Unravelling the Double Helix Read online

  UNRAVELLING

  THE DOUBLE HELIX

  The Lost Heroes of DNA

  GARETH WILLIAMS

  With love and thanks to:

  Caroline, Tim, Jo and Tessa

  For putting up with me while I did another one

  Dorothy Strangeways

  For giving me the idea over tea in Hartington Grove

  Gordon ‘Doc’ Wright

  For helping to keep me afloat in Cambridge, 1971–4

  We all stand on each other’s shoulders.

  Rosalind Franklin, March 1953

  On hearing that James Watson and Francis Crick

  had deduced the double helical structure of DNA

  A science which hesitates to forget its founders is lost.

  Alfred North Whitehead, September 1916

  Address to the British Association for the Advancement of Science

  CONTENTS

  Timeline

  Who’s Who

  Preface: Not another one

  1Rewind

  2In the beginning

  3Bag of worms

  4Gardening leave

  5Of grasshoppers and flies

  6Bausteine

  7A whirlwind from Russia

  8Crystal gazing

  9The sad demise of a promising candidate

  10Inventions and improvements

  11Movable type

  12Transformational research

  13Up North

  14Unholy Grails

  15Applications of science

  16Dreams of geneticists

  17Tidying up

  18Tipping points

  19Twists and turns

  20Meetings of minds

  21Team building

  22Whizz kid

  23Handicap race

  24Photo finish

  25Aftershocks

  26Retrospective

  Glossary and Abbreviations

  Notes

  Bibliography

  Acknowledgements

  Illustration Credits

  Index

  TIMELINE

  1833

  Robert Brown describes the nucleus in cells of orchids

  1866

  Gregor Mendel publishes ‘Studies of plant hybridisation’

  1868

  Friedrich Miescher discovers ‘nuclein’ (DNA) in pus cells

  1878

  Albrecht Kossel isolates ‘yeast nuclein’ (later shown to be RNA)

  1880

  Walther Flemming describes nuclear ‘threads’ made of ‘chromatin’ during cell division (‘mitosis’) in the salamander

  1882

  Flemming suggests that chromatin and nuclein are identical

  1885

  Kossel extracts two bases, guanine and adenine, from thymus nuclein, followed by thymine (1893), cytosine (1894) and uracil (1900)

  1888

  Wilhelm Waldeyer renames Flemming’s threads ‘chromosomes’

  1889

  Richard Altmann renames nuclein ‘nucleic acid’

  1900

  Mendel’s work is ‘rediscovered’ by Carl Correns, Hugo de Vries and Erich von Tschermak

  1903

  Walter Sutton formulates the ‘chromosome theory of inheritance’

  1904

  William Bateson begins a pro-Mendel crusade and coins the word ‘genetics’

  1909

  Wilhelm Johannsen invents the words ‘gene’, ‘genotype’ and ‘phenotype’ Phoebus Levene identifies the sugar in yeast nucleic acid (RNA) as ribose

  1912

  Levene proposes that nucleic acids are a small ‘tetranucleotide’, containing one of each of the four bases Max von Laue takes the first X-ray photograph of a crystal

  1914

  Lawrence Bragg formulates Bragg’s Law of X-ray crystallography; with his father William, develops ‘a new crystallography’

  1915

  Thomas Hunt Morgan publishes The Mechanism of Mendelian Inheritance, based on mutations in the fruit fly

  1927

  Fred Griffith shows that dead pneumococci bacteria can ‘transform’ (change the genetic characteristics of) live pneumococci, when injected into living mice

  1928

  Levene and Kossel both claim that genes are made of protein, not nucleic acid

  1929

  Levene identifies the sugar in thymus nucleic acid (DNA) as deoxyribose Martin Dawson, in Oswald Avery’s lab at the Rockefeller, confirms Griffith’s finding of transformation of pneumococci, also in living mice

  1931

  Dawson and Richard Sia achieve transformation in vitro

  1932

  Lionel Alloway in Avery’s lab extracts the ‘transforming principle’ responsible for transformation but cannot identify it chemically

  1937

  Torbjörn Caspersson deduces that DNA molecules are very long, thin cylinders, and much bigger than a ‘tetranucleotide’

