The Rise and Fall of Modern Medicine (55 page)

The editor of the New England Journal was sceptical. The outcome for most 87-year-olds, he argued, could well be very different – culminating in a ‘protracted debilitating and dehumanising stay in the intensive care unit' without their ever returning to ‘an active social schedule'. This would give a rather different gloss to the proposition that major heart surgery was appropriate at the ‘extreme of life'.

But the die was cast. In the aftermath of ‘Too Old for What?', the question ‘Should We?', when confronted by the dilemma of whether or not to replace the aortic valve in an ‘independent and active' 80-year-old, rapidly became ‘Why Shouldn't We?'. Ten years later cardiac surgeon Matthew Bachetta of the New York Presbyterian Hospital would raise the ante: over the previous decade he had operated on forty-two nonagenarians with an average age of 91.4 years, of whom thirty-eight had survived on average two and a half years after surgery. His review of the statistics of cardiac surgery in the elderly stretching back over the previous thirty years revealed a fascinating pattern where every decade the ‘maximum age' for
the procedure had also risen by a decade – from seventy in the 1970s to eighty in the 1980s to ninety in the 1990s. In each instance the initial high mortality rate in the immediate aftermath of surgery of around a quarter had, with greater experience, fallen to around 7 per cent. And the further the boundaries were pressed, the greater the number who might (theoretically) benefit from this type of surgery – where almost one in ten nonagenarians have narrowing of the aortic valve of such severity as to warrant surgery.
¹⁹

The following year, in 1994, Raymond Tesi of the University of Ohio would add a further important and unexpected twist in his review of kidney transplants in the elderly.
²⁰
The risk of failing kidneys is strongly age-determined – in the United States, 14,000 people over the age of seventy-five are now on dialysis – but the definitive treatment of a kidney transplant is constrained by two considerations: firstly that younger patients are, by definition, more likely to benefit for longer from the limited number of available kidneys, and secondly it would be reasonable to suppose that the complication rate from rejection of the transplanted kidney and similar problems is likely to be considerably higher. Yet Professor Tesi's review revealed the precise opposite – that the chances of rejection
lessened
with age. Specifically, just one in ten of those over the age of sixty experienced an ‘immunologically induced kidney graft loss' compared to one in three of the younger patients – which one might reasonably attribute to the probability that an ageing immune system is more likely to tolerate a transplanted organ. And if that is the case, then the same should apply for those requiring liver transplants. (It does.) So, yet again, ‘the line has advanced', with thousands of those with kidney failure who previously would have been discriminated against on the basis of age becoming candidates for transplantation.

It is scarcely necessary to reiterate the profound significance of these events not just on their own account but more generally, where the extrapolation of the benefits of interventions such as cardiac surgery and kidney transplants to (virtually) all major medical interventions exemplifies how the inevitable vicissitudes of ageing have become only so many medical problems warranting a technical solution – which, in the progressively ageing populations of Western nations, must inevitably result in the cost of health care spiralling upwards.
²¹

T
he fortunes of the New Genetics, the driving force of biomedical research over the past three decades, are obviously central to any analysis of the current state and future prospects of medicine. Here the verdict of just over ten years ago that ‘despite all the enthusiasm and excitement, the tens of thousands of scientific papers and acres of newspaper coverage, its practical benefits are scarcely detectable' seem rather premature. There are numerous instances where many years may pass before the full realisation of some major scientific development. Famously, nearly 300 years elapsed between William Harvey's description of the circulation of the blood in the seventeenth century and its practical application in the form of cardiac surgery. Why should the New Genetics be any different?

And, as if to emphasis the prematurity of that verdict, the completion of the first draft of the Human Genome Project (HGP) in the year 2000 could scarcely have been more propitious. The truly astonishing ability to spell out the full sequence of human genes signposted the way towards an ever profounder
understanding of human biology and the phenomena of illness.
¹
The announcement, at a full press conference in the White House Presidential Office, was suitably impressive: ‘Nearly two centuries ago, in this room, on this floor, Thomas Jefferson spread out a magnificent map . . . the product of a courageous expedition across the American frontier all the way to the Pacific,' President Bill Clinton declared. ‘But today the world is joining us here to behold a map of even greater significance. We are here to celebrate the completion of the first survey of the entire human genome. Without a doubt this is the most important, most wondrous map ever produced by mankind.'

The following year, in February 2001, the two leading science journals,
Nature
and
Science
, each published a complete version of that ‘most wondrous map ever produced' as a large, multi-coloured poster displaying the full complement of around 20,000 human genes.
²
It was, as
Science
observed, ‘an awe-inspiring sight'. Indeed, it was awesome twice over. Back in the 1950s, when Francis Crick and James Watson described the structure of the double helix, they had no detailed knowledge of a single gene, what it is or what it does. Now, thanks to the techniques of the New Genetics, those involved in the Human Genome Project had, in just over a decade, successfully culled from the 3 billion chemicals of DNA strung out along those intertwining strands the hard currency of each of the 20,000 or so genes that determine who we are.

The human genome map, like Thomas Jefferson's map of the United States, portrays the major features of the genetic landscape with great precision. Whereas, in the decade prior to its completion, it had taken the best part of seven years to find the defective gene responsible for the common lung disorder cystic fibrosis, now anyone could locate it on that multi-coloured poster in as many seconds. Here too at a glance you can pick out
the gene for the hormone insulin, which controls the level of sugar in the blood, or the gene for haemoglobin which transports oxygen to the tissues. To be sure, the functions of many of those genes remained obscure, but now, knowing their precise location and the sequence of which they are composed, it would be only a matter of time before they too would be known. ‘Today will be recorded as one of the most significant dates in history,' insisted one of the major architects of the HGP, Dr Michael Dexter of the Wellcome Trust. ‘Just as Copernicus changed our understanding of the solar system and man's place within it, so knowledge of the human genome will change how we see ourselves and our relationships to others.'

