On paleovirology

Like most nerds, I like reading science fiction. It’s not that I think that these fantastical futures will come to pass, it’s more just appreciating the imagination and optimism of those who are unfettered by the realities of experimental failure. Even dystopias seem like Nirvana compared to a day at the bench; the skin jobs actually worked in Blade Runner, didn’t they?

There’s a pretty good science fiction book, the Dooms Day Book, by Connie Willis. Won both the Hugo and Nebula Awards (sez so right on the cover). Anyway, one of the neat things in this book is the appearance of a viral epidemic from the past, against which future humanity is defenseless. “I’m afraid Gilchrist was right after all. The virus did come from the past. Out of the knight’s tomb.” (p. 404) Is this art nudging life? There are those who worry greatly about the illicit recovery of either the 1918 pandemic influenza strain or the almost-but-not-really-extinct smallpox from victims frozen in permafrost. Both the fictional and non-fictional scenarios seem equally fantastical to me, not because they’re not possible, but because there’s just so many other good diseases already out there, ready to roll, and because it would be more straightforward (although not necessarily easy) to just engineer a disease.

Still, the notion that you’re a disease jumping the ages, gaining an advantage on a herd that’s long forgotten you, has a certain appeal.

My friend Sara Sawyer and I continue to spar over disease evolution. My position is that we’re bags of meat that attenuated diseases keep around to feed off of. Her position is that our valiant immune systems have fought the vicious pathogens to a stand still. I point out that pathogens evolve thousands of times faster than their hosts, and thus that there is no freaking way that we could keep up. She points out that complex genetic systems may be able to constrain the evolution of simpler genetic systems in a way that boxes the simpler genetic systems into a limited portion of a fitness landscape, where they go through a sort of viral Groundhog Day, waking up and mutating through the same set of genotypes over and over again. Hey, if Chris Rock can be an immune cell (Osmosis Jones), then Bill Murray can damn well be a virus.

It would be pretty awesome if Sara and I were, like, the smartest people ever and we could eventually recollect in our uber-famous recollections those office conversations that set the tone for the revolution in predictive evolution, yada, yada. Nah. We all stand on the shoulders of giants, count on it. Sara (who is also a formidable scholar) pointed out an article from 1973 to me (VanValen, A New Evolutionary Law):

“We can think of the Red Queen Hypothesis in terms of an unorthodox game theory. To a good approximation, each species is part of a zero-sum game against other species. Which adversary is most important for a species may vary from time to time and for some or even most species no one adversary may ever be paramount. Furthermore, no species can ever win, and new adversaries grinningly replace the losers.

From this overlook we see dynamic equilibria on an immense scale, determining much of the course of evolution by their self-perpetuating fluctuations. This is a novel way of looking at the world, one with which I am not yet comfortable. But I have not yet found evidence against it, and it does make visible new paths and it may even approach reality.”

Gives ya shivers, right? It’s like that other famous non-statement, “It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material.” You just know that had to be Crick.

Anyway, again, there is credence to the notion that the past can sneak up on us, that a Lovecraftian virus out of Space and Time could do some damage. Or maybe we would laugh at it, stuck in its rut, one foot of its genome nailed down by our superior immune systems so that it ran in endless circles on its fitness landscape.

Let’s assume the former, just for fun. Besides Ipswich (or perhaps Miskatonic University), where would you look for this virus? Sara also had the great foresight to invite Robert Gifford, from the Aaron Diamond AIDS Research Center, to recently give a seminar on “Paleovirology: investigating the origin and evolution of viruses using genomic fossils.” This was just a kickass seminar, where we got to see all of the dead retroviruses littering our collective genomes. Insertions that swept a population long ago, and that are left in part or in whole, slowly atrophying as they are run over and over and over by DNA polymerases. But that’s the point: they’re very old. Very, very old, in many cases.

And we Know. Their. Sequences. Just like we know the sequences of those youngsters, the 1918 flu and smallpox. But those are just two, and there are literally thousands of retroviral fossils being discovered in the NextGen sequencing revolution that is exploding all around us.

Could it be that we could … recreate … one of these old viruses? And what would it do? I of course immediately suggested the experiment to Sara, and I was pretty excited for about six seconds until she showed me Soll et al. (2010), PNAS 107:19496, “Identification of a receptor for an extinct virus.” But wait, how could researchers actually recreate the virus if, as I’ve asserted, these are dead, atrophied fossils? Ah, the miracles of sequence reconstruction. Based on comparative analysis of many examples of Chimpanzee Endogenous Retrovirus fossils, a consensus, functional envelope gene for CERV was generated. When the protein was expressed on the outside of modern Murine Leukemia Virus particles, it was shown that the so-called psuedoptyped virus could readily enter a variety of primate cells, including human cells.

Wow. Just wow. For all of the depression engendered by bench science, this is the payoff: a story better than any fiction (even yours, Connie Willis). A virus waiting patiently and silently in primate genomes to be reactivated by researchers millions of years later. It wasn’t The Virus Out of Time, The Virus from Another Dimension … it was The Virus from Within!


- originally posted on Wednesday, March 9th, 2011