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Louis Pasteur: a light that brightens more and more.

On June 14, 1940, when the German army entered an undefended Paris, the seemingly unstoppable Nazi forces took full control of the city. But one door remained, at least temporarily, closed to them. When the Wehrmacht arrived at the Pasteur Institute and attempted to enter the basement crypt where the bodies of Louis Pasteur and his wife, Marie, were interred, they found an aging concierge blocking the path. The guard steadfastly and courageously refused to permit them entry to the tomb. (1)

This guard was not alone in his devotion to Pasteur. In a 1922 speech, the French ambassador to the United States, Jules Jusserand, described the incredibly high esteem in which Pasteur was held among the French people:
  In the course of its history, France has produced many great men.
  There is no one of whom we are prouder than Pasteur. ... Some years
  ago, before the war, a newspaper organized a kind of plebiscite and
  asked its readers who in their view were France's greatest sons.
  2,300,000 replies came, and in this militaristic nation of ours ...
  the emperor Napoleon came seventh and Pasteur came first. (2)


Nor was Pasteur's popularity limited to his home country. In 1936, his life and achievements formed the basis of a major Hollywood film, The Story of Louis Pasteur, for which the great actor Paul Muni won his first and only Academy Award. The film was a tremendous success--it grossed $665,000 and was viewed by an estimated thirteen million people in the United States, a full 10 percent of the population at that time. (3)

Unfortunately, things have changed. Pasteur, once internationally revered, is now largely unknown--remembered, if at all, only for his invention of pasteurization. But Pasteur deserves to be remembered as more than a portmanteau on the side of a milk jug. He led an amazing life, tirelessly working to advance science. He made crucial, fundamental discoveries in chemistry, launched the science of microbiology, cured multiple diseases, and inspired an entire generation of scientists to pursue and apply vital truths. If anyone is deserving of renewed interest, Louis Pasteur is.

Early Life and Education (1822-1846)

Louis Pasteur was born on December 27, 1822, in the city of Dole in the county of Franche-Comte in eastern France. His father, Jean-Joseph Pasteur, was a former officer in Napoleon's imperial army who owned and operated a modest tannery while his mother, Jeanne-Etiennette, ran the household.

In 1827, Pasteur's family moved to the nearby city of Arbois. There Pasteur attended primary school, where he was an unremarkable student for most of his childhood, preferring instead to fish with his friends and draw. By the time Pasteur was fourteen, however, he had transformed into the star pupil at the college of Arbois and a talented artist who was well known in the town for his striking pastels. Indeed, Pasteur strongly considered pursuing a career as an artist but ultimately settled upon more academic ambitions.

Upon his graduation in 1839, Pasteur enrolled in a bachelor's degree program at the college royal of Besancon, the capital of Franche-Comte, and received his bachelor of letters (i.e., arts) degree after one year of study. By this time, however, Pasteur had set his sights on graduate school at the elite ecole Normale Superieure, acceptance into which required a bachelor of science degree and adequate performance on two rigorous entrance examinations.

Pasteur elected to remain at Besancon for another year to complete his BS. It was during this time that he, simultaneously studying for his courses and working as a tutor, began to develop his passion for science. "Once one is used to working [in science]," he wrote to his family in Arbois, "one can no longer live without it. And of course, everything in the world depends on it; in science, one is happy; in science one rises above all others." (4)

Receiving his bachelor of science degree in 1842, Pasteur chose to spend a year of intense postbaccalaureate study at the College Saint-Louis in Paris to prepare for the entrance examinations to the ecole Normale. He graduated first in physics and placed fourth in the nation on the entrance examinations. While studying for the examinations, he had risen early in the morning, before his scheduled classes, to attend the lectures of the great chemist Jean-Baptiste Dumas at the Sorbonne. Now, as a Normalien, Pasteur received private lessons in laboratory technique from Dumas's assistant--in addition to his twelve daily hours of study for his courses.

When, upon his graduation in 1846, Pasteur received a prestigious appointment as a lecturer of physics in the faraway city of Tournon, he turned it down, instead hoping to remain in Paris to finish his doctorate and prepare for a research career in chemistry. Fortunately, Pasteur was able to obtain a job as an assistant in the laboratory of Jerome Balard, the famous discoverer of bromine. There Pasteur would make his first indelible mark on the history of science.

"Knowledge of the Crystalline Forms" (1846-1853)

Early in his tenure in the Balard laboratory, Pasteur had the opportunity to collaborate closely with Auguste Laurent, an eminent scientist known for his expertise in the nature of chemical crystals. During their collaboration, Pasteur learned a great deal about crystallography and, in particular, became a scrutinizing observer of the subtlest differences between crystals. In his personal notes, Pasteur documented that
  M. Laurent ... showed me under the microscope that [sodium
  tungstate], though very pure in appearance, was a mixture
  of three distinct kinds of crystals. This example and
  several others of the same kind made me appreciate how
  useful a knowledge of the crystalline forms is for
  chemical analyses. (5)


This knowledge would prove particularly useful when Pasteur explored the chemical nature of two closely related organic compounds. The first compound, tartaric acid, was found naturally in wine and was produced industrially in France because of its usefulness in textile production. It was also used widely in crystallography studies because it readily formed into large crystals. The second compound, racemic acid, was discovered in 1819 in the tartaric acid factory of an industrialist named Kestner. German chemist Eilhardt Mitscherlich had studied these two compounds and found that they have almost identical chemical characteristics--the same atomic weight, the same number and types of atoms--with only one important difference. Tartaric acid was "optically active," meaning that a beam of plane-polarized light, when directed through crystallized or dissolved tartaric acid, would be rotated when it came out the other side. Racemic acid did not share this property.

