Searching for a Scientific Home, 1919-1930
When World War I ended in late 1918, Albert Szent-Györgyi had a medical degree, a wife and daughter, and little money--the family fortune had been considerably diminished through his elder brother's mismanagement. Even so, he could have settled down in Budapest and set up a medical practice, drawing on the family's good social connections. But Szent-Györgyi still had a burning desire to do laboratory research. Two years' work in his uncle's anatomy lab during medical school had convinced him that his interests lay in more dynamic fields such as physiology or medical chemistry. Medical education in Hungary at the time provided little intensive training in the sciences; if one wanted to excel in science, one obtained a medical degree and then arranged to get scientific training elsewhere, often in Germany or England.
Budapest was in chaos, as a revolution was followed by several political regime changes just after the war. Partly to escape the upheaval, Szent-Györgyi took a research position in Pozsony, about one hundred miles from the capital. From January to September 1919 he worked with Professor Géza Mansfeld in the Pharmacological Institute of the Hungarian Elizabeth University. Mansfeld's lab provided both a good learning environment for Szent-Györgyi and new friends, including Carl Cori, who later would win the Nobel Prize (with his wife and collaborator, Gerty) for work on the metabolism of glycogen. A short war between Hungary and the newly-formed Republic of Czechoslovakia ended the arrangement, however; Pozsony was taken from Hungary and renamed Bratislava, and in September all non-Czechs were ordered to leave. Szent-Györgyi and the other Hungarians returned to Budapest, but smuggled out much of their lab equipment with them.
Szent-Györgyi soon moved on, first to the German University in Prague to learn about measuring the electric potentials in cells at Armin von Tschermak's laboratory. He then went to Berlin, where he worked briefly with Leonor Michaelis and gained a better understanding of the pH system in chemistry. Unable to find paid research work to support his family, Szent-Györgyi resorted to his back-up plan: studying tropical medicine at the Institute of Maritime and Tropical Diseases in Hamburg, so he could seek employment as a colonial physician. (Such positions paid well and were always available, partly because tropical diseases often killed the doctors who went to fight them.) He and his family spent some difficult months in Hamburg, often near starvation, before he secured another research assistantship, this time with Dr. Storm Van Leeuwen, a pharmacologist at the University of Leiden. Szent-Györgyi produced seven papers with Van Leeuwen, and continued to expand his command of chemistry. He felt obliged to leave the job in 1922, however, due to Van Leeuwen's inappropriate attentions to Nelly.
Once again, Szent-Györgyi fell back on the tropical medicine plan, traveling to Groningen to finish his course and take the Dutch qualifying exams. He was again saved from a career in the tropics when H. J. Hamburger, a physiologist at the University of Groningen, sought his help with some animal experiments and then offered him an assistantship. For the next four years, Szent-Györgyi worked in the physiology lab during the day and continued his biochemistry work in the evenings.
He was productive in both areas, and published over twenty papers during that time. More important, he found the research direction that would occupy him, in various ways, for the rest of his life: the question of intracellular respiration, i.e., the ways that cells transform nutrients into energy through a complex series of reactions. This was a central problem in biochemistry at the time. It was clear that the reactions involved oxidation and reduction, in which the reacting substances were transformed by giving up or accepting electrons from each other. Two eminent biochemists, Heinrich Wieland and Otto Warburg, had developed competing theories about the exact mechanism; Wieland believed hydrogen activation to be the essential feature, while Warburg argued that oxygen was the key. Szent-Györgyi's research at Groningen resolved the question, showing that both elements played a role in the process, and that certain intermediary substances--in particular succinic acid--were needed for respiration, thus sketching the basis of the respiratory cycle later known as the citric acid or Kreb's cycle.
Szent-Györgyi also began investigating plant respiration, specifically the phenomenon of browning. Some plant tissues turn brown rapidly when cut and exposed to the air. Plants containing peroxidases (e.g., cabbages and citrus fruits), however, resisted browning. He noted that if peroxide is added to a mixture of peroxidase and benzidine, the solution turns bright blue as the benzidine is oxidized. If he replaced the pure peroxidase with juice from a peroxidase-containing plant there was a short delay in the benzidine reaction, indicating that the plant juice contained a reducing agent. Szent-Györgyi wondered if the skin-bronzing characteristic of Addison's disease--caused by failure of the adrenal glands--was related to lack of a similar reducing agent. Working with beef adrenals, he found an analogous substance present in large amounts. In late 1924 he reported his discoveries to British physiologist H. H. Dale and asked to spend a few months at Dale's laboratory to do further work on them. Dale arranged it, and, though the work proved disappointing, the visit gained him allies in Britain.
When he returned to Groningen, his mentor, Hamburger, had died, and his successor was unsupportive of biochemical research. Szent-Györgyi continued to work on plant respiration, completing several studies now regarded as his most important. However, by mid-1926 he despaired of furthering his scientific career. He sent his wife and daughter back to Budapest, and considered suicide. Fortunately, he decided to attend one last scientific meeting, the International Physiological Society conference in Stockholm. There, to his surprise, he heard Sir Frederick Gowland Hopkins, an eminent British biochemist, give a presentation in which he praised several times Szent-Györgyi's recent article on the respiration of the potato. Szent-Györgyi introduced himself afterwards, and Hopkins invited him to come to Cambridge, then arranged a Rockefeller Foundation fellowship to make it possible.
At Cambridge, free of financial worries, Szent-Györgyi was finally able to isolate and purify a small amount of the reducing substance that he had found in adrenal glands, cabbages, and citrus fruit. From this sample, he determined that the substance was a carbohydrate, most likely a sugar acid, with the chemical composition C6H8O6. Hopkins urged him to publish his results in the Biochemical Journal. This required that the substance be named. Szent-Györgyi jokingly suggested calling it "Ignose" (from "ignosco"--I don't know--and "-ose" to indicate a sugar.) The journal's editor rejected both that suggestion and Szent-Györgyi's next choice, "Godnose." Finally the editor proposed "hexuronic acid" (using "hex" to indicate the six carbon atoms and assuming that it was a sugar acid similar to glucuronic acid), which Szent-Györgyi accepted. Cambridge awarded Szent-Györgyi a PhD in biochemistry at the end of 1927 for the isolation of hexuronic acid.
The years at Cambridge, with Hopkins mentoring him, and the congenial company of other scientists, were happy and productive ones for Szent-Györgyi. He published steadily, and became well-known in the scientific community. In 1929 he visited the United States for the first time, to attend the International Physiological Congress in Boston. After that meeting (which included a visit to the Marine Biological Laboratory at Woods Hole), he traveled to Rochester, Minnesota, where he had been invited to work on hexuronic acid at the Mayo Clinic. There, with a limitless supply of adrenal glands from nearby slaughterhouses, Szent-Györgyi was able to purify a much larger amount of hexuronic acid--nearly one ounce! He mailed part of this back to England, to be analyzed by Norman Haworth, an authority on carbohydrate chemistry. Unfortunately, Haworth was unable to pin down its chemical constitution with the small sample provided. So, after almost ten years' work, the identity of "Szent-Györgyi's substance" was still unknown.