IRA FLATOW: They’ve learned to live pretty much anywhere in the world and to use nearly any living thing for a host. And here is the astounding statistic: Viruses kill half the bacteria in the ocean every day. Every day, viruses kill half the bacteria in the ocean. And they invade a microbe host 10 trillion times a second around the world. But are the viruses alive themselves? How do you – how did they get there? How did they get here? And now that so many bacteria are developing resistances to antibiotics, is it time to unleash viruses on them? Are these just astounding to me or did you – when you did your research for this book – these are just amazing.
Mr. ZIMMER: Yeah. Yeah. I just had to keep going over and over it again, because I would look up, for example, how many viruses there on earth. And the number I get is, I keep finding, is 10 to the 31st power. That’s one with 31 zeroes after it, which is 10 billion trillion, trillion. That’s more stars than are in the universe. If you had a lot of spare time and you want to stack all those viruses end to end, they would go about 100 million light years.
FLATOW: Tell me about the oceans. They eat half the bacteria in the oceans every day?
Mr. ZIMMER: Yeah. It’s funny. There used to be a time when people thought the oceans are pretty much virus-free. But now we realize that there might be, say, maybe a billion viruses in every teaspoon of water. And they’re attacking the bacteria. There’s lots of bacteria in the ocean. And so they will just do a slaughter of these bacteria every day. Of course, the bacteria grow back pretty fast, but still it’s a tremendous thing because all those bacteria contain carbon and lots of nutrients. And so they’re constantly cycling all this to the ocean and into the atmosphere.
FLATOW: You know, when you said that there are 10 to the 31 viruses…
Mr. ZIMMER: Mm-hmm.
FLATOW: …then it seems almost incredible that our body is fighting off so many viruses every day. It must be being attacked all the time by viruses. And we’re fighting them off if they’re everywhere, right?
Mr. ZIMMER: Well, they’re also inside of us.
Mr. ZIMMER: So you look pretty healthy today. There are probably about -from the latest estimates I saw – about four trillion viruses inside of you right now. And they’re not making you sick, because they’re infecting all the bacteria that live inside of you.
FLATOW: So they’re holding off the bacteria from attacking me, also, possibly.
Mr. ZIMMER: Right. Or they might actually be helping the bacteria. They might be balancing the ecosystem in there so that some species do well and others don’t.
FLATOW: Now these bacteria that are all over the ocean and killing half – the viruses that are killing half the bacteria, how does that affect the ecosystem if you’ve got all these dead bacteria raining down in the ocean all the time?
Mr. ZIMMER: That’s right. So you got a lot more carbon that’s freed up and moving around. And there’s actually a big question about where exactly that carbon goes. Do the bacteria there just suck it back up again, or does it rain back down? What would the world be like without all these viruses? One pretty dramatic idea is that, actually, you know, all that carbon that’s coming out and then getting sucked back up could be affecting the Earth’s climate because any of that carbon that gets back up in the atmosphere is going to be trapping heat. So, you know, the temperature we’re at is partly set by viruses.
FLATOW: Mm-hmm. Let’s talk about one of my favorite topics I’ve been talking about over the years. And you have a chapter in your book about bacteriophages, viruses that eat, attack bacteria. And this was first discovered when?
Mr. ZIMMER: This was first discovered in World War I. So people knew a bit about viruses before then for about 30 years, but they had found them in people, in animals and in plants. But then a doctor, a Canadian doctor named Felix d’Herelle discovered that there were viruses that could wipe out bacteria. He would treat a dish of bacteria with fluid that he had filtered out from – actually from patients who are sick with dysentery. And he found that he could just kill these bacteria. And, eventually, what he concluded was that these were viruses that were attacking them. And it was a pretty radical idea at the time. People didn’t believe him. Nobel Prize winners were going after him. But he held to it. He actually became the hero – fictionalized hero in a novel called “Arrowsmith,” made a movie out of it. And he actually did quite well. He actually started a whole business of using these viruses to treat bacterial infections. In France, you could go out and buy these things.
FLATOW: And so there were viruses that could – that are – that exist in nature that could kill the worst bacterial infections, the bacteria that cause these infections we know. MRSA, all these things, there are natural occurring viruses that could kill them.
Mr. ZIMMER: Yeah. Every species of bacteria has a bunch of different species of phages that can kill it. That’s just evolution. It’s been going on for billions of years. And you can just go out, I mean, every time scientists go out, they’ll find a new phage for attacking a particular species of bacteria.
FLATOW: So why aren’t they sitting in our medicine cabinet? Or are the doctors giving us injections of these things?
Mr. ZIMMER: It’s a strange, wonderful, historical fluke. Basically, what happened was in the 1930s, scientists started to discover antibiotics. And here were chemicals, they were reliable, they knew how to make them, and everyone said, oh, these are the silver bullet. And so phage therapy disappeared, except for the Soviet Union. Everywhere else, everyone switched over to antibiotics. And that was -we’ve had a pretty good run with antibiotics, but now it’s not looking so good, because we’re getting bacteria that are resistant to them, as you said.
FLATOW: And so why don’t we have FDA approval of some of these things?
Mr. ZIMMER: You know, the FDA has a lot of – the FDA’s kind of sluggish.
FLATOW: That’s diplomatic.
Mr. ZIMMER: And if you go to them and say, hi, I’ve got a virus, and I want to go infect patients with it because it’ll kill bacteria, it’s kind of hard to get them to sign off on. In fact, they’re not even sure how to approve it, ironically. And so, there’s a lot of research going on right now, here in the United States, to develop them. They’re just starting to crack that barrier. So now there are actually food sprays where you – companies can spray phages on their food to stop food poisoning.
FLATOW: So, there might be some hope, because I’ve been talking about this for decades with other scientists that say this is just silly, basically.
Mr. ZIMMER: Yeah. It gets sillier all the time, because we’re getting better at selecting the right phage for the job, you know? You can create, what they call, libraries of these viruses, and you could imagine them being in a hospital. So you come in with an infection, and they take a sample, and then they go check out their library of phages and see which one will do the best job. And then they send them after your bacteria.
FLATOW: And the almost magical thing to me is even as the bacteria mutates to become resistant to that virus, you’ll get another virus that mutated with it, or knows how to attack that bacteria.
Mr. ZIMMER: That’s right. Antibiotics can’t evolve. Viruses can. And not only that, but we know how to engineer them now, so you can actually insert genes to make them more effective.
FLATOW: I’m just – you know, some things are just so illogical.
Mr. ZIMMER: Yeah. Maybe in 10 years.
FLATOW: The kinds of – 10 years from now. At least it’s not 30.
FLATOW: Let’s go to John in Bethesda. Hi, John.
JOHN (Caller): Hello. Good afternoon.
FLATOW: Hi, there.
JOHN: So my question is – I use United Streaming in my classes, and they have a video on viruses. And in this particular – or this video, it says that viruses are the oldest form of – and I think they use life loosely. But if viruses require a living host, how could they be the oldest living thing on Earth?
Mr. ZIMMER: Well, you know, it could be what they’re saying there is that their hosts are long since gone and they’re still around. There are actually some viruses that are weirdly primitive. So, for example, plants can get infected with things that are called viroids. They don’t even have a protein shell. They’re just naked genes that can infect plants, and they’re tiny, tiny little things.
