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Colistin Resistance: “The Pig is Out Of The Barn”

Klebsiella pneumoniae
Klebsiella pneumoniae
Courtesy the Public Health Image Library, CDC.

The scientists who this week reported dangerous drug resistance in seagulls aren’t the only researchers looking for mcr-1, the gene that confers protection against the last-resort antibiotic colistin.

Since the discovery of the gene was announced last November by English and Chinese researchers, microbiologists the world over have been scouring their “collections”—the thousands (or more) of bacterial isolates they keep in frozen storage—to see whether the sample banks contain any evidence that the gene has passed through. Almost 100 instances of finding the gene have been announced, many of them out of such collections, some from five or more years ago—and that has researchers quietly convinced that more are coming, and that MCR resistance may be more widely distributed than we know.

If their hunch is correct, then that would be trouble. MCR resistance resides in gut bacteria, chiefly E. coli, and can lurk in the intestines an undetermined period of time. Someone who unknowingly carries the bug could pass it to others in a chain of transmission that would go undetected until, in some unlucky person, an infection blooms.

Last weekend, MCR and the urgency of determining how far it has spread was the talk of the hallways at ASM Microbe, the largest infectious-disease conference of the year. During the conference, I grabbed some time with Barry Kreiswirth, a professor of medicine at Rutgers University and founding director of the Public Health Research Institute Center there. In the 2000s, Kreiswirth’s lab led the discovery of the last wave of dire superbugs to hit the United States: a form of the bacterium Klebsiella pneumoniae known as KPC because it was resistant to the formerly last-ditch drugs carbapenems. (Losing carbapenems made medicine take colistin, a very toxic antibiotic, off the shelf where medicine consigned it in the 1950s.)

Kreiswirth and his lab have made three of the almost 100 MCR discoveries made so far, all in China thanks to Chinese collaborators. They are now searching their collections to see whether there are domestic discoveries to be made. (I edited and condensed our conversation.)

Maryn McKenna:  You’re very accustomed to superbugs. Tell me why, from your perspective, the arrival of mcr-1 is alarming.

Barry Kreiswirth: The problem with resistance such as KPC, and now MCR, is that the resistance DNA is on mobile elements, plasmids. That’s a whole different game from stopping the spread of an infection from one person to another. Plasmids move. They move from one strain to another. They move from one bacterial species to another. You can have a person that has an E. coli and a Klebsiella in their gut, and those bacteria will actually swap their plasmids, from E. coli into Klebsiella and vice versa. Trying to control that type of epidemic is completely different. We don’t have a strategy, because you can’t stop plasmids moving.

MM: You have begun looking for this already?

BK: We have published three papers. The most striking one was, we had a colleague from China in my lab who, when he went back to China, took out any colistin-resistant strains and screened them for the presence of mcr-1, and found it. Now everyone is looking for mcr-1 genes retrospectively, and finding them. That means that there’s probably a fairly large reservoir out there of strains carrying mcr-1. But we don’t have a clue how big that reservoir is. We don’t know how much, we don’t know where. Why is this concerning? Because colistin, even though it’s not a very good drug, it’s still one of our salvage drugs for carbapenem resistance. If we lose that, we’ve lost another antibiotic, and we don’t have many. You know the old joke, the horse is out of the barn. In this case, the pig’s out of the barn.

We don’t have a clue how big that reservoir is. We don’t know how much, we don’t know where.

MM: Because the resistance originated with pig farms.

BK: China uses colistin in animal feedlots—which is sort of the history of antibiotic resistance; in the U.S. as well as in Europe, we have a history of using antibiotic remnants in animal feed, so that story is not new. But the Chinese don’t use colistin to treat [humans]. And because they don’t use it, they don’t test for resistance to it. The problem is, this is a global community, and other people do use colistin [in human medicine]. And you can’t stop strains or people moving from China to elsewhere.

MM: Where do you think the biggest concern should be now?

BK: My doomsday scenario is that someone in medicine is going to start thinking, Do we do high-risk procedures? Some of what we do now is remarkable. If you ever talk to the guys who do bone-marrow transplants, God. As one doctor said to me, “We kill the patient and then bring them back to life.” If 50 percent of liver transplant patients die of a bacterial infection, what’s the point?

MM: Aside from searching the bacterial collections that you hold—which by definition is looking backward, to when the samples were taken—what else could be done to define how much trouble we’re in?

BK: We don’t do a good job of screening healthy people [for pathogens], mainly because people don’t want to fund it. I would love to have a project where we could start screening. But those are difficult studies to do. They’re hard to get funded. There are a lot of logistics. For an example, my wife’s a nurse practitioner, and we tried to do a study of the prevalence of community-acquired MRSA. We made an attempt to go to doctors’ offices. But how do you do an [institutional consent] with 50 different offices? And then [obtain consent from] every patient that walks in? No one’s paying them to do that. For MCR, we hope to be able to screen liver transplant patients, bone-marrow transplant patients. When you consider how much those procedures cost, additional screening would be trivial. So that’s one intervention I think we could do.

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Seagulls Are Carrying a Dangerous Superbug Through the Skies

A European Herring Gull (Larus argentatus) takes off.
A European Herring Gull (Larus argentatus) takes off.
Photograph by Ben Cranke

A superbug that’s resistant to the absolutely last-ditch antibiotic colistin has been reported in seagulls on two continents—pinpointing one way, though almost certainly not the only way, that this dangerous drug resistance is moving around the world.

Since last November, when researchers in England and China announced the discovery of bacteria able to survive colistin, there has been an explosion of people looking for that resistance, and finding it. Scientists have published almost 100 reports of colistin resistance—known as MCR and conferred by a gene that’s been dubbed mcr-1—in almost two dozen countries.

It has been found in human patients, including a woman in the United States in May; in livestock, which get the drug on intensive farms, and are probably the original source of the problem; and even in pets.

Now, in letters to the Journal of Antimicrobial Chemotherapy, two research teams in Lithuania and Argentina report that they trapped birds and swabbed their butts, or scooped up seagull droppings, and found the resistance-conferring gene in E. coli being carried by two species: herring gulls in Lithuania (Larus argentatus) and kelp gulls in Argentina (Larus dominicanus). 

Both teams think the birds probably picked up the resistant E. coli by eating garbage, which may have contained sewage or medical waste. (The organisms in the South American gulls also contained another important type of antibiotic resistance, known for short as ESBL.)

This isn’t the first time that gulls have been identified as possible carriers of antibiotic-resistant bacteria. In 2011, French researchers found multi-drug resistant E. coli in seagull droppings in Miami Beach, and those researchers and others earlier found resistant bacteria in gulls in Portugal, France, Russia, and Greenland.

The point in all those stories, as well as in the new reports, is that gulls migrate, from hundreds to thousands of miles depending on the species—so they could serve as a vehicle for carrying resistant bacteria somewhere new.

Gulls migrate, from hundreds to thousands of miles, so they could serve as a vehicle for carrying resistant bacteria somewhere new.

“The lifestyle of gulls allows them to carry and disseminate pathogenic and resistant microorganisms despite country borders,” the Lithuanian researchers say in their report. “Water contaminated by feces of birds should be foreseen as an important risk factor for transmission of resistant bacteria.”

The undetected movement of bacteria is especially important in the case of MCR, because the discovery of colistin resistance is truly alarming. Colistin is an old drug that medicine consigned to the back of the shelf in the 1950s because it is toxic, and only recently started using again because so many other antibiotics have been undermined by overuse in medicine and agriculture.

The gene that creates colistin resistance is on what is called a plasmid, a loop of DNA that isn’t bound up in chromosomes but can move easily between bacteria. That has scientists worried that the gene could move into disease organisms that already possess resistance to other antibiotics, creating a superbug that would be completely untreatable.

Kelp gull (Larus domicanus) perched on rock, Caldera, Chile.
Kelp gull (Larus domicanus) perched on rock, Caldera, Chile.
Photograph by Chris Mattison

So far, mcr-1 has been found in the United States three times: in two stored samples from slaughtered pigs that were stashed in a U.S. Department of Agriculture database, and in a 49-year-old woman in Pennsylvania, not identified by name, who went to a clinic for help with a urinary tract infection.

At a meeting Tuesday afternoon in Washington, D.C., of the Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria, federal officials relayed that the woman has recovered from her infection, but still continues to carry the highly resistant bacterium in her system. Dr. Beth Bell, director of the National Center for Emerging and Zoonotic Diseases at the Centers for Disease Control and Prevention, also said that 99 of the woman’s family members and close contacts have been checked, and none of them are carrying bacteria containing mcr-1, reinforcing the mystery of how the resistant bacteria reached her.

Bell and representatives of the U.S. Department of Agriculture said the gene remains rare in the U.S.: The CDC has checked more than 55,000 stored samples collected from patients, animals, and food, and the USDA is checking 2,000 additional samples that it has stored. So far, that search has revealed only the two samples from pigs that were slaughtered in Illinois and South Carolina.

The officials commenting Tuesday agreed that there may be no way of tracing the path that MCR took to reach the U.S.—the bacteria may have spread from another person, or on food—and that the key thing now is to build surveillance systems that alert health planners as it moves.

