A Planet of Viruses

by Carl Zimmer

  Before he could test this hypothesis, Herelle first needed to be sure phages were safe. So he swallowed some to see if they made him sick. He found that he could ingest phages, as he later wrote, “without detecting the slightest malaise.” Herelle injected phages into his skin, again with no ill effects. Confident that phages were safe, Herelle began to give them to sick patients. He reported that they helped people recover from dysentery and cholera. When four passengers on a French ship in the Suez Canal came down with bubonic plague, Herelle gave them phages. All four victims recovered.

  Herelle’s cures made him even more famous than before. The American writer Sinclair Lewis made Herelle’s radical research the basis of his 1925 best-selling novel Arrowsmith, which Hollywood turned into a movie in 1931. Meanwhile, Herelle developed phage-based drugs sold by the company that’s now known as L’Oreal. People used his phages to treat skin wounds and to cure intestinal infections.

  But by 1940, the phage craze had come to end. The idea of using live viruses as medicine had made many doctors uneasy. When antibiotics were discovered in the 1930s, those doctors responded far more enthusiastically, because antibiotics were not alive; they were just artificial chemicals and proteins produced by fungi and bacteria. Antibiotics were also staggeringly effective, often clearing infections in a few days. Pharmaceutical companies abandoned Herelle’s phages and began to churn out antibiotics. With the success of antibiotics, investigating phage therapy seemed hardly worth the effort.

  Yet Herelle’s dream did not vanish entirely when he died in 1949. On a trip to the Soviet Union in the 1920s, he had met scientists who wanted to set up an entire institute for research on phage therapy. In 1923 he helped Soviet researchers establish the Eliava Institute of Bacteriophage, Microbiology, and Virology in Tbilisi, which is now the capital of the Republic of Georgia. At its peak, the institute employed 1,200 people to produce tons of phages a year. During World War II, the Soviet Union shipped phage powders and pills to the front lines, where they were dispensed to infected soldiers.

  In 1963, the Eliava Institute ran the largest trial ever conducted to see how well phages actually worked in humans, enrolling 30,769 children in Tbilisi. Once a week, about half the children swallowed a pill that contained phages against Shigella. The other half of the children got a pill made of sugar. To minimize environmental influences as much as possible, the Eliava scientists gave the phage pills only to children who lived on one side of each street, and the sugar pills to the children who lived on the other side. The scientists followed the children for 109 days. Among the children who took the sugar pill, 6.7 out of every 1,000 got dysentery. Among the children who took the phage pill, that figure dropped to 1.8 per 1,000. In other words, taking phages caused a 3.8-fold decrease in a child’s chance of getting sick.

  Few people outside of Georgia heard about these striking results, thanks to the secrecy of the Soviet government. Only after the Soviet Union fell in 1989 did news start to trickle out. The reports have inspired a small but dedicated group of Western scientists to investigate phage therapy and to challenge the long-entrenched reluctance in the West to use them.

  These phage champions argue that we should not be worried about using live viruses as medical treatments. After all, phages swarm inside many of the foods we eat, such as yogurt, pickles, and salami. Our bodies are packed with phages too, which is not surprising when you consider that we each carry about a hundred trillion bacteria—all promising hosts for various species of phages. Every day, those phages kill vast numbers of bacteria inside our bodies without ever harming our health.

  Another concern that’s been raised about phages is that their attack is too narrowly focused. Each species of phage can only attack one species of bacteria, while one antibiotic can kill off many different species at once. But it’s clear now that phage therapy can treat a wide range of infections. Doctors just have to combine many phage species into a single cocktail. Scientists at the Eliava Institute have developed a dressing for wounds that is impregnated with half a dozen different phages, capable of killing the six most common kinds of bacteria that infect skin wounds.

