Fritz Lipmann (1899-1986) was one of the leading architects of the golden age of biochemistry.
With his landmark paper, "Metabolic Generation and Utilization of Phosphate Bond Energy, " published in 1941, Fritz Lipmann laid the foundation for biochemical research over the next three decades, clearly defining such concepts as group potential and the role of group transfer in biosynthesis. Most biochemists clearly recognized that Lipmann had revealed the basis for the relationship between metabolic energy production and its use, providing the first coherent picture of how living organisms operate. His discovery in 1945 of coenzyme A (CoA), which occurs in all living cells and is a key element in the metabolism of carbohydrates, fats, and some amino acids, earned him the 1953 Nobel Prize in physiology or medicine. Lipmann also conducted groundbreaking research in protein synthesis. He was an instinctual researcher with a knack for seeing the broader picture. Lacking the talent or inclination for self-promotion, he struggled early in his career before establishing himself in the world of biochemistry.
Fritz Albert Lipmann was born on June 12, 1899, in Königsberg, the capital of East Prussia (now Kaliningrad, Russia). The son of Leopold, a lawyer, and Gertrud Lachmanski, Lipmann grew up in happy and cultured surroundings and fondly remembered the peaceful years at the turn of the century. He counted his only brother Heinz, who would pursue the arts as opposed to science, as one of the two people who most influenced him in his formative years. The other was Siegfried (Friedel) Sebba, a painter who would remain his friend for life. From these two, he first learned to appreciate the arts, an avenue of interest that he used to escape the confines and pressures of his laboratory investigations.
Early on, Lipmann demonstrated a diffidence in academic pursuit that would belie his future success. He admitted that he was never very good at school, even when he reached the university. After graduating from the gymnasium, Lipmann decided to pursue a career in medicine, largely due to the influence of an uncle who was a pediatrician and one of his boyhood heroes. In 1917 he enrolled in the University of Königsberg but had his medical studies interrupted in 1918 as he was called to the medical service during World War I. Serving near the front during the last days of the war, he first learned to exert authority and never forgot the grim experience of severely wounded men receiving bad care.
In 1919 he was discharged from the army and went to study medicine in Munich and Berlin. Lipmann's brother was a literature student in Munich, and Lipmann became involved with his brother's circle of artistic friends while he lived in Schwabing, which Lipmann called the Greenwich Village of the city at that time. Throughout his life he maintained fond memories of Berlin. He eventually returned to Königsberg to complete his studies and obtained his medical degree from Berlin in 1922. Even though he cared about patients, Lipmann became more intrigued by what went on inside the human body. This interest was further cultivated when during his practical year of medical studies he worked in the pathology department in a Berlin hospital and took a three-month course in modern biochemistry taught by Peter Rona. At the same time, Lipmann was troubled by his concerns over the ethics of profiting from providing necessary medical services. The final turning point came when he went to the University of Amsterdam on a half-year stipend to study pharmacology. There, he first became versed in biochemical problems and the working of a biological laboratory. He left Amsterdam bent on a new career as a researcher.
Returning to Königsberg, Lipmann, who had no money, lived with his parents while he studied chemistry in the university for the next three years. Looking for a laboratory to do research in for his thesis, he chose to work with biochemist Otto Meyerhof, whose physiological investigations focused on the muscle. For the most part, Lipmann worked on inhibition of glycolysis (the breakdown of glucose by enzymes) by fluoride in muscle contraction and did his doctoral dissertation on metabolic fluoride effects. During this time in Berlin, Lipmann met many of the era's great biochemists, including Karl Lohmann, who discovered adenosine triphosphate (ATP—a compound that provides the chemical energy necessary for a host of chemical reactions in the cell) and taught Lipmann about phosphate ester chemistry, which was to play an important role in Lipmann's later research. Lipmann also met his eventual lifelong companion while attending one of the masked balls popular at that time. Freda Hall, an American-born German and an artist, would become his wife.
Over the next ten years, Lipmann continued with a varied but not very lucrative research career. In The Roots of Modern Biochemistry, Freda remembered her husband as a very "unusual young man" who "seemed to be certain of a goal" but "had no position, no prospects, and it did not seem to trouble him." Although he was interested in his work, Freda recalled that "at no time was Fritz the obsessed scientist without other interests. He always had time for fun, " which included tennis matches, bicycle races, and the theater.
