Universidad de Murcia, Spain (Winter 2013)
According to Alfred Nobel’s (1833–1896) last will and testament, signed on November 27, 1895, the largest share of his fortune would be dedicated to a series of awards bestowed on those people who deserved great merit for their intensive work in favor of mankind. That year the Nobel Prize was born, which, year after year, has increased in fame and prestige. One of the established categories sought to recognize “the person who shall have the most important discovery within the domain of physiology or medicine.”
The promulgation of the award coincided with an explosion of great advances in microbiology, which reached their coming of age at the beginning of the 20th century. It became one of the central basic sciences from which other disciplines—such as biochemistry, immunology, virology and protozoology—were later derived.1,2 This unprecedented progress took within 60 years, roughly between 1850 and 1915. It was then that remarkable advances demonstrated the crucial role played by microscopic organisms in every facet of the biosphere. This period is thus named the Golden Age of Microbiology. In what follows, some of the outstanding achievements will be reviewed.
Up until this crucial moment, almost 150 years had passed since A. van Leeuwenhoek (1632–1723) constructed rudimentary microscopes and observed a completely new world of invisible and ubiquitous beings, the world of the animalcules. Although Leeuwenhoek documented his findings and conferred on them a scientific focus, maintaining passionate correspondence with the Royal Society of London, advancement of knowledge of those strange microbes was at first slow. The intrinsic invisibility of the microbes to the human eye impeded the study. Therefore, before microbiology was to come of age, it was necessary to perfect the optical technology leading to the invention of compound microscopes, but above all, to develop methods that would permit the dying of preparations, the sterilization of equipment, and the disinfection of tools to cultivate and aseptically transfer the microorganisms.
|Louis Pasteur (A) and Robert Koch (B)|
In France, a seminal figure emerged who propelled the new discipline, Louis Pasteur (1822–1895). Together with a prestigious school that had risen around him, Pasteur discovered the complex metabolism of the microscopic organisms and had a decisive role in the transformations of the organic matter (fermentation and putrefaction), including the discovery of life in the absence of air. In an elegant and unequivocal way, Pasteur resolved the classic controversy about spontaneous generation, introducing the key concept of sterility (1869). Subsequently, Ferdinand Cohn (1828–1898) and Johan Tyndall (1820–1893), corroborated its validity, discovering the existence of thermo–resistant bacterial structures and developing methods for their correct treatment. However, in the middle of the 19th century, the origin of infectious diseases remained an unresolved problem and the word “infection” was synonymous with curse. A panoply of esoteric beliefs based on superstitions and witchcraft coexisted with the ancient theories of Hippocrates and Galen, relating the appearance of illnesses to geography, climate, nutrition, and lifestyle. The innovative concept of illnesses provoked by “invisible seeds,” proposed by Fracastoro, or the transmission of infection by means of “contagion” had not yet taken root in the scientific community—in spite of the observations of A. Bassi (1773–1856) in 1835 and of M.J. Berkely (1812–1886) that silkworm disease and the mildew of the Irish potato were caused by fungus.
Nevertheless, the question of whether finding a pathogen in a patient implicated causality or was the consequence of the infection process, remained subject to debate. A definitive contribution came from a doctor of Hungarian origin, P.I. Semmelweis (1818–1865), who introduced simple aseptic practices (hand washing) in obstetrics as an effective method of controlling postnatal fevers. J. Snow (1813–1858), pioneer of urban epidemiology, was able to demonstrate how public fountains were the origin of severe outbreaks of cholera in London and implemented sanitation measures in cities. Equally important were the aseptic prophylaxis measures advocated by the British surgeon Joseph Lister (1827–1912) who by the introduction of carbolic acid (phenol), greatly reduced surgical infections.