  Skeptics have also argued that even if scientists could design an effective phage therapy, evolution would soon render it useless. In the 1940s, the microbiologists Salvador Luria and Max Delbruck observed phage resistance evolving before their own eyes. When they laced a dish of E. coli with phages, most of the bacteria died, but a few clung to existence and then later multiplied into new colonies. Further research revealed that those survivors had acquired mutations that allowed them to resist the phages. The resistant bacteria then passed on their mutated genes to their descendants. Critics have argued that phage therapy would also foster the evolution of phage-resistant bacteria, allowing infections to rebound.

  The advocates for phage therapy respond by pointing out that phages can evolve, too. As they replicate, they sometimes pick up mutations, and some of those mutations can give them new avenues for infecting resistant bacteria. Scientists can even help phages improve their attacks. They can search through collections of thousands of different phages to find the best weapon for any particular infection, for example. They can even tinker with phage DNA to create phages that can kill in new ways.

  In 2008, James Collins, a biologist at Boston University, and Tim Lu of MIT published details of the first phage engineered to kill. Their new phage is especially effective because it’s tailored to attack the rubbery sheets that bacteria embed themselves in, known as biofilms. Biofilm can foil antibiotics and phages alike, because they can’t penetrate the tough goo and reach the bacteria inside. Collins and Lu searched through the scientific literature for a gene that might make phages better able to destroy biofilms. Bacteria themselves carry enzymes that they use to loosen up biofilms when it’s time for them to break free and float away to colonize new habitats. So Collins and Lu synthesized a gene for one of these biofilm-dissolving enzymes and inserted it into a phage. They then tweaked the phage’s DNA so that it would produce lots of the enzyme as soon as it entered a host microbe. When they unleashed it on biofilms of E. coli, the phages penetrated the microbes on the top of the biofilms and forced them to make both new phages and new enzymes. The infected microbes burst open, releasing enzymes that sliced open deeper layers of the biofilms, which the phages could infect. The engineered phages can wipe 99.997 percent of the E. coli in a biofilm, a kill rate that’s about a hundred times better than ordinary phages.

  While Collins and other scientists discover how to make phages even more effective, antibiotics are now losing their luster. Doctors are grappling with a growing number of bacteria that have evolved resistance to most of the antibiotics available today. Sometimes doctors have to rely on expensive, last-resort drugs that come with harsh side effects. And there’s every reason to expect that bacteria will evolve to resist last-resort antibiotics as well. Scientists are scrambling to develop new antibiotics, but it can take over a decade to get a new drug from the lab to the marketplace. It may be hard to imagine a world before antibiotics, but now we must imagine a world where antibiotics are not the only weapon we use against bacteria. And now, ninety years after Herelle first encountered bacteriophages, these viruses may finally be ready to become a part of modern medicine.

  The Infected Ocean

  Marine Phages

  Some great discoveries seem at first like terrible mistakes.

  In 1986 a graduate student at the State University of New York at Stony Brook named Lita Proctor decided to see how many viruses there are in seawater. At the time, the general consensus was that there were hardly any. The few researchers who had bothered to look for viruses in the ocean had generally found only a scarce supply. Most experts believed that the majority of the viruses they did find in sea water had actually come from sewage and other sources on land.

  But over the years, a handful of scientists had gathered evidence that didn’t fit neatly into the consensus. A marine biologist named John Sieburth had publi
shed a photograph of a marine bacterium erupting with new viruses, for example. Proctor decided it was time to launch a systematic search. She traveled to the Caribbean and to the Sargasso Sea, scooping up seawater along the way. Back on Long Island, she carefully extracted the biological material from the seawater, which she coated with metal so that it would show up under the beam of an electron microscope. When Procter finally looked at her samples, she beheld a world of viruses. Some floated freely, while others were lurking inside infected bacterial hosts. Based on the number of viruses she found in her samples, Proctor estimated that every liter of seawater contained up to one hundred billion viruses.

  Proctor’s figure was far beyond anything that had come before. It would have surprised few scientists if she had turned out to have added on a few extra zeroes by accident. But when other scientists carried out their own surveys, they ended up with similar estimates. Scientists came to agree that there are somewhere in the neighborhood of 1,000,000,000,000,000,000,000,000,000,000 viruses in the ocean.