JOHN: Are these like prions in humans?
Mr. ZIMMER: Well, no, because they’re actually made out of a single strand of DNA – RNA. So prions are proteins. These are viruses. They’re made of RNA.
Mr. ZIMMER: But these or something like them could be just relics of the earliest stages of life, back when maybe there weren’t even any cells. You have to just think of kind of a soup of genes, and maybe some genes were good at parasitizing others and getting them to make copies of themselves.
JOHN: And then would there be a possibility if these bacteria phages mutating to become pathogenic to humans if you use them on the bacteria?
Mr. ZIMMER: No, because, you know, bacterial biology and human biology are profoundly different. And, so, you know, it, you know, these phages are specific just for one species of bacteria. But, you know, we share a common a ancestry with bacteria that lived, I don’t know, maybe three-and-a-half, four billion years ago. So you – and, you know, you have phages with you right now in your body when you’re perfectly healthy. Every time you have yogurt or eat pickles, you’re eating phages. So you don’t have anything to worry about with them.
FLATOW: Going to have some (unintelligible) yogurt and pickles today. We’re talking with Carl Zimmer, author of “A Planet of Viruses,” a really interesting book. And it’s a quick read. It’s chockfull of all kinds of interesting facts. For example, there’s a chapter in your book that deals with retrovirus DNA in our own genome. How do we get viruses in our genome?
Mr. ZIMMER: Well, they’re everywhere. Well, retroviruses – we’re most familiar with HIV. That’s a retrovirus. And what – the way the retroviruses reproduce is they actually take their genetic material and insert it into our own chromosomes. And then our chromosomes then make new viruses. Every now and then, on very rare occasions, a retrovirus will end up in, say, a sperm cell or an egg and insert its genes there. And then suddenly, if that sperm or egg become – gives rise to a new organism, a new animal, a new person, every cell in that body has got that virus. And it turns out that over tens, hundreds and millions years, our ancestors have been picking up viruses like this, and they’ve been clogging our genomes. So now they are probably about 100,000 elements in the human genome that you can trace to a virus ancestor. It makes up about 8 percent, all told, of our genome. Just bear in mind that all of the genes that encode proteins only make up 1.2 percent of our genome. So we’re much more virus than human, really.
FLATOW: Nathan in Denver. Hi, Nathan.
NATHAN (Caller): Hello. Thanks for taking my call.
FLATOW: Hi, there.
NATHAN: Hey. I have a biochemist friend that recently told me that he’s under the impression that climate change could potentially have a big effect on releasing viruses – maybe in frozen soils, I don’t know all the details – that we’ve never been exposed to or never encountered. Can you talk a little bit about how climate change is going to affect the world of viruses?
Mr. ZIMMER: Well, I doubt that it’s going to be unleashing viruses from the soil to make us sick. I mean, viruses are pretty delicate things. However, it could mean that insects that carry viruses could move into new territories and start making people sick with things like dengue fever, for example. And so those kind of shifts are things that we need to worry about. I mean, we also need to be concerned just about viruses hopping from one species to another. So SARS, you may recall, came from bats, actually. And through animal markets in China and things like that, they were able to get into our species. And fortunately, in the case of SARS, we seemed to have beaten that thing down. But in the case of HIV, that was a chimpanzee virus that got into humans several times, and with horrible consequences.
FLATOW: Hmm. So we should be saying that just like we – there’s a phrase, oh, there’s an app for that, if you have a bacteria, oh, there’s a virus for that.
Mr. ZIMMER: There’s a virus for everything.
FLATOW: To conquer MRSA, you could – there’s a virus that could conquer MRSA or these other…
Mr. ZIMMER: Potentially. Potentially, yeah.
FLATOW: And we could genetically engineer one.
Mr. ZIMMER: That’s right. I mean…
FLATOW: If we had to.
Mr. ZIMMER: Yeah. You can add in new genes. So, for example, there are viruses that have been engineered with extra enzymes to actually break up biofilms. So bacteria protect themselves by forming these gooey carpets. And so scientists at MIT have engineered viruses that can just blast that biofilm away.
FLATOW: In the minute or two we have left, let’s talk about papillomavirus. You have a story in your book on how scientists were studying rabbits with horn-like warts on their heads, a sort of jackalope kind.
Mr. ZIMMER: Yeah…
FLATOW: I think we have on our website, a picture of that. It’s just amazing.
Mr. ZIMMER: Yeah. Well, if you ever go out West, you see pictures, postcards of jackalopes, which are just rabbits with little prong or antlers stuck on them. But, in fact, rabbits do sometimes form these horn-like things on their heads, and it’s caused by papillomaviruses which get into their skin and actually sort of speed up the growth of the skin cells. And it was through – partly through the discovery of these, quote, unquote, “jackalopes” that scientists discovered that viruses can be an important cause of cancer. Fifteen percent of all human cancers are caused by viruses, and the papillomavirus causes cervical cancer.
FLATOW: Is there anything about viruses you don’t know… that you want to more of, or you think we should know more about? Are there questions that still remain about viruses?
Mr. ZIMMER: Yes. Because I’m sure that the more that scientists explore extreme places, the weirder the viruses are that they’re going to discover. I mean, they’ve even discovered now viruses that infect other viruses. So there’s no telling what they’re going to be finding out next.
FLATOW: And they could – and they would be living in even the hostile areas, deep in those thermal vents, things all over the oceans.
Mr. ZIMMER: Yeah. Oh, well, like, I write on the book about a cave, about a mile underground with these gigantic, 60-foot long gypsum crystals. It’s a bizarre place. And there’s a little bit of water in there, and – which has some bacteria in it, and those have viruses in them. So anywhere that there is life, you’re going to find viruses -maybe even on other planets.
The New York Times calls Carl Zimmer “as fine a science essayist as we have.” In his widely admired books, essays, and blogs, Zimmer charts the frontiers of biology. Booklist acclaimed his most recent title A Planet of Viruses as “absolutely top-drawer popular science writing.” Zimmer is a lecturer at Yale University, where he teaches writing about science and the environment. He is also the first Visiting Scholar at the Science, Health, and Environment Reporting Program at New York University’s Arthur L. Carter Journalism Institute. W. Ian Lipkin, MD, is the director of the Center for Infection and Immunity, John Snow Professor of Epidemiology, and professor of neurology and pathology in the Mailman School of Public Health and the College of Physicians and Surgeons at Columbia University. His specialty is detecting new viruses and testing links between viruses and diseases. In A Planet of Viruses, Zimmer describes Lipkin’s discovery of West Nile Virus in the United States, as well as his work uncovering hidden strains of the common cold. Zimmer also profiled Lipkin in November 2010 for the New York Times.
I just finished A Planet of Viruses. It’s a compelling read that explores new frontiers in microbe hunting and the complex path from disease association to disease causation, a path we have not fully traveled. As with any book there are holes to be filled; nonetheless, this is an excellent roadmap!
