The Pasteur Institute

After one hundred years of service, this French institution is still at the forefront of medical research.

The Pasteur Institute , which constitutes part of France's national pride, will soon celebrate its centennial. For one hundred years, the institute has been dedicated to public health and has continually worked to solve contemporary medical problems. Two recent events have brought world attention to its contributions and on-going research. These are the discovery of the AIDS virus and the astounding donation to the institute by the Duchess of Windsor.

What, then, is the Pasteur Institute? It all began on July 6, 1885, when three people from Alsace appeared at Louis Pasteur's laboratory. Among them was a nine-year-old boy who had been bitten by a dog that had all the symptoms of rabies, which was then a fatal disease. The boy's parents had heard that Pasteur had just perfected an effective vaccine for animals. Could it be used on humans as well? Pasteur hesitated, then decided to try the vaccine on the boy. Joseph Meister was saved from death.

The press, naturally , spread the news of the success. There was widespread excitement, and on March 1, 1886, Pasteur requested the French Academy of Sciences to construct a special institute for the administration of his new vaccine. The institute was built in Paris under Pasteur's name, and public donations were solicited in France and from aboard to support it. The site chosen was originally rue Dutot, but the street was renamed and the institute is now headquartered at 25 rue du Dr. Roux.

In the original statues, which Pasteur insisted on drawing up himself, he formulated three goals: (1) it would be a center for the rabies vaccination; (2) microbiologic research would be carried on; and (3) special training programs would be set up.

The First Fifty Years

By the time of Pasteur's death, many of the bacteria that caused major infectious illnesses had been identified. Only a few important germs remained undiscovered: the bacillus causing the bubonic plague would be identified by Alexander Yersin, anaerobic bacteria would be studied by M. Weinberg, and useful bacteria that live in the soil would be researched by Sergei Winogradsky all at the institute.

Two of Pasteur's disciples, Emile Roux and Yersin, learned that certain bacteria, such as the diphtheria and tetanus bacilli, kill living beings, especially humans, because these bacilli excrete extremely virulent poisons called toxins.

The cause of rabies is not a bacterium, however, but a virus. By 1900 scientists knew that viruses could cause animal and plant diseases. In 1903 Emile Roux published Viruses, Intelligent Beings, the first general study on this subject. In 1916 Frederick Twort in England and Felix D'Herelle at the Pasteur Institute discovered that bacteria themselves could be infected. The bacterial viruses were name bacteriophages.

Other pathogens studied included the causative agent of syphilis, a spirochete, and the agent of malaria, which is a parasite. Alphonse Laveran, then a French military doctor serving in Algeria, discovered the malaria virus. Later, he, too, worked at the Pasteur Institute.

Soon scientists learned that the transmission of some diseases requires the participation of certain arthropod vectors, for example, mosquitoes, in the case of malaria. Shortly before World War I, Charles Nicolle, then director of a branch of a Pasteur Institute in Tunis, succeeded in demonstrating the role of the louse in spreading epidemic typhus fever.

Mechanisms Of Immunity

More is needed to trigger an infectious disease than for a pathogen to penetrate a living organism. Often the germ is destroyed before it causes great harm. But through what mechanism? Elie Metchnikoff, a zoologist born in the Ukrainian city of Odessa on the Black Sea, thought that the defense system relied on certain specialized cells he called phagocytes. In 1888, Metchnikoff worked at the Pasteur Institute, where he confirmed his assumptions.

It was later found that another antimicrobial group of agents were not cellular but chemical substances called antibodies. Also, in Metchnikoff's own laboratory, Jules Bordet, a young Belgian trainee, discovered another substance in the blood besides antibodies, alexine. This substance, soon renamed complement, can, in a number of cases, enhance the antibodies' action.

The existence of microbial toxins had no sooner been demonstrated than two scientists, the German Emil Behring and the Japanese Shibasaburo Kitasato, established that the blood of animals treated with repeated injections of small doses of a toxin becomes enriched with a new substance having a remarkable antitoxic power, hence the name antitoxin. Very naturally, then, came the idea of using sera rich in antitoxins, which are antibodies to the toxin, to treat those suffering from tetanus or diphtheria. This was first proposed by three members of the Pasteur Institute: Roux, Louis Martin, and Auguste Chaillou. The results, presented at the the Tenth International Congress of Hygiene in Budapest (1894), were met with enthusiasm. In the following years, numerous scientists confirmed the limits of this new treatment, which is known today as immunotherapy.

New Vaccines

In 1992, two members of the Pasteur Institute, Albert Calmette and Camille Guerin, developed a vaccine against tuberculosis by using an avirulent strain of the organism causing the disease. This was called the BCG (Bacillus Calmette-Guerin) vaccine. The next year, Gaston Ramon, another Pasteur Institute member, succeeded in transforming the dreaded diphtheria and tetanus toxins into harmless and effective vaccines. These new vaccines, called toxoids or (in France) anatoxins, have been used worldwide ever since.