  It is hard to find a point of comparison to make sense of such a huge number. Viruses outnumber all other residents of the ocean by about fifteen to one. If you put all the viruses of the oceans on a scale, they would equal the weight of seventy-five million blue whales. And if you lined up all the viruses in the ocean end to end, they would stretch out past the nearest sixty galaxies.

  These numbers don’t mean that a swim in the ocean is a death sentence. Only a minute fraction of the viruses in the ocean can infect humans. Some marine viruses infect fishes and other marine animals, but by far their most common targets are microbes. Microbes may be invisible to the naked eye, but collectively they dwarf all the ocean’s whales, its coral reefs, and all other forms of marine life. And just as the bacteria that live in our bodies are attacked by phages, marine microbes are attacked by marine phages.

  When Felix d’Herelle discovered the first bacteriophage in French soldiers in 1917, many scientists refused to believe that such a thing actually existed. A century later, it’s clear that Herelle had found the most abundant life form on Earth. Ever since Proctor’s discovery of the abundance of marine viruses, scientists have been documenting their massive influence on the planet. Marine phages influence the ecology of the world’s oceans. They leave their mark on Earth’s global climate. And they have been playing a crucial part in the evolution of life for billions of years. They are, in other words, biology’s living matrix.

  Marine viruses are powerful because they are so infectious. They invade a new microbe host ten trillion times a second, and every day they kill about half of all bacteria in the world’s oceans. Their lethal efficiency keeps their hosts in check, and we humans often benefit from their deadliness. Cholera, for example, is caused by blooms of waterborne bacteria called Vibrio. But Vibrio are host to a number of phages. When the population of Vibrio explodes and causes a cholera epidemic, the phages multiply. The virus population rises so quickly that it kills Vibrio faster than the microbes can reproduce. The bacterial boom subsides, and the cholera epidemic fades away.

  Stopping cholera outbreaks is actually one of the smaller effects of marine viruses. They kill so many microbes that they can also influence the atmosphere across the planet. That’s because microbes themselves are the planet’s great geoengineers. Algae and photosynthetic bacteria churn out about half of the oxygen we breathe. Algae also release a gas called dimethyl sulfide that rises into the air and seeds clouds. The clouds reflect incoming sunlight back out into space, cooling the planet. Microbes also absorb and release vast amounts of carbon dioxide, which traps heat in the atmosphere. Some microbes release carbon dioxide into the atmosphere as waste, warming the planet. Algae and photosynthetic bacteria, on the other hand, suck carbon dioxide in as they grow, making the atmosphere cooler. When microbes in the ocean die, some of their carbon rains down to the sea floor. Over millions of years, this microbial snow can steadily make the planet cooler and cooler. What’s more, these dead organisms can turn to rock. The White Cliffs of Dover, for example, are made up of the chalky shells of single-cell organisms called coccolithophores.

  Viruses kill these geoengineers by the trillions every day. As their microbial victims die, they spill open and release a billion tons of carbon a day. Some of the liberated carbon acts as a fertilizer, stimulating the growth of other microbes, but some of it probably sinks to the bottom of the ocean. The molecules inside a cell are sticky, and so once a virus rips open a host, the sticky molecules that fall out may snag other carbon molecules and drag them down in a vast storm of underwater snow.

  Ocean viruses are stunning not just for their sheer numbers but also for their genetic diversity. The genes in a human and the genes in a shark are quite similar—so similar that scientists can find a related counterpart in the shark genome to most genes in the human genome. The genetic makeup of marine viruses, on the other hand, matches almost nothing. In a survey of viruses in the Arctic Ocean, the Gulf of Mexico, Bermuda, and the northern Pacific, scientists identified 1.8 million viral genes. Only 10 percent of them showed any match to any gene from any microbe, animal, plant, or other organism—even from any other known virus. The other 90 percent were entirely new to science. In 200 liters of seawater, scientists typically find 5,000 genetically distinct kinds of viruses. In a kilogram of marine sediment, there may be a million kinds.

