12 May

Microbe  hunting  was not uncommon in the first-half of the nineteenth century,  and  Louis  Pasteur   (1822–1895) was  not  the  first  to  argue that infectious diseases were caused by germs, but his work was of paramount importance in demonstrating the relevance of germ theory to infectious disease, surgery, hospital management, agriculture, and indus- try.  Pasteur’s  work  illuminated  many  areas  of the  nineteenth-century science, including  stereochemistry,  fermentation, biogenesis,  the  germ theory   of  disease,  immunology,   virology,   disinfection,   sterilization, and the preparation of protective  vaccines. Generally,  Pasteur  and  his associates  were involved  in several research  problems  simultaneously. The  interaction  between  Pasteur’s  many  interests  makes  it impossible to  discuss his work  as an  orderly  chronological  progression,  but  this complexity reflects his belief that ‘‘the sciences gain by mutual support.’’ His  career  can  also  serve  as  a  case  study  for  the  interplay  between researches devoted to practical problems and so-called pure or basic scientific knowledge.

As a youth,  Pasteur  was a diligent student  and talented  artist,  but his high  school  work  in chemistry  was rated  only  mediocre.  (Stories about  such ludicrous  errors  in judgment  by teachers  of the gifted and talented  seem to be a required  part  of the hagiography  of great scien- tists,  perhaps  to  give hope  to  underachieving students  and  to  make teachers  more  humble.)  Pasteur’s  first attempt  at  student  life in Paris in 1838 led to homesickness so acute that he had to return  to his family. Portrait painting during this period seemed to provide a form of therapy and the energy to return  to his studies. Eventually,  Pasteur  decided to abandon art  in order  to devote all his energies to science. He went on to study chemistry and physics with distinction,  but the most important

lesson  he  learned  from  his  studies  at  the  prestigious  E´ cole Normale

Supe´rieure  of  Paris  was  a  willingness to  apply  the  experimental  ap- proaches  he had learned  in chemistry to a broad  range of problems  in biology and medicine, areas in which he had no specific training.

The research problems  and methods  that  Pasteur  assimilated  as a doctoral  student led to studies of many different problems. Nine specific

Louis Pasteur studying rabies

Louis Pasteur  studying rabies.

aspects of his work were carved into the marble  walls of the chapel at the Pasteur  Institute  in Paris  where he was buried:  molecular  dissym- metry, fermentations, studies of so-called spontaneous generation,  stud- ies of wine, diseases of silkworms,  studies of beer, contagious  diseases, protective  vaccines,  and  the  prevention   of  rabies.  Although   Pasteur was actually more interested in broad  philosophical  questions and basic scientific issues than specific medical problems, in terms of the history of medicine,  he is primarily  remembered  for  the  practical  aspects  of his work  that  are  most  directly  related  to  understanding and  preventing infectious diseases.

Studies  of crystal  structure,  stereoisomerism,  and  molecular  dis-

symmetry   seem  remote   from  medical  microbiology,   but   this  work

provided  the unifying thread  that  guided Pasteur  through  the labyrinth of  research.  Pasteur  discovered  that  certain  organic  molecules  could exist as mirror images, that is, as right-handed and left-handed  versions, rather  like gloves or mittens.  As Pasteur  pursued  this remarkable trait from  the  behavior  of crystals  to  that  of microorganisms, he came to see molecular dissymmetry as a fundamental criterion that distinguished the chemical processes of vital phenomena from those of the inanimate world.

Among  the aphorisms  of Louis Pasteur,  the most quoted  have to do with the importance of theory  and the role of chance in discovery. He  insisted  that   the  theoretical   was  as  important  as  the  practical, although  he accepted  the idea that,  for the good of the state,  scientific education  should be made relevant to industrial  and commercial needs.

