The Rise and Fall of Modern Medicine (56 page)

Prior to the completion of the Human Genome Project the quest for the genetic defect in those single gene disorders such as sickle cell anaemia or cystic fibrosis was relatively straightforward, though extremely arduous. Compare the sequence of, say, the haemoglobin genes in those with and without sickle cell disease and it is possible to infer that any difference in the arrangement of the CGAT letters is likely to be the genetic cause. But the situation with common disorders such as diabetes is much more difficult. They are, to start with, ‘polygenic'; that
is, the genetic predisposition lies not in a single gene but in the interaction of many genes and the proteins that they code for.

The possibility of pinpointing what those genes might be derives from the observation that while, by definition, we humans all share an identical complement of genes, the comparison of one genome with another reveals that 10 million or so of those 3 billion CGAT letters will differ between individuals. These single-letter differences (known as Single Nucleotide Polymorphisms or SNPs) might then serve as a reference point or signpost of genetic variation between individuals and thus might account for why some people are predisposed to have diabetes and others are not.

The relevant investigations pursuing this possibility (known as Genome Wide Association Studies, or GWAS) are massive undertakings, where blood samples from tens of thousands of people are processed through sophisticated sequencing machines that can identify half a million or so of these variant SNPs in a single swoop, the findings being stored and analysed in powerful supercomputers.
¹³

Some sense of the scale of this enterprise is illustrated by a study involving the collaboration of fifty groups of scientists who examined the SNP genetic variants at 500,000 different positions in the genomes of 17,000 individuals to identify those that might be implicated in seven common diseases – arthritis, raised blood pressure, Crohn's, heart disease, manic depression and diabetes. The cumulative biological data generated by 600 of these GWAS studies have identified dozens of genetic ‘loci' – forty involved in determining height, almost thirty for Crohn's, twenty for obesity and diabetes, and so on. But when it came to adding up the contribution of each, it soon became clear that the genetic basis for these disorders remained as elusive as ever.
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,
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Thus, it is possible to estimate from twin and family studies
that genes contribute between 80 and 90 per cent of the difference between the tall and the short. But the net contribution of the forty or so ‘height genes' identified by the GWAS add up to less than 5 per cent of that ‘heritability'. So too with diabetes, where the two dozen implicated genes explain less than one part in twenty of its inheritance liability. Put another way, there could be as many as 800 different genes (potentially many more) contributing to these common disorders – each with a tiny predictive value. ‘Our chances of being born with a predisposition to a common illness are not represented by the roll of a single die,' observed Professor of Genetics Steve Jones, ‘but a gamble involving huge numbers of cards. People, rather than drawing one fatal error, lose life's poker game in complicated and unpredictable ways. So many small cards can be shuffled that everyone fails in their own private fashion.'
¹⁸

It is scarcely necessary to spell out the significance of what
Nature
subsequently described as ‘The Case of the Missing Heritability'. For the best part of thirty years The New Genetics, as the driving force of medical research, was predicated on the assumption that finding the genetic cause of disease would open the way to new and much more effective treatment. But when it takes the interaction of 800 or more genes (780 of which might as yet remain unknown) to predispose to (say) diabetes, the notion that it might be possible to develop targeted gene-based therapies is indeed ‘no longer a foregone conclusion'. And so too the promise of ‘personalised genomics' that it might be possible to tailor treatments on the basis of a person's genetic endowment to maximise their effectiveness, no matter how rapid or cheap the sequencing process might eventually become.
¹⁹
‘It is now pretty clear this talk about personalised risk profiles for most common diseases and a whole flood of new drugs targets is wishful thinking,' remarks David Goldstein of Duke University.

The New Genetics can scarcely be allowed to fail, as it has become so massive an enterprise, employing legions of scientists, the cost of whose projects routinely run into tens of millions of pounds. So while the findings of those genome-wide association studies may, as
Science
tactfully puts it, ‘not have broken any floodgates of understanding', there is no shortage of similar projects organised on semi-industrial lines, capable of generating gigabytes of biological data.
²⁰
Still, that ‘missing heritability' must eventually influence public perceptions as to what genetics can reasonably be expected to achieve. The biology of life is complex, billions upon billions of times more complex than the inanimate physical world. And part of that complexity is that genes for the most part do not act as discreet independent entities with specific properties – that would make them suitable targets for those gene-based therapies. Rather they contribute to a network of interactions with quite different functions in different tissues.

