At the time of writing, Watson is ninety years old and still active. It is sixty-five years after he declared himself too old to be unusual, and it would appear that this was one of the things that he got wrong.
Last words
With such a rich and diverse cast, there are plenty of candidates who could round off the story in style. My own choice is a man who hovered on the periphery of the action, but who determined the course of this particular stretch of history: John Randall. Without him, the structure of the double helix would still have been solved – but Francis Crick, Jim Watson, Maurice Wilkins and Rosalind Franklin would probably have played no part in that discovery.
It is mid-November 1950, just a couple of weeks before Randall is due to write to Rosalind Franklin in Paris, telling her that DNA – not proteins – will be the focus of her fellowship at King’s. On Randall’s desk is a letter from an American friend which ends, ‘I hope that this will bring you joy.’ This’ is not the result of some clever experiment, but a poem. The American had quoted from it during a lecture, and Randall had written to ask him for the source.
The poem is from ‘Sonnets and Poems’ and is entitled simply, ‘XII’. It is by John Masefield, Poet Laureate, but could almost have been written by Erwin Schrödinger, Nobel laureate and author of the little book that inspired Wilkins, Crick and Watson. It begins:
What am I, Life? A thing of watery salt Held in cohesion by unresting cells.
This is of course poetic licence, because salt and water are not enough to create life. To do that, we need to add in all the building-blocks of metabolism and the legions of proteins that give the unresting cells both structure and function. And at the heart of it all is a twist – more accurately, a double twist – of deoxyribonucleic acid.
* In 1966, the Prize for Physiology or Medicine was awarded to 87-year-old Peyton Rous, for having discovered a cancer-inducing virus in 1911.
GLOSSARY AND ABBREVIATIONS
A: abbreviation for adenine.
A form of DNA: the ‘crystalline’ form with a low water content, characterised by Rosalind Franklin.
Å: Ångström, atomic level unit of length. 1 Å = 10-10 metres, or one ten-millionth of a millimetre.
Adenine: a purine base in DNA.
Paired with thymine by hydrogen bonding in the double helix.
Alleles: the alternative forms of a particular gene, occupying the same location on the chromosome.
Alpha-helix: the spiral configuration commonly adopted by stretches of amino acids in proteins. Discovered by Linus Pauling in 1948.
Amino acids: a series of twenty organic compounds with common structural features, which are the building-blocks of proteins.
B form of DNA: the helical form with a higher water content, characterised by Rosalind Franklin.
Backbone of DNA: the spiral strands of phosphate alternating with deoxyribose which form the outside of the double helix.
Bacteriophage (also ‘phage’): viruses which prey on bacteria by injecting them with their DNA.
Base: nitrogen-containing organic molecules with a flat structure comprising either one ring (pyrimidines) or two rings (purines).
Base-pairing: pulled together by hydrogen bonding, the attraction of adenine for thymine, and of cytosine for guanine. Zips together the two DNA strands of the double helix.
Bausteine: German for ‘building-blocks’. The simple compounds that make up complicated biological molecules. In the case of DNA: phosphate, the sugar deoxyribose, and the bases adenine, guanine, cytosine and thymine.
Biophysics: see Molecular biology.
C: abbreviation for cytosine.
Capsule: the protective outer coating of pneumococci, containing specific antigens made of carbohydrate.
Cell, unit: basic building-block of a crystal structure.
Chargaff’s Rules: formulated by Erwin Chargaff. (1) The base composition of DNA is constant for all tissues of a given species but varies between species. (2) In DNA from all sources, the contents of adenine = thymine, and of cytosine = guanine (the consequence of base-pairing).
Chromatids: the two thread-like strands into which each chromosome divides longitudinally during cell division. This is after DNA replication; each chromatid contains a double helix of DNA.
Chromatin: the heavily stained substance of chromosomes, corresponding to DNA.
Chromosin: DNA with associated proteins, extracted from cell nuclei by Alfred Mirsky.
Chromosomes: thread-like structures in the nucleus, consisting of DNA and proteins and carrying the genes.
‘Crystalline’ DNA: the A form, with regular distortions introduced into the helical structure by the removal of water.
Cytidine: the nucleoside consisting of cytosine linked to desoxyribose.