‘‘Without  theory,’’  Pasteur  argued,  ‘‘practice  is but  routine  born  of habit.’’ When asked the use of a purely scientific discovery, Pasteur liked to pose the question: ‘‘What is the use of a newborn child?’’ By chance, Pasteur  discovered  that  mold  growing  in solutions  of certain  organic chemicals fermented  the right-handed form  but  not  the mirror  image. In keeping with his conviction  that  ‘‘in the field of observation, chance favors  only  the  mind  that  is prepared,’’  Pasteur  followed  the  impli- cations  of this  observation on  to  fundamental studies  of  the  role  of microorganisms in fermentation.

When  Pasteur  was appointed Professor  of Chemistry  and  Dean

of Sciences at the University of Lille, he was urged to assist local indus- tries. Applying the methodology  he had used in his studies of crystals to fermenting vats of beet juice, Pasteur observed microorganisms  and optically  active  products  of  fermentation. His  stereochemical  studies led him to the hypothesis  that  the fermentation process was dependent on  living  germs  or  ferments.   Previous  speculations   about   the  role of yeasts in fermentation had been ridiculed by Justus von Liebig (1803–1873), Jo¨ ns Jacob  Berzelius (1779–1848), and  Friedrich  Wo¨ hler (1800–1882), the most  illustrious  organic  chemists  of the period,  who argued that fermentation was a purely chemical process and that microorganisms were the product rather  than the cause of fermentation. Although  today Pasteur is universally known, Liebig has been called the greatest organic chemist of the nineteenth  century. Like Pasteur,  Liebig was known for his combative personality, quarrelsome  nature, pro- ductivity,  and his ability to pursue  many projects simultaneously.

Further experiments  on a variety  of fermentations led Pasteur  to

the conclusion  that  all fermentations are caused by specific, organized ferments. Changes in environment, temperature, acidity, composition  of the  medium,  and  various  poisons  affected  different  ferments  in  par- ticular  ways. Moreover,  Pasteur  suggested  that  living ferments  might be the  cause of infectious  diseases as well as fermentation. Although Joseph  Lister’s work on the antiseptic  system of surgery owed a great

deal to Pasteur’s fermentation studies, most physicians rejected the idea that the diseases of wine and beer were related to human disease. Never- theless, Pasteur’s fermentation studies made it possible to improve  the production of wine, beer, vinegar, and so forth.  Establishing  controlled conditions  for  fermentation, partial  sterilization  (pasteurization), and the preparation of pure  inocula  were developments  that  were immedi- ately applicable  to  many  industrial  problems  of substantial economic importance.

Studies  of  fermentation led Pasteur  to  a  declaration of  war  on the  ancient  doctrine  of spontaneous generation.  Friends  warned  him against  being drawn into a contest that  could not be won, for one can- not  prove  a universal  negative.  That  is, one  cannot  prove  that  spon- taneous  generation  never occurred,  never occurs,  or  never will occur. Certainly, Pasteur did not enter the battle with an open mind. Although his private  notebooks reveal that  he was fascinated  by the doctrine,  in public  he  was  passionately  dedicated  to  destroying  advocates  of  the doctrine  of spontaneous generation  and their allies in the medical pro- fession. Building on an experimental  approach that  can be traced  back to  Francesco   Redi’s  (1626–1698) studies  of  the  alleged  spontaneous generation of flies in rotting meat, Pasteur set out to prove that microbes do not spontaneously arise in properly  sterilized media and that  all the so-called evidence in support  of the contrary  proposition was the result of careless technique  and experimental  artifacts.

Philosophical  arguments  about  the origin of life, materialism  and

atheism,  or religion and  spiritualism  were irrelevant  to the daily con- cerns of wine-makers  and  surgeons.  The practical  point  established  in the context of the spontaneous generation  controversy  was that,  under present  conditions,  fermentation, putrefaction, infection,  and epidemic diseases were caused by specific microbes found  in the air and on sur- faces, including  instruments, bandages,  sponges,  and  the hands  of the surgeon. The germ-carrying  capacity of air could be measured by suck- ing air through  cotton  filters to trap  the germ-laden dust particles. The numbers  and kinds of germs in the air depended on many environmen- tal factors; for example, the germ content  of hospital  air was quite high compared  with that  of mountain air.