We typically think of viruses as pathogens, but there is abundant and increasing evidence that they had an important and positive role in our evolution as mammals and the planet we live in. Retroviruses, a special kind of RNA virus of which HIV is the most famous, intercalate their genetic code into their host’s. When host cells replicate their DNA, the virus replicates with it. If the virus makes its way to a sperm or egg cell, the virus wins the (rare) opportunity to get passed on from parent to child, over and over again. These genetic infiltrators, known as endogenous retroviruses, have integrated themselves into mammalian genomes over millions of years. They activate genes during pregnancy to produce proteins that prevent rejection of a fetus as a foreign body, likely facilitating the evolution of the placenta and live birth. Marine viruses, known as bacteriophages, which are the most abundant viruses on earth, shape our ecosystem by infecting and lysing bacteria in deep-sea sediment, thus affecting how nutrients are recycled.
Initiatives like the Human Microbiome Project, which surveys the human body’s resident microorganisms and how they interact with our genes to influence health and disease, have mostly focused on bacteria. However, scientists cannot continue to ignore viruses, fungi, and other bugs! Traditionally, we have focused on bacteria because they are easy to clone, allowing us to replicate parts of their genome that may shed light on our own evolution. With the advent of newer and “sexier” technologies like virus detection microchips and high throughput sequencing, we can turn our attention to studying our interactions with viruses in more detail. As we learn more about the viruses in our gastrointestinal and respiratory tracts, I will be very much surprised if there are no helpful inhabitants among them.
Carl, you also discuss zoonotic diseases like AIDS, influenza, SARS, and Ebola, but let’s not forget that how investigators decide where and when to sample for potential pathogens is also important. Hotspot modeling allows us to target surveillance efforts to ‘hot spots’ for human disease—the areas where human pathogens are most likely to emerge. The EcoHealth Alliance is a pioneer in this field and an advocate for the idea of One Health, which promotes collaboration among environmental scientists, vets, and clinicians.
And what about those curious about how microbe hunters do what we do? What are the platforms we use to find known and novel agents? How do we prove relationship to disease (or equally important, disprove a causative relationship)? Carl, let’s give them directions! The work we do the Center for Infection and Immunity helps to answer some of those queries. We provide links to papers and interviews that address these challenges as well as video demonstrations of some relevant technologies
Last (but not least), as this is not a peer reviewed publication, and I have been encouraged to let my imagination run free, I wonder whether you might consider a chapter in a potential sequel focused on how microbes may alter host behavior to enhance their growth and dissemination. For example, rabies is associated with the inability to swallow, leading to the accumulation of saliva that contains rabies virus, and with aggressive (rabid) behavior that facilitates its spread. It is possible, though I have no experimental proof, that when herpes simplex virus infects the sacral ganglia, it may (in)advertently stimulate nerve endings in the pelvic area , promoting sexual activity and increasing the likelihood it will move into another host.
Carl, thanks again for sending me a preview copy of your book. I look forward to many spirited discussions!
W. Ian Lipkin
Thanks for your reflections. There’s a lot to ponder in them, but I’m most intrigued by your most speculative ideas—namely, whether viruses manipulate their hosts for their own benefit. As we discover more and more viruses, I suspect that scientists will indeed find good evidence that at least some viruses act like puppet masters.
I first became familiar with this sort of strategy while writing my previous book, Parasite Rex. Some of the most spectacular examples of parasite manipulation come from animal parasites. The lancet fluke—a parasitic flatworm—has a life cycle that takes it from snails to ants to grazing mammals like cows or sheep. Getting from one species to another is no simple feat. The lancet fluke has ways of manipulating one host after another to make its way through life. Mammals release the fluke eggs in their droppings, which are then eaten by snails. The snails defend themselves by coating the eggs in slime and then “coughing” them up. Ants passing by find the slime delicious, and devour it, along with the eggs inside.
Once inside the ant, the fluke eggs hatch, and the parasites develop. When they’re ready for their next host, they begin to alter the ant’s behavior. At twilight, the ant crawls up a blade of grass and clamps onto the tip. That’s when grazing mammals are likely to pass by and devour the grass, and the ant, and the parasites inside. If the ant does not get eaten by dawn, the parasite causes it to release its grip and crawl down to the ground, where it can enjoy the shade until the end of the next day—when it feels the urge to climb again.
There are many such examples, and for some reason most of them come from parasitic animals—tapeworms, parasitoid wasps, thorny-headed worms, and the like. I don’t think that this bias reflects the superior sophistication of parasitic animals over non-animal parasites like viruses. I think it’s just another case of the drunk looking for his keys under a lamp post—not because the keys are there, but because that’s where it’s easier to look.
Consider, for example, the fungus Cordyceps. This little mushroom has no animal nervous system. It’s just a mass of fungal cells. Yet Cordyceps manages to manipulate ants as well as lancet flukes. Ants pick up its spores on the ground, whereupon the fungus penetrates its host exoskeleton and starts to grow inside. It doesn’t kill its host, however. Instead, it feeds on the ant’s internal fluids until it’s ready for its next stage of life. The ant then starts to climb—not to the tip of a blade of grass, but to the underside of a leaf a few feet off the ground. The ant clamps onto a vein in the leaf, whereupon the fungus sprouts a flower-like stalk out of its head, which showers spores on the ants below.
While Cordyceps may not have the complexity of the animal nervous system, however, it’s not simple. Fungi have big genomes. Yeast, for example, has about 6,500 genes. There’s a lot of storage capacity in such a genome to encode lots of sophisticated strategies. A parasitic fungus might be able to use some of its many genes to make proteins that interacted with its host’s nervous system to direct it to just the right spot on a leaf. Viruses, on the other hand, typically only have a handful of genes.
Are ten genes enough for a virus to manipulate a host? I suspect they may well be. After all, scientists have already shown how viruses can manipulate us in other ways, such as the way that human papillomaviruses can speed up the growth and division of their host cells. There’s nothing particularly special about behavior that would make it beyond the reach of viruses. They’d just need to make proteins that could shut down certain genes in neurons or switch other ones on to produce big changes. And as I mention in A Planet of Viruses, scientists are now finding giant viruses that contain over a thousand genes. Perhaps they have unappreciated powers of manipulation, too.
Parasitologists have one big piece of advice for anyone who wants to investigate whether viruses manipulate their hosts: don’t be fooled by mirages. It is very tempting to see any change in a host as the product of a fine-tuned adaptation in its parasite. But it’s also possible that a strange host behavior is merely a byproduct of being infected. It’s not easy to distinguish between these alternatives. One way is to measure just how big of a difference these “manipulations” make to parasites. Robert Poulin of the University of Otago has studied a parasitic fluke that infects cockles on the beaches of New Zealand. It then needs to get into the shore birds that eat the cockles to move to the next stage of its life cycle. And it just so happens that the infected cockles lose the ability to burrow. So if you walk around on the beach in New Zealand, a lot of the cockles you see may be infected and unable to dig back down into the sand.
Seems like a great way for the parasite to boost its odds of getting into a bird, right? Well, Poulin worked through a detailed model of the parasite life cycle and discovered that it actually makes little difference. For one thing, the cockles also get eaten by other predators in which the parasite can’t survive. So Poulin concludes that this case of “manipulation” could not have evolved because it benefited the parasites. Instead, it’s just a side-effect. If someone wants to see if the aggression caused by rabies is a manipulation, they could try to carry out a similar test. It wouldn’t be easy, but it would be interesting.
