Darwin was also impressed by recent work that had shown that micro-organisms could reproduce extremely rapidly. Then a few days later he read Malthus’s Essay on Population, with its emphasis on the enormous over-productivity of nature without any checks on fecundity, and ‘it at once struck me that under these circumstances favourable variations would tend to be preserved, and unfavourable ones to be destroyed. The result would be the formation of new species.’ Thus was born the theory of evolution by natural selection. Reading Malthus enabled him to realize that natural selection would not only select out non-adapted variants but would also favour those variants that were better adapted than others.
It is quite clear that Darwin’s theory required a long incubation period and many false starts. It also required fine judgement, great persistence, intellectual coverage and, finally, genius. The path towards the solution had not been straightforward.
Gruber emphasizes that ‘attacking the most difficult tasks requires the highest level of aspiration, and consequently puts stressful demands on the ego system.’ There must be a sense of special mission, and also a degree of psychic courage in taking on a very difficult problem in such a way that if the project fails there is nothing to show for it. There are probably many examples of this, but most scientists adopt a safer strategy, such that something positive will come out of the research. For example, if Watson and Crick’s attempt to determine the structure of DNA had failed, they would have had very little to show for their efforts.
Another example is the American molecular biologist Mark Ptashne’s search for the repressor protein. In 1965, at the age of twenty-five, Ptashne decided to try to isolate the key repressor protein that had been postulated by the model of the French biologists François Jacob and Jacques Monod. This protein had been postulated to bind to a specific region of a gene in a bacterial virus and in so doing to play the crucial role of switching a gene off. Control of gene activity, that is turning genes on and off, is fundamental to cell behaviour, whether it be in normal development of the embryo or in pathological conditions like cancer. Isolating the first protein which could turn a gene on and off would be a major advance and would enable the process to be understood in molecular terms. Evidence for the existence of the controlling protein was at this time only indirect and came from genetic experiments. As he told the science journalist Philip J. Hilts, Ptashne saw it as a great problem:
as I looked into it more … it became clear that the others were willing to take risk only to a certain point. The question was, how hard are you willing to work, are you willing to work with the possibility that you’ll have nothing at all to show for it? You may work for two or three years, simply fail and look like a fool. If not a fool, at least empty-handed.
Ptashne took that risk.
One floor below Ptashne in the same Harvard laboratory was another molecular biologist, Wally Gilbert, who was also trying to isolate the repressor, but by a different route. (He later won a Nobel Prize for other work on sequencing DNA.) Their research was independent and competitive, but with mutual support and openness. Ptashne worked unbelievably hard, even to illness through exhaustion. ‘I think the most important experience you have as an experimental scientist is realizing the extent to which you can be fooled, the extent to which your impulses and aspirations lead you to believe things which have nothing to do with the way things actually work.’ As Hilts puts it, the chief experience of science is failure. But within eighteen months Ptashne had isolated the repressor, and so had Gilbert: the honours were shared.
Ptashne’s style is still unashamedly aggressive: ‘I do needle and goad students, at least those for whom I have the greatest respect. The reason is most people do not understand just how difficult science is, how difficult it is to do something truly first rate or original.’ Persistence in the face of failure is a repeated theme in successful science.
The discovery of messenger RNA provides an example of the complex nature of scientific discovery and of a case where illumination was of the ‘Eureka!’ type. Proteins are synthesized on small particles in the cell called ribosomes. Messenger RNA is a key molecule carrying the information for proteins from the DNA to the ribosomes – it specifies the sequence of the protein’s amino acids (Chapter 1). Ribosomes themselves are made up of protein and another sort of RNA.
Francis Crick has related how it was not at all easy in the late 1950s to get across to other scientists the idea of the genetic code, namely that sequences of DNA were coded for specific amino acids and so provided the code for protein structure. There was a feeling in the larger scientific community that Crick and his colleagues were oversimplifying things. Moreover, they were having great difficulty finding out what the code actually was. They had, however, got the main outlines right. ‘But we made one terrible, terrible bloomer. In modern terms we would express it by saying we thought that the ribosomal RNA was the messenger RNA, and that held us up, oh, for several years. The penny dropped one day, one Good Friday, I think it was.’ They thought that, because proteins were synthesized on ribosomes which contained RNA, it was ribosomal RNA that carried the code. They experienced a moment of great insight – similar in a way to the discovery of the structure of DNA – when, in a very short time, the whole subject came to look quite different. Only once this step had been taken could there be real progress, and in this case the genetic code was worked out within a few years.
The bloomer came about as follows. By 1957 Crick’s ‘central dogma’ was generally accepted, namely that DNA makes RNA which makes protein. It was also known that proteins were made on ribosomes, which also contain RNA. It was thought that the RNA in the ribosome was the same as the RNA that coded for the protein, but this posed a severe problem for the control of protein synthesis. François Jacob had shown that changes in the amount of synthesis of specific proteins are rapid and under genetic control. Ribosomes, by contrast, are rather stable, and this was inconsistent with the rapid turning on and off of protein synthesis. How, for example, could new ribosomes be made so quickly? Crick and his colleagues were stuck and searched for some way out. Even heretical ideas, such as DNA making protein directly, were considered.