One   of   Pasteur’s   simplest   and   most   convincing   experiments involved the use of specially constructed swan-neck flasks. When liquids were properly  sterilized  in flasks  with  long  necks  drawn  out  into  an S-shaped curve under a flame, the medium remained sterile even though ordinary air could enter the flask. Critics could not argue that some mysterious  life force had  been tortured out  of the medium,  because if the flask was tipped  so that  sterile medium  mixed with the germ-laden dust  particles  trapped  in the bend  of the swan neck, the medium  was soon  teeming with microbial  life. Although  almost  all kinds  of media could be sterilized by fairly simple means, certain  apparent exceptions

were eventually traced to the existence of heat-resistant spores that gave rise to microbes under  appropriate conditions.  Convinced  that  a revo- lution  in medicine would only become possible when the defenders  of spontaneous generation  were totally defeated, Pasteur  and his disciples created the sterile techniques  that  made modern  microbiology  and sur- gery possible. Despite  the apparent futility of jousting  with the advo- cates of spontaneous generation,  Pasteur  warned  that  the development of rational methods for the prevention and treatment of disease depended on annihilating  the erroneous  doctrine  of spontaneous generation.

Well aware of the skepticism with which the conservative  medical

profession  regarded  his theories,  Pasteur  was apparently reluctant  to begin a direct  assault  on the diseases of higher  animals.  However,  in

1865, at  the  request  of  his  friend  Jean  Baptiste  Dumas  (1800–1884) and  the  Minister  of  Agriculture,  Pasteur  became  involved  in  studies of silkworm diseases. By 1870, Pasteur  had demonstrated the existence of two microbial  diseases in silkworms.  The condition  that  was threat- ening the silkworm industry  of France,  however, was the result of com- plex interactions among environmental factors,  nutritional deficiencies, and  microbes.  Research  on  silkworms  provided  a transition  between Pasteur’s studies of fermentation and his studies of the microbial agents that  cause anthrax, chicken cholera,  swine erysipelas,  puerperal  fever, cholera,  and  rabies.  As Pasteur  became more confident  of the general applicability  of the germ theory  of disease, he acquired  collaborators with the skills that  made it possible to carry out experiments  on higher animals and even human  patients.  Contrary to the Pasteur  mythology, not  all of these studies  were successful. For  example,  his studies  of a microbe found in victims of childbed fever led him to warn hospital per- sonnel that  they carried  the microbe  from  infected women  to healthy women, but, like Oliver Wendell Holmes and Ignaz Philipp Semmelweis, he failed to convince physicians of the need to change their approach to obstetrics and gynecology. Indeed, an outraged opponent challenged Pasteur to a duel for this assault on the honor of the medical profession. Such violent and personal animosity was not characteristic  of the entire medical  and  public  health  community.  Many  of France’s  statistically based hygienists, for example, enthusiastically  accepted  Pasteur’s work as an asset to their own public health reform campaigns. Although  some French  physicians  resisted  Pasteur’s  ideas  because  they  anticipated a new form  of preventive  medicine  that  would  threaten  the  profession and practice of medicine, by about  1895 this opposition  was essentially disarmed by the prospects of powerful new therapeutic tools that strengthened the medical profession.  Ultimately,  of course, Pasteur  and the research institute  dedicated  to him became icons of French  science. According to Nobel Laureate  Franc¸oise  Jacob (1920–), when a Cabinet minister  suggested  making  some  changes  to  the  Colle`ge  de  France, General  de  Gaulle  (1890–1970) retorted:   ‘‘There  are  three  things  in

France  that  are inviolable: the Colle`ge de France,  the Pasteur  Institute, and the Eiffel Tower.’’

