Paolo Lagonia

Casimir Funk: His Discovery of the Vitamins and Their Deficiency Disorders

The history of the discovery of vitamins is the history of their deficiency disorders. Their discoverer was Casimir Funk, who is considered the ‘father of vitamin therapy’. In his experimental research, Funk studied the interrelationships in the human body of those elements that Eijkman had demonstrated in animals, particularly in birds. In his experimental research, Funk identified the dietetic factors whose lack caused the ‘deficiency disorders’, as he called human beri-beri, scurvy, rickets and pellagra. In 1911, he designated these factors ‘vitamins’ (‘vita’ = life, and ‘amine’ = a nitrogenous substance essential for life); this name was accepted by the scientific community in 1912.

Karl Landsteiner: a hundred years later.

A hundred years after the publication of his first work on the human blood groups, we celebrate Karl Landsteiner (Fig. 1), recognizing his role as father of the science of blood transfusion (1, 2), and one of the fathers of the population genetics (3), the tissue transplantation (4), and immunology (5). He was a man who, without funds or assistance, developed a deep understanding of the individual differences in human blood. Landsteiner was so averse to praise, so honest and so good, that he never achieved complete happiness in his personal life, finding his greatest satisfaction in his solitary scientific work. Indeed, he was so sad and melancholy that Hans Zinsser, a famous colleague in immunology who taught at the Harvard Medical School, told him repeatedly: “Karl, you are always crabby, always complaining.” Karl Landsteiner was born on 14 June 1868, son of the enterprising reporter Leopold Landsteiner, from whom he inherited great self-control, a notable fondness for logical thought, and a strong tenacity. Karl Landsteiner, however, maintained that his father’s seriousness and methodical habits were irritating. However, Landsteiner inherited from his mother, Fanny Hess, great modesty and reserve, attributes that ought to distinguish all great and famous men. Although it is usually recorded that Karl Landsteiner was born in the city of Vienna, he was actually born in the Jewish quarter, referred to as Baden bei Wien. His Jewish origin caused many difficulties for him during his scientific career. He was a precocious and model student. After completing primary school and the first 4 years of secondary school, in 1880 he attended the Staatsgymnasium in Linz as an “honours student”. During these studies he developed a great interest in the natural sciences and mathematics. Landsteiner entered the University of Vienna in 1885 and studied under the most famous scientists of the day: Langer, with whom he studied anatomy; Claus, who specialized in zoology; and Schenk, from whom he learned histology. He also studied hematological chemistry and the metabolism of the blood with Mauthner and Ernst von Fleishl. However, organic chemistry remained his first love, and his experimental work was conducted in the footsteps of Professor Ernst Ludwig. All his publications in this field anticipated his subsequent serological studies. On February 21, 1891, Landsteiner took a degree in medicine. He then began work in the laboratory of the medical clinic directed by Otto Kahler, who discovered and described the Kahler syndrome, today called “multiple myeloma.” From 1891 to 1893 Landsteiner completed his apprenticeship under two experts in the field of organic chemistry. First, in Würzberg, he studied under Emil Hermann Fischer (6), who was awarded the Nobel Prize in 1902 for his works about the organic synthetic approaches to glucose, oligopeptides, and caffeine. Later, in Munich, Landsteiner worked with Eugen von Bamberger in the laboratory of the Academy of Sciences and published jointly with him a treatise on the reaction of diazobenzol to calium permanganate. It was during this period that Karl 1 Address correspondence to: Antonio Tagarelli, Istituto di Medicina Sperimentale e Biotecnologie-CNR, Contrada Burga 87050 Mangone (CS), Italy.

Paul Ehrlich: The Nobel Prize in Physiology or Medicine 1908

We wish to commemorate Paul Ehrlich on the centennial of his being awarded the Nobel Prize in Physiology or Medicine in 1908. His studies are now considered as milestones in immunology: the morphology of leukocytes; his side-chain theory where he defined the cellular receptor for first time; and his clarification of the difference between serum therapy and chemotherapy. Ehrlich also invented the first chemotherapeutic drug: compound 606, or Salvarsan. We have used some original documents from the Royal Society of London, where Ehrlich was a fellow, and from Leipzig University, where he took a degree in medicine.

Genetic characterization of the historical Albanian ethnic minority of Calabria (Southern Italy)

Three historical ethnic minorities are present in Calabria: Albanians, Greeks, and Occitans. The Albanian ethnic minority is the more populous, having settled in Calabria between the 15th and 17th centuries, and these populations are now located in the provinces of Cosenza and Catanzaro. In the present study the Albanian population structure is analyzed based on the allele frequencies of six classic genetic markers: ACP, GC, PGM1, AK, ADA, and 6PGD. The results show a significant heterogeneity between the Albanian population in Calabria and the population in Molise. Therefore the cultural and reproductive isolation of the Albanian ethnic minority of Calabria is related to a great genetic peculiarity. Moreover, the frequencies of some alleles, particularly those of the PGM*1W31 variant, and the analysis of the R matrix still show the actual peculiar genetic structure of the Albanians of Calabria, although the genetic flow is evident in the decrease of endogamy and in the increase in the degree of mixing.

Archibald Edward Garrod and alcaptonuria: "Inborn errors of metabolism" revisited.

