HISTORY 735 CHIMIA 2003, 57, No.11 Chimia 57 (2003) 735–740 © Schweizerische Chemische Gesellschaft ISSN 0009–4293 Signer’s Gift – Rudolf Signer and DNA Matthias Meili* Abstract: In early May 1950, Bern chemistry professor Rudolf Signer traveled to a meeting of the Faraday Society in London with a few grams of DNA to report on his success in the isolation of nucleic acids from calf thymus glands. After the meeting, he distributed his DNA samples to interested parties amongst those present. One of the recipients was Maurice Wilkins, who worked intensively with nucleic acids at King’s College in London. The outstanding quality of Signer’s DNA – unique at that time – enabled Maurice Wilkins’ colleague Rosalind Franklin to make the famous X-ray fiber diagrams that were a decisive pre-requisite for the discovery of the DNA double helix by James Watson and Francis Crick in the year 1953. Rudolf Signer, however, had already measured the physical characteristics of native DNA in the late thirties. In an oft-quot- ed work which he published in Nature in 1938, he described the thymonucleic acid as a long, thread-like molecule with a molecular weight of 500,000 to 1,000,000, in which the base rings lie in planes perpendicular to the long axis of the molecule. Signer’s achievements and contributions to DNA research have, however, been forgotten even in Switzerland. Keywords: Bern · DNA · Double helix · History · Signer, Rudolf · Switzerland 1. Signer’s Early DNA Years With the advancement of research, Helix’, pointed out that Rudolf Signer made however, insight into the nature of macro- important contributions in two places: “It 1.1. Introduction molecules grew. This development was de- was no accident that the finest X-ray pic- The search for the structure of nucleic acids cisive in the discovery of the double helix tures of DNA available in 1953 had been had already occupied science for years pri- structure and its central meaning in trans- taken using material supplied by a former or to the 1953 discovery of the double helix mitting life. Regarding this change in para- student and colleague of Staudinger, Rudolf by biologist James Watson and physicist digm, science historian Robert Olby in his Signer” ([2] p.21). Francis Crick. In 1869, the Swiss chemist important book ‘The Path to the Double Friedrich Miescher had discovered nucleic acids in Tübingen, Germany, where he had isolated them from salmon sperm. Then, just after the turn of the century, an entire series of researchers turned towards the chemical analysis of nucleic acids, among them especially the chemist Phoebus Aaron Theodor Levene, an American of Russian origin. Levene coined the so-called tetra- nucleotide hypothesis, according to which nucleic acids are built non-covalently from smaller units. These were the four bases cytosine, guanine, thymine, and adenine, four molecules of the pentose sugar de- oxyribose (DNA) or ribose (RNA) as well as four phosphate residues. This is not the place to tell the entire story of the analysis of the chemical constitution of DNA [1]. *Correspondence: M. Meili NZZ am Sonntag Ressort Wissen Falkenstrasse 11 CH–8021 Zürich Tel.: +41 1 258 14 14 Fax: +41 1 258 24 14 E-Mail: [email protected] HISTORY 736 CHIMIA 2003, 57, No.11 1.2. Signer’s Path Towards and was able to confirm his earlier re- tance. According to Olby, Caspersson was DNA Prior to 1938 sults obtained from flow birefringence [7]. thinking of a high-polymer molecule, even As a student of Hermann Staudinger, In all this early work, Signer upheld the though he still spoke of ‘complexes’ in the pioneer of macromolecular chemistry, macromolecular model and defended with 1934. Nevertheless, Caspersson believed Signer was convinced of the existence of word and deeds through which his passion that the nucleic acids in the chromosomes large macromolecules. Staudinger, who in for research is evident. Moreover, he had no had merely a supporting function for the the first part of his career worked on the or- fear of inter-disciplinary work. Indeed, one proteins ([2], pp. 100–107). It is not known ganic synthesis of ketenes and polyketenes, of his achievements was to help to intro- how far Signer thought then about the bio- had developed his ideas on the existence of duce physical methods into organic chem- logical function. His later statements allow high polymers primarily after his switch istry. us to conclude that he guessed that nucleic from the ETH Zurich, Switzerland to In the early thirties, Signer was not yet acids had some biological significance ([8], Freiburg-im-Breisgau, Germany. In 1924, working with DNA or chromosomes. How- p. 17). He was, however, not a cell biolo- when he was still active at the ETH Zurich, ever, Signer always had a special relation- gist, but rather an organic chemist. With his he