The Clue to Next Year's Flu

Strain Could Be Inside You

Sometimes, a little snot goes a long way. And not just in the physical, stretchy sense. Today, some decade-old snot
collected from the sinuses of cancer patients revealed a new technique to forecast how flu evolves.
Every winter, scientists try to predict which flus will be prominent during the following season. While the infection is simply a
pesky use of sick days for some, it also causes millions of hospitalizations and hundreds of thousands of deaths annually. So
to shore up prevention for the next year, the World Health Organization releases its predictions based on global flu
monitoring and animal studies to test the limits of herd immunity to vaccine-makers. (Next years flu, FYI, is supposed to be
an A/Michigan/45/2015 (H1N1)pdm09-like virus, an A/Hong Kong/4801/2014 (H3N2)-like virus, and a B/Brisbane/60/2008-
like virus.)
But the methods arent perfect, because the flu is constantly evolving, and fast. So scientists have been trying to find better
ways to predict flu strains by studying their evolution. Enter that really
old snot. Or, more precisely, sinus fluid collected from four cancer
patients back in 2006 and 2007.
Normally, a person has the flu for just a week, which isnt much time
to study viral evolution. But these cancer patients were on
medications that suppressed their immune systems so when they
caught the flu, their infections lasted for more than two months. In
these patients, virus mutants were born, with roughly one random
mutation arising in each virus every six hours. Some of those
mutations made the virus survive better, so more and more of those
showed up over time. And different mutants would battle for viral
dominance what evolutionary biologists call clonal interference, and
we might as well call going viral.
Scientists were able to track that evolution thanks to the patients
weekly nasal washespreserved for almost a decade at Fred Hutchinson Cancer Research Center in Seattle. Starting in
2016, collaborators at the center sequenced the DNA of all the viruses, using a relatively new, high-resolution method called
deep sequencing. Unlike your average genome sequencing, which gets an average estimate of the DNA or RNA sequence
in question, deep sequencing checks and rechecks the sequence thousands of times, reading out all the different variants of
flu living in that snot and recording how much of each mutant is present.
The researchers were curious about how flu evolution worked, and thought that cancer patients might have some weird
biological forces acting inside them. So they deep sequenced for all the different mutants of one strain of flu called H3N2.
Going into the project, I thought the study wouldn't really tell us that much, says Jesse Bloom, a biochemist at Fred Hutch
and the senior author on the study. I thought that the type of evolution that flu undergoes in any given individual
particularly cancer patients who are going to have unique, odd medical histories might end up being very idiosyncratic.
But that's not what they saw at all. Rather than observing unique dynamics in the four patients, the scientists found that the
same mutations would eventually go viral in multiple patients: The virus populations inside each patient trended toward the
same mutations. Some of these people werent even sick at the same time as one another.
Crazier still, some of those mutations ended up spreading across the globe a few years later. It was incredibly surprising to
see these kinds of similarities, says Katherine Xue, the genetics grad student in Blooms lab who led the project. Looking
inside cancer patients, the researchers discovered trends in flu evolution that could help scientists predict and monitor flu
variants all over the place.
While the authors point out that the study is still just a proof-of-principle, being able to narrow down the possibilities for flu
mutations would be exciting, says Katia Koelle, an infectious disease biologist at Duke who was not involved in the study. It
could serve as an additional piece of the flu prediction machine. If this was done on a large scale, looking across
immunocompromised patients who have the flu, that might bound the set of mutations that might be interesting to follow up
with surveillance, Koelle says. And that type of study seems more feasible, says Xue, as high resolution gene sequencing
gets cheaper.
This technique of following disease in patients with long infections could also become handy as researchers create new flu
drugs. Unlike flu vaccines, which simply prime the immune system to kill a virus, flu drugs would stop an infection once its
already started, hitting the virus directly. Thats great for high-risk individuals like cancer patientsbut also risky, since
putting pressure on the virus with a drug could create a drug-resistant super-flu. By deep sequencing the virus population
before and after treatment with flu drugs, scientists could monitor drug resistance and determine how much of a problem
resistance could be, says Bloom.
The study also let Bloom and Koelle nerd out on the cool evolutionary battle going on inside patients. For decades,
evolutionary biologists have just grown lab organisms like yeast and E. coli for long stretches to see how they evolve. Some
of the dynamics, like the battles between rival mutants they call clonal interference, seem to be working exactly the same
way in the lab and in the natural environment of a flu-infected human. So the study also showed that evolutionary biologists
basically had it right, says Bloomadding confidence to lab studies of viruses from flu to Zika. Not bad for a little snot.
https://www.wired.com/story/the-clue-to-next-years-flu-strain-could-be-inside-you/