“The good news is we found it,” observed Dr. Martin Blaser, a professor of medicine and microbiology at NYU Medical Center and chair of the Presidential council. “The bad news is, it’s here.”

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Gut Microbes Can Evolve From Foe to Friend—And Do It Fast


Bacteria grow quickly, and can evolve quickly.
Bacteria grow quickly, and can evolve quickly.
Photograph By HansN/Flickr

Dangerous microbes can evolve rapidly. When we throw antibiotics at them, new strains can quickly shrug off the drugs and cause untreatable cases of tuberculosis, gonorrhoea, or staph. But most microbes don’t cause disease. Many share our bodies and those of other animals, and these residents—our so-called microbiome—are important parts of our lives.

And they can evolve too.

A microbe can even evolve quickly from a parasite into an allyKayla King from the University of Oxford found an excellent example of this in the guts of nematode worms. She showed that a bacterium called Enterococcus faecalis, which causes mild disease, can suddenly turn into a protector if its host is challenged by another more dangerous threat, Staphylococcus aureus or Staph.

King began by infecting worms with either Enterococcus or Staph. The two microbes behaved very differently. Enterococcus caused mild infections, killing fewer than one in a hundred worms, and only then after a week. By contrast, Staph killed half the worms within a day and all of the after a second. When mixed, Enterococcus protected the worms from its more virulent peer, slashing the death rate from 52 percent to just 18 percent.

To see if this dynamic would change over time, King picked out some infected worms, removed Enterococcus from their bodies, grew the microbes up, and then fed them to another generation of worms. She repeated 15 times. And in each new round she added the Enterococcus to genetically identical worms from the same stock, along with the same strains of Staph.

By the experiment’s end, Enterococcus had become an exceptional guardian, saving all but one percent of its hosts. It had evolved the ability to produce large amounts of superoxides—highly reactive oxygen molecules that are toxic to many microbes, Staph included. Enterococcus, by poisoning its rivals, was saving the worms.

This change depended entirely on the presence of Staph. When King exposed 15 generations of worms to Enterococcus alone, the mildly harmful bacterium became slightly more harmful. “On its own, it’s a little bit of a parasite,” says King. “But when it interacts with this much more virulent organism, it shifts along the continuum to be much more beneficial.”

She was surprised at how quickly the protective powers evolved (within just five of the 15 generations), how total they were (almost all the worms survived), and how broad it was. She challenged the worms with seven different strains of Staph, including the drug-resistant MRSA strains that give us humans so much grief. The protective Enterococcus strains beat them all.

There are many examples of microbes protecting animal hosts from parasites and diseases by producing antibiotics. They can also protect us simply by taking up space or using up resources, leaving no opportunities for more dangerous microbes to invade, and no room for them to grow. “We often consider ways in which the microbiome directly impacts host responses to infections,” says Nichole Broderick from the University of Connecticut. “This  paper [shows] how the community can evolve traits that indirectly benefit the host.”

Note: indirectly. Enterococcus wasn’t evolving to protect the worms. It was suppressing a competing microbe, and benefiting its host almost by accident. This isn’t a story of altruism or good will, but of incidental beneficence. (It’s the mirror of another effect that I’ve written about, where microbes become coincidentally better at harming us when they’re exposed to predators or stressful environments.)

King’s study illustrates two other crucial themes in the world of microbiomes. First, as I’ve stressed before, it’s extremely contextual. The same bacterium can be a harmful pathogen (a microbe that causes disease) in one context but a helpful mutualist when its host is challenged by an even worse enemy. Likewise, the insect bacterium Hamiltonella protects aphids from parasitic wasps and becomes commonplace when such wasps are abundant; but it exacts a cost upon its hosts and is lost when wasps are absent. There are no good bacteria or bad bacteria; they live their own lives, and their impact upon our lives depends on all kinds of circumstances.

Second, microbes evolve quickly. In doing so, they can change the lives of their hosts with equal speed. The worms in King’s experiment didn’t need to evolve their own defences against Staph infections when they had Enterococcus to take up the slack. This all happened in the confines of a laboratory, but you can easily imagine how wild worms that consumed the right strains of bacteria would suddenly become immune to some infections (just like some bugs can become instantly resistant to insecticides by swallowing the right microbes).

“We’ve taken a very reductive approach,” says King. “In the future, we want to understand how these interactions play out in a much more diverse community.” Such as those in our bodies, for example. What happens when thousands of species of native microbes are challenged by Staph and other pathogens? How would they evolve in response?

And could we, perhaps, develop ways of directing that evolution to improve our health? “It’s very speculative, but I’d hope this would get people thinking about the possibility of engineering microbes using their natural evolutionary potential,” says King.

For more about the defensive power of microbes, and their ability to quickly change the lives of their hosts, check out my book I Contain Multitudes, out on August 9.

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More Countries Are Seeing a Last-Ditch Antibiotic Failing

An E. coli bacterium.
An E. coli bacterium.
Photograph by the Public Health Image Library, CDC.gov.

(This post has been updated; read to the end.)

More news is emerging about the dire new antibiotic resistance factor announced last month: MCR-1, a gene that disables the action of colistin, a very last-resort drug in human medicine. (If you’re just coming to this, my past posts are here and here.)

Quick recap: A gene conferring resistance to colistin was found in pigs, retail meat, and human patients in China; then it was spotted in Malaysia; then in Portugal. Then, in the next major development, researchers in Denmark announced they had identified the gene in one human patient and five samples of imported meat.

Here’s the newest news: The Danish researchers tell me that they have identified another patient who was infected with a bacterium bearing that same resistance factor. And Public Health England has announced that it has found the gene in 15 stored bacterial samples in its databases: 10 Salmonella bacteria and three E. coli that came from hospitalized patients, and two Salmonella on a single sample of imported poultry meat.

The news is both alarming—more instances of this gene that creates resistance to last-ditch drugs, and that can transfer easily between bacteria—and also puzzling. The British samples were taken between this year and 2012. The Danish samples announced 10 days ago date back to 2012, and the newly discovered one comes from 2011. So the gene has been circulating for several years, without causing any outbreaks.

Is that a bullet dodged? Perhaps. But researchers studying the new gene say it may be a slow-burning fuse.

In human medicine, colistin is a rarely used drug, a survivor from the earliest decades of antibiotic development that was left on the shelf for decades because it was toxic. But in veterinary medicine, colistin has had wide use, which is probably what caused this resistance factor to emerge. Now, with the loss of other antibiotics to resistance, colistin use in humans is climbing, and that could set the stage for this effectively untreatable resistance to bloom.

“This seems to have been around for five to six years,” Robert Skov, MD of the Statens Serum Institut in Copenhagen, and the senior author in the Danish team’s rapidly produced article on their discoveries, told me by phone. “One thing is for sure: We are using more and more colistin in humans due to the increase in [bacteria resistant to carbapenems, the next-to-last-resort drug], and thus we are probably selecting for this colistin resistance to emerge.”

How the gene—which resides on a plasmid, a mobile piece of DNA that can move between bacteria— is traveling the world is a puzzle. Skov said the Danish government has done an emergency survey of the country’s animal herds and found no trace of the gene. (Which, before now, no one would have been looking for.) The chicken meat in which the gene was found in Denmark was imported from Germany. The two people in whom the MCR gene has been found had not traveled to Asia. In Britain, three out of 10 patients had been to Asia, and the meat on which two MCR-bearing Salmonella strains were found was imported from elsewhere in Europe.

When NDM, the last last-resort resistance threat, began to spread across the world, it did so in the guts of patients who visited India, where it first emerged, and then traveled home to Europe and Britain. It’s possible a similar thing is happening with MCR. “We have five chicken isolates [bacterial samples] and one human isolate, and when we compare the plasmids in the chicken and human isolates and what has been published from China, the greatest resemblance to the Danish human isolate is the isolates from China and not from the German chicken,” Skov said. “This suggests it was brought, not by chicken, but by people coming from Asia to Denmark.”

In the past few days, I asked antibiotic resistance experts in various parts of the world whether they had seen MCR yet, and whether they were looking for it. All of them were looking; outside of Britain, none had discovered it yet in any national collections of bacterial isolates. (Or, given that disclosing a finding might keep them from publishing in major medical journals, were willing to admit to discovering it.)

Lance Price, PhD of the Antibiotic Resistance Action Center at George Washington University, told me that additional analysis of the isolates found in Denmark shows two troubling things. All of the bacteria in which the gene was found were unique—six different strains of E. coli—and the gene has found a home in two different plasmids. Together those suggests that it has no difficulty moving among bacteria and finding a comfortable home in them. “It’s real world, empiric evidence that this thing can spread very widely,” he said. “Its’s almost like it possesses a universal key.”

Price told me that one concern at this point will be which bacterial strains the gene jumps into: indolent ones that cause little disease, or fast-moving virulent ones that cause infections in many body systems and are already resistant to many other drugs. One of the Danish isolates that carries MCR, he said, is an E. coli of a type known as ST131—which in the United States is already multi-drug resistant and causes thousands of serious bladder and bloodstream infections every year. “At this point we don’t know what the denominator is going to be,” he said. “We don’t know how many different strains this is going to get into, and this underscores the possibility it will jump into something really bad.”