Still, it would be a mistake to look only for the most fine-tuned adaptations in viruses. Just consider a single-celled protozoan called Toxoplasma, which normally has a life cycle that takes it from cats to rats and other mammal prey and back to cats again.Toxoplasma does not make rats sick. Instead, it forms harmless cysts in rat brains. And there it seems to manipulate rats in a very precise way: it causes them to lose their fear of cat odor. This change may make them easier prey for cats, boosting the reproductive success of the parasite.
Toxoplasma is a serious health problem for humans. Pregnant women need to avoid contact with cat litter or garden soil, because they may pick up the parasite and accidentally ingest it. While healthy adults can keep Toxoplasma in check, fetuses with immature immune systems cannot. Toxoplasmosis can thus cause serious brain damage, as the parasite grows unchecked. Toxoplasmosis is also a serious concern for adults with compromised immune systems—due to AIDS or immune-suppressing drugs taken after organ transplants.
In human adults, the parasite may be benign, but it does appear to cause some shifts in personality. Some studies suggest that people with Toxoplasma are more likely to get into car accidents, for example. It would be a mistake to see these personality shifts as the parasite’s strategy for getting us eaten by cats. For one thing, Toxoplasmawas probably not a common disease in humans until the domestication of house cats—when we came into close contact with their parasite-laden droppings. For another, I doubt my pet cats would ever consider me a potential breakfast.
Still, the fact that these personality shifts are not fine-tuned adaptations does not make them unimportant. Could some psychological disorders, like depression, be the result of viruses that alter the behavior of their regular animal hosts? And as virologists like you discover new viruses moving into our species from other animal hosts, I wonder if they’ll bring their puppetmaster tricks with them.
DESTROY THEM ALL? or LEARN SOMETHING?
Should Smallpox Be Put To Death?
Richard Preston is the author of seven books, includingThe Hot Zone, The Cobra Event, and The Demon in the Freezer. He is a regular contributor to the New Yorker, and his awards include the American Institute of Physics Award and the National Magazine Award. Preston also the only person who isn’t a medical doctor ever to receive the Centers for Disease Control’s Champion of Prevention Award for public health.
There’s a debate in the scientific community about what to do with the remaining stocks of smallpox virus on the planet. Should the virus be preserved so that it can be studied? Or should the virus be destroyed, so that—in theory at least—it would become extinct and would not threaten the human species again?
Smallpox virus, or Variola major, is the cause of probably the worst infectious disease in human history. During the nineteenth and twentieth centuries, experts believe that smallpox killed half a billion people, accounting for far more deaths than all the wars of the time. Smallpox is a grisly and supremely painful disease. The disease has around a 33 percent case-fatality rate in unvaccinated patients. That is, a third of the disease’s victims who haven’t been vaccinated die. The victims suffer from an incredibly painful rash—blisters known as pustules stud the body. The survivors are typically left with scars for life. About ten percent of fatal smallpox cases consist of hemorrhagic smallpox, a manifestation of the disease in which the victim dies with hemorrhagic symptoms, including bleeding from the orifices. Smallpox virus spreads in the air from person to person, traveling in tiny droplets spewed when an infected person speaks or coughs. The vast majority of the world’s population today has little or no immunity to smallpox, because vaccination ceased during the 1970s.
Smallpox was declared eradicated globally in 1980 by the World Health Organization (WHO), after a remarkable and heroic WHO-led effort to eradicate the virus worldwide. Today, the only remaining samples of live smallpox virus are stored in just two locations: a high-security lab at the Centers for Disease Control in Atlanta, Georgia, USA, and in the Vector State Research Center in Siberia, Russia. For a number of years, now, various member nations of the WHO have been pressing the WHO to order those stocks destroyed.
The smallpox virus stock at the CDC occupies a volume about the size of a basketball; the virus samples are frozen in small plastic tubes the size of pencil stubs. The Russian stock is probably similar. It would be very easy to destroy the virus: just heat it up. But should it be destroyed? A series of defectors from the old Soviet Union have revealed that the Soviet Union weaponized smallpox; that the virus was a mainstay of the clandestine Soviet biowarfare program. Illicit stocks of smallpox may have been taken out of Russia; nobody knows where the virus might exist on earth today in the form of undisclosed, secret stocks of the virus.
Researchers using live smallpox virus at the CDC have been studying the virus in an effort to develop antiviral drugs that would be effective against a smallpox infection. The drugs might also be effective against genetically engineered smallpox. The genome sequence of smallpox virus is publicly available and can be downloaded from the Internet. Some day it will probably be technically feasible to recreate live smallpox from its genome sequence. Even if all the living smallpox were destroyed, it might be brought back to life in a lab somewhere, some day.
D. A. Henderson, who led the WHO eradication of smallpox, argues that the virus should be destroyed, regardless of whether it can be recreated. He argues that if the WHO makes smallpox extinct, then anyone who later had the live virus would be committing a crime against humanity and could be prosecuted in international courts. On the other hand, researchers who are developing defenses against smallpox argue that the disease is simply too dangerous to destroy; they argue that we must continue to study it under the principle of Sun Tzu, “Know thy enemy.”
What do you think?
Your question is a timely one. On May 16, the World Health Organization will be having their annual meeting, and one of the items on their agenda is a global consensus about what to do with the world’s remaining smallpox stocks. If WHO does decide on eradication, it will be an historical moment. We humans have only eliminated two viruses from the wild. Smallpox was the first. The second, as of last October, is rinderpest, a devastating scourge of cattle. For now, both smallpox and rinderpest remain in laboratory stocks. But if WHO decides to get rid of the smallpox lab stocks, too, the virus may be eliminated from the planet.
The prospect of such a milestone raises the question of why we haven’t been able to wipe out any of the other viruses that plague us. In some cases, it’s because viruses have escape routes. In 2004, for example, SARS burst on the scene, killing 774 people in total before quarantines and other public health measures beat it back. There have been no reported cases of SARS since then in humans, but SARS is probably thriving. It spread from animal hosts—bats and civets—to humans, and it doubtless retreated back to them.
Some viruses are hard to eradicate because they’re lurkers. HIV takes years to produce symptoms, making it hard to recognize and treat infected people. By the time it makes itself known, people may have spread it to many other victims. And doctors still lack vaccines for HIV and many other viruses. In all these respects, smallpox is a peculiar virus. Unlike SARS, smallpox only infects humans. Unlike HIV, smallpox makes itself known in a matter of days. It’s also unusual in that there’s a cheap, effective smallpox vaccine. Combined, these three factors made it possible to effectively break the transmission cycle of smallpox and thereby drive it towards extinction.