Cytochemistry: the microscopical study of tissues and cells, using stains to highlight particular cellular components and substances, such as DNA.
Cytosine: a pyrimidine base in DNA. Paired with guanine by hydrogen bonding in the double helix.
Deoxyribose: the pentose sugar found in DNA and which gives it its name. Interlinked with phosphate groups, forms the spiral backbone of the double helix.
DNA: deoxyribonucleic acid (previously ‘desoxyribonucleic acid’).
DNase (deoxyribonuclease): enzyme which specifically breaks down DNA.
Dominant: an allele which masks the effect of another (the ‘recessive’).
Drosophila: the fruit fly, in which Thomas Hunt Morgan and others induced and mapped mutations, and defined their inheritance.
Eno: one of two interchangeable forms in which organic molecules such as the bases can occur. The other form, ‘keto’, prevails in vivo.
Eugenics: the belief that the genetic quality of a human population can be improved; and practical attempts to achieve this aim.
G: abbreviation for guanine.
Gene: a unit of heredity, carried on a chromosome and transferred from parent to offspring. Corresponds to a distinct sequence of DNA.
Genetic code: the sequence of DNA nucleotides which carry and transmit genetic information. Based on specific ‘triplets’, sequences of three consecutive nucleotides.
Genome: the complete set of genes, conveying the totality of genetic information, of a living organism.
Genotype: the genetic makeup of a particular inherited characteristic of a living organism, e.g. TT, Tt or tt for the height of pea plants. C.f. phenotype.
Guanine: a purine base in DNA. Paired with cytosine by hydrogen bonding in the double helix.
Heterozygote: possessing two different alleles of a particular gene, e.g. Tt for the height of pea plants. C.f. homozygote.
Histones: basic (alkaline) proteins in the nucleus that bind to and organise DNA.
Homozygote: possessing the same two alleles of a particular gene, e.g. TT or tt for height in pea plants.
Hydrogen bonding: attractive force which pulls together hydrogen and another atom in the same or different molecules.
Keto: one of two interchangeable forms in which organic molecules such as the bases can occur, and the form that prevails in vivo. Cf. Eno.
Meiosis: the special process of cell division in the formation of eggs and spermatozoa, resulting in four daughter cells each with half the normal number of chromosomes. Cf. Mitosis.
Mitosis: the process of cell division, yielding two daughter cells with a complete set of chromosomes. Cf. Meiosis.
Molecular biology: the interface between biology and physics, covering the structure and function of the complex cellular molecules essential for life. Synonymous with ‘biophysics’.
Mutation: a change in the DNA sequence of a gene, either occurring spontaneously or induced artificially with X-rays, chemicals or other means.
Nucleic acid: term that replaced ‘nuclein’ and originally embraced both DNA and RNA.
Nuclein: original name for DNA, isolated from pus cells by Friedrich Miescher in 1868.
Nucleoside: a nucleotide without the phosph
ate, i.e. deoxyribose joined to one of the bases (adenine, guanine, cytosine or thymine).
Nucleotide: the basic structural unit of DNA, consisting of phosphate joined to deoxyribose (forming part of the outer backbone), and an inwardly projecting base (one of adenine, guanine, cytosine or thymine).
Nucleus: the membrane-bound organelle which contains the chromosomes and controls all the activities of the cell by directing the synthesis of RNA and thus of proteins.
Paper chromatography: method for separating and measuring amounts of particular substances, such as the bases in samples of DNA.
Pentoses: simple sugars with a five-cornered ring structure. They include ribose and deoxyribose, found in RNA and DNA, respectively.
Phagocytosis: the engulfing of bacteria and other tiny particles, notably by white blood cells.
Phenotype: an observable physical characteristic of a living organism, e.g. tallness or shortness in pea plants.
Pneumococcus: bacterium which causes lobar pneumonia. The subject of Griffith’s ‘transformation’ experiments which led to the first evidence that DNA is the genetic material.
Protamines: basic (alkaline) proteins, tightly bound to DNA in the heads of spermatozoa. They replace the histones in the later stages of sperm formation.
Purines: two-ringed bases, such as adenine and guanine, occurring in both DNA and RNA.
Recessive: an allele which is masked by another (the ‘dominant’).
Ribose: a pentose sugar found in RNA, and which gives it its name. RNA: ribonucleic acid.
