Paul Ehrlich: Pathfinder in Cell Biology 1. Chronicle of His Life and Accomplishments in Immunology,Cancer Research,and Chemotherapy1: Paul Ehrlich's Recipe for Success: “Patience,Ability, Money and Luck”

The paper reviews the life of Paul Ehrlich and his biomedical accomplishments in immunology, cancer research, and chemotherapy. Ehrlich achieved renown as an organic chemist, histologist, hematologist, immunologist, and pharmacologist. He disliked the formality of school but managed to excel in Latin and mathematics. His role model was an older cousin, Carl Welgert, who became a lifelong friend. Ehrlich studied medicine at Breslau, Strasbourg, Freiburg, and Leipzig, coming under the influence of Wilhelm Waldeyer, Julius Cohnheim, Rudolf Heidenhein, and Ferdinand Cohn. As a medical student, Ehrlich was captivated by structural organic chemistry and dyes. When he was 23, his first paper was published on selective staining. His doctoral thesis, “Contribution to the Theory and Practice of Histological Staining” contained most of the germinal ideas that would guide his future career. Most of his early work was centered in Berlin at Charité Hospital, where he did pioneering studies on blood and intravital staining, and at Robert Koch's Institute for Infectious Diseases, where he undertook important investigations in Immunology. Ehrlich became an authority on antitoxin standardization and developed the “side-chain theory” of antibody formation for which he was later awarded the Nobel Prize. He became director of an Institute for Experimental Therapy in Frankfurt where he continued research in immunology and carried out routine serum testing. He developed new lines of investigation in cancer research and originated the field of chemotherapy. Using principles developed in his early work with dyes, he successfully treated certain experimental trypanosomal infections with azo dyes. His crowning accomplishment was discovering that the compound Salvarsan could control human syphilis. Ehrlich's legacy in immunology and chemotherapy is discussed and an intimate portrait is drawn of Ehrlich the person.     

Paul Ehrlich's passion: the origins of his receptor immunology.

In 1897, Paul Ehrlich published a selection theory of antibody formation that anticipated the theories of Jerne and Burnet by some 60 years. Ehrlich introduced into immunology the concept of the interaction of physiologically active substances with specific receptors, an idea that still dominates modern immunological thought. In this paper, we point out how Ehrlich's concept matured over 20 years, while it governed his studies in histological staining, in cell physiology, in hematology, and finally in his major contributions in experimental immunology.     

Elie Metchnikoff's and Paul Ehrlich's impact on infection biology

The 100th anniversary of the Nobel Prize for Medicine to Paul Ehrlich and Elie Metchnikoff gives us a good opportunity to reflect on their research about infectious diseases. Elie Metchnikoff was not only the first to describe phagocytosis of invading pathogens by specialized blood cells - macrophages and neutrophils - he also was interested in the impact of normal flora on well-being and in pre- and probiotic diet and their influence on the normal flora. Paul Ehrlich not only developed the concept of the side-chain theory of antibody formation but also discovered the first chemotherapeutic agent against microbial pathogens through a combination of chemical modification of a lead substance and experimental animal screening on a broad-scale. Hence, they are not only the founders of immunology but also were the first to envisage infection biology as the result of an interplay between host and pathogen.     

Pasteur, Pastorians, and the dawn of immunology: the importance of specificity

Throughout his career, the problems that attracted Louis Pasteur almost invariably involved considerations of specificity of structure and/or of action. Thus, his work on asymmetric crystals showed that chemical form not only specifies crystalline structure, but affects the affinity of ferments as well. In his studies of diseases of silkworms, of beer, and of wine, he could unerringly distinguish with the microscope the specific agents of disease. From this emerged his concept of the specificity of species and against the nonspecificity of spontaneous generation, whence the germ theory of disease. It was in the new field of immunology, however, where the manifestations of an exquisite specificity were most clearly seen. Here, Pasteur's vaccines worked because he chose the specific pathogen in order to induce a specific immunity, and he succeeded each time. But the two most prominent Pastorian successors in immunology, Elie Metchnikoff and Jules Bordet, were not equally successful. Although each contributed significantly to the birth of immunology, each advanced a theory that neglected the principle of specificity and paid a price in consequence. Metchnikoff's phagocytic theory of immunity could not survive the demonstrable specificity of humoral antibodies, while Bordet's physical adsorptive concept of the antibody-cell interaction quickly fell to Paul Ehrlich's demonstration of the stereochemical determination of immunological specificity.     

