Viruses are incredibly complex little buggers. The lab I work in studies just one aspect of herpesviruses (how they enter cells to infect them), and this involves just a handful of the many proteins that make up the virus. We have made great strides over the years to figure out herpesvirus entry, yet there is still so much more to learn. Knowledge is power. If we can figure out how the virus ticks, how it works, that knowledge could be useful in creating an anti-viral, or a vaccine. The knowledge gained could even translate to other related viruses. But we, as basic scientists, have to KNOW first. One of the tools we most often use to figure out how things work is to mutate the heck out of them. We use these changes to piece together virus functions: what gets worse (which is what happens most of the time) when we make change A to a protein? What gets better after change B? Virologists do this whether it’s herpes or flu or Ebola. Each virus carries its own set of risks, and there are standard biosafety levels (BSL) of containment set up to deal with each.1 For the most infectious/ deadly viruses, think “spacesuit”-wearing scientists, filtered air, and isolated rooms.
This brings us to the story of the man-made influenza virus that has been in the news recently. You may have seen the headlines, such as: “Scientists condemn ‘crazy, dangerous’ creation of deadly airborne flu virus.”2 What is going on at the University of Madison-Wisconsin? Are they planning to release a deadly flu virus to kill us all??!!??1?
Well, no. This adventure in influenza started back in 1918 when Mother Nature decided to release a deadly flu virus that ended up killing 675,000 Americans and 20-40 million people worldwide.3 Commonly called the “Spanish flu,” this was one of the worst disease outbreaks in human history. Sequence analyses identified the 1918 virus as originating in birds.4,5,6 The genetic code of flu is housed in multiple, individual segments and the virus gains a great deal of its genetic diversity through co-infection of a host (pig, human, bird, etc.) with one or more viruses and reassortment (mixing) of these segments. The question that Kawaoka and colleagues at the University of Madison-Wisconsin asked was whether or not they could generate a 1918-like flu virus using existing avian flu segments.7 To do this, they essentially cobbled together existing virus genetic material from ducks and seals and then tested it in ferrets (ferrets are a common animal model used to study flu infections in mammals). Although the ferrets infected with this Frankensteined “1918-like avian” virus became ill, none died, and the virus was not able to transmit to ferrets in neighboring cages; in contrast, control ferrets infected with the 1918 virus became sick (1 out of 3 animals died) and were able to pass the virus to neighboring ferrets. So, the Franken-flu wasn’t nearly as good as the original 1918 strain. The scientists then introduced additional mutations to the Franken-flu virus to see if they could induce ferret-ferret spread, which they successfully did. The authors were able to demonstrate that only a few specific changes conferred respiratory droplet transmission of the virus. Importantly, they also tested their new virus against the existing flu vaccine and anti-viral drug Oseltamivir. Both the 1918 and Franken-flu with the additional mutations (both of which were able to spread ferret-to-ferret) were recognized by human antibodies generated from vaccinated individuals, and both viruses were also sensitive to the antiviral drug. A similar outcome was observed by a second group of scientists: instead of directly mutating the flu virus, they essentially forced the virus on its own (by infecting ferrets over and over again) to change from a bird-only virus to one that could be passed among ferrets.8
Research into flu viruses such as this one was banned from publication initially, due to concern that it would be used as a blueprint to make the next pandemic flu by bioterrorists.9 As more of these types of studies are undertaken, some scientists are calling for a stop, citing the “possibility that these novel pathogens could be accidentally or deliberately released.”10 However, other scientists see the value in such experiments. “We know nothing about what controls aerosol transmission of viruses. The way to obtain this information is to take a virus that does not transmit by aerosol, derive a transmissible version, and determine why the virus has this new property.”11
There are a few important things to remember about these experiments before we freak out about them. First, these new flu viruses are no “better” (in terms of death rates or transmission in ferrets) than the 1918 control strain they were tested against – they are no more deadly than a virus already at-hand. Second, the original paper by Kawaoka and colleagues had the most detailed description of a BSL-3 facility (where the virus studies were performed) that I’ve ever seen, taking up half of the materials and methods section of their paper12 – this was obviously to show their attention to safety and calm fears. Has a scientist ever been accidentally infected in the past? Yes, we are humans after all and make mistakes. We have to weigh knowledge gained against personal risk (also, remember the first point, these new viruses are comparable to the positive control virus). Lastly, although ferrets are a good animal model, ferrets are not humans.13 Will these viruses behave the same in humans as ferrets? Probably….? Maybe….? One thing is for certain: Mother Nature is out there cooking flu viruses, and she doesn’t use a BSL-3 facility.
References/ Further Reading
4. Reid et al., 2004. Evidence of an absence: the genetic origins of the 1918 pandemic influenza virus. Nat. Rev. Microbiol. 2: 909-914.
5. Rabadan et al., 2006. Comparison of avain and human influenza A viruses reveals a mutational bias on the viral genomes. JVI. 80: 11887-11891.
6. Smith et al., 2009. Dating the emergence of the pandemic influenza viruses. PNAS. 106: 11709-11712.
7. Watanabe et al., 2014. Circulating avian influenza viruses closely related to the 1918 virus have pandemic potential. Cell Host Microbe. 15: 692-705.
8. Herfst et al. 2012. Airborne transmission of influenza A/H5N1 virus between ferrets. Science. 336: 1534-1541.
10. Lipsitch and Galvani. 2014. Ethical alternatives to experiments with novel potential pandemic pathogens. PLOS Medicine. 11: e1001646.
12. Imai et al., 2012. Experimental adaptation of an influenza H5 HA confers respiratory droplet transmission to a reassortant H5 HA/H1N1 virus in ferrets. Nature. 486: 420-430.