Frankenstein Can’t Come Out And Play Today

In the standard Frankenstein story, a scientist creates an unnatural monster that breaks out of the lab and runs amok. But why should unnatural make something unstoppable? The contrary is possible, too. Imagine a different story: Frankenstein’s monster escapes, realizes that it can’t survive in the outside world, and retreats back to the lab. This story line may not make for a satisfying movie, but it might be a good goal for real life.

The fear of the unstoppable unnatural has been with us ever since scientists began moving genes between species in the 1970s. In a 1973 experiment, researchers transferred a gene from a frog into Escherichia coli. The gut microbe used the frog gene to make a frog protein.

It wasn’t long before researchers figured out how to use genetic engineering to turn microbes into factories. When scientists inserted the gene for human insulin into E. coli, the bacteria were able to manufacture a drug that had previously been harvested from cow pancreases. E. coli became the workhorse of biotechnology, spewing out drugs, vitamins, and industrial materials. (For more on E. coli’s strange yet significant history, see my book Microcosm.)

At first, the prospect of foreign genes in E. coli was terrifying. Some critics warned that insulin-producing bacteria would escape from fermenting tanks, get into people’s bodies, and cause an epidemic of diabetic comas. That never happened, probably because insulin does E. coli no good at all. The human gene is a burden to the microbe, draining off energy and resources it could use to grow.

Nevertheless, it was conceivable that some other creation might turn out to be dangerous. The scientific community responded by laying down guidelines for working with genetically engineered creatures. Most of the guidelines involved creating physical barriers to keep organisms from escaping factories or labs. But scientists have also created biological barriers, by changing the creatures themselves to make it hard for them to survive outside the lab.

For example, scientists who study the plague engineered a safe strain of the bacteria Yersinia pestis that they could work with in their labs. Y. pestis needs iron to survive, and it uses special molecules to scavenge the element from our bodies. To make a safe strain, scientists shut down some of the iron-scavenging genes in the bacteria. The bacteria could still grow in a flask if they got a rich supply of iron. But inside people, where iron is scarce, they would starve.

At least that was the plan. In 2009, a University of Chicago scientist named Malcolm Casabadan got infected by a lab strain of Y. pestis and died of the plague. Unfortunately, neither he nor anyone else knew that he suffered from a genetic disorder called hemochromatosis, which caused him to accumulate high levels of iron in his blood. Investigators concluded that his body probably served the same role as an iron-rich lab flask. Inside him, the hobbled bacteria could grow.

Casabadan didn’t die because the engineered Y. pestis that infected him was unnatural. The problem was that it wasn’t unnatural enough. That is, it could still find a place in the natural world where it could thrive. Some scientists think a better safeguard would be to create life that is fundamentally unnatural–in other words, that cannot possibly survive without our help, because the natural world is alien to it.

Fortunately, this goal does not require scientists to create an utterly alien form of life, complete with some alternate form of heredity to take the place of DNA. Scientists can take advantage of the fact that all living things on Earth are incredibly similar, chemically speaking.

All living things build proteins from about twenty building blocks, called amino acids. By combining the amino acids in different sequences, life can produce a vast range of proteins. But there are hundreds of other kinds of amino acids in nature, and scientists have created many others that are never found in nature.

In theory, living things should be able to use these amino acids to build their proteins, too. They don’t, however, because all living things share a nearly identical code for translating the information in their genes into proteins.

Genes are made of a different set of building blocks, called bases. To build a protein, a cell reads three bases at a time (a codon) and then selects a corresponding amino acid. If a base called guanine appears three times in a row in a gene, for example, a cell will pick out an amino acid called glycine.

For the most part, all living things rely on the same genetic code. That’s why E. coli that acquires a human insulin gene makes insulin, too, instead of collagen or hemoglobin. It’s also why viruses can invade our bodies and use their own genes and proteins to hijack our cells to make new viruses. We all use the same language, and so our programming can be hacked.

About a decade ago, Farren Isaacs, then a postdoctoral researcher in the lab of George Church at Harvard, started tinkering with the genetic code, trying to change the rules. Last year, he and his colleagues reported that they had reassigned one codon in E. coli to an artificial amino acid. (It’s known as p-acetyl-L-phenylalanine, or pAcF for short.) They sprinkled the new codon across the genome of the bacteria, which then made some of its proteins using pAcF.

The recoding had a remarkable effect on the bacteria: they became immune to a virus that specializes on infecting E. coli. By changing the code, the scientists made the bacteria harder to hack. (I wrote about this work in more detail in 2013 in Nautilus.)

While these bacteria could make unnatural proteins, they didn’t depend on the proteins for survival. Growing on a regular diet of natural compounds, they could still thrive. Isaacs went on to Yale, where he continued his research, as have Church and his colleagues at Harvard. And in Nature, each team has now published the next logical experiment in this line of research. Each group has recoded E. coli so that it now depends on an artificial amino acid. Without it, the bacteria cannot build essential proteins, and they die.

Because these bacteria can’t find these artificial amino acids in the outside world, the scientists reasoned that they couldn’t survive on their own. To test that possibility, they transferred the recoded microbes to dishes where they got an ordinary diet. In all but one trial, the scientists found no evidence of the recoded bacteria surviving without their essential amino acid. And in the one trial where they did survive, they barely clung to life, easily outcompeted by ordinary E. coli.

To further reduce the odds of the bacteria surviving on their own, the researchers are now building in other features. Church’s group, for example, is reassigning other codons to other unnatural amino acids, further reducing the odds even more that mutations can rescue the bacteria. Ultimately, they hope to push these creatures into an alternate biological universe, walled off from our own.

What could we do with such creatures? We could potentially use them not just in protected labs, but in the outside world. They might clean up oil spills, for example, surviving as long as we supplied the artificial amino acids they needed to build proteins. When their job was done, we could shut off the supply and they’d die. It’s conceivable that scientists could recode plants as well, creating crops that could only grow with our help.

When I talked to other experts about this research, they were pretty impressed. “It’s a landmark moment,” Tom Ellis of Imperial College told me. “I think that it will have an immediate positive impact,” said Karmella Haynes of Arizona State University.

But when I talked to bioethicist Paul Wolpe of Emory University, he thought it unlikely that we’re home-free when it comes to risks from genetic engineering. In the past, people have introduced animal and plant species to new places with the best of intentions, only to see them cause unanticipated harm. “While I applaud these first steps, caution should be the guide here,” Wolpe said.

I expect that most of the conversations these odd bugs will inspire will be about practical matters–about making valuable stuff and avoiding risks to our health. But this research speaks to something deeper. When we try to figure out the definition of life, we look around at the life we know and look for the features all living things have in common. But scientists have also wondered if life as we know it may take up a tiny portion of the space of all possible forms that life can take.

These altered bacteria tell us that suspicion is likely true. With a few years’ work, they’ve made creatures that are probably unlike anything that ever lived on Earth. And within their universe–the universe of artificial amino acids that exists in Massachusetts, Connecticut, and a few other places on Earth–they are as alive as we are.

Can the Microbiome Mutiny?

It’s an ugly fact of life that getting old means getting infections. Old people get attacked more by pathogens, and the damage that these germs cause can speed up the aging process, leading to even more infections. The standard explanation for this vulnerability is that the immune system falters in old age, opening an opportunity for pathogens to invade. But in the journal Biology Direct, Viktor Muller of Eotvos Unversity and his colleagues propose that something else is also going on in the aging body. Maybe the microbiome senses that its host is in bad shape and rises up in rebellion. The scientists call their idea “the Microbiome Mutiny Hypothesis.”

It may seem like a strange notion, but several lines of evidence suggest it’s worth considering. First of all, a lot of the pathogens that attack the elderly come from within. They grow quietly and harmless for decades inside people’s bodies and then switch over to causing dangerous infections later in life. The answer to why old people get infections must address why harmless bacteria turn bad in old age.

To understand this turn, we have to abandon any strict division between “good” germs and “bad” ones. For the germs themselves, these are just two ends of a seamless spectrum. Depending on how they use their host, microbes may cause no harm, a little, or a lot. And the virulence of a microbe–the amount of harm it causes–can itself evolve over time. Under some conditions, natural selection may favor gentle handling. But in other situations, causing deadly disease may be the winning strategy.

A lot of factors go into determining which strategy will be a winner for a given microbe. For some microbes, the best way to multiply may be ripping open host cells and feasting on their contents. This may kill a lot of their hosts, but that may not matter to the microbes, since they can escape to a new host–say, by causing diarrhea that contaminates a water supply. But in other conditions, killing a host may be a bad long-term strategy–if, for example, the odds are low that a microbe will get from one host to the next.

It’s even possible for organisms to evolve the ability to switch between these strategies, using the best strategy for different environments. In a 2013 experiment, Oxford scientists observed this switch evolve before their eyes.

They studied phages, which are viruses that infect bacteria. A phage invades a bacterium and makes new copies of itself. The bacterium eventually ruptures, spilling out the next generation of phages.

The scientists reared phages under unusual conditions–they mixed together a very high concentration of phages with bacteria. As a result, each microbe tended to get infected by more than one phage. The phages would then make copies of themselves at different rates. When the microbe ruptures, out would come a mixture of phages. The faster breeders dominated over the slower ones.

The scientists let the phages evolve in these conditions for 50 days. When they were done, the phages could now adjust their speed. If they found themselves alone in a host cell, they grew slowly. But if they sensed other phages in the cell, they sped up, so as to outcompete their rivals. As a result, their host died faster.

Muller and his colleagues propose that some of the microbes that live in our bodies can also switch from benign to deadly for similar reasons. While we’re healthy, they growing slowly, causing us no harm. But as we approach the end of our lives, the microbiome shifts to a more aggressive strategy.

“Killing the goose that lays the golden eggs might not be such a bad idea if the goose is going to die soon, anyway,” the scientists write.

There’s good evidence that microbial residents can eavesdrop on our health. A pathogen called Pseudomonas aeruginosa, for example, can sense certain molecules our brains release in response to stress. They respond by unleashing a toxin that help them grow–while also damaging our lungs.