In this field, Pasteur again would play a decisive role in establishing in 1869 that pébrine, a disease harmful to silkworms, was caused by a protozoa (Nosema bombycis). This redirected his scientific activity towards studying microbial germs that infected healthy organisms and caused disease. As fruit of his investigation, Pasteur obtained vaccines that effectively combated sheep anthrax and the rabies virus through the procedure of ageing the cultures by reseeding of the pathogen. Pasteur also introduced the heat–treatment techniques known as pasteurization, now widely used in the food industry.
Another outstanding figure in the discovery of the microbial origin of infectious diseases was the doctor and scientist Robert Koch (1843–1910). On the peripheries of his studies concerned with the causal agents of carbuncle (anthrax), cholera, and tuberculosis, his work was awarded the Nobel Prize (see below): the conceptual, methodological and technical contributions of Koch proved essential to microbiology’s spectacular progress during the Golden Age. Koch developed the critical concept of “pure culture,” permitting one to study each microorganism in isolation in a complex mixture. He also introduced the culture medium, nutritionally equivalent to the constituents of bodily fluids, to favor a satisfactory growth of its bacteria.
An important conceptual modification was the solidification of the environments by means of adding gelatine to the nutritive mixtures at the beginning and agar at the end. With respect to the gelatine, the agar had the enormous advantage of being a cement polymer that liquefied at 100°C and, once melted, did not solidify until the temperature fell below 50–60°C. The school of Koch also developed a simple but crucial tool for microbiology’s advancement: the petri dish (in honor of its inventor, Richard Petri), which allowed microbes to be inoculated and incubated, replacing the awkward glass plates covered with a bell jar that had been used up to that point.
In another awe–inspiring contribution, Koch incorporated coloring agents derived from aniline, specific to the staining of bacteria (methylene blue, fuchsia, and crystal violet), which today are still used in microbiology laboratories. In collaboration with the powerful German optical industry (Abbé and Zeiss), they developed microscopes equipped with lenses without chromatic aberrations. A seed of this work was the development of microphotography, which allowed Koch’s school to document and present adequate observations and discoveries, independent of the place of work.3
Consequently, when Koch accepted the position of director at the bacteriology laboratory in the Imperial Health Office in Berlin, his team had the tools needed to study bacteria as agents responsible for grave human illnesses. These included not only precise staining methods, observation, and cultivation in solid environments, but also the techniques of sterilization and disinfection, the use of incubation cases and stoves, as models for animal experimentation.
Using this essential methodological and technical arsenal, in 1873 Koch undertook the study of Bacillus anthracis, based on some previous evidence (Davaine 1868; Eberth 1872) suggesting the causal role of these bacteria in anthrax. Applying the methodology of pure cultures, Koch isolated individual colonies of B. anthracis and successfully propagated them in vitro. His laboratory had the first microphotographs of preparations fixed and stained with methylene blue and defined the conditions for the formation and germination of the endospores, differentiated structures of vegetable cells possessing great resistance to a variety of agents.
However, Koch’s major interest at this time was to prove the operational capacity of those requirements proposed by his first teacher, Jacob Henle (1809–1885), to unequivocally establish the contagious nature of a patient. Working alone in his small private laboratory outside of the university,3 Koch succeeded in proving the validity of various postulates that established the presence of live contagion in sick organisms, including the isolation in pure culture of this contagion from the host and the reproduction of disease when transferring the contagion to a susceptible host, with a later re–isolation. In his famous publications: Die Äethiologie der Tuberkulose,4,5 Koch formulated the criteria, which in strict rigour should be denominated “The postulates of Koch-Henle.”
Later, Koch embarked on his pivotal studies concerned with the identification of the tuberculosis bacteria (Mycobacterium tuberculosis) and that of cholera (Vibrio cholerae) in India (see below). In addition, he postulated the principle of specific biological bacterial infection, deducing that each infectious disease was caused by distinct and unique bacteria.
