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Friday, February 15, 2019

Louis Pasteur (updated)

From Wikipedia, the free encyclopedia
Louis Pasteur

Louis Pasteur, foto av Paul Nadar, Crisco edit.jpg
Photograph by Nadar
BornDecember 27, 1822
DiedSeptember 28, 1895 (aged 72)
NationalityFrench
Alma mater
Awards
Scientific career
Fields
Institutions
Notable studentsCharles Friedel
Signature
Louis Pasteur Signature.svg

Louis Pasteur (/ˈli pæˈstɜːr/, French: [lwi pastœʁ]; December 27, 1822 – September 28, 1895) was a French biologist, microbiologist and chemist renowned for his discoveries of the principles of vaccination, microbial fermentation and pasteurization. He is remembered for his remarkable breakthroughs in the causes and prevention of diseases, and his discoveries have saved many lives ever since. He reduced mortality from puerperal fever, and created the first vaccines for rabies and anthrax.

His medical discoveries provided direct support for the germ theory of disease and its application in clinical medicine. He is best known to the general public for his invention of the technique of treating milk and wine to stop bacterial contamination, a process now called pasteurization. He is regarded as one of the three main founders of bacteriology, together with Ferdinand Cohn and Robert Koch, and is popularly known as the "father of microbiology".

Pasteur was responsible for disproving the doctrine of spontaneous generation. He performed experiments that showed that without contamination, microorganisms could not develop. Under the auspices of the French Academy of Sciences, he demonstrated that in sterilized and sealed flasks nothing ever developed, and in sterilized but open flasks microorganisms could grow. Although Pasteur was not the first to propose the germ theory, his experiments indicated its correctness and convinced most of Europe that it was true.

Today, he is often regarded as one of the fathers of germ theory. Pasteur made significant discoveries in chemistry, most notably on the molecular basis for the asymmetry of certain crystals and racemization. Early in his career, his investigation of tartaric acid resulted in the first resolution of what is now called optical isomers. His work led the way to the current understanding of a fundamental principle in the structure of organic compounds.

He was the director of the Pasteur Institute, established in 1887, until his death, and his body was interred in a vault beneath the institute. Although Pasteur made groundbreaking experiments, his reputation became associated with various controversies. Historical reassessment of his notebook revealed that he practiced deception to overcome his rivals.

Education and early life

The house in which Pasteur was born, Dole
 
Louis Pasteur was born on December 27, 1822, in Dole, Jura, France, to a Catholic family of a poor tanner. He was the third child of Jean-Joseph Pasteur and Jeanne-Etiennette Roqui. The family moved to Marnoz in 1826 and then to Arbois in 1827. Pasteur entered primary school in 1831.

He was an average student in his early years, and not particularly academic, as his interests were fishing and sketching. He drew many pastels and portraits of his parents, friends and neighbors. Pasteur attended secondary school at the Collège d'Arbois. In October 1838, he left for Paris to join the Pension Barbet, but became homesick and returned in November.

In 1839, he entered the Collège Royal at Besançon to study philosophy and earned his Bachelor of Letters degree in 1840. He was appointed a tutor at the Besançon college while continuing a degree science course with special mathematics. He failed his first examination in 1841. He managed to pass the baccalauréat scientifique (general science) degree in 1842 from Dijon but with a mediocre grade in chemistry.

Later in 1842, Pasteur took the entrance test for the École Normale Supérieure. He passed the first set of tests, but because his ranking was low, Pasteur decided not to continue and try again next year. He went back to the Pension Barbet to prepare for the test. He also attended classes at the Lycée Saint-Louis and lectures of Jean-Baptiste Dumas at the Sorbonne. In 1843, he passed the test with a high ranking and entered the École Normale Supérieure. In 1845 he received the licencié ès sciences (Master of Science) degree. In 1846, he was appointed professor of physics at the Collège de Tournon (now called Lycée Gabriel-Faure [fr]) in Ardèche, but the chemist Antoine Jérôme Balard wanted him back at the École Normale Supérieure as a graduate laboratory assistant (agrégé préparateur). He joined Balard and simultaneously started his research in crystallography and in 1847, he submitted his two theses, one in chemistry and the other in physics.

After serving briefly as professor of physics at the Dijon Lycée in 1848, he became professor of chemistry at the University of Strasbourg, where he met and courted Marie Laurent, daughter of the university's rector in 1849. They were married on May 29, 1849, and together had five children, only two of whom survived to adulthood; the other three died of typhoid.

