First contributors in the history of leukemia

Abstract

While the modern era of leukemia chemotherapy began recently, the recognition of leukemias has been mainly recorded in the second part of the nineteenth century. This brief historic review reports the first descriptions of the disease and the major advances in its history from its roots to the beginning of the twentieth century. Although most treatments for leukemia were ineffective until the middle of the twentieth century, it seemed of interest to review some pertinent exemples of the evolution in the knowledge of this disease (relied upon chronology as an organizing framework, while stressing the importance of themes), since our current knowledge about leukemia is still mainly based on the first accounts of scientific and medical discovery. Early in the nineteenth century, a small number of cases of patients with uncommon or peculiar alterations of the blood were published. Of the cases, four might suggest symptoms of chronic leukemia. The first published case was the detailed report prepared by John Hughes Bennett in the “Edinburgh Medical and Surgical Journal” October 1845. Leukemia gradually became accepted as a distinct disease and published case reports grew in number. Concomitantly, clinical and pathological description of the disease became more detailed.

Key Words: History; Leukemia; Discovery; Hematology

Core tip: Towards the end of the nineteenth century, a clearer definition of the classification of leukemia had been established leading to different subtypes. These well-defined subtypes of leukemia were used for the development of effective chemotherapy, which has represented the most important advance in leukemia research during the past half century.

INTRODUCTION

The oldest description of cancer was discovered in Egypt and dates back to approximately 1600 BC. The origin of the word “cancer” is credited to the Greek physician Hippocrates (460-370 BC). Hippocrates noticed that blood vessels around a malignant tumor looked like the claws of crab[1]. He named the disease karkinos (the Greek name for crab) to describe tumors that may or may not progress to ulceration. The credit for the discovery of leukemia goes to the ancient Greeks, who recognized this blood disease way back in the 4^th or 5^th century BC. However, the literature until AD 500 revealed no evidence of blood malignancies. Accounts and traces of leukemia in the literature are of relatively recent origin. It is obvious that modern knowledge about leukemia owes a debt to numerous European physicians.

In this brief historical review, we examined the major initial advances in the history of leukemia and the main characters involved in the first descriptions. Although “discovery” could not be attributed to one unique observation and that accurate knowledge and effective treatment of leukemia were not available until the middle of the twentieth century, it seemed of interest to review some pertinent examples of the first descriptions and advances in this disease. Targeted more specifically at the young hematologist and the general educated reader, this review aims to communicate accounts of scientific and medical discovery and initial practice in this disease. It relies upon chronology as an organizing framework, while stressing the importance of themes.

FIRST STUDIES OF BLOOD

Naked-eye inspection of blood by phlebotomy was practiced far back to ancient times. The ancients readily recognized the importance of blood as a life-giving substance, believing it to hold the body’s vital force. Hebrews back to the patriarchal age maintained that blood was the seat of the soul and demanded through the Mosaic laws that it be drained before an animal was prepared as food. The Romans drank the blood of their enemies, thinking it would confer on them the courage of their vanquished foes. The scientific study of blood had to wait for the invention of the microscope. While magnifying lenses were known to the monastic scholar and natural historian Roger Bacon (1214-1294), lenses of sufficient quality for scientific use were not available for another three centuries[2]. Invention of the compound microscope around 1590 by Hans and Zacharias Janssen made possible the examination of the content of the blood[3]. In 1658, the Dutch naturalist, Jan Swammerdam (1637-1680) was the first person to observe red blood cells under the microscope[4]. Another Dutch microscopist Anton van Leeuwenhoeck (1632-1723) who developed a number of primitive compound microscopes, described the size and shape of “red corpuscules” and rendered the first illustration of human red blood cells in 1695[5]. The white blood cells (“the globuli albicantes”) were first noted by Joseph Lieutaud (1703-1780)[6], some 20 years before William Hewson (1739-1774) first described the lymphocyte[7]. The earliest reports of leukemia were therefore made by pathologists who recognized early in the nineteenth century, first by gross observation and later through microscopy, that the blood was composed predominantly of white cells, but the evidence provided in the publications was insufficient to support a definite diagnosis of leukemia[8-12]. This is only in the 19^th century that several European physicians noticed that quite a few of their patients suffered from abnormally high levels of white blood cells.