Muller and his colleagues offer some ways to test their hypothesis. If they’re right, then infections in old age aren’t just the result of a slack immune system. Instead, bacteria and viruses sense a changed environment and respond by making new molecules, which they use to grow aggressively and cause harm. If scientists disable these molecules, then the pathogens should become tame again.

It would be interesting to see the Microbiome Mutiny hypothesis put to such a test. Conceivably, scientists could someday turn the test into a treatment. Rather than blasting the elderly with broad-spectrum antibiotics, doctors could just disarm the mutiny.

Antisocial Medicine

One of the biggest surprises to come out of microbiology in recent years is that bacteria have a social life. Rather than existing as lonely, autonomous creatures, bacteria live in communities, in which they cooperate, compete, and communicate. In the January issue of Scientific American, I have a feature about how some scientists are trying to translate their growing understanding of the social life of bacteria into a new kind of medicine. By preventing microbes from cooperating, we may be able to bring infections to a halt. Better yet, this kind of antisocial medicine may even be able to avoid–or at least slow down–the evolution of drug resistance in bacteria.

Here’s the introduction to my piece:

The Central Park Zoo Hidden From View

In 2003, an army of 350 scientists and volunteers swept out across Central Park. Their mission, called a BioBlitz, was to find as many species as possible over the course of 24 hours. At the end of the day, they had compiled a catalog of 836 species of plants and animals.

It’s impressive that Central Park–an 843-acre island in an ocean of Manhattan concrete–can play host to so many species. But that’s hardly a complete inventory of the biodiversity of the place. Along with its plants and animals, Central Park is home to invisible wildlife too.

The ground swarms with invertebrates, fungi, and a wealth of microbes. This underground diversity–especially the microbes–has been very hard to explore, not just in Central Park but around the world. For one thing, you have to dig. For another, you can’t usually can’t tell the species apart with the naked eye. It’s possible to distinguish between the five species of turtles in the Central Park’s Turtle Pond just by looking at them. But if you dig up a patch of dirt by the pond and look at the bacteria it contains, they might well look like just a bunch of rods and spheres. The diversity of microbes is instead a matter of chemistry. They have evolved a staggering range of ways to break down molecules and grow on them.

In recent years, scientists have developed powerful new tools for measuring that diversity. Rather than looking at feathers or stripes, they look at DNA.

Each dot represents a place where scientists scooped up dirt to look for DNA. From Ramirez et al 2014
Each dot represents a place where scientists scooped up dirt to look for DNA. From Ramirez et al 2014

A team of researchers has now used this approach to carry out a sort of MicroBioBlitz in Central Park. They marched their way systematically through the park, and every fifty 50 yards or so, they stopped, bent down, and scooped up some dirt. All told, they gathered 596 scoops. Back at their lab, they threw out everything from those scoops except for the DNA. And then they plucked out just one particular stretch of that DNA. To be more precise, they plucked out different versions of that stretch, each carried by a different species.

The scientists then looked at the sequence of each of those versions. In some cases, the DNA turned out to be identical to a known species, or nearly so. In other cases, the sequence was very different. A peculiar sequence of DNA told the scientists that it came from a species that’s new to science.

The results were, to be blunt, pretty insane. All told, the scientists identified over 167,000 species.* That’s about thirty times more species that all the mammals on Earth–everything from fruit bats to walruses, from musk ox to marmosets.

Diversity. Blue: known phylotypes (similar to species). Gray: unknown. Ramirez et al 2014
Diversity. Blue: known phylotypes (similar to species). Gray: unknown. Ramirez et al 2014

This chart shows just how ignorant we are of the life even in Central Park. In each chart, the blue bar shows number of species in the park that are already known to science. The gray bar shows the ones that don’t match anything we know of. The top chart shows bacteria and another group of microbes called archaea. (Archaea are single-celled microbes that, like bacteria, keep their DNA floating loose inside their cell.) The bottom chart shows our own branch of the tree of life, the eukaryotes. Eukaryotes include not just animals and plants, but fungi, amoebae, and other protozoans. In both cases, the unknown dwarfs the known.

The more you drill down into these numbers, the more insane they get. Even the “known” species in these charts aren’t very well known at all. For the most part, scientists have never seen the organisms from which they come. They’ve only fished out the same DNA segment from another sample.

The geography of Central Park’s microbes is also mind-boggling. It’s not as if all 167,000 species were present in every sample of the soil. Instead, different species showed up in different places. On average, each sample had about 7000 bacteria and archaea, and 1250 eukaryote species. When the scientists compared the diversity in the samples, they found that any pair picked at random shared only 19.3% of their bacterial and archaeal species, and just 13.5% of their eukaryote species. Even neighboring sites were no more similar to each other than ones on opposite ends of the park. And as the scientists scooped up more dirt, they kept finding more species. So the true number of species in Central Park is probably far higher. (It’s also worth noting that there are probably a lot of other microbes living on the trees, in the ponds, and in other places in the park the scientists didn’t even touch.)

Now, it might have turned out that many of the species in Central Park were closely related to each other. There are many, many species of beetles, for example. Perhaps Central Park only had microbial versions of beetle, and no microbial ants or termites.

That’s not how things turned out. Central Park has the microbial ants and the termites, too. In fact, its microbes span much of the tree of life. You’d get a similar span of species if you took the same number of soil samples from around the world, from jungles to deserts.

Some of the results of the study may be the result of Central Park’s own peculiar history. Its soil contains a high level of species that are considered potential human pathogens. In their report, the scientists hasten to note that this doesn’t mean you’re especially at risk of getting sick in the park. But it may be a sign of the presence of lots of people nearby.

For the most part, though, Central Park may just be a typical plot of microbial habitat. Soil, as a rule, is just rife with microbial richness on a scale we can barely understand. It’s loaded with dying plant matter and the remains of dead animals. Its particles and tunnels and other features make soil an incredibly complex environment, where microbes can specialize in all sorts of ways of making a living. It may turn out that the only thing that makes Central Park unusual is the many holes that scientists have dug there.

*I’m going to use the term species here for convenience. Determining exactly what a species is can be tricky for microbes, and the scientists only presented distinct lineages that might or might not be separate species–what they call phylotypes. Here’s a piece I wrote on why this whole problem is so challenging.

Taking the Yuck Out of Microbiome Medicine

I can still remember the shock I felt when I heard about fecal microbiota transplants for the first time. It is not the sort of thing you forget.

At a microbiology conference, a scientist was giving a lecture about the microbiome–the microbes that live harmlessly inside of us. She described one unusual case she was involved in where a doctor named Alexander Khoruts used the microbiome to save a patient’s life. The patient had taken antibiotics for a lung infection. While the drugs cleared that infection, they  also disrupted the ecology of her gut, allowing a life-threatening species of bacteria called Clostridium difficile to take over. The pathogen was causing horrific levels of diarrhea. Khoruts couldn’t stop it, because it was resistant to every antibiotic he tried.

So Khoruts decided to use an obscure method: the fecal transplant. He took some stool from the patient’s husband, mixed it with water, and delivered it to her large intestines like a suppository. In a matter of days she was recovering.

Since I first heard about these transplants in 2010, they’ve hit the big time. Last year, a team of Danish and Finnish doctors reported clinical trials in which the transplants 94 percent effective against C. difficile. It appears that some species in the transplant from a healthy gut will grow quickly and outcompete the pathogen, returning a sick person’s intestines to its former state. Scientists have been exploring using fecal transplants for other disorders of the gut, along with conditions beyond the gut, such as diabetes and obesity.

But there are many obstacles left to putting fecal transplants into widespread practice. For one thing, the FDA is very cautious with this kind of living medicine. For another thing, fecal transplants are conceptually crude. Doctors simply give a patient a random sample of hundreds of different species from a healthy person’s gut, assuming that at least some of them will restore the patient to health. When the patients get better, they can’t say precisely why.

And then there is the yuck factor. In 2012, scientists conducting a survey about attitudes towards feccal transplants, politely summed up the problem this way: “patients recognize the inherently unappealing nature of FMT.”

But now there’s a potentially promising development in the quest to harness the microbiome. At an American Gastroenterological Association conference in Chicago this weekend, researchers will be describing how they cured C. difficile not with a fecal transplant, but with a pill full of bacterial spores.

The pill is the work of a small Boston-area company called Seres Health. They came up with a combination of certain harmless microbe species that naturally live in our gut. These species  all form spores, which are rugged enough to survive inside a pill. Once they reach the warm refuge of the gut, they pop out of their spores and multiply. In previous studies, Seres researchers showed they could treat C. difficile infection effectively in mice and hamsters. (Technology Review described the company’s efforts in this article from last December.)

Recently, doctors at the Mayo Clinic, the Miriam Hospital in Providence, and Massachusetts General Hospital ran a clinical trial on people to see if the pills from Seres were safe and effective. They gave the pill to fifteen people. The results were striking: the overall cure rate was 100 percent. (The detailed abstract pdf is here.)

I contacted Khoruts to see what he thought of the study. “It looks very promising,” he told me.

But Khoruts also raised a few caveats. He pointed out that the authors excluded very sick patients from the study because of the risk of adverse events. So the 100 percent cure rate might be higher than it would be in the real world.

Khoruts also pointed out a few potential problems with taking a pill full of spores as opposed to getting stool from a donor. Scaling it up to industrial production will require making sure that the factory stocks don’t get contaminated by strains of bacteria that would harm patients, for example.

In those factory stocks, Khoruts pointed out, the microbes will continue to evolve and adapt to their surroundings. If they become too well adapted to life in a factory, they may not do as well inside of people’s bodies.

Nor does the initial report on these pills actually explain how these particular species are conquering C. difficile. I’m sure that the fifteen people who were cured of these awful bugs aren’t clamoring for a detailed  mechanistic explanation of what happened when they swallowed the pills.

But if scientists are going to rationally design microbiome treatments for a lot of different conditions, they’re going to have to open this microbial black box.