  1938

  Florence Bell takes X-ray photographs of DNA; she and Bill Astbury suggest that the bases in the DNA molecule are stacked ‘like a pile of pennies’

  1940

  Colin MacLeod in Avery’s lab detects DNA in extracts of ‘transforming principle’ but does not follow up the observation

  1941 Alfred Mirsky extracts ‘chromosin’ (DNA with associated protein) from cell nuclei

  1942

  Maclyn McCarty and Avery show that the ‘transforming principle’ consists of DNA, with tiny amounts of contaminating protein

  1944

  Erwin Schrödinger suggests in his book What is Life? that genes are ‘aperiodic crystals’ Avery, MacLeod and McCarty publish their landmark paper showing that DNA is the ‘transforming principle’ and the genetic material in pneumococci

  Mirsky insists that protein, not DNA, mediates transformation and is the genetic material

  1947

  Rollin Hotchkiss shows that DNA contains unequal amounts of the four bases, thus ruling out the hypothetical ‘tetranucleotide’ André Boivin proves that DNA also transforms other bacteria (E. coli)

  Masson Gulland proposes that the DNA molecule is held together by hydrogen bonding between bases

  Gulland’s PhD student Michael Creeth proposes that DNA consists of two straight strands of DNA, linked by hydrogen bonding between bases on opposing strands

  1948

  Erwin Chargaff reports that amounts of adenine and thymine are equal, as are those of cytosine and guanine, in different sources of DNA Linus Pauling discovers the alpha-helix, crucial in shaping protein molecules

  1949

  Sven Furberg works out that the bases lie perpendicular to the backbone of DNA, and proposes a single-stranded, helical structure for DNA

  1950

  Ray Gosling at King’s takes an X-ray photograph showing a regular ‘crystalline’ appearance of DNA (the A form)

  1951

  January: Rosalind Franklin joins the Biophysics Unit at King’s, to work on the X-ray structure of DNA May: Wilkins presents the crystalline DNA structure at a meeting in Naples and inspires Jim Watson to solve its structure

  Elwyn Beighton in Leeds takes an X-ray photograph that shows the helical features of DNA (B form). The photograph is ignored

  July: Wilkins presents DNA structures at a meeting in Cambridge and is told by Franklin to stop working on DNA

  Alec Stokes at King’s predicts the X-ray pattern of a helical molecule

  October: Jim Watson joins Francis Crick at the Cavendish Laboratory in Cambridge and persuades him to pursue the structure of DNA

  November: Wilkins meets Watson and Crick and tells them that the most likely structure contains three helical strands of DNA

  Watson attends a colloquium a
t King’s where Wilkins and Franklin present their work on DNA

  Bruce Fraser at King’s builds a model of DNA containing three helical strands, which Wilkins rejects

  December: Using data from King’s, Crick and Watson build a three-stranded model of DNA, which is fatally flawed; Wilkins breaks off their collaboration

  1952

  January: Franklin and Gosling characterise the A and B forms of DNA April: John Griffith in Cambridge calculates that hydrogen bonding will attract adenine to thymine, and cytosine to guanine

  May: Gosling takes Photograph 51, showing the helical features of DNA (B form)

  July: Franklin decides that ‘crystalline’ DNA (A form) cannot be a helix, causing Wilkins to have doubts about the helical nature of DNA in general

  December: Pauling proposes a DNA model with three helical strands, also fatally flawed

  1953

  February: Watson visits King’s; Wilkins shows him Photograph 51, in which Watson sees the diagnostic features of a helical structure March: Franklin leaves King’s to study viral structure at Birkbeck College, London

  Watson realises that the pairing of bases on opposing strands is the key to the structure of DNA. Using Franklin’s data and without her knowledge, he and Crick construct the double helix

  April: Nature publishes three papers on the double helix, by Watson and Crick; Wilkins et al; and Franklin and Gosling

  July: Watson and Crick publish a follow-up paper in Nature on the self-replication of DNA

  1958

  16 April: Rosalind Franklin dies of ovarian cancer, aged 38

  1962

  Watson, Crick and Wilkins share the Nobel Prize for Physiology or Medicine

  1968

  Watson publishes The Double Helix

  2001

  Independent scientific tribunal clears Gregor Mendel of having falsified his data

  WHO’S WHO

  Astbury, William (Bill) (1898–1961)

  English crystallographer who was fascinated by the ‘fabrics of Nature’ and the molecular structure of fibres, and introduced the term ‘molecular biology’. His team in the Department of Biomolecular Structure in Leeds took early X-ray photographs of DNA (see Elwyn Beighton). Astbury believed that DNA acted as a direct template for protein synthesis and that its structure was too simple to carry genetic information.