FIRST DESCRIPTIONS OF LEUKEMIA

Similar to most discoveries in medicine, it is not clear who first actually discovered leukemia. Early in the nineteenth century, a small number of cases with uncommon alterations of the blood were published[13]. The earliest report of the illness is generally considered to have been made by Velpeau[12] (Figure 1). Velpeau[12] reported a case of a 63-year-old woman who had fever, a swollen stomach, as well as being generally weak. At autopsy, she was found to have an enormous spleen (twenty times larger than normal) and whose blood was “thick like gruel such that one might have asked if it were not rather laudable pus, than blood”. However, at the time no official name was assigned to the condition and the scant evidence provided in the publication was insufficient to support a definite diagnosis of leukemia. The disease might well have been first observed by Alfred Donné of Paris, the founder of French clinical microscopy (Figure 2). In 1839, Dr. Barth and Dr. Chomel requested his consultative services for a woman patient aged 44 suffering from a painless left-sided abdominal tumor filling the left side of the abdomen. After requesting a specimen of blood for examination, Donné indicated that the large excess of white blood cells which might resemble purulent matter, was not in fact such and concluded that the patient presented with a new disease[14]. Donné wrote Barth as follows: “The blood you sent me shows a remarkable and most conspicuous change. More than half of the cells were mucous globules. You know that normal blood contains three types of cells: (1) red cells, the essential cells of the blood; (2) white cells or mucous cells; and (3) the small globules. It is the second variety which dominates so much, that, one wonders, knowing nothing about the clinical course, whether this blood does not contain pus. As you know the pus cells cannot yet be differentiated with accuracy from mucous cells”[15]. In a later case, he reported far more accurately on leukemia and wrote the following text for a chapter entitled “De l’altération des globules blancs” which appeared in his book “Cours de microscopie complémentaire des études médicales”: “There are conditions in which white cells seem to be in excess in the blood. I found this fact so many times, it is so evident in certain patients, that I cannot conceive the slightest doubt in this regard¡ I had an opportunity of seeing these cells in a patient under Dr. Rayer at the La Charité Hospital. This man was affected by arteritis especially in his leg vessels. Both legs showed ecchymoses and gangrenous blisters. The blood of this patient showed such a number of white cells that I thought his blood was mixed with pus, but in the end, I was able to observe a clear-cut difference between these cells and the white cells¡ In fact, I believe that the excess of white blood cells is due to an arrest of maturation of blood¡ From my theory on the origin of blood cells, the overabundance of white blood cells should be the result of an arrest of development of intermediate cells”[16]. Here we find leukemia linked with abnormal blood pathology for the first time in medical history. He made this description of the disease in 1844, calling it an unknown disease whose findings were not published until 1855[17]. Among other published cases, two might suggest symptoms of chronic leukemia and the blood examined after death showed that the purulent matter and lymph has been mixed with the blood and had been circulated[10,18]. John Hughes Bennett (Figure 3), pathologist at the Royal Infirmary Edinburgh, gave leukemia its first published recognition as a clinical entity and as a blood-related disease. He was then often referred to as the person who first discovered leukemia because his description was more complete and scientific in nature. Bennett became interested in the disorder when his mentor, Dr. David Craigie, observed two patients admitted to the Royal Infirmary in Edinburgh with unusual blood consistency and a splenic tumor. The first patient was observed in 1841 but was dismissed as unusual until 1844 when a 28-year-old man presented with similar symptoms. John Bennett was given permission to perform an autopsy and study the pathology of this second case. Bennett had attended the lectures on clinical microscopy given by Alfred Donné in Paris and supported Donné’s ideas to use the microscope as a clinical instrument. His report entitled “Case of hypertrophy of the spleen and liver in which death took place from suppuration of the blood” was published in the “Edinburgh Medical and Surgical Journal” in October 1845[19]. The symptoms described together with the extensive post mortem report would today be diagnosed as chronic granulocytic leukemia. His drawings were the first illustrations of the blood cells of a patient with leukemia[20]. The second case of leukemia, published 6 wk later, was reported by Virchow[18] (Figure 4), a demonstrator in pathological anatomy at the Charité Hospital in Berlin, who described a similar case with enlargement of the spleen specifying, however, that the excess of cells was not purulent matter but instead originated in the blood. A 50-year-old woman was admitted to the Charité Hospital in Berlin complaining of fatigue, nosebleeds, swelling of the legs and abdomen, and died within 4 mo. Virchow noted the enlarged spleen and liver, but also described blood vessels filled with material resembling pus. Virchow described the disparity between white and red blood cells as “weisses blut” (white blood). Few years later, Henry Fuller, a physician at St George’s Hospital in London described the first case of childhood leukemia[21]. In 1852, Bennett published the first data collection of 35 cases of leukemia or cases which might suggest leukemia. These first series demonstrated a wider geographical distribution of the disease.

