Frank Wollheim
Lund, Sweden

My title refers to two Swedish hospitals: one in Uppsala with its old and famous university, the other in Malmö, where academic activity started only in 1950 but soon acquired fame thanks to some charismatic leaders. My teachers, Jan Waldenström and Carl-Bertil Laurell, both started training in Uppsala, but crowned their career in Malmö and contributed to the success of the new teaching hospital.

In 1884 the young Swedish PhD student Svante Ahrrenius (1859-1927) defended his thesis in Stockholm where he showed that ions in solution, unlike solid salt or water, conducted electricity. The committee did not realize the importance of this fundamental observation. Ahrrenius was disappointed and sent his book to the famous Baltic German chemist Wilhelm Ostwald (1852-1932), then in Riga, who received it with enthusiasm and promptly offered him a position in his institute. Ahrrenius, however, stayed in Sweden and moved to Uppsala, where he continued to study colloidal solutions. His career was crowned with a Nobel Prize in 1903.

In 1904 a student fresh out of high school, Theodor “The” Svedberg (1884-1971), entered the Ahrrenius laboratory. This young man defended his PhD thesis, “Studien zur Lehre von den kolloiden Lösungen” (Studies on the science of colloidal solutions), in 1908. Svedberg was exploring whether centrifugation could be used to separate mixtures of proteins and described a powerful ultracentrifuge in 1924. The impact of this instrument was immediate, and he was awarded a Nobel Prize two years later.

In 1925 Arne Tiselius (1902-1971) joined the laboratory and Svedberg gave him the task of investigating electricity as an analytic tool for proteins. So while the master continued to work on ultracentrifugation, the pupil developed free electrophoresis in the form of an instrument about five meters in length which filled the space of a medium sized laboratory. Using an optical system, the “schlieren” technique, Tiselius was able to show that purified proteins migrated as homogenic bands.¹ The electric current however caused heat convection to blur the bands. By changing from round tubes to flat vessels and cooling the instrument to +4⁰C, Tiselius was able to separate normal serum into albumin, and distinct alpha-, beta-, and gamma-globulin bands.² The seminal paper was first submitted to a chemical journal but rejected as “too physical.” Months later Tiselius was able to publish a paper on electrophoresis in a chemical journal, and, in that same year, 1937, he was rewarded and became professor of a newly created chair, biochemistry.

Uppsala now was attracting leading immunologists from the USA. Michael Heidelberger and Svedberg’s pupil K. O. Pedersen studied the size of antibodies with help of the ultracentrifuge, and Elvin Kabat joined Tiselius and could show that antibodies migrated in the gamma fraction and could be quantified by immune absorption.³ The impact of the Tiselius apparatus soon equaled that of the Svedberg ultracentrifuge, and Tiselius became Nobel Laureate in 1948. Next year he was able to move his department into a new and spacious laboratory building.

Working with free electrophoresis was however laborious and time consuming, and several laboratories started work on using supporting media. Moistened filter paper was a promising candidate. A young physician at the Rockefeller Institute in New York City, New York, decided to spend time in the Tiselius laboratory to study the new techniques. His name was Henry Kunkel. During a most fruitful post doc year in Uppsala, Kunkel and Tiselius perfected the method of paper electrophoresis which became an all important research tool and later a routine method in clinical practice.⁴ Kunkel returned to the Rockefeller and became one of the leading investigators of immunoglobulin diversity and biology. He trained several brilliant students who were instrumental in the emerging modern rheumatology.

In 1950 Malmö General Hospital became a teaching hospital affiliated with Lund University. The first professor and chairman of internal medicine was Jan Waldenström, recruited from Uppsala. This charismatic physician and master of translational medicine before the invention of the term, had with the help of Pedersen described macroglobulinemia in 1943.⁵ In Malmö he started a most fruitful collaboration with another brilliant import from Uppsala, the professor of clinical chemistry Carl-Bertil Laurell. Together they started to explore conditions with gammaglobulin derangements in a systematic fashion as well as clinical correlates of monoclonal and polyclonal gammopathies.⁶ Through their work they delineated the occurrence and clinical significance of so-called M-components. Laurell discovered the first cases of alpha-1 antitrypsin deficiency⁷ and also refined the use of electrodiffusion into agarose gels containing specific antibodies to individual plasma proteins into the “rocket” technique.⁸ This allowed convenient exact routine analysis of individual proteins as complement to “electrophoresis.” Laurell also invented the crossed immunoelectrophoresis method for studying protein complexes and heterogeneity.⁹ This is still a useful research method.

References

1. Tiselius, A. The Moving Boundary Method of Studying the Electrophoresis of Proteins. Nova Acta Soc. Sci upsal. 1930; IV, 7, No 4.
2. Tiselius, A. A new apparatus for electrophoretic analysis of colloidal mixtures. Transactions of the Faraday Society 1937;33: 524–531.
3. Tiselius, A. and Kabat, E. A. An electrophortic study of immune sera and purified antibodypreprations. J Exp Med. 1939 Jan 1;69(1):119–31.
4. Kunkel, H. G. and Tiselius, A. Electrophoresis of proteins on filter paper. J Gen Physiol. 1951 Sep;35(1):89–118.
5. Waldenstöm, J. Incipient myelomatosis or “essential” hyperglobulinemia with fibrogenopia. Acta Med Scand 1944;117:216–47.
6. Laurell, C. B. and Laurell, H., Waldenström J. Glycoproteins in serum from patients with myeloma,macroglobulinemia and related conditions. Am J Med. 1957.
7. Laurell, C. B and Eriksson, S. The electrophoretic a1- globulin pattern of serum in a1-antitrypsin deficiency. Scand J Clin Lab Invest 1963; 15:132–140.
8. Laurell, C. B. Quantitative estimation of proteins by electrophoresis in agarose gel containing antibodies. Anal Biochem 1966;15:45–52.
9. Laurell, C. B. and Lundh, B. Electrophoretic studies of the conversion products of serum β1C-globulin. Immunology. 1967 March; 12(3): 313–319.