The subsequent discovery of new infectious agents made certain light modifications necessary in the formulation of the Koch-Henle postulates. Thus, T.M. Rivers extended its validity to viruses6 by their nature as obligate intracellular pathogens. In 1988, S. Falkow formulated a molecular version with the end of clarifying which bacterial genes are capable of conferring pathogen capacity to microorganisms.7,8 Curiously, by means of the strict application of the Koch-Henle postulates, the Australians B.J. Marshall and J.R. Warren were able to demonstrate unequivocally that the bacteria Helicobacter pylori was the etiological agent causing peptic ulcers.9 They were awarded the Nobel Prize in 2005, exactly one century after it was conferred to R. Koch.10
The Golden Age of Microbiology reached its zenith with the application of these simple postulates. The laboratory of bacteriology at the Imperial Health Office in Berlin, conclusively demonstrated how specific microbes caused grave illnesses with high morbidity and mortality. In parallel, the decisive role of immunity and the prevention and treatment of severe pathologies was made clear, fostering the development of chemotherapy and surgery, as well as of prophylactic vaccines. In this way, at the beginning of the 20th century, the casual pathogen agents of various devastating pathologies had been identified, cases such as gonorrhea (Neisser 1879), cholera (Koch 1883), diphtheria (Loeffler 1884), tetanus (Nicolaier 1885 and Kitasato 1889), meningitis (Weichselbaun 1887), the bubonic plague (Yersin 1894), and syphilis (Schaudinn and Hoffman 1905).
Microbiologists awarded the Nobel Prize (1901–1910)
Taking this picture as a whole, it was not surprising that after the initial launch in 1901, the first designations corresponding to the so–titled Nobel Prize for Physiology or Medicine, were intended to reward new and capital advances in our understanding of the essential role played by the microscopic organisms as causative agents of infectious diseases. In the next paragraphs, I will survey the laureates in microbiology during this decade (1901–1910), highlighting the main advances which led the Swedish Academy to grant the award.
Emil A. von Behring (1901)
|Emil A. von Behring was awarded the first Nobel Laureate in Physiology or Medicine (1901).|
The microbiologist Emil von Behring (1854–1917) was the first laureate to be awarded with the Nobel Prize, in 1901. Trained as a military doctor in Berlin, he at first worked as a surgeon in several military campaigns. However, his practical experience with wounded soldiers led him to become interested in problems related to septic illnesses and the effect of certain chemical substances that do not kill germs but render the toxins they secrete inactive. In 1889, von Behring left the army to enlist as an assistant to R. Koch in the famed Institute of Infectious Diseases in Berlin. Subsequently, he became professor in the University of Halle (1894) and in 1895 he moved to the Institute of Hygiene in Marburg.
The pioneering studies of von Behring in partnership with the Japanese bacteriologist Shibasaburo Kitasato (1853–1931) were inspirational in the field of immunology. Both discovered that the bacillus of diphtheria produced a toxic substance. The injection of treated serum containing the inactive toxin in rabbits induced a protective state. Therefore, receptor animals should produce some substance capable of neutralizing the toxin and controlling the infection (antitoxins). These advances were applicable to other infectious diseases such as tetanus. A key point was to prove the specific nature of the reaction: the antitoxins that battled diphtheria did not protect against tetanus and vice versa. These serums could be successfully applied to the immunization of other healthy animals and people, being the basis of serum therapy.11
The conceptual importance of this discovery was enormous, clearly demonstrating that resistance to diseases is not an intrinsic property of bodily cells, but that it resides in the specific and induced components of blood serum, free of cells. This contribution was recognized in the laudation of the Karolinska Institute, justifying his selection: “for his work on serum therapy, especially its application against diphtheria, by which he has opened a new road in the domain of medical science.”10
Questions concerning Kitasato’s fall into obscurity
Since the first edition and throughout its long and extensive course, the awarding of the Nobel Prize for Physiology and Medicine has not been without controversy. To begin then with an intriguing question: Why did Kitasato not share the Nobel with von Behring in 1901? This Japanese scientist moved to Germany to do research in Koch’s laboratory and is considered to be the first scientist to isolate the tetanus bacillus in pure culture, developing an anti–tetanus serum with von Behring and stimulating passive immunity in animals. He also worked at obtaining antitoxins effective against tuberculosis and anthrax.