Figure 1 Alfred Velpeau (1795-1867). A: Alfred Armand Louis Marie Velpeau was born on 18 May 1795 in the Touraine village of Bréches in France, where his father was a farrier. He was expected to follow his father’s footsteps, but a chance event changed his life. Interested in medicine, in an attempt to dispel the sadness of a depressed young girl, he poisoned her with hellebore. The local physician called for help was so impressed by his knowledge and intelligence that he introduced him to Vincent Gourand, surgeon at the hospital of Tours, who in turn passed him to Pierre-Fidéle Bretonneau in 1816; B: Velpeau was 21 years old[49,50]. Bretonneau was one of the outstanding physicians of his day in France. He quickly recognized the exceptional talent of his young assistant, treated him like a son, and trained him in clinical medicine and pathology. By 1819, Velpeau was “officier de santé” at the hospital. In 1820, Bretonneau sent him to Paris and obtained for him a position in the Saint-Louis hospital. There Velpeau gained both the anatomy and physiology prizes, while also teaching junior medical students. In 1823, Velpeau qualified and was appointed “agrégé de medicine” with honors, writing his thesis in Latin under the direction of Laennec on intermittent and chronic fevers, based on studies made with Bretonneau in Tours. At the age of 29 years, Velpeau came to be appointed to the junior surgical staff of various hospitals: Saint-Antoine, La Pitié, and La Charité. In 1828, he passed the “Chirurgical”, a higher degree in surgery, and was appointed surgeon to La Pitié. Five years later, he took the university chair of clinical surgery, a position he then held for the next 33 years. Throughout his life, his work was enormous. His published works included 340 titles. There were texts on surgical anatomy, obstetrics, operative medicine, embryology, and diseases of the uterus and breast. Velpeau’s “hernia”, “canal”, “deformity”, and a “pressure bandage” for the treatment of phlebitis and burns are among the items linked with his name that have come down to us. Velpeau was elected to the Academy of Medicine in 1832 and to the prestigious Academy of Science in 1843. In 1860 honoured and famous, he visited Bréches, where he had been born. He gave a substantial sum of money to renovate the village church; C: His generosity is still remembered in a stained glass window there, in which he is represented in his professional dress with the inscription “Hommage de reconnaissance au Docteur Velpeau, fondateur de cette église”. In 1867, Velpeau caught flu. He died on 24^th of August, few days after performing an amputation. His funeral at Saint-Thomas d’Aquin and at the cemetery of Montparnasse was magnificent. It was a fitting end to the life of a man who, from humble origins, had by his own endeavours risen to the front rank of his profession as one of the leading surgeons of the century.