  One reason for all this diversity is that marine viruses have so many hosts to infect. Each lineage of viruses has to evolve new adaptations to get past its host’s defenses. But diversity can also evolve by more peaceful means. Temperate phages merge seamlessly into their host’s DNA; when the host reproduces, it copies the virus’s DNA along with its own. As long as a temperate phage’s DNA remains intact, it can still break free from its host during times of stress. But over enough generations, a temperate phage will pick up mutations that hobble it, so that it can no longer escape. It becomes a permanent part of its host’s genome.

  As a host cell manufactures new viruses, it sometimes accidentally adds some of its own genes to them. The new viruses carry the genes of their hosts as they swim through the ocean, and they insert them, along with their own, into the genomes of their new hosts. By one estimate, viruses transfer a trillion trillion genes between host genomes in the ocean every year.

  Sometimes these borrowed genes make the new host more successful at growing and reproducing. The success of the host means success for the virus, too. While some species of viruses kill Vibrio, others deliver genes for toxins that the bacteria use to trigger diarrhea during cholera infections. The new infection of toxin-carrying viruses may be responsible for new cholera outbreaks.

  Thanks to gene borrowing, viruses may also be directly responsible for a lot of the world’s oxygen. An abundant species of ocean bacteria, called Synechococcus, carries out about a quarter of the world’s photosynthesis. When scientists examine the DNA of Synechococcus samples, they often find proteins from viruses carrying out their light harvesting. Scientists have even found free-floating viruses with photosynthesis genes, searching for a new host to infect. By one rough calculation, 10 percent of all the photosynthesis on Earth is carried out with virus genes. Breathe ten times, and one of those breaths comes to you courtesy of a virus.

  This shuttling of genes has had a huge impact on the history of all life on Earth. It was in the oceans that life got its start, after all. The oldest traces of life are fossils of marine microbes dating back almost 3.5 billion years. It was in the oceans that multicellular organisms evolved; their oldest fossils date back to about 2 billion years ago. In fact, our own ancestors did not crawl onto land until about 400 million years ago. Viruses don’t leave behind fossils in rocks, but they do leave marks on the genomes of their hosts. Those marks suggest that viruses have been around for billions of years.

  Scientists can determine the history of genes by comparing the genomes of species that split from a common ancestor that lived long ago. Those comparisons can, for example, reveal gen
es that were delivered to their current host by a virus that lived in the distant past. Scientists have found that all living things have mosaics of genomes, with hundreds or thousands of genes imported by viruses. As far down as scientists can reach on the tree of life, viruses have been shuttling genes. Darwin may have envisioned the history of life as a tree. But the history of genes, at least among the ocean’s microbes and their viruses, is more like a bustling trade network, its webs reaching back billions of years.

  Our Inner Parasites

  Endogenous Retroviruses

  The idea that a host’s genes could have come from viruses is almost philosophical in its weirdness. We like to think of genomes as our ultimate identity. We know who our biological parents are because they gave us our DNA. In our DNA are not just the instructions for the color of our skin or our susceptibility to diabetes. Our very nature lurks there. That’s why the idea of cloning is so abhorrent: no one should have to carry secondhand genes.

  But if most of an organism’s genes arrived in its genome in a virus, does it even have a distinct identity of its own? Or is it just a mishmash of genes, cobbled together by evolution? It’s as if the world was filled with hybrid monsters, with clear lines of identity blurred away.

  Microbiologists have been getting used to the viral roots of the microbes they study for decades now. And as long as microbes were the only organisms with much evidence of virus-imported genes, we could try to ignore this philosophical weirdness by thinking of it merely as a fluke of “lower” life forms. But now we can no longer find comfort this way. If we look inside our own genome, we now see viruses. Thousands of them.