Archibald Edward Garrod (1857–1936) had a unique role in the history of medical biochemistry. Early in his career, he was recognized by the Royal Society of Medicine1 for his elucidation of the disorder alcaptonuria and the resultant demonstration of the special relationship between biochemistry, genetics, and their close overlap in the practice of medicine.1 Garrod showed great interest in genetics even as a youth when he published “The Tiger.”2 This brief work described in simple language the genetic significance of the interspecies mating of a tiger and a lion, suggesting the transmission of hereditary characteristics: “There has been an instance of a lion being the father and a tigress the mother of cubs ... [that] had the heads of the lion but the tigerine stripes on the body ....”2 The alcaptonuria study was the main interest of Garrod when, in 1892, he was appointed Assistant Physician in the Hospital for Sick Children in London. Keying off his sense that urine provided especially useful biological material for diagnostic purposes, he focused on the “black urine” of the children ultimately recognized to have alcaptonuria. In his book, The Inborn Errors of Metabolism,3 Garrod considered alcaptonuria as an “inborn error of metabolism” after the manner of diabetes and gout, where “inborn” meant “hereditary,” although he also clarified the biochemical and distinctive clinical features of the disorder: “Of inborn errors of metabolism, alcaptonuria ... attracts attention because an infant stains its clothing or the urine has a peculiar appearance. As the years go on, the cartilages become blackened, giving a blue tint to the hollows of the ears, brown marks develop on the conjunctivae, and there is a great tendency to osteoarthritic and osseous lesions .... Homogentisic acid, the excretion of which is the essential feature of alcaptonuria, was isolated, analyzed, and fully investigated by Wolkow and Baumann ... [in a work] published in 1801 ....”3 Garrod continues: “... the administration of tyrosine by mouth to ... an alcaptonuric subject ... caused a very conspicuous increase of the output of homogentisic acid .... A corresponding increase follows an augmented intake of protein food, and especially of such proteins that are unusually rich in the aromatic fractions ... the tyrosine and phenylalanine of proteins are the only parent substances of the alcapton acid [homogentisic acid] .... It will be obvious ... that the error of metabolism, which is the basis of alcaptonuria, is a failure to deal with the aromatic fractions of proteins .... It is an unquestionable fact that the great majority of aromatic compounds, when introduced into the human organism, escape with their benzene ring intact and are excreted in the urine .... Not so tyrosine and phenylalanine, which are in no sense foreign substances, but important constituents of proteins, for these suffer disintegration of the aromatic nucleus and are completely destroyed ....”3 Garrod believed that the human organism does not suffer from a disease when there is homeostasis of “metabolism” and “catabolism,” that is, when there is a stable equilibrium among the different enzymatic reactions. He considered that properly balanced enzymatic reactions were fundamental to having “good” or healthy chemistry.3 Thus, he says regarding alcaptonuria: “The anomaly locates the error in the penultimate stage of the catabolism of the aromatic protein fractions, which is in accord with the fact that both exogenous and endogenous tyrosine and phenylalanine contribute to the excreted homogentisic acid in alcaptonuria. We may further conceive that the splitting of the benzene ring of homogentisic acid in normal metabolism is the work of a special enzyme [and] that in congenital alcaptonuria this enzyme is wanting, while in disease its working may be partially or even completely inhibited.”3 In 1901, Garrod gave the Croonian Lecture4 to the Royal Society of Medicine. In this milestone in the field of genetics, he ascribed direct responsibility to the consanguineous parents for the alcaptonuria in their children without his having had any knowledge of Mendelian genetics. “It is evident ... that the proportion of alcaptonuric families and individuals who are the offspring of first cousins is remarkably high, and, on the other hand, it is equally clear that only a minute proportion of the children of such unions are alcaptonuric ... there is no reason to suppose that mere consanguinity of parents can originate such a condition as alcaptonuria in their offspring, and we must rather seek an explanation in some peculiarity of the parents, which remain latent for generations, but which has the best chance of asserting itself in the offspring of the union of two members of a family in which it is transmitted ... it is not the mating of first cousins in general but of those who came of particular stocks that tends to induce the development of alcaptonuria in the offspring. For example, if a man inherits the tendency on his father’s side his union with one of his maternal first cousins will be no more liable to result in alcaptonuric offspring than his marriage with one who is in no way related to him by blood. On the other hand, if member of two families who both inherit the strain should intermarry the liability to alcaptonuria in the offspring will be as great as from the union of two members of either family, and it is only to be expected that the peculiarity will also manifest itself in the children of parents who are not related ....”4 As part of an ongoing project to celebrate the history of medical genetics, the authors are pleased to remind our colleagues in genetics, and in medicine in general, of the creative insights and pioneering work of Archibald Edward Garrod. From the National Council of the Researches, Institute of Neurological Sciences, Mangone (Cosenza), Italy; and Institute of Neurology, “Magna Graecia” University, Catanzaro, Italy.

Walter Stanborough Sutton: a hundred years after the chromosomal theory of heredity

A hundred years after the publication of his paper “The chromosomes in heredity” (Sutton 1903) we must celebrate Walter Stanborough Sutton (Fig. 1), recognizing him as the father of the discipline of Human Genetics. He was, as his family said of him, “a man with a mind above the smallnesses of human nature”; and each year proved the greatness of his abilities, and brought out more and more of the nobility and simplicity of his nature and emphasized the absence of all the petty and unhappy traits which so often mar the characters of the greatest men. His whole personality was magnetic and impressive. His smile was singularly frank, sincere and pleasing. He was a friend maker; he liked people; the simplicity and sincerity with which he greeted new acquaintances at once aroused their interest in him and wherever he went he bound friends to him with hoops of steel.