Figure 2 Alfred François Donné (1801-1878). Alfred François Donné was born on 13 September 1801 at Noyon (France). At the age of 20 years, he moved to Paris with his family. Although he had a dislike of law as a career, he embarked on this discipline at his parents’ insistence. He qualified as a lawyer but did not practice, and then became a late starter as a medical student, when he entered the Paris Faculty at the Sorbonne at 25 years of age. A few years later he married Marie Antoinette Joantho, and through his wife, became linked with a well known medical family, the des Essarts. Donné graduated in 1831 at the age of 30 years. His clinical work was concentrated at the Charité hospital under the very experienced clinician Bouillaud. His qualities were recognized by the University Council and they appointed him to the honorary post of sub-librarian to the Faculty of Medicine[51]. In 1836, he made one of his greatest contributions to medicine by discovering the protozoon, Trichomonas vaginalis, in vaginal secretion of Parisien prostitutes[52] and recorded it in a publication addressed to the Academy of Sciences. During this period of intensive research and clinical work, Donné had realized that microscopes were invaluable for the proper illustration and understanding of his lectures. His pediatric successes with feeding difficulties of premature infants led to his election as a Chevalier of the Legion of Honor and his nomination as Inspector General of Medicine. His successful researches into hematology have not received the publicity and fame they deserve. In1842, he announced his discovery of blood platelets to the Academy of Sciences and these were incorporated in his “Atlas de microscopie médicale”[53]. After loosing his office of Inspector General following the 1848 revolution, he was installed in 1853 as the new Rector of the University of Strasbourg, then became in 1855 Rector of the University of Montpellier. During his stay of almost 20 years at Montpellier, he became interested in theories and studies on spontaneous generation. On retiring from office in 1875, he returned to Paris where he died of a cerebral vascular accident on 7 March 1878[51]. He remains virtually unknown outside of France, never obtained the title of professor and was a practical man fond of microscope and laboratory work, but his contribution to medical and scientific progress is inestimable.

Figure 3 John Hughes Bennett (1812-1875). Born in London on 31 August 1812, Bennett (Figure 3) was educated at Exeter (England) and being destined for the medical profession, he entered an apprenticeship with a surgeon in Maidstone (Kent). In 1833, he began his studies in Edinburgh. He published his first article in “London Medical Gazette” in 1836. He graduated in 1837 with the highest honors and gold medal, with a dissertation entitled “The physiology and pathology of the brain”. During the next 4 years, he studied in Paris, where he founded the English-speaking Medical Society, and then in Germany. On his return to Edinburgh in 1841, he published a “Treatise on cod-liver oil as a therapeutic agent” and became physician at the Royal Public Dispensary of Edinburgh. He began to lecture as an extra-academic teacher on histology, drawing attention to the importance of the microscope in the investigation of diseases[54]. In 1843, he was appointed professor of the Institute of Medicine in Edinburgh. Opposed bloodletting and the indiscriminate use of drugs, he was an important influence in changing British therapeutic practices during the second half of the nineteenth century. In 1845, he published a paper entitled “Case of hypertrophy of the spleen and liver in which death took place from suppuration of the blood” in the “Edinburgh Medical and Surgical Journal”. In 1846, he became editor and later proprietor of the Monthly Journal of Medical Science. In 1851, Bennett founded and became the first president of the Physiological Society of Edinburgh. His publications were very numerous including “Lectures on clinical medicine” (1850-1856), “Clinical lectures on the principles and practice of medicine”, “Leucocythaemia” (1852), “Outlines of physiology” (1858), “Pathology and treatment of pulmonary tuberculosis” (1853), “Textbook of physiology” (1871-1872). In 1869, he supported the admission of women medical students in Edinburgh. In 1873, he was elected a member of the French Academy of Medicine and granted recognition by the French government to practice medicine in France. In 1875, after his participation at the meeting of the British Medical Association, he was compelled to have the operation of lithotomy performed. He sank rapidly and died on September 25 at Norwich. In 1901, the University of Edinburgh inaugurated the John Hughes Bennett Laboratory of Experimental Pathology. A second laboratory with his name was opened in 1998, in a joint venture between Britain’s Leukaemia Research Fund, the University of Edinburgh and the Western General Hospital Trust.

