The Rise and Fall of Modern Medicine (40 page)

Finding the gene
: It is all very well chopping up human DNA into little bits and ‘photocopying' them, but what one really wants to know is what those bits mean and particularly whether they contain the sequence of nucleotides that make up a gene that codes for a protein. This was the really intractable problem to which the molecular biologists prior to 1970 believed there could be no answer. But they were wrong. In 1970 two Americans, Howard Temin and David Baltimore, discovered quite independently yet another very special enzyme, this time
made by a certain type of virus. As this is the really crucial moment, it requires some elaboration.
¹¹

Consider the hormone insulin, made by the pancreas, which controls the level of sugar in the blood and whose deficiency results in diabetes. The sequence of nucleotides or the section of DNA coding for insulin (the insulin gene) within the nucleus of these pancreas cells will be generating a lot of messenger RNA, which then moves from the nucleus out into the main part of the cell, or cytoplasm, to be picked up by the protein factory (ribosome), whose reading of the ‘triplet code' will ensure the correct arrangement of the amino acids that make up the insulin protein. This is all in line with the central dogma of genetics: ‘DNA makes RNA makes protein'. Doctors Temin and Baltimore's momentous discovery was that an enzyme produced by a certain type of virus reverses this process, converting the RNA back into DNA (it ‘reverses the transcription', hence the enzyme's name ‘reverse transcriptase'). Theoretically, then, if the RNA coding for the insulin protein could be isolated from the pancreas cell, the addition of ‘reverse transcriptase' would turn it back into the gene from which it originated, so the strand of hay of the insulin gene can be plucked out of the haystack of the human genome. What a coup!

So is that all there is to it – extract the RNA for a protein from the cell, add reverse transcriptase and you end up with the gene? Not quite. There had to be vast amounts of the relevant RNA in the cell for the process to work, and there were really only two situations in which this applied. First, there is a benign tumour of the pancreas known as an insulinoma, producing vast quantities of insulin and whose cells therefore contain abundant insulin RNA, to which the reverse transcriptase could be added to convert it back into the original insulin gene. The second is the red blood cell which, for important reasons relating to its
function, contains masses of RNA coding for the haemoglobin protein, which carries oxygen to the tissues. Here, adding the reverse transcriptase converts the RNA in the blood cells back into the haemoglobin gene. The insulin and the haemoglobin genes were thus the first to be identified – whose significance, it is easy to appreciate, was profoundly important.
¹²

Deciphering the gene
: There is one final technical development to complete the quartet that underpinned The New Genetics. In 1977, again almost simultaneously, Frederick Sanger in Cambridge, England, and Walter Gilbert of Harvard University described two quite different methods of working out the precise sequence of nucleotides in any strand of DNA. So now it was possible not just to find the insulin gene but to know the precise sequence of the nucleotides of which it was made up.
^13
,
14

Thus within the ten years of the 1970s, molecular biologists had moved from a situation where the details of DNA were completely unknown, locked away in the trillion-times-miniaturised forty-three Webster volumes' worth of information, to knowledge of the precise nature of certain genes. It is necessary to acknowledge that this potted description cannot begin to convey the true complexity of the intellectual problems involved and the scale of achievement in their resolution. By 1980 all that was required was a name, something that would encompass the potential of these techniques. In an editorial in the
American Journal of Human Genetics
in 1980 the editor David Comings observed: ‘Since the degree of departure from our previous approaches and the potential of these procedures are so great, one will not be guilty of hyperbole in calling it “The New Genetics”.' ‘The New Genetics' it became.
¹⁵

Now imagine, for a moment, the situation in 1980. Sir Colin Dollery has just written the epitaph for the Age of Optimism,
Nature
is bemoaning the Dearth of New Drugs, and the clinical scientist is becoming an Endangered Species. Then suddenly and quite unexpectedly, like the mounted cavalry, The New Genetics arrives just in time to rescue medicine from this pessimism and despondency. It restores medicine's faith in its future, placing it back on the rails of the relentless upward curve of knowledge that had started back in 1945. It bolsters the public perception of the intellectual status of the profession that, besides everything else, can understand the arcane mysteries of the genes and can pull, like rabbits out of a hat, the gene for this and the gene for that. And most importantly of all The New Genetics restored medicine's status as an intellectual discipline. This was real science, of the sort that earned people Nobel Prizes and made genuinely new and important discoveries. There was more than enough to be getting on with, forty-three Webster-sized volumes of information whose meaning was just waiting to be clarified. The New Genetics was ‘the new dawn' with the potential to have ‘the most significant effect on health since the microbiological revolution of the nineteenth century'.

There were only two unnoticed flies in the ointment. The first, already alluded to, is that genes are, for obvious evolutionary reasons, not a particularly important cause of disease in humans, so the medical applications of this new knowledge was likely to be limited. Second, despite the elucidating power of the techniques of The New Genetics, the genes are so obviously very complex as to defy any profound understanding of how they work. Perhaps Isaac Newton's famous observation more adequately expresses what might be hoped for: ‘I do not know what I may appear to the world, but to myself I seem to have been only like a boy playing on the seashore, diverting myself now and then, finding a smoother pebble than ordinary, whilst the great ocean of truth lay all undiscovered before me.'

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.

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.

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.