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.”
Much
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.