Rabies,  a rare  but  fatal  human  disease, and  its invisible microbe

provided  Pasteur’s most famous triumph. In his development  of a pro- tective vaccine against rabies, Pasteur  provided  ample proof of his con- tention  that  microbiology  was a demonstration of how the role of the

‘‘infinitely small in nature  is infinitely  great.’’ The  first  step in all his previous  studies of specific diseases had  been to find the microbe,  but all efforts to identify the causative agent for rabies proved  futile. At a time  when  scientists  were  just  beginning  to  formulate   the  technical and  theoretical  problems  of immunization, Pasteur  was able to  make the intellectual  leap of developing  a vaccine against  an invisible virus. During this period, the term virus was traditionally used in a nonspecific sense in referring  to  an  unknown  disease-causing  agent  or poison.  In terms  of modern  virology,  rabies  is an acute  fatal  encephalitis  caused by neurotropic viruses in the genus Lyssavirus, family Rhabdoviridae. The  majority  of rabies  cases are  caused  by bites  by rabid  mammals. After an incubation  period of several weeks to months,  the virus makes its way to the central  nervous  system where it replicates.  Rabies  virus can then  be disseminated  to the salivary  glands  and  other  organs  via the nerves. Modern  medicine has provided an unanticipated mechanism for the transmission of rabies from person to person. Three people died of rabies in 2004 after  receiving infected organs  (lungs, kidneys,  liver) from  the  same  donor.  The  donor  had  shown  no  symptoms  of rabies before  his death  from  a brain  hemorrhage. Previous  reports  indicate that  at  least  eight  people  have  contracted the  rabies  virus  through cornea  transplants.

Given  the difficulties involved  in pursuing  this project,  Pasteur’s

decision to study a disease as rare as rabies when there were so many common   diseases  that   might  have  been  easier  to  work  with  seems puzzling. Several answers have been offered. Perhaps  it really was the haunting  memory of the howls of the mad wolf that had invaded Arbois when Pasteur  was a boy and the screams of its victims as their wounds were cauterized.  Alternatively,  the choice may have reflected Pasteur’s ambition  and  his flair  for  the  dramatic.  However,  Pasteur  had  done enough to achieve immortality  before embarking on what was obviously a dangerous  project,  for research on rabies must begin with one of the most feared of all creatures,  the mad dog.

Another  factor influencing Pasteur’s choice may have been the ten-

sion between his condemnation of experimentation on human beings and his desire to prevent  human  disease. Human  experimentation, Pasteur believed, was not only immoral,  but also criminal. Moreover,  his entry into  the study  of human  diseases was apparently inhibited  by a deep antipathy for  vivisection and  his ambivalence  towards  physicians.  To reconcile  these  conflicts,  Pasteur  needed  a disease shared  by humans

and animals that was invariably fatal so that an experimental  treatment could  not  make  the  outcome  any  worse.  Whatever  the  motive  might have been, Pasteur  had chosen well; the success of his quest for a rabies vaccine was greeted throughout the world as the greatest  achievement of  microbiological  science. (Those  old  enough  to  remember  the  fear aroused  by polio might reflect upon  the similar outbursts of joy, hope, and gratitude  that greeted Jonas Salk (1914–1995) and the polio vaccine in the 1950s.) The real Pasteur,  a great scientist who certainly  had  his faults and failures, all but disappeared  under the weight of myth, romanticism, and  adoration. Venerated  by the public  as genius, hero, and  saint,  Pasteur,  or  the  mythic  Pasteur,  became  the  target  of  late twentieth-century historians  of science.

The  difficulty  of  predicting  the  outcome  of  the  bite  of  a  rabid

animal  is a  complicating  factor  in assessing Pasteur’s  rabies  vaccine. That is, rabies was invariably fatal if contracted, but not all encounters with mad dogs result in human rabies; and not all ‘‘mad dogs’’ are actu- ally rabid. Moreover,  the incubation  period for rabies is so variable that in some cases the association  between bite and disease was difficult to assess. The  English  surgeon  John  Hunter  (1728–1793) noted  a report of a dog  that  allegedly bit  21 people.  None  of these  people  received any medical attention, but only one became ill. If all of them had been treated,  the attending  doctors  would have claimed 20 cures. Neverthe- less, physicians were unlikely to forego treatment, even if their remedies did more harm than good. For example, the distinguished medieval physician  Arnau   de  Villanova  (c.  1235–1311) believed  that  wounds resulting  from  the  bites  of mad  dogs  should  not  be allowed  to  heal. Leeches, cupping  vessels, and  noxious  dressings  should  be applied  to the  open  wound  for  at  least  40 days.  The  notion  that  like cures like was the basis for remedies containing  either the worms found  under  a mad dog’s tongue  or the heart  of a hound.  According  to Anglo-Saxon folklore,  even mad  dogs had  medical virtues.  Mixing  a powder  made from the head of a mad dog with wine was said to produce a cure for scrof- ula (a form of tuberculosis  that  affects the lymph nodes of the neck).