Figure 4 Rudolph Virchow (1821-1902). Born in Germany in 1821, he studied medicine and chemistry in Berlin at the Prussian Military Academy from 1839 to 1843. After graduation in 1843, he went to serve as assistant at the Charité Hospital. In 1847, he qualified as a lecturer at the University of Berlin and participated in founding the “Archiv für pathologische anatomie und physiologie and für klinische medizin”. Virchow is credited with multiple important discoveries. Besides his role in recognizing leukemic cells, he was one of the first to accept the work of Robert Remak who showed that the origin of cells was the division of preexisting cells. He also described that an enlarged left supra-clavicular node is one of the earliest signs of gastrointestinal malignancy. He elucidated the mechanism of pulmonary thromboembolism and founded the medical fields of cellular pathology and comparative pathology. He also developed a standard method of autopsy procedure. In 1861, he was elected a foreign member of the Royal Swedish Academy of Sciences. In 1862, he was awarded the Copley Medal. In 1869 Virchow founded the Society of anthropology, ethnology and prehistory which was very influential in coordinating German archaeological research[55,56]. More than a laboratory physician, Virchow was an impassioned advocate for social and political reform. He made himself known as a pronounced democrat in the year of revolution, 1848, and his political activity caused the government to remove him from his position. In 1859, he became a member of the Municipal Council of Berlin, and began his career as a civic reformer. Elected to the Prussian Diet in 1862, he became leader of the Radical or Progressive party, and from 1880 to 1893 he was a member of the Reichstag. He is widely regarded as a pioneer of “social medicine”, focusing on the fact that disease is never purely biological, but often socially derived or spread[57]. Virchow died of heart failure in 1902.

CONTROVERSY ABOUT THE PRIORITY OF THE DISCOVERY

Controversy ensued from 1854 on the naming of the new disease and on the priority of its discovery: Bennett arguing precedence on the basis of the publication date and Virchow[22] suggesting that Bennett’s claim was false because of his incorrect determination of purulent matter. In 1847, Virchow[22] reported a second case and for the first time used the name “leukämie” (leukemia) (the name leukemia is a combination of the Greek words “leukos” and “heima” which means “white blood”) to describe this newly observed disease. This refers to the abundance of white blood cells in the body. In 1852, Bennett recommended the term “leucocythaemia”, meaning increased white blood cells, which was better accepted[23]. In 1854, Kölliker[24] wrote the history of the discovery as it was understood in Germany. Bennett[23] replied in the same journal and defended his position. However, there was mutual respect between the two men. Virchow wrote testimonials in support of Bennett’s candidature for two chairs in Edinburgh in 1848 and then in 1855: “I hereby testify, that having for a long time assiduously followed the very valuable researches of Dr. J Hughes Bennett of Edinburgh, I entertain the highest esteem for his scientific contributions, and consider them as among the most important of those which have enriched the Pathology now struggling for a physiological basis. It appears to me, therefore, that it would be only a well-merited reward, if the Chair of Physiology and Pathology should be given to him, who is able to fill it so worthily”. The question of priority was resolved publicly by Virchow in a lecture he delivered in 1858, in which he stated that Bennett observed a case of indubitable leukemia few months before he saw his first case: “It is moreover the same conclusion which Bennett came to in the much discussed matter of priority between us when he observed a case of individual some months before I saw my first case”.

IDENTIFICATION OF LEUKEMIA AS A SEPARATE DISEASE

Pus and inflammation continued to dominate hematological thoughts until the middle of the nineteenth century. In a third publication (1856), Virchow[25] was credited with concluding that the disorder was not the result of an infectious process but rather was caused by the tissue that produced the white blood cells. The debate centred upon whether leukemia was in fact a separate disease was then conducted by some of the leading physicians in France. Among the minority that supported the autonomy of leukemia, Gabriel Andral, Professor at the University of Paris (Figure 5), proposed the study of the blood as a clinical discipline and defended the use of the microscope in clinical medicine. He was the founder of the science of hematology and is credited with the integration of that science into clinical and investigative medicine. Leukemia gradually became accepted as a distinct disease and clinical and pathological description became more detailed. However, the definition of leukemia was far from precise until a first classification was introduced in 1857 by Nikolaus Friedreich, a pathologist in Würzburg (Figure 6).