This is not to suggest that the Human Genome Project was futile. On the contrary it must in time be seen as one of the most influential achievements of the twentieth century – if not quite for the reasons anticipated. Rather we have here, as the historian of science Evelyn Fox Keller puts it:

There is no ready explanation for that gap between ‘genetic information' and ‘biological meaning', but the two most important (if hardly acknowledged) findings of the many genome projects on diverse forms of life hint at the deep inscrutability of the relationship between those genetic instructions and the structures to which they give rise. Those projects were predicated on the entirely reasonable assumption that spelling out the full gene sequences of worm, fly, mouse, man and many 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 predicted, with a near equivalence of a (very modest) 20,000 genes across the whole range of organismic complexity, from a millimetre-long worm to ourselves.
²²

Next comes the astonishing revelation of the interchangeability of the regulatory genes, where, for example, the gene that orchestrates the formation of the fly's compound eye does the same job for our very different camera-type eye, and so on.
²³
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 that we have no conception what they might be.

It might seem pointless to enquire why this might be so, but the explanation must lie at least in part in the simple elegance
of the two intertwining strands of the double helix, which for so long has held out the promise that it might be possible to understand ‘the secret of life'. That simple elegance cannot be because the double helix
is
simple, but because it
has
to be simple, if it is to copy the genetic material every time the cell divides.
²⁴
And that
obligation
to be simple requires the double helix to condense within the one-dimensional sequence of the CGAT chemicals of the genes strung out along the two intertwining strands the billion-fold biological complexities of the three-dimensional forms and attributes that so readily distinguish one form of life from another – flies from worms from frogs from humans. This is not to deny the substantial contribution of genetics, but it cannot conceal ‘the higher truth' that the question of what might conjure the richness of biological meaning from the monotony of that genetic information would seem, in the current state of knowledge, insoluble.

T
he respective contributions of technical innovation and the pharmaceutical industry to the medical expansionism of the last decade might seem to run in parallel with doctors not just
doing
more but
prescribing
(vastly) more – in Britain an additional 300 million prescriptions a year in just ten years. This therapeutic enthusiasm has, as noted, proved enormously beneficial to the drug companies, doubling their annual revenues from $400 billion to $800 billion – with just a single drug such as the cholesterol-lowering Lipitor earning its manufacturer Pfizer a staggering $12 billion a year, or almost half Google's entire annual revenue.

Those parallel trends can, however, be deceptive. No one would dispute the value of such technical innovations as coronary angioplasty in promptly relieving the anginal symptoms of heart disease, but the benefits of those 300 million additional prescriptions are much more difficult to quantify. Here the suspicion, hinted at in ‘Looking to the Future', that the drug companies may have orchestrated this massive upswing
in drug prescribing to their advantage would seem to be confirmed by the publication within the past ten years of a shelf-ful of highly critical books with such self-explanatory titles as
On the Take
;
Our Daily Meds: How the Pharmaceutical Companies Transformed Themselves into Slick Marketing Machines and Hooked the Nation on Prescription Drugs
;
Overdosed America
;
Overtreated: How Too Much Medicine is Making Us Sicker and Poorer
;
Selling Sickness: How the World's Biggest Pharmaceutical Companies Are Turning Us All Into Patients
; and, the most influential of all,
The Truth About the Drug Companies, How They Deceive Us and What to Do About it
by Dr Marcia Angell, the chief editor of the most prestigious of all US medical journals, the
New England Journal of Medicine
.
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These are no mere populist jeremiads against the drug companies for profiting from illness, but numerous variations on the same theme of how the pharmaceutical industry has come to exert a most ‘unhealthy' influence on the medical enterprise. Behind a veneer of beneficence and commitment to scientific progress, they engage in ‘disease mongering' while manipulating the findings from clinical trials to suggest their drugs are much more effective than they really are. The pharmaceutical industry has metamorphosed into the powerful and sinister ‘Big Pharma' which, Marcia Angell alleges, ‘has moved very far from its original high purpose of discovering and producing useful new drugs. Now principally a marketing machine to sell drugs of dubious benefit, it uses its wealth and power to co-opt every institution that might stand in its way, including the US Congress, the Food and Drug Administration, Academic Medical Centers – and the medical profession itself.'
³
The driving force behind this dramatic shift in its purpose and ethos is best illustrated by examining the extraordinary phenomenon of the rise and rise of the ‘blockbuster' drug.

Back in 1975, Henry Gadsden, chief executive of the drug company Merck, expressed in a candid interview his frustration that the potential market for his company's products was limited to those with some treatable illness – as ideally he would like to ‘sell to everyone'. Three decades on, medical commentator Roy Moynihan observes, ‘Henry Gadsden's dream has come true . . . the marketing strategies of the world's biggest companies now aggressively target the hundreds of millions of the apparently well and healthy persuading them they have some medical condition that warrants treatment.'
⁴
During this period the pharmaceutical industry, though always a lucrative business, would begin to generate profits on so stupendous a scale as almost to defy imagination. By 2002 the combined profits for the top ten drug companies in the Fortune 500, at $35.9 billion, would be greater than those for all the other 490 businesses combined.