The Rise and Fall of Modern Medicine

by James Le Fanu

  These matters will become clear as we follow the practical application of The New Genetics to medicine, which can conveniently be discussed in three areas. The first, Genetic Engineering (often referred to as biotechnology), starts with the insertion of the gene for insulin into bacteria to produce human insulin. Next comes Genetic Screening. There are approximately 4,000 diseases resulting from a defect in just one gene – the so-called single-gene disorders. Luckily they are all very rare, except for a handful including Huntington’s chorea, cystic fibrosis and the congenital blood disorders such as sickle cell anaemia. The discovery of the relevant genes opens the way to the prevention of these disorders by testing the foetus before it is born and selectively aborting those shown to carry defective genes. And thirdly there is Gene Therapy, where doctors seek to insert a normal copy of an abnormal gene into a cell in the hope that, by generating the correct rather than the garbled genetic message, it might be possible to actually cure genetic diseases.

  (ii) GENETIC ENGINEERING

  Genetic engineering may sound sinister, but it is only a method for making new types of drugs and could not be more straightforward and uncontroversial. The human body is made up of thousands of specialised types of protein – neurotransmitters, hormones, enzymes and so on. Self-evidently, when one or other of these proteins is deficient or absent then illness will result. Thus diabetes is (probably) the result of viral inflammation of the insulin-producing cells of the pancreas, while haemophilia arises from a defect in the blood-clotting protein factor VIII. Treatment of these conditions is obvious: replace the ‘missing’ protein from another source. Thus insulin can be obtained from the ground-up pancreases of pigs and cattle and factor VIII from the concentrated plasma of blood donors. Genetic engineering simply offers an alternative source for these proteins. Once the relevant gene has been discovered – say, the gene for insulin – it can be inserted into a plasmid (the ring of DNA within a bacterium), so now a bacterium will make human insulin. That is all. Certainly the ‘engineering’ – getting the gene into the plasmid and making the bacteria produce insulin in sufficient quantities – is technically highly sophisticated, but there is nothing unsavoury about it.

  The concept of genetic engineering positively vibrates with a sense of limitless possibilities, as illustrated by the first commercially successful medical biotechnology product, insulin. This takes us back to the earliest days of The New Genetics in the early 1970s and two personalities in particular: Herbert Boyer of the University of Southern California, who discovered the first of the restriction enzymes (‘text-cutters’) for cutting up DNA; and Stanley Cohen of Stanford University, who had been studying the plasmids in bacteria so useful for the ‘photocopying’ already described. During a scientific meeting in Hawaii in November 1972, Stanley Cohen heard Herbert Boyer describe his text-cutters and saw the possibilities: ‘That evening,’ he recalled later, ‘at a delicatessen across from Waikiki Beach I proposed a collaboration with Boyer’, from which emerged the first successful experiment of The New Genetics. Cohen used Boyer’s text-cutters to cut up the DNA from the cell of the African clawed toad, Xenopus laevis, which he ‘spliced’ into a plasmid from the bacterium E. coli. He then reintroduced the plasmid back into the bacterium and – lo and behold – the erstwhile amphibian DNA was replicated, along with that of the bacterium. Although technically very ingenious, this experiment had no practical applications and it was to be another two years before Herbert Boyer – at least publicly – made the intellectual leap to see where it might lead. ‘I think this has a lot of implications for utilising the technology in a commercial sense,’ he observed, ‘that is, bacteria could be used to make hormones such as insulin.’ This was the first indication that the central dogma of genetics was to be rewritten to read ‘DNA makes RNA makes protein makes money’.

  Meanwhile, a 28-year-old venture capitalist, Robert Swanson, anticipating that these new methods of manipulating DNA could prove to be a gold mine – without, it would seem, really understanding what they involved – had been ringing round distinguished molecular biologists trying to set up a meeting. They all declined, until Herbert Boyer agreed to see him ‘for a few minutes on a Friday afternoon’ in 1976.

