Flexner, Simon, 1863-1946

Simon Flexner was a physician, administrator, professor of pathology at the University of Pennsylvania, director of the Rockefeller Institute for Medical Research (1901-1935).

Rufus Ivory Cole served as the the director and physician-in-charge (1909-1937) of the Hospital of the Rockefeller Institute for Medical Research, the first hospital in the United States devoted primarily to the investigation of disease. Cole's medical research centered on problems relating to immunity to diseases of the respiratory system, particularly pneumonia

Pathologist and bacteriologist, 1863-1946. In 1901 Flexner was appointed to the Board of Scientific Directors of the newly formed Rockefeller Institute for Medical Research; he served as director of the Rockefeller Institute from 1924 until his retirement in 1935.

Simon Flexner studied medicine at the University of Louisville (M.D. 1889) and afterwards studied pathology under William H. Welch at Johns Hopkins University. He was a professor of pathology at University of Pennsylvania (1891-1919) and was director of the Rockefeller Institute for Medical Research (1903-1935).

Max Bergmann (February 12, 1886-November 7, 1944) was a biochemist, whose research proved key for the study of biochemical processes. His work on peptide synthesis and protein splitting provided a starting point for modern protein chemistry and the study of enzyme-substrate interactions. He is most noted for developing the carbobenzoxy protecting group, for the synthesis of oligopeptides, using any amino acid in any sequence. He co-authored with his colleague Joseph S. Fruton (1912-2007, APS 1967) several reviews in protein and enzyme chemistry, notably “Proteolytic Enzymes,” in the Annual Review of Biochemistry 10 (1941): 31-46 and “The Specificity of Proteinases,” in Advances in Enzymology 1 (1941): 63-98.

Bergmann was born in Fürth, Germany, the son of a coal merchant named Solomon Bergmann and his wife Rosalie Stettauer. He entered the University of Munich, initially interested in botany, but shifted to chemistry, after being convinced that biological questions could only be answered by the methods of organic chemistry. He received a bachelor’s degree in 1907, and afterward became a student of Emil Fischer (1838-1914, APS 1909), the foremost protein and carbohydrate chemist of the day at the University of Berlin. In 1911 Bergmann received a Ph.D. with a dissertation on acyl polysulfides and became Fischer’s research assistant. In 1912 Bergmann married Emmy Miriam Grunwald with whom he had two children. The marriage ended in divorce, and he remarried Martha Suter in 1926. During World War I Bergmann was exempted from military service because of his research work with Fischer. While working with Fischer, Bergmann made important contributions to carbohydrate, lipid, tannin and amino acid chemistry, developing new methods for the preparation of α-monoglycerides. In 1920 Bergmann was appointed Privatdozent at the University of Berlin and head of the chemistry department at the Kaiser Wilhelm Institute for Textile Research.

Bergmann left the University of Berlin in 1921 to become the director of the new Kaiser Wilhelm Institute for Leather Research and Professor of chemistry at the Dresden Technical University. At Dresden, Bergmann created one of the world’s leading laboratories for the study of protein chemistry. After Adolf Hitler’s rise to power, Bergmann, a Jew, emigrated to the United States. From 1934 until his death Bergmann was affiliated with the Rockefeller Institute for Medical Research in New York.

Bergmann represents the tradition of German organic chemistry applied to biological problems. Working with his mentor Fischer, who sought effective methods to separate and identify amino acids, and who identified the peptide bond as the structure that connects amino acids, Bergmann made many basic contributions to protein and amino acid chemistry. In Dresden he extended Fischer’s work of separating and identifying the amino acid constituents of proteins. In order to establish the conjecture of some protein chemists that proteins were, in fact, polypeptides, containing thousands of amino acids, Bergmann developed new methods of peptide synthesis. The most important discovery came in 1932, when he and his colleague Leonidas Zervas created the carbobenzoxy method allowing them to use any amino acid in any sequence to produce peptides and polypeptides that closely resembled naturally occurring proteins.

Bergmann continued this work in New York at the Rockefeller Institute, stressing two new lines of research: (1) expanding the carbobenzoxy method to form peptides that could serve as substrates for protein-splitting enzymes, and (2) unraveling the total structure of proteins. After becoming head of the chemistry laboratory at the Rockefeller Institute in 1937, Bergmann recruited several talented biochemists. Along with his colleague Joseph Fruton, he discovered the first synthetic peptide substrates for which several enzymes were catalysts. When they demonstrated that the enzyme pepsin was able to catalyze the hydrolysis of synthetic peptides, they implicated the peptide bond in protein structure, but also provided the first clear evidence that specific enzymes split peptides at exact linkages in the chain. Their discovery cleared the path for study of how enzymes act as catalysts for every biological function.