RNase (ribonuclease): enzyme which specifically breaks down RNA.
Sepia: the cuttlefish, which provided sperm for studies of DNA in living cells.
Sex-linked: a gene which is associated with one sex or the other, e.g. white eye colour, only in male fruit flies.
Sodium thymonucleate: alternative name for DNA.
SSS (Soluble Specific Substance): the carbohydrate antigen in the capsule which gives each pneumococcus its immunological identity.
Tetranucleotide: a hypothetical structure for DNA, proposing a short, boring molecule that contains just one of each of the bases and is therefore incapable of carrying complex information such as heredity.
Thymine: a pyrimidine base in DNA. Paired with adenine by hydrogen bonding in the double helix.
Thymus: organ in the neck or thorax of mammals that is a gastronomic delicacy as well as a rich source of DNA.
Thymus nucleic acid (also ‘thymonucleic acid’): old name for DNA.
Transformation (of pneumococci): changing the genetic characteristics of a bacterium with extracts of dead bacteria, first achieved by Fred Griffith in 1928.
Transforming principle (also, ‘transforming factor’): the chemical substance mediating transformation in bacteria, which Avery’s team showed in 1944 to be DNA.
Type, of pneumococcus: classification of pneumococci based on the immune reactions of the antigens in the capsule.
Uracil: a pyrimidine base not found in DNA but in RNA, in which it replaces thymine. Paired with adenine by hydrogen bonding.
X-ray crystallography: X-ray diffraction used to elucidate the structure of molecules that can form crystals.
X-ray diffraction: the scattering of X-rays by regularly spaced obstructions, exploited to define the structures of mineral crystals, virus particles and biological fibres such as DNA.
Yeast nucleic acid: old name for RNA.
NOTES
References that are not cited in full can be found in the Bibliography, under the first author’s name and date of publication.
Astbury Papers: Papers and correspondence of William Thomas Astbury, Special Collections, Brotherton Library, University of Leeds.
Randall Papers: Papers of Sir John Randall, Archives of Churchill College, Cambridge, GBR/0014/RNDL.
Wilkins Papers: Papers of M.H.F. Wilkins, Archives of King’s College, London.
Preface
xxviiione eminent historian: Robert Olby, in Olby 1974, pp. xix–xxi.
Chapter 1: Rewind
1Case No. 1: Jennings C. From Bosnia to Syria – the investigators identifying victims of genocide. Guardian, 10 Nov 2013; Emric A., Cerkez A. Bosnian Mom buries two sons 19 years after massacre. San Diego Union-Tribune, 10 July 2014.
1Case No. 2: Fackenthal J.D., Olopade O.I. Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations. Nature Reviews Cancer 200; 7:937–48. The BRCA1 gene encodes a protein that repairs breaks in DNA which cause uncontrolled cell division; mutations such as this one prevent the protein from performing its normal role and predisposes to cancer.
2Case No. 3: Haensch S., Bianucci R., Signoli M. Distinct clones of Yersinia pestis caused the Black Death. PloS Pathog 2010; 6:e1001134. doi: 10.1371/journal.ppat.101134. DNA from the plague bacterium (Yersinia) survives best in the teeth and bones of its victims.
2Case No. 4: Wang H-L., Yan Z-Y., Jin D-Y. Reanalysis of published DNA sequences from Cretaceous dinosaur egg fossils. Mol Biol Evol 1997; 14:589–91.
3Ötzi: Keller A., Graefen A., Zink A. New insights into the Tyrolean Iceman’s origin and phenotype as inferred by whole-genome sequencing. Nature Communications 2012; 3:698. Ötzi probably had brown eyes, belonged to blood group O and was lactose-intolerant.
7A brief paper published in Nature: Watson & Crick 1953a.
Chapter 2: In the beginning
Miescher’s letters are detailed in the extensive references in Dahm; the originals are in Miescher, Histochemischen und Physiologischen Arbeiten, vol. 1 (scientific correspondence) and vol. 2 (personal correspondence).
10Friedrich Miescher was born in August 1844: Dahm, Miescher pp. 275–6; Buess, pp. 256–8.
11he discovered something: Dahm, pp. 276–9.
12‘completely naked’ nuclei: Dahm, p. 278.