  Swanson hadn’t really done his homework. He had no idea that in Boyer he was talking to a co-inventor of the very techniques he sought to exploit commercially. He was excited, he recalls, that anyone sounded even vaguely encouraging. On the agreed upon afternoon Swanson dropped by Boyer’s laboratory. The two men liked what they heard from each other and continued the discussion over beer at Churchill’s, a local bar. ‘After that meeting,’ Swanson says, ‘we did some thinking, him on the technology side, me on the business side, to see what was possible. We started out with a list of known proteins and looked at which markets were the most interesting.’ The decision to plunge ahead in those heady days does not seem in retrospect to have been horribly costly. The businessman (Swanson) and the molecular biologist (Boyer) each coughed up a modest $500 and that $1,000 became the initial operating capital for the new company – Genentec.16

  Top of the list of ‘known proteins’ was insulin, whose gene had still not been identified but was imminently anticipated. Then it would only be necessary to replicate the original Cohen–Boyer experiment by introducing the insulin gene into a plasmid, and by reinserting the plasmid into a bacterium to produce limitless quantities of genetically engineered ‘human’ insulin. Insulin was an obvious choice – with a ready market in the millions of diabetics around the world – with the only drawback that there was more than enough insulin already obtainable from the ground-up pancreases of pigs and cattle. Further, and importantly, the structure of this pig insulin is virtually indistinguishable from that of the human variety, and certainly fulfils its therapeutic purpose of controlling the blood sugar very well. There would thus seem to be little incentive for setting out to make human insulin by means of an as yet untried technology requiring an initial capital investment to the tune of tens of millions of dollars. But the collective genius of Boyer and Swanson was their appreciation that they were selling an idea – that genetic engineering had enormous potential. Their credibility depended on making something that potential investors might have heard of, and everyone knew about insulin. Their great selling point was that their genetically engineered insulin – made by a bacterium – would be ‘human’ and therefore by implication superior to anything from a pig or a cow. Further – though there was no evidence for their claim – they maintained that the traditional sources of insulin would be insufficient to meet demand in the future, which would then have to be met by their genetically engineered product.

  In 1977, the year after the meeting at Churchills, the insulin gene was, as had been predicted, discovered thanks to – as already described – the ‘reverse transcriptase’ enzyme. And the following year, on 24 April 1978, Boyer reported that he had managed to obtain small amounts of human insulin after ‘splicing’ the insulin gene into a plasmid of the bacterium E. coli. Two weeks later, almost exactly three years since their first meeting, Boyer and Swanson signed a contract with the pharmaceutical giant Eli Lilly for the mass production of genetically engineered insulin. The genetic engineering boom was now under way. When their company, Genentec, was launched on the New York stock market in 1981 – still without human insulin or any of its other potential products having reached the marketplace – the $35 ‘asking’ price for each share leaped to $89. Howard Boyer’s initial $500 investment was now worth – on paper at least – in excess of $80 million.

  Stock markets rely on credibility, which is precisely what Swanson and Boyer had set out to acquire by choosing as their first target one of the best-known of human proteins, insulin. Their strategy had paid off. In the unprecedented reaction to the flotation of Genentec it is possible to discern what was to be a central feature of biotechnology in the coming years – the credulousness of investors in believing in the commercial possibilities of something they did not really underst
and. Few, if any, of the punters buying Genentec shares at $89 apiece understood molecular biology well enough to grasp the limits of its therapeutic potential. They could only infer that something big was about to happen, ‘big’ enough for Time to put Herbert Boyer on its front cover:

  He looks just like a leftover from the 1960s in his faded jeans and open leather vest, with a can of Budweiser in his hands. Back then he marched regularly in the streets of Berkeley, California, taking part in civil rights and anti-war demonstrations but despite his casual look, Herbert Wayne Boyer is a millionaire many times over, at least on paper. More important, he is in the forefront of a new breed of scientists, entrepreneurs who are leading gene splicing out of the university laboratory and into the hurly burly of industry and commerce.17

  In a similar vein, James Erlichman, the Guardian’s expert on the pharmaceutical industry, observed that ‘the rewards for genetic engineers will be immense’, a rosy view of the future that reflected the prevailing opinion:

