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My brother Bill Hamilton, Professor of Evolutionary Biology at Oxford, died two years ago, aged 63, following complications of malaria acquired on a field trip to the Congo. He is mainly known for his theory of the evolution of altruism, or self sacrifice, known as 'kin selection'.2 Bill's genetic interpretation of altruism, which had previously appeared to have been in conflict with Darwin's theory of 'survival of the fittest', has been brilliantly explained and developed in Dawkin's book, The selfish gene'1. The kin selection hypothesis generated new ideas and new fields of enquiry in social behaviour. Recently, Bill has probably been equally well known for his controversial 'Parasite Red Queen' theory of the evolution of sex (meiosis).3 In this theory, Bill postulates that pluricellular organisms like animals and plants necessitate constant genetic recombinations in order to counteract attacks by continually coadapting parasites (diseases). He thought that such perpetual gene to gene interaction between hosts and parasites could explain the extraordinary importance (and burden) of sex in nature better than alternative theories such as the 'deterministic mutation hypothesis' which proposes that it exists to prevent accumulation of bad mutations.3 Inevitably, Bill's interest in these theories led him to consider their implications for medicine. He was very worried about the fate of our species if modern medicine continues to develop without an evolutionary approach to the biological environment in which we evolved and are still evolving. In this context he thought that the power of pharmaceutical companies plays a huge role. In this paper I try to explain some of his fears from my own medical viewpoint.
Bill's and my father was a consulting engineer who designed bridges. He became aware of the need for strong, adaptable bridges with components which could easily be transported and erected in remote and difficult terrain when he was building a road in Kurdistan in the late '20s.5 Later, in association with British Insulated Callenders Cables, now Balfour Beattie, he developed the Callender-Hamilton bridge. This was widely used during and after World War 11 and is still being sold today. The modest income which the bridge generated was the main support for our family of six children, of which Bill was the second eldest. Because of its ease of transport and erection, with steel parts which were simply bolted together rather like an enormous meccano set, the Callender-Hamilton bridge was popular with the army. This contributed to the development of the similar Bailey bridge which my father thought infringed his patent. This caused him much concern and was the basis of a successful Claim to the Royal Commission for Awards to Inventors. Although I never heard my father swear, no words were too bad for Bailey. Dad was an honest man, but he was unable to admit that Bailey's innovation, which consisted of box sections which could be assembled probably more quickly than the individual components of the Callender-Hamilton bridge, had any advantages. This example gave me early insight into the forces of self interest, or need, which influence people's judgement and behaviour.
Experience in my own career of geriatric medicine has added to this. My major interest has been in preventing pressure injuries, or bed sores, which are common in sick old people. With the help of various manufacturers of medical products, I was able to develop a large celled alternating pressure mattress derived from a less effective small celled model which had been invented in the USA.6 Unlike my father being a salaried employee in the National Health Service I did not have to worry about patents, but only to try to work with manufacturers to produce a support which I felt would meet as far as possible the combined needs for efficacy, practicability and economy.
But I was dismayed to discover how difficult this was. It at once became obvious that commercial, not patients', interests were paramount. Whether or not patients developed sores which caused them great suffering and were in some cases fatal did not concern manufacturers who were only interested in the marketability and demand for their product. The latter was mainly generated by their efforts to persuade consumers, in this case nurses, that their particular product had differences and advantages over their rivals'. This made for run away development of either very cheap, semi-disposable machines which continually broke down in use allowing pressure injuries to occur, or of ridiculously expensive models, some of which were so over sophisticated that they were scarcely still able to perform their essential function of changing the pressures under the patient. The manufacturers were also able to dictate which patients required the more expensive, and therefore more profitable, machines. As a result, effective care was, (and still is), only affordable for a small number of patients, mainly those who had already developed sores because of inadequate prevention, out of the hundreds of thousands of old people requiring it.
This situation might have been avoided if doctors had had more interest in preventing pressure sores so that they could be responsible for specifying the necessary equipment. Unfortunately, the opposite has happened and is gaining momentum. Rather than asking manufacturers to provide them with what they need, health authorities now a days are relying more and more on manufacturers to provide not only the equipment - or the drug - but the basic research and education in its use as well. Some employers even forbid staff to disobey manufacturer's instructions on pain of dismissal in case it increases the chances of successful litigation against them.
