Julius Citron

Julius Bernhard Citron (October 26, 1878 – January 18, 1952) was an early German Jewish researcher in bacteriology, immunology, and serology, specialties devoted to the prevention of infectious disease. Best known for his contribution to the development of the Wassermann serodiagnostic test for syphilis, he was a clinical physician; during the First World War, a German Army field doctor; a Professor of Internal Medicine at the University of Berlin; the Chief of the Charite Hospital’s Bacteriological-Serological Scientific Laboratory and later the Physician in Chief for its 2nd Medical Clinic. He ended his career as the Physician-in-Chief at Cairo’s Jewish Hospital, L'Hopital Israelite du Cairo. He wrote early medical textbooks in bacteriology and immunology and dozens of research papers published in leading medical journals. Proficient in five languages, German, English, French, Hebrew, and Arabic, he cared for patients in each.
An American colleague wrote in 1910 about Citron that "he is a genial, earnest worker and a delightful gentleman, thoroughly interested in his work, an excellent teacher and in all probability one of the best laboratory men on the [European] Continent," a testament to Citron’s international reputation from a young age. Citron, though, should be known as more than one of the best laboratory men. Citron laid the groundwork for integrating the laboratory sciences with clinical practice.
 
In the emerging field of serology, Citron developed the world’s first clinically viable serodiagnostic test for disease, a test and that would shape the field for decades. For his test, he pioneered the use of human antibodies, sampled from a broad range of stratified human medical data strictly controlled for sample variability. He used this method rather than the then prevalent use of small numbers of ad hoc samples of blood sera from animals to test for antigens as a marker for animal disease. Citron anticipated modern statistical methods to verify positive diagnostic results and using his method, developed the first clinically viable test to diagnose syphilis. His test would remain in use for over fifty years and would be popularly known either as the "Wassermann Test", or the "Wassermann Reaction". He also developed the first clinically viable blood test to diagnose tuberculosis.
 
August von Wassermann, Albert Neisser, and Carl Bruck are frequently cited as the developers of the Wassermann test. They were the first to attempt a diagnostic test for syphilis. Their method involved using blood sera from small numbers of syphilitic monkeys to test for the presence of antigens. Their method yielded low true positive results of about 20%, too low to be of clinical value. Recognizing their results' shortcomings, Wassermann assigned Citron to develop a method. Citron’s method achieved verifiably true positive results in humans of about 80%. 
 
The important and immediate impact of Citron's contribution was the rapid and widespread adoption of his test for clinical use. With the adoption of Citron's test, clinicians worldwide changed the treatment protocol for patients who test positive for syphilis. With a positive test result, clinicians would initiate the treatment of their patients with mercury even in the absence of symptoms and would continue the treatment until their patients tested negative. This is important because syphilis often does not manifest symptoms. 
Citron would also be known for the breadth of his research. He was a leading authority for syphilis, and he made contributions to the understanding of the disease processes for gonorrhea, tuberculosis, typhus, meningitis, cholera, tetanus, and the swine flu among other infectious diseases. He studied the treatment of diabetes using insulin within a couple of years of insulin's discovery in the US, when in Germany there were only a handful of vials of experimental insulin and only a couple of researchers. He pioneered research in the relationship of oral health to endocrine and metabolic disorders, and he contributed to the study of the pathogenesis of various tumors. His research was published in leading medical journals, and he wrote very early textbooks in bacteriology and immunology for students and practitioners that were revised through four editions, were translated into multiple languages and were used internationally for several decades. As a Professor of Internal Medicine at the University of Berlin for over two decades, he taught hundreds of medical students until the Nazi era. 
Citron died and was buried in the Bassatine Jewish Cemetery of Cairo, Egypt.
==Early life and career==
Citron was born on October 26, 1878, in Berlin, Germany to religiously observant Jewish parents, Judah David Leib Citron and Lina Citron (formerly Aronsohn). His parents were wealthy sponge merchants one generation removed from the impoverished east Prussian shtetls of Vyekshnya and Kaunas. Family memoirs mention that Citron was a precocious child who made regular visits to his ancestral shtetls where the future bacteriologist-hygienist was said to enjoy riding on manure wagons. 
