Junk Store Opened: Millions of Bargains

Many moons ago, when I was nobbut a lad and sequencing the human genome was 30 years away, we nevertheless knew that there was something very odd about our genetic code. We knew there were three thousand million base pairs but that only a tiny fraction of that (a few percent) was necessary to encode all the proteins found in our bodies. What was the rest doing? As a sort of explanation two terms came into vogue: ‘selfish DNA’ (meaning stuff that just reproduced itself because it was there) and ‘junk DNA’ meaning everything that didn’t code for proteins.

One of the few predictions I’ve made that turned out to be right was embodied in a refusal to use either term – and if there’s anyone who can recall anything of my supervisions (that is, what the rest of the world calls tutorials) they might back me up on this. It’s true that, as time went by, we increasingly appreciated that non-coding DNA is important in controlling whether individual genes are switched on or off – that is, whether they make RNA and from that protein, according to sequences embedded in the DNA, or whether they make nothing.

Ewen's scheme

However, getting a real grip on what all that seemingly spare DNA is doing has turned out to be so challenging that it is only now, 10 years after the first human sequence was produced, that we have hard data to go on. That unveiling has come from a follow-up called the ENCODE (Encyclopedia Of DNA Elements) programme – an international cooperative of extraordinary scale, with its heart at The Sanger Centre just outside Cambridge and with its head one Ewan Birney. Birney is a computational biologist – a new breed of scientist whose strength lies in bringing to bear methods that make sense of the vast amounts of data generated by current DNA sequencing techniques.

A glance at the summary of what ENCODE involved suggests that, in the unlikely event of his getting bored with science, Birney would make a pretty good fist as Secretary-General of the United Nations. I’d like to try and persuade you that scientists are wonderful and lofty forms of our species but, alas, in fact they are generally ambitious, driven, self-centred, ruthless and intolerant. To make matters worse, quite a few are very smart. To get nearly 500 of the world’s best to sink self-interest and focus on one aim in a multi-national, multi-lingual, multi-racial collaboration that requires rigorous assessment of data and in which the scope for individual glory is almost negligible might well qualify as the greatest feat of man-management in the history of the human race.

So Birney’s a star but what did the world get for its money? The short answer is that we now know that, far from being ‘junk’, most of our DNA – over 80% – does something useful. Whilst only 1.6% carries protein-coding genes, much of the rest is important in regulating the activity of proteins generated from coding genes. The regulatory activity comes in the form of RNA: as we noted just now, DNA makes RNA makes protein – and the DNA sequences involved are called genes. But there’s a second class of genes, ones that transcribe DNA sequence into RNA – but then things stop. The RNA doesn’t go on to direct the making of proteins but rather goes off and regulates well, almost everything. So this second group are non-coding genes – because they don’t ‘make’ proteins.

How does the RNA of non-coding genes work? Well, in essence by sticking to other RNAs and to proteins themselves. What ENCODE has revealed is a panoply of types of RNA that comes in a wide range of sizes and has a finger in almost every bit of the cellular pie. So these varied RNAs act as cellular controllers at many levels and because cancers result from the subversion of normal control you would correctly guess that mutations in non-coding genes can be every bit as important as those that affect protein function directly.

Does this help in dealing with cancer and are there any bargains in the junk store? The short-term answers are ‘no’ and ‘lots – in theory’. As units of this army of RNAs help to control how we work normally, they also can go wrong – become mutated – so we have a new set of potential players in the cancer game. Detecting when individual RNAs join in won’t be so difficult: the real cancer challenge now is not target-spotting, it’s making the bullets to hit the targets.

Reference

Maher, B. (2012). ENCODE: The human encyclopaedia. Nature 489, 46-48.

Birney, E. (2012). The making of ENCODE: Lessons for big-data projects. Nature 489, 49-51.

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Don’t Read This!!

Now here’s something I bet you’ve never thought about. Well I certainly hadn’t when I stepped outside the boundary of ‘science’ and into the world of ‘pop sci’ – aka Betrayed by Nature.