Figure 5 Gabriel Andral (1797-1876). Gabriel Andral was born in Paris, the son of a well-known physician who was a member of the academy and personal physician to the French revolutionary leader Jean-Paul Marat. Andral received his doctorate in 1821 with a thesis on expectoration. He was habilitated in 1824 and became “agrégé”. The faculty appointed him professor of hygiene in 1828 on the death of René-Joseph-Hyacinthe Bertin. When baron René-Nicolas-Dufriche Desgenettes retired, he became professor of internal pathology, and in 1839 he succeeded François-Joseph-Victor Broussais in the chair of general pathology and therapy, holding this tenure for 27 years. Besides he was physician at the Charité. In 1823, Andral became a member of the Academy of Medicine. In 1843 he became member of the Institute, and in 1858 was made a commander of the Legion of Honor. In 1866 he abandoned his chair and retired, but still he took part in the advance of science and participated in the transactions of learned societies. He died of a heart condition on February 13, 1873. His main oeuvre “Clinique médicale”, a five-volume work, comprises almost every aspect of medicine. This treatise on general medicine may be considered a summary of French medicine as it had developed in the first decades of the 19^th century. He was the founder of the science of hematology. He is said to be the originator of the word “anemia” and was the first physician to see the potential of chemical analysis of the blood.

Figure 6 Nikolaus Friedreich (1825-1882). Born in Würzburg in 1825, Nikolaus Friedreich received medical training in this city where his father and grandfather had been professor of medicine. He received his doctorate in 1850. He became Assistant at the clinic of clinician Karl Friedrich von Marcus and in 1853 was habilitated as Privatdocent of special pathology and therapy. When Virchow came to Würzburg, Friedreich became an ardent student of this great pathologist and considered abandoning clinical medicine for pathology. In 1857, he was appointed professor of pathological anatomy at Würzburg, and in 1858 moved to the tenure of professor ordinarius of pathology and therapy at Heidelberg, a post which he held for the remainder of his career. He was also director of medical clinic. He took an interest in all branches of medicine, especially neurology. He has left 8 major and 51 larger and smaller treatises, among them a number of monographs. These include works on leukemia. He died in 1882 from a ruptured aortic aneuvrysm.

THE MORPHOLOGICAL ERA OF HEMATOLOGY

During his period of intensive research and clinical work, Donné had realized that microscopes were invaluable for the proper illustration and understanding of his lectures. In spite of hostility, he organized a microscopy course (the first microscopic workshop in medicine) that attracted French as well as foreign students. One of Donné’s foreign students was John Hughes Bennett. After Louis Daguerre, one of the inventors of photography presented his discovery to the Academy of Sciences, Donné become most interested in these photographic reproductions and resolved to incorporate them in his lectures. In 1844 he described his procedure in a book entitled “Cours de microscopie complémentaire des études médicales” which demonstrated the scope of the instrument[16]. The first reported use of the microscope to diagnose leukemia in a living patient was performed by Fuller[26]. The neoplastic nature of leukemia and the origin of the disease in organs of blood formation having been established, the clinical and biological science of hematology were given a tremendous boost in the period between 1878 and 1888, when it became possible to examine the microscopic details of blood cells. The event that provided this opportunity was biological stains. At this point of medical history, despite the fact that iodine, suffron, and ammonia carmine were available for staining tissues and cells, practically no advances were made in morphology of blood cells. The state of hematology from the 1850s to the 1870s was delineated by Beale[27] (1828-1906), a British professor, in a book that went through several editions. Beale[27] illustrated and described “the various corpuscules met within healthy blood”. A major advance in understanding leukemia pathophysiology came in 1877 when Ehrlich[28] (Figure 7) developed a triacid stain and introduced the names acidophil (later changed to eosinophil), basophil and neutrophil for the three different granulocyte types. His techniques initiated the true morphological era of hematology. In 1891, the triacid stain was replaced by the eosine methylene blue stain invented by DL Romanowsky (1861-1921) of St. Petersburg in Russia. The “Romanowsky stain” was further modified by Richard May of Munich in 1902, Gustav Giemsa (1867-1948) of Hamburg in 1905, and JH Wright of Boston in 1906. However, all of these modifications were direct descendants of Ehrlich’s original ideas.

