At the time, the discovery of the structure of DNA was hard – not intrinsically, but because its importance and uniqueness were not well recognized. The discovery was hard also because the data were scattered, confusing, in some respects meagre, in others overabundant. To begin with, it was not clear what was most relevant in all that was known of the chemical composition of nucleic acids. Neither Watson nor Crick was a biochemist. They were ignorant of a long and erudite scientific tradition, but at least they were not blinded by it. In the middle of the last century, the focus of biological investigation was moving – in pursuit of the steadily greater resolving power of the microscope and then outrunning it – down from the organ and the tissue to the cell. For a hundred years or more, the cell and its contents were to be the domain of the biochemists, whose interest lay in what they could detect and infer about the subtle flux of materials and energy therein.
Biochemists early sorted out the principal distinctive substances they found in living beings into four broad categories – fats (the lipids), sugars and starches (the polysaccharides), proteins, and nucleic acids. The nucleic acids were the last of these to be isolated. In 1868, Johann Friedrich Miescher, a Swiss, twenty-four years old, went to Tübingen to study with Ernst Felix Hoppe-Seyler, an ingenious chemist, the man who gave hemoglobin its present name, and who founded and edited the first journal of biochemistry. Miescher was particularly interested in the chemistry of the cell nucleus. Even with present-day methods, cell nuclei can be hard to separate intact from the cytoplasm and outer membranes surrounding them. Miescher succeeded first with white blood cells from pus, which have big nuclei and not much cytoplasm, and which he got from discarded surgical bandages from the local surgical clinic.
In 1869, he found a new, unexpected compound, acidic, rich in phosphorus, and made up of molecules that were apparently very large. He named it “nuclein”. The stuff was so unlike other substances already known in the cell that Hoppe-Seyler repeated the work himself before allowing Miescher to publish in his journal.
What Miescher had discovered, at that point, was a complex of DNA and the protein normally associated with it in higher organisms. In 1870, Miescher returned to his native Basel; there, at the headwaters of the Rhine, he found an excellent and more pleasant source of nuclear material in the sperm of the salmon for which, a century ago, the river was celebrated. The nuclei are large in any sperm cells, remarkably so in the salmon’s. From these he first extracted a pure DNA. He and his laboratory went on to characterize these discoveries more precisely; in 1889 a pupil of his, Richard Altmann, introduced the term “nucleic acid”.
Miescher’s work was technically accomplished, lit by flashes of intuition. The biochemist Erwin Chargaff wrote, several years ago, that “Miescher, much more than his successors, realized the labile character and the macromolecular behavior of DNA” – although, in life, molecules of DNA are hundreds or even thousands of times larger than the sizes Miescher was able to deduce from his preparations. “Miescher was a sleepwalking kind of scientist”, Chargaff said in the course of a conversation. “He never could give reasons for doing what he did.” There was no basis for Miescher to guess correctly at the function of the substance he had found. The physical reality of such relatively immense molecules, and even the fact that proteins and nucleic acids occur in long chains, was imperfectly comprehended. The chemistry for handling them had not been invented. The requirements of a science of heredity were still obscure.
Three years before Miescher arrived in Tübingen, Gregor Mendel had presented a paper, “Experiments in Plant-Hybridization”, to the Society of Natural Science in Brünn, Moravia, then a quiet corner of the Austrian empire, and in the paper he proposed, as all the world now knows, the idea of a simple, highly regular algebra of heredity in which discrete units – he called them elements; the word “gene” came later – combine and recombine down the generations. But the concept lay entirely dormant until it was rediscovered, along with Mendel’s paper, in 1900. Yet at the end of 1892, Miescher pointed out in a letter to his uncle that some of the large molecules encountered in biology, composed of a repetition of a few similar but not identical small chemical pieces, could express all the rich variety of the hereditary message, “just as the words and concepts of all languages can find expression in twenty-four to thirty letters of the alphabet”. The history of science is full of speculative asides, and they must not be credited with foresight unduly; Miescher’s notion was fatally imprecise. The molecules he offered as examples were albumin and hemoglobin, both proteins. Miescher died in 1895, of tuberculosis, aged fifty-one. “There are people who seem to be born in a vanishing cap. Mendel was one of them … and so was also Miescher”, Chargaff wrote. “If a glance at the portrait forming the frontispiece to the collection of his papers were not enough to tell us this, his letters show us a man, reticent and intense.”
of the elementary chemistry of the nucleic acids was settled early, by Miescher
and his pupils and in other laboratories as well. Their presence in all cells
was as quickly demonstrated. Their function remained unknown. By the beginning
of this century the three constituents of nucleic acids had been described. The
first of these is a sugar, called ribose, built up from a ring of carbon atoms
like all sugars, but in this case a pentagonal ring and five carbon atoms,
rather than, say, the linked hexagon-to-pentagon and twelve carbons of common,
or table, sucrose. The second constituent is simply a phosphorus atom
surrounded by four oxygen atoms, and called a phosphate. The phosphates are
responsible both for the acidity and for the richness in phosphorus that were
so surprising when nucleic acids were first observed; by labyrinthine series of
chemical trials and inferences that took years to perform, it was shown at last
that the phosphate groups link and space the sugars, third carbon of one sugar
ring to fifth carbon of the ring beyond, over and over in monotonous alternation.
The last sort of constituent is called a base, and is built up mostly from
nitrogen and carbon atoms – and while the ribose and phosphate constituents are
simple, repetitive, and altogether predictable, the bases come in several
different kinds and were the central mystery of the nucleic acids. The
three-piece subassembly of a bas linked to a sugar, with a phosphate also
pivoting off the sugar in order to bridge to the next, is called a nucleotide:
a homely word, precise, indispensable, and ubiquitous in this science, indeed
much like the word “iamb” in poetics, for it expresses not just a particular
sort of construction but a unit of length and even a category of significance.