13an excited letter to his parents: Dahm, pp. 276–8.
13Neurology in Leipzig: Buess, p. 256.
14Hoppe-Seyler took months: Dahm, p. 279.
14The three papers: Miescher 1871; Plosz, P. Über das chemische Verhalten der Kerne der Vogel- und Schlangenblutkörperchen Ibid 4: 461–462; Hoppe-Seyler F. Über die chemische Zusammensetzung des Eiters. Ibid 4:486–501.
15Miescher’s working day: Dahm, p. 281.
16He christened this nuclear protein: Miescher 1874a.
16sperm from frogs, carp and chickens: Miescher 1874b.
16heavy weather of teaching: Dahm, p. 275.
16he called it ‘liquidation’: Miescher F. Über das Leben des Rheinlachses im Süsswasser. Arch Anat Physiol, Anat Abt 1881; 193–218.
17On the morning of 21 March: Suter F. Prof. F. Miescher: Persönlichkeit und Lehrer. Helv Phys Pharm Acta 1944; suppl. 2:6–17.
17The diagnosis: Portugal & Cohen, p. 28.
18a letter from Carl Ludwig: Miescher, Arbeiten, p. 12.
19A friend and colleague had died: Baumann E., Kossel A. Zur Errinnerung an Felix Hoppe-Seyler. Zeitschrift für physiologische Chemie 1895; xxi:1; Anonymous. Obituary – Felix Hoppe-Seyler. Brit Med J 1895; 2:687–8.
19a labour of love: Miescher J.F. Die Histochemischen und Physiologischen Arbeiten von Friedrich Miescher, eds His W., Schmiedeberg O., vols 1 and 2. Leipzig: Verlag F.C.W. Vogel, 1897.
20‘As long as I have not paid’: Buess, p. 257.
20‘Only when I come across’: Buess, p. 258.
21these instructions could be conveyed: Olby R., Posner F. An early reference to genetic coding. Nature 1967; 215:556–7.
21only proteins were sufficiently large: Miescher, Arbeiten, pp. 116, 122, 127.
22a dramatic new drug: Carnrick J. Protonuclein and method of preparing same. US Patent Office No. 587, 278, filed 4 Jan 1895.
22a dazzling presentation: Summers T.O. Leucocytes and nucleins. J Am Med Ass 1895; 24:963–6.
Chapter 3: Bag of worms
23The summer 1858 issue: Anonymous. Obituary Notice. Robert Brown, Esq. Annals & Magazine of Natural History, Series 3. 1858; 2:80–2.
24‘a prof
esssed naturalist’: letter from José Correia da Serra to Joseph Banks, cited in Mabberly, pp. 59–60.
24the botanist-scoundrel: Mabberly, p. 65.
24Brownian motion: Brown R. A brief account of the microscopical observations … on the particles contained in the pollen of plants … Edin New Philosoph 1828; 5:358–71. Available online: sciweb.nybg.org/science2/pdfs/dws/Brownian.pdf In 1905, Einstein proved that the phenomenon was due to the buffeting of particles in suspension by water molecules: Einstein A. Über die von der molekularkinetischen Theorie der Wärme geforderte Bewegung von in ruhenden Flüssigkeiten suspendierten Teilchen. Ann Phys 1905; 17:549–560.
24The microscope: Pearle P., Collett B., Bart K. What Brown saw, and you can too. Am J Physics 2010; 78:1278–89. Proof that Brown’s microscopes could detect Brownian motion.
25the sex life of orchids: Brown R. Trans Linn Soc London 1833.
26the ‘nucleus of the cell’: Ibid, p. 110.
27Huxley named it Bathybius: Coleman W. Cell nucleus and inheritance: an historical study. Proc Amer Phil Soc 1965; 109:128–38.
27Haeckel wrote that: Haeckel E. Generelle Morphologie der Organismen. Berlin: G. Reimer, 1866, vol. 2, pp. 287–8.
28‘the Guild of Dye-Makers’: Miescher F., Arbeiten, letter 1897; i: 107–8.
28the lining of the gut: Spalding K., Bhardwaj R.D., Bucholtz B.A. Retrospective birth dating of cells in humans. Cell 2005; 122:133–43.
29Van Beneden called ‘bâtonnets’: Van Beneden.
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