Citron, an early and lifelong Zionist, was a founding member of the Bar Kochba youth group of Berlin in 1898, just a year after Theodor Herzl’s first Zionist Congress in Basel, Switzerland in 1897. Citron almost certainly attended at least the 5th Zionist Congress in 1901 and maybe earlier Zionist Congresses as a spectator, where he formed relationships with Theodor Herzl and Chaim Weizmann. 
By August 1899, Citron had studied medicine at the universities of Munich, Freiburg, and Berlin, and passed the preliminary medical examination with the grade of ‘very good,’ a rare distinction. He began his obligatory military service as a field doctor where after partial fulfillment in 1902, at the age of 24, he completed his dissertation, was awarded a degree as a medical doctor cum laude from Freiburg University and passed the state medical exam with the grade of ‘good.’ 
He served in the German Army as a field doctor in 1902, completing his military service in October 1903. He then continued his education at the highly selective Royal Institute for Infectious Disease (Robert Koch Institute) where important discoveries in the cause of infectious disease were first made. The Robert Koch Institute, along with the Charite Hospital, were recognized as two of the world’s leading medical research centers of the era, both affiliated with the University of Berlin. He joined the Koch Institute as a research assistant in January 1904, the last year of Nobel Laureate Robert Koch’s leadership, joining a select group of colleagues including Nobel Laureate Paul Ehrlich and August von Wassermann.
In his first year at the Koch Institute, and within a few years of Jules Bordet’s test of Ehrlich’s complement-fixation theory, Citron applied the combined action of antibody and complement-fixation theory to author five papers evaluating the immunity of various animals from diverse infectious diseases. He co-authored another four papers with Wassermann and other researchers on related topics, demonstrating in part that “antitoxins can be formed anywhere in the body when the toxin is fixed,” a phenomenon they described as local immunity. William Bulloch, a leading historian of bacteriology, described Citron’s animal studies with Wassermann as important for demonstrating Ehrlich’s theory of immunity.
Citron also participated in the Koch Institute’s activities to combat Berlin’s limited cholera outbreak of 1905, an outbreak of that year that took few lives.
In 1906, Wassermann and Carl Bruck developed a serodiagnostic test for tuberculosis using bacterial extracts. Concurrently and independently, Citron developed a serodiagnostic test for tuberculosis using the entire bacterium. With a reliably high rate of true positives, these would be the world’s earliest successful blood tests.
With his success in the laboratory, and following the practice of Koch, Ehrlich, Neisser, and other leading researchers of infectious disease, Citron traveled abroad to study infectious disease in the field. Citron traveled to Italy where he worked as a clinical physician for several months, and to Ottoman Turkey, Palestine, and Egypt for his practical field studies. Through his travels, Citron developed an affection for the cultures of the eastern Mediterranean.
In the same year, 1906, Wassermann, newly appointed director of the Koch Institutes’ Division for Experimental Therapy and Serum Research, with Carl Bruck and Albert Neisser attempted to develop a practical serodiagnostic test for syphilis. Their method, which used a small number of ad hoc samples from monkeys to test for syphilitic antigens, is often cited as the basis for the Wassermann Test. However, the number of true positive results for this test was too low to be of any practical value. Wassermann, recognizing the limitation of his approach, assigned Citron to develop a test. Among competing methods developed in different laboratories, of which there would be many, only Citron’s method achieved reliably high true positive results. It would come to be used as the cornerstone diagnostic tool in the general population.
Citron used human sera from almost a thousand human patients with known health profiles from the Charite hospital that he personally collected. His predecessors used sera from a small number of monkeys for which there were no health profiles. By using a large number of strictly controlled human samples, Citron could correlate the outcomes of his serological lab results with a patient’s medical data and clinical profiles. Citron would know whether the patient acknowledged having a syphilitic infection in the past, whether the symptoms of an infection were present or absent, the stages of the disease, whether primary, secondary, or tertiary, and the post-syphilitic condition of the patient. In 1907, Citron’s use of large, stratified samples to control for the variability in human disease and variation in sample quality was an unknown practice then and would only become a common practice in the 1950’s.