Kitasato moved back to Japan in 1891 and began a notable scientific career by founding the Institute for the Study of Infectious Diseases alongside A. von Wasserman, one of his first assistants. Among other achievements, Kitasato identified, in Hong Kong, the bacteria that caused the bubonic plague, independently of Yersin, as well as the etiological agent of dysentery alongside his collaborator Shiga Kioshi. His exclusion from the first election in 1901 has been an object of controversy.12 It is argued that perhaps the committee interpreted the words of Alfred Nobel—“the person who has made the most important discovery”—too literally. In any case, while von Behring published his paper on diphtheria alone,13 the decisive importance of the anti–tetanus serum11 was not recognized until the outbreak of the First World War.
Ronald Ross (1902)
|Ronald Ross (A) and Charles L. A. Laveran (B) were awarded the Nobel Prize in Medicine in 1902 and 1907 for their research into malaria.|
One collateral aspect following from the microbial theory of disease was that the European colonial powers saw themselves obliged to study the tropical endemics infections in Africa and Asia, which were devastating their troops. Their involvement led to the demystification of the biological cycles of infectious organisms, often complex and of a non–bacterial nature. In this way, Koch himself identified Asian cholera in 1883, followed by discoveries of the causes of malaria (Schaudin 1901) and Maltese fever (Bruce 1897).
In 1902, the Nobel Prize was given to the British doctor Ronald Ross (1857–1932), “for his work on Malaria, by which he has shown how it enters the organism and thereby has laid the foundation for successful research on this disease and methods of combating it.”10 Though born in Nepal, Ross studied medicine in London, acquiring simultaneously a solid foundation in mathematics and zoology; he was equally fond of art and literature. After failing in his exams to obtain a position in the British MRCS, he enlisted in the Indian Medical Service (1881). In this period his dedication to research was almost absent as he lived like a doctor of the British aristocracy (ie, playing golf, fishing, shooting, etc). However, he did write his first novel, The Child of the Ocean.
It would be in his second stay in India when Ross, supplied with microscopes and instruments of microbiology, began his studies of malaria. This came as a suggestion from the scientist P. Manson, who supported the proposal made by the Frenchman C. A. Laveran (see below) concerning the function of insects as carriers of the plague. Ross dealt with one of the most pressing issues of the disease: the transmission process and the development of symptoms. His first observations correctly held that the Anopheles mosquito was the host of malaria. Later, through his classical experiments with birds, he demonstrated how the disease was contracted by bites from the female mosquito, which allowed the development of the parasite’s eggs. Ross then focused on the study of the distinct phases that made up the biological cycle of the pathogen. For their part, and having mutual knowledge of their work, a group of reputed Italian malariologists (Bignami, Bastianelli, Celli, Golgi, Grassi and Marchiafava) verified the transmission of human malaria by mosquitoes and completed the biological cycle of Plasmodium falciparum.14
Ross returned to England and incorporated himself in the Liverpool School of Tropical Medicine and later moved to King’s College Hospital in London. He completed his work by introducing hygienic methods of prevention and massive eradication campaigns in the South of Europe and the North of Africa. It deserves to be mentioned that Ronald Ross had an elevated cultural and intellectual level thanks to his training in mathematics. He designed complicated models that he applied in his epidemiological studies; also, he had a marked literary inclination that led him to publish novels and books of poetry. However, his last years were shadowed by a certain controversy concerning the source of the discoveries between Ross, his mentor P. Mason, and the Italian malariologists.