The director of the Project, Francis Collins, spelled out the implications for the future of medicine.
³
Within the next few years, he anticipated, scientists would have identified the ‘five to ten' genes involved in common diseases. By the year 2010 there would, he anticipated, be predictive tests that would inform healthy people of their risk of subsequently developing numerous serious conditions such as diabetes, Alzheimer's and several forms of cancer. This would, he anticipated, transform the whole process of pharmaceutical innovation, which would focus on developing ‘gene-based designer drugs'. For those with cancer it would even be possible to categorise the genes that had gone awry and target specific therapies tailored to the individual patient, thus minimising the hazard of side-effects. ‘This is a time of dramatic change,' Francis Collins wrote, where before long most family doctors would ‘become practitioners of gene-based medicine capable of advising their patients on how to enhance their chances of staying well'.

These optimistic predictions conceal a most ambitious change in direction that needs emphasising. The two major research priorities in the twenty or so years leading up to the Human
Genome Project (as outlined in ‘The Brave New World of the New Genetics') were, first, to identify the genes for those hormones and proteins whose deficiency could be corrected by the techniques of biotechnology – insulin for diabetes, growth hormone for dwarfism, clotting factors in haemophilia, and so on. The second priority was the protracted search for the genes involved in one or other of the genetic disorders due to a defect in a single gene – cystic fibrosis, Huntington's disease, Duchenne's muscular dystrophy. The completion of the Human Genome Project would of course enormously simplify this process, resulting in the identification of the genetic mutations responsible for more than 1,000 of these single gene disorders. They are, however, all extremely rare, while the practicalities of doing something about them – whether preventing them by prenatal screening or curing them with gene therapy – remain intractable for the reasons already described.

The crux then of Francis Collins's ambitious prospectus might best be described as the ‘relevance imperative', where genetics would have to transcend its concern with these (relatively rare) single gene disorders to become of general relevance to the mainstream by proffering solutions to the common disorders that afflict tens of millions – diabetes, arthritis, cancer and so on. And even more ambitiously, he suggested the Project would usher in the era of ‘personalised genomics' where it was possible to imagine a situation where everyone might have their genome sequenced, and the knowledge so generated could not only predict the disorders they might encounter but determine the most appropriate treatments for them to receive.

This might seem rather over-ambitious. It had taken the best part of a decade and $3 billion to sequence that first human genome; what chance then that ‘personalised genomics' would ever become a viable proposition? But, as ever, it is a mistake to
underestimate the pace of technological innovation, and no more so than here, as over the next ten years the speed of genome sequencing increased 50,000-fold, telescoping that decade down to a few days – and all for a few thousand dollars.
⁴

The New Genetics, liberated now to investigate the intricacies of the human genome by techniques faster and cheaper by several orders of magnitude, has proved immensely productive: typically a dozen or more groups of scientists working in vast citadels of research routinely generate millions of megabytes of basic biological data every week.
⁵
It has, in short, become Big Science, whose sequencing projects now extend to hundreds of other forms of life, traversing the full range of its complexity from the very simplest bacteria and viruses to the worm, fly, mouse, chimpanzee and many others. Biomedical research has as a result become the major game in town, whose funding, doubling and doubling again to more than $100 billion a year, now dwarfs that of all the other sciences combined.

The tenth anniversary of the completion of the Human Genome Project in 2010 provided an obvious opportunity to reflect on not just the progress so far but the difficulties encountered and how they might be overcome. Francis Collins, in an article in
Nature
, ‘Has the Revolution Arrived?', affirmed it had – with the one important caveat that ‘the consequences for the practice of medicine have so far been modest'.
⁶

This caveat was spelled out rather more emphatically elsewhere in the journal, with the observation that the notion of the tailoring of treatments based on the knowledge of a person's genetic endowment was ‘not on the horizon' – while the prospect of those gene-based designer drugs for common illnesses ‘no longer seems a foregone conclusion'.
^7
,
8
The Lancet
echoed this scepticism, observing how ‘so far the benefits from the Human Genome Project are scarce', while noting that
‘therapeutic returns from the substantial investment in genomics are badly needed'.
⁹
Nicholas Wade, science correspondent for the
New York Times
, noted pessimistically how ‘after ten years of effort' scientists were ‘almost back to square one in knowing where to look for the [genetic] basis of common diseases'.
¹⁰
‘The mountain has laboured', Steve Jones, Professor of Genetics at London's University College, observed tartly, ‘and brought forth a mouse.'
¹¹

So what had happened? The official view emphasises the astonishing progress in the speed and cost of sequencing and the prodigious quantities of biological data so generated, but concedes that the practicalities of what those 20,000 human genes actually do, and how they interact together, have proved vastly more complex than originally supposed. This is undoubtedly true – as is its necessary corollary, that it will take much longer to ‘work it all out' before there can be any hope of reaping all those therapeutic benefits that Francis Collins so confidently predicted.

But the more substantial – and indeed apparently insurmountable – difficulty is the quite unexpected discovery that 95 per cent of the genetic heritability in the predisposition to common illnesses such as diabetes or arthritis is ‘missing'.
¹²
This sounds very serious and clearly requires clarification.