Whenever a species goes extinct, we lose the opportunity to get to know it better. I’m sure no one would shed a tear at the extinction of smallpox, but, as you note, there’s a lot we still don’t understand about the virus. I don’t think getting the opportunity to try people for crimes against humanity is worth giving up the chance to learn more about smallpox. Even if smallpox never rears its ugly head again, that knowledge could still be valuable. Studies on smallpox DNA suggest that it evolved just a few thousand years ago from a pox that infected African rodents. Many closely related pox strains infect animals today, and they have plenty of chances to evolve into a new human pox. In 2003, for example, people in the Midwest came down with monkeypox, an African virus that is closely related to smallpox. It was baffling at first that an African pox could infect American victims. Eventually public health workers determined that the victims got the virus from prairie dogs they all bought at the same Missouri pet store. If smallpox can help us prepare for the next pox, we should resist the urge to annihilate it.
Bacteriophages are the most abundant biological particles on earth, but due to their size, and perhaps ubiquity, most of us don’t think of them very often. Phages are essentially just bacterial viruses. When it comes to viruses, the popular notion is that they are bad entities that are responsible for disease and suffering. The truth is, however, that phages are very different from human viruses. Phages do not infect human cells and are not responsible for the viral diseases that plague mankind, such as AIDS, herpes, cervical cancer, and the common cold. Furthermore, phages have had a tremendous impact on modern biology and biotechnology.
Much of our early scientific efforts to understand genetic regulation were carried out in the humble phage. Phage proteins called recombinases are an integral component for the construction of “knockout animals,” which cannot express particular genes—an indispensable tool in modern biological research. Phage display, a technique for sticking a library of peptides on phage surfaces and panning for targets to which these peptides will bind, has been used to make nanowires for batteries, identify new antibodies to treat human diseases, and understand the basic science which underlie protein-protein interactions.
Despite their importance as major research tools in the biomedical community, however, research into the use of phages as human therapeutics has garnered a mixed reputation in the Western world. Soon after their discovery in the early twentieth century, phages were tried as novel antimicrobial agents. Indeed, one can imagine the excitement that the early phage researchers must have experienced when observing the lysis—or clearing of bacterial cultures—by the addition of a newly discovered biological agent! However, early reports claiming impressive successes at treating bacterial infections with phages were later tempered by failures in other settings and repeated trials.
Looking back, it is likely that a lack of detailed understanding of phage biology was responsible for much of these failures. Unlike antibiotics, which act like broad-spectrum bombs that blast all bacteria, good or bad, in their paths, phages are targeted warriors, the biological equivalent of a sniper or laser-guided missile. This targeted behavior is beneficial because it avoids killing bacteria which are good for us, as opposed to antibiotics which cause collateral damage. However, this targeted behavior also has its flaws because to effectively treat a specific bacterial contamination with phages, one must understand the bacterial compositions in detail and know what mixture of phages to use against them. Such capabilities were not available or known during the early days of phage therapy.
Thus, the subsequent discovery of antibiotics, along with their simplicity and miracle successes, largely displaced phages from antimicrobial research in Western medicine in the latter half of the twentieth century. As a result, the notion of phage therapy often elicits justifiable skepticism when discussed as an alternative to antibiotics today, even though the antibiotics pipeline has dried up and we are in desperate need of new strategies to combat the rising tide of antibiotic-resistant superbugs.
Fortunately, in the past few decades, there has been a renaissance brewing in the phage world. Commercial, government, and academic labs have begun to tackle the fundamental issues that have held back phage therapy using rigorous molecular tools. To use phages to effectively treat bacterial contaminations, these labs have been developing technologies for classifying bacterial populations, identifying the right combination of phages to use, and optimizing phage properties using evolutionary or engineering approaches.
Instead of tackling the high hurdles that need to be crossed for direct human use, many labs and companies have chosen to apply phages to other applications in industrial, environmental, and diagnostic settings. For example, Intralytix makes phages to treat listeria contaminations of food, Omnilytix makes phages that control bacterial infections on tomatoes and peppers, and Microphage makes phages that can detect and report on the presence of harmful antibiotic-resistant superbugs, such as MRSA. A company called Novophage is advancing the use of phages for industrial applications, where they have the potential to enhance energy inefficiency and decrease biofouling (for full disclosure, I am a founder of this startup). Major advantages of phages compared with chemical biocides and pesticides include greater biocompatibility and decreased environmental toxicity. Using natural biological particles to combat biological problems is consistent with our society’s continuous drive to reduce the use of harmful chemicals and is, I believe, a great application for phages in the modern era of biotechnology.
The hurdle that has yet to be overcome is the use of phages for human therapeutics, the original application area for phage therapy. Nonetheless, given the great need for new antimicrobial therapies and the inroads that these laboratories have been making into optimizing phages for practical applications, the prospect of effective phage therapy being applied to human infectious diseases in Western medicine seems to be growing!
In all my work as a science writer, I can’t think of a story as strange as the history of phage therapy. It’s been nearly a century since the Canadian physician Felix d’Herelle discovered viruses that infect bacteria. And yet, despite great promise, phage therapy has yet to become a mainstay of medicine.
What makes the story even stranger is that Herelle could see the promise of phage therapy as soon as he discovered the viruses. He was soon using them to treat 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. He went on to conduct large-scale public health campaigns for the British government in colonial India. Phage therapy became so well-known that Herelle inspired the central character in Sinclair Lewis’s 1925 best-selling novel Arrowsmith. Phage therapy became big business: Herelle developed commercial drugs that were sold by the company that’s now known as L’Oreal, which were used to treat skin wounds and to cure intestinal infections.
But by the time he died in 1949, Herelle had sunk into obscurity. Doctors had abandoned phage therapy for antibiotics. His dream did not vanish entirely, however. On his travels, Herelle met Soviet scientists who wanted to set up an entire institute for research on phage therapy. In 1923 Herelle helped 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 1200 people to produce tons of phages. In World War II, the Soviet Union shipped phage powders and pills to the front lines, where they were dispensed to infected soldiers.
Soviet scientists continued to investigate phage therapy after World War II. They conducted the best trial of the viruses in 1963. They enrolled 30,769 children in Tbilisi. Once a week, about half the children swallowed a pill that contained phages against dysentery. The other half of the children got a pill made of sugar. To minimize the influence of the environment as much as possible, the Eliava scientists gave the phage pill only to children who lived on one side of each street, and the sugar pill to the children who lived on the other side. The Eliava 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 dysentery.
Phage therapy only began to attract interest in the West after the fall of the Soviet Union, when Soviet scientists could communicate more freely with the rest of the world. And yet, as you point out, the U.S. government has been leery of approving viruses for medical treatments. Gone are the days when a physician like Herelle could pretty much do as he pleased. As a result, many companies and investors are reluctant to embrace his phages.
If phage therapy can leap over these hurdles, I think that there are a vast number of potential applications. Treating a skin infection is just the start. Phages, after all, are part and parcel of every person’s inner ecology. Our bodies are home to 100 trillion bacteria and other microbes. Recent surveys estimate that these microbes play host to about four trillion phages, which come in about 1,500 different species. In some cases, our phages kill their hosts, and thus maintain an ecological balance in our mouths, noses, guts, and other nooks and crannies. In other cases, phages insert genes into their microbial hosts, giving them new powers.
The human microbiome is not merely an infestation we tolerate. It plays many different roles in our bodies. Microbes synthesize vitamins for us, regulate how much energy we get from our food, fight off invading pathogens, nurture our immune system, and potentially even influence our behavior. It may be possible to manipulate the microbiome through the phages that have coevolved with it for millions of years.