Career

Louis Pasteur in 1857
Pasteur in 1857
 
Pasteur was appointed professor of chemistry at the University of Strasbourg in 1848, and became the chair of chemistry in 1852. In 1854, he was named dean of the new faculty of sciences at University of Lille, where he began his studies on fermentation. It was on this occasion that Pasteur uttered his oft-quoted remark: "dans les champs de l'observation, le hasard ne favorise que les esprits préparés" ("In the field of observation, chance favors only the prepared mind").

In 1857, he moved to Paris as the director of scientific studies at the École Normale Supérieure where he took control from 1858 to 1867 and introduced a series of reforms to improve the standard of scientific work. The examinations became more rigid, which led to better results, greater competition, and increased prestige. Many of his decrees, however, were rigid and authoritarian, leading to two serious student revolts. During "the bean revolt" he decreed that a mutton stew, which students had refused to eat, would be served and eaten every Monday. On another occasion he threatened to expel any student caught smoking, and 73 of the 80 students in the school resigned.

In 1863, he was appointed professor of geology, physics, and chemistry at the École nationale supérieure des Beaux-Arts, a position he held until his resignation in 1867. In 1867, he became the chair of organic chemistry at the Sorbonne, but he later gave up the position because of poor health. In 1867, the École Normale's laboratory of physiological chemistry was created at Pasteur's request, and he was the laboratory's director from 1867 to 1888. In Paris, he established the Pasteur Institute in 1887, in which he was its director for the rest of his life.

Research

Molecular asymmetry

Pasteur separated the left and right crystal shapes from each other to form two piles of crystals: in solution one form rotated light to the left, the other to the right, while an equal mixture of the two forms canceled each other's effect, and does not rotate the polarized light.
 
In Pasteur's early work as a chemist, beginning at the École Normale Supérieure, and continuing at Strasbourg and Lille, he examined the chemical, optical and crystallographic properties of a group of compounds known as tartrates.

He resolved a problem concerning the nature of tartaric acid in 1848. A solution of this compound derived from living things rotated the plane of polarization of light passing through it. The problem was that tartaric acid derived by chemical synthesis had no such effect, even though its chemical reactions were identical and its elemental composition was the same.

Pasteur noticed that crystals of tartrates had small faces. Then he observed that, in racemic mixtures of tartrates, half of the crystals were right-handed and half were left-handed. In solution, the right-handed compound was dextrorotatory, and the left-handed one was levorotatory. Pasteur determined that optical activity related to the shape of the crystals, and that an asymmetric internal arrangement of the molecules of the compound was responsible for twisting the light. The (2R,3R)- and (2S,3S)- tartrates were isometric, non-superposable mirror images of each other. This was the first time anyone had demonstrated molecular chirality, and also the first explanation of isomerism.

Some historians consider Pasteur's work in this area to be his "most profound and most original contributions to science", and his "greatest scientific discovery."

Fermentation and germ theory of diseases

Pasteur was motivated to investigate fermentation while working at Lille. In 1856 a local wine manufacturer, M. Bigot, whose son was one of Pasteur's students, sought for his advice on the problems of making beetroot alcohol and souring.

According to his son-in-law, René Vallery-Radot, in August 1857 Pasteur sent a paper about lactic acid fermentation to the Société des Sciences de Lille, but the paper was read three months later. A memoire was subsequently published on November 30, 1857. In the memoir, he developed his ideas stating that: "I intend to establish that, just as there is an alcoholic ferment, the yeast of beer, which is found everywhere that sugar is decomposed into alcohol and carbonic acid, so also there is a particular ferment, a lactic yeast, always present when sugar becomes lactic acid."

Pasteur also wrote about alcoholic fermentation. It was published in full form in 1858. Jöns Jacob Berzelius and Justus von Liebig had proposed the theory that fermentation was caused by decomposition. Pasteur demonstrated that this theory was incorrect, and that yeast was responsible for fermentation to produce alcohol from sugar. He also demonstrated that, when a different microorganism contaminated the wine, lactic acid was produced, making the wine sour. In 1861, Pasteur observed that less sugar fermented per part of yeast when the yeast was exposed to air. The lower rate of fermentation aerobically became known as the Pasteur effect.

Pasteur experimenting in his laboratory.
 