Figure 7 Paul Ehrlich (1854-1915). Paul Ehrlich was born on March 14, 1854 at Strehlen in Silesia (Germany). Educated at the Gymnasium at Breslau and subsequently at the universities of Breslau, Strassburg, Freiburg-im-Breisgau and Leipzig, he obtained his doctorate of medicine in 1878 by means of a dissertation on the theory and practice of staining animal tissues. In 1882 he published his method of staining the tubercle bacillus that Koch had discovered. This method was the basis of the subsequent modifications introduced by Zhiel and Neelson and of the Gram method of staining bacteria. In 1882 Ehrlich became Titular Professor and in 1887 he qualified as a Privatdozent in the faculty of medicine in the University of Berlin. Later he became an Associate Professor and Senior House Physician to the Charité Hospital in Berlin. After becoming Robert Koch’s assistant in 1890, he began immunological studies. He worked out the details of preparing an antitoxin for diphteria, which represented the first use of immunotherapy to specifically treat an infection. In 1896 he was appointed Director of the Institute for the control of therapeutic sera at Steglitz in Berlin, and formulates his side-chain theory of immunity. In 1897 Ehrlich was appointed Public Health Officer at Frankfurt-am-Main and in 1899 became director at the Royal Institute of Experimental Therapy. He then began another phase in his varied researches and devoted to chemotherapy with the aim to find chemical substances which have special affinities for pathogenic organisms and would be “magic bullets” which would go straight to the organisms at which they were aimed. He produced trypan red and established the correct structural formula of atoxyl effective against tryptosomes. This open the way of obtaining new organic compounds with trivalent arsenic. One arsenic drug was found very effective against syphilis. Ehrlich announced it under the name of “Salvarsan”. Another arsenical substance named “Neosalvarsan” became more easily administered. During the later years of his life, Ehrlich was concerned with experimental work on tumors and on his view that sarcoma may develop from carcinoma, also on his theory of athreptic immunity of cancer. In 1908 he shared with Metchnikoff the highest scientific distinction, the Nobel price. On August 20, 1915 a stroke ended his life.

THE ORIGIN OF LEUKEMIA

A vital discovery came in 1868 when Neumann[29] (Figure 8), professor of Pathological Anatomy at Königsberg, reported changes in the bone marrow in leukemia and established the link between the source of blood and the bone marrow. One year later, he published an extensive description of cells in the marrow, and, 1 year later again, that the circulating red cells were derived from an ancestral cell[30]. Around the same time, Bizzozero[31,32] (1846-1901) of Pavia confirmed the observation that non-nucleated red blood cells were formed from nucleated red cells in the bone marrow and that the blood formation function of the bone marrow also included white blood cells. He also identified the platelet[33]. Neumann[34] stated in 1872 that leukemia was a disease of the marrow. Shortly thereafter, Mosler[35] introduced bone marrow puncture as a means of antemortem diagnosis of leukemia. For some years, the mystery remained of how the cells were able to travel through the bone to the circulatory blood system.

Figure 8 Ernst Neumann (1834-1918). Ernst Neumann was born in 1834 at Königsberg, capital of eastern Prussia, as great son of Karl Goofried Hagen (professor of chemistry and pharmacy) and son of Franz Ernst Neumann (a pioneer in the mathematical physics). In 1850, he enrolled at the famous university of Königsberg (Albertina). In 1855, he took his doctors advice degree. After studies in Prague, Berlin (under Rudolf Virchow) and Königsberg, he became a lecturer in medicine in 1859. He got interested in the rising field of pathological anatomie and was appointed professor of pathology at Königsberg in 1866. He described the presence of nucleated red blood cells in bone marrow sap of humans and rabbits obtained by squeezing bones. He was the first to conclude that during postembryonic life, erythropoiesis is taking place in bone marrow. Further studies pointed to the fact that leukocytes are also formed in the bone marrow. He postulated a common stem cell for all hematopoietic cells. He later was made Geheimer Medicinalrath - privy medical councellsor, and received honorary doctorate from the universities of Tübingen and Geneva, in 1898 and 1915. He died in 1918.