After the turn of the century, progress was made in combating diseases such as syphilis, but diseases caused by bacteria and viruses remained incurable. In 1934 the German scientist Gerhard Domagk demonstrated that the synthetic chemical prontosil was effective against the bacteria causing strep throat. Two years later, scientists at the Pasteur Institute demonstrated that the sulfonamide radical of prontosil was the active agent and responsible for the antibacterial effect. This work led to the development of sulfa drugs, which are useful in treating a variety of diseases and represent the beginnings of the use of chemotherapeutic agents.

Changes At The Institute

Throughout the fifty years just surveyed, there were many changes in the Pasteur Institute, notably in its personnel. Pasteur died in 1895. As director, he was succeeded by Emile Duclaux (1895-1904), Emile Roux (1904-33), and then Louis Martin (1934-40).

When it began, the entire institute was housed in only one building. Throughout the years, other buildings appeared: one especially dedicated to chemistry, another for tuberculosis studies, and yet another for studies of the BCG vaccine. A hospital had also been established. Overseas branches of the institute existed in Africa, Southwest, Asia, and South America.

Despite the expansion the institute remained relatively modest. Its resources came from the sales of vaccines and sera prepared in its laboratories and, no less important, from generous gifts. Its budget was balanced and, especially noteworthy, after its first fifty years the institute was still a completely independent entity, not dependent on the government or a university for funding.

In its first half-century, the contributions of the institute were of considerable importance. The unparalleled scientific accomplishments of Pasteur Institute members, both in and outside of France, had been recognized with four Nobel Prizes: Alphonse Laveran, 1907; Elie Metchnikoff, 1908; Jules Bordet, 1919; and Charles Nicolle, 1928. Based on the example of the Pasteur Institute, the Koch Institute in Germany, the Lister Institute in England, the Rockefeller Institute in the United States, and the Serotherapy Institute in Denmark were founded.

Another reason for the institute's growing importance was the tremendous prestige France accrued after 1918. Many nations in Europe saw furnace in the position of the Great Protector. At the same time, France carried the weight of a colonial empire.

Finally, we should not forget the special character of the scientists who, from 1888 to 1939, maintained the reputation of their institute. For the most part, these early members of the Pasteur Institute were rather unique characters. They came from various backgrounds and native lands. In most cases they were accepted at the institute simply because their love of science was sincere, and their personal detachment absolute. Through their coherence, they formed a kind of family or - and this analogy is not too far-fetched - a religious order. For thirty years after the death of Pasteur, their "abbot" was the famous Dr. Roux, one of Pasteur's early collaborators.

The Second Fifty Years

World War II broke out in September 1939, and Paris was not liberated until August 1944. In December 1940, Jacques Trefouel replaced Gaston Ramon, who had been made director six months earlier. A younger man and a clever diplomat, he came to terms honorably with the occupying force, and therefore the institute's work continued and, despite deplorable conditions, led to interesting results. During this time, Paul Giroud perfected a vaccine against typhus. When the French Resistance began fighting the Nazis, some members of the institute assumed the responsibility for obtaining such things as bandages, surgical equipment, and medicine. Unfortunately, several of the members were arrested and deported, never to return from captivity.

In 1929, Alexander Fleming, a Scottish scientist, had discovered penicillin. Through the occupation years in France, the production of penicillin was perfected, and soon many other antibiotics became available. The growing use of antibiotics diminished the use of antisera, but there was a continuing need for new vaccines. A "killed" vaccine for poliomyelitis was perfected by the American Jonas Salk. This vaccine was replaced by the more effective "live" polio vaccine perfected by Albert Sabin. At the Paris Pasteur Institute, Pierre Lepine favored the 'killed" vaccine and perfected its mode of preparation.

Since the end of the nineteenth century, scientists knew that among the chemical components of the organism, proteins such as enzymes and antibodies played a key role in immunity. What was not known, however, was the relationships among the other components of the organism. In 1944, the first demonstration that deoxyribonucleic acid (DNA) was the basis of the genetic code was made.

This led to an understanding of how hereditary characteristics are transmitted from one generation to the next. This new discipline, molecular biology, was pioneered by three investigators at the Pasteur Institute: And Lwoff, Jacques Monod, and Francois Jacob, who were jointly awarded the Nobel Prize for medicine and physiology in 1965. In Lwoff's laboratory, Jacob and Monod made discoveries that led to an understanding of the control of gene expression in bacteria. These discoveries allowed the Pasteur Institute to regain its place in the forefront of research work. This was undoubtedly true. Unfortunately, the general situation had greatly changed.