The Zoo In the Mouth

There’s a philosophical quandary breeding in your mouth.

Fantail. Photo by Jim Gifford via Flickr/Creative Commons
Fantail. Photo by Jim Gifford via Flickr/Creative Commons

Ever since Aristotle, philosophers and scientists have searched for the right way to classify living things. We call living things with feathers “birds,” but we can also divide birds up into smaller groups, like pigeons and storks. We can drill down even further, to different species of pigeons. But it doesn’t feel right to classify birds all the way down to every individual feathered creature on Earth. The fundamental unit of life’s biodiversity has long been the species. Charles Darwin named his book The Origin of Species for a reason.

Darwin threw older notions of species into doubt, challenging the idea that they were fixed since creation or only able to change slightly over time. adjusted over time. In fact, old species give rise to new ones like shoots from a tree. Darwin concluded that where we choose to draw a line to mark the boundary of a species is a matter of convenience.

While Darwin created the modern foundation for biology with his theory, biologists didn’t abandon the word species. It’s still a helpful term for describing how life evolves–even if it’s left scientists arguing about which definition can hold up best against the churning complexity of evolution.

In the 1940s, the biologist Ernst Mayr declared that “species are groups of interbreeding natural populations that are reproductively isolated from other such groups.” In other words, it’s all about sex.

Other scientists didn’t like Mayr’s definition, because reproductive isolation is a squishy term. Stick a squirrel on a remote island, and it can’t reproduce with its fellow squirrels on the mainland. Have you made a new species? Biologists now know that populations gradually become more and more reproductively isolated over thousands or millions of years. Do we have to wait till they’re totally isolated before declaring the two populations new species?

Some scientists suggested that we think of a species in terms as a branch of the tree of life–as the smallest group of organisms that all descend from a common ancestor, and which we can distinguish from other groups. (I wrote a feature a few years ago about these debates over species in Scientific American, which you can read here.)

These definitions work tolerably well for animals and plants. But they’ve turned out to be pretty lousy for microbes. And that’s left scientists in a quandary, because it’s now clear that the vast majority of the genetic diversity on Earth belongs to bacteria, viruses, and other life forms invisible to the naked eye.

bacteria panorama
Jane Hurd/National Geographic
Artwork by Jane Hurd/National Geographic

When microbiologists started to study microbes in the nineteenth century, they went about their business like zoologists or botanists. They’d describe a microbe based on its appearance, what it fed on, and other features they could study in their laboratory. If it seemed different from other microbes that had been previously described, they’d give it an official species name, like Escherichia coli. When later microbiologists would come across a microbe–say, in the blood of a sick patient–they’d identify its species by systematically inspecting its traits, in much the same way a bird-watcher would look at a bird’s plumage and listen to its song.

In the late 1900s, microbiologists were abandoning this method in favor of a new one: identifying species by their DNA. Zoologists and botanists were making the shift, too, but microbiologists were in for a particularly big shock. The diversity of microbes turned out to be mind-bogglingly exuberant. Microbes that had been considered almost identical before the age of DNA turned out to be more genetically different from each other than maple trees and penguins.

As I describe in my book Microcosm, a single species–E. coli–turned out to contain multitudes, from beneficial bacteria that can heal a baby’s dysfunctional gut to all sorts of pathogens that make us sick in frightfully different ways, from making our cells spill their contents to slithering into them like tapeworms.

Making matters even more confusing was the discovery that microbes don’t simply pass down their genes to their offspring the way we do. They are constantly swapping genes with each other, with little respect for any so-called species barrier. Scientists sometimes try to represent this gene traffic by drawing a web of life instead of a tree of life.

Trying to fit microbes into a definition of species based on animals and plants is a bit like trying to herd a flock of flamingos into a school bus. Mayr’s definition is not much help, since microbes don’t have sex like animals do. The branch-of-the-tree-of-life definition is not much help, either.  Theoretically, any microbe that picks up a mutation is distinct from other microbes and should be considered its own species. And if it passes that particular mutation to a distantly related microbe, the whole tree-based approach collapses.

The situation is such a mess that some microbiologists have given up on species altogether. In 2012, W. Ford Doolittle wrote an awesomely titled commentary called, “How Bacterial Species Form and Why They Don’t Exist.”

This confusion can make life hard for microbiologists when reporters call. Like many other journalists, I’ve been reporting a lot on the remarkable explorations scientists have been making of the human microbiome–the collection of germs that call us home.

I’ve repeatedly asked, “So, how many species are in us?”

And each time, the microbiologists I talked to would squirm out of a real answer.

As deeply uncomfortable as microbiologists may be with the whole idea of species, they still need some way to measure the diversity of, say, the microbiome. Instead of species, they typically end up using something species-ish.

When microbiologists were shifting to using DNA, they chose one gene as a way to distinguish different kinds of microbes from each other. The gene, found in all living things, is called 16S rRNA. Microbiologists compared the variations in 16S rRNA genes from individual microbes that belonged to a single species–that is, a species as microbiologists would traditionally identify it.

They found that the gene varied by up to three percent. So they decided that if two microbes were 97% identical in this one gene, they belonged to the same group. Instead of a species, they called this group an operational taxonomic unit.

But it eventually turned out that this 97% cut-off was wrong. A good example of how it can lead scientists astray is the case of two species of bacteria that live on our bodies, Streptococcus pneumoniae and Streptococcus mitis. Back in the barbaric pre-sequencing days, microbiologists decided they were two separate species, deserving of two separate names. When you look at how these two microbes make a living, that decision makes ample sense. S. pneumoniae causes pneumonia, while S. mitis can live harmlessly on teeth.

Yet the 16S rRNA sequences of these two “species” are over 97% identical. In fact, they’re 99% similar. While their 16S rRNA genes have remained nearly identical, some of their other genes have veered off in different directions.

In the face of all this delicious confusion, microbiologists need a more powerful way to sort microbes into groups. But there’s been a limit to how fine they can draw their distinctions. Even the best DNA sequencers are not perfect. Here and there, they will make an error in reading a microbe’s genes. When microbiologists are distinguishing different kinds of bacteria with 97% thresholds, those little errors don’t matter. But if microbiologists want to distinguish microbes by tiny differences, making those errors would be akin to mistaking a wolf for a chihuahua.

A. Murat Eren, a microbial ecologist at Marine Biological Laboratory in Woods Hole, Massachusetts, and his colleagues have come up with a powerful new way to chart the diversity of microbes. They call it oligotyping. They line up the 16S rRNA genes from a group of microbes, and then they look for spots in the gene that have the most differences from one microbe to another. The scientists narrow down their search to the fewest spots that can distinguish the largest number of groups, which they call oligotypes. This approach allows them to avoid depending on tiny, error-prone differences that might only be present on a single microbe’s gene.

Photo by Darwin Bell, via Creative Commons
Photo by Darwin Bell, via Creative Commons

Recently, Eren and his colleagues tested out oligotyping on the microbiome. They searched the DNA sequences collected by the Human Microbiome Project, a massive survey of microbial genes from over 200 people. Eren and his colleagues limited their search to just the microbes from people’s mouths. That still left them with over 10 million sequences to sift through.

All told, they found at least 362 oligoytpes of bacteria.* Most of their oligotypes belonged to conventional species, but often the scientists found that a single so-called species contained several distinct oligotypes.

These oligotypes are not just minor variations on a theme. They lead different lives. Our mouths are like jungles, with lots of ecological niches. The environment on a tooth is very different from that on the tongue, which is different in turn from the gums. Eren and his colleagues found that each oligotype dwelled in just one or a few parts of the mouth–and did so consistently from one person to the next.  Some oligotypes only live on teeth, for example, while others live mostly on the tongue. The evidence for all this diversity already existed in the Human Microbiome Project’s databases, but until now it was hiding in plain sight.

There are plenty of solid, practical reasons for inventing a better way to measure the diversity of microbes–even just in our mouths. Some bacteria that live there can potentially make us sick–not just by causing cavities, but by causing diseases in other parts of the body, such as heart disease. Old-fashioned definitions of species can lead scientists to overlook these pathogens, lumping them into the same group as harmless microbes.

But this research is also important for a more basic reason–because it helps us to wrap our minds around the staggering diversity of life on Earth. One way to start appreciating how vast that diversity is to just open our mouths.

*The paper will be posted at some point this week by the journal. The reference is: Eren et al., “Oligotyping analysis of the human oral microbiome,” PNAS.

Evolution Hidden in Plain Sight

It’s hard to believe that Escherichia coli could have any secrets left.

For over a century, scientists have picked the microbe apart–sequencing its genes, cracking its genetic code, running experiments on its metabolism, earning Nobel Prizes off of it, and turning it into, arguably, the most-studied organism in history.

But as deep as scientists dive, they have yet to touch bottom. That’s in part because Escherichia coli is not fixed. It continues to evolve, and even in the most carefully controlled experiments, evolution leaves behind a complicated history.

Twenty-five years ago, Richard Lenski used a single microbe to seed twelve lines of bacteria. He fed each line a meager diet of glucose, and the bacteria have been adapting to this existence in his lab at Michigan State University ever since. (Here I’ve gathered together a few pieces I’ve written over the years about the 58,000-generations-and-counting Long-Term E. coli Evolution Experiment.)

In 2003, Lenski’s team realized that something utterly unexpected happened. One of the hallmarks of Escherichia coli as a species is that when there’s oxygen around, it can’t feed on a compound called citrate. But one day a flask turned cloudy with an explosion of E. coli that were doing just that. The change was so profound that it may mean these bacteria had evolved into a new species.

For the past 11 years, the scientists have been trying to figure out how the bacteria gained this ability to feed on citrate. Thankfully, Lenski decided at the outset of the experiment to freeze some of the evolving bacteria every 500 generations. As a result, he and his colleagues can resurrect ancestral microbes, sequence their genomes, and probe their biology for clues.

After sifting through the frozen history of citrate feeding for a couple years, the scientists discovered an important step in this evolution. It involves a gene called citT.

