Making viruses the natural way

By Carl Zimmer | December 2, 2011 12:57 am

When it comes to viruses, we humans like to pretend we know much more than we really do. It’s understandable. The influenza virus, for example, has only ten genes. It is just a shell that delivers genes and proteins into a host cell, where it hacks the biochemistry to manufacture more viruses. It seems like such an easy biological problem to solve.

Yet the flu and other viruses hide a complexity which virologists have only partly uncovered. The idea that someone could intentionally design a super-lethal virus from scatch–as plausible as it may seem–is, for now, a delusion.

If you’ve been following the news this past week, you may think I’ve just been proven wrong. Reports have surfaced about two teams of scientists producing flu viruses that could potentially kill millions if they escaped from the labs. The scientists have the viruses locked up tight for now, and government officials are debating whether they can publish their results. (New Scientist and Science have excellent reports.)

So is this evidence that scientists have become viral Frankensteins, who can engineer pathogens at will? Hardly.

The new research is part of a long-running struggle to understand how new flu strains arise. It’s clear that all flu viruses that infect humans ultimately evolved from viruses that infect birds. From time to time, people can pick up these viruses, which infect their airway. Depending on the strain, bird flu may be harmless or lethal to humans. But for the most part, it can’t get from one human to another. It’s too well adapted for life in birds.

On rare occasion, a bird flu does manage to adapt to humans. It may experience natural selection, it may pick up some genes from human flu viruses, or both. Scientists are still trying to figure out what it takes for a flu virus to make this transition. It’s an important question, not just as a matter of fundamental biology but as a matter of global health. When new bird flus jump to humans, we lack immune defenses against them, and they can thus cause worldwide pandemics.

Flu experts have had their eye on one strain of bird flu in particular for a while now: H5N1. It’s proven extraordinarily lethal, and yet, since it first came to light in 1997, it hasn’t managed to make the big leap and start spreading from person to person. If you get H5N1, you’re in big trouble. But not many people get it. Yet.

Does this mean that H5N1 just doesn’t have what it takes to become the next great pandemic? Or does it mean the virus simply hasn’t evolved the right recipe yet?

Scientists have tried to answer this question by tinkering with the virus. Instead of trying to make a virus that spreads among people, they infected ferrets, which turn out to have much the same experience with the flu as we humans do. In April, CDC scientists published the latest of these studies. They focused their attention on a protein called hemagglutinin, which flu viruses use to get into host cells. Based on earlier experiments, the CDC scientists reasoned that the right tweak to the structure of hemagglutinin in H5N1 could switch it from binding strongly to bird cells to mammal cells.

But their rational tweaks failed. They concluded that there was a lot more to becoming a human flu that we don’t yet understand.

The studies that have now hit the news have succeeded where other experiments have failed. The difference is that instead of trying rational tweaks, the scientists sat back and let evolution do the tweaking.

According to the news reports, the scientists used a tried-and-true method known as serial passage. You infect an animal. It gets sick. You wait for the virus to replicate inside its animal host–as new mutants arise and natural selection favors some mutants over others–and then take some viruses from the sick animal and infect a healthy one. You repeat this, moving the virus from host to host.

Interesting things can happen when you let viruses evolve under these conditions. Natural selection can produce viruses with many new mutations, which together let them reproduce faster in the lab than their ancestors. And those viruses, in some cases, can be a lot more dangerous than their ancestors.

Back in 2007, for example, a virologist named Kanta Subbarao and her colleagues transformed the SARS virus this way. SARS evolved from a bat virus, crossing over into humans in 2003. It killed over 900 people before it mysteriously disappeared. Subbarao wanted to find a way to study SARS in lab animals, such as mice. Mice normally don’t get sick from human SARS viruses, though, even though the virus can replicate at a low rate inside them. Even when mice are genetically engineered so that they can’t develop an immune system, SARS can’t harm them.

So Subbarao and her colleagues that instead of changing the mice, they’d change the virus. They inoculated mice with the SARS virus, gave it a chance to replicate inside them, and then isolated the new viruses to infect new mice.

Over the course of just 15 passages, it changed from a harmless virus into a fatal one. One sniff of SARS was now enough to kill a mouse.

As Martin Enserink reports in Science, the new experiments on bird flu were similarly effective. They turned H5N1 into a ferret flu in just 10 generations. By the time the scientists were done, they no longer had to ferry the flu from one ferret to the next. A healthy ferret just had to be placed near a sick one; the virus could travel through the air. When they examined the new strain, they discovered five mutations in two genes. All five mutations have been found in natural H5N1 viruses–just not all in one virus.

A mammal-ready flu virus was beyond human reason, in other words, but it was fairly easy for evolution to find, given the right condtions. That suggests that H5N1 may not have far to evolve to make us its host. Of course, a serial passage experiment is not identical to the flu’s natural world, where it circulates among millions of birds and sometimes encounters people. But it’s disturbingly close.