Bergmann’s methods of analysis and synthesis proved incapable of solving the riddle of protein structure. He applied methods for separation and quantitative analysis to every amino acid in a protein in an attempt to establish their sequence in the polypeptide chain. In 1938 he proposed a theory of the systematic recurrence in the location of every amino acid residue in the peptide chain of a protein. However, his hypothesis proved an oversimplification. Two biochemists in his working group, Standford Moore and William Stein, showed him that the analytical data did not support his “periodic theory,” and Bergmann was forced to abandon it. Moore and Stein later collaborated in developing novel methods for quantitative analysis of amino acids in protein hydrolysates, methods they perfected after World War II. By 1949 it was possible to determine the order of the links of each amino acid in a protein. The Englishman Frederick Sanger was the first to establish the complete amino acid sequence in a protein, the hormone insulin. Moore and Stein followed by identifying the sequence of a more complex protein, the enzyme ribonuclease.

Bergman died of cancer in New York City on November 7, 1944. His mastery of peptide synthesis and protein splitting constituted the beginnings of modern protein chemistry. Bringing to the United States a background in German organic chemistry, he laid the foundations for the work of others, who would fulfill Bergmann’s goal of understanding and mapping the molecular structure of proteins and enzymes. His research colleagues found him a supportive leader and collaborator. He coauthored a number of publications with other members of his research group.

Simon Flexner was born on March 25, 1863, in Louisville, Kentucky to Helen and Morris Flexner, a Jewish German-speaking couple who'd arrived in the United States just 12 years prior. Morris Flexner had achieved moderate success with a wholesale hat business until the depression in 1872 caused the business to fail, a financial setback from which the large family never fully recovered. As a result, the Flexners were forced to move to increasingly marginal neighborhoods where the schools were inadequate and the neighbors anti-Semitic, an experience that deeply affected young Simon. He did poorly in school and was considered a failure in the Flexner family when he dropped out of school permanently at the age of 14, abandoning the eighth grade and formal education for the remainder of his youth. No longer a student, Simon trudged from one menial job to the next in order to make a contribution to the household.

Simon continued to disappoint his family with his failed efforts at keeping even the most menial of jobs. Simon managed to get fired from even a photographer's studio owned by an uncle; he was then hired out to lowly shopkeepers who couldn't afford to pay the boy more than a couple of dollars a week for his labor. Circumstances were dire; Flexner wouldn't attend school and couldn't sustain any kind of worthwhile employment. Just when it seemed circumstances couldn't be more desolate, Flexner contacted typhoid fever and death appeared imminent for the unfortunate youth. Far from killing him, however, the debilitating illness seemed to give Simon a new lease on life. The illness left him introspective and serious and as the teenager convalesced, he focused his attention on improving not only his health but also the course of his future. His new contemplative state reinforced conviction and focus in the teenager and for the first time in his life, Flexner considered the possibility that he could make a worthwhile contribution not only to his family but even to society.

The Flexner family happily supported the newly ambitious Simon and arranged for him to be apprenticed to a respected area druggist. It was a fortunate pairing; the druggist, while not overly ambitious, was kind and encouraging and Simon flourished under his tutelage. Part of his apprenticeship included a series of courses at the Louisville School of Pharmacy, where to his surprise and to the delight of his family, Flexner excelled. It was a proud moment when Simon presented the gold medal for scholastic achievement to his mother and dying father. In the evenings, Simon would take the store microscope home and conduct his own studies under the single gaslight shared by the entire family. Once a poor student, Flexner now devoted himself to learning.

In 1882, Flexner clerked at his eldest brother Jacob's drugstore where his thirst for knowledge grew. At the pharmacy, he listened intently to the gathered physicians' shoptalk and spent his evenings poring over borrowed books to familiarize himself with rudimentary medical principles. His interest in microscopy led Flexner to study histology and then pathology, an uncharted discipline at that time especially in Louisville. Local doctors increasingly brought Simon specimens and sought his opinion. It was soon apparent that Simon had learned all that he could from borrowed books; the time had arrived to pursue formal education.

Flexner dreamed of pursuing a medical education which would facilitate his dream of opening and operating but brother Abraham's course at Johns Hopkins altered his path. Abraham, who'd been attending classes at Johns Hopkins University for two years, kept Simon abreast of university news. Upon hearing of university plans to open a medical college and, more importantly, the recent faculty hire of a professor of pathology, Simon decided to attend Johns Hopkins but in order to be admitted to the university he first would have to get a medical degree. This, as it turned out, was actually accomplished quite easily with a little help from the physicians who'd gathered at Jacob Flexner's drugstore.