Reports of this unexpected difference intrigued Pasteur enough that he chose to study the two compounds himself. In studying the crystals of the two molecules under the microscope, Pasteur made a remarkable discovery--although ammonium sodium tartrate (a salt of tartaric acid) was composed of only one type of crystal, ammonium sodium racemate was composed of an equal mixture of two very slightly different crystals. Pasteur noted that the tartrate crystal was asymmetric--when viewed from a certain angle, it possessed a small oblique facet on the upper right corner that was not present on the upper left. The racemate crystals were also asymmetric, but although half of the crystals were identical to the right-handed tartrate crystals, the other half of the racemate crystals had their oblique facets on the upper left corner--the exact mirror image of the tartrate crystals.

Pasteur hypothesized that the optical activity of tartaric acid was related to its asymmetry, which prompted him to think that racemic acid lacked optical activity because its asymmetric crystals were equal but opposite, thereby canceling one another's light-rotating effects. He proved this hypothesis by meticulously separating the left- and right-handed crystals of racemic acid. He then showed that the right-handed crystals of racemic acid--fully identical in shape to tartaric acid--are able to rotate plane-polarized light in the same direction (clockwise) and to the same degree as tartaric acid. Moreover, the left-handed crystals of racemic acid rotated light in the opposite direction but still to the same degree. Perhaps most importantly, these light-rotating properties remained when the crystals were dissolved in water. This, Pasteur realized, indicated a crucial discovery--far from being a peculiarity of formed crystals, the asymmetry of the left-handed and right-handed forms of tartaric acid was a property of the very molecules of which they were composed.

Balard was stunned by Pasteur's discovery and convinced him that they should have the research reviewed and confirmed by the leading expert in tartaric acid chemistry, Jean-Baptiste Biot. Pasteur traveled to Biot's laboratory and repeated his experiment, once again carefully separating the crystals of racemic acid, allowing Biot to double-check every measurement and procedure. Pasteur later wrote of Biot's reaction to the results:
  [Biot] prepared the carefully weighed solutions in the proper
  amounts, and when the time came to look at them in the polarization
  apparatus, he again called me to his laboratory. He first placed into
  the apparatus the most interesting solution, namely the one that was
  supposed to rotate light to the left. Without even taking a
  measurement, Biot realized from the mere sight of the two images in
  the polarimeter, one ordinary and one extraordinary, that there was
  indeed a strong rotation to the left. Then the illustrious old man,
  visibly moved, took me by the arm and said: "My dear boy, I have
  loved science so much all my life that this stirs my heart." (6)


Pasteur showed conclusively that certain compounds can exist in two asymmetric forms, each the mirror image of the other. His discovery was a watershed moment in the history of chemistry and was the first discovery in yet another field launched by Pasteur--stereochemistry, the branch of chemistry that studies the three-dimensional arrangement of molecules and the properties that arise therefrom. Biot went on to sponsor Pasteur's seminal report of these findings to the French Academy of Sciences, giving Pasteur his first--but far from his last--taste of fame in the scientific community of Europe.

Asymmetry and the "Living World" (1853-1859)

Although Pasteur's work on the asymmetric forms of crystals was a huge achievement in itself, Pasteur was not satisfied with only recognizing that tartaric acid was composed of only one of the oppositely asymmetrical forms present in racemic acid--he wanted to know why. Why was it that tartaric acid sometimes formed in an equal mixture of opposite forms and sometimes formed in a pure mixture of only one form? Pasteur sought the answer to this question by going to the only known source of racemic acid at the time--Kestner, the industrialist in whose factory racemic acid had been discovered. In his quest for an answer, Pasteur also visited tartrate refineries in Saxony and Vienna to obtain precious samples of racemic acid. In these efforts, he was able to determine that unrefined tartrate contained racemic acid and that the refining process consumed the left-handed tartrate molecules, transforming them into the right-handed version--ordinary tartaric acid.

Encouraged by this discovery, Pasteur soon broadened the scope of his driving purpose. No longer content with seeking the reason for asymmetry only in tartaric acid, he became obsessed with understanding the nature of all asymmetrical molecules. "I am really afraid," he wrote in 1853," that this time I have taken on the impossible. I want to track down the cause of one of nature's greatest mysteries, whose unraveling, it seems to me, would have the most far reaching consequences." (7) In order to explore this question, he began laboratory studies on how to transform asymmetric molecules, such as tartaric acid and quinine, into their mirror-image counterparts. His spectacular success in these experiments earned him the 1853 prize from the Society of Pharmacy in Paris.

Pasteur's exhaustive study of optically active substances--substances he had learned were composed of only one of two asymmetrical forms--led him to notice that all of them came from living sources. Pasteur concluded from this that asymmetry was a distinctive characteristic of life:
  Every chemical substance, whether natural or artificial,
  falls into one of two major categories, according to a
  spatial characteristic of its form. The distinction
  between those substances that have a plane of symmetry
  and those that do not. The former belong to the
  mineral, the latter to the living world. (8)


The very nature of living things, he thought, was to be asymmetrical--for every molecule to favor one mirror-image counterpart over the other.

The seeds of these studies would bear further fruit and change the very course of Pasteur's career when, in 1854, he was appointed as a professor of chemistry at the University of Lille, a regional capital in northern France and a major industrial center for textile factories, chemical refineries, breweries, and distilleries. In 1856, the father of one of Pasteur's students, a distillery owner named Bigo, came to the university to meet with Pasteur and discuss with him a problem in the fermentation of beet root juice into alcohol. In recent years, explained Bigo, many distillers had run into significant problems with the quality of their alcohol, which had become sour and malodorous. He implored Pasteur to employ his scientific acumen to solve this problem.

