The viral accelerator

It's virus season, which thus far I've been able to avoid participating in, but seems like half the people I see are hacking and snorting and coughing so even with caution and mask-wearing I figure it's only a matter of time.  Viruses are odd beasts; they're obligate intracellular parasites, doing their evil work by hijacking your cellular machinery and using it to make more viruses.  Furthermore, they lack virtually all of the structures that cells have, including cell membranes, cytoplasm, and organelles.  They really are more like self-replicating chemicals than they are like living things.

Simian Polyoma Virus 40 [Image licensed under the Creative Commons Phoebus87 at English Wikipedia, Symian virus, CC BY-SA 3.0]

What is even stranger about viruses is that while some of the more familiar ones, such as colds, flu, measles, invade the host, make him/her sick, and eventually (with luck) are cleared from the body -- some of them leave behind remnants that can make their presence known later.  This behavior is what makes the herpes family of viruses so insidious.  If you've been infected once, you are infected for life, and the latent viruses hidden in your cells can cause another eruption of symptoms, sometimes decades later.

Even weirder is when those latent viral remnants cause havoc in a completely different way than the original infection did.  There's a piece of a virus left in the DNA of many of us called HERV-W (human endogenous retrovirus W) which, if activated, can trigger multiple sclerosis or schizophrenia.  Another one, Coxsackie virus, has an apparent connection to type-1 diabetes and Sjögren's syndrome.  The usual sense is that all viral infections, whether or not they're latent, are damaging to the host.  So it was quite a shock to me to read a piece of recent research that there's a viral remnant that not only is beneficial, but is critical for creating myelin -- the coating of our nerve cells that is essential for speeding up nerve transmission!

The paper -- which appeared last week in the journal Cell -- is by a team led by Tanay Ghosh of the Cambridge Institute of Science, and looked at a gene called RetroMyelin.  This gene is one of an estimated forty (!) percent of our genome that is made up of retrotransposons, DNA that was inserted by viruses during evolutionary history.  Or, looking at it another way, genes that made their way to us using a virus as a carrier.  Once inside our genome, transposons begin to do what they do best -- making copies of themselves and moving around.  Most retrovirus-introduced elements are deleterious; HIV and feline leukemia, after all, are caused by retroviruses.  But sometimes, the product of a retroviral gene turns out to be pretty critical, and that's what happened with RetroMyelin.

Myelin is a phosopholipid/protein mixture that surrounds a great many of the nerves in vertebrates.  It not only acts as an insulator, preventing the ion distribution changes that allow for nerve conduction to "short-circuit" into adjacent neurons, it is also the key to saltatory conduction -- the jumping of neural signals down the axon, which can increase transmission speed by a factor of fifty.  So this viral gene acted a bit like a neural accelerator, and gave the animals that had it a serious selective advantage.

"Retroviruses were required for vertebrate evolution to take off," said senior author and neuroscientist Robin Franklin, in an interview in Science Daily.  "There's been an evolutionary drive to make impulse conduction of our axons quicker because having quicker impulse conduction means you can catch things or flee from things more rapidly.  If we didn't have retroviruses sticking their sequences into the vertebrate genome, then myelination wouldn't have happened, and without myelination, the whole diversity of vertebrates as we know it would never have happened."

The only vertebrates that don't have myelin are the jawless fish, such as lampreys and hagfish -- so it's thought that the retroviral infection that gave us the myelin gene occurred around the same time that jaws evolved on our branch of the vertebrate family tree, on the order of four hundred million years ago.

So even some fundamental (and critical) traits shared by virtually all vertebrates, like the myelin sheaths that surround our neurons, are the result of viral infections.  Just proving that not all of 'em are bad.  Something to think about the next time you feel a sore throat coming on.

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Inner space

Donald Rumsfeld famously said, "There are known knowns.  These are things we know that we know.  There are known unknowns.  That is to say, there are things that we know we don't know.  But there are also unknown unknowns.  There are things we don't know we don't know."

At the time, much fun was made of his choice of words.  But although I wouldn't choose this as an exemplar of clarity, I have to admit the point he was making is valid enough.  Sometimes discovery starts with determining exactly what it is we don't yet know, with sketching out what astrophysicist Neil deGrasse Tyson (more eloquently) called "the perimeter of our ignorance."

This is the point of the Unknome Project, which is an effort to take our own genome and figure out what parts of it are, at present, unstudied and unexplained.  Cellular biologist Seth Munro and his colleagues at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England, have developed a catalogue of thirteen thousand gene families found in humans (or other mammals that have been sequenced), coding for over two million proteins, and assigned each a "knownness score" -- a number describing to what extent the function of each is understood.  And three thousand of the families -- a little less than a quarter of them -- have a knownness score of zero.

That's a lot of genes that were (at least before Munro et al.) unknown unknowns.

[Image licensed under the Creative Commons Christoph Bock, Max Planck Institute for Informatics, DNA methylation, CC BY-SA 3.0]

What's even cooler is that the group is working to chip away at this bit of the perimeter of our ignorance, and to learn something about the mysteries of our own genetic inner space.  They found 260 genes with low knownness scores that are also present in fruit flies -- a much easier species to study -- and used a technique to suppress the expression of those genes.

Astonishingly, reducing the expression of sixty of these hitherto-unknown genes killed the flies outright.  Dampening others inhibited such important functions as reproduction, growth, mobility, and resistance to stress.

If these poorly-studied genes have analogous effects in humans -- and it's suspected that they do, given that they were evolutionarily conserved since the last common ancestor of humans and fruit flies, something like a half a billion years ago -- that's a lot of critical parts of our genome we don't yet understand.

What it got me wondering is how many of these are involved in diseases for which we haven't yet determined the causes.  There are so many disorders -- like, unfortunately, most mental illnesses -- for which the treatments are erratic at best, in part because we don't know for sure what the underlying origin of the condition is.  In my own case, I know for sure that depression and anxiety run in both sides of my family -- my mother and maternal grandmother both suffered from major depression, and a paternal great-grandmother committed suicide after (according to the newspaper article that reported it) "becoming mentally unbalanced by the illness of her husband."  Part of the problem with these sorts of things is, of course, that it's hard to tease apart the genetic from the environmental factors.  Growing up with mental illness in the family certainly doesn't make for an easy childhood; as my wise grandmother once said, "Hurt people hurt people" -- something that was certainly true enough within her own family.

It's fantastic that Munro and his colleagues are working to try and elucidate the functions of these mysterious genes, and I hope that perhaps some of them might turn out to be good targets for medications to alleviate conditions that have heretofore been resistant to treatment.  Certainly, anything we can do to reduce the perimeter of our own ignorance -- to eliminate some of those unknown unknowns -- is a good thing.

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