The Medical Institute of the University of Louisville had never established an academic department and was therefore staffed entirely by a group of practitioners who conducted lectures - and granted degrees - rather casually. This same group, luckily for Simon, agreed to take him on as a student at a reduced rate and allowed him to attend lectures during the spare hours that he wasn't clerking at the drugstore. The physicians sympathized with Simon's familial financial obligations and since Flexner insisted that he never planned to practice medicine, they were willing to be more lenient with him. In 1889, Simon Flexner graduated from the University of Louisville with a medical degree. He immediately applied for a fellowship at Johns Hopkins.

To his disappointment, Simon wasn't chosen for the fellowship. Adding to his regret was the realization that he simply couldn't teach himself any further. Abraham offered to send Simon to Baltimore for a year of instruction as sibling Jacob had done for him. While the family, which had grown dependent on Simon's salary, wasn't entirely supportive of the decision, Simon nonetheless set off to make his mark at Johns Hopkins University with $500 from his brother Abraham.

Although Flexner had neither the benefit of a formal medical school education nor the financial stability of his classmate, the autodidact nonetheless did remarkably well with his drugstore background and extraordinary sense of discipline. Finances were Flexner's only setback. His funds were quickly running out and he faced an unwanted return to Louisville. His professors, however, refused to let a lack of finances interfere with the young man's promising future; he was offered a fellowship at the end of his first year and despite his family's fear that he would never return to Louisville, happily accepted.

In the fall of 1891, Flexner began his fellowship but under slightly different circumstances. Instead of rooming in a boardinghouse, as he'd done the previous term, he now lived with the superintendent of the hospital, which meant that he constantly interacted with clinical as well as pathology students. This proved to be a most stimulating environment for the young scientist. At the same time, the fields of bacteriology and pathology were so new that nothing but groundbreaking research opportunities awaited pioneering students. Although Flexner was slightly self-conscious about his lack of education and upbringing, for the first time in his life, close relationships with his fellow students, some of whom would also go on to become quite famous for their work in infectious disease research. Meanwhile, the medical school, which had been postponed due to lack of funding, was now slated for a fall 1893 opening.

Flexner began his work on meningitis in early 1892 when an epidemic broke out in the coal-mining region of Cumberland, Maryland. Flexner and another scientist performed an autopsy on a young girl and although the bereaved parents insisted that the body remain intact, Flexner sneaked tissue samples out of the house in order to determine whether the epidemic was actually spotted fever as originally believed or an outbreak of meningitis. Flexner determined that it was definitely an outbreak of meningitis and set off on a course of study linking meningitis with pneumonia. While his theory eventually proved wrong, it launched Flexner's lifetime research on the disease.

Simon completed his second year at Johns Hopkins and saw some of the pathology faculty leave the university for opportunities elsewhere. Torn between leaving Johns Hopkins for a faculty position or staying and hoping for a promotion that might never materialize due to his lack of experience, Flexner was uneasy about his prospects. He perceived stiff competition among his fellow students but when his mentor and faculty member, William T. Councilman decided to leave for Harvard, Flexner received the assistant in pathology appointment. Within two years of arriving at Johns Hopkins, Flexner became not only a faculty member but also slated to succeed Councilman's successor as resident pathologist at the hospital. This time the entire Flexner family supported Simon's appointment.

Flexner spent the next year doing autopsies, research, and lecturing and although he was confident in his abilities, he recognized that he could benefit from a period of German study, standard for young medical students at that time. At the end of the first semester in 1893, he set sail for Germany. It was a successful trip in the sense that although Flexner visited many universities abroad, he returned with a deeper appreciation for the Johns Hopkins University, which employed a much more egalitarian approach than the medical schools he'd seen in Eastern and Western Europe.

By the time Flexner returned from Europe in the fall of 1893, the eagerly awaited medical school was finally open but more importantly, the pathology department had been expanded to twice the size. The medical school student body consisted of fourteen men and three women; the inclusion of the latter was not included in the original plan but became a condition of funding. Stringent admission requirements further reduced enrollment. Upon his return, Flexner resumed his exhausting schedule of supervising the pathology laboratory and assisting with pathology courses. At the same time, he continued his research on diphtheria and toxins, which introduced him to the new field of immunology. Flexner also managed to write extensively in conjunction with his research, ultimately publishing more than seventy articles between 1893 and 1899.