A Billion Viruses in the Sea
Sallie W. “Penny” Chisholm is the Lee and Geraldine Martin Professor of Environmental Studies and professor of biology at MIT. Her research lab seeks to advance our understanding of the ecology and evolution of microbes in the oceans, and how they influence global biochemical cycles. In January 2010, she was awarded the Alexander Agassiz Medal, for “pioneering studies of the dominant photosynthetic organisms in the sea and for integrating her results into a new understanding of the global ocean.”
Thank you for giving viruses the recognition they deserve. As you point out, the discovery of viruses in the oceans is relatively recent. It seems that about once every decade there are similar major discoveries in oceanography that change the way we think about ocean ecosystems. One of these—a discovery by the late John Martin—was that iron availability limits the growth of phytoplankton (your ‘geoengineers’) over large regions of the oceans. This changed the major ‘drivers’ of carbon dioxide absorption by the oceans, and climate models had to be changed accordingly.
Evidence that iron—carried from land to ocean via atmospheric dust—limits the ocean’s capacity to draw carbon dioxide out of the atmosphere has fueled the idea that large scale ocean iron fertilization could be used for engineering Earth’s climate. What does this have to do with viruses (you are wondering)? Well, it turns out that iron has been used to flocculate viruses for wastewater treatment, and to concentrate them from ocean water for scientific study. What if iron dust deposition does the same in the oceans? What if it not only stimulates phytoplankton growth, but also reduces phytoplankton death rates by ‘precipitating viruses’ and settling them out of the system? Might this phenomenon help explain the observed relationships between iron dust deposition and atmospheric carbon dioxide in ice cores? This has been proposed by MIT’s Hyman Hartman, who has also suggested that we might enhance phytoplankton’s capacity to draw carbon dioxide from the atmosphere by (somehow) killing off viruses in the oceans. I doubt he is truly serious. But I also doubted the seriousness, twenty years ago, of people proposing ocean iron fertilization (OIF) as a means of carbon sequestration. Today, research on OIF for geoengineering is endorsed by leading scientists.
Whether or not one takes seriously the idea of global geoengineering with anti-virals, a thought experiment along these lines quickly exposes the complexity of marine microbial systems (give it a try!). In fact, recent field experiments have revealed one of the many possible unexpected consequences; it turns out that when you reduce all the viruses in a sample of seawater you actually decrease the carbon fixation of cyanobacteria, because reduced lysis of heteotrophic bacteria deprives cyanobacteria of essential nutrients they need to grow optimally. In a nutshell, even these simple microbial systems are so complex that it is impossible to predict the consequences of removal of one component.
Just some food for thought.
It is funny how what at first seems absurd when it comes to virus can eventually become conventional wisdom. The very idea that the ocean harbored many viruses was absurd as late as the 1980s. Seawater just seemed like a terrible place for viruses to survive. But when scientists began to give a close look at the ocean, they discovered otherwise. A single spoonful of seawater might harbor a billion viruses. Most of those viruses proved to be bacteriophages—in other words, they infect bacteria. That’s not surprising, because the most abundant hosts in the oceans are microbes. But what is surprising is the effect that those marine phages have on life in the sea. Viruses kill half of all the bacteria in the oceans every day. As you note, the rupturing of all those cells (known as lysis) dumps vast supplies of nutrients into the ocean, possibly fertilizing other microbes to grow faster. Since the microbes of the ocean pull down huge amounts of heat-trapping carbon dioxide from the atmosphere (and also return a lot of it back there), the overall effect that viruses have on the climate could potentially be huge. I can’t help but find the idea of viruses influencing the climate a bit absurd—but the more I learn about viruses in the ocean, the more accustomed I get to it.
Your speculations about viral geoengineering bring a fitting close to the discussions we’ve been having on this blog over the past month. Once scientists discovered viruses, they began to acquire the power to control them. They were able to develop vaccines and public health measures that could sometimes slow their spread. In many cases, we’ve only had moderate success in controlling viruses, but in a few case—such as those of smallpox and rinderpest—we are now at the point where we could soon eradicate entire species of virus from the face of the Earth.
But the discovery of viruses has also revealed to us that they are not merely things that make us sick and must be eradicated. Phages can kill life-threatening bacteria, for example. For now, however, phage therapy is not standard medical procedure, in part because governments are a bit queasy about approving viruses as living drugs. As your MIT colleague Tim Lu explained last week, he’s taking his research in a different direction, using phages to destroy the biofilms that grow in heating and cooling systems in buildings. In effect, he’s trying to heal architecture. It’s a natural progression from bodies to buildings to the entire planet. At least it’s natural to speculate about using anti-virals to change the global climate. Still, I can’t help but think—what kind of drug store could fill that prescription?
EVOLUTION in DAYS
Evolution in a Petri Dish
by Carl Zimmer / 2006
Charles Darwin never thought he could witness evolutionary change. He relied instead on indirect clues. He looked at its effects after millions of years — in the fossil record and in the similarities and differences among living species. He got clues to the workings of evolution from the work of pigeon breeders, who consciously chose which birds could reproduce and thus created birds with extravagant plumage. But that was artificial selection — not natural selection that had been operating long before humans came on the scene. Darwin was pretty sure that natural selection worked too slowly for him or anyone else to witness. Darwin got a great many things right, but on this score, he was most definitely wrong. Just ask Paul Turner. In his lab at the department of ecology and evolutionary biology, Turner and his colleagues watch evolution play out in a matter of days. They observe organisms acquire new traits, adapt to new habitats, and become new species in the making.
Turner can hold one of these experiments in his hand. It’s a sealed petri dish. “So here we have a lawn of bacteria,” he says, gesturing to a cloudy smear in the dish. Then he points out a large clear spot in the middle of the lawn, where millions of the bacteria have died. “That’s a beautiful example of a plaque,” he says. There’s a tinge of admiration in his voice. The plaque was made by an organism Turner is particularly fond of: a virus known as phi-6. The virus invades bacteria and uses their cellular machinery to make hundreds of copies of itself. The bacteria rupture, and the new viruses escape. As the bacteria die, they leave behind a clear spot. The plaques are evidence of the virus’s staggering powers of reproduction. In a day, a single virus can produce a billion offspring. From generation to generation their genes mutate, creating opportunities for the viruses to evolve. They evolve so quickly, in fact, that scientists can set up experiments to test ideas about how evolution works. And because viruses carry just a handful of genes, scientists can identify exactly which mutations provide an evolutionary edge. “They’re really one of the few organisms we can study in the lab from nuts to bolts,” says Turner. “We can see the molecular changes.”
Turner has become a leader in a relatively young field: experimental evolution. He is using bacteria and viruses — especially phi-6 — to investigate some of the most profound questions about life on Earth. How do new species emerge? Why do so many species reproduce sexually, when they could just clone themselves? Why do organisms evolve into peaceful cooperators in some cases and ruthless competitors in others? In many of these experiments, Turner and his colleagues are searching for rules that may govern the evolution of all living things. But the research also has a practical side. While phi-6 infects bacteria, viruses similar to phi-6 like to infect humans — including HIV and influenza. New viruses such as SARS are also now emerging. Their emergence is a case of evolution in action: the viruses acquire mutations that allow them to shift from an animal host to humans. Turner’s research may help scientists better understand how that transition happens. “Within our lifetime we’re going to see more and more viruses shift onto humans,” he says. “What are the next likely pathogens to emerge? That’s something we’d like to predict.”