The citT gene encodes a protein that lets E. coli feed on citrate when oxygen levels get low. The protein sits in the microbe’s membrane and helps pull in citrate molecules from the environment. As it draws citrate in, however, it pumps another molecule–succinate–out. The pushing and pulling of these two molecules helps keep the chemistry of the cell in balance.

A small segment of DNA next to citT serves as a switch. If the microbe detects oxygen, a protein grabs onto the segment and shuts citT down. The microbe no longer feeds on citrate, instead feeding on better sources of energy, such as glucose.

The scientists found that around generation 31,500, a microbe that was copying its DNA in order to divide made a big mistake. It accidentally made an extra copy of a segment of DNA. That segment, it just so happened, contained citT. The microbe inserted the copy next to the original one, so that one of its daughter cells now had two copies of citT.

This sort of gene duplication happens from time to time in all living things. Human DNA regularly gets copied, too. And it can lead to important changes, because the two copies can start to do two different things. And that’s what happened to the E. coli. In Lenski’s experiment, the new copy of citT ended up near a new bit of DNA that controlled genes in a different way. Instead of shutting down genes in the presence of oxygen, it keeps them always switched on. Thanks to this mutation to citT, the bacteria could start feeding on citrate in Lenski’s oxygen-rich lab.

But the scientists found that this mutation was only one part of the story. The citT mutation allowed the bacteria to grow on citrate, but only slowly. Only after 1500 more generations had passed did the citrate-feeding bacteria begin growing quickly enough to dominate their flask.

During those 1500 generations, the scientists found, the bacteria made more copying mistakes, turning the new citT gene into four duplicates. Those extra copies enabled the bacteria to make more citrate-pulling proteins. But other mutations arose from generation 31,500 to 33,000, and the scientists had no way of knowing if they were important as well.

The story also turned out to have an earlier chapter. The scientists went back through the frozen archive to the very beginning and thawed out some microbial ancestors. They inserted the evolved citT genes into the ancestors, and found that the microbes could not feed on citrate. So the evolved citT gene alone was not enough to turn a microbe into a citrate-feeder.

The scientists did the same thing to bacteria from generation 20,000 and got a different result. When those more evolved bacteria got the citT gene, they could feed on citrate. Results like these suggested that early in the evolution of the bacteria, they picked up mutations that would later make it possible for the citT mutation to turn them into citrate feeders.

So, to recap: the scientists now had a story in three parts. Up to 31,500 generations, it was a story of groundwork mutations. Then came the big citT duplication. And after that came refining mutations, leading to world domination by generation 33,000. (The world, in this case, being a shot-glass-sized flask.)

In order to read this story in its full details, the scientists would need to understand the order by which every mutation arose, step by step. And they’d have to understand how each mutation helped produce a new kind of organism.

Despite the carefully controlled conditions of the experiment, this was a fiendishly hard problem. By the time the bacteria had evolved into full-strength citrate feeders at generation 33,000, they had acquired 79 mutations not found in their ancestor. Many of those mutations probably had nothing to do with citrate feeding. They may have helped the early bacteria grow better on glucose. Some might have had no effect on the bacteria one way or the other.

One of the scientists studying the citrate eaters was post-doctoral researcher Jeffrey Barrick. In 2011, he moved to the University of Texas to set up his own lab, and there he continued to study the citrate eaters, developing new methods to tease apart the evolutionary history of the citrate feeders.

He and his colleagues developed a new method of engineering bacteria in order to identify the mutations that were absolutely essential for full-blown citrate feeding. They combined portions of the citrate-feeding genome with that of the ancestral genome and then dropped these hybrids into dishes with only citrate to feed on.

Most starved to death. But a few grew. The scientists then plucked out the surviving hybrids and put parts of their DNA into other ancestral bacteria. Round after round of experimenting let them zero in on the essential segments for growing on citrate. Eventually, they could pinpoint the specific mutations.

Their results were weirdly few.

One result was no big surprise. Barrick and his colleagues found that in order to feed on citrate with maximal gusto, bacteria needed extra copies of the rewired citT genes.

But, as Barrick and his colleagues reported in a recent paper, they found just one other essential mutation.

This mutation affects a gene called dctA. When the scientists inserted the evolved versions of citT and dctA into an ancestral microbe, it became a full-blown citrate feeder. Neither gene on its own could achieve the same result. And no other genes were required for the metamorphosis.

This discovery prompted the scientists to look closely at the dctA gene. It encodes another membrane protein that’s responsible for pumping molecules in and out of the microbe. While citT pumps succinate out of the microbe, dctA pumps it in.

Barrick and his colleagues suspect that the evolution of a new kind of dctA gene allowed the bacteria to keep up a supply of succinate, which they needed on hand in order to feed on citrate. Together, the mutations to citT and dctA turned the mutant microbes into winners.

Which leaves the role of all the other mutations shrouded mystery. In the new study, none of the mutations that came before generation 31,500 proved to be vital for being a full-blown citrate feeder. They didn’t lay the groundwork in any essential way. And yet the previous research clearly indicated that things were afoot before generation 31,500.

Given the new results, Barrick and his colleagues have a few ideas for what was going on before then. It’s possible that some of the early, mysterious mutations were favored by natural selection because they helped the bacteria grow on their regular diet of glucose. And as a side effect, they helped build up a small supply of succinate. That succinate turned out to be a big benefit later on, when citT mutated. Now the bacteria had enough succinate (or some related molecule) to push out as it pulled citrate in. If the citT mutation had arisen before those mutations, the bacteria might not have been able to feed on citrate. And then later on, the dctA mutation arrived, kicking the citrate feeding into overdrive.

I contacted Lenski, who was not a co-author on Barrick’s new study, to see what he thought of the results. “I love the fact that this paper shows just how complex evolution can be,” he replied, “even for one little species in a tiny flask world for just a couple of decades.”

(For more on E. coli’s strange scientific history, see my book Microcosm.)

A Long Way Left Up Darwin’s Mountain

One of the things I like about a long-running blog is that I can revisit long-running stories whenever I feel like it. And one of the longest of those stories has been unfolding in a lab at Michigan State University since 1988. That year, a biologist named Richard Lenski began rearing Escherichia coli from a single microbe. The bacteria, which he raised in a dozen separate flasks, all faced the same challenge: endure a starvation diet that their lab-pampered ancestors had not suffered.

The twelve flasks that contain the bacteria in Lenski’s long-term experiment. Photo by Michael Wiser
The twelve lines of E. coli in Lenski's experiment live in these flasks. Photo by Michael Wiser

Every few hours, the bacteria reproduced. Each morning, the scientists took a few drops from each flask and moved these colonists to a fresh flask. Mutations arose, which the descendants inherited. Some helped the bacteria grow faster than their cousins, and natural selection spread them across the population.

It’s been 25 years–and 50,000 generations–since Lenski started the experiment, and it just won’t quit. Here are a few of the pieces I’ve written about it over the years:

–In 2007, I wrote about Lenski and the field of experimental evolution for the New York Times.

–In 2008, I dedicated a chapter to Lenski’s work in my book, Microcosm, which is a biography of E. coli. If Google will cooperate, I’m going to embed the chapter here. The blog post continues below it…

–In 2009, I wrote a magazine feature for BBC Knowledge

–One of Lenski’s lines of bacteria even went off in an unexpected direction, evolving the ability to feed on citrate in the presence of oxygen. This might represent the birth of a new species. I blogged about that research here and here.

Yet there is still more to learn from these bugs. In this week’s Science, Lenski and two members of his lab–Michael J. Wiser and Noah Ribeck–took a close look at the evolution of the bacteria over the course of the entire experiment.

One of the great strengths of this experiment is that Lenski is an obsessive hoarder. He and his team freeze bacteria every 500 generations, filling freezer after freezer with them. They can then thaw out a few of the bacteria and put them in a dish with the latest generation and see how fast they each grow under identical conditions. Think of it as microbial Hunger Games.

These contests allow the scientists to precisely gauge what’s known as relative fitness–a measurement of natural selection. In the early years of the experiment, the fitness of the bacteria rose very fast. Within 5,000 generations, all twelve lines were growing 50% faster than the original microbe Lenski started the experiment with. Then they slowed down. By 20,000 generations, they were 75 percent faster.

These results lead to an obvious question: were the bacteria coming to the end of their increase in fitness? You can think of evolution in these cases like a mountain, with the elevation of any spot on the mountain as the average fitness of a population. Perhaps the mountain the bacteria in Lenski’s lab were climbing had steep slopes at low elevations. But now they were getting to the gentle climb just before reaching the mountain’s peak.

So the scientists thawed out some bacteria and pitted them against each other. Even at 50,000 generations, it turns out, the bacteria are still getting faster. Between generations 40,000 and 50,000, their fitness increased by 3 percent.

The scientists then competed the newest bacteria against ancestors from 41 generations across the past 25 years. They plotted the data on a graph and then looked for the curve that fit the dots best. The data do not indicate the mountain is going to flatten out. Instead, the best curve is generated by a mathematical relationship called a power law. In this model, the bacteria will improve by smaller steps in the future, but they will never stop improving. The power law is so powerful that the scientists can plug data into it only up to generation 20,000  and then accurately predict the next 30,000 generations.

fitness graph
Fitness of E. coli over 50,000 generations. (Ancestor=1) Blue curve from a power law; red curve asymptotic. Wiser et al Science 2013
From Wiser et al, Science 2013. The blue line shows a power law curve. The red line shows a curve that approaches a flat line (asymptotic).

To explain this result, the scientists turned to some of the previous experiments that researchers  have  carried out on Lenski’s bugs. Over the years, they’ve  looked closely at the DNA of some of the bacteria, in order to pinpoint new mutations and track them over the generations. By 20,000 generations, the bacteria had already acquired several dozen beneficial mutations. If the scientists engineered the ancestral bacteria with each of those mutations, they grew faster.

These adaptations arose thanks to the fact that mutations spontaneously occur at random in the bacteria. Most of the mutations are harmful, either killing the bacteria outright or slowing down their grow so that their descendants eventually disappear from their flask. But a few are beneficial.