And if it’s so easy for mutations to turn H5N1 into a human flu, the experimental viruses have a lot to tell us about what we may be facing in the future. There’s no point in condemning the scientists for tampering with nature. They were watching nature do what it does disturbingly well.

[Update: The excellent podcast This Week in Virology discusses the new research. They think the hype to reality ratio is very high.]

[Image: Virology Blog]

CATEGORIZED UNDER: A Planet of Viruses, Top posts

Comments (14)

  1. brookc

    but doesn’t one serial passage equate to what the virus couldn’t naturally do yet? mammal to mammal transition? what sort of unlikely accident will allow this to happen multiple times between humans with H5N1 or similiar?
    don’t get me wrong, i think the research was worthwhile, to show what genetic changes might be necessary, but doesn’t it avoid that fundamental issue of initial transmission?

  2. Paul

    A sufficiently devoted terrorist group could conduct the same procedure with humans, either with prisoners or volunteers.

  3. How is this research – and others like it – being used to predict the behavior of influenza outbreaks before they happen? Is it that we are trying to compile a hot list of potentially dangerous mutations? The major bottlenecks will be of course finding these mutations out in the lab but also looking in nature for them as they arise, which requires a massive amount of screening of isolates worldwide. Lets hope we can complete both of these parts of the puzzle.

  4. Zephyr

    @Paul, or just with ferrets.

  5. Influenza scientists know that when you isolate a new influenza virus in one species, serial passage in another species usually yields a new reassortant virus that replicates efficiently and often transmits well in the second species. Thus, Ron Fouchier’s important experiment demonstrates something influenza virologists have known for some time. The only thing that’s different is that his experiment started with a really hot H5N1 influenza virus.

    The current debate over whether to publish his findings, as detailed by Martin Enserink in this week’s Science, overlooks the more important issue of what could be done to treat people who might be infected with this new laboratory-generated H5N1 virus, the current circulating (and thus far poorly transmissible) H5N1 virus or an ordinary seasonal influenza virus. This is a critically important question because, as was demonstrated in the recent H1N1 pandemic, influenza scientists, vaccine companies and public health officials lacked the capacity to rapidly produce and distribute affordable supplies of pandemic vaccines and antiviral agents in time to affect the course of pandemic disease for more than 90% of the world’s people. Simply put, a global public health strategy that targeted the H1N1 virus, although scientifically sound, could not be implemented in the real world.

    Fortunately, a growing body of evidence suggests it should be possible to modify the dysregulated host response (largely innate immunity) and improve survival in patients with severe influenza by treating them with immunomodulatory agents (see Influenza Other Respi Virus 2009; 3: 129-42). Cardiovascular physicians and endocrinologists already use statins, fibrates, glitazones and metformin to treat the dysregulated host responses seen patients with chronic heart diseases and diabetes. The clinical benefits and safety of these agents have been accepted for many years. A small number of studies have shown that glitazones, fibrates and metformin (but not statins) improve survival in influenza-infected mice, and do so without increasing virus replication. Observational studies show that outpatient statins reduce hospital admissions for pneumonia and inpatient statins reduce hospital mortality for laboratory-diagnosed influenza. Moreover, all of the immunomodulatory agents mentioned above are now produced as inexpensive generics in developing countries and are available to anyone who has access to basic health care. If these agents could be convincingly shown to reduce mortality in patients with severe influenza, short-term treatment of an individual patient would cost less than one dollar.

    A clue to the promise of treating the host response to influenza comes from a consideration of the disparity in the case fatality rates of children and young adults seen in the 1918 and subsequent influenza pandemics (and in acute lung injury due to many other infectious and non-infectious causes; see Influenza Other Respi Virus 2009; 3: 129-42). The 1918 pandemic is notorious because it caused exceptional mortality in young adults. Many scientists have ascribed this to secondary bacterial pneumonia, but this explanation is unsatisfactory because it ignores an overwhelmingly important observation: children were infected more frequently with the virus that killed young adults and their nasopharyngeal passages were colonized more frequently with the same bacteria found in the lungs of young adults who died, yet case fatality rates in children were far lower. Why was this so? Influenza scientists have sought to explain why young adults died by studying the 1918 and other influenza viruses. Yet, despite the extraordinary contributions of influenza scientists to our understanding of the virus itself, they still cannot explain why young adults died. The question they should have been asking of the 1918 pandemic is different; they should have been asking, “why did children live?”