This type of problem would have evoked disdain from other scientists of the day, most of whom subscribed to the view that so-called "pure" science--seeking understanding for the sake of understanding--was far superior to "applied" science, which was tainted by its connection to technological and industrial pursuits. Pasteur outright rejected this notion, writing that "[t]here is no such thing as a special category of science called applied science; there is science and there are its applications, which are related to one another as the fruit is related to the tree which has borne it." (9) Pasteur was a great supporter of industry, and he routinely showed this support in his manuscripts on molecular asymmetry, never failing to give credit to Kestner and Fikentscher, the industrialists who had aided him in procuring samples of racemic acid.

Pasteur tackled Bigo's problem with zeal. His wife, Marie, would write to her father that he was "up to his neck in beet juice ... [and] spends his days in an alcohol factory." (10) Scientists at the time were unsure of how fermentation worked. Most scientists, most conspicuously Justus von Liebig, thought fermentation to be a purely inanimate process. Liebig, in 1839, had characterized fermentation as a process in which "[y]east from the malt ... [transfers] its own state of decomposition to that which is around it. The movement that disturbs the balance imprinted in its own elements also communicates with other elements of bodies in contact with it." (11) Although yeast was a living thing, its role, according to Liebig, was just to start the nonliving process of fermentation.

Pasteur, however, was unmoved by Liebig's confusing explanation. He had noticed that many of the molecular products of fermentation, such as amyl alcohol, were asymmetrical, and that fermented mixtures contained only one of the mirror-image forms of these molecules. Recalling his earlier studies that pure solutions of only one asymmetrical form were distinctive to life, Pasteur hypothesized that fermentation was a process that relied on living things, albeit living things so small that they could not be seen with the naked eye. In his experiments, he discovered that the production of beet juice alcohol required fermentation of beet sugars into alcohol by these tiny microorganisms--yeast cells. However, if other microorganisms--which Pasteur called "lactic bacilli"--contaminated the beet juice, they could ferment the beet sugar into other products, such as lactic acid, which would ruin the quality of the alcohol.

In 1857, Pasteur returned to Paris as the new administrator and director of scientific studies at his alma mater, the ecole Normale Superieure. Also in 1857, Pasteur published his now famous study of "lactic fermentation." In this manuscript--which many consider "the birth certificate of microbiology" (12) --Pasteur characterized the chemical production of lactic acid through fermentation and showed that this process occurred only in the presence of microscopic organisms and never in their absence. "[F]ermentation," Pasteur wrote, "far from being a lifeless phenomenon, is a living process ... all phenomena of fermentation correlate with the development of mycodermic cells and plants which I have prepared and studied in an isolated and pure state." (13) His experiments did not convince Liebig, who became a bitter adversary and critic of Pasteur. It was in response to Liebig's missives that Pasteur gained a reputation for energetically and self-righteously defending his conclusions on the floor of the Academy of Sciences. Fortunately, the other members of the Academy were well convinced of his conclusions, and Pasteur's achievements earned him full Academy membership in 1863.

Refuting Spontaneous Generation (1859-1865)

The idea of tiny, invisible living things was not novel in 19th-century Europe. In 1676, Dutch scientist Anton van Leeuwenhoek had invented the microscope and documented his observations of tiny "animalcules" in seemingly clean water. But in the nearly two hundred years that passed between Leeuwenhoek and Pasteur, no one had been able to figure out where these "animalcules" came from. The scientific community was divided between those who believed that these microorganisms simply appeared out of nowhere--a hypothesis known as spontaneous generation--and those who believed that, like plants and animals, microorganisms were born of other microorganisms. The relevance of this debate was not lost on Pasteur, who in 1861 wrote:
  Having reached this point in my studies on fermentation, I had to
  form an opinion on the question of spontaneous generation.
  Perhaps it would furnish me with a powerful weapon in favor of
  my ideas on fermentation. ... This is how I came to work on a subject
  which has hitherto only engaged the sagacity of the naturalists. (14)


One such naturalist was physician and museum director Felix-Archimede Pouchet, to whom, in 1859, Pasteur sent a letter on the topic of spontaneous generation. Pasteur explained that he was disinclined to agree with the doctrine of spontaneous generation because his experiments with fermentation had showed that cultures of yeast could be killed (i.e., sterilized) through heating them. It also showed that new fermentation could only resume when these cultures were exposed to the air, leading Pasteur to conclude that the microorganisms, rather than spontaneously generating in the culture broth, must move from the air into the broth where they can then reproduce. Pouchet, a well-known advocate of the spontaneous generation hypothesis, took offense at Pasteur's disagreement--bringing Pasteur yet again into conflict with a respected scientist.

Pasteur's experiments testing the hypothesis of spontaneous generation would prove to be among his most elegant, and his work in this area led him to invent and perfect many innovative techniques in the culturing of laboratory microorganisms. For these experiments, Pasteur developed a culture broth composed of a mixture of sugar and the extracts of yeast--a type of culture broth used to this day in laboratories across the world. Pasteur filled small glass bulbs with this sterile culture medium and then pulled the glass out into a sealed ampule. He was then able to open these ampules anywhere, reseal them, and incubate them to see if microorganisms would therein grow.