Pasteur's research also showed that the growth of micro-organisms was responsible for spoiling beverages, such as beer, wine and milk. With this established, he invented a process in which liquids such as milk were heated to a temperature between 60 and 100 °C. This killed most bacteria and moulds already present within them. Pasteur and Claude Bernard completed tests on blood and urine on April 20, 1862. Pasteur patented the process, to fight the "diseases" of wine, in 1865. The method became known as pasteurization, and was soon applied to beer and milk.

Beverage contamination led Pasteur to the idea that micro-organisms infecting animals and humans cause disease. He proposed preventing the entry of micro-organisms into the human body, leading Joseph Lister to develop antiseptic methods in surgery.

In 1866, Pasteur published Etudes sur le Vin, about the diseases of wine, and he published Etudes sur la Bière in 1876, concerning the diseases of beer.

In the early 19th century, Agostino Bassi had shown that muscardine was caused by a fungus that infected silkworms. Since 1853, two diseases called pébrine and flacherie had been infecting great numbers of silkworms in southern France, and by 1865 they were causing huge losses to farmers. In 1865, Pasteur went to Alès and worked for five years until 1870.

Silkworms with pébrine were covered in corpuscles. In the first three years, Pasteur thought that the corpuscles were a symptom of the disease. In 1870, he concluded that the corpuscles were the cause of pébrine (it is now known that the cause is a microsporidian). Pasteur also showed that the disease was hereditary. Pasteur developed a system to prevent pébrine: after the female moths laid their eggs, the moths were turned into a pulp. The pulp was examined with a microscope, and if corpuscles were observed, the eggs were destroyed. Pasteur concluded that bacteria caused flacherie. The primary cause is currently thought to be viruses. The spread of flacherie could be accidental or hereditary. Hygiene could be used to prevent accidental flacherie. Moths whose digestive cavities did not contain the microorganisms causing flacherie were used to lay eggs, preventing hereditary flacherie.

Spontaneous generation

Bottle en col de cygne (swan-neck bottle) used by Pasteur
 
Louis Pasteur’s pasteurization experiment illustrates the fact that the spoilage of liquid was caused by particles in the air rather than the air itself. These experiments were important pieces of evidence supporting the germ theory of disease.
 
Following his fermentation experiments, Pasteur demonstrated that the skin of grapes was the natural source of yeasts, and that sterilized grapes and grape juice never fermented. He drew grape juice from under the skin with sterilized needles, and also covered grapes with sterilized cloth. Both experiments could not produce wine in sterilized containers.

His findings and ideas were against the prevailing notion of spontaneous generation. He received a particularly stern criticism from Félix Archimède Pouchet, who was director of the Rouen Museum of Natural History. To settle the debate between the eminent scientists, the French Academy of Sciences offered the Alhumbert Prize carrying 2,500 francs to whoever could experimentally demonstrate for or against the doctrine.

Pouchet stated that air everywhere could cause spontaneous generation of living organisms in liquids. In the late 1850s, he performed experiments and claimed that they were evidence of spontaneous generation. Francesco Redi and Lazzaro Spallanzani had provided some evidence against spontaneous generation in the 17th and 18th centuries, respectively. Spallanzani's experiments in 1765 suggested that air contaminated broths with bacteria. In the 1860s, Pasteur repeated Spallanzani's experiments, but Pouchet reported a different result using a different broth.

Pasteur performed several experiments to disprove spontaneous generation. He placed boiled liquid in a flask and let hot air enter the flask. Then he closed the flask, and no organisms grew in it. In another experiment, when he opened flasks containing boiled liquid, dust entered the flasks, causing organisms to grow in some of them. The number of flasks in which organisms grew was lower at higher altitudes, showing that air at high altitudes contained less dust and fewer organisms. Pasteur also used swan neck flasks containing a fermentable liquid. Air was allowed to enter the flask via a long curving tube that made dust particles stick to it. Nothing grew in the broths unless the flasks were tilted, making the liquid touch the contaminated walls of the neck. This showed that the living organisms that grew in such broths came from outside, on dust, rather than spontaneously generating within the liquid or from the action of pure air.

These were some of the most important experiments disproving the theory of spontaneous generation, for which Pasteur won the Alhumbert Prize in 1862. He concluded that:
Never will the doctrine of spontaneous generation recover from the mortal blow of this simple experiment. There is no known circumstance in which it can be confirmed that microscopic beings came into the world without germs, without parents similar to themselves.