Robert Koch (1905)
Despite all the exceptional conceptual, methodological, and technical contributions Koch made—reviewed above—which by themselves would constitute an indisputable merit that would justify, from the outset, the Nobel distinction, it would not be until 1905 that this brilliant investigator was presented the award for his specific work on tuberculosis, so briefly synthesized by the Karolinska Institute: “for his investigations and discoveries in relation to tuberculosis.”10 For this reason, Koch’s work with the tuberculosis bacillus will be reviewed in what follows.
In the 19th century, tuberculosis represented one of the most devastating health threats in all of Europe, with elevated mortality rates in big cities and affecting essentially newborns, adolescents, and the elderly.3 When Koch took up the problem, there was already evidence that pointed to the contagious nature of the disease. However, initially Koch had to face two types of difficulty: (i) in the conceptual order, the ideas of Virchow relating defects and poor functioning of the organism as the cause of the pathology still prevailed, ruling out the existence of external inducing agents, and (ii) unforeseen consequences of the investigation itself, given that Mycobacterium tuberculosis is one of the most complicated microbes to grow and stain in the laboratory.
With the end of proving his hypothesis, he strictly followed the protocol of the Koch-Henle postulates. In this way, he first identified the bacillus dyed in sick patients’ tissues, after using distinct staining procedures (ie, methylene blue, brown vesuvine, heating to 40°C to reduce the length of time, etc), until succeeding in dying the complex and robust wall of the mycobacteria (P. Ehrlich later perfected the method by introducing anilines, see below). Koch also described the macrophages as a reservoir of the bacteria.
To obey the second law (pure culture in the laboratory), Koch had to design complex media containing saline solution, and, after inoculating with selected samples from infected patients (ie, bronchitis, pneumonia or brain and intestinal tuberculosis, etc), he had to wait patiently for at least 10 days until he could check for the appearance of the first faint spots of growth.3 However, after various transfers, he succeeded in obtaining bigger and more numerous colonies. This capacity of propagating individual colonies of bacteria by means of successive sowing in plates of culture, preserving the genotypic and phenotypic identity of the cells, should be considered an underlying advancement of modern cloning techniques.
Following this, many guinea pigs and rabbits, as well as other animal species, were inoculated with tuberculosis from patients or isolated bacilli from the laboratory. The successful infection satisfied the requirements of the third postulate3 and, therefore, unequivocally proved that M. tuberculosis is the bacterium responsible for this life–threatening disease. Following exactly the same procedure, Koch’s laboratory succeeded in isolating and identifying the etiological agent of cholera, introducing hygienic means of control for its prevention as well as treatment and purification of public water systems.
In spite of his colossal work, it is necessary to mention Koch’s great failure with regards to tuberculosis when, in 1890, he announced that he had encountered an effective remedy to fight the disease called “tuberculin.” However, a series of clinical studies demonstrated that tuberculin did not act directly against the bacillus, but stimulated the defensive cells of the host, being the base of delayed–type hypersensitivity. This test is still used today to diagnose individuals infected with tuberculosis. Trials began immediately using tuberculin as a therapeutic vaccine, but the results were clearly unsatisfactory. Very few patients were cured, and in some cases tuberculin seemed to facilitate the bacterial dissemination to organs that previously had not been colonized.3
Charles Louis Alphonse Laveran (1907)
Born into the heart of a French family with a long military tradition, Charles L. A. Laveran (1845–1922) studied medicine in Paris and Strasburg, achieving his doctorate in 1867 with a thesis about nerve regeneration. He participated in the Franco–Prussian War in 1870, acting as a military surgeon in Metz. In 1874 he took a position as professor of diseases in epidemiology in the School of Val-de-Gráce, a position previously occupied by his father and one in which he established an active teaching career.