Update: On Dec. 17, Dutch authorities announced they too had identified MCR-1 in a bacterial collection in the Netherlands. The Central Veterinary Institute, housed at Wageningen University, said it found three bacterial isolates containing the MCR-1 gene in a collection of 3,274 Salmonella strains from 2014 and 2015. Two similar strains came from chicken meat that originated in the Netherlands, and a different strain from imported turkey. (It does not give the source of the turkey.) They are now undertaking a broader search through other bacterial collections.

There will no doubt be more such discoveries as other health authorities complete searches through whatever national collections they have. But as Lance Price says above, this is further evidence that this gene has great facility for jumping among different bacteria and bacterial species.

Meanwhile, if you’re interested in more on this, Price, Skov and I were on the NPR show On Point on Dec. 16, discussing MCR. Replay and podcast instructions at the link.

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You’re Surrounded by Bacteria That Are Waiting for You to Die

Antibiotic-resistant Staphylococcus aureus bacteria (yellow) killing and escaping from a human white blood cell.
Antibiotic-resistant Staphylococcus aureus bacteria (yellow) killing and escaping from a human white blood cell.
Photograph by NIAID

You are filled with bacteria, and you are covered in them. And a whole lot of them are just waiting for you to drop dead.

As soon as you die, they’ll swoop in. This week, we learned exactly how microbes chow down on us. A brave and strong-stomached team of scientists spent months watching dead bodies decompose, tracking all the bacteria, fungi, and worms, day by day. Forensic scientists can use this timeline, published in Science, to help determine time—and even place—of death. (More on that in a previous Gory Details.)

The microbes in your intestines get first dibs, the scientists found. As soon as you die, they’ll start decomposing you from the inside out. Meanwhile, other bacteria on your skin or in the soil beneath you start mounting an attack from the outside in. As Michael Byrne at Motherboard so nicely summed it up, “Earth is just waiting for you to drop dead.”

That’s a little unsettling, if you think about it. And it begs the question: What keeps all those bacteria from decomposing you alive?

That’s silly, you say. I’m alive. Only dead things decompose.

Yes, but why?

What keeps all those bacteria from decomposing you alive?

As the new study points out, two of our most crucial defenses against being decomposed are toppled as soon as we die. Our immune system shuts down, and our bodies cool off. Bacteria like this; they don’t have an easy time growing in a hot body. (Think about it: When we have an infection our bodies develop a fever to ward it off.)

Basically, a big part of life involves your cells waging a battle to the death with bacterial cells. As long as you’re alive and healthy, your cells are winning. Decomposition is when your cells lose. 

One of the clearest descriptions I’ve read comes from Moheb Costandi’s “This is what happens after you die“:

Most internal organs are devoid of microbes when we are alive. Soon after death, however, the immune system stops working, leaving them to spread throughout the body freely. This usually begins in the gut, at the junction between the small and large intestines. Left unchecked, our gut bacteria begin to digest the intestines—and then the surrounding tissues—from the inside out, using the chemical cocktail that leaks out of damaged cells as a food source. Then they invade the capillaries of the digestive system and lymph nodes, spreading first to the liver and spleen, then into the heart and brain.

As soon as you die, your body essentially gets its first break from a war that it has been fighting every moment of your life.

When the bacteria start to win that war in a living person, we call it an infection, and we try to flush the invaders out of a wound. Or we go in with antibiotics to poison them.

Let’s pause for just a moment to appreciate those antibiotics. We thought we had outwitted bacteria. But now we’ve overused and misused antibiotics, giving the bacteria a chance to figure out our defenses. They’re adapting, becoming resistant to our weapons, and we’re already seeing the failure of some of our last lines of defense, leading to more infections, illness, and death.

Ultimately, we lose our battle with bacteria when we die. But until then, it’s pretty amazing to think of the fine line between life and becoming bacteria food. Imagine the evolutionary arms race that has led to an immune system so vigilant that it can fend off constant attack for decades. 

I’m just grateful not to be decomposing right now.

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MRSA In Sports: Long-Standing, Simple to Prevent, Still Happening

Big news in sports the past few days: Daniel Fells, tight end for the New York Giants, is battling a MRSA infection so severe that he has been hospitalized in isolation and had multiple surgeries. Some news stories have speculated doctors may amputate his foot in an attempt to corral the infection.

It’s a tragic situation for the player, and no doubt frightening for the team, which is reported to have sought medical advice and scrubbed down their locker rooms to prevent any additional cases.

What it’s not, unfortunately, is new. MRSA—the acronym for methicillin-resistant Staphylococcus aureus, staph bacteria that are resistant to multiple classes of antibiotics—has been dogging sports teams for more than 20 years. And for at least 10 of those years, we’ve known what to do to prevent it. But it’s not at all clear that teams treat that prevention as a routine thing they should be doing—and because of that, every athlete’s infection seems like a random tragedy, instead of an avoidable mistake.

Among the long litany of MRSA cases in athletes, some have been high-profile: Lawrence Tynes, who is suing the Tampa Bay Buccaneers over a career-ending infection (two of his teammates were infected as well); Brandon Noble of the Washington Redskins, who lost his pro career over a knee infection (six of his teammates developed infections too); Kenny George of  the University of North Carolina-Asheville, who had part of his foot amputated.

But the list of those known to have been affected (and this is certainly not complete) is much longer. Some other names: Kellen Winslow (and five teammates) of the Cleveland Browns, Peyton Manning, Drew Gooden, Mike Gansey, Sammy Sosa, Alex Rios, Paul Pierce, Kenyon Martin, Braylon Edwards, and Grant Hill. And, in addition, the St. Louis Rams, the USC Trojans, and dozens of college and high school teams going back to 1993.

MRSA infections seem like they sweep in out of nowhere, especially the apocalyptically bad ones (such as MRSA pneumonia, which can kill a child in days). But in fact, some MRSA cases are very predictable. They are more likely to occur in what the Centers for Disease Control and Prevention call the “5 C’s“: places where there is crowding, skin-to-skin contact, compromised skin from cuts or abrasions, contaminated items and surfaces, and lack of cleanliness.

Add all those together, and you have a pretty good description of a football field, and a locker room after a game.

MRSA is simple to catch: The bacterium lives on the surface of our skin, and in our nostrils and other warm, damp body crevices, and causes an infection when the skin is breached and the bacteria slip into tissue or the bloodstream. In hospitals, where MRSA first became a problem in the 1960s, that breach could come from surgery, or an incision made to allow for a catheter or an IV. But in the everyday world, where MRSA has been a problem since the mid-1990s, the source is more likely to be a cut or a scrape—in the kitchen, in the outdoors, or, in sports, from a razor, training equipment, artificial turf, a wrestling mat, or pads or straps cutting into a shoulder or a shin. (And sometimes, nothing at all. Toxins manufactured by the bacterium can break down the skin, causing the hot pinpoint infections that people often mistake for spider bites.)

Fells is supposed to have been infected at some point in the past few weeks, after a toe and ankle injury and a cortisone shot to the ankle. I don’t have inside intel on his treatment, or on what the Giants do in their locker rooms. But I know what teams that had MRSA problems in the past did to shut their outbreaks down. It wasn’t complicated—but it required commitment and attention, and it took a while.

Between 2002 and 2006, the Trojans, the Rams, and the Redskins were all so spooked by epidemics among their players that they asked the CDC and local health departments for help. (The stories of the outbreaks are told in my last book, Superbug.) They learned that stopping the infections and protecting their players took many steps: requiring everyone to shower post-game. Scouring the hydrotherapy tubs. Disinfecting the training equipment and massage tables. Discouraging body shaving, even though it makes taping up—and untaping—a lot less uncomfortable. Raising the water temperature in the laundry machines. Making sure no one shared bars of soap in the shower or towels on the field.

After Noble’s injury, the Redskins ripped out their entire training facility and installed a new one, spraying germ-killing coatings on the lockers and discarding the shared benches for individual stools. The teams practiced these steps over and over, chastising and sometimes fining players who didn’t bother, and shut their outbreaks down.

MRSA is also a serious problem for school teams; in fact, it was school outbreaks—in a Vermont high school in 1993, a Pennsylvania college in 2000, a Connecticut university in 2003, and throughout Texas high schools for several years in a row—that first alerted researchers that athletes might be at special risk. When I was writing Superbug, I spent a lot of time with trainers and coaches, and it was striking how open they were about the problem. Whether because of affection for their students, responsibility to parents, or fear of lawsuits, athletic programs all over the US were educating kids and staffs about the danger, and teaching them how to protect themselves.

Pro teams, which clamp down on information about players’ injuries as competitive intelligence, mostly don’t talk about their MRSA plans. But it’s not clear they are training and protecting as comprehensively as schools do. A year ago, the Washington Post took a look back at Brandon Noble’s career-ending infection, and reported that MRSA prevention is not uniform across NFL teams. This season, Duke University’s Infection Control Outreach Network Program for Infection Prevention in the NFL, known for short as DICON, began working with the NFL Players Association to distribute a manual on infection prevention to all 32 teams and to train their personnel. That the teams agreed to participate is a big step—but that the program was needed suggests how vulnerable some players still are. Until MRSA prevention becomes routine in locker rooms, other players may end up as ill as Fells now is.

