Abstract
For James Watson, ‘A structure this pretty just had to exist’. 1 For Maurice Wilkins, ‘The structure was too perfect to be wrong’. 2 Horace Judson, in his magisterial history of molecular biology The Eighth Day of Creation, described it as ‘flawlessly beautiful … truly for the first time at the ultimate biological level structure had become one with function’. 3 And, ever since Watson and Crick's letter to Nature of April 25 1953 – with its famous throwaway line ‘it has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material’ – science has been seduced by the elegant simplicity of the double helix into supposing that if we could only decode its genetic instructions, we would understand the programme that makes an organism. 4
And, from the mid 1970s onwards, the massive onslaught of the techniques of modern genetics promised to do just that. ‘The search for the Holy Grail of who we are has now reached its culminating phase,’ observed Professor Leroy Hood of the California Institute of Technology at the launch of the Human Genome Project in 1991. 5 Those techniques would, anticipated Professor John Savill of Nottingham's University Hospital, ‘like a mechanical army systematically destroy ignorance … promising unprecedented opportunities for science and medicine’. 6 The explosion in basic biological data generated by those techniques has long since ‘gone nuclear’ with dozens more genomes sequenced from mouse to platypus, the ‘variomics’ of the SNP studies, with many more gigabytes worth of data from proteomics and epigenomics still to come.
And yet, for all that new knowledge has delineated the genetic mutations responsible for cystic fibrosis, the haemoglobinopathies and other monogenic disorders, and the ingenious techniques of biotechnology that have given us human insulin and other therapeutically useful compounds, the practical benefits of all this endeavour seem surprisingly modest, while the mechanisms of genetic inheritance now appear more elusive than ever.
The recent unexpected findings of the massive Genome Wide Association Studies (GWAS) are a case in point. We know from twin and adoption studies stretching back over the past 100 years that the genetic contribution to the physiological variables of height and weight is between 80–90%. But while the GWAS studies have successfully identified no less than 40 genetic determinants of stature, together they turn out to account for less than 5% of height heritability. 7, 8, 9, 10 And it is the same story for those common disorders such as diabetes, schizophrenia and cancer where, as the journal Nature has pointed out, ‘Even when dozens of genes have been linked to a trait, both the individual and cumulative effects are surprisingly small and nowhere near enough to explain earlier estimates of heritability’. 11
‘The Case of the Missing Heritability’ as it has been dubbed, prompted Steve Jones, Professor of Genetics at University College, to argue in an article in the Daily Telegraph early last year that the current direction of genetics research ‘is just plain wrong … The mountain has laboured and brought forth not much more than a mouse’. 12 His remarks struck a resonant chord, with a clutch of prominent surgeons commending ‘so eminent a geneticist’ for confirming ‘what clinicians have felt in their bones for years – that little of value is likely to emerge from the massive investment in genetic research’. 13
But their reasonable plea for a redirection of funding to clinical research will be of little avail without some intellectual understanding of why those ‘unprecedented opportunities for science and medicine’ have so conspicuously failed to materialize. The standard response would be that it has all turned out to be much more complicated than previously supposed but that with time (and yet more generous funding) all will eventually become clear. The two most significant (if hardly acknowledged) findings of the genome projects of the past decade would suggest otherwise.
Those projects were predicated on the entirely reasonable assumption that spelling out the full sequence of genes of worm, fly, mouse, man and others must, to a greater or lesser extent, account for those particularities of form and attribute that so readily distinguish one form of life from another. But, on the contrary, the situation has turned out to be virtually the reverse of that anticipated with a near equivalence of a (modest) number of around 20,000 genes across the entire range of organismic complexity all the way from the millimetre-long worm Caenorhabditis elegans to ourselves. 14
Next comes the (astonishing) revelation of the interchangeability of the regulatory or homeotic genes where, for example, the same Pax 6 gene that orchestrates the formation of the fly's compound eye, does so, too, for our very different camera-type eye – and so on. 15 There is, in short, nothing in the genomes of fly and man to account for why a fly should have two wings, four legs and a dot-sized brain and we should have two arms, two legs and a mind capable of understanding the origins of the universe.
The genetic instructions must be there of course for otherwise the diverse forms of life would not reproduce themselves with such fidelity from generation to generation. But we have moved, in the light of these extraordinary findings, from supposing those instructions are at least knowable in principle to recognizing we have no conception of what they might be.
It might seem futile to enquire why this might be so but the explanation must lie in that flawless beauty of the double helix that for so long has held out the promise of understanding ‘the secret of life’. The simple elegance of its structure cannot be because it is simple, but because it has to be simple – if it is to ‘copy the genetic material’ every time the cell divides.
And that obligation to be simple requires the double helix to condense within the one dimensional sequence of nucleotides strung out along its intertwined strands, the billionfold biological complexities that determine the unique three dimensional form and attributes that so readily distinguish flies from ourselves – and the tens of millions of species, living and long since extinct. The semblance of simplicity then becomes a measure of the double helix's inscrutable profundity. Or, as Philip Gell, Professor of Genetics at the University of Birmingham, anticipated so presciently 20 years ago ‘The gap in our knowledge is not merely unbridged, but in principle unbridgeable, and our ignorance will remain ineluctable’. 16
This is not to deny the substantial contribution of genetics of the recent past, but that cannot obscure the ‘higher truth’ that the question of what might conjure the near infinite diversity of the living world from the monotonous sequence of nucleotides strung out along the double helix would seem, in the current state of knowledge, irresoluble. For the moment it would be good to think, as those prominent cancer surgeons urged, that funding and grant-giving bodies might favour potentially more fruitful avenues of research over yet more genomic and proteomic studies whose gigabytes of undigested facts threaten to bury the true spirit of scientific enquiry.
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