The Faber Book of Science

by John Carey

  LW: So you really were a crystallographer at heart from the beginning?

  DH: Well, again, there’s a quite interesting thing about that period. You see, my mother was very much interested in my choice of subject. She approved of it. She and my father were not scientists at all, they were both archaeologists as far as they had a profession, though they were at that time working mainly in education. She bought me, amongst other things, W. H. Bragg’s books based on the subjects of his Christmas Lectures to children at the Royal Institution. If you come across them, they’re very good and still perfectly readable. One is called Concerning the Nature of Things and the other one is called Old Trades and New Knowledge. My mother was particularly interested in Old Trades and New Knowledge. I think she got it because she was interested in weaving and potting and things of that kind. But the one Concerning the Nature of Things describes the X-ray diffraction of crystals and has in it the words: ‘by this means you can “see” the atoms in the crystals’. And so I really decided then that this was what I would do. It was very exciting.

  LW: Now when you started work you began with insulin, but you didn’t solve it straight away.

  DH: No, no, good heavens no. The first measurements on insulin, like Bernal’s first measurements on pepsin which I was a little involved in a year before, were wholly ahead of their time as far as there being any conceivable chance that we could work out the structure. We were both really totally inexperienced in even simple structure analysis at the time. We were faced with an enormously complex problem and though, right at the very beginning, Bernal suggested the way in which it could be solved, it seemed to me that no way was I, at the age of twenty-four, going to set out on that path without trying the proposed method on very much simpler problems first.

  LW: So did you abandon insulin then?

  DH: I never wholly abandoned it. I left it, yes, but in a curious way I didn’t even really leave it. I went on doing the sort of things that would eventually have to be done, but in rather imperfect ways. Very slowly and gradually during the war, doing the measurements out in this house where I brought my little child to be safe away from possible bombing. I knew they weren’t really good enough measurements to solve the structure, yet I couldn’t help going on doing them somehow. But I put my real effort, when I was back in the lab again, into soluble problems. The first one was a carryover from the work that I was doing in Cambridge with Bernal, which was concerned with finding the structure of the sterols, and particularly of cholesterol. The next one was penicillin.

  LW: Why did you choose penicillin?

  DH: Penicillin was just historical accident. The work on penicillin began in Oxford just before the war and one of my friends at that time was Ernst Chain. In Oxford we go up and down South Parks Road, and going along South Parks Road one morning I met Ernst Chain in a state of great excitement having just been carrying out the experiment that is now famous. They had four mice which they injected with streptococcus and penicillin and four mice which they had injected with streptococcus alone. One group, the last group, died and the other group lived. And, as they were trying to isolate penicillin, Ernst was extremely excited, and said ‘Some day we’ll have crystals for you.’

  LW: Now, when you chose to work on penicillin, was it that you really cared about penicillin, or was it that here was an important molecule which offered you the pleasure of finding out its structure?

  DH: I think that both elements went into that particular operation. I mean nobody who lived through the first year or two of the trials of penicillin in Oxford could possibly not care about what it was. But also it’s difficult not to enjoy just growing the crystals.

  LW: Now, the structure of penicillin was soluble, unlike insulin which you were still holding in the background. Was that because it was simpler?

  DH: Yes, there’s all the difference in the world between working out the arrangement of atoms in the space of a small molecule in which you’ve got 16 or 17 atoms in the assymetric unit and one in which you’ve got a thousand.

  LW: How complicated, then, was vitamin B12?

  DH: That’s intermediate. That’s of the order of 100. We didn’t know it was intermediate when we started. Vitamin B12 came about through the fact that I got to know the people in the pharmaceutical industry rather well through the penicillin work, and Dr Lester Smith of Glaxo was working on the isolation of vitamin B12 just after the war. He got crystals first in 1948, within a week or two of crystals being obtained in America by the Merck Group. But to get its structure was again a long process because of the number of atoms in the molecule. The fact was, of course, at that moment we knew nothing, but nothing, about the structure, and what really held us up was just the state of computing in the world. You see electronic computers were being built, but when we started the beginning of the B12 work they hadn’t been used at all in X-ray crystallography. They weren’t really in a fit state. We did the end of the penicillin calculations on an old punched card machine and we brought this back again for the beginning of the B12 calculations. But it was very slow. A calculation which at the end of the story was taking, well, still a few hours on one of the early electronic computers, took us three months on punched cards …

  LW: At some stage you must have realized that you had talents or abilities that set you apart from your friends and colleagues. When was that?

  DH: I don’t think it was so very obvious, you know, because, in a curious way, of the sketchiness of my education. In the early period, before the age of eleven, when my parents came home and I started secondary education, I had moved from one school, one little sort of private school, to another, and one year we’d spent actually being taught entirely by my mother, which was a very fascinating time. So when I first went to secondary school, I was rather behind, if anything. I was terribly behind in arithmetic, and it was only at the end of my time there, at the very end of the last year, that I was first in the form. One of the other girls was also very good indeed, and she was generally first. Actually, she did better in chemistry in school certificate than I did. She was very, very good.