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Why Sea Monkeys Love Salt: A Fable on the Cost of Symbiosis

Time and again, microbes have opened doors for animals, allowing them to exploit niches that would have otherwise been denied to them by their basic animal-ness. By providing nutrients that are missing from the sap of plants, bacteria have allowed bugs to subsist on a diet of nothing else, turning them into the bane of greenery and greenhouses worldwide. By breaking down the tough and typically indigestible carbohydrates in plant matter, bacteria allowed mammals to become extreme grazers and gave rise to the thundering herds of Africa’s plains. By providing a source of energy that isn’t tied to sunlight, bacteria allowed worms, clams, and hundreds of other creatures to colonise the abyssal oceans, and lose their mouths and guts in the process.

These examples inform the common view that symbioses (partnerships) between animals and microbes lead to mutual benefit and expanding opportunities. But symbiosis also comes with costs and constraints. Microbes can bar animals from valuable opportunities, restrict their options, and place burdens upon them—all without causing infections or disease.

Odrade Nougué and Thomas Lenormand from the University of Montpellier have found a great example of such constraints in an animal that will be familiar to anyone who grew up in the 70s and 80s: the sea monkey.

These little creatures are more formally known as brine shrimp, or Artemia. As their name suggests, they live in salty water, but they evolved from freshwater ancestors. They cope with salt by efficiently pumping it out of their own bloodstreams. The saltier the water, the harder they have to work and the more energy they burn.

So you’d expect that Artemia does best in mildly salty water. In fact, they can’t tolerate the stuff. At more than 40 grams of salt per litre, they’re fine. Below that threshold, they’re less likely to survive. Bizarre! Surely, it should be the other way round?

Nougué discovered that Artemia’s gut microbes are behind this weird paradox. When Nougué raised Artemia larvae in sterile cultures, so they grew up without their usual coterie of microbes, these germ-free shrimp did better in low-salt water. Likewise, when she fed them a diet of yeast instead of their usual meals of algae, they also did better with less salt. Their usual preference for high-salt water only exists when they eat algae and carry microbes. Why?

These bacteria help to break down the carbohydrates in the algae, as well as detoxifying the many poisons in those mouthfuls. Without them, the shrimp wouldn’t be able to survive on their usual meals. And here’s the rub: the bacteria like salt. They grow less well at low salinities. So Artemia, to provide these partners-in-digestion with the ideal living conditions, is forced to live in water that’s saltier than it would naturally prefer, and is effectively barred from mildly salty places.

Here, then, is a case where microbes expand an animal’s ecological opportunities (by allowing it to eat an otherwise inaccessible source of food) but also constrain it (by forcing it out of low-salt environments). They provide a valuable service, but they inadvertently issue demands in return. These aren’t mild demands, either. Salinity is the single biggest factor that defines where Artemia lives, more so than temperature or predators or parasites.

There are other examples of such constraints. Insect symbionts, of the kind that allow bugs to suck on sap, tend to be more sensitive to high temperatures than their hosts, so their numbers plummet in hot weather. (What happens to those partnerships in a warming world, you might ask?) And in some cases, hosts and microbes could become so dependent on each other that they risk both becoming extinct—consider the case of the 13-year-cicada and its ridiculously degenerate bacteria.

Reference: Nougué, Gallet, Chevin & Lenormand. 2015. Niche Limits of Symbiotic Gut Microbiota Constrain the Salinity Tolerance of Brine Shrimp. American Naturalist. http://www.jstor.org/stable/10.1086/682370

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Bug Stops Food Halfway Down Its Gut to Make Room for Microbes

Your gut is a long continuous tube. Food goes in one end, gets digested and stripped of nutrients, and is shunted out the other end. That’s the case in ants and elephants, lions and sea lions, hawks and hawk moths. But not in stinkbugs. In the guts of these sap-sucking, shield-shaped insects, food goes in one end, gets digested and stripped of nutrients… and then stops. It never flows into the back half of the gut. That end of the organ has been transformed from a site of digestion, into an apartment complex for microbes.

Our guts are full of bacteria and other microbes too, but they live among the currents of food and help us to digest our meals. The stinkbugs have a very different arrangement. Their guts consist of several chambers in a row. The first three (M1, M2, and M3 in the diagram) are for storing and digesting food, and absorbing nutrients. The fourth (M4 and M4B) consists of many branching sacs and crypts, all densely filled with symbiotic bacteria.

Stinkbug gut. Credit: Ohbayashi et al, 2015. PNAS
Stinkbug gut. Credit: Ohbayashi et al, 2015. PNAS

Now, Tsubasa Ohbayashi and Yoshitomo Kikuchi from Hokkaido University in Japan have discovered that this separation is enforced by a special organ—an extremely narrow corridor (CR in the diagram) that separates the third and fourth chambers. It’s  thin and inconspicuous, which is why no one had noticed it before.  But it plays a vital role: it allows certain bacteria to colonise the back half of the gut, while keeping food and other microbes in the front half.

This discovery speaks to two of the most important sides to the wide-ranging partnerships between animals and microbes. The first is conflict. Even beneficial bacteria aren’t an inherent good. They have their own evolutionary interests and can cause severe problems for their hosts if they get into the wrong body parts. So, they need to be contained and controlled. We do so with a wall of mucus that coats our guts, and with immune cells that patrol that wall. Other animals have special compartments, in which they house their bacteria. The back half of a stinkbug’s gut is one example of such specialised living quarters.

That brings us to the second issue: selectivity. The microbes that live in animal bodies aren’t just the same ones the surrounding environment. Only some species have the abilities to thrive in an animal host, and only some are allowed to do so. In stinkbugs, just one bacterium called Burkholderia can colonise the gut. (It’s not entirely clear what Burkholderia does for its host, but we know that it’s important because bugs that don’t encounter it can’t reach their full size and die early.)

The stinkbugs’ newly discovered corridor is responsible for this extreme selectivity. It’s a symbiont sorter. Last year, Kikuchi’s team fed young bean bugs with Burkholderia that had been labelled with a glowing green molecule. They saw that the bacteria formed a queue at the entrance of the narrow corridor and, over several hours, slowly squeezed through. Only Burkholderia does this. Other bacteria can’t make the same journey.  

Neither can food or liquid. More recently, the team fed young bedbugs with water that had been stained red with food colouring. The wave of red dye slowly made its way through the gut, and then completely stopped at the narrow corridor. Whatever the organ was, it was impervious to food and liquid, as well as to most microbes.

By studying it under a microscope, the team discovered its secret. For a start, it is impossibly thin: just a few millionths of a metre wide. It is also filled with mucus, which acts as a physical plug. Only Burkholderia can power its way through, partly because it’s a strong swimmer. It propels itself with a powerful whip-like tail, called a flagellum. When Kikuchi’s team engineered mutant Burkholderia that couldn’t assemble a proper flagellum, these strains also couldn’t pass through the corridor.

Then again, other bacteria like E.coli and B.subtilis have their own flagella, and they can’t pass, either. There must be something else that bars their way, and no one knows what that might be. It’s possible that Burkholderia alone can make enzymes that break down the mucus, so that it tunnels as well as swims. Alternatively, Burkholderia might uniquely resist a battery of digestive enzymes and antibacterial chemicals that the bug releases to restrain other microbes.

It’s likely that both the bug and the bacteria have their roles to play in ensuring the fidelity of their partnership. The same is true in other natural alliances. The dinky Hawaiian bobtail squid is colonised by a single species of glowing bacterium called Vibrio fishceri, which it houses in crypts within its body. Despite the legions of bacteria that swarm in the surrounding seas, only V.fischeri can enter and colonise the squid’s crypts. And as I have written about previously, this selectivity depends on both the squid and the microbe.

The squid and the bug have another thing in common: they both have to get their microbes from the environment with each new generation. So, selectivity is really important to them. They need precise ways of yanking the right partners out of the surrounding milieu. The same is true for most species of stinkbugs, which is why the corridor organ seems to exist throughout the family’s 40,000 or so members.

The only exceptions also prove the rule. Some stinkbugs have evolved very specific ways of handing down the right beneficial microbes to their babies. Some lay capsules full of microbes next to their eggs. Others slather their clutches in a bacteria-rich mucus. Either way, the young bugs are guaranteed to find the appropriate microbes, so the symbiont-sorting corridors in their guts are less useful. So, as is often the way in evolution, they have vanished. When these bugs grow up, their corridor withers into a thread-like strand, and the two halves of the gut essentially become disconnected.

How, then, do these insects excrete waste? Kikuchi’s experiment with the red food colouring revealed the answer. Food gets absorbed in the front half of the gut, channelled to the insect equivalent of kidneys, and then sent back into the very end of the gut to be excreted in faeces. Perhaps that’s as clear a sign as any that these microbes matter. To accommodate them, the bugs have re-routed the entire flow of food in their bodies, bypassing the fourth chamber of their guts, where their bacteria reside.

Reference: Ohbayashia, Takeshita, Kitagawa, Nikoh, Koga, Meng, Tago, Hori, Hayatsu, Asano, Kamagata, Lee, Fukatsu & Kikuchi. 2015. Insect’s intestinal organ for symbiont sorting. PNAS http://dx.doi.org/10.1073/pnas.1511454112

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The Bacteria That Turn Amoebas Into Farmers

Most people think of bacteria as germs, signs of filth, or unwanted bringers of disease. Slowly, that view is changing. It is now abundantly clear that the bacteria that live on the bodies of other creatures help their hosts by digesting food, providing nutrients, protecting against disease, detoxifying poisons, slaughtering prey, and even creating light. The list of surprising abilities is extensive, and just when you think it might run out, someone comes along and shows that bacteria can turn amoebas into farmers.