Flexner conducted important research on toxins and diphtheria during 1893-1894, which contributed to the discovery of a cure and led him to inadvertently stumble on the phenomenon of anaphylaxis. He was invited to speak before the Pathological Society of Philadelphia on his toxin research; this presentation he later claimed established his reputation in Philadelphia, then considered to be the capital of American medicine. Continuing to do autopsies also presented Flexner with valuable research opportunities. A case of acute pancreatitis, for example, led Flexner to study the pancreas carefully and after thirty years of continuous research ultimately led to the isolation of insulin.

Elected to the American College of Physicians in 1895, Flexner was also promoted to associate professor of pathology, a remarkable feat for one who'd arrived at Johns Hopkins less than five years prior as a very inexperienced student. Other universities offered Flexner, who was lamentably underpaid, faculty positions at higher salaries but with fewer research opportunities. His mentor, William Welch, encouraged Flexner to be selective in light of his growing reputation as one of leading pathologists in the country. Although uncertain about his future, Flexner decided to stay at "the Hopkins" when they offered him a slight increase in salary; he felt comfortable there and his research benefited from the network he'd established with the other researchers.

Even the appointment of full professorship didn't seem to assure Flexner of a secure future at Johns Hopkins. He decided to resume negotiations with Cornell and also the University of Pennsylvania when he learned of the opening in pathology. Flexner decided on the University of Pennsylvania despite the lower salary and rumors of anti-Semitism. While the negotiations continued, he decided to go to the Philippines on a research expedition with his close friend and colleague, Lewellys F. Barker. The University of Pennsylvania confirmed his appointment as the men prepared for their expedition giving Flexner reservations about leaving just as the position of his dreams had finally opened. Eventually he decided to go and the trip proved a great success, scientifically speaking.

The beauty of Japan, where the group decided to spend some time, enchanted Flexner but he found himself craving structure and anxious to begin working. The group traveled to Tokyo, the center of infection disease research where Shibasaburo Kitasato, a codiscoverer of the diphtheria antitoxin, invited them into the laboratories. Flexner's introduction to scientist Hideyo Noguchi was most significant. Noguchi immediately expressed a desire to work with Flexner. Flexner's response was polite; at the time, he had no idea of the impact Noguchi would have in his own personal life, his career, and even the history of science itself.

The group traveled next to Hong Kong and then into the Philippine Islands. The "plague" and other infectious diseases were on the rise in Manila, offering plentiful virology research opportunities. The commission studied typhoid fever, malarial fevers, tuberculosis, and dengue fever, topical ulcers and dysentery, in which Flexner had the greatest interest. Aside from the research opportunities, Flexner found Manila depressing and the group decided to leave early. Flexner took a long voyage home and was back in Philadelphia with time to spare before his new position started.

Meanwhile there was an implosion in the tightly knit Flexner family, which left Abraham, the founder of a very successful school for boys, trying to keep the family afloat. Jacob Flexner, the acting patriarch since the death of their father years before, revealed that he was overextended financially and close to losing his drugstore. Abraham refused to let the family declare bankruptcy and for a time managed to juggle the debt incurred by various Flexner family members. It was a losing battle, however, and although he somehow saved the newly constructed family houses from foreclosure, Jacob lost his drugstore.

Jacob decided to try his hand at medicine. At Abraham's urging he joined Simon at Johns Hopkins. It was an uncomfortable time for Simon. Jacob, never prone to humility even in the face of his financial failures, embarrassed the quiet Simon with his overbearing and belligerent manner. Luckily, he attended the university for just a few months and then went on to New York for further training. In the end Simon felt as if the declaration of bankruptcy had liberated the Flexner family; everyone could now pursue desired careers without considering the family finances.

Flexner arrived in Philadelphia in 1899 to begin his professorship at the University of Pennsylvania. It was not smooth sailing. The faculty resented Flexner and resisted change. Senior faculty members were cool towards Flexner and opposed his ambitious plans to expand the pathology department. Flexner was barred from even hiring his own assistants. But students immediately responded warmly and enthusiastically to Flexner who lectured three days a week.

Soon after he began in Philadelphia, Flexner was surprised by the arrival of Hideyo Noguchi, the bacteriologist from Japan. Flexner had written to Noguchi that there wasn't a position available in Philadelphia but Noguchi had taken upon himself to make the trip prior to Flexner's discouraging response. There was nothing to do but put Noguchi to work in the pathology lab. Though Noguchi needed training, like Flexner he proved to be a quick study and an invaluable assistant. Noguchi went on to do brilliant research work on syphilis and yellow fever. The two developed a close relationship and it is most telling that when Flexner moved on to the Rockefeller Institute, Noguchi was the only member of his Philadelphia group who was chosen to join the staff at the new facility.