Immunology and vaccination

Chicken cholera

Pasteur's later work on diseases included work on chicken cholera. He received cultures from Jean Joseph Henri Toussaint, and cultivated them in chicken broth. During this work, a culture of the responsible bacteria had spoiled and failed to induce the disease in some chickens he was infecting with the disease. Upon reusing these healthy chickens, Pasteur discovered he could not infect them, even with fresh bacteria; the weakened bacteria had caused the chickens to become immune to the disease, though they had caused only mild symptoms.

In 1879, his assistant, Charles Chamberland (of French origin), had been instructed to inoculate the chickens after Pasteur went on holiday. Chamberland failed to do this and went on holiday himself. On his return, the month-old cultures made the chickens unwell, but instead of the infections being fatal, as they usually were, the chickens recovered completely. Chamberland assumed an error had been made, and wanted to discard the apparently faulty culture, but Pasteur stopped him. He inoculated the chickens with virulent bacteria that killed other chickens, and they survived. Pasteur concluded that the animals were now immune to the disease.

In December 1879, Pasteur used a weakened culture of the bacteria to inoculate chickens. The chickens survived, and when he inoculated them with a virulent strain, they were immune to it. In 1880, Pasteur presented his results to the French Academy of Sciences, saying that the bacteria were weakened by contact with oxygen.

Anthrax

In the 1870s, he applied this immunization method to anthrax, which affected cattle, and aroused interest in combating other diseases. Pasteur cultivated bacteria from the blood of animals infected with anthrax. When he inoculated animals with the bacteria, anthrax occurred, proving that the bacteria was the cause of the disease. Many cattle were dying of anthrax in "cursed fields". Pasteur was told that sheep that died from anthrax were buried in the field. Pasteur thought that earthworms might have brought the bacteria to the surface. He found anthrax bacteria in earthworms' excrement, showing that he was correct. He told the farmers not to bury dead animals in the fields.

Louis Pasteur in his laboratory, painting by A. Edelfeldt in 1885
 
In 1880, Pasteur's rival Jean-Joseph-Henri Toussaint, a veterinary surgeon, used carbolic acid to kill anthrax bacilli and tested the vaccine on sheep. Pasteur thought that this type of killed vaccine should not work because he believed that attenuated bacteria used up nutrients that the bacteria needed to grow. He thought oxidizing bacteria made them less virulent. In early 1881, Pasteur discovered that growing anthrax bacilli at about 42 °C made them unable to produce spores, and he described this method in a speech to the French Academy of Sciences on February 28. Later in 1881, veterinarian Hippolyte Rossignol proposed that the Société d'agriculture de Melun organize an experiment to test Pasteur's vaccine. Pasteur agreed, and the experiment, conducted at Pouilly-le-Fort on sheep, goats and cows, was successful. Pasteur did not directly disclose how he prepared the vaccines used at Pouilly-le-Fort. His laboratory notebooks, now in the Bibliothèque Nationale in Paris, show that he actually used heat and potassium dichromate, similar to Toussaint's method.

The notion of a weak form of a disease causing immunity to the virulent version was not new; this had been known for a long time for smallpox. Inoculation with smallpox (variolation) was known to result in a much less severe disease, and greatly reduced mortality, in comparison with the naturally acquired disease. Edward Jenner had also studied vaccination using cowpox (vaccinia) to give cross-immunity to smallpox in the late 1790s, and by the early 1800s vaccination had spread to most of Europe.

The difference between smallpox vaccination and anthrax or chicken cholera vaccination was that the latter two disease organisms had been artificially weakened, so a naturally weak form of the disease organism did not need to be found. This discovery revolutionized work in infectious diseases, and Pasteur gave these artificially weakened diseases the generic name of "vaccines", in honour of Jenner's discovery.

In 1876, Robert Koch had shown that Bacillus anthracis caused anthrax. In his papers published between 1878 and 1880, Pasteur only mentioned Koch's work in a footnote. Koch met Pasteur at the Seventh International Medical Congress in 1881. A few months later, Koch wrote that Pasteur had used impure cultures and made errors. In 1882, Pasteur replied to Koch in a speech, to which Koch responded aggressively. Koch stated that Pasteur tested his vaccine on unsuitable animals and that Pasteur's research was not properly scientific. In 1882, Koch wrote "On the Anthrax Inoculation", in which he refuted several of Pasteur's conclusions about anthrax and criticized Pasteur for keeping his methods secret, jumping to conclusions, and being imprecise. In 1883, Pasteur wrote that he used cultures prepared in a similar way to his successful fermentation experiments and that Koch misinterpreted statistics and ignored Pasteur's work on silkworms.