After the discovery of antibiotics, the discovery of anti-inflammatory medicines encouraged manufacturers to build huge industrial plants. Because of its limited resources, the institute had difficulty competing. Its commercial monopoly had been sharply affected by the war. At the same time, laboratory experiments had become very costly. There were also fewer donations in an impoverished France.

The members of the Institute were not united. In fact, there were ten years of grouping under different directors. Initiatives to remain autonomous were undertaken, but efforts were insufficient to provide the necessary funds. In 1971 they appealed to Jacques Monod, honored by the Nobel Prize and by the success of this book, Chance and Necessity, to direct the institute. The scientist's qualities were evident, but the man surprised and even shocked the members of the institute by his decisions. In short, he was a good scientist but a poor administrator. Certain services were severely curtailed, a new factory was built near Rouen, and private support was more actively solicited. As a last resort, they appealed to the government for financial support. Lwoff liked to say, "We are a mendicant order."

Monod left the directorship in 1976, and Francois Gros took over. After six years, Ramond Dedonder succeeded him. Under these directors, the institute became solvent again.

Modern Times

With the discovery of the role of DNA, genetics research was pursued vigorously by biologists. A few years later, immunology became an important discipline as well. Some of the early immunological discoveries included immunoelectrophoresis by Pierre Graber and Jacques Oudin's discovery of allotypes and idiotypes. Nicolas Jerne used Oudin's work as a basis for detecting cells that formed antibodies.

The study of cellular immunity was also begun. Lymphocytes, cells ignored until then, were gaining attention as scientists learned that their functions are diverse and important. After 1945, the French immunologist Dausset, former student at the Pasteur Institute, isolated groups of white blood cells and surmised the existence of antigens of histocompatibility. The reward for this magnificent discovery was a Nobel Prize in 1980.

In 1970, scientists observed that genes, once isolated, could be transmitted from one species to another and that as a result of this "graft," the subject thus treated began to gain traits linked to the transmitted genes. Now known as genetic engineering, this process serves as the basis for biotechnology.

In 1980, humankind was confronted with a previously unknown disease: AIDS. Basically, AIDS results from an attack on the lymphatic system. Research pointed toward a retrovirus as the origin of the disease. In 1983 a team from the Pasteur Institute, Luc Montagnier, Jean-Claude Chermann, and Françoise Barre-Sinoussi, discovered the causative agent of AIDS. (This agent was codiscovered by a group headed by Robert Gallo at the U.S. National Institutes of Health.) Suddenly, and on the verge of celebrating its 100^th anniversary, the Pasteur Institute found itself once more making medical history.

The Institute Today

The institute is, naturally, very different from what it was even in 1939. New buildings continue to appear on the campus of the rule du Dr. Roux. After the end of France's colonial rule, the various satellite institutes abroad were administratively detached from the Parisian Institute, but their loyalty is undiminished.

At the same time, the range of research pursued at the institute has greatly increased. A special laboratory has been created to study the mechanisms of the nervous system and the brain. However, bacteria, viruses, and parasites remain in the foreground of our research, as well as all that pertains to biochemistry.

All of this, however, is extremely expensive. The Pasteur Institute has been obliged to combine with other groups, and in 1987 the institute was subdivided into three divisions. One is the Pasteur Foundation, which still remains a private foundation and is synonymous with the original Pasteur Institute. The other two divisions include the Pasteur Institute for Diagnosis and the Pasteur Institute for Vaccines, which are for-profit companies that share their earnings with the Pasteur Foundations. The Merieux Institute, involved in the research of vaccines for the Third World, especially malaria, and Elf Aquitaine, a prominent French pharmaceutical company, are today its principal technical assistants. They share personnel, equipment, and some of the research costs.

The institute counts on the sale of vaccines, sera, and many biological products and patents to support it. Donations are now plentiful and considerable, and the French government offers some support. Regarding donations, the recent auction of the Duchess of Windsor's jewels, the proceeds of which were donated to the institute as designated in her will, amounted to approximately $35 million. This windfall has made possible the addition of a $16 - million department for the study of retroviruses and AIDS, and the rest will be used for other long-term developments and research.

And the members of the Pasteur Institute? Something irreplaceable remains: the fervor, the faith, the enthusiasm for work. Today's Pasteur Institute members still come from diverse backgrounds, but they do not embody the slightly bohemian eccentricity of their predecessors. They are physicists, not naturalists. They are younger, generally speaking, and there is a greater turnover in personnel. Whenever this retired member walks among them, I sometimes, find it difficult to see myself there. Like Heraclitus' river, the old institute is forever changing and remaining the same. It is better that way.