Flexner's time at the University of Pennsylvania was perhaps the most social period of his life. Most of the faculty members eventually warmed to the young man and included him in social gatherings. The salary increase also allowed him to go out more often. It wasn't long after he'd arrived at Pennsylvania though that he met his future wife, Helen Thomas. The sister of former Johns Hopkins colleague and friend Harry Thomas, she taught at nearby Bryn Mawr College where older sister Carey was dean.

During 1900-1901, his second year at the University of Pennsylvania, Flexner gained a hospital pathologist position as well as an appointment as director of the university's Ayer Clinical Laboratory which Flexner insisted should be used for research in conjunction with medical school classes. His background in plague research led him to be appointed head of a federal commission to investigate an outbreak in San Francisco that same year. At the same time, he continued with his own research on immunology with Noguchi. They worked together to study the toxic effects of snake venom, a research project suggested by Dr. Weir Mitchell who'd studied the effects of snake venom on humans and wanted Flexner to pursue experimental immunology.

That same year, 1901, Flexner received an appointment to the Board of Scientific Directors of the newly formed Rockefeller Institute for Medical Research, endowed by John D. Rockefeller. The next year the Institute offered Flexner the opportunity to direct laboratories and organize operations, a brilliant opportunity. To leave the university was risky because Rockefeller had guaranteed funding for only ten years. Flexner agonized over leaving his prestigious position at Penn but in the end, he accepted. By this time, Flexner and Helen Whitall Thomas were engaged.

Flexner and his new bride spent much of 1903, the first year of his appointment, visiting research laboratories in Europe seeking a model for the Rockefeller Institute. Realizing that chemistry, physics, and experimental biology were increasing becoming a central component of virology research, Flexner hired only scientists with a command of the basic sciences. When the Institute opened in 1906, the staff included Samuel J. Meltzer, Phoebus A. Levene, Eugene L. Opie, Hideyo Noguchi, Alexis Carrel, Jacques Loeb, Rufus I. Cole, and Peyton Rous.

Flexner's own research, meanwhile, rapidly gained attention and acclaim by the general public. This translated into winning public support for the new Institution and assured Rockefeller's continued financial backing. When New York City suffered a severe cerebrospinal meningitis epidemic during 1904 and 1905, Flexner studied the disease and by 1907 was able to develop an antiserum that acted against the bacterial agent and reduced the mortality rate by fifty percent. The Institute developed and distributed the serum to the general public free of charge. In 1907 Flexner took the same approach with polio and while his conclusions proved to be incorrect, he nonetheless laid important groundwork for researching the disease.

John D. Rockefeller, completely confident in Flexner, agreed to finance a research hospital at the Institute in 1910. During World War I, Flexner implemented a program to train medical officers and technicians and taught bacteriology himself. Serving in the Army Medical Corps from 1917-1919, Flexner attained the rank of colonel and assumed responsibility for inspecting the expeditionary forces laboratories in Europe.

While hired to just direct the laboratory, Flexner's superior administrative skill had essentially made him acting director of the entire facility. In 1924, he was formally named Director of the Rockefeller Institute, an amazing accomplishment that the entire Flexner family celebrated.

In addition to overseeing the daily operations of the Institute, Flexner worked tirelessly to aid other agencies in promoting medical and scientific education. He served as a charter member of the Rockefeller Foundation, the largest medical education and research benefactor, and helped the National Research Council secure funding for medical and mathematical research. He served on the Johns Hopkins Medical School board of trustees and chaired the Public Health Council of New York State.

A participating member of many scientific organizations throughout his career, Flexner served as president of the Association of American Physicians in 1914 and the American Association for the Advancement of Science and the Congress of American Physicians and Surgeons in 1919. The National Academy of Sciences recognized his contributions with a membership in 1908.

Flexner acted as director of the Rockefeller Institute until his retirement in 1935. During 1937 and 1938, he traveled to Oxford University as Eastman Professor acting as a consultant on medical professorships. During his time in England, Flexner wrote The Evolution and Organization of the University Clinic . In 1942, Flexner and his son, James Thomas Flexner, co-authored a well-received biography, William Henry Welch and the Heroic Age of American Medicine . Simon Flexner died in New York City at the age of 83.