It is not difficult to see from this relatively simple example how commercial enterprises are dominating medicine. Within the last year, I have been informed of a randomised trial comparing a simple large celled alternating pressure mattress overlay with a more sophisticated and expensive mattress replacement system (both made and donated by the same manufacturer) which showed that they were equally effective for normal weight patients, for which publication has been refused by the manufacturer (D Gray personal communication). Another colleague has told me of a projected study of a nutritional supplement for preventing pressure sores, for which a grant of £70,000 is being offered by the manufacturer on condition that the results will only be published if they prove positive (GCJ Bennett personal communication).
In the past few years, all the major medical journals have carried articles about 'the tightening grip of big pharma'.7 The British Medical Journal discusses an article in a pharmaceutical magazine in which drug companies' instruct their staff about how to educate doctors, especially 'key figures' and 'opinion leaders', to market their goods.8 Selected doctors are referred to as 'trainees' and marketers are advised to gain their confidence by asking them for their 'advice'. The journal editor commented that educational and promotional activities 'seemed to work well together'. In the US, the revenue of the medical education service suppliers (MESS), private businesses which provide education, increased by 19% between 1998 and 2000. An average of 76% of their clients were drug manufacturers.9 The implications for continuing medical education (CME) programmes, most of which are sponsored by drug companies, are especially worrying.
Recently, Angell, former Editor in Chief of the New England Journal of Medicine, asks to whom is the pharmaceutical industry accountable?10 She questions the validity of the companies' claims that their drugs are necessary to 'extend and increase the quality of life', that 'research is risky' and therefore very expensive, and that interference with their activities will suppress innovation. She points out that with profits of 30%, they are by far the most profitable business in the USA. In addition, they enjoy government protection and subsidies. Seventeen year patents, which can sometimes be extended by the development of 'me too' drugs, allow them to fix their prices according to what the market will bear free from competition. Their 40% marketing budgets include 'education' which she says is like 'beer companies teaching us about alcoholism'. She agrees that private drug development is probably the only way, but contends that the industry should be made to accept social responsibilities. In reply, a manufacturer protested that 'we are accountable to patients (my italics); we will continue to fight proposals for price control which would hurt (them) by reducing our ability to fund the search for treatments and cures'. 11 But what does this mean in fact?
Horton 12 relates the story of the development of a new drug for irritable bowel syndrome which was manipulated through the safety channels by the company concerned, including 'an internal struggle to suppress dissenting opinion', which was withdrawn within one year after it had caused the deaths of patients. He said the US Food and Drug Administration (FDA) appeared to have become the 'servants of industry'. Similarly, Gale 13 describes the development of an oral hypoglycaemic drug which had to be withdrawn in the UK within weeks because of liver toxicity, but not before it had had sales of over $2 billion in the USA. He criticises the company for allowing only the publication of abstracts, not of full papers. He notes that individuals may not be to blame, but 'corporate behaviour determined by market forces'. Other examples are an attempt by Bristol-Myers Squibb Canada to prevent the dissemination of a report about a statin, 14 and an unsuccessful attempt to block a report on a failed AIDS vaccine. 15
The remarkable rise in popularity of calcium channel blockers for the treatment of hypertension, 90 fold since 1990,16 has raised questions about how much of this is due to science and how much to advertising? The New England Journal of Medicine 17 has documented the financial pressures put on authors of papers on calcium antagonists to publish positive and not negative results. Ghost writing of reports and reviews by companies gives similar opportunities for bias. 18 At the same time, advertising has become more aggressive, not only in Third World 19 and company sponsored journals, 20 but in leading medical journals themselves. The aim is to make doctors feel guilty if they do not prescribe a particular pill for their patients.21 But even improper advertising is rarely challenged.22
Medical societies and their journals which are reliant on drug companies include The Journal of the American College of Cardiology, Annals of Internal Medicine, Journal of the American Medical Association, The American Journal of Respiratory and Critical Care Medicine, Clinical Infectious Diseases and the New England Journal of Medicine.23 The revenue of organisations from advertisements in their journals may amount to $18 m, over 10% of the gross income of some societies and sometimes more than that of membership fees.