  LW: So what were your special qualities? Why didn’t she go on and do all the things that you did?

  DH: I’ve always thought that her case is really a case history for the problems of girls’ education in this country. You see, a girl’s future has depended a good deal on ambition and the advice that the young get given. She just didn’t think in terms of going to a university, although there’s no reason at all why she shouldn’t have. I think in terms of the present organization, she would have done so, and would very likely have ended up in research.

  LW: Are these same attitudes reflected in the headline in the Daily Mail which read: ‘British Wife gets Nobel Prize?’

  DH: Oh, I thought it said ‘Grandmother’!

  LW: But do you mind that sort of thing?

  DH: I didn’t mind that one, no. The one I was slightly worried about concerned the penicillin work. The headline on my election to the Royal Society read ‘Mother was first’. I wasn’t quite sure that my chemical colleagues would have really appreciated that.

  LW: Have you felt strongly about the position of women in science?

  DH: No. I think it’s because I didn’t really notice it very much, that I was a woman amongst so many men. And the other thing is, of course, that I’m a little conscious that there were moments when it was to my advantage. My men colleagues at Oxford were very often particularly nice and helpful to me as a lone girl. And at the time just after the war, when there was an air of liberalism abroad and the first elections of women to the Royal Society were made, that probably got me in earlier than one might have as a man, just because one was a woman.

  Source: Lewis Wolpert and Alison Richards, A Passion for Science, Oxford, Oxford University Press, 1988.

  The Plan of Living Things

  The most famous breakthrough in modern science was the discovery of the structure of DNA – the genetic material of all organisms in nature –
by Francis Crick and James Watson. The term ‘gene’ was coined in 1909 by Wilhelm Johannsen, and by the mid-1930s it had been established that genes were physical entities. By the early 1950s it was known that the chemical material of the gene was DNA (deoxyribonucleic acid). Watson and Crick, in 1953, proposed a model for the DNA molecule in the form of a double helix, with two distinct chains wound round one another about a common axis. They also suggested that to replicate DNA the cell unwinds the two chains and uses each as a template to guide the formation of a new companion chain – thus producing two double helices, each with one new and one old chain. In this extract from his autobiography, What Mad Pursuit (1989), Crick explains the process of earlier discovery that made possible his and Watson’s advance. RNA, mentioned in the extract, is ribonucleic acid.

  At the time I started in biology – the late 1940s – there was already some rather indirect evidence suggesting that a single gene was perhaps no bigger than a very large molecule – that is, a macromolecule. Curiously enough, a simple, suggestive argument based on common knowledge also points in this direction.

  Genetics tells us that, roughly speaking, we get half of all our genes from our mother, in the egg, and the other half from our father, in the sperm. Now, the head of a human sperm, which contains these genes, is quite small. A single sperm is far too tiny to be seen clearly by the naked eye, though it can be observed fairly easily using a high-powered microscope. Yet in this small space must be housed an almost complete set of instructions for building an entire human being (the egg providing a duplicate set). Working through the figures, the conclusion is inescapable that a gene must be, by everyday standards, very, very small, about the size of a very large chemical molecule. This alone does not tell us what a gene does, but it does hint that it might be sensible to look first at the chemistry of macromolecules.

  It was also known at that time that each chemical reaction in the cell was catalysed by a special type of large molecule. Such molecules were called enzymes. Enzymes are the machine tools of the living cell. They were first discovered in 1897 by Edouard Buchner, who received a Nobel Prize ten years later for his discovery. In the course of his experiments, he crushed yeast cells in a hydraulic press and obtained a rich mixture of yeast juices. He wondered whether such fragments of a living cell could carry out any of its chemical reactions, since at that time most people thought that the cell must be intact for such reactions to occur. Because he wanted to preserve the juice, he adopted a stratagem used in the kitchen: he added a lot of sugar. To his astonishment, the juice fermented the sugar solution! Thus were enzymes discovered. (The word enzyme means ‘in yeast’.) It was soon found that enzymes could be obtained from many other types of cell, including our own, and that each cell contained very many distinct kinds of enzymes. Even a simple bacterial cell may contain more than a thousand different types of enzymes. There may be hundreds or thousands of molecules of any one type.

  In favourable circumstances an enzyme could be purified away from all the others and its action studied by itself in solution. Such studies showed that each enzyme was very specific, and catalysed only one particular chemical reaction or, at most, a few related ones. Without that particular enzyme the chemical reaction, under the mild conditions of temperature and acidity usually found in living cells, would proceed only very, very slowly. Add the enzyme and the reaction goes at a good pace. If you make a well-dispersed solution of starch in water, very little will happen. Spit into it and the enzyme amylase in your saliva will start to digest the starch and release sugars.

  The next major discovery was that each of the enzymes studied was a macromolecule and that they all belonged to the same family of macromolecules called proteins. The key discovery was made in 1926 by a one-armed American chemist called James Sumner. It is not all that easy to do chemistry when you have only one arm (he had lost the other in a shooting accident when he was a boy) but Sumner, who was a very determined man, decided he would nevertheless demonstrate that enzymes were proteins. Though he showed that one particular enzyme, urease, was a protein and obtained crystals of it, his results were not immediately accepted. In fact, a group of German workers hotly contested the idea, which somewhat embittered Sumner, but it turned out that he was correct. In 1946 he was awarded part of the Nobel Prize in Chemistry for his discovery. Though very recently a few significant exceptions to this rule have turned up, it is still true that almost all enzymes are proteins.