Pasteur's results forever laid to rest the hypothesis of spontaneous generation. He first showed that a sealed ampule with culture broth would never grow microbes without exposure to air--in other words, nothing spontaneously generated. Additionally, Pasteur showed that, even in the air, microbes were relatively sparse--the vast majority of these opened-and-then-sealed ampules would never grow microorganisms, no matter how long they were incubated. He found moreover that the air density of the microbes could change from place to place. One hundred ampules opened on a busy city street, for example, might yield twenty microbe-contaminated ampules. One hundred such ampules opened on the Mer de Glace, a pristine glacier high in the French Alps, might yield only one contaminated ampule.

Pasteur did not stop there. He designed many clever containers with convoluted necks--swan-necked, or twisted many times--to show that microorganisms readily grew in open flasks but, unable to navigate mazelike twists and turns in the openings, were unable to grow in his homemade flasks. He also showed that he could use sterilized, porous material to filter out the organisms in the air:
  [Using] wads of asbestos previously calcined and not filled with
  dust, or filled with dust but heated afterwards, no turbidity, nor
  Infusoria, nor plants of any kind were ever produced. The
  liquids remained perfectly clear ... never once did any of my
  blank experiments show any growth just as the sowing of dusts
  has always furnished living organisms. (15)


In the ongoing debate, Pouchet claimed that he repeated Pasteur's experiments and showed growth of microorganisms in every instance. Pasteur, however, dismissed these results as arising from carelessness in the sterilization of the culture media--Pouchet had simply not adequately removed all of the germs from the media to begin with so, of course, more would grow regardless of being exposed to the air. Nevertheless, the debate between Pouchet and Pasteur reached a fever pitch, and the Academy of Sciences determined to end the debate by convening a jury of scientists to directly observe the experiments of both men. When the jury observed Pasteur's ampules, they saw plainly that the results were exactly as he had reported them--most of the ampules remained sterile of microorganisms, whereas a minority of them had been contaminated by exposure to the air. The evidence was clear: The theory of spontaneous generation was done for.

In 1864, Pasteur was invited to defend his refutation of spontaneous generation at the Sorbonne. True to form, he delivered a thrilling lecture to a standing ovation. "As I show you this liquid," he dramatically intoned:
  I too could tell you, I took my drop of water from the immensity
  of creation, and I took it filled with that fecund jelly, that is, to
  use the language of science, full of the elements needed for the
  development of lower creatures. And then I waited, and I observed,
  and I asked questions of it, and I asked it to repeat the original
  act of creation for me; what a sight that would be! But it is
  silent! It has been silent for several years, ever since I
  began these experiments. Yes! And it is because I have kept
  away from it, and am keeping away from it to this moment, the
  only thing that it has not been given to man to produce, I
  have kept away from it the germs that are floating in the air,
  I have kept away from it life, for life is the germ, and
  thegerm is life. (16)


Turning Toward Disease (1865-1877)

The germ was life indeed, but Pasteur was not ignorant of how life-thwarting microscopic germs could be as well. In 1864, Pasteur delivered a paper to the Academy of Sciences on the "diseases" of wine caused by microscopic germs, but his mind was already turning to the diseases of animals and human beings that might also be caused by such germs. Pasteur's first steps in the direction of human disease took place in 1865, when he patented a process for preserving beverages by heat-killing the resident germs--a process that he called "pasteurization." Although at first used only to improve the quality of beer and wine, the process would soon become a powerful preventive step against food-borne disease.

In 1865, the French government asked Pasteur to join a commission to study the causes of an epidemic of cholera in Paris. Pasteur was eager to test his germ theory of disease against such an epidemic, but, due to his experiments on fermentation, he was too focused on the idea of germs moving through the air. He carefully tested the air in the hospitals full of cholera victims but found no evidence of a cholera-causing germ--not realizing, as others later would, that the germ was liquid-borne.

Also in 1865, Pasteur's work came to the attention of a British physician named Joseph Lister. Lister immediately realized that the airborne germs that cause spoilage of alcohol might also be responsible for the infection of surgical wounds. Lister began experimenting with ways to prevent surgical infections by employing antiseptic techniques, including wound dressings and hand washings with dilute carbolic acid. Lister's experiments proved that infections could be dramatically reduced through the use of antisepsis. Lister went on to be viewed as the father of antisepsis (he is the namesake of the brand Listerine), but he always gave substantial credit to Pasteur. "Allow me to take this opportunity," Lister wrote in a personal letter to Pasteur in 1874,
  to tender you my most cordial thanks for having, by your brilliant
  researches, demonstrated to me the truth of the germ theory of
  putrefaction, and thus furnished me with the principle upon which
  alone the antiseptic system can be carried out. Should you at any
  time visit Edinburgh it would, I believe, give you sincere
  gratification to see at our hospital how largely mankind is being
  benefitted by your labours. (17)


From 1865 into the mid-1870s, Pasteur, at the request of Emperor Napoleon III, applied his knowledge of germs to yet another industrial problem--an epidemic disease that was wiping out the silkworms, and thus the silk industry, of France. Pasteur set to work on this problem with his usual ardor, going so far as to temporarily move his whole family to Ales so he could directly study at the silkworm nurseries. Not originally trained as a naturalist or veterinarian, Pasteur proved an apt pupil of veterinary science and soon mastered the known facts concerning silkworms. He then determined that not one but two diseases were afflicting the silkworms in France. The first, called pebrine, was transmitted through the silkworm eggs. Pasteur created a method of identifying the infected eggs and separating them from the noninfected eggs, allowing for new stocks of disease-free silkworms to be created. Pasteur discovered that the second disease, known as flacherie, resulted from contamination of the silkworm food, mulberry leaves.