  Human insulin is just an introductory skirmish in a far more lucrative commercial campaign. The company that unlocks the secrets of human insulin production on a large and cost-effective scale will have gained the scientific and technical knowledge to repeat the feat, and beat the competition to a host of related and even more profitable breakthroughs in biotechnology ranging from other drugs through to cheap food proteins and ‘biomass’ energy supplies.18

  But Genentec’s immediate priority was to sell sufficient human insulin to make it profitable. This was not a straightforward matter as there was certainly no sign that the supplies of the considerably cheaper insulin from pigs and cows would be incapable of meeting demand. Two tactics were adopted. First, the intrinsic superiority of human insulin was vigorously promoted on the lines that patients with diabetes, who might have to be injecting themselves with insulin for several decades, deserved ‘the best’, even if it was structurally very similar and much more expensive. Second, just in case doctors did not ‘get’ the message, Eli Lilly decided to ‘phase out’ its production of animal-based insulin so it was less readily available.

  The general verdict on ‘human’ insulin could be that, besides being a triumph for biotechnology, its advantages are more apparent than real. It held out the promise that this new way of producing drugs, so different from and so much more ‘scientific’ than what had gone before, it would seem, could not fail to deliver. But that is not how it has turned out. Rather, human insulin remains biotechnology’s commercially most successful product (see opposite). Indeed, the few biotechnology drugs that can genuinely be described as representing a significant therapeutic advance are a vaccine against the viral infection of the liver hepatitis B; erythropoietin (EPO), a hormone secreted by the kidney that stimulates the production of red blood cells, and Gleevec for the treatment of chronic myeloid leukaemia.19

  Biotech products in use in 1995

  DRUG USES

  Human insulin Diabetes

  Interferon alpha Hairy cell leukaemia; hepatitis B & C; keeps lymphoma, leukaemia in remission

  Human growth hormone Dwarfism

  Interferon beta & gamma Chronic granulomatous disease (decreases infections); multiple sclerosis; hepatitis B & C

  Tissue plasminogen activator Clot-buster drug

  Erythropoietin Treatment of anaemia in kidney failure

  G-SCF, GM-CSF Stimulates white blood cells after cancer chemotherapy

  Ceredase Gaucher’s disease

  Hepatitis B vaccine Immunisation against hepatitis B

  DNAse Cystic fibrosis; chronic bronchitis

  Interleukin-2 Kidney cancer; melanoma; leukaemia; ovarian cancer

  Factor VIII Haemophilia

  Anti IIb IIIa Antibody Prevents narrowing of coronary arteries after angioplasty

  (Adapted from a list provided by Dr Richard J. Wurtman, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology.)

  It is testament to the power of the idea of genetic engineering that the limits to its therapeutic potential were not appreciated earlier, but the reason is quite obvious. Biotechnology may be a technically dazzling way of making drugs but it is severely constrained by the fact that the only things that genes can make are proteins, so the only therapeutic use for biotechnology products is in conditions where either a protein is deficient and needs replacing (such as the use of insulin in diabetes) or where it is hoped that giving a protein in large enough doses might in some way or other influence a disease, such as cancer.

  Genetic engineering by definition cannot come up with the sorts of surprises that drove the therapeutic revolution, completely novel chemicals that just happened, like chlorpromazine, to improve the symptoms of schizophrenia, or just happened, like azathioprine, to prevent the rejection of transplanted organs. Further, the technical complexities of biotechnology markedly constrained its innovatory capacity, in contrast to the ease with which medicinal chemists in the 1950s and 1960s synthesised thousands of variations of a single chemical. In 1996, a decade and a half after human insulin launched the genetic engineering revolution, the editor of The Lancet mordantly observed that despite the ‘millions of dollars poured into biotechnology research worldwide’, there is ‘very little to show for such investment’. Perhaps, he speculated, a new anti-cancer drug, Marimastat, developed by the firm British Biotechnology at a cost of £150 million, would be the ‘breakthrough that the biotech industry has been waiting for’? A month later Marimastat was shown to be no more effective than no treatment at all.20