In 1878, Laveran was sent to Algeria as a military doctor, and he stayed until 1883. At that time, malaria constituted a real epidemic and Laveran began to study the black corpuscles that appeared in the blood of those infected. He discovered the presence of a tiny parasite in all of the patients, and he considered it to be the etiological agent,14 initially calling it Haemamoeba laverani. As often happens, the discovery was met with great skepticism by the scientific community. However, years later its validity was proven by distinct malariologists. R. Ross centered himself in the work of Laveran to support the parasite’s mechanism of transmission (see above).
In 1897, Laveran retired from the army and joined the Pasteur Institute where he dedicated himself to the study of tropical diseases such as trypanosomiasis, sporozoa, and African sleeping sickness. In 1907, he was awarded the Nobel Prize “in recognition of his work on the role played by protozoa in causing diseases.”10He donated half of the prize money to the Pasteur Institute.
In the field of disease transmission by vector mosquitoes, we must also mention the extraordinary work of the Cuban doctor Carlos J. Finlay (yellow fever). Both Laveran and Ross recognized his contributions and supported his candidature.
Paul Ehrlich and Ilya Metchnikov (1908)
|Paul Ehrlich (A) and Ilya Mechnikov (B) shared the Nobel Prize corresponding to physiology or medicine in 1908 for their essential discoveries in the foundation of a new speciality: immunity (immunology).|
In 1908 the second shared Nobel Prize in Medicine (after that given in 1906 to Golgi and Ramón y Cajal) to the German doctor Paul Ehrlich (1854–1915) and Ilya Metchnikiov (1845–1916) a scientist of Ukrainian origin who had settled in France. The justification of their merits was too concise: “In recognition of their work on immunity.”10 However, the contributions recognized carried with them transcendental repercussions of a scientific and clinical order, difficult to foresee within the frame of that historical context as did Prof. K. Horner, Karolinska’s rector. In a memorable speech in honor of the two winners, Horner correctly pointed out that the preventing of these infectious diseases constituted the biggest challenge faced by modern medicine at the beginning of the 20th century. He pointed to two courses of action: (i) Discover and destroy the pathogen agents responsible for the disease (which was being carried out) and (ii) Equip the body with the necessary strength to resist their attacks.15Seeing as Ehrlich and Mechnikov were responsible for distinct contributions, their work will be summarized separately.
Paul Ehrlich and immunity
Ehrlich was born in German Silesia (which now belongs to Poland). He studied medicine in several universities (Breslau, Strasburg, and Freiburg) and received his doctorate at the University of Leipzig with a thesis about the staining of animal tissue using aniline coloring. He described an appropriate method to stain tuberculosis bacillus that was the base used for the subsequent modifications introduced by Ziehl and Neelsen, still used currently as “staining of acidic–alcohol resistance.” In 1890, Koch himself offered Ehrlich a position as an investigative assistant. This stable position allowed him to begin his fundamental work on immunity. Ehrlich showed how specific toxin–antitoxin reactions are accelerated by heat and slowed by cold, due to their chemical character. In collaboration with von Behring, he designed a method to standardize the exact content (measured in units) of antitoxins in saline solution, which established the basis for future procedures for serum typification and its routine use in diagnostic tests. His immunological studies permitted Ehrlich to postulate his crucial “side chain theory,” with the end of explaining the specific immune response and the synthesis of antibodies.
The magic bullet
In 1899, Ehrlich moved to Frankfurt where he began a new important line of investigation, a seed of modern chemotherapy, defined as the control of infectious diseases by treatment with synthetic chemical compounds. Ehrlich took up an old idea, related to the singular property of chemically used drugs whose composition had to be examined in relation with their mode of action and their affinity for cells of the organism against which they were directed. His intention was to obtain chemical substances with elevated affinity towards those pathogens and, simultaneously, innocuous for the host organism that should be capable of preserving their cellular integrity intact (selective toxicity). Ehrlich himself named these peculiar compounds “magic bullets.”