THE CONCEPT OF THE “STEM CELLS”

The concept of “stem cells” was first proposed by German zoologists and medical scientists[36]. Adopting the term “stammzelle” from Ernst Haeckel (1834-1919), a controversial Darwinist and professor of zoology at Jena[37], Theodor Boveri (1862-1915) was influential in making these cells known as carriers of the so-called “germ plasm” and as the starting points in embryological development of differentiated body cells as well as germ cells[36]. The essential characteristic of a “stem cell” was a capacity for self-renewal as well as for differentiation into specific types of somatic cells or germ cells. Valentin Haecker (1864-1915), who was made director of the Zoological Institute at the University of Stuttgart and subsequently at the University of Halle, propagated the notion of “pluripotency”, which he ascribed to the “germ plasm” of an organism[38]. In 1896, Artur Pappenheim (1870-1916), who worked at Virchow’s Pathological Institute in Berlin on the formation of red blood cells, developed the conception that “stem cells” or “mother cells” (“mutterzellen”) (as he called them) were embryonic cells that had the potential to differentiate into different cell lines and to form the basis of different types of blood cells[39]. Papenheim also argued that myelocytes and lymphocytes originated from the same “multipotent stem cell’[40]. Julius Cohnheim’s theory was also widely discussed at the end of the nineteenth-century. He defined tumors as “atypical neoplasms of tissue based on an embryonic rudiment”[41]. The lymphocyte was described as the “common, indifferent stem cell” for erythrocytes and granulated granocytes by Dantschakoff[42] or even as the “common stem cell” of all types of blood cells by Maximow[43]. These authors were committed to the “Unitarian” view of the different types of blood cells. In contrast, Ehrlich[44] was the first scholar to propose the “dualist doctrine”, which assimed that the lymphocytes and leucocytes originated from morphologically different precursor cells in different organs: lymph nodes and spleen for the first ones and bone marrow for the second ones. In 1900, the Swiss hematologist Naegeli described a new cell in the myeloid cell line, which he named the myeloblast, as an ancestor of granulocyte cells[45]. He also showed the lymphoblast as an ancestor of lymphocytes. The presence of myeloblasts or lymphoblasts in the circulating blood formed a classic diagnosis of acute leukemia. Monocytic leukemia was first described by Reschad et al[46], and leukemic cells recognized as unusual forms of myeloblasts.

CLASSIFICATION OF LEUKEMIAS

In 1856, Virchow[25] categorized two types of the disease - the splenic and the lymphatic forms - by the starting site of the disease, which we now know as leukemia and lymphoma, respectively. A first classification was introduced in 1857 by Nikolaus Friedreich. A distinction between acute and chronic forms of leukemia was appreciated. He reported at length on a case which he described as acute leukemia, the first time the term was used[47]. Few years later, Mosler added the classification myelogenous leukemia to the splenic and lymphatic types of the disease[48]. The development of a triacid stain by Paul Ehrlich in 1877 simplified the classification of leukemia into the myeloid group and the lymphoid group. Towards the end of the nineteenth century, a clearer definition of the classification of the subtypes of leukemia had been established, but there was still a lack of any form of effective therapy. This is only in 1913 that leukemia was classified into four types: chronic lymphocytic leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, and acute myelogenous leukemia.

CONCLUSION

While the modern era of leukemia chemotherapy began recently, the recognition of leukemias has been mainly recorded in the second part of the nineteenth century. This brief historic review reports the first descriptions of the disease and the major advances in its history from its roots to the beginning of the twentieth century. Although most treatments for leukemia were ineffective until the middle of the twentieth century, it seemed of interest to review some pertinent exemples of the evolution in the knowledge of this disease (relied upon chronology as an organizing framework, while stressing the importance of themes), since our current knowledge about leukemia is still mainly based on the first accounts of scientific and medical discovery. Towards the end of the nineteenth century, a clearer definition of the classification of leukemia had been established leading to different subtypes. These well-defined subtypes of leukemia were used for the development of effective chemotherapy, which has represented the most important advance in leukemia research during the past half century (Figure 9).

Figure 9 First contributors in the history of leukemia. CLL: Chronic lymphocytic leukemia; CML: Chronic myeloid leukemia; ALL: Acute lymphocytic leukemia; AML: Acute myeloid leukemia.