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ScienceWeek
HISTORY OF BIOLOGY: ON DNA IN 1944
The following points are made by Heather Dawes (Current Biology 2004 14:605):
1) The work reported in February of 1944 by Oswald Avery (1877-1955), Colin MacLeod, and Maclyn McCarty has been called the century's greatest biological discovery, but also the "undiscovered discovery". It broke the seal on modern biology, but famously failed to win a Nobel prize. It showed that DNA possessed genetic information that could transform the heritable character of cells, but the world of biological research in 1944 had enough in the way of distractions, assumptions, and divisions to withhold its attention from such a revolutionary idea.
2) In some ways, the story wasn't all that new, having begun with a paper sixteen years before. As an officer of Britain's Ministry of Health, the bacteriologist Fred Griffith (1881-1941) had in 1928 published the outcome of his latest efforts at characterizing the puzzle of serological types present among pneumococci. Samples collected from pneumonia patients routinely yielded multiple pneumococcal types representing various subsets of the known serological categories. The basis for this phenomenon, and its clinical relevance, were unclear to medical bacteriologists.
3) Pneumonia was a leading killer of the day, but bacteriologists had few tools with which to study the cell biology and virulence of the organism responsible. Armed with sputum samples, chocolate blood media plates and an assortment of type-specific sera, Griffith set about characterizing the pneumococcal types present from samples collected at various points during illness, using sequential antibody neutralization and inoculation into mice as an assay. Critically, though perhaps surprisingly, he did not assume as an explanation for the type results an etiology of multiple infection, and pursued experiments testing the possibility of in vivo type-switching. In doing so, he succeeded in demonstrating that type transformation could occur in mice. Subcutaneous inoculation of a mixture of live -- but avirulent --pneumococci of a first serotype, and heat-killed, virulent cells of a second serotype led to virulent disease in an injected mouse; moreover, he subsequently isolated virulent cells of the second serological type.
4) Avery was at that time involved in characterizing the antigenic nature of the pneumococcal capsule, working at what was then the Hospital of the Rockefeller Institute for Medical Research. Upon seeing Griffith's paper he was reportedly intrigued but not wholly convinced by the findings, at least until they were confirmed shortly afterwards by Fred Neufeld working at the Koch Institute in Berlin. At about the time Griffith's study appeared, it so happened that one of Avery's associates, Martin Dawson, was writing up his own observations regarding pneumococcal transformation. Griffith had attempted to demonstrate the transforming effect in vitro but had failed; Dawson saw an opportunity and succeeded with Richard Sia in recapitulating in vitro the virulence switching he'd seen in mice. With a test-tube assay in hand, Avery's group had the stage set for a concerted biochemical analysis of the transformation phenomenon, but the ensuing story took nearly 14 years to play out.
5) In the 1930s, progress and insight into the nature of the "transforming principle", as it came to be called, was accompanied by efforts to make a complex and chronically troublesome assay simple and stable. A primary problem was contamination of the system by what was later recognized to be DNase. Once recognized for its relevance, DNase later proved a critical tool for proving the identity of the transforming principle. On another front, efforts were made to identify the serum factor necessary to support in vitro transformation.
6) In 1935 Avery and MacLeod had yet to fully recognize that they were dealing with a genetic phenomenon - the transformation seemed to be cast in one report in terms of induced systems of presumably extant, but latent, synthetic enzymes. But that year also saw a notable advance in the finding that the transforming principle survived chloroform extraction, arguing against a protein factor. 1940 marked a renewed effort, and the investigators began to appreciate an association between the transforming principle and nucleic acids in their preps. This wasn't an expected result. As McCarty has written, "Knowledge of the occurrence and distribution of the nucleic acids in nature had not yet reached the point where one could assume that all living cells contained both RNA and DNA. Indeed, the notion had only recently been discarded that there were two general classes of nucleic acid: plant nucleic acid and animal nucleic acids."
7) Despite growing evidence equating DNA with the transforming principle, it wasn't until the early '40s that the group recognized that the shiny precipitate they'd been observing in their active preparations might itself be DNA, and not polysaccharide contaminant as they had once assumed.
Current Biology http://www.current-biology.com
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HISTORY OF BIOLOGY: MAURICE WILKINS AND DNA
The following points are made by Walter Gratzer (Current Biology 2003 13:R945):
1) Maurice Wilkins sprang from nonconformist, Unitarian stock, and the austere Victorian moral principles that this background imposed marked him for life. He writes pleasantly of his happy and secure childhood in New Zealand and later in Dublin, London and Birmingham. By the time he was twelve he was building apparatus in his home workshop. A clergyman taught him to grind telescope lenses and the local blacksmith helped make the mounting for the instrument. Wilkins inevitably read physics in Cambridge, and like many of his generation, was drawn towards biology by Erwin Schroedinger's book, /What is Life?/ His first serious disappointment was his indifferent degree and failure to find a position in a laboratory in Cambridge. Searching despondently for jobs, he suddenly remembered that his undergraduate supervisor in Cambridge, M.L. Oliphant, now occupied the chair of physics at Birmingham University. Wilkins went to see him and was directed to a newly appointed lecturer by the name of John Randall. So began a close but never easy relationship that was to last for 40 years. Wilkins got his PhD in quick time, having had his first clash with Randall, over the authorship of a publication.