The amoeba in question is Dictyostelium discoideum, or Dicty to its friends. It mostly lives as a single cell that engulfs and eats bacteria. But when food is scarce, these solitary cells congregate and merge into a many-celled slug. The slug oozes about until it finds a good spot, whereupon it stretches skywards to form a ball at the end of a stalk. The ball is full of spores, which eventually blow off, seeding some far-off (and hopefully more bountiful) area with new amoebas.

Back in 2011, Debra Brock and her colleagues showed that Dicty sometimes packs several species of edible bacteria in its slugs and spores. When the spores land somewhere new, their bacteria cargo multiples, creating a ready supply of food. Brock described these bacteria-carrying amoebas as “farmers”. They lugged their ‘crops’ around and ‘planted’ them to provide bountiful meals in unfamiliar terrain.

The metaphor is apt but, like all of them, comes with baggage. It suggests that the amoebas are actively in control of their passive bacterial crops—and that’s not entirely true. The same team of scientists, led by Joan Strassmann and David Queller at the Washington University in St Louis, have now found that some bacteria can turn Dicty into farmers in the first place!

The team already knew that the farming strains of Dicty carry diverse communities of bacteria. These include species like Klebsiella which serve as food, and other inedible microbes that just go along for the ride. And though these inedible bacteria varied from one amoeba to the next, postdoc Suzanne DiSalvo found that one species—Burkholderia—was universal. It turned up in all the farmers.

Burkholderia has a penchant for symbiosis—that is, for forming associations with other organisms. There are strains that cause opportunistic infections in people, that allow bugs to instantly resist insecticides, that donate antibiotic-producing genes to animals, and that provide various benefits to plants. What do the ones in Dicty do?

DiSalvo eventually figured out that they are largely (maybe even entirely) responsible for Dicty’s farming lifestyle. She could turn non-farming amoebas into bacteria-carrying farmers by giving them the right Burkholderia strains. And she could permanently “cure” these farmers of their ability to transport bacteria by treating them with antibiotics. “This was very exciting and amazing,” says Strassmann.

It’s not clear how Burkholderia does this, but the fact that the amoebas can’t eat it is probably important. “I think the Burkholderia are infecting Dicty and disrupting some process whereby it digests its bacterial food,” DiSalvo speculates. Inadvertently, this also means that Dicty can now carry around other bacteria that it would normally digest. That’s the core of its farming behaviour: the ability to harbour microbes without harming them, rather than immediately destroying them for food. Burkholderia, by selfishly protecting itself from digestion, also gives the amoebas the basis of their agriculture.

This transformation comes with costs. Dicty faces obvious disadvantages if it can’t efficiently digest its food. Indeed, DiSalvo found that if there’s a lot of food around, the farmers produce fewer spores than non-farmers, and are less successful. But when food is scarce, the balance of benefits and costs flips. Now, the farmers, which can carry bacteria to new pastures, do better than their non-farming peers.

These results illustrate one of the most important aspects of symbiosis, and one that is often overlooked: it is contextual. The same microbe can be harmful to its host in one setting but beneficial in another. In one context, it’s a parasite; in another, it’s a mutualist. “This work highlights the fragility of incipient symbioses,” says John McCutcheon from the University of Montana, who reviewed the paper. “It shows how pathogenic and mutualistic outcomes can teeter along a rather thin edge, tipping one way or the other in a manner dependent on complex environmental factors.”

It’s also a great example of how bacteria can directly influence the behaviour of more complex hosts, McCutcheon adds. While many scientists are studying the microbes of the human body, and their effects on our health and behaviour, these studies are almost entirely correlative. That is, they simply compare the microbial communities in different groups of people. But with simple organisms, like Dicty, Strassmann’s team isn’t so limited. They can do experiments.

The team are now trying to slowly knocking out Burkholderia’s genes to identify those that help it to colonise Dicty. They’re studying the cycle of infection under the microscope. And they’re looking at the chemicals that the two partners use to communicate with each other. “It’s a blast,” Strassmann adds.

Reference: DiSalvo, Haselkorn, Bashir, Jimenez, Brock, Queller & Strassmann. 2015. Burkholderia bacteria infectiously induce the proto-farming symbiosis of Dictyostelium amoebae and  food bacteria. PNAS http://dx.doi.org/10.1073/pnas.1511878112

Previously on this story:

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Look Up! There’s an Invisible Zombie Highway Right Above You

Step outside on a clear day this summer and look up.

What do you see? Blue. Nothing more. Or so you think.

But surprise! In July and August, an enormous herd of animals is passing directly over our heads. There are so many creatures up there, creatures that are so busy, so athletic, so tiny, so invisible. I’m talking about three to six billion of them every month soaring through the air directly above us. You should meet them. They are insects. High-flying insects. When I read about them in a science paper five years ago (I was at NPR at the time), I made this video, which provides a short introduction:

And now for the update.

It turns out, as you just saw, that the highest flying insect made it to 19,000 feet above sea level. That’s almost the height of Mount McKinley in Alaska. But more recently scientists have found another, even higher zone that’s also home to live critters that soar way, way up—miles higher, to the upper edge of the Earth’s atmosphere.

They are Earthlings that spend days, even weeks, practically in outer space.

What Are They?

According to David J. Smith and his team at the University of Washington and Kostas Konstantinidis and his team at Georgia Tech, there are thousands of species of very small, simple Earth life—bacteria, fungi, viruses—that get swept up by storms and make it to where there’s hardly any oxygen, where the temperatures are fiercely cold, and where they’re no longer protected from solar radiation by the Earth’s ozone layer.

And yet, write Peter Ward and Joe Kirschvink in their new book A New History of Life, most of these microbes will eventually come back down to Earth no worse for wear. They’re teeny. You can’t see them without a microscope. Typically, it would take almost 40,000 of them laid end to end to make it around your thumb.

Drawing by Robert Krulwich
Drawing by Robert Krulwich
Drawing by Robert Krulwich

But there are lots of them up there, so many that Ward and Kirschvink say this zone is becoming “the most newly discovered ecosystem on Earth,” a vast territory (many, many times greater than our oceans) where microbes routinely spend time dancing in the air.

Drawing by Robert Krulwich
Drawing by Robert Krulwich
Drawing by Robert Krulwich

Some bacteria have been in this high zone so regularly or for so long that they’ve adapted to life in the sky. Some species develop pigments that mimic sunscreen; some, says the New York Times, feed only on cloud water; and some can reproduce within clouds.

Drawing by Robert Krulwich
Drawing by Robert Krulwich
Drawing by Robert Krulwich

Scientists call this new family of creatures-in-the-sky “high life,” and it is a biological zone with its own rules. Up there is not like down here.

How Do They Survive Up There?

For one thing, scientists differ about how microbes at the upper end of the zone stay alive. When deoxygenated and freezing, do they slow way, way down like a hibernating bear? Or do they go dormant and essentially suspend their lives until they return? Or, as Ward and Kirschvink suggest, do they spend a brief period being dead?


This is one of the most provocative passages in Ward and Kirschvink’s book. “Most of us would agree,” they write, “that for mammals, and perhaps all animals, dead is dead.” You don’t come back from “dead.” But then they go on:

“… in simpler life, such is not the case. It turns out that there is a vast new place to be explored between our traditional understanding of what is alive and what is not.”

What if, in this new airy realm high above the planet, there could be “a place in between,” where bacteria might take wing, arrive in that freezing, irradiated zone, lose their life-giving machinery, and then, somehow, on the trip back down, build it back again?

Ward and Kirschvink are both well-respected senior scientists. Ward studies mass extinctions, Kirschvink magnetofossils. Neither is given to overstatement, which is why when I hit this line in their book, I put down my copy, stared out the window and thought, What?

How can anything be undead?

In the chapter I was reading, Ward and Kirschvink explore how life came to be four billion years ago. They suggest that instead of a single Genesis-like event (a bag of inert chemicals suddenly sparks into living chemistry), maybe “in the beginning,” chemistry switched back and forth, sometimes alive (on), sometimes not (off), and maybe, just maybe, in the simplest creatures, this may still be a habit—in fact, it may be happening to this day. Very simple creatures high in the sky, they say, might be alive, then not, then alive again, or as they put it:

“Life, simple life at least, is not always alive.”

Woah! This is a new idea to me. I tried to talk more with Peter Ward, but he’s in Papua New Guinea doing ocean research in a dugout canoe and doesn’t have a good internet connection, and Kirschvink is not answering email at Caltech, where he teaches. But I’m curious: Have any of you readers bumped into this notion? Life de-animating, then reanimating? It seems wonderfully preposterous—and very intriguing.