Lipmann spent a short time in Heidelberg when Meyerhof moved his laboratory there but then returned to Berlin and worked with Albert Fischer on tissue culturing and the study of metabolism as a method to measure cell growth. But soon uniformed followers of Hitler began to appear in the streets of Berlin; both Lipmann and Freda had unpleasant encounters, and once Lipmann was beaten up. Realizing that they would soon have to leave Germany, Lipmann, through Fischer's intervention, received an offer to work at the Rockefeller Foundation (now Rockefeller University). Before leaving for the United States, Lipmann and Freda Hall were married on June 21, 1931. As it turned out, Freda's birth in Ohio made her an American citizen, thus greatly reducing obstacles to immigration. At the Rockefeller Foundation, Lipmann worked in the laboratory of chemist Phoebus Aaron Theodor Levene, who had conducted research on the egg yolk protein, which he called vitellinic acid, and found that it contained 10 percent bound phosphate (that is, phosphate strongly attached to other substances). Lipmann's interest in this protein, which served as food for growing animal tissues, led him to isolate serine phosphate from an egg protein.
At the end of the summer of 1932, Lipmann and his wife returned to Europe to work with Fischer, who was now in the Biological Institute of the Carlsberg Foundation in Copenhagen, Denmark. Free to pursue his own scientific interests, Lipmann delved into the mechanism of fermentation and glycolysis and eventually cell energy transformation. In the course of these studies, Lipmann found that pyruvate oxidation (a reaction that involves the loss of electrons) yielded ATP. Lohmann, who first discovered ATP, had also found that creatine phosphate provides the muscle with energy through ATP. Further work led Lipmann to the discovery of acetyl phosphate and the recognition that this phosphate was the intermediate of pyruvate oxidation. A discovery that Lipmann said was his most impressive work and had motivated all his subsequent research.
Despite his belief in his work, Lipmann had still to make his mark in research. In his book, Wanderings of a Biochemist, Lipmann would remember his efforts at the institute and throughout that decade as a time of personal scientific development that set the stage for his later discoveries. "In the Freudian sense, " said Lipmann, "all that I did later was subconsciously mapped out there; it started to mature between 1930 and 1940 and was more elaborately realized from then on."
But before Lipmann could piece together his formula for the foundation of how organisms produce energy, once again the rise of the Nazis forced him and his wife to flee to the United States; they were nearly penniless. Fortunately, Lipmann acquired a research fellowship in the biochemistry department of Cornell University Medical College. His work with pyruvate oxidation and ATP had germinated and set him on a series of investigations that led to his theories of phosphate bond energy and energy-rich phosphate bond energy. During a vacation on Lake Iroquois in Vermont, Lipmann began his essay "Metabolic Generation and Utilization of Phosphate Bond Energy, " in which he introduced the squiggle (~) to represent energy-rich phosphate, a symbol subsequently used by other researchers to denote energy-rich metabolic linkages. In this essay, Lipmann also first proposed the notion of group potential and the role of group transfer in biosynthesis.
This essay was the turning point in Lipmann's career. Prior to its publication, Lipmann had contributed disparate pieces to the puzzle of biosynthesis, but through his natural scientific instinct and the ability to see the broader picture, he had now laid the foundation for the basis of how living organisms function. Although his essay covered a wide range of topics, including carbamyl phosphate and the synthesis of sulfate esters, his elucidation of the role of ATP in group activation (such as amino acids in the synthesis of proteins), foretold the use of ATP in the biosynthesis of macromolecules (large molecules). In more general terms, he identified a link between generation of metabolic energy and its utilization. A prime example of ATP's role in energy transmission was the transfer of phosphor potential from ATP to provide the energy needed for muscles to contract.