Turner, now 39, started out with an interest in larger fauna and flora. He grew up in upstate New York, where he loved to wander through the forests. “I was the kid who always liked to go to the zoo,” he says. As an undergraduate at the University of Rochester he thought he might like to be a biologist, and in 1989 he started graduate work at the University of California-Irvine. It was when he got to know Richard Lenski that he made the jump from macroscopic to microscopic. Lenski had started his career studying beetles in North Carolina forests, but he had been frustrated by how long it took to run experiments to tease out the forces controlling their populations. Many of the same basic forces also govern the existence of microbes, which breed far faster. And microbes are an ideal lab organism — so small and fast-breeding that scientists can run many trials of the same experiment simultaneously to make sure their results are valid.
So Lenski began running experiments on harmless strains of the gut bacteria Escherichia coli. In one series of experiments, he founded 12 colonies from the genetically identical offspring of a single microbe. Each colony was allotted only a meager supply of glucose. Lenski expected that, with food so scarce, natural selection would favor individuals that grew faster than others. He froze samples of bacteria from many generations; he would thaw them out later to compare them with their descendants. The experiment is still running today, some 40,000 generations later. The bacteria in all 12 colonies have evolved to the point where they can reproduce nearly twice as fast as the microbe Lenski started out with. Lenski (who now teaches at Michigan State University) interviewed Turner at Irvine when he was a prospective student. “Paul had some ideas about investigating carrion — rotting meat — and some of the interesting ecological interactions that might take place there,” he remembers. “Anyone who was attracted to that system, I figured, must be more interested in the questions themselves than in nature and all its beauty.” Lenski suggested that hauling rotting meat into a laboratory might make for difficult experiments, and described his own work. Turner was immediately interested. “I knew then that Paul was my kind of scientist,” Lenski says. At first, admits Turner, “the faith you put into working with things you cannot see was a very foreign concept for me.” But he started running experiments on E. coli to track how genes were gained and lost over the generations. It was only when he had almost finished graduate school that he shifted his research down to the even smaller scale of viruses. A scientist named Lin Chao, then at the University of Maryland, gave a talk at Irvine about his research on phi-6. Chao was using the virus to answer a particularly deep and difficult question in biology: why does sex exist?
Although sex is the only way humans naturally reproduce, some other species do well enough without it. Whiptail lizards in the southwestern United States, for example, are all female. Their eggs require no sperm to begin developing into healthy baby lizards; in essence, they just clone themselves. The late great biologist John Maynard Smith once pointed out that sex should put organisms at an evolutionary disadvantage. It takes two individuals to reproduce sexually, but just one to clone. Over a few generations, that difference should allow a population of cloners to become far bigger than one of sexual reproducers. “Our problem is to explain why sex arose, and why it is today so widespread,” Maynard Smith wrote in 1999. “If it is not necessary, why do it?”
Viruses, Chao recognized, would allow scientists to explore this question like never before. Billions of them can reside on a dish, they reproduce quickly, and some, including phi-6, sometimes engage in their own sort of sexual reproduction. When a single phi-6 invades a host cell, it makes clones of itself. Its genetic material is inserted into the host, and the host begins producing copies of the virus’s genes and pieces of the virus’s protective protein shell. These chunks of genes and shell float around inside the microbe before assembling themselves into new viruses. All the new viruses are clones of the original invader, differing only by whatever mutations emerged as their genes were produced. If two or more phi-6 viruses invade the same cell at the same time, their host produces new copies of both sets of genes — which can then mix together. The new viruses carry combinations of genes from the original invaders. In other words, the new viruses have two (or more) parents. They are the product of viral sex.
Turner was fascinated by the way Chao was using viruses to study a big evolutionary question. And he was struck by the fact that phi-6 could serve as a model for similar viruses that have sex and infect humans — viruses such as influenza and HIV. “I’m living in southern California, and the AIDS crisis is starting to become a big deal,” he recalls. “It was becoming clear that HIV was doing major damage. It all dovetailed.” Turner joined Chao’s lab as a postdoctoral student. They proceeded to design a series of experiments to explore the interplay of sex and evolution in phi-6. They created lines of promiscuous viruses and celibate ones. To make celibate viruses, they kept the ratio of viruses to hosts low, so that each microbe was invaded by just one virus. For the promiscuous line, they made sure the viruses outnumbered their hosts, so that each microbe was infected on average by five different viruses. They allowed the viruses to invade new hosts and replicate for many generations. They then measured how quickly the evolved lines of viruses could replicate compared with their ancestors.
Turner and Chao discovered that the promiscuous viruses sped up their replication. Turner suspects that one important factor behind their success was their ability to trade genes. Imagine that two viruses invade a single microbe. One of them carries an inferior gene that slows down its replication, and the other virus is slowed down by a different inferior gene. When they invade their host, they can produce a superior virus by combining their good genes and leaving the bad ones behind. Viruses may not be alone in benefiting from stripping out bad genes with sex. Other researchers have been examining sexual reproduction in other organisms, and they’ve found similar patterns. Susanne Paland and Michael Lynch at Indiana University recently published a study on water fleas. Some species of water fleas reproduce sexually, while some do not. Paland and Lynch discovered that the asexual water fleas accumulated harmful mutations four times faster than the sexual ones. This sort of genomic hygiene may have played a role in the evolution of our own distant ancestors as well, as they shifted permanently to sexual reproduction.
But the mystery of sex is far from solved. Turner and Chao’s work is proof of that. Viruses that have lots of sex, their experiments revealed, evolve into cheaters. Natural selection favored viruses that could use the proteins made by other viruses in the same cell. By exploiting their neighbors, these cheaters could put more resources into reproducing quickly. “Why do something for yourself, if you can get someone else to do it for you?” says Turner. Cheating is a classic puzzle of science. In 1968, the ecologist Garrett Hardin wrote an influential essay known as “The Tragedy of the Commons.” Hardin asked his readers to picture a pasture open to all the herders in the region. The rational choice for each herder would be to add more animals to his herd. But since all the herders are increasing their herds, they’re making a collective demand on the commons larger than it can support. The herders might try to stave off destruction of the commons by limiting their herds. But this solution can easily come undone, since individuals may still be tempted to cheat. “Ruin is the destination toward which all men rush, each pursuing his own best interest,” Hardin wrote.
The evolutionary parallel might be a species of birds that live on a remote island, eating seeds from a single species of plant. For their long-term survival, it would make sense for the birds not to gorge themselves on the seeds and drive the plant extinct. But natural selection cannot shape instincts to reach some long-term goal. It can only shape the behavior of individuals based on their reproductive success. Turner and Chao demonstrated this in their virus work when they showed that too much sex may be a bad thing (at least from an evolutionary point of view). Viruses that had evolved with lots of sex, they found, became too good at cheating. When viruses that had adapted to a promiscuous life were forced to reproduce on their own, they reproduced far more slowly. “It’s a beautiful study,” comments Lenski. “It’s like the tragedy of the commons on a microscopic scale.”