became the first to use the term macro- ship with living nature. While still a stu- research on polymers, he was active in a molecules and set out to prove the existence dent, he enthusiastically took part in natural field that was new and contested from many of these molecules through viscosity meas- science projects, and, in the excursions of sides. urements [3]. Signer, who had followed the ETH botanist Carl Schröter, he was ac- Signer’s method of flow birefringence Staudinger from Zurich to Freiburg in tive as ‘court photographer’, as Signer him- had worldwide fame at that time, which was 1926, used his experimental measurements self later commented with pride. A beauti- probably why Caspersson came to Bern. to help the idea on towards a breakthrough ful collection of plant photographs that With this method it was possible to deter- from a second direction. In particular, he Signer later destroyed existed from this pe- mine the ratio of the length to the diameter developed and optimized the optical riod ([8], p. 5). Signer continued to have a of a thread-like molecule. Indeed, “after method used by Vorländer in the twenties great love of flowers for the rest of his life, half a day, we knew the molecular weight, for the measurement of flow birefringence his favorite being the narcissus [9]. and we wrote a small publication the next and used it to measure the so-called homol- Signer’s teacher, Hermann Staudinger, day”, Signer said later in an interview for ogous polymer rows of synthetic and natu- also saw his goal in the study of Nature’s the Chemical Heritage Foundation ([8], p. ral polymers, especially the polystyroles macromolecules. As known from various 17). This work was published in January and cellulose [4][5]. In flow birefringence, lectures, he firmly believed that the natural 1938 in Nature [11] and consisted of only the dependence of optical behavior on flow high molecular weight polymers had evad- about 400 words. From their measure- conditions, concentration and the dissolved ed chemical study up to that time because ments, Signer and Caspersson determined substance is examined. A solution of the they were only able to exist under natural the viscosity and flow birefringence of thy- substance is allowed to flow through a glass conditions and quickly decomposed in the monucleic acid in water and drew the fol- tube that is illuminated with a ray of light. laboratory [3]. It is not surprising that Sign- lowing conclusions: The molecules orient themselves parallel to er, too, always lent great weight to the sci- 1) The molecules of sodium thymo- the direction of flow and the resulting entific observation of the substances that nucleic acid have the form of thin rods, anisotropy splits the light into two plane po- are important to life in animal and plant whose length is approximately 300 times larized beams. The longer the molecules cells [10]. greater than their width. are, the greater is the flow birefringence and 2) The molecular weight lies between the greater the difference between the re- 1.3. An Astonishingly 500,000 and 1,000,000, in agreement with fractive indices. Using this method in com- High Molecular Weight previous filtration and ultracentrifugation bination with measurements of viscosity Signer was prepared when Torbjörn studies. and sedimentation rates, Signer was able to Caspersson came to Bern with a sample of 3) The flow birefringence was negative, determine the form, size and molecular thymonucleic acid to determine its molecu- indicating that the polarization plane is per- weight of macromolecules [6][7]. lar weight and shape. Depending on avail- pendicular to the longitudinal axis. From flow birefringence, it had been able sources, this should have been in the 4) The optical anisotropy was very shown in the thirties that some virus parti- year 1936 ([2], p. 15) or 1937 ([8], p. 17). great, indicating that the molecules had cles have a roughly spherical shape. Also Cell biologist Caspersson had been a strongly double-refracting components in a from measurements of flow birefringence, student of Einar Hammarsten, who had very definite pattern. Obviously, the publi- Maurice Wilkins had gathered the first in- worked on chromosome research since the cation states, the purine and pyrimidine dications of the intra-molecular structure of early twenties. Hammarsten had isolated rings lie in planes perpendicular to the long DNA ([2], p. 16). The method is not very nucleic acids from calf thymus in 1924 and axis of the molecule. precise and has in the interim been replaced had described the product as ‘snowy white Finally, it is stated that “these results by better analysis procedures. However, it and of a curious consistency, like cotton will, it is hoped, be useful with reference to permitted making measurements quickly, wool’.