Sydney Brenner was acutely aware of the problem, and on Good Friday 1960 several of the key people, who were in London for a meeting, came to his rooms in King’s College, Cambridge. Jacob took them over his experiments on the rapid change in synthesis again; these experiments had been repeated and were now even more persuasive. If the synthesis of a new protein could be rapidly turned on and off, it was hard to reconcile this with it being the gene that controlled this protein if the protein was being made on a ribosome. It may be relevant that the French group, to which Jacob belonged, was more interested in genetic switches than in the problem which occupied the British group, namely the genetic code. In the discussion in Brenner’s room, Jacob described an experiment which had been done by some Americans in Berkeley which showed that, for the protein to be synthesized, the gene had to be there all the time. It seemed that the gene needed to be active all the time its protein was being synthesized. This suggested that the gene might be involved by producing an unstable intermediary which would decay and disappear in the absence of the gene. ‘That’s when’, as Cricks says, ‘the penny dropped and we realized what it was all about.’ They then recalled an experiment by some other American workers, who had found a species of RNA that resembled DNA but which they had thought to be some precursor of DNA synthesis. Now Crick and Brenner realized that this RNA was an unstable messenger that carried the information for making the protein from the DNA to the ribosome. It had already been discovered, but the Paris group had not realized it. The ribosome was a structure for making proteins, but its RNA was something with a different function and the ribosome required an RNA message from the DNA which specified which protein was to be made. Brenner now saw how they could test the idea of a messenger RNA, and he and Jacob planned the experiment that day. Brenner and Jacob were already going to the California
Institute of Technology, and they planned to do the experiment in Mesehlsohn’s laboratory there, since he had the right techniques available.
Their new ideas were treated by most Americans with scepticism; the great Delbrück told them, ‘I don’t believe it.’ Their planned experiment was to infect bacteria with a bacterial virus – a phage – which resulted in new protein synthesis for making a new phage, to find out if new ribosomes were made or whether, as they predicted, a new messenger RNA went to the pre-existing ribosomes. The experiment involved density centrifugation to separate out the ribosomes according to whether or not they had incorporated heavy isotopes of carbon and nitrogen. Things went badly wrong. They couldn’t get the isotopes into the ribosomes. With only a few days left, they spent the afternoon on the beach. Brenner was uncharacteristically silent but suddenly leapt up shouting ‘It’s the magnesium.’ Running through the experiments in his mind, he had suddenly realized that they hadn’t added enough magnesium and thus had damaged the ribosomes. They rushed back to the laboratory and repeated the experiment with the addition of more magnesium – an apparently trivial but crucial component. The experiment worked and the existence of messenger RNA was established. It took six months more of hard work to complete the work in Cambridge.
This discovery is a nice example of sudden insight coming to a group who were making no progress with a problem. Its solution required both imagination and knowledge, and a large infrastructure of work by others. Crick, Brenner and Jacob had an enormous knowledge, in detail, of many, many of the experiments. The trick was to know which experiments were the relevant ones. It may not be easy to find an analogy to this sort of creativity in the arts.
The discovery of messenger RNA is particularly satisfying because the moment of discovery can be pinpointed, the moment of insight recorded. But this is not necessarily typical of progress in science, which is often by slow accumulation such that the breakthrough comes without drama. It is certainly possible to imagine a scenario in which the structure of DNA and the revolution it brought came piecemeal and involved players less charismatic than Crick and Watson; the discovery might then never have acquired its enormous appeal and public exposure. One can see such a case with an equally important advance – the recognition, during the second half of the nineteenth century, that chromosomes were the carriers of heredity. This came by the accumulation of small but crucial advances, but without drama or association with any one scientist.
Thus there is a question about the essential role of genius in science. To what extent are new ideas, and the whole progress of science, really determined by the work of scientists of genuis? The Ortega hypothesis, taken from José Ortega y Gasset’s The Revolt of the Masses, asserts that genius is not necessary and that ‘experimental science has progressed – thanks in great part to the work of men astoundingly mediocre, and even less than mediocre.’ Science accommodates and even needs the intellectually commonplace. According to this view, science proceeds, in certain areas at least, by addition of small if not tiny steps, and there are no real breakthroughs.
Some evidence against this idea comes from analysis of the use of the scientific literature. It turns out that 85 per cent of science literature – that is, papers in scientific journals – is quoted in other papers once or not at all each year, while only 1 per cent is quoted five or more times. In the arts and humanities, 98 per cent of papers published are not cited in the following four years, compared to about 40 per cent in science. This supports the argument that an extremely small proportion of the literature is dominant. In cell biology the evidence is similar. About ten key journals dominate the field, but a further 150 journals publish occasional papers which are regarded as being essential. While such key journals may dominate a field, it is far from clear to what extent they rely on the infrastructure created by lesser scientists. The question is less one of breakthroughs than of significant contributions.