In 1996 in the UK, the drug industry was selling £4 billion worth of drugs to the NHS and was bidding to increase this by offering 'patient focussed' total healthcare (including) disease prevention and health promotion. By 'improving compliance'(and thus potentially reducing hospital admissions), eg, 'in diabetes, asthma, drug abuse, HIV, end stage renal failure, hypertension and infertility', it was hoping to acquire the £36 billion not being spent by the NHS on prescription medicines. 24 Similar efforts are directed at persuading people to accept medication to ward off ageing and other infirmities. Early intervention, eg, for Alzheimer's disease or hypercholesterolaemia, is profitable. 25 This approach is encouraged by the media. The New England Journal of Medicine, 26 carried out a study of newspaper and television coverage of popular drug treatment which showed financial ties in the majority of the promoters and lack of information about risks. The current EC proposal to allow �direct to consumer' advertising of prescription drugs27 for AIDs, diabetes and asthma opens a new dangerous door.
The industry spends vast sums on promoting prescribing, including helping to develop protocols and guidelines to increase intervention for sometimes doubtful gains. 28 Once achieved, repeat prescriptions which become 'set in steel and concrete', and which have been shown to be uncontrolled in up 70% of general practices, pour money into the industries' coffers which could instead be being used for nursing or social care.29 The care business of the pharmaceutical business is not management of health care but marketing drugs. 24 In Britain, 25% of the population is now on regular medication, including over 90% of people aged over 75 years.28 6.7% of hospital admissions in the USA are for serious adverse drug reactions. These result in 100,000 deaths annually. 30 This is said to be the price we pay for the modern management of disease. A growing sense of public harm has focussed, not surprisingly, on doctors rather than on their sponsors. 30 But doctors themselves who have become addicted to high incomes are not free from blame. 31
Patients are �clients' to serve the 'business'. In the USA, all social activity is valuable only if it benefits investors. 32 The American Medical Association was naïve when it averred in response to the uproar caused by its deal with Sunbeam Corp, that 'Sunbeam is as serious about maintaining America's health as we are'.33 Ren-Zong Qui, chairman of ELSI Committee of the Human Genome Project in China summed it up when he said that the greatest danger to the medical profession (and he could have added 'to the world') is 'commercialisation'.34
Governments have made sporadic attempts to check the landslide. In 1998, Israeli doctors were banned from attending a conference in Turkey organised by a pharmaceutical company. 35 Merck Sharp and Dohm have been prosecuted for �pampering' Dutch doctors, 36 and 'drug free practitioners' lists' have been organised in the US. 37 Promotion of medicines to the general public on the Internet has been banned in Australia.38 Italy is planning to review drug licences every ten years..39 Other countries hope that institutions such as the National Centre for Clinical Excellence (NICE) in the UK 40 and the FDA and managed care in the US, 28 will act as curbs. However, it is going to be difficult if not impossible to ensure that the 'evidence based medicine' on which these organisations pride themselves is free from commercial influence.13,40 Australia has already 'loosened it grip' by allowing pharmaceutical members onto its Pharmaceutical Advisory Committee. 41
Journal editors like to think of themselves as 'watch dogs', 7,42 but this is becoming increasingly difficult. Besides drug revenues, editors are dependent on their journal's owners and subscribers and cannot afford to offend them. Thus an editor agreed to publish an article of mine only after he had removed a sentence in which I had compared methods of marketing drugs to that of cigarettes. Editors who try to exercise their freedom, like Lundberg who extolls the importance of necropsies in revealing medial 'mistakes' 42 condemns greedy US doctors and advocates rationing, 31 are liable to be sacked. Similarly, the former editor of the New England Journal of Medicine resigned because he could not agree to financial deals which the owners, The Massachusetts Medical Society, were arranging for the journal. It is perhaps significant that the present editor has already been accused of partiality in over praising an asthma drug made by a company for which he has acted as a consultant.43 Even independent editors may not always be scrupulous once they have accepted (or rejected) an article or an idea.44
You may wonder what all this has to do with Bill? However, we are now reaching an era in which the same market forces which I have described are becoming involved in supplying not just drugs which we can take or not more or less as we please, but procedures which have the potential to cause epidemic and endemic disease in populations far removed from the individuals being treated. Some procedures may even alter the human genome itself and be passed down through the generations. Many people do not seem to appreciate the difference.