Swine erysipelas

In 1882, Pasteur sent his assistant Louis Thuillier to southern France because of an epizootic of swine erysipelas. Thuillier identified the bacillus that caused the disease in March 1883. Pasteur and Thuillier increased the bacillus's virulence after passing it through pigeons. Then they passed the bacillus through rabbits, weakening it and obtaining a vaccine. Pasteur and Thuillier incorrectly described the bacterium as a figure-eight shape. Roux described the bacterium as stick-shaped in 1884.

Rabies

Pasteur produced the first vaccine for rabies by growing the virus in rabbits, and then weakening it by drying the affected nerve tissue. The rabies vaccine was initially created by Emile Roux, a French doctor and a colleague of Pasteur, who had produced a killed vaccine using this method. The vaccine had been tested in 50 dogs before its first human trial. This vaccine was used on 9-year-old Joseph Meister, on July 6, 1885, after the boy was badly mauled by a rabid dog. This was done at some personal risk for Pasteur, since he was not a licensed physician and could have faced prosecution for treating the boy. After consulting with physicians, he decided to go ahead with the treatment. Over 11 days, Meister received 13 inoculations, each inoculation using viruses that had been weakened for a shorter period of time. Three months later he examined Meister and found that he was in good health. Pasteur was hailed as a hero and the legal matter was not pursued. Analysis of his laboratory notebooks shows that Pasteur had treated two people before his vaccination of Meister. One survived but may not actually have had rabies, and the other died of rabies. Pasteur began treatment of Jean-Baptiste Jupille on October 20, 1885, and the treatment was successful. Later in 1885, people, including four children from the United States, went to Pasteur's laboratory to be inoculated. In 1886, he treated 350 people, of which only one developed rabies. The treatment's success laid the foundations for the manufacture of many other vaccines. The first of the Pasteur Institutes was also built on the basis of this achievement.

In The Story of San Michele, Axel Munthe writes of some risks Pasteur undertook in the rabies vaccine research:
Pasteur himself was absolutely fearless. Anxious to secure a sample of saliva straight from the jaws of a rabid dog, I once saw him with the glass tube held between his lips draw a few drops of the deadly saliva from the mouth of a rabid bull-dog, held on the table by two assistants, their hands protected by leather gloves.
Because of his study in germs, Pasteur encouraged doctors to sanitize their hands and equipment before surgery. Prior to this, few doctors or their assistants practiced these procedures.

Controversies

A French national hero at age 55, in 1878 Pasteur discreetly told his family never to reveal his laboratory notebooks to anyone. His family obeyed, and all his documents were held and inherited in secrecy. Finally, in 1964 Pasteur's grandson and last surviving male descendant, Pasteur Valley-Radot, donated the papers to the French national library (Bibliothèque nationale de France). Yet the papers were restricted for historical studies until the death of Valley-Radot in 1971. The documents were given a catalogue number only in 1985.

In 1995, the centennial of the death of Louis Pasteur, a historian of science Gerald L. Geison published an analysis of Pasteur's private notebooks in his The Private Science of Louis Pasteur, and declared that Pasteur had given several misleading accounts and played deceptions in his most important discoveries. Max Perutz published a defense of Pasteur in The New York Review of Books. Based on further examinations of Pasteur's documents, French immunologist Patrice Debré concluded in his book Louis Pasteur (1998) that in spite of his genius, Pasteur had some faults. A book review states that Debré "sometimes finds him unfair, combative, arrogant, unattractive in attitude, inflexible and even dogmatic".

Fermentation

Scientists before Pasteur had studied fermentation. In the 1830s, Charles Cagniard-Latour, Friedrich Traugott Kützing and Theodor Schwann used microscopes to study yeasts and concluded that yeasts were living organisms. In 1839, Justus von Liebig, Friedrich Wöhler and Jöns Jacob Berzelius stated that yeast was not an organism and was produced when air acted on plant juice.

In 1855, Antoine Béchamp, Professor of Chemistry at the University of Montpellier, conducted experiments with sucrose solutions and concluded that water was the factor for fermentation. He changed his conclusion in 1858, stating that fermentation was directly related to the growth of moulds, which required air for growth. He regarded himself as the first to show the role of microorganisms in fermentation.

