Jules Bordet: The Science Behind Complement Fixation and Immune Mechanisms (1919)

Nobel Information Card

• Award Year: 1919
• Field: Physiology or Medicine
• Award Rationale: For his discoveries relating to immunity.
• Birth: 13 June 1870, Soignies, Belgium
• Death: 6 April 1961, Brussels, Belgium
• Nationality: Belgian
• Institution: Pasteur Institute of Brussels

Life and Education

Jules Jean Baptiste Vincent Bordet was born on June 13, 1870, in Soignies, Belgium. His father, Charles-Henri Bordet, was a school teacher. His mother, Célestine Vandenabeele, came from a humble family. Young Julius, when he moved to Brussels with his family, was inspired by the city's vibrant intellectual atmosphere. Bordet completed his secondary education at the Athénée Royal in Brussels, showing a strong interest in natural sciences from an early age.

In 1886, Bordet enrolled at the Free University of Brussels (Université Libre de Bruxelles) Faculty of Medicine, where he developed a particular interest in microbiology and immunology during his medical studies. He received his medical degree at just twenty-two years old in 1892. With a grant from the Belgian government, he went to the Pasteur Institute in Paris, where he joined Ilya Mechnikov's laboratory. At that time, Mechnikov was intensely working on phagocytosis theory, which played a decisive role in shaping Bordet's scientific formation.

During his seven years at the Pasteur Institute (1894-1901), Bordet made his most significant discoveries in immunology. This period in Paris was when Bordet's scientific identity took shape. Although influenced by Mechnikov's cellular immunity approach, Bordet focused his research on humoral (fluid) immune mechanisms. This preference placed Bordet in a unique position between Ehrlich's German school and Mechnikov's French school.

In 1901, Bordet returned to Brussels and was appointed as the director of the newly established Pasteur Institute in the province of Brabant. This institute became the central hub for Bordet's scientific activities for the remainder of his life. Under Bordet's management, the Brussels Pasteur Institute gained international recognition as a leading research center. In 1907, he also began teaching bacteriology as a professor at the Free University of Brussels.

Bordet's personal life was in harmony with his scientific career. He married Marthe Levoz in 1899 and had one son and two daughters from this marriage. His son Paul Bordet would also become a microbiologist. Bordet was humble, calm, and diligent; he led a life dedicated entirely to science, far removed from showiness.

Scientific Work

Bordet's scientific career centered around elucidating the mechanisms by which blood sera eliminate bacteria. In the 1890s, immunology was rocked by intense debates between cellular (Mechnikov) and humoral (Ehrlich) immunity camps. Bordet made significant contributions to this debate through experimental studies of humoral immune mechanisms.

In 1895, Bordet discovered that serum bacteriolysis occurs through the collaboration of two separate factors. The capacity of immune serum (serum from sensitized animals) to eliminate bacteria was shown to be possible not only with a heat-resistant component (antibody/ sensitizer), but also with a heat-sensitive component (alexin/complement) together. When the serum was heated to 56 degrees Celsius, its bactericidal activity was lost; however, when fresh normal serum was added, this activity was regained. This finding proved that bacteriolysis requires a two-component system.

Bordet named the heat-sensitive component alexin (it would later be renamed complement by Ehrlich). Alexin was a non-specific factor found in all normal sera. The antibody, on the other hand, was a specific factor produced as a result of the immune response. Bacteriolysis followed a mechanism in which the antibody binds to the bacterium and the complement then attaches to this antibody-bacterium complex, bringing about cell lysis.

In 1898, Bordet discovered that hemolysis (the breakdown of red blood cells) shared the same mechanism as bacteriolysis. When foreign red blood cells were injected into an animal, antibodies (hemolysins) forming in its serum to break down those cells were observed. Like bacteriolysis, hemolysis required both the presence of an antibody and a complement. This observation highlighted the universality of immune mechanisms.

The Discovery That Led to the Nobel Prize

The most effective discovery by Bordet was the complement fixation test he developed with his colleague Octave Gengou in 1901. This test made it possible to indirectly detect the antibody-antigen reaction through a serological method and revolutionized laboratory diagnosis of infectious diseases.

The principle behind the complement fixation test was as follows: when an antibody and antigen came together, the complement bound to this complex (became fixed). If complement fixation had occurred, there would be no free complement left in the environment. This situation could be detected using an indicator system. Bordet and Gengou used sensitized sheep red blood cells as indicators: if free complement was present, hemolysis occurred (positive control), while if complement was fixed, hemolysis did not occur (negative result). The absence of hemolysis indicated that the desired antibody-antigen reaction had taken place.