    The dramatic switch in the mortality experiences of children and young adults in 1918 seems to have occurred at the time of puberty/menarche, and it can only be explained by fundamental differences in their host responses to influenza virus infection. This difference might reflect changes in energy metabolism: in childhood, energy metabolism is focused on growth; after puberty and menarche, it is focused on reproduction. The innate immune system has evolved to allow maximal growth in children in order to ensure their survival until the time when reproduction becomes possible. During this period, inflammatory responses take second place to growth. For those individuals who manage to survive (and for most species, only a few survive), the priority for energy metabolism becomes reproduction, and the innate immune system changes to reflect this new imperative. Now it must generate a vigorous inflammatory response to defend against attack from the outside, but it must also allow for a certain degree of immunosuppression to ensure that the fetus (foreign tissue) is not rejected. This aggressive/immunosuppressive innate immune response of reproduction-capable adults acts to ensure the continuation of the species. If on occasion it kills a few individuals, in evolutionary terms this is a small price to pay to guarantee species survival.

    Theodosius Dobzhansky once wrote, “nothing in biology makes sense except in the light of evolution,” and several scientists have begun to explore the connections between energy, evolution and human disease (see Am J Clin Nutr 2011; 93(suppl): 875S-883S). Nonetheless, although studies of innate immunity have finally merited the award of the Nobel Prize, immunologists surprisingly seem to have left unexplored the different characteristics of innate immunity before and after puberty. This is more than unfortunate because, although it would be enlightening to be able to explain these differences, we already have an indication we could actually do something about them. In a unique experiment, “children” and “young adult” mice were subjected to ischemia reperfusion injury of the liver. In young adults more so than in children, this condition is highly inflammatory and often fatal. Yet glitazone treatment was able to “roll back” the often harmful host response of young adults to the more benign response of children, and this improved survival (see Influenza Other Respi Virus 2009; 3: 129-42). This singular experiment and its implications for patient care have been widely ignored.

    Despite compelling scientific arguments for undertaking the laboratory and clinical research needed to show definitively that these agents would work in severe acute infections such as influenza, scientists, their paymasters and public health officials (including those at WHO and the Gates Foundation) are still focused on attacking the virus. They seem not to realize that success with host-directed treatment for influenza might be extended to the management of other diseases in which the loss of homeostatic defense mechanisms determines outcome; for example, pneumococcal sepsis, cerebral malaria, dengue hemorrhagic fever and critical illness associated with trauma and burn injury. These agents might even mitigate the pathological effects caused by pathogens considered possible agents of bioterrorism, something that $19 billion in public funding by the US government over the past decade has failed to achieve.

    Almost half a century ago, physicians and public health officials learned that syndromic treatment of severe acute diarrheal illness could be accomplished with an inexpensive oral rehydration solution. Although vaccines that target a few of the pathogens responsible for these diseases have been developed since then (e.g., cholera, rotavirus), it is syndromic treatment of acute diarrheal disease with ORS that has saved millions of lives. Had decisions been made to ignore the possibility of simple and inexpensive treatment and focus solely on vaccine development, these millions would have died.

    We have to ask why we have not learned from this history. Why have we not recognized that the dysregulated host response of people with acute lung injury that is seen in severe influenza and in many other conditions might be treatable with safe, inexpensive and widely available immunomodulatory agents? It takes little imagination to recognize that such treatment could be of immense importance to global public health. Yet it is remarkable that influenza scientists (and those who support their work) have been reluctant (or refused) to undertake practical experiments that seek ways to modify the host response to severe infection. Instead of explaining every last nuance of virus behaviour, they could instead try to find simple ways that physicians could use to manage their patients. By continuing to ignore the broader insights of 21st Century cell and molecular biology, they have left public health officials no alternative other than to recommend confronting global pandemic threats with hand washing and social distancing. These “technologies” represent the best of 19th Century public health practice. In the 21st Century, we can and should do much better.

  6. tzontag

    “There’s no point in condemning the scientists for tampering with nature. “??!!!
    Are you on crack? This virus wouldn’t even be doing what it is doing to ferrets without the scientists’ “help”. I can’t believe there isn’t more of an uproar about this type of “scientific” nonsense…because its not a matter of IF this type of tinkering turns bad for humanity, its a matter of WHEN…And at that time when millions are dying, all the mia culpas and finger pointing won’t bring back the dead and suffering. These guys should be locked up, their papers burned and the project halted.
    Just unbelievable…

  7. “These guys should be locked up, their papers burned and the project halted.”

    What if in a few decades, this same technique is used for good? Or has it already happened? I’m guessing that the yeast used in bread and wine making as well as some probiotics was developed using this method, although it may be accidental

    Serial passage done by “infecting” a batch of dough or some grape juice works just the same as with animals

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The Loom

A blog about life, past and future. Written by DISCOVER contributing editor and columnist Carl Zimmer.

About Carl Zimmer

Carl Zimmer writes about science regularly for The New York Times and magazines such as DISCOVER, which also hosts his blog, The LoomHe is the author of 12 books, the most recent of which is Science Ink: Tattoos of the Science Obsessed.

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