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CYTOMETRY 2012—What would Ehrlich do?

2012; Wiley; Volume: 81A; Issue: 6 Linguagem: Inglês

10.1002/cyto.a.22076

1552-4930

Howard Shapiro, John P. Nolan, Attila Tárnok,

Historical Medical Research and Treatments

CYTO 2012, the 27th Congress of the International Society for Advancement of Cytometry (ISAC), finds us in Leipzig, a city with deep roots in science, industry, and the arts. Leipzig was an artistic home to Bach, Mendelsohn, and Goethe and sites featured in their lives and work can be found throughout the city center. Leipzig is also an historic center for trade, founded at the crossing of two ancient trade routes, Via Regia and Via Imperii, and has served as a major market town for nearly 1,000 years. Trade activities shaped the architecture of the courtyards and passageways of the city center and, in more recent times, the Congress Centre Leipzig, the venue of CYTO 2012. Finally, Leipzig holds a special distinction as a home to the very roots of cytometry. Paul Ehrlich received his medical degree from the University of Leipzig in 1878, after writing a dissertation on “Contributions to the Theory and Practice of Histological Staining.” His supervisor Julius Friedrich Cohnheim was the inventor of intra-vital microscopy. Strongly influenced by his cousin Karl Weigert, a great microscopist in his own right and an assistant to the preeminent pathologist Rudolf Virchow, Ehrlich made use of aniline dyes to identify different cell types in blood by the staining patterns of their organelles after treatment with mixtures of acidic and basic dyes, discovering the Mast cells. The dye industry itself was then driven primarily by the needs of fashion, having originated in the 1850s with the serendipitous synthesis of mauve in London by William Perkin in a failed attempt to produce quinine, an expensive natural product then the only available treatment for malaria. The stains used in hematologic microscopy and malaria diagnosis today are but a few steps removed from Ehrlich's eosin–methylene blue mixtures [recently used for in vivo flow cytometry (1)]; his “acid-fast” staining procedure for Mycobacterium tuberculosis and related bacterial species is similarly close to today's venerable Ziehl–Neelsen and auramine O stains for TB, and Ehrlich's work inspired Hans Christian Gram to develop his own well-known stain for bacteria.1, 2 This unique document shows the page in the so called “Promotionsbuch” of the University of Leipzig with the registration of the doctoral title of Paul Ehrlich from June 26, 1878. Promoter: Prof. Justus Radius; Examinators: Prof. Carl Siegmund Franz Credé, Prof. Carl Ludwig (discovered the mechanism of urine production). Copyright reserved and original in the ownership of the Universitätsarchiv Leipzig. Reproduced with permission. Promotion announcement from the University of Leipzig including the notice of the award of Ehrlich's doctorate. Albert I got the full treatment; it's good to be the King. Leuckart, an organic chemist, had a reaction named after him. Anatomist Wilhelm His is today best known as the father of cardiologist Wilhelm His, Jr., discoverer of the Bundle of His. If that malfunctions, we need pacemakers, providing modern cardiologists additional bundles. Future Nobel Prize winners don't always get top billing. Copyright reserved and original in the ownership of the Universitätsarchiv Leipzig. Reproduced with permission. Ehrlich's concept of chemical specificities in cells, arising as it did when nucleic acids were just being discovered and the structure and function of proteins remained mysterious, led him in several significant directions. Although his 1908 Nobel Prize reflected his contributions to immunology, it was his development of chemotherapy for syphilis after screening hundreds of dyes for activity against the pathogen that brought him worldwide fame (2). Recognizing the efficacy of methylene blue for staining malaria parasites, he introduced it as a drug; the compound is even now incorporated into combinations under test for treating the disease (3). More significantly, many of the dye companies evolved into drug companies, eventually yielding compounds such as ethidium bromide that are now far more useful in cytometry than in clinical medicine. Ehrlich also studied color changes in dyes due to metabolic activity, and used fluorescein as a fluorescent tracer of circulation. Practical fluorescence microscopy and antibody staining did not arrive until decades after his death, by which time it had become recognized that his methyl green-pyronin staining mixture stained DNA and RNA stoichiometrically. Pyronin fluorescence is now routinely used for RNA quantification in cytometry (4), combined with the fluorescent Hoechst dyes, which, like methyl green, have a strong affinity for adenine and thymine in DNA; we tend to forget that cytometry pioneers such as Torbjörn Caspersson and Jean Brachet, using the original dye mixture and UV microspectrophotometry, had suggested that DNA was the genetic material years before molecular biology existed. One can only imagine where Ehrlich might have gone had biochemistry been better known in his time; exploring some roads not taken might be appropriate and productive.