By the late 1870s, Pasteur turned his attention to another veterinary concern. Chicken cholera was causing substantial losses to farmers in France. For his studies of chicken cholera, Pasteur collaborated with a bright young scientist named Charles Chamberland. In their early experiments, Pasteur and Chamberland painstakingly isolated the microorganism responsible for the disease and developed a method of culturing the organism in the laboratory. They then began characterizing the effects of the organism by infecting chickens in the lab. As the story goes, (18) Chamberland accidentally left a container of the germs out of the incubator. Even though the culture was probably ruined, Chamberland upon his return decided to try to use the spoiled germs anyway to infect some chickens. It didn't work--the chickens remained healthy. The somewhat niggardly Pasteur, however, was loath to waste perfectly good chickens and bade Chamberland to infect them with a properly virulent culture of the disease-causing microbes. This he did, but the chickens remained completely unaltered. Pasteur and Chamberland realized that the chickens had been made resistant to chicken cholera through their inoculation with weakened chicken cholera germs. Pasteur and Chamberland had created a preventive treatment for chicken cholera. When Pasteur presented these results to the Academy of Sciences in 1880, he made clear that he had found a new purpose:
  It would seem superfluous for me to point out the principal
  consequences of the facts I have had the honor of presenting to this
  academy. There are two, however, which may be worth mentioning
  in particular. They are ... the hope of obtaining artificial
  cultures of all viruses ... and ... an idea of how to find
  virus-vaccines of the virulent diseases, which have brought and
  still bring so much desolation to humanity. (19)


Lifting the Curse (1877-1881)

The idea of inoculating people against disease was not unknown in Pasteur's day--it was widely used against the ravages of smallpox. Inoculation against smallpox, a process known as variolation (the Latin name of smallpox is variola), involved pricking the skin of a noninfected person with some material from a smallpox pustule. Most persons who were thus inoculated would develop a very mild course of smallpox but would thereafter be permanently immune to the disease. The practice originated in ancient China, but it was popularized in Europe by Lady Mary Wortley Montagu, whose husband had observed the procedure being done by the Ottoman Turks when he served as the British ambassador to the Ottoman Empire in the early 18th century. (20) The popularity of inoculation grew throughout the 18th century, and George Washington even used it to great effect when he ordered the variolation of every soldier in the Continental Army. (21)

In 1796, however, the widespread use of variolation came to a rather abrupt end. The reason was the advance of a new, better way to prevent smallpox. The man responsible for this groundbreaking discovery was an English physician named Edward Jenner. Jenner was a committed doctor, and he often traveled far into the English countryside to treat his patients. In these travels, he observed that a piece of folk wisdom was widely known by English farmers--cow maids who became infected with a certain cow disease became forever immune to smallpox. This disease was known as cowpox, and the course of the disease was much milder even than the weakened form of smallpox that resulted from variolation. Jenner developed a method of systematically using cowpox to engender immunity against smallpox. (22)

When Pasteur discovered his method of inoculating chickens against chicken cholera, he immediately realized the theoretical connection with Jenner's work--the use of a weaker version of a disease to inoculate against the full-strength disease. Because the French term for cowpox is vaccine, Pasteur called this process of inoculating with an artificially attenuated pathogen vaccination, explaining that "I have given to the term vaccination an extension which science, I hope, will adopt as an homage to the merits and the immense services rendered by ... Jenner." (23)

Given his new interest in vaccination, Pasteur was understandably interested to read, in August 1880, reports that a young veterinarian named Jean-Joseph Toussaint had created a vaccine against anthrax. Toussaint claimed to have weakened the anthrax germ by heating it. Pasteur was excited but skeptical. He eagerly repeated Toussaint's experiments but found that this heat-weakened anthrax germ soon regained its virulence and that Toussaint's vaccine was useless. (24)

Pasteur had been involved with studies of anthrax since 1877, when the French minister of agriculture personally requested that he give it some attention. Anthrax was a major problem for 19th-century cow and sheep farmers, as described by Louisiana farmer Louis Leonpacher in his diary: "An animal which has a strong [anthrax] infection ... lives or dies within 3 days. [The place where it dies] will remain for years a spot of troubles." (25) As Leonpacher observed, any animal feeding where an animal had previously died from anthrax was likely to contract the disease. An anthrax infection would not only kill a farmer's animals but would render his land completely inhospitable to future herds--destroying the farmer's livelihood. The French had come to call these infected pastures les champs maudits--the cursed fields.

Pasteur thought he could solve the problem of anthrax by applying the same methods he had used with chicken cholera. He and his associates, Emile Roux and Charles Chamberland, immediately began work to develop and test vaccines against anthrax. The key question in this project was how to weaken the anthrax germ. The Pasteur lab actually developed two methods by which to accomplish this. One was to prevent the anthrax germs from transforming into a heat-resistant spore by growing it at forty-two degrees Celsius, followed by oxidation of the germs by exposure to oxygen. The other method of weakening the anthrax germ, developed chiefly by Roux and Chamberland, was to use the chemical potassium bichromate to oxidize the germ.

Pasteur published his findings in 1881, but many doubted that he had actually achieved a working vaccine against anthrax. Pasteur responded to his detractors with a flamboyant defense of his work--a feature that had become his trademark--this time enlisting the aid of a friend. His friend, a veterinarian named Rossignol, convinced the Society of French Farmers in Melun to sponsor a public experiment testing the efficacy of Pasteur's anthrax vaccine. Between May 5 and May 31, Pasteur would treat twenty-five sheep three times with his anthrax vaccine, leaving another twenty-five unvaccinated. On May 31, all fifty sheep would be infected with full-strength anthrax germ. Pasteur's expectation was that the vaccinated sheep would live, the unvaccinated would die. His detractors held that all the sheep would die.