Of all the possible beneficial mutations, most of them provide a small benefit, while a few provide big ones. After a few thousand generations, most of the big mutations probably occurred, leaving only small ones to continue improving the bacteria. And each time a new mutation arises, it has to interact with all the mutations that came before it. Some of those interactions may actually be harmful to the bacteria, reducing the overall benefit. The more time passes, the more mutations there are that may impose that cost.

Yet the experiment also shows that the bacteria still have the capacity to grow even faster. There’s a creativity in the genome that is inexhaustible–despite the fact that just about every spot in the microbe’s DNA has mutated by now. Again, the interaction between mutations gets the credit. In some cases, mutations can’t be beneficial until a series of other beneficial mutations have first evolved.

The creativity of evolution means that this experiment will keep yielding results for a long time. It’s possible that eventually the bacteria will hit some ceiling imposed by physics. There may be an upper limit to how fast DNA can be copied, for example, or how thick cell walls can get.

But no one knows when the bacteria will hit that wall. Lenski and his colleagues estimate that if they could run the experiment for another million years, the bacteria would keep speeding up. Today it takes one microbe 55 minutes to become two. In a million years (or 2.5 billion generations) it would take 23 minutes.

Lenski’s getting towards retirement, so he won’t be running a million-year experiment. Perhaps someone can create a robotic, solar-powered time capsule to take over. As long as the experiment can run, these bacteria will be ready to surprise.

PS: After 25 years, Lenski has evolved too–he has started to blog. Here’s his own post on the new paper.

A Living Drug Cocktail

We know that the 100 trillion microbes in the human body are important to our health. What’s harder to know is how to use them to make us healthy.

Normally, our resident microbes–the microbiome–carry out a number of important jobs for us, from fighting off pathogens to breaking down food for us. If they get disrupted, we  suffer the consequences. Sometimes antibiotics can upset the ecological balance in our bodies so severely, for example, that rare, dangerous species can take over.

For decades, doctors and scientists have searched for microbes that can promote our health by taking up residence in our bodies. They’ve had some modest success in treating people by giving them a single species at a time. (Don’t be fooled by all the so-called probiotic foods and pills you can buy over the counter–few, if any, have ever been scientifically shown to be effective.) Part of the problem has been that scientists haven’t been terribly systematic about searching for microbes. Very often, their most important standard for a probiotic germ is not its healing power, but its ability to survive in food, or packed into a pill.

Scientists have also had some limited success at the other end of the spectrum, by exploiting much of the microbiome’s diversity at all once. For some people with deadly gut infections, for example, the only cure is to get a so-called fecal transplant from a healthy donor. Fecal transplants show a lot of promise, but scientists don’t have a clear idea of how they work. A stool sample is loaded with hundreds of different species, any one of which might be either essential for overthrowing pathogens or just along for the ride.

In Nature today, a team of scientists report taking an important step forward in microbiome-based medicine. They searched for species methodically, in the same way medicinal chemists search for new drugs. They have pinpointed a handful of species living in the human gut that collectively show signs of fighting effectively against some autoimmune diseases.

Scientists have long suspected that the immune system would benefit from microbiome-based medicine. That’s because immune systems depend on the microbiome to develop normally in the first place. As a child’s immune cells grow and divide, they pick up signals from the microbes. Those signals teach the immune system to become tolerant. They can still recognize a dangerous pathogen and kill it, but they spare the beneficial bugs. And they also become less likely to overreact to a harmless molecule or our own tissues.

One important group of immune cell involved in this tolerance are known as Tregs (short for the CD4+ FOXP3+ T regulatory cells). They are abundant in the microbe-packed gut, where they help to broker a truce between host and the germs that live there. Tregs also depend on the microbiome for their very existence. When scientists rear mice without any germs at all, the animals develop very few Tregs. And as a result their immune system becomes prone to raging out of control.

A number of experiments have hinted that abnormal levels of Tregs are behind some autoimmune gut diseases, such as colitis, which causes chronic inflammation in the large intestines and diarrhea. This raises the possibility that a treatment for colitis would be to bring Tregs back to normal levels. Perhaps among all the bacteria in the gut, scientists could find the ones that sent the signals to the Tregs.

Over the past few years, Kenya Honda of the University of Tokyo and his colleagues have been hunting for those species. They started by testing out subsets of the microbiome to find groups of species that could foster the growth of Tregs. Raising healthy mice, they collected the mouse droppings, which contained lots of bacteria. They treated the droppings with chloroform, which kills most bacteria. The only microbes that survived were species that make spores tough enough to withstand the chemical.

When the scientists gave those spore-forming bacteria to germ-free mice, the level of Tregs in the animals went up. That didn’t happen when the scientists gave the mice other kinds of bacteria instead.

This discovery didn’t pinpoint exactly which bacteria were fostering Tregs. But it certainly narrowed down the line-up of suspects dramatically. And it also prompted Honda and his colleagues to start acting more like a drug company testing promising new compounds. In fact, Honda co-founded a company called Vedanta Biosciences for that express purpose.

Their goal now became finding a species, or a group of species, that live in humans, and which promote the growth of Tregs in the gut. Rather than taking the kitchen-sink approach of fecal transplants, they would try to deliver a surgically precise germ.

They took stool samples from a healthy Japanese volunteer and doused them with chloroform, so that once more they only had to contend with spore-forming species. Then they inoculated germ-free mice with different combinations of the surviving bacteria. After letting the bacteria grow in the mice, they then inspected the animals to see if any of them had high levels of Tregs as a result. They did find some of those combinations, and they went on narrowing down the suspects until  they were left with just seventeen species, along belong to a type of bacteria called Clostridia.

One particularly interesting result of the experiment was that they couldn’t get these good results from any fewer than those seventeen species. On its own, each of the species was unable to foster the immune cells. It may be a combination of signals from all seventeen species that promotes the Tregs.

The researchers wondered if these seventeen species played a special role in autoimmune diseases in humans. To find out, they looked at the microbiomes from health people and people with colitis. The seventeen species tended to be rarer in the sick people.  Perhaps, the researchers reasoned, losing this network of microbes weakens the signals that keep Treg levels normal. The immune system spins out of control, leading to colitis.

If that were true, then giving someone a pill with all seventeen species might be an effective way to fight colitis. But Honda and his colleagues weren’t ready to start inoculating people with Clostridia. Clostridia is a huge group of species that includes some very nasty characters that cause diseases like tetanus and botulism. They would have to do some preliminary work first.

All seventeen species were new to science (something that’s pretty typical for microbiome research), so the scientists sequenced their genomes. None of the seventeen species carried genes for toxins or other disease-causing proteins. From an inspection of their DNA, at least, the microbes looked safe.

Next, the scientists tested the bacteria out on mice. They gave the microbes to animals either suffering from colitis or from allergy-triggered diarrhea. In both cases, the bacteria raised the level of Tregs dramatically in the guts of the mice. The mice also partly recovered from their diseases. The mice with colitis had less inflammation, and the mice with diarrhea had healthier stool.

From here, the Vedanta researchers eventually hope to get to clinical trials on humans. As I wrote in April, turning bugs into drugs is a big challenge on many levels. For one thing, the FDA doesn’t have a long tradition of approving such research. And while Honda and his colleagues have certainly gone a long way to pinpointing how microbes foster Tregs, they have yet to work out the precise balance of signals that really matters to the immune system.

Nevertheless, a seventeen-bug cocktail would be appealing in many ways. For one thing, the microbes are regular residents of the human gut, dwelling there for people’s entire lifetime. And they only live in the gut, and not the heart or the liver or some other organ. Both these facts suggest that such a cocktail would be unlikely to cause harmful side effects. What’s more, the microbes would be able to deliver a steady, long-running dose of the chemicals necessary to keep Treg levels healthy.

The new study also points to a way to systematically search the microbiome for treatments for other diseases. It’s possible that small teams of other species handle other jobs in the body. They may nurture other types of immune cells, for example. Or they may send signals into the body that regulate body weight. By winnowing down the microbiome, scientists may be able to deploy those elite units to fight other diseases.

[Update: Nature paper link fixed]

“I Think I’ve Just Thought Up Something Important”–Francois Jacob (1920-2013)

Francois Jacob. Image from
Francois Jacob. Image from

I just learned the sad news that the great biologist Francois Jacob has died. He won the Nobel Prize for his work in the 1950s that showed how cells switch genes off–the first crucial step to understanding how life can use the genome like a piano, to make a beautiful melody instead of a blaring cacophony.

Jacob was also a wonderful writer, and so I had enormous pleasure mining his memoirs for my book Microcosm: E. coli and the New Science of Life. I hope this passage gives a sense of what he was like–

One day in July 1958, François Jacob squirmed in a Paris movie theater. His wife, Lise, could tell that an idea was struggling to come out. The two of them walked out of the theater and headed for home.

“I think I’ve just thought up something important,” François said to Lise.

“Tell!” she said.

Her husband believed, as he later wrote, that he had reached “the very essence of things.” He had gotten a glimpse of how genes work together to make life possible.

Jacob had been hoping for a moment like this for a long time. Originally trained as a surgeon, he had fled Paris when the Nazis swept across France. For the next four years he served in a medical company in the Allied campaigns, mostly in North Africa. Wounds from a bomb blast ended his plans of becoming a surgeon, and after the war he wandered Paris unsure of what to do with his life. Working in an antibiotics lab, Jacob became enchanted with scientific research. But he did not simply want to find a new drug. Jacob decided he would try to understand “the core of life.” In 1950, he joined a team of biologists at the Pasteur Institute who were toiling away on E. coli and other bacteria in the institute’s attic.

Jacob did not have a particular plan for his research when he ascended into the attic, but he ended up studying two examples of one major bio- logical puzzle: why genes sometimes make proteins and sometimes don’t. For several years, Jacob investigated prophages, the viruses that disappear into their E. coli host, only to reappear generations later. Working with Élie Wollman, Jacob demonstrated that prophages actually insert their genes into E. coli’s own DNA. They allowed prophage-infected bacteria to mate with uninfected ones and then spun them apart. If the microbes stopped mating too soon, they could not transfer the prophage. The experiments revealed that the prophage consistently inserts itself in one spot in E. coli’s chromosome. The virus’s genes are nestled in among those of its host, and yet they remain silent for generations.