René Stet’s impact on the study of teleost major histocompatibility genes: evolution from loci to populations

René Josephus Maria Stet pursued a 35-year-long scientific career contributing to human immunology, shrimp immunity and teleost immunity. His most significant contributions, however, were to the field of teleost major histocompatibility (MH) gene research from 1988 to 2007, a field in which he was a leader and an innovator. This review will discuss his work on these genes, highlighting the impact he had in three temporally overlapping phases of his career that can be characterized as MH gene discovery, MH gene function and evolution and population dynamics of teleost MH genes.     

Biology and war--American biology and international science

The German-born American scientist Jacques Loeb (1859-1924) was one of the most important promoters of experimental biology around 1900. He was best known for his physico-chemical explanations of psychological processes and his biotechnological approach to artificial parthenogenesis. At the start of the First World War, Loeb was deeply troubled by the deterioration of the international scientific community and the growing alienation of his German and American colleagues. The aim of this paper is to examine Jacques Loeb's activities aimed at advancing scientific internationalism before, during, and after the war. Loeb, for example, tried to negotiate the publication of German authors in American journals during the war, at a time when this was categorically rejected by publishers. Immediately after the war, he tried to create a specific system aimed at disseminating scientific literature and funding selected European colleagues, in order to overcome what he considered reactionary and hegemonic forces within German scientific institutions. His correspondence with eminent scientists from all over the world (amongst them Albert Einstein, Richard Goldschmidt, Otto Meyerhof, Otto Warburg, Paul Ehrlich, Wolfgang Ostwald, Wilhelm Roux, and Ross Harrison) will serve as a source for the analysis. Special emphasis will be placed on the question how Jacques Loeb integrated epistemology, his particular world view, and his social commitment into the workings of his own life and how he tried to extend his scientific goal of controlling biological systems to the sphere of international science.     

The bacteriophage, its role in immunology: how Macfarlane Burnet's phage research shaped his scientific style

The Australian scientist Frank Macfarlane Burnet-winner of the Nobel Prize in 1960 for his contributions to the understanding of immunological tolerance-is perhaps best recognized as one of the formulators of the clonal selection theory of antibody production, widely regarded as the 'central dogma' of modern immunology. His work in studies in animal virology, particularly the influenza virus, and rickettsial diseases is also well known. Somewhat less known and publicized is Burnet's research on bacteriophages, which he conducted in the first decade of his research career, immediately after completing medical school. For his part, Burnet made valuable contributions to the understanding of the nature of bacteriophages, a matter of considerable debate at the time he began his work. Reciprocally, it was while working on the phages that Burnet developed the scientific styles, the habits of mind and laboratory techniques and practices that characterized him for the rest of his career. Using evidence from Burnet's published work, as well as personal papers from the period he worked on the phages, this paper demonstrates the direct impact that his experiments with phages had on the development of his characteristic scientific style and approaches, which manifested themselves in his later career and theories, and especially in his thinking regarding various immunological problems.     

A tribute to Stanislao Cannizzaro, chemical informationist and photochemist

Stanislao Cannizzaro is known widely for the Cannizzaro reaction, the "disproportionation" of benzaldehyde upon reaction with alkali, for his approach to teaching chemistry, "Sunto di un corso di filosofia chimica", which he presented at the Karlsruhe Congress of 1860, and for his work on the photochemistry of santonin. In Cannizzaro's laboratory two research associates, Giacomo Ciamician and Paul Silber, and a senior colleague, Emanuele Paternó, became acquainted with the basic methods of sunlight-inducd photochemistry.     

Paul Polani and the development of medical genetics

Paul Polani (1914–2006) was one of the key figures internationally in the beginnings and development of medical genetics. Best remembered scientifically for his highly original work on the basis of human sex chromosome disorders, notably Turner syndrome, he pioneered the application of basic biological research to clinical genetic problems. The unit that he founded in 1960, at Guys Hospital, London, provided an unparalleled model for combined research and service in medical genetics across a wide range of laboratory areas and helped to establish medical genetics as a specific discipline.     