Despite the growing acknowledgement that Lipmann had written a groundbreaking paper in biochemistry, he soon found himself without a solid job prospect when Dean Burk, whose lab Lipmann worked in, left for the National Institutes of Health. Burk was reluctant to take Lipmann with him because of Lipmann's lack of interest in Burk's cancer research. While Lipmann's renown had grown, he had also antagonized other researchers, especially by his insistence that the term "bond energy" had been misused and his replacement of the term with "group potential" to refer to the capacity of a biochemical bond to carry potential energy for synthesis. It also took many years for the squiggle to be fully accepted as a way to denote energy-carrying bonds. Fortunately, Lipmann gained an unusual appointment in the Department of Surgery at the Massachusetts General Hospital through the support of a Ciba Foundation fellowship. "This was really one of the lucky breaks in my life, " Lipmann recalled in his autobiography. Soon he received growing support from the Commonwealth Fund as more and more people began to recognize the importance of his work. Building upon his group transfer concept, Lipmann delved into the nature of the metabolically active acetate, which had been postulated as an "active" intermediary in group activation. In 1945, working with a potent enzyme from pigeon liver extract as an assay system for acetyl transfer in animal tissue, Lipmann and colleagues at Massachusetts General Hospital discovered Coenzyme A (CoA), the "A" standing for the activation of acetate. (Coenzymes are organic substances that can attach themselves to and supplement specified proteins to form active enzyme systems.) Eventually, CoA would be shown to occur in all living cells as an essential component in the metabolism of carbohydrates, fats, and certain amino acids. In 1953 Lipmann received the Nobel Prize in physiology or medicine for his discovery specifically of the acetyl-carrying CoA, which is formed as an intermediate in metabolism and active as a coenzyme in biological acetylations. (Lipmann shared the prize with his old colleague and friend, Hans Krebs, from Berlin.) Although proud of the Nobel Prize, Lipmann often stated that he believed his earlier work on the theory of group transfer was more deserving.
In 1957 Lipmann once again found himself at the Rockefeller Institute, twenty-five years after his first appointment there. He was to spend the next thirty years at the institute, primarily working on the analysis of protein biosynthesis. He and his colleagues contributed greatly to our understanding of the mechanisms of the elongation step of protein synthesis (stepwise addition of single amino acids to the primary protein structure).
Lipmann's productive career included 516 publications between 1924 and 1985. His 1944 paper on acetyl phosphate is a citation classic, having been cited in other works more than seven hundred times. His work on high-energy phosphate bonds and group transfer discoveries propelled biochemistry to the forefront of physiological research for nearly three decades. In addition to the Nobel Prize, Lipmann received the National Medal of Science in 1966 and was elected a foreign member of the Royal Society in London.
In 1959 the Lipmanns, who had a son Stephen Hall, bought a country home with Fritz's Nobel Prize money. Although his wife described him essentially as a city person, Lipmann enjoyed the country and often strolled the twenty acres of woods that surrounded his home with his Australian terrier, Pogo, named after the satiric comic strip character popular in the 1960s and 1970s. A private man who avoided political and social issues, Lipmann did, however, sign the Nobel laureate public appeal letters seeking prohibition of the hydrogen bomb and asking for freedom for the Polish Worker's Union. Lipmann's talent for writing was evident in the easy-to-follow and informative format of his scientific essays and in his autobiography. Still, he was given to preoccupation, and a colleague fondly recalled Lipmann once combing an auditorium after a lecture in search of his shoes, which he had left behind in going to the podium.
Lipmann's unique ability to see the entire scientific picture set him apart from many of his contemporaries. Interestingly, this ability also translated into his noted penchant for spotting four-leaf clovers almost anywhere. He kept them in books, manuscripts, and wallets, perhaps reflecting his own estimation that he had been fortunate in a life and career that allowed him to follow his instincts so successfully.
Despite failing strength, Lipmann continued to work until he suffered a stroke on July 17, 1986, and died seven days later. "One evening I heard him say: I can't function anymore, " recalled Freda Hall in The Roots of Modern Biochemistry, "and that was that." Lipmann's ashes were scattered along his walking path in the woods that surrounded his home.
Lipmann Symposium: Energy, Regulation, and Biosynthesis in Molecular Biology, Walter de Gruyter, 1974.
McGraw-Hill Modern Men of Science, McGraw-Hill, 1966.
The Roots of Modern Biochemistry, Walter de Gruyter, 1988. □