Citron also noticed there were two groups of patients that exhibited strong clinical indications of syphilis but had differing antibody test results: one group acknowledged their infection, and another group had the infection but had not acknowledged an infection. Citron had the insight that those who acknowledged an infection would have been treated with the then standard mercury treatment. The treatment, he surmised, probably suppressed the patient’s antibody production. Those that did not acknowledge an infection would not have been treated and would have higher antibody production. Citron’s insight is that medical therapy has an influence on antibody production, which is important to know for a testing laboratory. Citron surmised that Wassermann, Neisser, and Bruck’s results might have been so poor in part because they used sera from monkeys that had been medically treated with mercury first. Such an insight could only have been discovered using rigorously controlled clinical data. 
Citron’s discovery had the immediate impact of changing the medical profession's use of mercurial therapy for syphilitic patients. From then on, testing, using Citron’s method would determine the treatment regime. A treatment would be initiated when there was a positive antibody reaction even in the absence of known symptoms and would continue until the reaction was shown to be persistently negative through testing. The prior practice was to treat with mercury only in the presence of observable symptoms and would continue until the symptoms disappeared.
Citron made several unique contributions. Rather than animals, he used human test subjects with known clinical profiles that included syphilis infection status. He evaluated the blood samples for antibodies, rather than antigens, using rigorous laboratory controls and compared those results with the known infection status of the patients. Anticipating the later use of more formal statistical methods, Citron used large numbers of well-controlled patient samples to allow the stratification of his results by disease stage rather than the prevailing method of utilizing small numbers of ad hoc samples.
Citron’s method achieved true positive test results of about 80% and was quickly recognized for its diagnostic value. Following Citron’s active efforts at persuasion through journal articles, his textbook of 1910, numerous lectures, and his engagement with individual researcher–clinicians over an extended period, which he understood to be a part of the scientific process, his method was adopted by a majority of bacteriologist – serologists and clinical hospitals around the world.
With his breakthrough in 1907, Citron as the sole author published the technical details for his Wassermann Test.
Still in 1907, Citron left the Koch Institute for a position with the 2nd Medical Clinic of the Charite Hospital and Medical Research Center, under clinic director, Fredrich Kraus. He published his first comprehensive book of bacteriology, Clinical Bacteriology Protozoa and Immunodiagnostics (1908) (4th ed. 1924). Kraus, as editor of a collection of related papers, published Citron’s general clinical and laboratory approach for the serodiagnosis of disease. 
In 1910, Citron published a revised version of his Wassermann Test with co-author, Munk.
Citron published his next medical textbook, (Immunity, Methods of Diagnosis and Therapy and Their Practical Application) (1910) (4th ed. 1923), which became a standard text for students and medical practitioners in German, English, Russian, Spanish, and Italian. He would regularly revise it through four editions. His book was published a couple of years after the creation of Germany’s first Journal of Immunology in 1908 , before America’s first professional society, the American Association of Immunologists in 1913 and well before America’s first journal, the ‘Journal of Immunology’ in 1916.
It was from this textbook that the scientific paradigm for the first generation of serologists was created, and which Ludwig Fleck would describe as the “catechism” in the field of serology through at least the mid-1930’s. The textbook also set off what Fleck described as an “avalanche” when he noted that over 1,500 papers cited Citron’s “serodiagnosis of syphilis” in 1927 and about 10,000 papers cited it by 1935. It was from Citron’s contribution to “a meaningful discovery” that a “thought collective” was formed and that created the “social conditioning” for the practice of their new science, serology.
Citron was appointed the Charite’s Chief of the Bacteriological-Serological Scientific Laboratory in 1912, the year that he published his updated comprehensive book of bacteriology, Clinical Bacteriology and Protozoa (1912) (2nd ed. 1924), and soon after, to the position of Professor of Internal Medicine, at the University of Berlin in 1913, at a time when the University of Berlin was the leading medical research center in the world. Germany had 30% of all Nobel Prizes in medicine and 50% of them were at the University of Berlin.