E. coli offered Jacob another opportunity to study genes that some- times make proteins and sometimes don’t. To eat a particular kind of sugar, E. coli needs to make the right enzymes. In order to eat lactose, the sugar in milk, E. coli needs an enzyme called beta-galactosidase, which can cut lactose into pieces. Jacob’s colleague at the Pasteur Institute, Jacques Monod, found that if he fed E. coli glucose—a much better source of energy for E. coli than lactose—it made only a tiny amount of beta- galactosidase. If he added lactose to the bacteria, it still didn’t make much of the enzyme. Only after the bacteria had eaten all the glucose did it start to produce beta-galactosidase in earnest.

No one at the time had a good explanation for how genes in E. coli or its prophages could be quiet one moment and busy the next. Many scientists had assumed that cells simply churned out a steady supply of all their proteins all the time. To explain E. coli’s reaction to lactose, they suggested that the microbe actually made a steady stream of beta-galactosidase. Only when E. coli came into contact with lactose did the enzymes change their shape so that they could begin to break the sugar down.

Jacob, Monod, and their colleagues at the Pasteur Institute began a series of experiments to figure out the truth. They isolated mutant E. coli that failed to eat lactose in interesting ways. One mutant could not digest lactose, despite having a normal gene for beta-galactosidase. The scientists realized that E. coli used more than one gene to eat lactose. One of those genes encoded a channel in the microbe’s membranes that could suck in the sugar.

Strangest of all the mutants Jacob and Monod discovered were ones that produced beta-galactosidase and permease all the time, regardless of whether there was any lactose to digest. The scientists reasoned that E. coli carries some other molecule that normally prevents the genes for beta- galactosidase and permease from becoming active. It became known as the repressor. But Jacob and his colleagues had not been able say how the repressor keeps genes quiet.

In the darkness of the Paris movie theater, Jacob hit on an answer. The repressor is a protein that clamps on to E. coli’s DNA, blocking the production of proteins from the genes for beta-galactosidase and the other genes involved in feeding on lactose. A signal, like a switch on a circuit, causes the repressor to stop shutting down the genes.

Another similar repressor might keep the genes of prophages silent as well, Jacob thought. Perhaps these circuits are common in all living things. “I no longer feel mediocre or even mortal,” he wrote.

But when François tried to sketch out his ideas for his wife, he was disappointed.

“You’ve already told me that,” Lise said. “It’s been known for a long time, hasn’t it?”

Jacob’s idea was so elegantly simple that it seemed obvious to anyone other than a biologist.

Bugs As Drugs

Let’s say you want to buy things with germs in them. There’s yogurt, of course, but there’s so much else.

You can buy pills for your gut, creams for your face, tablets for your breath. You can buy blueberry juice with germs, and pizza with germs. And a lot of these products make big promises about the benefits their germs will bring you. “Fungal Defense is specially formulated with ingredients that help maintain a balanced, healthy digestive environment,” for example. Natren Natasha’s Probiotic Face Cream “is enriched with DNA fragments of beneficial bacterial cells, which speed up the skins own natural renewal process.”

Did that last statement make not so much sense to you? Are you struggling to find the results of the clinical trials that demonstrated that Fungal Defense really will make you healthy? Relax! Somewhere on the labeling for the germ-laden product you just bought, you’ll probably find these words: “This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.”

There’s ample evidence that the 100 trillion microbes that call us home–the microbiome–exert important influences on our biology. While some of them can make us ill, for the most part they help maintain our health–nurturing our immune system, moisturizing our skin, breaking down food and toxic compounds. (Here are a couple pieces I’ve written for the New York Times for a sampling of this field.)  For the most part, though, the research has been fairly remote from the doctor’s office.

A huge amount of research has been carried out on mice rather than humans, for example. That’s because scientists can rear the rodents without any bacteria in their bodies and then observe what happens when they add in certain species to their microbiome. Scientists have also carried out a lot of research on humans, but it’s mostly been observations, not manipulation–what does someone’s microbiome look like before and after a gastric bypass, for example?

Actual experiments on people have been a lot rarer, not surprisingly. (Any parents willing to put their newborns in a plastic bubble to keep them germ free for the first five years of life? Hello? Anyone?) That’s not to say there are no such experiments. Scientists will sometimes test out bacteria on people to see if it can help their disorders. Some of these experiments are promising. The remarkable results with fecal transplants for people with dangerous gut infections have become a veritable poster-child for the microbiome’s application to medicine. But none of them have been the subject of exhaustive research that’s been given to an FDA-approved drug like, say, the cancer-fighting compound Gleevec.

There are many reasons for this shortfall. Scientists have only been able to study the microbiome with much clarity in the past couple decades, so they’ve got a late start. Another reason is that the microbiome is different from our own cells and organs. It’s an ecosystem made up of hundreds of species, with lots of diffuse, interlinked effects on our bodies.

Making matters worse (or a more exciting challenge, if you’re of a sunny disposition) is the fact that there isn’t any one microbiome. While the microbiomes of humans are similar to one another, each of us has a mix of species and strains that’s unique–a mix that also changes from day to day. That variability makes it hard to say that adding in one particular species is going to make a difference to anyone who’s sick with a particular disease. Even an exquisitely rare microbe might play a crucial part in the overall ecosystem.

None of these hurdles has blocked the growth of the business of the microbiome. But the $8.7 billion industry has thrived because the microbiome occupies a fuzzy middle ground in the regulatory landscape. Purveyors of germ-loaded products can vaguely hint that their wares will bring you medical benefits. But to the U.S. government, their products are not, officially speaking, medicine. They’re food or cosmetics.

It’s possible that the bottle of probiotics you buy in the drug store really will help your digestion, or your immune system, or your bad breath. But it’s also possible that the bacteria you’re buying will get annihilated in the ruthless jungle that is your body. A lot of species you’ll find in probiotic products do not actually belong to the dominant groups of species in the human microbiome. Stop eating them, and they’ll disappear from your body.

The fact that you feel better after taking probiotics might be due to entirely different reasons. Who knows–maybe the very notion that a pill can “restore your ecosystem” will have a powerful placebo effect. As long as companies don’t make any specific drug-like claims about their germs, they can say whatever they want. (Dannon got nailed in 2010 for claiming Activia yogurt can cure colds.) Such is no longer the case in Europe, however; at the end of 2012, companies were no longer able to tout health benefits of the germs in their products.

While these products may not harm you, they can’t stand in for medical treatment. If you’ve got a serious case of diabetes, you shouldn’t just randomly start popping probiotic pills because you’ve heard that your microbiome influences insulin signaling. That’s not to say that someday there might not be clinically proven microbiome treatments for diabetes. We’re just not there yet.

According to Nature Biotechnology, however, we’re getting there. The current issue has a special focus on the microbiome (behind a paywall, alas). As reporter Charles Schmidt notes in an article for the journal, biotech startups are setting out on the drug-approval road in order to prove that some bacteria are indeed safe and effective. Enterologics in Minnesota is testing out a strain of E. coli as a treatment for a type of gut inflammation called pouchitis. Bernat Olle, the co-founder of Vedanta Biosciences in Boston, also contributes an essay to Nature Biotechnology, in which he mentions that his company is testing out a cocktail of species that can restore gut ecosystems degraded by diseases.

All well and good, but the fact is that the bacteria that these companies are studying have been known for a long time. That’s because they were comfortable enough in laboratories to thrive. Most microbes in our bodies require much more exotic conditions. As a result, scientists are just starting to discover them by fishing out their DNA from our bodies. Some companies are trying to mine this newly discovered diversity for keystone species that could have important effects on our health. These new species could also serve as diagnostic tests for diseases. Certain microbes in the mouth are associated with a risk of heart disease, for example. Frederik Bäckhed of the University of Gothenburg in Sweden and his colleagues have patented a way to assess that risk by examining the bacteria in your spit.

Olle also notes that some companies are engineering bacteria that we could consume.  This year marks the fortieth anniversary of the first insertion of an animal gene into E. coli. Today, E. coli and other engineered microbes pump out vast amounts of medicine and other products. But they do so in giant fermentation tanks, not in our guts. People with diabetes must wait for companies to harvest insulin from E. coli, purify the molecule, and sell it in vials which they can then inject into their bloodstream. (For more, see my book Microcosm.) Imagine, instead, that people could swallow bacteria that could take up residence in the gut and produce a life-saving drug right where it’s needed.

A company called Actogenix is trying to do that. They’ve carried our early human trials on a species called Lactococcus lactis they’ve engineered to carry a gene that encodes an anti-inflammatory protein. Another company, Osel, has engineered Lactobacillus jensenii to carry a gene for cyanovirin N, a protein that may help prevent HIV infection. They’re in preclinical trials.

This wave of efforts will not change medicine in the short-term. But in the medium-term it may. Nature Biotechnology surveyed experts on the microbiome about its future in medicine.  “The potential for gut microbiota manipulation is enormous, and so is the market,” declared Jeroen Raes of Vrije Universiteit in Brussels. “In 15 years, we will all be drinking specific, personalized probiotic cocktails. I suggest that every healthy person freezes a fecal sample now so they will be able to treat themselves in the future.”

The “Nightmare Bacteria”: An Explainer

Earlier this week, the Centers for Disease Control warned that we’re facing an onslaught of “nightmare bacteria”–a group of highly resistant, highly deadly microbes. Talk of the Nation, the National Public Radio Show, asked me to join them to talk about these bugs yesterday. You can listen to it here:

This is the sort of story that seems tailor-made for confusion, thanks to the squirrelly nature of microbiology. As my fellow guest on the show, NPR science correspondent Rob Stein, observed, we are not dealing with an out-of-control plague that will wipe out the planet. On the other hand, as I pointed out, these nightmare bacteria are killing people, and will probably kill more people in the future. I’m sure that listeners were left scratching their heads a bit. So I wanted to take a moment this snowy morning to explain the news at more length.