His laboratory tried many substances; although very few of them were effective. The major success was achieved with the oxide of arsenic (atoxyl) against the spirochaete that caused syphilis, despite some adverse effects such as optic atrophy. This achievement provoked a new strategy based on the modification of arsenicals by chemical synthesis, with the end of obtaining safer and more efficient derivatives to treating syphilis, culminating in 1910 with the discovery of the famous salvarsan (composed 606 of all the analyzed series).
In addition, Ehrlich pioneered the introduction of new concepts and methodologies, which were indispensable in chemotherapeutic investigation.16 For example, the simultaneous sampling of a large number of potentially interesting compounds (screening), or the synthesis of a collection of variant molecules from a substance that possesses relevant antimicrobial effects, with the objective of improving its power and diminishing its toxicity. Ehrlich showed the process of metabolic activation, which some drugs experience inside the body, while remaining inactive in vitro.15 In addition, during his initial work on trypanosomes, he detected the impossibility of completely eliminating the microbes after treatment with trypan and atoxyl, and he called attention to the problem of microbial resistance to chemotherapeutics.
Ilya Mechnikov and phagocytosis
Mechnikov was born in Jarkov (Ukraine), where he was a brilliant student, graduating in natural sciences. Later, he would visit diverse German universities (Göttingen and Munich), returning to Russia in 1870 and being named professor of zoology at the University of Odessa.
Mechnikov made a radical turn in his life when he travelled all the way to Messina to continue his previous investigations into compared embryology. He studied starfish larvae and, later, samples of Daphnia, a fresh water crustacean—observing the presence of mobile cells that attack the spores of various pathogenic fungus, deducing that they could serve as part of the defensive system of these organisms.17 He obtained additional proof of phagocytic activity in his microbiological studies with the bacillus that caused carbuncle; in this way he was able to demonstrate that the most virulent strains were capable of resisting attacks on the host organism, while the least infectious were more susceptible.
In 1884, Mechnikov proposed his general theory of phagocytosis, understood as the capacity certain specialized cells possess (principally the leucosis) to protect the integrity of the organism by ingesting and destroying bacteria and other foreign particles. He postulated that phagocytosis was a general mechanism amply developed in the biosphere and conserved in the course of evolution. Mechnikov returned to Odessa and tried to implant Pasteur’s rabies vaccine. However, he found a strong hostility amongst the local population, in part due to the fact that he was not a doctor. In 1888, he left Odessa and went to Paris. There Pasteur offered him a laboratory and a permanent position in the future Pasteur Institute, where Mechnikov stayed for the rest of his life, reaching the position of vice director of the Institute.15
In cooperation with Roux, he undertook an extensive investigation into the transmission mechanisms of syphilis and its treatment (introducing certain techniques that later were used by Ehrlich). He also occupied himself with the microflora common in the human intestine, formulating a peculiar theory stating that the cause of senility was the poisoning of the body through the accumulation of metabolites and waste products released by enteric bacteria. Mechnikov also developed an important career as a scientific writer and thinker and in 1892 published two volumes of the book The Comparative Pathology of Inflammation, which had a notable repercussion in the scientific community.
Microbiology has played an essential role in the development and foundation of modern science from the middle of the 19th century. The study of the microbial world, faced with systematic and multidisciplinary characters, has been the central trunk from which other disciplines were derived. These disciplines presently enjoy a spectacular level of importance: biochemistry, immunology, virology or chemotherapy. The proof of microorganisms as the real etiological agents of infectious diseases marks the zenith of the period between 1850 and 1915 known as the Golden Age of Microbiology. This landmark coincided with the promulgation and promotion of the Nobel Prize in 1901. For this reason, during only the first decade, microbiologists of universal fame were honored with the prestigious award on five occasions. Since then, the contribution of microbiology to scientific knowledge has been of incalculable value, deserving the recognition of the Nobel Prize on several occasions, fulfilling the famous aphorism attributed to Pasteur: “The role of the infinitely small in nature is infinitely great.”