As an evolutionary biologist, Bill was very aware of the dangers of these projects and of the power of the blind commercial forces behind them. This was why he was so concerned to discover the truth about the theory that an oral polio vaccine in the 1950s might have been the unwitting source of a cross species transfer of a simian immune deficiency virus (SIVcpc) from chimpanzees to humans and given rise to AIDS (the OPV-HIV-1 theory).45 He thought that if it proved to be true, (which seemed to him likely), it might act as a powerful example of the dangers to which modern medical practice can expose us and make people more aware of the need for caution in embracing every medical 'fix' dangled before them. Bill was convinced that an unwanted transmission of a virus from another species via a vaccine was possible; and that if it did not happen in this case, it could have happened; and that it could happen with vaccines or other treatments in the future if we are not properly aware of the possibility. He was also angered and worried by the difficulties which Hooper, the theory's chief exponent, and he encountered when they tried to persuade the medical and scientific world to agree that the hypothesis should be investigated. In the event, this took ten years and my brother's death. This should not surprise us in view of what I have tried to describe of the industry. The question is, has the effort been in vain? Even if the OPV-HIV1 theory is disproved we still need to know how the AIDS pandemic started and what it can teach us. Few people deny that it started in Africa and that it was almost certainly spread as a result of medical activity, eg, the reuse of non reusable needles which cannot be resterilised46 (again resulting from commercial availability), and by changes in sexual partner acquisition rates47 and social upheaval in the post colonial continent and the rest of the world. The implications are as pressing as ever.
Bill was equally concerned about xenotransplantation as another route for the possible transfer of unknown viruses from other species to humans. In the Preface of his forthcoming book, Narrow roads of geneland Volume 11,4 he says, �In making these 'ethical' gifts we will be setting aside those extremely well founded concerns about pig viruses jumping to humans from living pig tissues. Those wonderful millions of immuno-suppressed human bodies the prepared feather-beds for potentially vaster billions of virus bodies to lie in and try in as cosy as kicking babes, and a few of them hatching, via mutations and recombinations, great hopes for the future. Evolution is relentless, undirected, caring not whom it slays: those viruses too, in a few years may be acquiring capacity almost to end a species. Nobel prizes (may be) awarded in heaven on the long taught principles of 'humaneness', 'immediacy' and 'primacy of the individual' (with just a little subtracted perhaps about selfish market forces)
Fishman, 48 a consultant of Biotransplant and other companies, agrees there is 'no proof yet of safety or danger'. Infections are common after allografts49 because of immuno-suppression and still more draconian measures are likely to be needed for xenografts. 50 Xenografts are more worrying because of 'novel animal pathogens', including retroviruses some of which are oncogenic51 and which are integrated into the genome of every living cell. In inbred strains the latter may be at too low levels to detect, but can still infect human cells, and could become integrated into the human genome for reactivation in the patient or their descendents. 49 The greater genetic distance of the pig compared with chimpanzees from humans may not be a safeguard. Techniques being developed to try to isolate the grafted tissue so that it is not exposed to the host's immune processes, or to raise transgenic animals which do not provoke them, may increase the potential for recombination and reassortment.49 Prions are also a worry although they are thought not to have epidemic potential. 49
Researchers have found that it is difficult or impossible to remove viruses from the pig germ line. 52 Similar viruses in mouse tissues have caused leukaemia when grafted into macaques. Pro-viral DNA is present in all tissues and inherited. After xenotransplantation it can be recombined causing tougher hybrids which can cause illness.49 Goldman53 asks: have we learned nothing from the AIDS epidemic?
Meanwhile advocates, mostly 'researchers, surgeons and consultants to industry', 54 emphasise the number of waiting patients and the dearth of organs. 55,56,57,58 They dismiss suggestions for improving the supply of human organs, for example, by 'presumed consent' laws as 'coercion' and inadequate.59
The World Health Organisation 60 and US49 and UK 61,62 governments have set up regulating bodies which stipulate that patients with xenotransplants and their contacts, including carers, will need to be registered and followed up for their lifetimes.63 However, the WHO discussion group has been accused of pro-industry bias,64 and Weiss,65 comments that the ethical and technical problems of maintaining vigilance over xenotransplantation should not be underestimated. It now appears that HIV-1 may have been present in humans for as long as 50 years before causing an epidemic and the effects of xenotransplantation could be similarly delayed. Both in the US 66 and in the UK 67 promotors have tried to confine permission for clinical trials to local bodies. A report in the British Medical Journal about the ITV program, 'Organ farm', stresses that 'we need to be wary of the creeping deregulation of our health and environment - the toothless tigers that pass for our regulatory bodies does not auger well for effective control of the vast commercial interests that drive much of the current scientific agenda.'68 Successful programs could generate $6 billion.69 Fano, Director of the Campaign for Responsible Transplantation, 70 says "It is naïve to believe that xenotransplantation is being propelled by desire to relieve human suffering - and not (for) billions of dollars in profits for sale of humanised pig parts and anti-rejection drugs - there are better ways of dealing with organ shortages'.
