Water Street Press Speaks

Writing a pop science book (or more precisely, getting one published) has, to use the contemporary argot, been something of a life-changing experience. That simply means finding yourself doing strange things and meeting wonderful people that otherwise you would never have encountered. In the former category comes giving a stand-up routine on the stage of The Cambridge Union Society  as part of a Science Festival show compered by the comedian Robin Ince. In the latter comes Lynn Vannucci. An author herself, she was simply amazing in editing the final version of the book, and from this has blossomed a friendship that I treasure. She has since set up her own publishing company, Water Street Press, the aims of which promise a new world for authors. This review is from the WSP website.

Water Street Press review of Betrayed by Nature: The War on Cancer:

“When one door closes another opens but we often look so long and regretfully upon the closed door that we do not see the one that has opened for us” – Alexander Graham Bell.

Lynn Vannucci, founder of Water Street Press

Lynn Vannucci, founder of Water Street Press

The fall of 2011 was a time of closing doors. Some of those doors I pulled shut myself. I was just starting to get a grip on both the enormous workload of, and the enormous opportunity in, becoming a publisher; clarity of purpose brought with it the need to clean house or clear paths or otherwise remove obstacles, and cleaning and clearing, while sometimes necessary, are time sucks and can be absolute spirit sappers.

Other doors felt as if they were being slammed in my face. A man named Daniel G. Reinhold—biologist, silversmith, computer genius, art collector, raconteur, crack shot, dog lover, father figure and (affectionately) Ogre—passed away, as did, in his absence, a part of my youth.

In the midst, then, of what was not a little bit of personal turmoil, I was asked to work on a book that was, at the time, called “Delinquent Genes,” about understanding cancer from the perspective of genetics—both the history of the disease and the strides that have been made in treating it. Now, if any of my old high school science teachers are reading this, they will be guffawing at the notion that I would be asked to work on such a book; none of them will remember me as their best student. But that’s exactly the value I bring to a book like this: I’m a filter. If I can understand the science, then the vast reading public, who are like me and not scientists, are going to understand it, too.

That doesn’t mean that biochemistry isn’t a stretch for me. But Robin Hesketh, the author of the book, has been a teacher in the Department of Biochemistry at the University of Cambridge and a fellow of Selwyn College for over twenty-five years; fortunately for me, and for his readers, he is a very, very good teacher.

The best part of working on the book, however—indeed, the best part of the book itself—is Robin, himself. The life of one out of every three people is going to be impacted by cancer; Robin was passionate about writing a book that would be of use to them—people who needed to understand the disease but who started out, as I had, with very little scientific background. When I didn’t understand a piece of the material, he was not only patient about explaining it yet again, his enthusiasm to do so never faltered. Cancer can be a devastating disease; Robin has spent his life studying it—has, like so many of us, suffered loss from it—and yet has not lost a charming, open optimism.

Optimism, like passion, is contagious. In the midst of a few tough months, working on a book about cancer was exactly the cure I needed. Betrayed by Nature is an important book—and it opened the door to a new and wonderful friendship.

Go here to buy Robin’s book, http://www.amazon.com/Betrayed-Nature-War-Cancer-Macsci/dp/0230338488, and go here, to his blog, for ever more information from this tireless and excellent teacher https://cancerforall.wordpress.com.

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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