In order  to isolate the rabies virus and prepare  a vaccine, Pasteur needed  a laboratory culture  of the causative  agent.  Obviously,  it was difficult to find rabid dogs on a routine  basis and even harder  to secure their  cooperation. Not  surprisingly,  kennels  for  rabid  dogs  were  as welcome in any neighborhood as an AIDS clinic in the 1980s or a toxic waste  dump.   A  reliable  and  relatively  safe  system  of  transmitting rabies,  which  involved  trephining  experimental  animals  and  inocula- ting infectious material  through  the dura  mater,  was used to study the disease  in  rabbits   and  other  animals.  Rabies  was  transmitted  from rabbit   to  rabbit   so  that   ‘‘fixed  virus’’  with  a  reproducible  degree of virulence and  a shortened  incubation  period  was always available. Finally,  Pasteur  and  his colleagues  discovered  that  when the  isolated

spinal  cord  of a rabid  animal  was subjected  to  increasing  periods  of air-drying,  the  rabies  virus  became  progressively  weaker.  To  test  the use of the air-dried  material  as a preventive  vaccine, dogs were inocu- lated  daily  with  suspensions  of  increasingly  virulent  preparations  of spinal cord. At the end of this procedure,  dogs were resistant  to rabies even if the most virulent preparations were inoculated  directly into the brain.  By  1885,  Pasteur   was  satisfied  that  he  could  reliably  induce immunity  to rabies in dogs.

The  question  of  the  safety  and  effectiveness  of  this  vaccine  in human  beings could  not  be avoided  once the results on dogs became known.  Protecting  people  by immunizing  all the  dogs  in France  was surely an impossible task; moreover,  wild animals served as an infinite reservoir of disease. Obviously,  rabies vaccine was not a candidate  for mass  immunizations because  human  rabies  was too  rare  a condition to justify a dangerous  series of painful  injections.  However,  Pasteur’s vaccine was the only hope  against  the pain,  suffering,  and  death  that were inevitable  for those who contracted the disease. On July 6, 1885, nine-year-old  Joseph  Meister  was brought  to Pasteur’s  laboratory. He had  sustained  at  least 14 wounds,  some very deep, when attacked  by a mad dog two days before. Physicians who examined the boy did not doubt that he would contract  rabies and that death was inevitable. After consultation  with  colleagues  at  the  Academy  of  Medicine,  Pasteur initiated  the immunization procedure.  Despite  the discomfort  entailed by  the  long  course  of  injections,  Joseph  made  a  complete  recovery. The next well-known patient  was a 15-year-old boy who had been sav- agely bitten by a rabid dog six days before treatment began. News of the apparently successful use of Pasteur’s vaccine created  both  bitter  criti- cism and excessive hope. Pasteur was attacked  by physicians, veterinari- ans, antivivisectionists,  and antivaccinators, while terrified victims of the bites of rabid  (or presumably  rabid)  animals besieged his laboratory.