The experiment was carried out on Rossignol's own farm in the nearby village of Pouilly-le-Fort. On May 31, all fifty sheep were infected with anthrax. When Pasteur returned on June 2, the farm at Pouilly-le-Fort was swarmed by onlookers and members of the press who saw firsthand that all the unvaccinated sheep lay dead, whereas all the vaccinated sheep were still alive and well. Though applauded by the crowd, Pasteur resisted their cheers and, in an admirable display of his scientific integrity, told them that "[t]he experiment will not be complete until 5 June, when we have decisive proof for the vaccinated animals." June 5 brought complete proof of the effectiveness of Pasteur's vaccine--only one vaccinated animal had died, and an autopsy had proven that the animal had died not of anthrax but of a miscarriage.

Pasteur's vaccine practically ended the problem of anthrax in France. Where nearly 10 percent of untreated livestock had died of anthrax, Pasteur's revolutionary vaccine reduced the mortality of this terrible disease to 1 percent. Moreover, in other experiments, Pasteur had solved the problem of "the cursed fields." He showed that anthrax was transmitted via earthworms, which carried the germ from stricken animals buried underneath the ground to the surface where new animals could be infected. The solution was simple--the farmers need only to bury anthrax-killed animals in sandy soil, rather than in clays where earthworms thrive. His work brought him widespread recognition, but Pasteur was always one to give credit where credit was due. When the French government sought to honor him for his achievements in the treatment of anthrax, Pasteur refused to be decorated unless Chamberland and Roux shared the honor.

Defeating Le Rage (1881-1886)

On July 4, 1885, a nine-year-old Alsatian boy, Joseph Meister, was ferociously mauled by a stray dog. Saved by a mason who chased away the dog with an iron bar, little Joseph suffered fourteen deep bites on his arms and thighs. When the dog was caught, the worst was confirmed--the dog was rabid.

The horror of rabies was well known since ancient times. Called le rage in French, its very name meant "madness." It loomed large in the public imagination as a sickness--caught from the bite of a slavering, monstrous beast--that slowly transformed the victim into a crazed monster himself.

The first signs of rabies are deceptively benign--fever and headache. They are followed shortly thereafter by anxiety and agitation. The patient becomes completely unable to swallow, and so begins to drool and foam at the mouth. What follows is the most terrifying symptom of rabies, a condition known as hydrophobia. Though desperately thirsty, the patient is overcome with fear of water. Hallucinatory delirium soon overtakes the patient, punctuated by periods of cruel lucidity during which the patient is fully aware of his plight and his fate. When, three days after the onset of symptoms, coma and death finally come--as they once did for all those infected with rabies--it is a blessing.

Perhaps the worst psychological torment for the dog-bitten victim was the waiting. From the time of the bite, these poor souls could go weeks to months with no symptoms whatsoever, not knowing whether they would live ... or die a horrifying death. With no knowledge of the cause of rabies, superstition and quackery dominated efforts to prevent the onset of the dreaded disease. In centuries past, victims bitten by mad dogs often made long journeys to Liege, in France, to undergo ritualistic Catholic exorcism at the Abbey of Saint Hubert, the patron saint of the hunt and protector of the dog-bitten. Meister's mother, however, had a better option. She knew that the great Louis Pasteur was working on developing a vaccine for rabies and she rushed with her son to the Pasteur laboratory in Paris.

By this time, Pasteur had been working for four years on developing a rabies vaccine. In order to create the vaccine, the rabies microbe had to be cultivated in the laboratory and then weakened so that the vaccine itself wouldn't cause the disease. The method of weakening the rabies microbe was in fact developed by Pasteur's talented collaborator, Emile Roux, who had the idea that carefully drying the brain and spinal cord tissue of rabid animals would progressively weaken the virus contained in these nerve tissues.

Even with this method discovered, the problem remained of acquiring the rabies virus for study. Pasteur and his associates had to undertake the perilous task of capturing and housing rabid dogs and, worse still, extracting the infectious saliva from these fierce animals. Rene Vallery-Radot, Pasteur's son-in-law, witnessed one such scene in which Pasteur took a sample from a rabid bulldog:
  Two youths ... threw a cord with a slip loop over the dog, as a
  lasso is thrown. The animal was caught and drawn to the edge
  of the cage. There they managed to get hold of him and to
  secure his jaws; and the dog, sufocating with fury, his eyes
  bloodshot, and his body convulsed with violent spasm, was
  extended upon the table and held motionless, while Pasteur,
  leaning over his foaming head, at the distance of a finger's
  length, sucked up into a narrow tube some drops of saliva. ...
  [W]itnessing this formidable tete-a-tete, I thought Pasteur grander
  than I had ever thought him before. (26)


Pasteur and his colleagues would take these saliva samples and use them to infect rabbits with rabies. After several weeks, they would euthanize the rabbits and extract their spinal cords for Roux's drying procedure. Even this was fraught with peril. As Roux's niece, Marie Cressac, explained:
  If the animal, despite all the precautions, caused them to make a
  false move, if one of them had cut himself with his scalpel, and if
  a small piece of the rabid spinal cord had penetrated into the cut,
  there would have been weeks and weeks filled with the anguished
  question: will he or will he not come down with rabies? ... At the
  beginning of each session, a loaded revolver was placed within their
  reach. If a terrible accident were to happen to one of them, the
  more courageous of the two others would put a bullet in his head ...
  They were no longer just "researchers" absorbed in the meticulous
  work of their laboratory; they were pioneers, adventurers of
  science. (27)


Thanks to this daring work, upon the arrival of Meister and her son in July 1885, Pasteur had a vaccine that might help young Joseph. The vaccine was only a prototype--it had been used to successfully vaccinate dogs against rabies, but it had not yet been successfully used in humans. Pasteur had made a futile effort to save two people who had already developed the full symptoms of rabies, but he learned that the vaccine was of no use at this late stage of the disease. Meister had been bitten only two days before his arrival at the Pasteur laboratory and likely would not manifest symptoms for weeks or even months. Nevertheless, Pasteur knew that Joseph was certain eventually to die a horrifying death if he did not try to save him.