I truly thank my colleague Dr. Rafael Nájera for his critical reading of the manuscript and useful suggestions. I am also indebted to the financial contract provided by Cespa, S.A.
This article is dedicated to Dr. César Nombela for having created a renowned, cohesive and leading research team in the investigation of yeast; for his effort to encourage the development of Spanish microbiology and for his important work as a representative of Spanish science.
- Brock, TD. Milestones in Microbiology. Washington: ASM Press; 1999.
- The microbe’s contribution to biology. International Microbiology. 2006;9(3): 155–172.
- Kaufmann, SHE and Schaible, UE. One-hundredth anniversary of Robert Koch’s Nobel Prize for the discovery of the tubercle bacillus. Trends Microbiol. 2005;13: 469–475.
- Koch, R. Die aetiologie der tuberculose. Mittheilungen aus dem Kiserlichen Gesundheitsamte. 1884;2: 1–88. (English translation in Brock 1999).
- Koch, R. Die aetiologie der tuberculose. Berliner Klinische Wochenschrift. 1882;19: 221–230. (English translation in Brock 1999).
- Rivers, TM. Filterable viruses: a critical review. J Bacteriol. 1927;14: 217–258.
- Falkow, S. Molecular Koch’s postulates applied to microbial pathogenicity. Rev Infect Dis. 1988;10: S274–S276.
- Falkow, S. Molecular Koch’s postulates applied to microbial pathogenicity—a personal recollection 15 years later. Nature Rev Microbiol. 2004;2: 67–72.
- Marshall, BJ and Warren, JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet. 1984;323(8390): 1311–1315.
- Nobel Foundation Web. http://www.nobelprize.org/nobel_prizes/medicine/laureates.html Accessed March, 2012.
- Von Behring, E. and Kitasato, S. Ueber das Zustandekommen der Diphterie—Immunität und der Tetanus—Immunität bei thieren. Deutsche Medizinische Wochenschrift. 1890;16: 1113–1114. (English translation in Brock 1999).
- Kantha, SS. A centennial review; the 1890 tetanus antitoxin paper of von Behring and Kitasato and the related developments. Keio J Med. 1991;40: 35–39.
- Von Behring, E. Untersuchungen über das zustandekommen der Diphteria—Immunität bei thieren. Deutsche Medizinische Wochenschrift. 1890;16: 1145–1148. (English translation in Brock 1999).
- Cox, FE. History of the discovery of the malaria parasites and their vectors. Parasites & Vectors. 2010;3: 5.
- Argüelles, JC. Los microbios y el premio Nobel de medicina en 1908 (Ehrlich y Mechnikov). Anales de Biología. 2008;30: 65–71.
- Ehrlich, P. Ueber moderne chemotherapie. Beiträge zur experimentellen pathologie und chemotherapie. Akademische Verlagsgesellschaft m.b.H.: Leipzig; 1908, 167–202. (English translation in Brock 1999).
- Mechnikov, E. Ueber eine sprosspilzkrank heit der Daphnien. Beitrag zur Lehre über den kampf der phagocyten gegen krankheitserreger. Archiv f. pahtologische Anatomie und Physiologie und f. klinische medicin. 1884;96: 177–195. (English translation in Brock 1999).
JUAN–CARLOS ARGÜELLES, PhD, full professor of microbiology, tries to engage an audience in polemic questions concerning the ethical and humanistic aspects of medicine and the social repercussions of scientific advances. In this respect, he has published articles in El País and writes regularly for La Verdad. Argüelles is the author of two books on historical assays (written in Spanish): La Doble Hélice de ADN: mito y realidad, in which the main facts and the controversy surrounding the discovery of the “Double Helix” by Watson & Crack are surveyed, and El Milagro del rector Lousatu. The second book deals with the origins of the IVº historical foundation of the University of Murcia in 1915. In addition, his articles in newspapers devoted to medicine and general science have been collected in the book La inspiración del genio.