The uncertainties inherent  in the course of human  rabies and the crudeness of the vaccine led to tragic failures and successes. Successful immunization depends on how soon the inoculations  are begun and the individual’s reaction  to the vaccine. A certain number  of deaths due to reactions to the vaccine were inevitable. Critics could always charge that success measured  only  by the  failure  of patients  to  die of rabies  was meaningless. When some patients  developed  paralysis,  Pasteur’s critics called him an  assassin  and  charged  him with  infecting  human  beings with ‘‘laboratory rabies.’’ However, when victims of dog bites compared the risks of the Pasteur  treatment to rabies, thousands decided that  the vaccine was a great victory in the battle between science and disease and chose the vaccine. Throughout the world, people echoed Joseph Lister’s tribute  to Louis Pasteur:  ‘‘Truly there does not exist in the whole world a person  to  whom  medical science owes more  than  to  you.’’ Perhaps Pasteur’s German  counterpart Robert  Koch would have quarreled  with

that  assessment.  The hostility  between Koch  and  Pasteur  was due, at least in part,  to nationalistic  rivalries inflamed  by the Franco-Prussian War,  but  there  were also  major  differences  in their  goals,  objectives, scientific style, and personalities.

Pasteur’s account  of Joseph  Meister’s treatment was presented  to the  Academy  of  Science of Paris,  in October  1885. Newspapers  and journals  quickly disseminated  news of the rabies vaccine and generated interest  in  the  germ  theory  of  disease  and  expectations  of  imminent cures  for  other  deadly  diseases.  Victims  of  bites  by  rabid  dogs  and wolves were  soon  appealing  to  Pasteur  for  treatment. For  example, when  a  rabid  dog  bit  seven  dogs  and  six children  in  Newark,  New Jersey, the boys were sent to France,  where they received the Pasteur vaccine. When the boys returned,  they were widely exhibited, which cre- ated  additional interest  in Pasteur’s  work  and  his germ theory  of dis- ease.  During  the  twentieth  century,  efforts  to  prevent  rabies  in  the United  States  were largely directed  at  domestic  animals,  which repre- sented most reported  cases before 1960. Because of the success of such campaigns, by 2000, only 10 percent of rabies incidents were attributed to domestic animals. Rabies-related human deaths dropped  from more than one hundred  a year in the early 1900s to about  two a year. However, about  40,000 people in the United States are treated  for rabies exposure annually, primarily because of contact with rabid raccoons, coyotes, and bats.  Federal  and  state  officials  have  attempted to  eradicate  raccoon rabies  by dropping  bait  containing  oral  rabies  vaccine from  aircraft. Switzerland and France used oral vaccine to become rabies-free. Statistically,  however, rabid  bats pose a greater danger  than  raccoons.

In public,  Pasteur  insisted on a rational  scientific method,  but  in private he pursued a more empirical approach, often guided by theories that  might  be considered  irrational. His colleague,  the clinician Emile Roux,  urged  more  caution  and  was critical  of Pasteur’s  approach to human   experimentation.  Some  historians   of  science  have  depicted Pasteur  as ‘‘authoritarian, politically reactionary, self-deceiving, overly concerned with priority and credit, ungenerous  to his assistants, ruthless with  his  adversaries,  and  recklessly  overconfident   in  putting  human patients  at  risk.’’ However,  other  scholars  and  scientists  argue  that Pasteur  took  calculated  risks that  were appropriate to the information available  to him and the dangers  that  his human  subjects were already facing. Pasteur was a public figure and a scientist and he was very adept at  attracting attention  and  converting   people  to  his  views.  Pasteur apparently chose to conceal  ambivalent  or unfavorable aspects  of his work on rabies and anthrax. At least two patients  had been inoculated with  rabies  vaccine  before  Joseph  Meister,  but  the  results  were con- sidered inconclusive and they were not published. Not surprisingly, Pasteur’s  critics called his rabies  vaccine dangerous  and  his defenders insisted  on  the  relative  safety  of  the  vaccine  in the  face of a  deadly

disease. Pasteur’s advocates emphasized the fact that there are unknown risks inherent  in all medical therapies  and known  risks inherent  in the diseases that  scientists selected for their research.  Historians of science have  also  subjected  Pasteur’s  work  on  vaccines to  scathing  criticism, but,  it should  be noted,  many of the difficulties and  uncertainties that Pasteur  and  his  contemporaries faced  in  attempting to  develop  safe and effective vaccines remain unresolved.

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