gum disease, Porphyromonas gingivalis, may also play a role in causing Alzheimer’s disease.
Article amended on 16 May 2019
We corrected the number of bacteria per square centimetre of skin