Let me know …

Peter Ward and Joe Kirschvinck’s new book “A New History of Life: The Radical New Discoveries About the Origins and Evolution of Life on Earth” goes after the hardest questions in life’s history, how did we begin, how simple life grew more complex, the origin of sex; they attack these puzzles carefully, feasting on the latest and especially the wildest research, so if you want an up-to-date primer guaranteed to keep your inner-college-sophomore up all night arguing, binging on ideas, going “no way”—this is a pretty good book. I also relied on David Montgomery and Anne Bikle’s “The Hidden Half of Nature, The Microbial Roots of Life and Health,” to get my head around itty bitty bits of life, the fungi, the bacteria, the archaea, the viruses, the protists. Their book took me into intestines, soil, and, yes, to the sky. It comes out in November. Also, my artist for the video, Benjamin Arthur, is about the most elegant, sly, multi-talented illustrator around; give him a tale, he’ll give you a perfect look to tell it with. Each of our ventures has a completely different visual style. Check out Why Can’t We Walk Straight? Last year he even turned in a piece (not with me, alas) on microbes. You can find it here.

Editor’s Note: This post has been updated to correctly reflect the spelling of Anne Bikle’s name.

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How To Make Better Health Predictions From Our Gut Microbes

We all know people who act very differently depending on the company they find themselves in. They can be delightful in some circles, and obnoxious in others. The same principles apply to the microbes in our bodies—our microbiome. They have important roles in digestion, immunity, and health, but none of them is inherently good. They can be helpful in one part of the body and harmful in another, beneficial when paired with certain partners and detrimental when teamed up with others.

This means that, as I’ve written before, there’s no such thing as a “healthy microbiome”. Context matters. And contrary to what some companies might tell you, we’re still not very good at looking predicting what any particular community of microbes means for our health. One common approach is to compare microbiomes in people with or without a disease, single out species that distinguish the two groups, and use their presence or absence to make predictions. But those same bugs might have the opposite effect, or none at all, in another setting.

Alyxandria Schubert from the University of Michigan used a less reductionist approach—one that embraces the complexity of the microbiome rather than shoving it aside.

She studied Clostridium difficile: a weedy bacterium, known colloquially as C-diff, which can cause debilitating bouts of diarrhoea. A thriving community of gut microbes can hold C-diff at bay, but when those communities are cleared by antibiotics, the weed can bloom freely. That’s why C-diff is the single biggest cause of hospital-acquired infections in the USA.

But not everyone who takes antibiotics gets infected. What separates them from those who succumb? Is it just luck? Is it the specific drugs they take? And can you look at someone’s microbiome after they take antibiotics, and accurately predict their risk of contracting C-diff? To find out, Schubert put mice on seven different antibiotics, and then exposed them with C-diff. Each drug changed the rodents’ gut bacteria in different ways, giving some species a boost while repressing others.

None of these changes could consistently account for an animal’s susceptibility to C-diff. For example, mice with a particular Bacteroides species were more likely to be colonised by C-diff if they had taken streptomycin, but a lower risk if they had taken cefoperazone.

Akkermansia, a microbe that seems to protect against both obesity and malnutrition, also failed to show a clean pattern. “If you picked the right antibiotic, you’d say Akkermansia is protective. Pick another one, and you’d see mice with just as much Akkermansia and high levels of C-diff,” says Pat Schloss, who led the study. “This is a bug that’s being used in probiotic trials, but we find it associated with inflammation and other stuff. It’s a pretty strong example of context-dependency.”

It’s not the actions of any one microbe that protects a gut from C-diff incursions, but the interactions between them. So, rather than trying to identify a particular protective species, we need to study the community as a whole.

To do that, Schubert turned to a technique called random forest machine-learning. She fed her data from the various post-antibiotic microbiomes into a computer program, and asked it to pick features that could predict the level of C-diff colonisation. The program then built a “decision tree” based on those features—imagine a game of Twenty Questions. Does the community have lots of Bacterium A but little of B? Lots of C and D? Neither E nor F? Any one tree might be wrong a lot of the time, so the program generated a lot of them—an entire “forest”. It could then run any new microbiome through all of the trees, aggregate their responses, and make a prediction.

When Schubert it to predict the degree of C-diff colonisation, it explained 77 percent of the variation from the antibiotic experiment. When she gave it the simpler task of just predicting whether C-diff would colonise or not—yes or no—it got the right answer 90 percent of the time.

This is encouraging. Still, the team needs to test their program on a different data set than the one they used to build it. And although they measured how accurate it is, they need to show that it’s both sensitive (it rarely misses when a person is at risk) and specific (it doesn’t sound a false alarm when the risk is low). And obviously, they need to test it on people, rather than mice.

Still, it’s the right sort of approach. When humans look at complicated data sets, we try to pare things back to manageable simplicities: this bacterium is protective and this one isn’t. Machine-learning avoids this problem, and grapples with all the complexities hidden in the data. “You’re not just looking at one organism but the whole collection,” says Schloss.

Other teams are doing the same. Last year, Sathish Subramanian and Jeff Gordon built a mathematical model that could work out if a baby’s microbiome was maturing at the right pace—if its microbiological age matched its biological one. And Schloss is using the same method to try and predict a person’s risk of colon cancer from their gut microbiome. “Maybe you’d go into the intensive care unit and we’d put you on antibiotics, we could predict your risk of C-diff or colon cancer or any number of diseases,” he says.

If the predictive models work, they could also be used to personalise treatments—another future goal for microbiome research. Rather than just offering everyone the same probiotics, or giving them a faecal transplant (yes—that’s a thing), doctors might be able to tailor a prescription of microbes to a person’s existing community. Given what they’ve got now, what do they need to make them healthier?

“One of my fears with microbiome research is that we’re finding all these associations and not doing anything with it. We have no deliverables,” Schloss says. “My hope is that we could translate this into humans.”

Reference: Schubert, Sinani & Schloss. 2015. Antibiotic-Induced Alterations of the Murine Gut Microbiota and Subsequent Effects on Colonization Resistance against Clostridium difficile. mBio. http://dx.doi.org//10.1128/mBio.00974-15

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This Beetle is Ruining Your Coffee With the Help of Bacteria

I am writing a book about partnerships between animals and microbes. In the process, I have consumed a frankly obscene amount of coffee, to the extent that the dedication might just read “To coffee, with thanks”. So, it is with mixed emotions that I now write this post, about an animal that is ruining coffee with the help of bacteria.

The coffee berry borer is a small, black beetle, just a few millimetres long. The females bore holes into coffee berries and then lay their eggs in the seeds within—the bits that we know as “coffee beans”. The larvae devour the seeds when they hatch, destroying them. In Brazil alone, its antics lead to some 300 million dollars worth of losses, and it has spread to coffee-making nations all over the world. This tiny pest is the single greatest threat to your cup of blissful java.

Coffee berry borer beetle. Credit: L. Shyamal (CC BY-SA 3.0)
Coffee berry borer beetle. Credit: L. Shyamal (CC BY-SA 3.0)

The beetle is the only animal that can feed solely on coffee beans. Others might occasionally nibble the seeds or other parts of the coffee plant, but they don’t dedicate themselves to the task. There’s a reason for that: caffeine. This stimulant draws many of us to coffee, but it effectively deters plant-eating animals. Not only does it taste bitter, but at the doses found in coffee seeds, it can poison and paralyse any wayward insect. Any insect, that is, except for the coffee berry borer. As a larva, it’s practically bathed in caffeine, and yet it survives. Even the most caffeine-rich beans fail to deter it.

Javier Ceja-Navarro from the Lawrence Berkeley National Laboratory has discovered its secret: it has bacteria in its guts that can detoxify caffeine.

When he fed the beetles with coffee beans and analysed their faeces for traces of caffeine, he couldn’t find any. None. Something in their gut had completely destroyed the would-be poison. Bacteria seemed like the obvious candidates, so Ceja-Navarro fed the beetles with antibiotics. This time, when they ate coffee beans, their poo was laden with caffeine. And when they got a chance to breed, they utterly failed. Most of their eggs and larvae died outright, and none of the survivors made it to adulthood. Without their microbes, they couldn’t handle their caffeine.

Ceja-Navarro’s team, led by Eoin Brodie, found that the bacteria in the coffee berry borer’s gut vary from country to country, but some species turn up everywhere. At least a dozen of these can grow on caffeine and nothing else, and one—Pseudomonas fulva—was especially good at it. It’s was the only microbe with a gene called ndmA, which starts the process of metabolising caffeine.

When Ceja-Navarro fed P.fulva to the antibiotic-treated beetles, he restored their ability to metabolise caffeine. Then again, the insects still couldn’t reproduce, which suggests that other bacteria also affect its health, and perhaps its ability to withstand its toxic meals.

Whether this discovery will help coffee farmers is not clear. It would be a truly terrible idea to start spraying coffee plants with antibiotics, but perhaps there might be subtler ways of breaking the alliances between the beetles and their detoxifying microbes.

Detoxification is only one part of the coffee berry borer’s success. There’s also digestion. Coffee berries are 60 percent carbohydrates, and since the beetle larvae eat nothing else, they need some way of breaking down these large, tough molecules.

In 2012, Ricardo Acuña from Cenicafé, a Colombian coffee research centre, discovered its trick by analysing the genes that are switched on in its guts. One of them – HhMAN1 – stood out for two reasons. First, it creates a protein called mannanase that breaks down galactomannan, one of the major carbohydrates in coffee beans. Second, insects aren’t meant to have mannanases.

