Skeptophilia (skep-to-fil-i-a) (n.) - the love of logical thought, skepticism, and thinking critically. Being an exploration of the applications of skeptical thinking to the world at large, with periodic excursions into linguistics, music, politics, cryptozoology, and why people keep seeing the face of Jesus on grilled cheese sandwiches.

Friday, August 11, 2023

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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