On key lesions and all that: a tribute to Paul Lohman

This paper is a tribute to Paul Lohman at the occasion of his retirement from the position of Professor in the Medical Faculty at the Leiden University in The Netherlands and as Director of its Department of Radiation Genetics and Chemical Mutagenesis. Paul's contributions to the science of genetic toxicology are discussed in the context of more recent insights as to how mammalian cells process DNA damage, and how this may lead to cancer and, possibly, aging. Starting with his work on the characterization of UV-induced DNA repair in cultured cells from xeroderma pigmentosum patients and the development of methodology for monitoring the removal of UV-induced lesions in human cells, the concept of the key lesion is introduced. Among the myriad of DNA lesions that can be induced in DNA as a consequence of exposure to a range of natural or synthetic mutagens, key lesions are the ones responsible for subsequent adverse effects, for example, because they give rise to mutation. The development of methods using immunofluorescence microscopy to detect and identify such key lesions and quantitate them at the single cell level, is one of the highlights of Paul's career. Based on the perceived need to evaluate mutational end points in vivo in relation to specific lesions identified by his immunofluorescence methods, Paul subsequently made crucial contributions to the development of the first transgenic mouse model to measure mutations in chromosomally integrated reporter genes. In parallel to his experimental work, Paul greatly contributed to genetic toxicology at the theoretical level by his work on the development and evaluation of methods for assessment or prediction of risks of exposure to environmental mutagens. Finally, Paul has served the discipline of genetic toxicology in a more administrative role in various ways, both locally as one of the founders of the Medical Genetics Center South-West Netherlands and internationally by playing a prominent role in organizations such as ICPEMC. Here, his numerous contributions to the journal Mutation Research, both as author on many papers and as Executive Managing Editor should not go unmentioned.     

Restoring grassy ecosystems – Feasible or fiction? An inquisitive Australian's experience in the USA

Many small‐scale projects in Australia suggest that ground‐layer elements of ecosystems can be restored, but scaling up of grassland and grassy understorey restoration has not occurred to date. Paul Gibson‐Roy recently travelled through the USA, where well‐developed markets for restoration have created a large, financially viable native‐herbaceous seed production and restoration sector. Here, he shares his observations, which show how much about the USA situation can be a model and inspiration for Australian grassy ecosystem restoration.     

The Case of Paul Kammerer: Evolution and Experimentation in the Early 20th Century

To some, a misguided Lamarckian and a fraud, to others a martyr in the fight against Darwinism, the Viennese zoologist Paul Kammerer (1880–1926) remains one of the most controversial scientists of the early 20th century. Here his work is reconsidered in light of turn-of-the-century problems in evolutionary theory and experimental methodology, as seen from Kammerer’s perspective in Vienna. Kammerer emerges not as an opponent of Darwinism, but as one would-be modernizer of the 19th-century theory, which had included a role for the inheritance of acquired characteristics. Kammerer attempted a synthesis of Darwinism with genetics and the chromosome theory, while retaining the modifying effects of the environment as the main source of favorable variation, and he developed his program of experimentation to support it. Kammerer never had a regular university position, but worked at a private experimental laboratory, with sidelines as a teacher and a popular writer and lecturer. On the lecture circuit he held forth on the significance of his science for understanding and furthering cultural evolution and he satisfied his passion for the arts and performance. In his dual career as researcher and popularizer, he did not always follow academic convention. In the contentious and rapidly changing fields of heredity and evolution, some of his stances and practices, as well as his outsider status and part-Jewish background, aroused suspicion and set the stage for the scandal that ended his career and prompted his suicide.     

From the laboratory to the patient and back--an interview with Marc Mareel. Interview by Marc E. Bracke

The career of Marc Mareel is a synthesis of scientific research and clinical activity. During his medical studies, he already made his first enthusiastic steps in research via experimental work on avian developmental biology. Later, during his training as a radiotherapist, he founded his own laboratory for experimental cancer research. There he built up his international reputation as a pioneer in invasion research. Although invasion is the hallmark of tumor malignancy, he also kept an open mind about invasion in non-cancer conditions, such as in placental behavior, developmental biology, immunology and parasitology. His contribution to our understanding of invasion mechanisms has been both technical and conceptual. A number of assays have been developed in his lab, such as the embryonic chick heart and collagen gel invasion models, that have been (and still are) useful for many other research teams. He also contributed to the discovery of a number of key elements in the process of invasion, such as the stromal influence (including its extracellular matrix) and the cadherin family of cell-cell adhesion molecules. Concerning metastasis formation, he developed the original concept that a number of interacting eco-systems are implicated, such as the primary tumor, regional lymph nodes, the bone marrow and the (pre)metastatic niches in distant organs. Since his retirement, Marc Mareel has continued to integrate clinical practice with research creativity. He favours the idea of translational research bringing the results of laboratory findings to medical applications, and exploiting the feedback to the laboratory. The team in the Laboratory of Experimental Cancer Research at Ghent University currently consists of about 25 collaborators, who continue to appreciate his inspiring ideas and suggestions.     