Not long after scientists invented antibiotics in the mid-1900s, they started observing bacteria that were becoming resistant to the drugs. Some of the microbes carried mutations that made them a little less susceptible, so that a few of them survived the onslaught and could reproduce. Their descendants mutated more, and some became more resistant.

At the same time, genes were slipping from one microbe to another–even leaping the species barrier–and that made things even worse. For one thing, the bacteria that make us sick could tap into the vast repository of resistance genes in the other bacteria dwelling in our bodies and in the soil. The bacteria could load several resistance genes into the same piece of DNA, becoming resistant not just to one drug, but to many.

For decades, microbiologists have been warning that resistance was rising, and that things were going to get worse. And worse they did become. Fearsome strains of bacteria emerged, such as methicillin-resistant Staphylococcus aureus, now familiar by its acronym MRSA. (For the full story of MRSA, read Maryn McKenna’s award-winning book Superbug. And then read all her other stuff too.)

This week the CDC raised a warning about a different kind of bacteria, called CRE for short. That stands for carbapenem-resistant Enterobacteriaceae. (I can hear you saying, “Um, is it okay if I just call it CRE?” I’m here to tell you yes.)

Enterobacteriaceae refers to a large taxonomic group of bacterial species. It includes some familiar bugs, like E. coli, as well as many you’ve never heard of. Only some of them live in the human body, and only some of those strains have the potential to make us sick. (You probably have a few billion E. coli in your gut right now. But if you get one of the nasty E. coli strains, you may get organ failure or die.)

Okay, that takes care of the E in CRE. CR refers to the ability of some of these strains to resist carbapenems, which are a class of potent antibiotics. When they were first developed, they were a godsend, because doctors could use them against bacteria that had become resistant to older drugs like penicillin. But in the 1990s and early 2000s, hospitals started seeing bacteria–members of the Enterobacteriaceae, spefically–that had evolved enzymes that they used to chop up the carbapenems.

One of the worst of these offenders is a strain of Klebsiella called KPC. I just wrote about an outbreak of KPC at a major research hospital for Wired, and I hope that my story gets across what a nightmare these outbreaks can be. These bacteria can ride silently on healthy people from room to room, from ward to ward, from hospital to hospital. And then they can strike vulnerable patients. Since these bacteria can resist carbapenems, doctors are left with few options. They can use a few truly nasty drugs that were abandoned decades ago because they were so toxic. And, as I write in my Wired feature, the bacteria can evolve resistance even to those drugs in the body of a single patient. And then it’s game over. As a result, CREs can be up to 50% fatal.

KPC is just one of the CRE bacteria doctors are worried about. In India, a new set of resistance genes has emerged that go by the name NDM-1. Several different species carry them, and they’re not limited to hospitals. Scientists have even found NDM-1 germs in ordinary tap water. Once these genes evolve, they don’t stay put. NDM-1 has made its way to the United States–possibly thanks in part to medical tourism. Meanwhile, KPC–which got its start on the east coast of the United States–has spread to many countries overseas.

Most of the trends for CRE are going in the wrong direction. New kinds of resistance genes are evolving and spreading to different species. Those resistant strains are showing up in more states and more countries. The percentage of these bacteria that are resistant is increasing. The CDC’s announcement this week was spurred by a recent survey they did. They found that 4.6% of the hospitals they surveyed had one CRE infection in the previous six months. And eighteen percent of long-term care facilities had one, too.

These are worrying figures, when you consider that previous generations of doctors simply didn’t have to contend with CRE. Strains like KPC just didn’t exist. On the other hand, the percentages are still fairly low. I asked a doctor who works at a hospital in a small Connecticut city what she thought about the report. She said, “Well, you hear about outbreaks at other hospitals, and you just hope it doesn’t come here.”

Unfortunately, there’s not much stopping it from coming here, and everywhere. That doesn’t mean that there’s nothing to be done. We just need to get our collective act together. Here are a few things that many experts are agreeing would help:

–Get the data. Right now, there are few states that demand that hospitals report the presence of CREs. If there was a nation-wide database, it would become possible to organize large-scale campaigns against the bacteria. If more hospitals get the means to sequence genes of the bacteria, they might even be able to track individual outbreaks from hospital to hospital.

–Get serious. Israel faced a KPC outbreak in 2007 and went a long way to reducing infection rates. They did so with a national campaign. When they saw hospitals getting hit by the bacteria, they required some tough measures be put in place. I describe some of those measures in my Wired story. Isolate the infected patients. Test other patients regularly with accurate tests. Dedicate nurses and doctors to the infected patients and don’t let them get near other patients. Bomb hospital rooms with bacteria-scrubbing chemicals. Wash hands. Wash them again. Put people in the wards whose job it is to go up to the chief of surgery and say, “You didn’t take two squirts of hand gel. That’s the rule.” Some experts are even suggesting that hospital doctors always wear gowns and gloves. It’s a pain in the neck, to be sure, but dentists already do it, so why not doctors?

–Become good stewards of antibiotics. It’s not surprising that NDM-1 took off in India, because you can walk into a drug store there and buy antibiotics without a prescription. That’s a fabulous way to breed resistant bacteria. Likewise, many scientists are warning that feeding antibiotics to farm animals breeds resistance and then make its way back to the bacteria that make us sick. The antibiotics free-for-all has to end.

Here’s one thing that’s especially scary about CREs: one of the biggest risk factors for acquiring them is having taken antibiotics to treat another infection in the previous few months. As I wrote here in December, antibiotics are not picky about who they kill. They can destabilize your microbial ecosystem, allowing invasive species to push their way in. Doctors have to become more careful with using antibiotics, and scientists have to explore alternatives, such as repopulating ecosystems with transplanted bacteria.

–Get the antibiotics pipeline flowing again. What makes the current crisis with CRE so scary is that we have just about nothing left in our arsenal, and we won’t be getting new antibiotics that are effective against CRE any time soon. The market incentives for developing antibiotics are dismal: these are very expensive drugs to develop and test, but the potential profits to be made from them are not enticing. In fact, if someone came out with a powerful new antibiotic against CRE today, doctors would say, “Thank you so much,” and then put it on their shelf, to save in case other antibiotics failed. There are bills being considered by Congress now to rejigger the incentives to get the antibiotics pipeline flowing again.

–Look beyond CRE.  MRSA were once the organisms du jour. Now it’s CRE. Hospitals are being told to stay vigilant against each of these types of bugs in isolation. But that would be a bit like telling a country to prepare for a naval invasion, when the enemy has planes, missiles, and ground troops, too. There are several groups of dangerous bugs invading hospitals, and there will be new ones evolving in years to come. And, to completely shatter my military metaphor, the genes from one group may end up in another. Unfortunately, hospitals can’t test for a dozen species or genes at once. They simply lack the technological capacity. They need it.

Making matters worse, going after one group of bacteria at a time may potentially make things worse overall. For example, one way to fight MRSA is to use an antiseptic called chlorhexidine. This turns out to favor CRE. If you use alcohol hand rubs to fight MRSA and CRE, you may open the door to bacteria called Clostridium difficile.

Richard Wenzel and Michael Edmond of Virginia Commonwealth University have dubbed this one-at-a-time strategy a vertical interventional control program. They call instead for horizontal programs–in other words, recognize that we are fighting against lots of species at once and develop strategies for them all.

Up to ten percent of patients admitted to hospitals will acquire an infection. At least 90,000 people die in the United States alone of these hospital-acquired infections. It won’t be easy to fight these bacteria, but just sitting back is unacceptable. We know that more people will die.

The Virus That Learns

If you don’t have an immune system, you don’t last long in this parasite-riddled world. Your body receives a steady stream of invaders–viruses, bacteria, and other pathogens–which it has to recognize and fight. In many cases, it’s a brutal battle with an ultimate goal of eradication. In other cases, the immune system simply keeps strangers in check, preventing them from spreading. As many as a third of all humans have cysts in their brains containing a single-celled parasite called Toxoplasma. As long as the parasite stays in its cyst, the immune system lets it be. If Toxoplasma breaks out and starts to multiply, however, the immune system picks off the new cells. And if people lose their immune system–due to HIV infection, for example–Toxoplasma runs rampant and causes devastating brain damage.

The cells and molecules we use to recognize these invaders are unquestionably amazing. What’s perhaps most amazing is that the immune system can learn. When a new pathogen turns up, our immune cells undergo a kind of interior version of natural selection. Over the course of several cell divisions, new variants emerge that do a better and better job of recognizing the newcomer. Our bodies can then mount a powerful, focused attack on, say, a particular strain of the flu. And once the immune system learns how to recognize that new enemy, it can store that memory away, enabling it to attack the same pathogen years later.

This is the sort of thing that people often have in mind when they refer to us as a “higher” form of life, and bacteria and viruses as a “lower” form. Bacteria are just simple individual cells. They’re not multicellular organisms that can dedicate billions of cells to making antibodies, spewing poisons, and carrying out the many other tasks required for an immune system to work. Viruses–forget about it–they’re just protein shells that package a few genes, which they insert into a host cell.

But the higher/lower dichotomy is a blinkered way to look at life. If you can’t believe that bacteria can have an immune system, then you will miss the clues that they, in fact, have one. And the evidence is overwhelming.

Bacteria, after all, live in the same parasite-riddled world as we do. They may not get infected by the same pathogens that infect us, but they are continually hounded by viruses. A microbe that can defend itself against a virus will have a huge edge in the evolutionary race against its fellow microbes.

The threat of viruses has driven the evolution of some pretty impressive defenses. Bacteria make enzymes that lock onto certain, short sequences of DNA and slice them apart. When a virus injects its genes, these so-called restriction enzymes shred them into genetic confetti, so that they can’t take over the cell.