Pasteur began to treat him immediately. He explained that Joseph would receive thirteen injections into his abdomen over ten days. The first vaccine would be the most weakened version of the rabies virus, and each injection thereafter would be a progressively stronger version of the virus. Meister's body would thereby be given the chance to fight increasingly stronger forms of the rabies virus--essentially training Meister's immune system to fight off the full-strength form of the rabies virus with which he had been infected.

In the days after Meister had been treated, fears ran high--if he were to develop rabies in spite of the vaccine, it would happen within a month. Pasteur was extremely anxious. Fortunately, when one month came, Meister proved to be in perfect health, and Louis Pasteur became a worldwide sensation.

Young Meister remained forever grateful to Pasteur. He went on to be employed as a guard in the Pasteur Institute; and, more than fifty years later, it was Joseph Meister who gallantly stood his ground against the Nazis to protect his patron's gravesite. (28)

Pasteur's Legacy (1886-present)

Pasteur was fully prepared to capitalize on the fame his rabies cure brought him. "It is my intention," he wrote in 1886, "to found in Paris a model establishment that does not require state funding but would be financed by gifts and international subscriptions." (29) With these words, Pasteur began a remarkable project to create a private scientific institution dedicated to "the treatment of rabies ... and the study of virulent and contagious diseases. "30 Soon, eleven newspapers put out calls for subscription donations from all over the world. Far from sitting on the sidelines, Pasteur personally called on potential donors, and he even donated 100,000 francs himself.

On November 14, 1888, the Pasteur Institute was inaugurated in Paris. Altogether, 2.5 million francs--more than $14 million today--had been raised to fund it. Pasteur was present at the opening but, unfortunately, had suffered a debilitating stroke and was unable to speak. His grandson, Jean-Baptiste, read on his behalf a speech that Pasteur had written. In the speech, Pasteur implored his listeners to support teaching and research and encouraged in his followers the highest levels of honesty and integrity in science. Here is an excerpt:
  What I am here asking of you, and what you in turn will ask of those
  whom you will train, is the most difcult thing the inventor has to
  learn. To believe that one has found an important scientific fact
  and to be consumed by desire to announce it, and yet to be
  constrained to combat this impulse for days, weeks, sometimes
  years, to endeavor to ruin one's own experiments, and to announce
  one's discovery only after one has laid to rest all the contrary
  hypotheses, yes, that is indeed an arduous task. But when after all
  these one finally achieves certainty, one feels one of the deepest
  joys it is given to the human soul to experience. (31)


As Pasteur's health failed, his thoughts remained on the work of the Pasteur Institute and the proteges whom he had trained. In one of his last private letters, he wrote:
  Our only consolation, as we feel our own strength failing us, is to
  feel that we may help those who come after us to do more and to
  do better than ourselves, fixing their eyes as they can on the great
  horizons of which we only had a glimpse. (32)


Pasteur died on September 28, 1895. The horizons he glimpsed at the end of his life were great indeed, and scientists of the Pasteur Institute no doubt surpassed his wildest dreams. Emile Roux, Pasteur's closest associate, went on to discover antiserum therapy for diphtheria. Elie Metchnikoff, a German-trained, Russian scientist whom Pasteur had personally appointed to the Institute in 1888, shared the 1908 Nobel Prize in Medicine for his discoveries on the nature of cellular immunity. Albert Calmette, who had worked with Pasteur, founded a new Pasteur Institute in Saigon, and another in Lille. Calmette's work led to the discovery of antivenom for snakebite and, with his assistant Camille Guerin, the discovery of a vaccine for tuberculosis. In 1894, Alexandre Yersin isolated the germ that caused plague--henceforth named Yersinia pestis--and discovered that it was harbored in rats. Charles Nicolle, who founded the Pasteur Institute of Tunis, earned a Nobel Prize in 1928 for his discovery that epidemic typhus was transmitted to humans by lice. He also discovered that leishmaniasis was an infection carried by dogs and transmitted to humans by the sand fly. Jules Bordet, after founding the Pasteur Institute of Belgium, won the 1919 Nobel Prize for his discovery of the germ that causes whooping cough--that germ would later bear his name, Bordetella pertussis.

The Pasteur Institutes remain at the forefront of medical research to this day. All in all, eight Pasteurian scientists have collected Nobel Prizes in Physiology or Medicine, most recently for the discovery of HIV as the causative agent of AIDS.

Pasteur and his institute changed the way people thought about medical science in the 19th century. Once accustomed to disease as a way of life, people began to hope for and expect medical advancements from science that could cure or prevent disease. As the century turned, a new legion of scientists would rise up and fulfill those hopes by following Pasteur's example.