With the start of the First World War on Aug 1, 1914, Citron served as “Doctor for the Armies” with the 36th Infantry Division in the Lazarett military hospital Nr. 290. In that role he treated the wounded and ill when tuberculosis, malaria, diphtheria, typhus among other infectious diseases were common. He also served as the division’s sanitation and hygiene officer where he would regularly inspect the sanitation and hygiene of the troops on the front lines. His division served on the Eastern Front during the battles of Tannenberg and Warsaw and on the Western Front during the major battles of the Somme and the Flanders, among many lesser battles. Citron would serve in the field hospital continuously from the start of the war, without a day's interruption for over three years, until Kraus made an urgent appeal for his return to the Charitie for the care of a neglected civilian population. Citron was discharged from the Army on Dec 31, 1917, having been awarded the honors of Iron Cross First and Second class.
Upon his return to the Charites 2nd Medical Clinic, and his appointment as Physician in Chief for the Polyclinic, he resumed the treatment of patients, broadened his research interests and, during the worldwide Spanish Flu of 1918, wrote a “clinical picture” of the deadly pandemic.
The Spanish Flu was not the only infectious disease of national concern. In Dec 1918, with the post-world war return of millions of soldiers, there was a heightened concern for a rising incidence of venereal disease, especially syphilis and gonorrhea, which were widely believed to be at epidemic proportions. Venereal diseases were thought to be destroying the German national strength, and it was the carrier’s national duty to seek the proper treatment to protect families and the nation from fertility destroying diseases. Germany passed an emergency decree that punished persons who knowingly engaged in sexual intercourse when infected with a venereal disease. As part of the official campaign against syphilis, public institutions would claim the disease could be passed to infants from the father at the moment of conception, from hotel sheets and toilet seats, and most usually from the lower social classes. Amid that heightened national concern, in 1919, Citron wrote, “Die Syphilis,” for a medical collection edited by Kraus. Citron’s contribution was perhaps the most authoritative and comprehensive review of the clinical and pathologic manifestations, the treatment for, and the serodiagnostic testing for syphilis in the German language and perhaps in any language of the era. Citron wrote that the transmission of syphilis would only occur from person to person, a scientific message quite different than the official, more fear-based message. In 1921, Citron published experimental results for the treatment of gonorrhea.
An early act of the League of Nations was to create their Health Organization’s Standardization Committee in 1921. The Standardization Committee’s first act as part of the worldwide concern about an epidemic of venereal diseases, was to evaluate Citron’s version of the Wassermann test. Used around the world with various levels of skill, the Wassermann Test was believed to be cumbersome and prone to poor results unless performed by skilled technicians. Many alternative tests flourished with a variety of claims made about their results. The Committee, composed of leading non-German serologists from around the world, held an international competition to evaluate which was the technically best method to diagnose syphilis. The Committee ran repeated replication tests of the many alternative methods and despite a remaining hostility toward German scientists, determined Citron’s Wassermann Test was in the words of the League of Nations, “superior.” The League of Nations’ effort at standardization contributed in part to Fleck’s concern about Citron’s ‘catechism’ in serology.
The American, Fredrick Banting first discovered insulin as a treatment for diabetes in 1922. Within a couple of years, Citron conducted experiments with the earliest and very scarce supply of insulin in Germany in 1924.
Kraus stepped down as director of the 2nd Medical Clinic in 1927 to be replaced by the longtime colleague of both Citron and Kraus, Prof. Dr. Gustav von Bregman. In the same year, Citron resigned from his position at the 2nd Medical Clinic’s Polyclinic to devote more time at the dental school where he continued as Professor of Internal Medicine and taught dental students in what he described as the intersection between internal medicine and dentistry. He published two articles on the topic during this period of his career.
As one of the last professional activities that Citron and Kraus conducted together, they examined Leon Trotsky who, only a few years after attempting to lead a revolution in Germany, was seeking asylum there in 1929. Citron and Kraus had previously examined Trotsky in 1926.
