Tiny But Perfectly Formed

Regular readers (assuming the plural is appropriate) will know that our remit is to explain new developments in cancer. So numerous, multi-faceted and remarkable are these that we have been obliged in the past to offer explanation, if not apology, for surfeits of superlatives. So there is no requirement to step outside the admittedly broad acres of cancer biology to inform, astonish and amaze. Nevertheless, a change is said to be as good as a rest and for this we will make a rather pathetic bipedal excursion into the six-legged world that makes up, we estimate, more than 90% of all the different life forms on earth.

Meet the family

Yes, it’s the insects that have caught our eye – specifically a species of planthoppers by the name of Issus coleoptratus. They’re members of the Issidae family which alone includes about 1000 distinct species – a staggering thought, although if you bear in mind that there are approaching 10 million insect species around, clearly each family needs to contribute its bit. The Issidae was first described by one Maximilian Spinola – who was indeed descended from the celebrated Genoese family, pre-eminent during the high-water period of that city-state between the 12th and 14th centuries.

Issus nymph. Photo by Malcolm Burrows

Issus nymph. Photo by Malcolm Burrows

The Issidae are common in Britain and Europe but they’re unusual in that, although they still have wings, they’ve lost the ability to fly. But if you didn’t know already you’ll have guessed that they’ve made up for this in terms of getting around by working hard on their leg muscles. So much so that the nymphs (which, delightfully, is what the insect folk call the immature form – just a couple of millimeters long before it metamorphoses into a grown-up) can jump up to 40 cm – more than 100 times their length.

As you might suppose, to achieve such calisthenic feats the nymphs need their back legs to be as coordinated as possible – not least to prevent them veering off in random directions, rather like the man-powered flight loonies who jump off London Bridge.

Electrical v. mechanical

Somewhat surprisingly, it’s emerged that electrical signalling via the nervous system isn’t good enough for this coordination. Malcolm Burrows and Gregory Sutton from Cambridge and Bristol Universities, respectively, have shown that to get both legs to kick off within 30 microseconds, the Issus make interacting gears that, in effect, lock their legs together. That’s an astonishing finding because although we know that proteins can do anything – form cables, bridges and travelators as well as pumps, rotating flagella and even motors (such as the ATP synthase of mitochondria) – a toothed wheel is a first. Even against a backdrop of such amazing, multi-component machines, it’s a staggering sight – the more so as Burrows and Sutton estimate that on take-off the gears whiz round to the tune of over 33,000 revolutions per minute!

Gearwheels of the flightless planthopper insect Issus

Gearwheels of the flightless planthopper insect Issus

There are, of course, other great leapers in the insect world but those that have been examined use friction for synchronization – grippy legs if you like. So it’s a bit of a mystery that this planthopper has come up with such a sophisticated locking system. But that’s not the only remarkable thing about these little chaps because as they grow into adolescents they go through a kind of moulting process in which they shed their exoskeleton for an upgrade – including progressively bigger gears. How incredible is that? But having gone to all this trouble the final amazing twist is that the gears vanish when nymph becomes adult! So for the rest of their lives they too rely on non-slip legs.

Burrows and Sutton hazard that, although mechanical gears are the most efficient way of linking both legs at kick-off, they carry a big risk for prolonged use – damage a tooth and the chances are you’ll end up on someone’s menu. So better a somewhat less efficient system that is not liable to failure. Exactly how I justified driving an Austin A35 for many years.

One Giant Leap For Mankind

So these marvellous juveniles, less than half a centimeter long, pull off a trick equivalent to me jumping the length of the Melbourne Cricket Ground with so much to spare I land somewhere in the stands. No question, it gives a new meaning to the term ‘jumping genes’ that, you may recall, are stretches of DNA that can be shifted around the genome. They were discovered 60-odd years ago in maize by Barbara McClintock who came from Hartford, Connecticut and remains the only woman to win the Nobel Prize for Physiology or Medicine on her own.

How Did You Know That?

Well, the thing is we now know that these athletic DNA fragments can sometimes land in the wrong place – meaning that they disrupt normal genes. If that sounds suspiciously like a type of mutation it is, and the insertion of a jumping gene can act as a cancer-promoter. By which ingenious piece of circuitry we bring ourselves back to cancer – where we should be – having nevertheless thoroughly enjoyed our visit to the insect Olympics.

References

Burrows, M. and Sutton, G. (2013). Interacting Gears Synchronize Propulsive Leg Movements in a Jumping Insect. Science 341, 1254-1256.

http://www.extremetech.com/extreme/166493-evolution-delivers-the-first-mechanical-gear-found-in-a-living-creature

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Dyslexic DNA

Writing in code

Did you notice a few months back that some boffins had written a book in DNA? No, that’s not a typo: what they did was to transcribe a 53,000 word book – plus pictures – into a synthetic DNA sequence. In essence, they re-wrote the book in binary by taking the four bases that make the genetic code of life and setting A and C to equal zero whilst G or T represented one. The result wasn’t without its typos: in the just over five million bits needed there were ten mistakes. So rather better than my touch-typing then. But there was a real commercial point behind this exercise, aside from showing, yet again, the astonishing coding capacity of our genetic material. One gram of DNA (you’ve got 500 grams) can store more than 100 billion DVDs, so not merely is it the ultimate in compacted data but it’s amazingly tough stuff – think of sequencing the woolly mammoth, in the freezer for thousands of years – by comparison with the latest software updates for my computer which usually mean I can’t read files 10 years old. And if I dig out my 20 year old 35 mm slides from the attic, chances are they’ll adorned by fungal growths.

