Just how different is one brain cell from another? I mean, every cell in our body has the same genome, so the differences in type (various neurons, glial cells) must be due to expression during development. And the differences between individual members of a class must be all due to local environment and growth – right?
Maybe not. I wasn’t aware of this myself, but there’s a growing body of evidence that suggests that neurons might actually differ more at the genomic level than you’d imagine. A lot of this work has come from the McConnell lab at the Salk Institute, where they’ve been showing that mouse precursor cells can develop into neurons with various chromosomal changes along the way. And instead of a defect (or an experimental artifact), he’s hypothesized that this is a normal feature that helps to form the huge neuronal diversity seen in brain tissue.
His latest work used induced pluripotent cells transformed into neurons. Taking these cells from two different people, he found that the resulting neurons had highly variable sequences, with all sorts of insertions, deletions, and transpositions. (The precursor cells had some, too, but different ones, suggesting that the neural cell changes happened along the way). And this recent paper suggests that neurons have an unusual number of transposons in their DNA, which fits right in with McConnell’s results.
The implication is that human brains are mosaics of mosaics, at the cell and sequence levels. And that immediately makes you wonder if these processes are involved in disease states (hard to imagine how they wouldn’t be). The problem is, it’s not too easy to get ahold of well-matched and well-controlled human brain tissue samples to check these ideas. But that’s the obvious next step – take several similar-looking neurons and sequence them all the way. Obvious, but very difficult: single-cell sequencing is not so easy, to start with, and how exactly do you grab those single neurons out of the tangle of nerve tissue to sequence them? Someone’s going to do this, but it’s going to be a chore. (Note: McConnell’s group was able to do the pluripotent-cell-derived stuff a bit more easily, since those come out clonal and give you more to work with).
Now, the idea that neurons are taking advantage of chromosomal instability to this degree is a little unnerving. That’s because when you think of chromosomal instability, you think of cancer cells (See also the link in that last paragraph. It’s interesting, as an aside, to see that those last two are to posts from this blog in 2002 – next year will mark ten years of this stuff! And I also enjoy seeing my remark from back then about “With headlines like this, I can’t think why I’m not pulling in thousands of hits a day”, since these days I’m running close to 20K/day as it is).
So, on some level, are our brains akin to tumor tissue? You really wonder why brain cancer isn’t more common than it is, if these theories are correct. There may well be ways to get “controlled chromosomal instability”, though, as opposed to the wild-and-woolly kind, but even the controlled kind is a bit scary. And all this makes me think of a passage from an old science fiction story by James Blish, “This Earth of Hours”. The Earthmen have encountered a bizarre civilization that seems to involve many of the star systems toward the interior of the galaxy, and a captured human has informed them that these aliens apparently have no brains per se:
“No brains,” the man from the Assam Dragon insisted. “Just lots of ganglia. I gather that’s the way all of the races of the Central Empire are organized, regardless of other physical differences. That’s what they mean when they say we’re all sick – hadn’t you realized that?”
“No,” 12-Upjohn said in slowly dawning horror. “You had better spell it out.”
“Why, they say that’s why we get cancer. They say that the brain is the ultimate source of all tumors, and is itself a tumor. They call it ‘hostile symbiosis.’ ”
“In the long run. Races that develop them kill themselves off. Something to do with solar radiation; animals on planets of Population II stars develop them, Population I planets don’t.”
The things you pick up reading 1950s science fiction. Blish, by the way, was an odd sort. He had a biology degree, and a liking for James Joyce, Oswald Spengler, and Richard Strauss. All of these things worked their ways into his stories, which were often much better and more complex than they strictly needed to be. Here’s a PDF of “This Earth of Hours”, if you’re interested – it’s not a perfect transcription, though; you’ll have to take my word for it that the original has no grammatical errors. It’s a good illustration of Blish’s style – what appears at first to be a pulpy space-war story turns out to have a lot of odd background dropped into it, along with speculations like the above. And for someone who didn’t always write a lot of descriptive prose, preferring to let philosophical points drive his plots, I find Blish’s stories strangely vivid, particularly the relatively actionless ones like “Beep” or “Common Time”. He’s pretty thoroughly out of print these days, but you can find the paperbacks used, and in many cases as e-books. Now if you’re looking for someone who always lets philosophical points drive his stores, then you’ll be wanting some Borges. (As it happens, I’ve had occasion to discuss that particular translation with an Argentine co-worker. But this is not a literary blog, not for the most part, so I’ll stop there!)