However, an editorial in the Lancet published 8 months after Bill's death said there should be no more 'dithering'.71 It claimed that with 'productive discussion and research, most of which has been conducted openly with little perceptible input from experts suborned by commercial interests - initial fears about possible transfers of animal pathogens - to patients have receded and processes for humanising pigs to abate rejection have been refined.' 'Inevitably,' it continued, 'there have been unhelpful contributions from extreme groups, an example of which is a glossy booklet produced by the British Union for the Abolition of Vivisection and Compassion in Farming - with a cover featuring a man's face with his nose replaced by a pigs snout', an image which guarantees that the innocuous title hides arguments within which are specious and based on pseudo-science and selective quotation' - a sally which backfires if we recall a previous cartoon in the journal itself.61 The editorial goes on to compare present doubts about xenotransplantation with those previously expressed about - in-vitro fertilisation (which has since) 'slid into routine'. But, as Bill predicts, in two generations, (or less),72 we may come to lament this practice too.
In his forthcoming book, Bill's graphic account of the evolution of sex in the living world is almost overshadowed by his vision of the loss of its effective benefit in human beings. He says that, 'in two generations damage done to the human genome by antenatal and post natal life saving efforts of modern medicine will be obvious to all and a big talking point in science and politics'.4 'In 40 years nations with the worst records of the practice of scientific medicine will be becoming dominant in sport and everyday health demanding activities'. Evolution works fast. The current fashion in the Western world for Caesarian section (already 1: 5 in the UK)73 may soon result in women's anatomical inability to give birth naturally, thus inevitably 'tethering our lives to the hospital'. In Bill's view, the First World is entering a phase of medical metastability (non self limiting breakdown) which natural selection, with early loss of defective embryos, prevents. Together with overpopulation, this may cause our extinction, or at least the extinction of those who practice it, more surely than an asteroid.
Whichever theory of sex we favour: the 'Deterministic Mutation Hypothesis', beating back bad mutation, or the Parasite Red Queen strategy for maintaining animals and plants in a world of co-evolving parasites 'as old as life itself' - or both - the degeneration of the human genome in the absence of natural selection, ie, allowing present 'kindness' with its concentration on the easiest, quickest (and most profitable) benefits, to run its course, carries ever greater dangers. At present, our chance of being affected by a bad mutation may be only about 1 in 10, but this will increase rapidly in our descendants. Bill stresses that in the coming century (not millennium) in order to avoid disaster it will be necessary for every thinking person to have some idea of the function of sex. This will require radical improvements in the teaching of evolutionary biology.
In response to the ready ripost, 'genetic engineering',74 Bill describes the impractical processes which would be required to correct perceived faults in every potential embryo, one by one.75 At the same time he points out that germ line gene engineering, the only type which could avoid the build up of 'the slow withdrawal of all our attributes as free living organisms', is unreasonable. We can never know which departures from the current genome �handbook', including some handicap genes, may in future turn out to be good for us and which bad in an environment that is permanently and unpredictably changing. Mendelian genetics of sexual reproduction which brings together bad genes and eliminates them quickly, and natural selection, are essential.
Modern medicine is miraculous and has been of enormous benefit to mankind, but before permitting radical and fast changing practices doctors (and still more important, the informed public) need to re-examine their approach to the patient: should individual life and health always be the priority or should we also try to think about the long term effect of a medical procedure on the population? Should we be more aware of the economic impetus that lies behind every new drug and technique? Should universities insist on more space being given to training in darwinian medicine in medical schools? Meanwhile, doctors should be cautious about accepting medical guidelines pushing them to ever more prescribed courses of action. We need to question accepted wisdom and cultivate a more open minded, less inquisitorial attitude towards differing opinion. It is not sufficient to put pressure on drug companies to extend their treatments to the developing world.76 I am sure they can see the benefits of that we need to decide what treatments we want for ourselves first.