  Avery, Oswald T. (1877–1955)

  Bacteriologist, biochemist and expert on pneumococci, the bacteria that cause lobar pneumonia. Led the group at the Rockefeller Institute for Medical Research, New York, which proved that DNA was the ‘transforming factor’ which could alter the genetic characteristics of pneumococci under laboratory conditions. A conspicuous non-recipient of a Nobel Prize.

  Beighton, Elwyn (1919–2007)

  One of Bill Astbury’s PhD students, notionally working on bacterial flagella. In May 1951, took an X-ray photograph of wet DNA fibres (B299), which showed the same X-shaped pattern of a helical molecule as in Ray Gosling’s famous Photograph 51, taken a year later. B299 was never published or presented.

  Bernal, John Desmond (1901–71)

  Nicknamed ‘Sage’ for his apparent omniscience. Charismatic polymath, impossible to summarise in a few lines. Passionate about X-ray crystallography, women, unexploded bombs, art and everything Soviet. Directed the Crystallography Department at Birkbeck College, London, where Rosalind Franklin worked on the structure of viruses after leaving her research into DNA at King’s College in early 1953.

  Bragg, Sir Lawrence FRS (1890–1971)

  The youngest ever recipient (aged 25) of a scientific Nobel Prize, jointly with his father in 1916. Formulated Bragg’s Law, one of the basic tenets of X-ray crystallography. Professor of Physics and Director of the Cavendish Laboratory in Cambridge from 1938 to 1954. His research group included the MRC Unit for the Study of the Molecular Structure of Biological Systems, led by Max Perutz, which recruited Francis Crick (1949) and James Watson (1951).

  Bragg, Sir William FRS (1862–1942)

  One of the fathers of X-ray crystallography. With his son Lawrence, won the 1916 Nobel Prize for Physics for deciphering the structures of numerous salts and minerals. While President of the Royal Institution in London during the 1930s, trained Bill Astbury and J.D. Bernal in X-ray crystallography.

  Chargaff, Erwin (1905–2002)

  Ukrainian-born American biochemist and erudite critic of the scientific scene and the world at large. While investigating the composition of DNA from different sources, noticed that the contents of adenine and thymine were identical, as were those of cytosine and guanine (‘Chargaff’s Law’). He was scathing about the contributions of Watson and Crick and felt that his own discovery was worthy of a Nobel Prize.

  Creeth, Michael (1924–2010)

  One of Masson Gulland’s PhD students in Nottingham, whose studies of the physical and chemical properties of DNA provided evidence that the molecule was held together by hydrogen bonds between bases. Creeth suggested in his unpublished PhD thesis (1947) that DNA was a double-stranded molecule, with the strands bridged by hydrogen bonds between bases on the opposing chains.

  Crick, Francis (1916–2004)

  ‘Tall, fair and very English’ physicist, biochemist and eventually neuroscientist. Rescued from an ‘unimaginably dull’ research project by a Luftwaffe bomb, he went to work at the Cavendish Laboratory in Cambridge on the structure of proteins. There, he met Jim Watson, who fired his interest in solving the structure of DNA. Their paper on the double helix was published in Nature in 1953, before Crick finished his PhD.

  Flemming, Walther (1843–1905)

  German microscopist and Professor of Anatomy at Kiel University, who deciphered the movements of chromosomes during cell division (which he called ‘mitosis’) in tissues of the fire salamander. Coined the term ‘chromatin’ for the heavily stained substance of chromosomes and suggested that this was identical to Friedrich Miescher’s nuclein.

