Graphic design, error, and accidental learning

Graphics: Cover design for The Scientist’s Guide to Writing (Princeton University Press, April 2016). Twirling DNA: by brian0918; own work, released to public domain, via wikimedia.org. DNA structures: by Thorwald, released to public domain via wikimedia.org.

Warning: an unusual foray into biochemistry is coming at you. Stick with it, though; there’s an interesting story here, on a couple of levels.

If you’ve been reading Scientist Sees Squirrel, you probably haven’t missed my occasional oh-so-subtle references to my forthcoming writing book, The Scientist’s Guide to Writing (Princeton, April 2016). I was very excited last month to finally see the cover design, and last week to be given the all-clear to release it publicly. I did so on Twitter, but within hours three sharp-eyed followers replied to my celebratory tweet with the news that there was something wrong with the graphic design. “Oh, sugar”* I said, and rushed off to consult with two molecular-biology colleagues to confirm my fears.

Can you spot the problem? (I’ve given you a hint mentioning my molecular biology colleagues.) I’ll give you a chance to think about it, then click here for the answer.
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There are two “errors”, actually. First, the DNA molecule arcing gracefully across the page is backwards: it’s a left-handed double helix, not a right-handed one – and we all know (don’t we?) that DNA is a right-handed helix. (If the molecule is oriented vertically like a ladder, the closer strand should go from lower left to upper right; the structure on the book cover does the reverse). Second, on the book cover the two strands are evenly spaced. Really, the distance between strands should be less than half the length of a turn, giving rise to alternating “major grooves” and “minor grooves”. You can see both of these features in the rather hypnotic animation at right. Now, I’d love to throw all the blame on the graphic designers who did the cover, but the truth is, they sent me the proposed design and I didn’t notice a thing. If you did notice, you’re a better molecular biologist than me**.

But wait – I put some quotation marks around “error” in that last paragraph. It’s time for your second test: why might I argue that the cover design isn’t wrong after all? Again, take a moment to think, then click here to find out.

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The answer?  Although I won’t pretend we did this on purpose, in fact the structure pictured does occur for DNA in nature. It’s Z-DNA (or at least, not a bad stylized representation of it): a left-handed conformation with little difference between major and minor grooves. I’d never heard of Z-DNA, but once someone mentioned it, I tracked it down. The Z conformation isn’t stable under most conditions, and the enormous majority of DNA in nature is in the typical B conformation instead (the graphic to the side shows A, B, and Z conformations, from left to right). The Z conformation is stable under some conditions, though: for instance, in a solution of high salinity, when supercoiled, when modified by cytosine methylation, or when its sequence alternates purine and pyrimidine bases (like …GCGCGCGCGCGCGCGC…). Every biology student learns how Rosalind Franklin’s X-ray diffraction data helped establish the double-helix model; but few learn that when single-crystal X-ray diffraction data came along in the 1970s, the first data showed not the right-handed helix but the left-handed Z conformation instead. Of course, this didn’t imply any biological importance for Z-DNA – only that it can form under crystallizing conditions.

It turns out, though, that the Z conformation does matter (Rich and Zhang 2003, Nature Reviews Genetics 4:566, provide a dated but readable review). For at least some genes, when DNA is unwound from nucleosomes to begin transcription, sequences near the transcription start site can temporarily take the Z conformation, and because they do, nucleosomes can’t reassemble and the DNA strands remain accessible for binding of the transcription machinery. On the other hand, Z -prone sequences in other locations can interfere with that same binding, and suppress the action of promoters and thus transcription (Huang et al. 2015, Acta Biochim Biophys Sin 47:567, but be warned this one isn’t written for the faint-of-heart). If that isn’t complicated enough for you, there’s also an enzyme (double-stranded RNA adenosine deaminase) that binds Z-DNA and edits base sequence such that a sequence in Z-conformation can yield a different protein product from the same sequence in B-conformation. Furthermore, Z-DNA binding proteins seem to be involved in pathogenicity of some viruses, including (probably) smallpox. Phew!

So Z-DNA is real, not just chemically but biologically. But what really fascinates me about Z-DNA is biochemists’ reaction to it. Rich and Zhang opened their review this way: “Biologists were puzzled by the discovery of left-handed Z-DNA because it seemed unnecessary”. In other words, Z-DNA didn’t – and still doesn’t – seem to provide cells with any functionality that couldn’t be established by other means. But this reaction is, of course, just (some) biochemists coming late to the evolutionary party! An evolutionary ecologist would never flinch at odd, kludgy, or suboptimal design – that’s what natural selection produces, and the origin of life’s incredible kludgy complexity by the supremely simple process of selection is what makes biology beautiful.

OK, let’s put down the chemical structures and back away. What can we learn from all this?

• Most obviously, I should pay closer attention to graphic art, especially when it pushes at the boundaries of my own expertise! Actually, I’m not the only one to be forced into this realization, even just with respect to structure of DNA, which is why I include this point on a list of what “we” can learn from #Z-DNAGate.
• What I think of as molecular mechanics – the physical interaction of molecules in the cell, and how their shapes and movements matter to that – is really cool, and even richer than I knew. Who could have imagined that the DNA double-helix inside your cells is occasionally, locally, and temporarily turning itself inside-out to reverse the handedness of its coiling, and that this could be involved in regulating gene transcription?
• The wonderful kludginess of biology isn’t just a matter of pandas’ thumbs. It’s kludges all the way down, to the very structure of the most fundamental of biological molecules.
• I’ve blogged before about kludginess and accidents in the way we do science. But there’s kludginess and there are accidents in the way we learn about science, too – providing we keep our eyes and ears open and respond to challenge with inquisitiveness, not defence. I was horrified by the “error” on my book’s cover when the issue was first raised – but now, with some learning behind me and the story of Z-DNA firmly impressed on my brain, I’m tickled pink. Well, maybe not quite that, but definitely pleased. I hope you’re the same.

© Stephen Heard (sheard@unb.ca) March 7, 2016

Thanks to Julie Blommaert, Matthew Cobb, Glendon Mellow, and Adam Rutherford for pointing out the non-canonical nature of my book’s DNA, and for hints that led me to track down the Z-DNA biochemistry discussed here. Also thanks to Bryan Crawford and Shawn MacLellan, my go-to colleagues in molecular biology, for walking me through “normal” DNA structure.

Related posts:

• The Scientist’s Guide to Writing
• Is biology beautiful?
• Wonderful Scientific Names 6: Syzygium aromaticum
• Creativity, play, and science

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*^Well, that may not have been exactly what I said. My mother used to say “Oh, sugar”, though, thus revealing her belief in a deity who was simultaneously omniscient enough to monitor everything she said, and dumb enough not to cotton onto how she was trying to fake Him out. This line of thought makes it really fascinating how many expressions we use that are paper-thinly veiled instances of things we wouldn’t actually say in the same circumstances.

**^Except don’t feel too proud: I’m not a molecular biologist at all, and I did give you the rather major hint that there was a problem to look for!

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