Professional evisceration

To get sciency stuff published you have to endure the dread process of ‘peer review’. Your paper is sent to experts who apply their giant brains, formidable grasp of the subject and sadistic natures to a completely impartial assessment of whether it is of sufficient merit to appear in whichever journal you have favoured with your attentions. Or, put another way, it gets put through a mincer that takes fiendish delight in dissecting every syllable, making ‘suggestions’ that amount to a total re-write and demanding a further series of experiments (to ‘solidify’ the data) that would see you past retirement, if not into the beckoning abyss beyond. If, by combining grovelling submission, bartering, and deviousness you finally get the thing into print, what happens next? Nothing. Not a squeak. The vast majority of papers disappear as surely as if dropped into the Mariana Trench in a lead-lined box. Just occasionally, if a few of the co-authors have Nobel Prizes, you might find your opus clambering up one or another citation index, meaning that some other bunch of numpties have mentioned it in their own feeble scribblings – doesn’t mean they actually read it, of course. And that’s it.

Pop in public

But out in the real world ‘pop’ stuff comes out – and then gets reviewed – so it’s like writing chick-lit (I’ve no idea what that is but I quite fancy having a go). And the critics turn up from all over the place. Their views get emailed to you by well-intentioned friends, someone in the coffee queue regales you (“just seen ….”) or you stumble over one when your surfing fingers inadvertently hit ‘sci reviews’ instead of ‘sex reviews.’

So Monty Python was wrong – you do expect The Spanish Inquisition – that any minute you’ll be dragged naked through the streets of Cambridge – well, emotionally at least. So, after all that, a lady friend has told me to be a man (very naughty to have peeked) and to bravely blog reviews received.

You have been warned!

Reviews of BETRAYED BY NATURE The War on Cancer by Robin Hesketh Palgrave Macmillan 272 pp. £16.99 (2012)

1.  William Hanson, MD, author of The Edge of Medicine: Dr. Hesketh brings an expert’s easy familiarity and depth to this comprehensive, at times almost affectionate, look at a deadly adversary. He tells us what cancer is, what causes it, what we can do to prevent it and how we are systematically battling the disease on many fronts.

2.  Kirkus Reviews (The World’s Toughest Book Critics) 1 March 2012:  Informative, optimistic tour of the science of cancer: Hesketh (Biochemistry/Cambridge Univ.), familiar to lay audiences from BBC radio and TV, opens Part 1 with a capsule history of cancer, ranging from papyrus records of ancient Egypt to the scientific breakthroughs of the 21st century. He follows with a look at the distribution of different types of cancers around the world and what the data suggests about cancer’s causes. Matters get technical in Part 2, but the author assumes little previous knowledge on the part of readers; he takes time to explain DNA, RNA, genes, chromosomes and how some genes mutate into cancer genes. In Part 3 he tackles cancer cells and the behavior of tumors. Throughout Parts 2 and 3, relatively simple diagrams and some black-and-white photographs help to clarify the technical discussions. For most readers, the final section – “Where Are We? Where Are We Going?” – will be of greatest interest. Here Hesketh explains how genome sequencing has begun to change how cancers are diagnosed and classified, and the promise this holds for therapy. We are at the beginning, he writes, of the era of personalized medicine, which holds the promise that we will someday be able to detect the threat of cancer long before it manifests itself by sequencing an individual’s genome and using that information to design an individualized therapeutic strategy. The back matter includes a helpful glossary and two delightful odes to cancer, one written in 1964 by the noted geneticist (and cancer patient) J.B.S. Haldane and the other a modern version by Hesketh.

Despite the author’s occasionally breezy style – “cancer is jolly complicated” – this is not a book to breeze through, but rather a solid account of how cancer works, how it has been combated and what the future holds for its treatment.

https://www.kirkusreviews.com/search/?q=hesketh&x=16&y=13

3.  Nature 485, 579 (31 May 2012): It afflicts one in three people globally and kills more than 7 million a year. Yet cancer is, at base, simply an abnormal growth of cells. In this admirably clear overview, biochemist Robin Hesketh gives us the history, basic science and characteristics of cancer cells, charting how tumours spread and detailing genetics, detection, therapies and drugs. There is much to fascinate — from eighteenth-century physician Percivall Pott’s deduction that there was a link between soot and scrotal cancer in chimney sweeps, to the challenges of treating the biological “hodgepodge” that is a tumour.

http://libsta28.lib.cam.ac.uk:2157/nature/journal/v485/n7400/full/485579a.html

4.  John P. Moore, Professor of Microbiology and Immunology, Weill Cornell: In Betrayed by Nature, Robin Hesketh melds medicine, science and history to create a clear and highly readable explanation of the complexities of cancer.

5.  Interview on The Leonard Lopate Show: lopate050812apod.mp3

6.  For Amazon reviews see their web site.