This was an extremely sensitive and versatile diagnostic tool. August von Wassermann applied the Bordet-Gengou principle to syphilis diagnosis and developed the Wassermann test in 1906. This test became the first reliable serological diagnostic method for syphilis and remained a standard diagnostic test throughout much of the twentieth century. The complement fixation principle later also applied to the serological diagnosis of many other infectious diseases.

One of Bordet's other significant contributions was the isolation of the whooping cough bacillus (Bordetella pertussis). In 1906, he identified the causative agent of whooping cough along with Gengou and successfully cultured it in a special medium (Bordet-Gengou agar). This discovery laid the foundation for the development of the whooping cough vaccine. The whooping cough bacillus is currently classified within the genus Bordetella and its taxonomic name is named in honor of Bordet.

Bordet also studied agglutination (clumping) and precipitation reactions in detail. He described the mechanisms of these serological reactions and developed their diagnostic applications. He also worked on blood-group serology and contributed to transfusion safety.

During World War I, Bordet was forced to remain in occupied Belgium. Research opportunities were severely limited during this period, but he continued his scientific work as much as possible. After the war, he rejoined the international scientific community and was nominated for the Nobel Prize.

The Prize and Its Aftermath

In 1919, the Nobel Prize in Physiology or Medicine was awarded to Jules Bordet for his discoveries related to immunity. However, due to the postponement of the award ceremony because of World War I, Bordet received the prize at the 1920 ceremony held in Stockholm. In his Nobel lecture, he explained the discovery process of complement fixation and the applications of immune mechanisms in serological diagnosis.

After receiving the Nobel Prize, Bordet continued his work at the Pasteur Institute in Brussels. He conducted research on bacteriophages (viruses that infect bacteria) and examined the mechanisms of bacteriophage lysis. These studies contributed to the development of virology and molecular biology fields. Additionally, he conducted research on blood coagulation mechanisms.

Renowned in the international scientific community, Bordet held honorary doctorates and membership titles from many countries. He headed the Brussels Pasteur Institute until 1940. Despite his advanced age during World War II, he remained in Belgium and attempted to continue the institute's activities.

Jules Bordet died in Brussels on 6 April 1961 at the age of ninety. After a long and productive life, he went down in history as one of the founders of the fields of immunology and serology.

Legacy and Impact Today

The scientific legacy of Jules Bordet continues to live on in the foundations of modern immunology and clinical microbiology. The complement system is considered one of the most important components of innate immunity. Classic, alternative, and lectin complement pathways play critical roles in defense against infection, inflammation, and tissue damage. The relationship between complement deficiencies and autoimmune diseases and recurring infections is an important topic of current research.

The complement fixation test has been the main tool for serological diagnosis throughout most of the twentieth century. It was used to diagnose syphilis, influenza, measles, and many other infectious diseases. Although modern diagnostic methods (ELISA, PCR, rapid antigen tests) have largely replaced the complement fixation test, Bordet's principle of antibody-antigen interaction remains the foundation of all serological diagnostic methods.

The isolation of Bordetella pertussis has led to the development of whooping cough vaccines. Today, the DTaP (diphtheria-tetanus-pertussis) vaccine is one of the basic components of childhood vaccination programs worldwide. Whooping cough has been largely brought under control in developed countries thanks to vaccination programs.

Complement-targeted therapies are one of the emerging areas of modern medicine. Medications such as eculizumab, an anti-complement monoclonal antibody, are used to treat paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome.

Lesser-Known Facts

• Although Bordet worked in Mechnikov's laboratory at the Pasteur Institute, he turned his own research toward humoral immunity. This shows that he followed a path independent of Mechnikov's cellular-immunity approach.
• Bordet's principle of complement fixation was adapted by Wassermann for syphilis diagnosis and became one of the most widely used serological tests of the twentieth century.
• The whooping-cough bacillus is classified in the genus Bordetella in Bordet's honor — an example of a scientist's name being immortalized in microbiological taxonomy.
• Bordet received his Nobel Prize a year late because of the First World War. He had spent the war years in German-occupied Belgium.
• Bordet lived to be ninety, making him one of the longest-lived Nobel laureates in Medicine. He continued to take an active interest in scientific affairs almost up to the end of his life.
• There was a debate between Bordet and Ehrlich over the terminology of complement. Bordet preferred the term "alexin," while Ehrlich proposed "complement"; in the end Ehrlich's term was the one that took hold.
• Bordet's son Paul Bordet also worked as a microbiologist and served at the Pasteur Institute of Brussels that his father had founded.