  Proteins are thus a family of subtle and versatile molecules. As soon as I learned about them I realized that one of the key problems was to explain how they were synthesized.

  There was a third important generalization, though in the 1940s this was sufficiently new that not everybody was inclined to accept it. This idea was due to George Beadle and Ed Tatum. (They too were to receive a Nobel Prize, in 1958, for their discovery.) Working with the little bread-mould Neurospora, they had found that each mutant of it they studied appeared to lack just a single enzyme. They coined the famous slogan ‘One gene – one enzyme’.

  Thus the general plan of living things seemed almost obvious. Each gene determines a particular protein. Some of these proteins are used to form structures or to carry signals, while many of them are the catalysts that decide what chemical reactions should and should not take place in each cell. Almost every cell in our bodies has a complete set of genes within it, and this chemical programme directs how each cell metabolizes, grows, and interacts with its neighbours. Armed with all this (to me) new knowledge, it did not take much to recognize the key questions. What are genes made of? How are they copied exactly? And how do they control, or at least influence, the synthesis of proteins?

  It had been known for some time that most of a cell’s genes are located on its chromosomes and that chromosomes were probably made of nucleoprotein – that is, of protein and DNA, with perhaps some RNA as well. In the early 1940s it was thought, quite erroneously, that DNA molecules were small and, even more erroneously, simple. Phoebus Levene, the leading expert on nucleic acid in the 1930s, had proposed that they had a regular repeating structure [the so-called tetranucleotide hypothesis]. This hardly suggested that they could easily carry genetic information. Surely, it was thought, if genes had to have such remarkable properties, they must be made of proteins, since proteins as a class were known to be capable of such remarkable functions. Perhaps the DNA there had some associated function, such as acting as a scaffold for the more sophisticated proteins.

  It was also known that each protein was a polymer. That is, it consisted of a long chain, known as a polypeptide chain, constructed by stringing together, end to end, small organic molecules, called monomers since they are the elements of a polymer. In a homopolymer, such as nylon, the small monomers are usually all the same. Proteins are not as simple as that. Each protein is a heteropolymer, its chains being strung together from a selection of somewhat different small molecules, in this instance amino acids. The net result is that, chemically speaking, each polypeptide chain has a completely regular backbone, with little side-chains attached at regular intervals. It was believed that there were about twenty different possible side-chains (the exact number was not known at that time). The amino acids (the monomers) are just like the letters in a font of type. The base of each kind of letter from the font is always the same, so that it can fit into the grooves that hold the assembled type, but the top of each letter is different, so that a particular letter will be printed from it. Each protein has a characteristic number of amino acids, usually several hundred of them, so any particular protein could be thought of crudely as a paragraph written in a special language having about twenty (chemical) letters. It was not then known for certain, as it is now, that for each protein the letters have to be in a particular order (as indeed they have to be in a particular paragraph). This was first shown a little later by the biochemist Fred Sanger, but it was easy enough to guess that this was likely to be true.

  Of course each paragraph in our language is really one l
ong line of letters. For convenience this is split up into a series of lines, written one under the other, but this is only a secondary matter, since the meaning is exactly the same whether the lines are long or short, few or many, provided we take care about splitting the words at the end of each line. Proteins were known to be very different. Although the polypeptide backbone is chemically regular, it contains flexible links, so that in principle many different three-dimensional shapes are possible. Nevertheless, each protein appeared to have its own shape, and in many cases this shape was known to be fairly compact (the word used was ‘globular’) rather than very extended (or ‘fibrous’). A number of proteins had been crystallized, and these crystals gave detailed X-ray diffraction patterns, suggesting that the three-dimensional structure of each molecule of a particular kind of protein was exactly (or almost exactly) the same. Moroever many proteins, if heated briefly to the boiling point of water, or even to some temperature below this, became denatured, as if they had unfolded so that their three-dimensional structure had been partly destroyed. When this happened the denatured protein usually lost its catalytic or other function, strongly suggesting that the function of such a protein depended on its exact three-dimensional structure.

  And now we can approach the baffling problem that appeared to face us. If genes are made of protein, it seemed likely that each gene had to have a special three-dimensional, somewhat compact structure. Now, a vital property of a gene was that it could be copied exactly for generation after generation, with only occasional mistakes. What we were trying to guess was the general nature of this copying mechanism. Surely the way to copy something was to make a complementary structure – a mould – and then to make a further complementary structure of the mould, to produce in this way an exact copy of the original. This, after all, is how, broadly speaking, sculpture is copied. But then the dilemma arose: it is easy to copy the outside of a three-dimensional structure in this way, but how on earth could one copy the inside? The whole process seemed so utterly mysterious that one hardly knew how to begin thinking about it.