Unlike other life forms, viruses lack the means to reproduce themselves. Viruses typically get into their hosts by latching onto proteins on the surface of cells and managing to gain passage inside. Different species have different proteins on the surface of their cells. If a virus’s key doesn’t fit a species’ lock, it cannot make that species a host. Turner is intrigued by how that key sometimes changes. A virus may mutate in such a way that allows it to slip into cells of another species. It often takes many of these mutations for a virus to complete such a transition. But it’s clear that viruses do manage to make the transition fairly frequently. Influenza viruses reside in birds and other animals; when a strain evolves the ability to spread quickly from human to human, it can become a pandemic — like the 1918 Spanish flu pandemic, which killed 20 million people before it was over. Scientists are now watching a new strain of bird flu spread across the world, acquiring mutations that allow it to infect humans. It still can’t spread from human to human, but it may be just a few mutations away.
Meanwhile, we are also encountering entirely new diseases thanks to host-shifting viruses. HIV-1 began as a chimpanzee virus. Hunters likely contracted the virus through cuts, and while most of the viruses died off, a few survived. In the 1930s strains of the virus began establishing themselves in humans, and eventually became specialized on our own species. SARS Coronavirus appears to have emerged from civet cats sold in Chinese markets. It’s just going to get worse, Turner predicts. “As the human population continues to grow, we’re a target. We’re also creating agricultural landscapes where there were wild landscapes. We’re driving native species out into the open, and those native species can be reservoirs for viruses.” As serious as the threat of emerging viruses is, scientists still know relatively little about how viruses shift hosts. They cannot, for example, confidently predict which viruses in animals are most likely to colonize human hosts in the future. They still need to understand some of the basic rules of this particularly dangerous sort of evolution.
Turner believes that phi-6 can shed light on some of those rules. Like HIV, it has its own host of choice. The strain that Turner studies lives on plant bacteria called Pseudomonas syringae. Turner is carrying out experiments to see which conditions favor its shift to other bacteria. “Right now we’re at the early stages of looking at those questions,” he says. Turner’s graduate student Siobain Duffy has been studying phi-6 to track the earliest stages of host-jumping. Previous research suggested that viruses face some serious challenges in jumping from one host to another. Instead of a clean leap, viruses apparently had to make a gradual shift. Early in a transition, the virus needed to live in both its new host and its old one. Yet being a jack-of-all-trades may not make much evolutionary sense for a virus. A mutation that made a virus able to invade a new species might interfere with its ability to invade its traditional host. Many studies on evolution hinted at such trade-offs.
Duffy began to search for signs of a trade-off. She prepared lawns of bacteria from 14 different types of Pseudomonas. She then added phi-6 to their dishes and allowed the viruses to infect their new hosts for one day. The vast majority of viruses failed miserably at the task. But Duffy identified 30 mutant viruses that succeeded in creating plaques. Duffy then looked at the genes of the mutants. She focused on a gene that encodes a protein called P3. The virus uses its P3 protein to attach to its host. Since each type of host has different proteins on its surface, it seemed likely that P3 would likely undergo mutations in viruses that could attach to new hosts. She discovered that each of the host-shifters did indeed carry a mutant P3 gene. Remarkably, the mutant genes differed only by a single “letter” from the normal code. That’s all it takes for phi-6 to invade a new host: one random mutation in a single gene could do it. And while the host species Duffy studied were all in the genus Pseudomonas, many are separated by millions of years of evolution.
All told, Duffy identified nine mutations that allowed host-shifting. In some cases only one virus carried a particular mutation; in others, nine shared the same one. To measure the cost of these mutations, Duffy then infected the original Pseudomonas host with viruses carrying each of the nine mutations. When she checked how quickly they reproduced, she found that seven out of the nine mutations caused the viruses to grow more slowly on their original host. The discovery, which she and Turner and their colleagues reported in the journal Genetics earlier this year, marks the first time that scientists have precisely measured the cost of being a jack-of-all-trades. But the other two mutations go against conventional wisdom: phi-6 strains with these mutations can still grow quickly on their old host. In other words, sometimes a virus can be a jack-of-all-trades for free. Duffy also discovered another unexpected result: some mutations discovered in a virus infecting one new host could also let it infect another new host that it had not yet seen.
Does this mean that we’re vulnerable to any virus with a host-shifting mutation? Not quite, says Turner. On their own, these sorts of mutations are not enough to allow a virus to spread into a new species: “It has to mutate and sustain itself long enough to take off.” Turner and his students have been closely observing one host-shifting strain of phi-6, and they find that it grows ten times slower in the new host than the old one. Slow growth can put a new strain of virus at risk. If the viruses aren’t producing enough offspring, they might not find new hosts to infect, and the new strain could become extinct. But Turner and his students have now shown that we shouldn’t take too much comfort in that fact. Turner and postdoctoral researcher John Dennehy are exploring what it takes for a new strain of virus to survive this dangerous passage. Dennehy put a host-shifting strain to the test by forcing it to shift back and forth, between its old and new hosts, four times.
The virus proved remarkably resilient. Dennehy and Turner had expected that, in the trials with small founding populations, the virus strain would become extinct in its new host. Instead, it survived and managed to expand its numbers. Somehow, reproducing in the old host gives viruses an extra boost when they infect the new host. Based on what scientists know about viruses, that shouldn’t make a difference. But it does. “And that’s mysterious,” says Turner. “There’s no good reason for that. It’s like an ecological hangover.” It’s possible, he thinks, that the virus grabbed one or more key proteins from the previous host.
These experiments are just the first steps in Turner’s study of host-shifting. Dennehy is now trying to create experiments that mimic natural conditions more accurately. He hopes to create dishes in which different species of bacteria live side by side. He’s curious to see how the viruses “decide” which species to infect. Duffy meanwhile has been allowing host-shifting mutants to evolve. She wants to see whether they can shift completely to a new host — becoming, in other words, a new species.
The research going on in Turner’s lab hints that viruses are even more adept at shifting hosts than previously thought. They may not have to sacrifice their ability to breed in their old host to begin breeding in their new one. And some viruses may not even need to be “trained” on human hosts. Mutations that allow them to infect rodents or other mammals may give them the ability to invade our cells as well. “It may be easy for viruses to enter a new host type even if they haven’t seen that new host type before. If something is hanging out in a mouse and jumps into a human, maybe that shouldn’t be so surprising,” Turner says. Turner pauses for a moment, noticing that he has caused a visitor some distress at the thought of viruses easily gliding into our species. Witnessing evolution is not always a happy thrill. “Scary,” he says. “Stay healthy. Wash your hands.”
Given the urgency of these risks, Turner finds the continuing debate over creationism versus evolution a dangerous distraction. “I could take somebody into the lab, and over the course of a week, I could prove to them that evolution actually happens in microbes,” says Turner. “And it has been profoundly important in the rise of antibiotic resistance and our inability to make effective anti-HIV drugs. We’d better be aware of it.” the end