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.
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