In 1930, with the Depression engulfing society and their clinical and teaching salaries cut (see below), Bregman, Kraus and Citron allowed their name and title to be used for the promotion of ‘the healthy use of Fleischmann yeast,’ a commercial product. Because physicians with public hospitals were prohibited from earning incomes in their private capacity and because they used the prestige of their positions to promote commercial products, the Prussian Health Ministry Court of Inquiry investigated their conduct. The Court determined this was a minor scandal and settled the matter for all three without consequence. Fleischmann’s use of the Citron name for the promotion of their products in the US was a measure of Citron’s continued international prestige.
==Later life==
With the end of the First World War, Citron married Lilli Alice Schayer on February 1, 1919. They lived on Kurfurstendamm 66 and had three children in the first four years of their marriage. Devoted to the German Jewish community and a committed Zionist, Citron, along with friend Albert Einstein, headed a group of prominent Jews including Rabbi Leo Baeck, Judah Magnus among others in support of the creation of the Hebrew University of Jerusalem. 
During the high era of the Weimar period, Citron enjoyed professional success working alongside Kraus and had a happy home life with Lilli. Germany’s revolutionary years, which started with the Great Depression, would change everything. 
Although a prominent researcher and physician, Citron lived on a modest civil servant’s salary. With a young family to support, Citron’s salary was cut by 6% in 1931, by another 20% in early 1932, and then another 20% later in 1932. With recurring Brownshirt-led anti-Jewish demonstrations and harassment of the Jewish residents along Kurfurstendamm and at his university throughout 1931 and 1932, Citron wanted to leave Germany. Lilli persuaded them to remain, perhaps aware of a growing illness that would soon take her young life. After 13 years of marriage, Lilli died of a brain tumor on December 1932.
With the appointment of Hitler as Reich Chancellor on Jan 30, 1933, and the Reichstag Fire Decree of late February 1933 that suspended the German Constitution, tension in the Berlin Jewish community was high. Brownshirts returned to again threaten the Jewish neighborhood along Kurfurstendamm during the first months of 1933. With the growing influence of National Socialism at the Charite, the knowledge that Jewish employees would be dismissed as part of the coming Nazi Civil Service Restoration Act of April 7, 1933, and the belief that Von Bergmann, Citron’s longtime colleague would be the “sober enforcer of the Nazi injustice,” Citron decided to leave. About 250 Jewish or dissident staff and faculty would be expelled from the Charite in those early months of the Nazi era and as part of a larger purge of Jewish doctors that began throughout Germany in March 1933. Citron is recognized as a persecuted colleague at the Charite, today.
Citron left Germany for British Mandatory Palestine with his young children on March 20, 1933. He arrived in Tel Aviv to an emerging nation without a medical school or place to teach. He lived at 27 Nachmani Street, Tel Aviv where he worked as a clinical physician in private practice, gave public lectures on health, mentored younger physicians, and was in gradual semi-retirement by 1945. He also offered shelter in his home to his cousin, Eduard Aronsohn, and his family, refugees from Nazi Germany for an extended number of years. They would remember Citron for saving their lives and continued generosity for years afterward.
In 1945, with the end of the Second World War, at the age of 67, Citron was recruited by his old friend and colleague from the Charite, Dr. Picard to leave his semi-retirement to join him at Cairo’s Jewish Hospital, L’ Hopital Israelite du Cairo. As a member of the Royal Society of Medicine of Egypt, Citron would serve as the Physician in Chief for the Jewish Hospital where he would practice medicine for the rest of his life. At the hospital, he joined several former students whom he had previously helped obtain their doctorates. The President of the Jewish Hospital was a former student. At the Jewish Hospital, he treated such renowned patients as Egypt’s King Farouk, Ethiopia’s Emperor Haile Selassie, and the Persian Shah of Iran. 
While in Cyprus to visit his Israeli children, the longtime smoker felt the first symptoms of the lung cancer that at first appeared benign but which he seemed to know would be terminal. He would die of the disease in January 1952. On the last day of his life, while sitting on his death bed, his close friend Picard found him reading a scientific volume, which his friend thought represented his life, the life of a leading medical mind, curious until the end.