Pasteur's contribution to medical science cannot be overstated. At the turn of the 20th century, the life expectancy in the United States was forty-nine years, and the three leading causes of death were all infectious diseases--influenza/ pneumonia, tuberculosis, and diarrheal infection. (33) Pasteur's groundbreaking research led to the creation of vaccine therapy, preventing millions of deaths. His techniques and influence led directly to the development of powerful antimicrobial therapies such that in 2008 life expectancy was seventy-eight years, and infectious disease was no longer even in the top five causes of death. (34)

Pasteur is one of the few scientists who have the distinction of inaugurating an entire field of study--in Pasteur's case, microbiology and immunology--and his work led the way in vanquishing many microbial diseases. In a lecture at Yale, the great physician William Osler gave voice to Pasteur's greatness:
  At the middle of the last century we did not know much more of the
  actual causes of the great scourges of the race, the plagues, the
  fevers and the pestilences, than did the Greeks. Here comes Pasteur's
  great work. Before him Egyptian darkness; with his advent a
  light that brightens more and more as the years give us ever
  fuller knowledge. (35)


Ranging from knowledge of crystalline forms to vaccines, Pasteur's achievements may at first glance appear to be disparate and random, yet nothing could be further from the truth. To the contrary, Pasteur was a master integrator, seeing the connections between wide-ranging phenomena: chemical crystals and molecular asymmetry; molecular asymmetry and microorganisms; microorganisms and disease; disease and immunity.

Today the academic Pasteur--with his characteristic skullcap, beard, and pince-nez--may seem too professorial for the role of crusading hero. But, in this case, looks are deceiving. In his day, his fire and courage were manifest to all who saw him, as reported by a journalist describing a 59-year-old Pasteur on his election to the Academie francaise: "The most striking thing about him is the characteristic energy. His features are strongly marked, his eyes are lively, his body robust. His masculine and clipped speech reveals a man for whom there is no such thing as obstacles or fatigue." (36)

In his speech at Yale, Osler emphasized that Pasteur left us not only with increased knowledge, but with an ideal we can look up to. "The story of Pasteur's life," he said, "should be read by every student. It is one of the glories of human literature, and, as a record of achievement and of nobility of character, is almost without equal." (37) Indeed, Pasteur--through his heroic life and world-changing, life-saving discoveries--is a supreme inspiration. To any who aspire to moral greatness in their own lives, Pasteur's story is a guiding light--a light that brightens more and more.

Endnotes

(1.) Patrice Debre, Louis Pasteur, translated by Elborg Forster (Baltimore, MD: The Johns Hopkins University Press, 1994), p. 496. Note that, where not otherwise indicated, the account of Pasteur's life contained in this article relies on the work of two of his best biographers, Patrice Debre and Rene Vallery-Radot.

(2.) Max Perutz, "The Pioneer Defended," The New York Review of Books, December 21, 1995, http://www.nybooks.com/articles/archives/1995/dec/21/the-pioneer-defended/.

(3.) Bill Wasick and Monica Murphy, Rabid: A Cultural History of the World's Most Diabolical Virus (London: Viking Penguin, 2012), p. 157.

(4.) Debre, Pasteur, p. 1.

(5.) Debre, Pasteur, p. 44.

(6.) Debre, Pasteur, p. 48.

(7.) Debre, Pasteur, p. 70.

(8.) Debre, Pasteur, p. 77.

(9.) Debre, Pasteur, p. 84.

(10.) Debre, Pasteur, p. 87.

(11.) Maxime Schwartz, "The Life and Works of Louis Pasteur," Journal of Applied Microbiology, vol. 91 (2001): pp. 597-98.

(12.) Debre, Pasteur, p. 504.

(13.) Schwartz, "Life and Works," p. 598.

(14.) Debre, Pasteur, p. 149.

(15.) Anthony Serafini, The Epic History of Biology (Cambridge, MA: Perseus Publications, 1993), p. 251.

(16.) Debre, Pasteur, p. 169.

(17.) Debre, Pasteur, p. 278.

(18.) Debre, Pasteur, pp. 378-79.

(19.) Debre, Pasteur, p. 379.

(20.) Dorothy H. Crawford, Deadly Companions: How Microbes Shaped Our History (New York: Oxford University Press, 2007), pp. 169-73.

(21.) Ron Chernow, George Washington: A Life (New York: Penguin Press, 2010), p. 199.

(22.) Crawford, Deadly Companions, pp. 173-75.

(23.) Debre, Pasteur, p. 380.

(24.) Debre, Pasteur, pp. 388-90.

(25.) Susan D. Jones, Death in a Small Package: A Short History of Anthrax (Baltimore: Johns Hopkins University Press, 2010), p. 13.

(26.) Rene Vallery-Radot, Louis Pasteur: His Life and Labours, translated by Lady Claud Hamilton (New York: D. Appleton and Company, 1885), p. 300.

(27.) Debre, Pasteur, p. 430.

(28.) Sadly, Meister, in his despair over the Nazi occupation, later took his own life.

(29.) Debre, Pasteur, p. 462.

(30.) Debre, Pasteur, p. 464.

(31.) Debre, Pasteur, p. 472.

(32.) Wasick and Murphy, Rabid, p. 146.

(33.) "Leading Causes of Death, 1900-1998," National Vital Statistics System, Centers for Disease Control, p. 67, http://www.cdc.gov/nchs/data/dvs/lead1900_98.pdf.

(34.) A. Minino et al., "Deaths: Final Data for 2008," National Vital Statistics Report, vol. 59, no. 10 (2011): p. 1.

(35.) William Osler, The Evolution of Medicine: A Series of Lectures Delivered at Yale University on the Silliman Foundation in April, 1913, Kindle Edition.

(36.) Debre, Pasteur, p. 375.

(37.) Osler, Evolution of Medicine.

Ross England is a student at Temple University School of Medicine in Philadelphia, where he will graduate in 2015 with an MD and a PhD in physiology. He is a graduate of the Schreyer Honors College of Pennsylvania State University, where he earned a bachelor of science in biology in 2008.
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