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Apr 1, 2013 (Vol. 33, No. 7)

The Genesis of a Discovery: First Steps

  • If it had not been for John Randall’s creation of an MRC Research Unit dedicated to the study of the physical and biological mechanisms of single cell division, the structure of DNA would not have been revealed in the U.K. Most likely it would have been discovered in Linus Pauling’s laboratories in America.

    Today, if you asked who discovered the structure of DNA, the response should be: Watson and Crick building atomic models in Cambridge and Wilkins and Franklin et al., exploring x-ray diffraction patterns at Kings College in London.

    Randall held the Wheatstone chair of physics and was director of the MRC unit, funded in perpetuity with the avowed intent of applying “The Logi of Physics to the Graphi of Biology”—in particular to the mechanisms causing division of living cells.

    In the 1940s it was still being debated as whether it was the nuclear protein, the DNA or both together that were instigating cell division. Randall was convinced by the work of Avery and others that DNA alone was the agent of division. Accordingly he had several avenues of research progressing in his laboratory concerned solely with DNA.

    Knowing that sperm heads were closely packed with DNA, he had directed me, as his Ph.D. student, to make flat flakes of rams’ sperm and expose them to x-rays, edge on, in the hope that the resulting diffraction pattern would reveal something of their DNA structure. The result was a disappointing, fuzzy fiber diagram.

    Meanwhile Maurice Wilkins had attended a lecture at the Royal Society by Rudolf Signer, a Swiss biochemist who had managed to extract DNA from calf thymus gland at a very high molecular weight—around 12 million.

    At the end of his lecture, Signer offered some freeze-dried samples of this sodium salt of the DNA, which Wilkins quickly accepted. Back in the lab he found that fibers drawn from a water gel of this material were highly birefringent. I asked him if I could try to get a diffraction pattern from a specimen of these fibers to compare as a gold standard with those from my various attempts to persuade rams’ sperm to lie flat.

    So Wilkins pulled the fibers varying from 5–10 µ in diameter and I wound them onto a paper clip. Testing the first specimen of 35 fibers with an x-ray machine produced a result not much better than my sperm flakes. This should not have been surprising since most of the atoms in the fibers were the same as the air within the camera. The next step was to displace the air with hydrogen.

  • Click Image To Enlarge +
    Figure. The first diffraction pattern of crystalline DNA from a bundle of 35 fibers using copper radiation; camera radius 3 cm, exposure 96 hours, taken in 1950 [Prof. Ray Gosling]

    To monitor how much hydrogen I was putting into the camera, and the room, I bubbled it through water. This serendipitous act, to avoid an explosive atmosphere, allowed the NaP ion complex in the fibers to take up water and so form micro crystallites throughout each fiber. The result is shown in the Figure.

    When in the spring of 1950, I first saw all those discrete diffraction spots emerging on the film in the developer dish, it was a truly Eureka moment. I realized that if DNA was the genetic material then I had just shown that genes could crystallize. Wilkins reacted enthusiastically to this news.

    At this stage Alex Stokes taught me some crystallography and armed me with the concept of the sphere of reflection and reciprocal space. The measurement of layer—the line separation in the pattern shown in the Figure gave the C axis repeat of the unit cell. Trial and error assignment of HKL index values (reciprocal lattice points) to the other reflections, suggested that the unit cell was Monoclinic C2 with values of A=22.0 Å, B=39.8 Å, Beta=96.5°, C=28.1 Å.

    Thus, in late 1950, we had a unit cell with a diad axis at right angles to the fiber axis and the space group of crystallized gene material.

  • Secret of Life

    At the beginning of 1950, Randall must have been quietly confident that his lab was getting close to the “secret of life.” We had brought together a novel high intensity x-ray tube, kindly lent to us by Ehrenberg and Spear at Birkbeck, and a microcamera allowing us to obtain diffraction patterns from single fibers of NaDNA. This was something that no other lab was currently able to do.

    Randall’s response to this was to headhunt for an experimental scientist versed in using x-rays to solve the molecular structure of para-crystalline material, such as was our sodium salt of DNA.

    In late 1950 he found Rosalind Franklin, then working in Paris, and asked her to join us at Kings and lead the effort in solving the puzzle of our beautiful diffraction pattern. Later that year there was a meeting of Franklin, Stokes, and myself in which I was formally handed over to Franklin as her assistant, i.e., transferred from the Wilkins/Stokes team to work exclusively with her.

    In retrospect the absence of Wilkins in this meeting was crucial. He was away from the lab at this time. It left Franklin with the impression, subsequently and surprisingly confirmed by a letter from Randall, that she would be in charge of the work of solving the structure. I realized later that she was unaware of the special position of Wilkins vis-à-vis Randall in the structure and politics of the laboratories as a whole.

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