Our own immune system always runs the risk of turning against us and causing autoimmune disorders like arthritis and lupus. We have lots of safeguards in place to minimize that risk. Likewise, restriction enzymes are a dangerous defense, because they can chop up the distinctive stretches of DNA in a bacterium’s own genes. It avoids attacking itself by capping those sequences in its own DNA, so that the restriction enzymes can’t reach them.

The restriction enzyme defense is just one wing of the immune system in bacteria. Some species can muck up the production of new viruses, stealing their proteins before they can form shells. Others commit suicide upon infection, so as to avoid becoming an incubator for new viruses that would then kill their nearby relatives.

But the most impressive–dare I say it, most human–part of the bacterial immune system is its ability to learn. About forty percent of bacteria carry a set of genes known as CRISPR. When a virus invades these bacteria, they capture fragments of its DNA and insert them into their CRISPR genes. The bacteria then use those captured fragments as a guide for building weapons against the virus.

Here’s how this weaponizing works. In order to turn a virus’s genes into new virus proteins, a microbe must first make a copy of the gene in a molecule called RNA. CRISPR genes can produce RNA molecules with a matching sequence. They grab onto the virus’s RNA and prevent them from being turned into proteins. The virus factory grinds to a halt.

This defense helps bacteria withstand a virus infection, but it does more. The bacteria hold onto an invading virus’s DNA, so that they are now prepared for a fresh attack. And over time, bacteria can build up little libraries of these virus barcodes. A single bacterium may carry dozens of these viral barcodes. Last year, scientists at Indiana University surveyed the bacteria in people’s mouths and discovered 8,000 different viral barcodes–many of them corresponding to viruses scientists have yet to discover.

A single microbe can thus build up memories of its pathogens, in a manner reminiscent of the way we build up memories in our own immune system. But if you build up a healthy store of antibodies to various strains of flu, smallpox, and other diseases, all that knowledge dies with you. If you have children, they have to learn the same lessons all over again.

Not so for bacteria. When a microbe reproduces, it passes down its CRISPR genes and all of their viral barcodes to its descendants–including the ones it acquired in its own lifetime. Maybe Lamarck would have been better off as a microbiologist.

Now let’s swing around and consider the immune system from the pathogen’s point of view. If you can evolve a way to avoid the defenses of the immune system of your host, you will thrive where other pathogens are killed. This evolutionary pressure has led to all sorts of remarkable evasions carried out by the pathogens that make us sick. They camouflage themselves with human-like proteins; they attack key molecules, bringing our defenses to a standstill.

Viruses that infect bacteria have evolved their own set of tricks to evade the bacterial immune system. Last fall, for example, University of Cambridge scientists discovered viruses that carry an antidote for the suicide toxin made by their hosts. When the bacteria want to die, the virus forces them to live on. And just last month, University of Toronto scientists even discovered anti-CRISPR genes in viruses, which the viruses use to shut down the production of virus-killing molecules.

ICP1, a virus with an immune system. Source: Seed et al 2011
ICP1, a virus with an immune system. Source: Seed et al 2011

Now comes news of the most bizarre counterweapon I’ve ever heard of in a virus–and a serious challenge to fans of the higher-lower dichotomy. In Nature today, scientists at Tufts University describe their discovery of a virus with its own immune system.

The scientists, led by Andrew Camilli, stumbled across the virus while studying the bacteria that causes cholera, known as Vibrio cholerae. Scientists have long known that V. cholerae gets infected by viruses. In fact, there’s some evidence suggesting that these viruses can bring cholera outbreaks to a halt. As the V. cholerae hosts multiply, their viruses multiply even faster, until they send the bacteria’s population crashing down. Camilli and his colleagues set out to survey these viruses, to see how many species were making life hard for the bacteria.

They revisited a decade of cholera outbreaks by analyzing frozen stool that Bangladeshi doctors had stored from patients between 2001 and 2010. In those samples, they came across 15 different cholera-attacking viruses–12 of which were new to science. Fourteen of those 15 viruses came and went over the decade-long period, causing outbreaks among their bacteria hosts before disappearing.

But one virus–dubbed ICP1–was ominpresent.

Kimberly Seed, a postdoctoral fellow in Camilli’s lab, started sequencing the genes of ICP1 to look for the source its special strength. She found something none of them expected: a full-blown set of CRISPR genes.

Why would a virus carry a set of genes that bacteria use to destroy viruses? To use them against bacteria, it turns out. The ICP1 virus carries barcodes in its CRISPR genes that match pieces of its host’s own DNA. In particular, they match bits of DNA from a set of genes in V. cholerae that interfere with the production of new viruses. In a series of experiments, the scientists demonstrated that the ICP1 virus uses its CRISPR immune system to attack its host’s virus-attacking genes.

In one particularly cool experiment, the scientists engineered the V. cholerae hosts so that their DNA no longer match the virus’s attack molecules. The mutant bacteria managed to destroy most of the viruses. But over time, a few of the viruses somehow managed to acquire bits of DNA from the host and insert them into their CRISPR genes. The viruses regained the ability to shut down their host’s defenses and were able to invade successfully again.

In other words, the viruses had learned something about their enemy.

The ICP1 virus didn’t evolve its own CRISPR genes on its own, the scientists conclude. It stole them. Viruses sometimes pick up host genes and incorporate them into their own genome. The CRISPR genes in ICP1 most closely match those of the bacteria that cause bubonic plague. Long ago, it seems, the ancestors of ICP1 grabbed an immune system from that lineage of bacteria. Later, they turned this bacterial immune system against bacteria.

There are lots of very practical reasons to study immunity in the microbial world–reasons that sometimes only become clear in hindsight. As I wrote in my book Microcosm, the discovery of restriction enzymes in the 1960s made modern biotechnology possible. Scientists used the enzymes to cut and paste genes from one organism to another, creating microbial factories such as E. coli that makes human insulin. Last year, scientists reported that they had harnessed CRISPR genes to create a far more powerful way to edit DNA.

The discovery of a virus with an immune system could open up still other doors. It might be possible, for example, to use viruses to fight bacterial infections. In 2008, Camilli and his colleagues showed that viruses can prevent mice from getting sick with cholera, presumably by killing off the microbes. The mice were not harmed by the viruses, because they are adapted to infect bacteria, not animals.

With an adaptive immune system, these viruses might be able to learn new tricks to overcome any new defenses the bacteria evolve. And just because Camilli and his colleagues first discovered a virus with an immune system in V. cholerae doesn’t mean that there aren’t more of them out there. Indeed, some preliminary database searches hint that they are. Scientists might be able to harness CRISPR-equipped viruses to treat other diseases.

But these practical benefits will take time to emerge, if they ever do. Right now, we can enjoy the brain-stretching experience of looking out at the oceans, the forests, and even in our own mouths, and contemplate the existence of viruses that can learn something about their world.

Lower life indeed.

(For more about viruses, see my book A Planet of Viruses.)

Mutants: A Story About Tracking A Hospital Killer

Klebsiella pneumoniae Photo: Dan Forbes/Wired

About 100,000 people die each year in the United States from infections they pick up in hospitals. Even the best hospitals in the country are not exempt from this disaster, and it’s getting worse: the bacteria that are attacking patients are becoming frighteningly resistant to antibiotics. Some are becoming resistant to everything doctors can throw at them.

I recently went to Bethesda, Maryland, to visit doctors who struggled with one of these outbreaks at the NIH Clinical Center, one of the country’s premiere research hospitals. Most hospitals stay pretty quiet about their outbreaks, but the Clinical Center staff was far more transparent. They were willing to take me around the hospital as they described their struggles to stop the bacteria, called KPC, as it crept mysteriously from patient to patient and from ward to ward.

The story of the outbreak is pretty grim. Months after it seemed over, another patient died from a KPC infection, meaning that the bacteria still lurk in the hospital. But there’s one ray of hope. The doctors at the hospital joined forces with genome-sequencing experts, who probed the DNA of the bacteria for clues to its spread. This was one of the first times that genome sequencing helped–in real time–in the fight against a hospital outbreak. In the next issue of Wired, I chronicle this extraordinary piece of detective work. You can read my feature online here.

As I write in the story, genome sequencing could potentially help a lot in the broader war against hospital-acquired infections. But it won’t make much difference unless hospitals are united in using the best tools possible. When the Clinical Center doctors headed out to other hospitals to offer the lessons they had learned, they were startled to find that KPC was a fixture in many of the other hospitals. The very fact that this information came as a surprise to them shows just how little communication there is between hospitals about their outbreaks.

Julie Segre, one of the genome experts who battled the KPC outbreak at the Clinical Center, is convinced that patients and their families can help push hospitals to start using genome sequencing and other new tools to battle outbreaks.

“When a patient thinks about where to go for a stem cell transplant or a chemotherapy treatment, they think about who has a better medical team,” she told me. “But if you’re really making that decision, one of the things you need to think about is, who has the best infection control? Who’s in the middle of an outbreak? That’s what I’d want to know.”

To see what twenty-first century infection control looks like, check out my story.

A Very Special Tree of Life

Yesterday I went to Rutgers University to give a talk about medical ecology. Afterwards, I got a delightful surprise: Amy Chen Vollmer, the president of the Waksman Foundation for Microbiology, got on stage to announce I had won the Byron H. Waksman Award for Excellence in Public Communication of Life Sciences.

Byron Waksman, who passed away this June, was an immunologist who made important discoveries about auto-immune diseases and the signals white blood cells send to each other. Spreading the word about science was another of his passions; after he retired from his scientific work, he became a middle-school science teacher. Waksman was also the director of a foundation set up by his father, Selman Waksman, who won the Nobel prize for discovering many of the antibiotics we depend on today.  Byron Waksman used the foundation’s resources to advance the understanding of science. One of the programs he initiated brings journalists to the Marine Biology Lab in Woods Hole to learn how science is done. All the journalists I’ve spoken to who have gone through it have sung its praises. It shows them the real science that lies beyond the press release and the phone call.

I’m hugely honored to get an award in Byron Waksman’s name. And it’s a particular pleasure to get an award decorated not with some non-descript humanoid, but with the Tree of Life. It’s a privilege to get to jump among its branches for a living.