  Franklin, Rosalind (1920–58)

  English X-ray crystallographer who was best known during her lifetime for her research into the structures of coal and viruses. While working in John Randall’s Biophysics Unit at King’s College, London, she identified the A and B forms of DNA; her PhD student Ray Gosling took the celebrated ‘Photograph 51’, demonstrating the helical structure of the B form. Franklin generated most of the data used by Watson and Crick to derive the double helix, and was seen as coming ‘within two half-steps’ of solving the structure herself.

  Furberg, Sven (1920–83)

  Swedish biochemist who learned X-ray crystallography for a PhD with J.D. Bernal. Worked out how the bases are joined to the sugar, deoxyribose, and proposed in his unpublished PhD thesis (1949) that DNA was a helical, single-stranded molecule.

  Gosling, Ray (1926–2015)

  While a PhD student at King’s, worked with both Maurice Wilkins and Rosalind Franklin. Took two classic X-ray photographs of DNA: the ‘crystalline’ image which inspired Watson to pursue the structure of DNA, and ‘Photograph 51’, which confirmed the helical nature of the molecule. Later, worked with Franklin to define the A (crystalline) and B (helical) forms of DNA.

  Griffith, Fred (1879–1941)

  Reclusive English bacteriologist who worked in a government service laboratory in London; hated scientific meetings and published infrequently. In 1928, described ‘transformation’ of pneumococci – the first transfer of genetic material between living organisms achieved in the laboratory. Avery later showed that the ‘transforming principle’ responsible was DNA.

  Gulland, Masson (1898–1947)

  Scottish biochemist whose lifetime ambition was to return to Edinburgh as Professor of Biochemistry. His research interests ranged from the nucleic acids to the use of Scottish seaweed to make waterproof clothing. While Professor of Biochemistry in Sheffield, supervised research which showed that the DNA molecule was held together by hydrogen bonds between the bases.

  Kossel, Albrecht (1853–1927)

  German
biochemist and man of principle who devoted his career to finding the building-blocks (Bausteine) of large, biologically important molecules, including the nucleic acids. Awarded the Nobel Prize in Chemistry (1910), mainly for his work on the proteins associated with DNA in the nucleus. His major book (published posthumously) on components of the nucleus concluded that DNA was less important than proteins, and so helped to undermine interest in its role in heredity.

  Levene, Phoebus (1869–1940)

  Russian-born American biochemist who worked at the Rockefeller from 1915 until the day before his death. Prolific researcher who ‘left no part of biochemistry’ untouched. Did seminal work on the components of DNA and wrote the influential book Nucleic Acids (1928). Became convinced that DNA consisted of repeating units containing one each of the four bases. This ‘tetranucleotide hypothesis’ implied that the structure of DNA was too dull to carry genetic information – an assumption that obstructed DNA research for over 30 years.

  MacLeod, Colin (1909–72)

  Canadian-born physician and bacteriologist who worked with Oswald Avery at the Rockefeller (1939–41) on the ‘transforming principle’ which could change the genetic characteristics of pneumococci. Found that the transforming principle contained deoxyribose, the diagnostic sugar of DNA, but failed to follow this up. Co-author on Avery’s paper (1944) demonstrating that the transforming principle was DNA, and therefore that DNA was the genetic material in pneumococci.

  McCarty, Maclyn (1911–2005)

  American physician, biochemist and bacteriologist who followed MacLeod in Avery’s lab at the Rockefeller. Performed the key experiments to prove that the transforming principle was DNA and therefore the genetic material in pneumococci; third author on Avery’s seminal 1944 paper. Regarded by many as ‘a scientist’s scientist’.

  Mendel, Gregor (1822–1884)

  Brother and later Abbot of the Augustinian Abbey of St Thomas in Brünn, Austrian Empire (Brno in the present-day Czech Republic). Wide-ranging research interests, notably meteorology and plant-breeding. Formulated the basic rules of inheritance, based on seven years of experiments on garden peas, in his ‘Studies of plant hybridisation’ (1866). Mendel’s work was essentially ignored until 1900, when it was ‘rediscovered’ almost simultaneously by three academic botanists; the acrimonious debate that followed included accusations that Mendel had faked his results.