2) Came the war, and Oliphant's laboratory was directed to work on radar. It was there that Randall and Boot constructed the cavity magnetron, which more than any other invention helped to win the war. Wilkins, however, was shipped off to E.O. Lawrence's cyclotron laboratory in California to play his small part in the Manhattan Project. Returning, he rejoined Randall, then already professor of physics at St Andrew's University, and began a rather forlorn search for a research project with a biological thrust. His colleagues in the biology departments were of little help: when he asked the Professor of Botany what the size was of a nucleolus, he received the answer, "as big as a full-moon". But it was not long before Randall was appointed to the Wheatstone Chair of Physics at King's College and Wilkins was glad to come south. Randall deployed his formidable political talents to gather in funds on an unheard-of scale for the establishment of a biophysics unit in the subterranean caverns by the Thames. So successful was he, indeed, that the academic administrators took fright at such hubris, and the College Principal secretly (and unsuccessfully) begged the Medical Research Council to restrict Randall's funding. Yet Randall's judgement was far from infallible. Wilkins had been impressed by Crick, and urged Randall to offer him a position in the department, but the professor would have none of it, for Crick, he thought, talked too much.
3) After a period of rather humdrum labor on microscopy of cells, Wilkins at last found what he wanted: Avery had proved that DNA was the genetic material, and Wilkins resolved to study its structure. Soon he had made fibers and had begun to take X-ray diffraction photographs. Then he had a stroke of luck: he attended a lecture at which Rudolf Signer from Berne spoke about DNA, and handed out samples of his preparations, which were far less degraded than any that had been seen before. Signer's DNA, in the hands of Wilkins and his student, Raymond Gosling, produced X-ray diffraction pictures of startling quality, with well-resolved spots. The gene, Wilkins noted, was crystalline (as Schroedinger had prefigured).
4) But fate was already slipping the lead into the boxing glove. At this moment of high optimism Randall received an inquiry from a young physical chemist, with experience in X-ray diffraction of carbons. He suggested to Rosalind Franklin, for it was she, a feeble project involving X-ray scattering from protein solutions, but Wilkins pressed him to invite her instead to join in the work on DNA. Randall acquiesced with unaccustomed alacrity, and Wilkins eagerly awaited the arrival of a new colleague to share his labors and his enthusiasm.(1)
References:
1. Maurice Wilkins: The Third Man of the Double Helix. Oxford University Press 2003.
Current Biology http://www.current-biology.com
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ON ROSALIND FRANKLIN (1920-1958)
The following points are made by Lynne Osman Elkin (Physics Today 2003 March):
1) In 1962, James Watson, then at Harvard University, and Cambridge University's Francis Crick stood next to Maurice Wilkins from King's College, London, to receive the Nobel Prize in Physiology or Medicine for their "discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material." Watson and Crick could not have proposed their celebrated structure for DNA as early in 1953 as they did without access to experimental results obtained by Ring's College scientist Rosalind Franklin. Franklin had died of cancer in 1958 at age 37, and so was ineligible to share the honor. Her conspicuous absence from the awards ceremony -- the dramatic culmination of the struggle to determine the structure of DNA -- probably contributed to the neglect, for several decades, of Franklin's role in the DNA story. She most likely never knew how significantly her data influenced Watson and Crick's proposal.
2) Franklin expressed an early fascination with physics and chemistry classes at the academically rigorous St. Paul's Girls' School in London, and she earned a bachelor's degree in natural sciences with a specialty in physical chemistry. The degree was earned at Newnham College, Cambridge in 1941.
3) From 1942 to 1946, Franklin did war-related graduate work with the British Coal Utilization Research Association. That work earned her a PhD from Cambridge in 1945, and an offer to join the Laboratoire Central des Services Chimiques de 1'Etat in Paris. She worked there, from 1947 to 1950, with Jacques Mering and became proficient at applying x-ray diffraction techniques to imperfectly crystalline matter such as coal. In the period 1946-49, she published five landmark coal-related papers, still cited today, on graphitizing and nongraphitizing carbons. By 1957, she had published an additional dozen articles on carbons other than coals. Her papers changed the way physical chemists view the microstructure of coals and related substances.
4) Franklin made many friends in the Paris laboratory and often hiked with them on weekends. She preferred to live on her own modest salary and frustrated her parents by continually refusing to accept money from them. She excelled at speaking French and at French cooking and soon became more comfortable with intellectual and egalitarian "French ways" than with conventional English middle-class customs. Consequently, she did not fit in well at King's College, where she worked on DNA from 1951 to 1953. Franklin chose to leave King's and, in the spring of 1953, moved to Birkbeck College. After the move to Birkbeck, she began her celebrated work with J. Desmond Bernal (1901-1971) on RNA viruses like tobacco mosaic virus (TMV). She was a cautious scientist who began to trust her intuition more as she matured. She published 14 papers about viruses between 1955 and 1958, and completed the research for three others that colleague Aaron Klug submitted for publication after her death.
5) In his obituary for Franklin, Bernal described her as a "recognized authority in industrial physico-chemistry." In conclusion, he wrote, "As a scientist, Miss Franklin was distinguished by extreme clarity and perfection in everything she undertook. Her photographs are among the most beautiful of any substances ever taken."
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