Acuña found that the beetle’s version of HhMAN1 is most closely related to genes from bacteria. He checked to make sure that he hadn’t sequenced some contaminating microbe, and indeed he hadn’t: HhMAN1 was surrounded by other typical insect genes and was clearly a bona fide part of the beetle genome.

So, at some point in their history, these beetles stole a gene from bacteria, perhaps the same ones that live in its gut. That gene now lives permanently in their genome and allows them to digest the signature carbohydrates found in coffee beans.

Bacteria, then, have helped the beetle in two ways—by donating a digestive gene at some point in the distant past, and by donating their detoxifying powers in the present. Boosted by microbial power, the beetle has become a worldwide pest, and a royal pain-in-the-espresso.

Reference: Ceja-Navarro, Vega, Karaoz, Hao, Jenkins, Lim, Kosina, Infante, Northern & Brodie. 2015. Gut microbiota mediate caffeine detoxification in the primary insect pest of coffee. Nature Communications http://dx.doi.org/10.1038/ncomms8618


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The Slow-Motion Symbiotic Train Wreck of the 13-Year Cicada

Round about now, in various US states, a vast swarm of cicadas will start crawling out of the ground. These black-bodied, red-eyed insects have stayed underground for 13 or 17 years, drinking from plant roots. When they greet daylight for the first time, they devote themselves to weeks of frenzied sex and cacophonous song, before dying en masse. They’ll be picked off by birds, snagged by squirrels, and crunched under shoes and tyres, but none of that will dent their astronomical numbers—which is perhaps the point of their lengthy underground stints, and their synchronous emergence.

But the cicada’s weird lifestyles have also left them with a different legacy. It involves the bacteria that live in their bodies, and it’s so weird that when John McCutcheon first discovered it, he thought he had made a technical error.

Many insects carry bacteria inside their cells. These ‘endosymbionts’ are especially common among sap-sucking bugs, like cicadas, and help their hosts to make nutrients that they can’t get through their food. They almost always have exceptionally tiny genomes. Once they get inside insect cells, they become isolated from other bacteria and restricted to small populations. This deprives them of opportunities for shuffling or acquiring genes, and allows harmful mutations to build up in their DNA. One by one, their genes break and disappear, leaving them with shrivelled minimalist genomes.

McCutcheon is one of a small cadre of scientists who, over the past 15 years, have deciphered the weird genomes of many insect symbionts. When he started his own lab at the University of Montana, he decided to look at Magicicada tredicim—one of the periodical 13-year species. He did the usual thing: he dissected out the organs where the bacteria live, pulled out their DNA, cut it into fragments, sequenced the pieces, and used a computer to assemble those portions into a coherent whole.

Except, it didn’t work. The sequences just wouldn’t assemble neatly. It was as if someone had taken several similar but incomplete jigsaw puzzles, and jumbled all the pieces together. “It was just such a mess,” he says. “I thought it was something technically wrong but I couldn’t figure out what.”

Perplexed, he moved on to a different cicada—a South American species called Tettigades undata. There, he found yet more weirdness. It contained a bacterium called Hodgkinia, which had somehow split into two distinct species inside its insect host. As I wrote last year, these daughter species are like two halves of their ancestor. They’ve each lost different genes so that individually, each is a pale shadow of the original Hodgkinia, but collectively, they complement each other perfectly.

When McCutcheon worked out what was going on in T.undata, he suddenly realised what was happening in the 13-year cicada. It also contained Hodgkinia symbionts that had split into separate lineages—and not just two.

Graduate students Matthew Campbell and James Van Leuven eventually showed that the DNA from this cicada’s symbionts form at least 17 distinct circles. It’s not clear if each of these represents a Hodgkinia chromosome, or an entire Hodgkinia genome on its own, but at least four of them are found in distinct cells You can see this in the images below, where the blue, green, purple, and orange dots all represent cells that have just one of the 17 circles.

Hodgkinia cells in cicada tissue. Credit: Campbell et al, 2015. PNAS.
Hodgkinia cells in cicada tissue. Credit: Campbell et al, 2015. PNAS.

As in the earlier discovery, these circles complement each other; they share sets of genes for making nutrients that matter to the host, but none of them has the full complement. They’re also found in other species of periodical cicadas. And they might just be the tip of the iceberg: the team could confidently identify 17 circles, but the insects likely harbour many more. “If I had to guess, I’d say there’s between 20 and 50,” says McCutcheon. “It’s incredible. It’s a mess.”

From Hodgkinia’s point of view, one lineage has clearly split into several, and irreversibly so. “That’s the baseline definition of speciation,” says McCutcheon. “It’s happening in an asexual population, but the lineage has fractured and it’s not going back.” But if you take the cicada’s perspective, the collective symbionts are still doing the same thing as the original. And while they parcelled their genes into separate cells, the total amount of bacterial DNA has increased. Each part became smaller, but collectively, their genome got bigger.

So are the Hodgkinia circles different species or lineages? Is the Hodgkinia genome the total of the circles in a single cicada, or does each distinct lineage have its own genome? It’s really hard to say. “The problem is that when we write a paper, we have to use words, and words mean something,” says McCutcheon. “It is very hard to put labels on this stuff, and I will not just give this a new name willy-nilly, because I don’t think we understand it well enough.”

There are other mysteries too. The cicada also has another bacterial symbiont called Sulcia, which shows no sign of this ridiculous fragmentation. There’s just one Sulcia and it’s the same in all cicada cells. Why has this microbe stayed whole, while its neighbour rent itself asunder? No one knows. A reasonable guess is that Hodgkinia evolves much faster than Sulcia, and more quickly builds up mutations that disable its genes.

Also, why has Hodgkinia fractured into many lineages within cicadas, when other insect symbionts have not in their respective hosts? McCutcheon thinks the answer lies in the insects’ long lives. Most sap-sucking bugs are lucky to make it past their first birthday. They lead short, fast lives, and if their symbionts developed detrimental mutations, they and their hosts would be weeded out by natural selection. Cicadas, by contrast, can live for 2 to 19 years, and for most of that time, they’re barely moving or growing. During those slow years, their symbionts aren’t that important, and are free to build up detrimental mutations without affecting their hosts or falling foul of natural selection—at least, not in the short term.

The long-term outlook may not be that rosy. Partnerships with microbes often furnish animals with incredible and valuable skills—in this case, the ability to drink plant sap without becoming deficient in important nutrients. But with great opportunity comes great risk. Once host and bacterium become dependent on each other, they can enter into a kind of symbiotic trap—or, as Nancy Moran puts it, they could jointly “spiral down the symbiosis rabbit hole”.

Take Hodgkinia. If it continues to fragment and degenerate, it—they?—may eventually be unable to sustain the cicada. “It just looks like it’s going off the rails,” says McCutcheon. “It’s like watching a train wreck or a slow-motion extinction event. It makes me think differently about symbiosis.”

Reference: Campbell, Van Leuven, Meister, Carey, Simon, and McCutcheon. 2015. Genome expansion via lineage splitting and genome reduction in the cicada endosymbiont Hodgkinia. PNAS http://dx.doi.org/10.1073/pnas.1421386112

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Can The Microbes You Leave Behind Be Used to Identify You?

When you touch a surface, you leave behind fingerprints—distinctive swirling patterns of oils that reveal your identity. You might also deposit traces of DNA, which can also be used to identify you. And you leave microbes. You are constantly bleeding microbes into your surroundings, and whenever you touch something, bacteria hop across from your skin.

It’s increasingly clear that everyone has a unique community of microbes—or microbiome—living on their bodies. We share species and strains but the exact roll call varies from person to person. “If you take a collection of people, their microbes will look very different but their genomes will look mostly the same,” says Curtis Huttenhower from the Harvard School of Public Health. So, could the DNA of these tiny variable residents also reveal our identity, just like fingerprints or our own DNA?

A few studies have suggested so. In 2010, Noah Fierer from the University of Colorado found that bacteria swabbed from keyboards and mice matched those on their owners’ skins more closely than those from other people. (The match wasn’t quite accurate enough for forensic use, although that didn’t stop CSI Miami from running with it.) And last year, Simon Lax and Jack Gilbert from the University of Chicago managed to identify people, from a pool of 18 volunteers, based on the microbes they left behind in their homes.

More recently, Lax and fellow student Sean Gibbons spent two days swabbing their mobile phones, the soles of their shoes, and the floor around them, on an hourly basis, to many strange looks. They found that the shoes and phones retained traces of their owners, so that an algorithm could accurately identify whose items any given sample came from. The objects were also heavily influenced by their environment; the shoes, in particular, quickly picked up microbes from the floors they walked over, suggesting that it might be possible to track a person’s movements from the microbes on their belongings.

But what would happen if you scaled these studies up to larger populations? Could you still accurately pinpoint a person using their microbes, without false alarms? Would the results be consistent? And while fingerprints and genomes are largely constant, microbiomes change a lot—so will a person’s abandoned microbes still identify them weeks or months later?

To answer these questions, Eric Franzosa and other members of Huttenhower’s team worked with data from the Human Microbiome Project, which collected microbes from the guts, skin, and other body sites of 120 people, at several points in time. They used an algorithm that took data from each volunteer’s first visit, extracted features like the presence of certain species, strains, or genes, and combined the most distinctive ones into a “code” that was unique to each individual, but also consistent over time. They then compared these codes to samples collected several months later to see if they could still identify the right owners.