==Major published works==
* Wassermann, A. von, and Julius Citron. "The local immunity of tissues." German med. Wochenschrift 15 (1905).
* Wassermann, A., and Citron, J., ‘Ueber die Bildungsstatten der Typhusimmunkorper. Ein Beitrag zur Frage der localen Im¬ munitat der Gewebe , Ztschr.f. Hyg. u. Infektionskrankh., 1905
* Citron, Julius. "Die Immunisirung gegen Schweineseuche mit Hülfe von Bakterienextracten." Zeitschrift für Hygiene und Infektionskrankheiten 52.1 (1906): 238-262.
* Citron, Julius. "Die Immunisierung gegen die Bakterien der Hogcholera (Schweinepest) mit Hilfe von Bakterienextrakten." Zeitschrift für Hygiene und Infektionskrankheiten 53.1 (1906): 515-553.
* Citron, Julius, “Ueber naturliche und kiinstliche Agressine," Zentralbl. Bakter., 41 (1906), 230
* Citron, Julius. "Ueber Komplementbindungsversuche bei infektiösen und postinfektiösen Erkrankungen,(Tabes dorsalis etc.) sowie bei Nährstoffen1." DMW-Deutsche Medizinische Wochenschrift 33.29 (1907): 1165-1171.
* Citron, Julius Bernhard. On tuberculosis antibodies and the nature of the tuberculin reaction. (1907).
* Citron, J. Erwiderung auf die Bemerkungen E. Weils. Deutsche medizinische Wochenschrift 33 (43) 1907: 90–91.
* Citron, J. Die Serodiagnostik der Syphilis. Berliner klinische Wochenschrift 44 (43) 1907: 1370–73
* Citron, Julius Bernhard. Klinische Bakteriologie und Protozoenkunde. Klinkhardt, 1908.
* Citron, Julius, and Fritz Munk. "Das Wesen der Wassermannschen Reaktion." DMW-Deutsche Medizinische Wochenschrift 36.34 (1910): 1560-1561.
* Aronsohn, Eduard, and Julius Citron. Experimentelle Untersuchungen über die Bedeutung der Wärmestichhyperthermie für die Antikörperbildung. Hirschwald, 1910.
* Citron, Julius. Die methoden der immunodiagnostik und immunotherapie und ihre praktische verwertung. G. Thieme, 1910.
* Citron, Julius Bernhard. Clinical bacteriology and protozoa. Klinkhardt, 1912
* Citron, Julius. Die methoden der immunodiagnostik und immunotherapie und ihre praktische verwertung. G. Thieme, 1912.
* Citron, Julius, and Erich Leschke. "Ueber den einfluss der ausschaltung des zwischenhirns auf das infectiöse und nichtinfectiöse fieber." Zeitschrift für experimentelle Pathologie und Therapie 14.3 (1913): 379-390.
* Citron, Julius Bernhard. Immunity, Methods of Diagnosis and Therapy and Their Practical Application. P. Blakiston's son & Company, 1914.
* Citron, Julius. "Das klinische Bild der spanischen Grippe." Vortrag Berliner medizinische Gesellschaft 17 (1918).
* Citron, Julius Bernhard. "Die Syphilis" (in the edition of the Specialist Pathol Ther. KRAUS / BRUGSCH, vol. 2,1), Berlin 1919
* Citron, Julius. "Die erfolgreiche Behandlung eines Falles von Gonokokkensepsis mit Meningokokkenserum1." DMW-Deutsche Medizinische Wochenschrift 47.31 (1921): 891-891.
* Citron, J. "Experimented Beitrage zur Insulinwirkung." Med. Klin 20 (1924): 1362-1365.[i]
* Citron, Julius Bernhard. “Paradentoses as a symptom of endocrine and metabolic disorders,” Z. klin. Med, 1928
* Citron, Julius Bernhard. “Significance of oral diseases for internal medicine " (Med. Welt 4: 466-71, 1930)
Category:1878 births
Category:1952 deaths
Category:Jewish German scientists
Category:People from Berlin
Category:German people