Human Natures: Genes, Cultures, and the Human Prospect

Human Natures: Genes, Cultures, and the Human Prospect. Paul R. Ehrlich. Washington, DC: Island Press, 2000. 31 pp.     

Paul Bert, scientist and politician

Paul Bert worked with Claude Bernard, one of the leading physiologists of the 19th century. In his laboratory at the Collège de France in Paris, Paul Bert carried out fascinating experiments in particular on respiratory processes, leading him to publish "La pression barométrique" in 1878. In this book are recalled his discovery of oxygen pressure decrease with altitude, divers diseases, the improved safety protocols in hyperbaric conditions, and the first development of gas anaesthetics for surgery. He was the third President of the Société de Biologie. Paul Bert was also a politician with strong convictions. Minister of Education under Gambetta's short term government, he initiated the fight for social equality and secular education and became one of the most prestigious figures of the developing socialist party. He received many distinctions and was given a state funeral.     

Charles Janeway Jr.

N.A. Mitchison pays tribute to Charles Janeway's contribution to the rapidly developing field of T-cell immunology marked by a prescience that kept his colleagues closely following his work and views about the wider field.     

Review

The Collected Papers of Paul Ehrlich. (in four volumes). Compiled and edited by F. H immelweit with the assistance of M artha M arquardt , under the editorial direction of S ir H enry D ale .     

Can epigenetics solve the case of the midwife toad?--a comment on Vargas

In a recent article in this journal, A. O. Vargas (2009. J Exp Zool B (Mol Dev Evol) 312:667-678) suggests to interpret the controversial midwife toad experiments of the early 20th century zoologist Paul Kammerer in the context of epigenetic inheritance. For information on Kammerer's work he resorts to a popular science book (Kammerer, '24. The Inheritance of Acquired Characteristics). However, the study of Kammerer's original publications reveals that there are substantial misunderstandings in Vargas' treatment of the subject. While Vargas' general idea-invoking epigenetic effects as an explanation of Kammerer's findings-remains attractive, at least two key aspects of his model need to be revised. Clarification of these issues is an important prerequisite for any experimental design with the aim to (dis)prove Kammerer and to establish a (potential) epigenetic basis of his observations about the mating behavior in midwife toads.     

The virtue of being too early: Paul A. Weiss and 'axonal transport'

The essay introduces how Paul A. Weiss (1898-1989) analyzed his data on neuronal outgrowth and axonal transport, supported by constriction experiments of thousands of living mature nerve fibers. At the University of Chicago his group measured the steady proximo-distal flow of nerve fibers. To visualize the data he used tissue culturing, light microscopy, radioactive tracers, time-lapse motion pictures and electronmicroscopy. The work resulted in the discovery of fasciculation of outgrowing nerves and a computation of the rate of axonal transport, published in a classical article in 1948. He stated that the outgrowth of nerve fibers occurs from nerve centers in their nucleated cell bodies by fasciculation and protein synthesis. However, at that time one suspected the published microphotograph to be an idealized image and, therefore, did not accept the analysis, or the 'new' knowledge. In the mid 1960s the improved technique of autoradiography confirmed in an indirect way Weiss data and analysis of axonal transport. The objective here is to show (1) how Weiss employed the visibility of micrographs and drawings to corroborate his observations and analysis on axonal dynamics, and (2) to offer some tentative suggestions why his colleagues did not accept the 'neuro-images' as an evidence of new knowledge.     

Schistosome immunology: more questions than answers

The past 30 years have seen research on the immunology of schistosomiasis move to encompass studies of responses in naturally exposed human populations, in addition to the studies in animal model systems. While animal systems still retain an important place in research on the immunology of schistosomiasis, recent debate has centred on aspects of human immunological responses that may or may not be associated with resistance or susceptibility to infection. In this article, Paul Hagan, Patricia Ndhlovu and David Dunne take stock of the present state of knowledge and offer their views on prospects for the future.