They only managed to recognise a third of their volunteers in this way. That’s nothing to sniff at, but it certainly doesn’t match the forensic utility of the human genome, or even fingerprints. The results were more promising when the team focused on gut microbes, which proved to be exceptionally stable; gut-based codes identified 86 percent of the volunteers.

“That’s a floor. The accuracy can only go up if we have more sequencing data and better algorithms,” says Huttenhower. He also notes that “since the microbiome changes over time, we wanted to get as few things wrong as possible, so we biased the algorithm in favour of false negatives.” That is, the program might fail to identify people based on their microbes, but it will almost never identify the wrong person.

Their results reflect our growing understanding of the human microbiome. Our bodies—and our guts, in particular—are colonised by a surprisingly stable set of bacterial strains. Their levels might fluctuate, but the same coterie persists for decades. Perhaps our genes or our immune systems determine who gets to stay. Perhaps there’s a “first-mover advantage”, where the first strains to set up shop then dictate which others get to immigrate. Either way, as Huttenhower says, “Not only are we robots for microbes, but each of us is a robot for a specific set of clones or strains that ride around with us for a long period of time.”

He doubts that these results are important for forensic science. “If you deposit your microbes, you’re probably depositing your DNA too and DNA forensics is so well developed,” he says. But he adds that microbiome researchers need to be wary of these issues to protect the privacy of study volunteers. The data from such studies is always anonymised, but if people have unique and consistent signatures, there’s a risk that information from different data sets could be compared in ways that break anonymity.

Consider what happened with Netflix. In 2007, the online media company released movie rankings from 500,000 of its customers, so that others could help to improve its recommendation algorithms. Even though the data were anonymised, researchers still managed to identify some of the individuals by comparing their rankings to non-anonymous profiles from IMDB, another movie site. And unlike movie rankings, our microbiome could reveal potentially sensitive information about what we eat, and whether we suffer from health problems.

“This isn’t an issue now and it’s not a high-risk issue, but it’s still important for us to consider,” says Huttenhower. “No one study has any danger of releasing private information but due to uniqueness, the ability to link across studies becomes a possibility.”

Reference: Franzosa, Huang, Meadow, Gevers, Lemon, Bohannan & Huttenhower. 2015. Identifying personal microbiomes using metagenomic codes. PNAS http://dx.doi.org/10.1073/pnas.1423854112

Lax, Hampton-Marcell, Gibbons, Colares, Smith, Eisen & Gilbert. 2015. Forensic analysis of the microbiome of phones and shoes. http://dx.doi.org/10.1186/s40168-015-0082-9


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Could Mothers’ Milk Nourish Mind-Manipulating Microbes?

Breast milk seems like a simple nutritious cocktail for feeding babies, but it is so much more than that. It also contains nutrients that feed the beneficial bacteria in a baby’s gut, and it contains substances that can change a baby’s behaviour. So, when a mother breastfeeds her child, she isn’t just feeding it. She is also building a world inside it and simultaneously manipulating it.

To Katie Hinde, an evolutionary biologist at Harvard University who specialises in milk, these acts are all connected. She suspects that substances in milk, by shaping the community of microbes in a baby’s gut, can affect its behaviour in ways that ultimately benefit the mother.

It’s a thought-provoking and thus far untested hypothesis, but it’s not far-fetched. Together with graduate student Cary Allen-Blevins and David Sela, a food scientist at the University of Massachussetts, Hinde has laid out her ideas in a paper that fuses neuroscience, evolutionary biology, and microbiology.

It begins by talking about the many ingredients in breast milk, including complex sugars called oligosaccharides. All mammals make them but humans have an exceptional variety. More than 200 HMOs (human milk oligosaccharides) have been identified, and they are the third most common part of human milk after lactose and fat.

Babies can’t digest them. Instead, the HMOs are food for bacteria, particularly the Bifidobacteria and Bacteroides groups. One strain in particular—Bifidobacterium longum infantis—can outcompete the others because it wields a unique genetic cutlery set that allows it to digest HMOs with incredible efficiency.

Why would mothers bother producing these sugars? Making milk is a costly process—mums quite literally liquefy their own bodies to churn out this fluid. Obviously, it feeds a growing infant, but why not spend all of one’s energy on filling milk with baby-friendly nutrients? Why feed the microbes too? “To me, it seems incredibly evident that when mums are feeding the microbes, they are investing on a greater return on their energetic investment,” says Hinde. By that, she means that setting up the right communities of microbes provides benefits for the baby above and beyond simple nutrition.

By taking up space and eating all the available food, B.infantis and its peers make it harder for pathogens—microbes that cause disease—to establish themselves. The HMOs deter these invaders more directly. Many pathogens launch their invasions by first recognising sugar molecules on the surface of intestinal cells. HMOs resemble those sugars, and so act like floating decoys that draw pathogens away from the gut itself. So, breast milk selects for beneficial microbes while also warding off harmful ones. It sets babies up with the right pioneers.

It’s important to get these first communities right. They steer the development of the immune system, creating a balanced set of sentries that can detect and respond to pathogens, without also going berserk at innocuous triggers like pollen or dust.

There’s also increasing evidence, at least in mice, that gut microbes can shape the early development of the nervous system. They can communicate with the brain via the vagus nerve—a long phone line that carries messages between the brain and gut. They can also release signalling chemicals like dopamine and serotonin. Through these means, they can affect an animal’s behaviour. Some groups have shown that mice which grow up inside sterile containers behave differently to their normal colonised peers: they tend to be less anxious and take more risks. And some teams have shown that specific microbes can reduce anxiety in normal, healthy rodents.

These mind-manipulating properties might be really useful to mothers. Parenting is costly. It takes time and energy. It’s in a baby’s best interests to monopolise as much of that effort as possible, so they get the strongest start in life. Mums, however, have to divide their effort over many children, both present and future ones. If they expend too much effort on one, they might not be in good enough shape to have more. If they can wean their current infant earlier, they can have another sooner.

These aren’t conscious decisions, mind you. I’m not trying to portray mums as cold and calculating. But it’s important to note that from a cold evolutionary standpoint, mothers and babies have slightly conflicting interests. Simply put, infants will tend to demand more investment than is ideal for a mother to give, and evolution has crafted ways for infants to get that investment—think of smiling, crying, nuzzling, and tantrums. Similarly, mothers should have countermeasures for giving themselves an edge in these inevitable conflicts.

Hinde thinks that the HMOs might act as one such countermeasure. If these sugars can nourish specific microbes, and if certain microbes can change a baby’s behaviour, then mothers could potentially change the HMO content o their milk to influence their babies. The infants might become less demanding. They might be less active, and spend more energy on simple growth rather than on play or exploration. They might be less anxious and more likely to become independent earlier.

Again, this isn’t far-fetched. In her own research, Hinde showed that the milk of younger monkey mothers contains fewer calories but more cortisol—a hormone involved in stress. Babies that drink this cortisol-laden milk tend to be more nervous and less exploratory. They also grow faster. Perhaps these things are connected. The cortisol could be a mother’s way of saying: “Don’t waste the precious calories in my milk; focus on getting bigger.” And perhaps the HMOs might convey similar messages, via microbial messengers.

“I liked the paper,” says John Cryan from University College Cork. “It further emphasises the importance of microbiota-brain interactions  in early life for health and development, and positions HMOs as positive drivers of such interactions. Indeed, this is very plausible.”

Plausible and, more importantly, testable. Scientists could see if different sets of HMOs promote the growth of bacteria that can affect the brain. What kinds of signalling chemicals are those microbes making? Do they affect parts of the brain involved in controlling emotions or motivation? Do these effects lead to noticeable changes in a baby’s behaviour? “Then we can look backwards at what are the HMOs that are really influencing the establishment and maintenance of those particular bacteria,” she says. If you load those specific microbes into germ-free mice, and load them with those specific HMOs, what happens?

“We can also look at the variation and abundance of those HMOs in various settings,” says Hinde. “Winning” the evolutionary conflict between parent and child might matter more to mothers who live in risky environments where food is scarce, or where they spend much of their energy on fighting diseases or evading predators. Likewise, younger mothers who are still growing might also fare better if they reserve more of their energy for themselves.

“This is likely to remain hypothetical for quite some time,” Hinde admits. “In humans, there’s hundreds of bacterial strains and oligosaccharides. Understanding what each one does will take forever, much less their complex interactions.” But as she writes in her paper: “An evolutionary perspective allows us to appreciate the essential tensions within the mother-infant dyad and recognize that the infant’s microbial ecology is a potential landscape for negotiating conflict and maintaining coordination. Among the many, many bacteria in the infant gut, may be lurking mother’s littlest helpers.”

Besides, as Hinde says, “Microbes are so hot right now.”

There will be more about milk, microbes, and mums in my upcoming book, I CONTAIN MULTITUDES, out next year.

Reference: Allen-Blevins, Sela, & Hinde. 2015. Milk Bioactives May Manipulate Microbes to Mediate Parent-Offspring Conflict. Evolution, Medicine, and Public Health. http://dx.doi.org/10.1093/emph/eov007  

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