Genetic switches

So DNA’s great for long-term information storage but this was by no means the first attempt to use biological molecules in ways we normally associate with electronic devices. When the code of DNA is ‘read’ to make an intermediate (RNA) from which, in turn, proteins can be made it’s acting as a biological transistor: a switch and amplifier that responds to an input signal. The DNA code ‘reader’ is a molecular machine called RNA polymerase (RNA pol) that moves step-wise along a strand of DNA, adding units one at a time to a growing molecule of RNA, complementary in sequence to the DNA template. This process is called ‘transcription’. In its wake another molecular machine can ‘translate’ the RNA codes into protein. RNA pol therefore ‘flows’ along a strand of DNA rather like a current of electrons through a transistor and, because RNA can makes lots of copies of a protein, the system has built-in amplification. Input control is via proteins that stick to segments of DNA called promoters and ‘switch on’ RNA pol (i.e., an analog input). After that the sequence of DNA itself can, in effect, say either ‘go’ or ‘stop’: short sequence motifs can wave RNA pol through or make it stall. The output signal is the protein made – and if you make green fluorescent protein (GFP) you can shine light on it and measure how much you’ve got from the fluorescence emitted.

Over the last few years a number of such gadgets have been made and inserted into bacterial cells to work as simple digital logic gates. In electronic-speak these have included DNA AND gates (giving a high output only if two inputs are high) and OR gates (a high output if one or both the inputs to the gate are high). They’re genetic transistors, processing signals like the logic gates built from transistors that, in combinations of billions, are the basis of computer memory and microprocessors.

Throwing a DNA switch

Throwing a DNA switch

So what’s new?

For biological gates the problem has been that each needs its own construct (a DNA plasmid) and to make more complicated bits {e.g., EXCLUSIVE OR (XOR) gates (high output only if the inputs are different) or EXCLUSIVE NOR (XNOR) gates (output high only if inputs equal)} lots of constructs are required, each having to be persuaded to enter bacteria and to work in a stable fashion.

Step forward Drew Endy and colleagues from Stanford who, by dint of some very clever molecular biology, have combined multiple logic elements into a single construct – which they call a ‘transcriptor’. The switching capacity of their devices comes from integrases – enzymes made by viruses that infect bacteria – that can invert (flip) short stretches of DNA. These can be designed as switchable ‘go’ or ‘stop’ signals for RNA pol. Back in the 1940s Barbara McClintock, working on maize, discovered that stretches of DNA can be shifted around within the genome – they’re called ‘transposons’ – and integrases do the same thing as the enzymes that switch transposons around. McClintock remains, incidentally, the only lady to win a Nobel Prize for Medicine on her own. The great thing about integrases is that they can be turned on simply by adding the appropriate activator to the medium surrounding the cells.

This remarkable advance means that essentially any kind of gate can be built into a single, synthetically made genetic transistor, regulated by a range of integrases. The potential is somewhat mind-boggling but includes being able to monitor in real time the effects of drugs on the behavior of individual cells.

When John Bardeen, Walter Brattain and William Shockley (a Brit by origin but really another Stanford man) invented the transistor (they got the 1956 Nobel Prize in Physics) they can have had little idea of the impact it would have on mankind. But they really would have been staggered to know that, 60 years on, their successors would be shaping our genetic material to act as semiconductors in living cells.

Anything else?

So, as far as I can see, Drew Endy and his chums have done pretty well everything except build an EOR gate that responds to any input with “Don’t blame me”. But they’re such smart guys I bet they’ve got one of those in the fridge too – it was just that the journal editor lacked a sense of humour and wouldn’t publish it. Science editors have form in this department – recall the tale of Albert Szent-Gyorgyi who, whilst a member of my department back in the 1920s, isolated ascorbic acid (the vitamin that stops you getting scurvy) and, convinced it was a sugar (so it should have the suffix -ose – it’s actually made from glucose by oxidation) but not knowing the exact structure, sent his results to the Biochemical Journal calling it ‘ignose’. When the editor said ignose was silly Albert suggested ‘godnose’, getting a predictable response!

References

http://www.guardian.co.uk/science/2012/aug/16/book-written-dna-codehttp://www.huffingtonpost.com/2013/03/29/biological-computer_n_2981753.html

Bonnet, J., Yin, P., Ortiz, M.E., Subsoontorn, P. and Endy, D. (2013). Amplifying Genetic Logic Gates. Science 28 March 2013 / Page 1/ 10.1126/science.1232758http://www.sciencemag.org/content/early/recent