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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Altering the message

It's always a little startling when something is discovered that ends up explaining... well, damn near everything.

If I exaggerate, it's not by much.  I'm referring to epigenetics, which is the modification of DNA or RNA by chemical changes that don't alter the gene sequence itself.  Usually this is accomplished by adding various "markers" to the strand that then change how it is expressed.  These alterations are at least sometimes inheritable; in 2008, a group of geneticists at Cold Spring Harbor came up with the definition of epigenetics as a "stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence," and that's pretty much the one that still is used today.

[Image is in the Public Domain]

It has led to some pretty startling discoveries.  In a paper in Nature in 2014, geneticist Moshe Szyl showed evidence that mice that were taught (using mild electric shocks) to fear an odor gave birth to offspring that feared the odor as well -- and that heightened fear response lasted for two further generations.  Szyl found that a particular olfactory gene was "demethylated" by the conditioning -- had a marker called a methyl group removed -- and this enhanced the mice's ability to detect the odor, and modified their response to it.  This led to some serious speculation that the children and grandchildren of people who had been through atrocities like the Holocaust might inherit similar enhancements, leading to significant changes in behavior.

If you think this sounds Lamarckian, you're not wrong.  It turns out there is a way to inherit acquired characteristics.  It doesn't work the way Lamarck thought it did, but there was a grain of truth in what the man said.

This comes up because of a paper in Science this week describing evidence that epigenetic marking influences everything from embryonic development to cancer susceptibility to memory formation.  In fact, one such modification -- called m6a -- can do all three depending on which RNA strand it's acting on.  The last one is the most interesting to me; a team led by Chuan He of the University of Chicago found that if you knocked out an enzyme that reads m6a in mice, they have memory defects but are otherwise normal.  They then injected a virus carrying the normal reader gene into the mice -- and the defects went away.

This sounds to me like the basis of as much of a revolution as Mendel's discovery of the gene itself, and the discovery of DNA's structure and function by Rosalind Franklin, Marshall Nirenberg, James Watson, Francis Crick, and Maurice Wilkins.  The idea that a relatively small alteration to our DNA could create inheritable changes without altering the base sequence runs so contrary to both Mendelian inheritance and the "Central Dogma of Molecular Biology" that it looks like it'll force significant revisions to every bit of genetics we thought we understood.

My guess is that they're only beginning to test the depth of this discovery.  "We just need … a lot more knowledge about these things,” He said.  "We need to stay open-minded. The field is still very young."

So maybe I need to change my declaration in yesterday's post that "the twentieth century was [past tense] the century of the gene."  If my intuition is right, we might be on the brink of a whole new chapter -- hell, a whole new textbook -- in our understanding of how genes work.  All of which reiterates something I've believed for years -- that if you're interested in science, you'll never run out of new discoveries to be amazed at.

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This week's Skeptophilia book recommendation is about a subject near and dear to me: sleep.

I say this not only because I like to sleep, but for two other reasons; being a chronic insomniac, I usually don't get enough sleep, and being an aficionado of neuroscience, I've always been fascinated by the role of sleep and dreaming in mental health.  And for the most up-to-date analysis of what we know about this ubiquitous activity -- found in just about every animal studied -- go no further than Matthew Walker's brilliant book Why We Sleep: Unlocking the Power of Sleep and Dreams.

Walker, who is a professor of neuroscience at the University of California - Berkeley, tells us about what we've found out, and what we still have to learn, about the sleep cycle, and (more alarmingly) the toll that sleep deprivation is taking on our culture.  It's an eye-opening read (pun intended) -- and should be required reading for anyone interested in the intricacies of our brain and behavior.

[Note: if you purchase this book using the image/link below, part of the proceeds goes to support Skeptophilia!]