  (iii) THE NEW EUGENICS

  Throughout the 1980s The New Genetics was blossoming out in all directions, the cumulative effect conveying the impression that the possibilities of medicine were being transformed. Thus in the same year, 1982, that the molecular biologist Herbert Boyer and the venture capitalist Robert Swanson launched human insulin, Judy Chang and Yuet Wei Kan of the University of Southern California described a technique for diagnosing the blood disorder sickle cell anaemia in the foetus while still in the womb, thus opening the way to a whole new medical venture: the elimination of genetic disease by prenatal screening and the selective abortion of foetuses found to carry abnormal genes.21

  The genetic mutation involved in sickle cell anaemia takes the form of the substitution of one triplet of nucleotides, GAG, with another, GTG. The messenger RNA then carries this ‘faulty’ message to the protein factory, the ribosome, which makes the haemoglobin protein, where the amino acid valine (coded for by GAG) is substituted with another, glutamic acid (coded for by GTG). This single substitution of the ‘wrong’ amino acid alters the physicochemical properties of the haemoglobin protein, as a result of which the red blood cell collapses inwards (it assumes a sickle shape). The tissues are therefore deprived of oxygen, resulting in ‘sickling crises’, which the patient experiences as pains in the chest and bones.

  Chang and Kan’s technique made use of the text-cutters that cut up DNA into fragments at the site of a particular sequence of nucleotides. Thus, a restriction enzyme that usually cuts the haemoglobin gene at the GAG sequence will not do so if it is replaced by the GTG mutation, so the resulting fragments of the haemoglobin gene will be of a different size in sickle cell anaemia. In theory this method can be applied to virtually any genetic disease where the gene is known, with the obvious corollary that a ‘positive’ prenatal diagnosis permits the prevention of genetic diseases by aborting those found to be affected. In reality, things, as might be expected, turned out to be a bit more complicated. So, to appreciate the principles of this type of genetic screening, it is necessary to take a step back and look at genetic diseases in general.

  There are more than 5,000 genetic diseases. This might sound a lot but virtually all are staggeringly rare, being the result of a ‘spontaneous mutation’ in the DNA a child inherits from its parents. Spontaneous mutations ‘just happen’; there are so many and they are so unpredictable that they cannot be ‘prevented’ by genetic screening. This leaves a handful of commoner
genetic diseases due to the inheritance of a faulty gene from one or both parents for which prenatal genetic screening might be appropriate. Most will be familiar and include the blood disorders such as sickle cell anaemia and thalassaemia; the bleeding disorder haemophilia, famously transmitted by Queen Victoria to the royal households of Europe and resulting from an abnormality of the gene that codes for the ‘clotting’ protein factor VIII; cystic fibrosis, a disease of the lungs that predisposes to chronic infections which destroy the lung tissue, leading to respiratory failure; muscular dystrophy, which causes a progressive weakness of the muscles; and Huntington’s chorea, which causes a dementing illness from the forties onwards and whose most famous victim was the American folk singer Woody Guthrie.

  These inherited genetic diseases are currently incurable, with the obvious exception of haemophilia which, as pointed out in the previous chapter, can be corrected by transfusions of the missing factor VIII. Their symptoms can sometimes be ameliorated, but they can only be prevented by prenatal genetic diagnosis and selective abortion. Put another way, most of these conditions can be diagnosed quite straightforwardly after birth, but by then the option of ‘prevention’ is lost as the postnatal equivalent of abortion, infanticide, has not – since the German eugenics programme of the 1930s and 1940s – been permitted in Western countries.

  The genetic screening of foetuses certainly can work, most obviously in the rather unusual circumstances where a particular genetic disorder is common in well-defined communities. Thus the abnormal haemoglobin gene involved in the blood disorder thalassaemia (responsible for a very severe form of anaemia) is common in Cyprus, with as many as a quarter of the population being carriers, resulting in fifty-one children being born with the disease in 1974. Ten years later, following the introduction of screening, this figure had fallen to two.22