The Ortega hypothesis is partly dealing with the issue of whether science proceeds gradually or with sudden jumps: whether progress is slow and gradual, with many contributions, or is due to the work of rare revolutionary scientists. The historian Thomas Kuhn, in his book The Structure of Scientific Revolutions, designated as advancers in science those who practise what he calls ‘normal science’. They contribute by determining significant facts, by matching facts with theory and by articulation of theory itself, but they remain within a given paradigm – that is, they work within the framework of the dominant ideas current at the time. By contrast, the revolutionary scientists, like Darwin and Einstein, change the paradigm. It has been asked why, if revolutionaries are accorded so much acclaim, everyone does not opt for that mode of science. An answer may be provided by the state of the science – whether, for example, the conditions are right for revolution – but a more likely answer is because it is very, very hard to think of revolutionary ideas.
There are usually lots of other scientists thinking very hard about the central problems, so there are many examples of multiple discoveries. Wallace arrived at evolution by natural selection at about the same time as Darwin. Methods for determining the sequence of bases in DNA – fundamental to genetic engineering – were discovered independently by Gilbert and Maxam in Harvard and by Sanger in Cambridge. The ‘rediscovery’ of Mendel’s laws of genetics at the end of the last century was made by at least three biologists. The unification of two of the fundamental forces of nature was achieved independently by several physicists (see Chapter 5). And the discovery of the AIDS virus was claimed by both American and French virologists. The list is long.
The traditional interpretation of multiple discoveries is that they show that scientific advance lies outside the individual and rather that the scientific milieu at a particular time – the Zeitgeist – determines the nature of the contribution. According to this view, discoveries are inevitable and science does not depend on acts of genius. (This is, of course, a non sequitur, for why should there not be several geniuses around at any one time?) There is, in a sense, a certain inevitability of discovery when the appropriate knowledge is available and enough gifted investigators are focusing on the problem.
There is a widely held view – which I believe to be mistaken – that serendipity plays an important role in discovery. This unfortunate word was coined by Horace Walpole in 1754 to describe people’s discoveries ‘by accident and sagacity, of things they were not in quest of’. I say ‘unfortunate’, for the word has been rather consistently misapplied to scientific discovery. Again and again one reads reports of accidental or chance discoveries. Examples of serendipity in science are said to abound: Fleming’s discovery of penicillin, Becquerel’s discovery of radioactivity, the discovery of tranquillizers, and on and on. In each case luck is ascribed a major role in the discovery. But was it really luck, or accident, that was important? May not the whole idea of serendipity be based on a misconception about the nature of science, and also about the nature of chance itself? Even a casual examination of each of the so-called examples of serendipity does, I believe, allow one to reach a quite different conclusion. It will confirm the intense self-awareness that is involved in scientific research: scientific research is based not on chance but on highly focused thoughts.
Louis Pasteur, the outstanding French biologist and doctor, had a reputation for being lucky. At the age of twenty-five, shortly after receiving his medical qualification, he was studying racemic acid, a chemical that is deposited in wine casks during the fermentation of grapes. Pasteur was puzzled by the already established observation that a solution of racemic acid had no effect on a beam of polarized light, whereas tartaric acid, with an apparently identical chemical composition, rotated the beam in a particular direction. So he prepared crystals of racemic acid, and when he examined them under the microscope he noticed that there were two kinds of crystal which, like left and right hands, were mirror images of each other. Distinguished chemists had examined the crystals before but had missed this subtle difference. Pasteur now s
howed that the right-hand crystals were like tartaric acid, and it was because racemic acid was a mixture of left-and right-hand crystals that it did not rotate the light. This research opened up the whole field of handedness of molecular structures. Life itself is largely built on one class of handed molecules: the left-handed amino acids which are the chemicals from which proteins are made.
The claim for Pasteur being lucky is based on some of the special properties of racemic acid: the particular form he studied is unique in providing crystals which can be recognized under the microscope, and also the separation into the two forms occurs only at temperatures below 26°C. But this is no more luck than that he actually decided to study racemic acid, had a microscope and so on.
Another example of Pasteur’s so-called luck was his discovery of immunization using dead bacteria. He was experimenting with the bacteria that caused cholera in chickens. The bacteria were grown on agar plates and were then used to infect the chickens. On one occasion the chickens were innoculated with an old culture in which the bacteria seemed to have died. The chickens did not get the disease. But when these same chickens were later innoculated with a fresh culture they survived the infection. Pasteur, fully aware of Jenner’s work on innoculation with cowpox to prevent smallpox, recognized the similarity, and in Jenner’s honour called the process vaccination, from the Latin vacca (cow), referring to the cowpox work.
The Unnatural Nature of Science Page 10