Pasteur started his experiments in 1857 and published his findings in 1858 (April issue of Comptes Rendus Chimie, Béchamp's paper appeared in January issue). Béchamp noted that Pasteur did not bring any novel idea or experiments. On the other hand, Béchamp was probably aware of Pasteur's 1857 preliminary works. With both scientists claiming priority on the discovery, a dispute, extending to several areas, lasted throughout their lives.

However, Béchamp was on the losing side, as the BMJ obituary remarked: His name was "associated with bygone controversies as to priority which it would be unprofitable to recall". Béchamp proposed the incorrect theory of microzymes. According to K. L. Manchester, anti-vivisectionists and proponents of alternative medicine promoted Béchamp and microzymes, unjustifiably claiming that Pasteur plagiarized Béchamp.

Pasteur thought that succinic acid inverted sucrose. In 1860, Marcellin Berthelot isolated invertase and showed that succinic acid did not invert sucrose. Pasteur believed that fermentation was only due to living cells. Hans Buchner discovered that zymase catalyzed fermentation, showing that fermentation was catalyzed by enzymes within cells. Eduard Buchner also discovered that fermentation could take place outside living cells.

Anthrax vaccine

Pasteur publicly claimed his success in developing the anthrax vaccine in 1881. However, his admirer-turned-rival Toussaint was the one who developed the first vaccine. Toussaint isolated the bacteria that caused chicken cholera (later named Pasteurella in honour of Pasteur) in 1879 and gave samples to Pasteur who used them for his own works. On July 12, 1880, Toussaint presented his successful result to the French Academy of Sciences, using an attenuated vaccine against anthrax in dogs and sheep. Pasteur on grounds of jealousy contested the discovery by publicly displaying his vaccination method at Pouilly-le-Fort on May 5, 1881. Pasteur gave a misleading account of the preparation of the anthrax vaccine used in the experiment at Pouilly-le-Fort. He used potassium dichromate to prepare the vaccine. The promotional experiment was a success and helped Pasteur sell his products, getting the benefits and glory.

Experimental ethics

Pasteur experiments are often cited as against medical ethics, especially on his vaccination of Meister. He did not have any experience in medical practice, and more importantly, a medical license. This is often cited as a serious threat to his professional and personal reputation. His closest partner Émile Roux, who had medical qualifications, refused to participate in the clinical trial, likely because he considered it unjust. However, Pasteur executed vaccination of the boy under the close watch of practising physicians Jacques-Joseph Grancher, head of the Paris Children's Hospital's paediatric clinic, and Alfred Vulpian, a member of the Commission on Rabies. He was not allowed to hold the syringe, although the inoculations were entirely under his supervision. It was Grancher who was responsible for the injections, and he defended Pasteur before the French National Academy of Medicine in the issue.

Pasteur has also been criticized for keeping secrecy of his procedure and not giving proper pre-clinical trials on animals. Pasteur stated that he kept his procedure secret in order to control its quality. He later disclosed his procedures to a small group of scientists. Pasteur wrote that he had successfully vaccinated 50 rabid dogs before using it on Meister. According to Geison, Pasteur's laboratory notebooks show that he had vaccinated only 11 dogs.

Meister never showed any symptoms of rabies, but the vaccination has not been proved to be the reason. One source estimates the probability of Meister contracting rabies at 10%.

Awards and honors

Pasteur was awarded 1,500 francs in 1853 by the Pharmaceutical Society for the synthesis of racemic acid. In 1856 the Royal Society of London presented him the Rumford Medal for his discovery of the nature of racemic acid and its relations to polarized light, and the Copley Medal in 1874 for his work on fermentation. He was elected a Foreign Member of the Royal Society (ForMemRS) in 1869.

The French Academy of Sciences awarded Pasteur the 1859 Montyon Prize for experimental physiology in 1860, and the Jecker Prize in 1861 and the Alhumbert Prize in 1862 for his experimental refutation of spontaneous generation. Though he lost elections in 1857 and 1861 for membership to the French Academy of Sciences, he won the 1862 election for membership to the mineralogy section. He was elected to permanent secretary of the physical science section of the academy in 1887 and held the position until 1889.

In 1873 Pasteur was elected to the Académie Nationale de Médecine and was made the commander in the Brazilian Order of the Rose. In 1881 he was elected to a seat at the Académie française left vacant by Émile Littré. Pasteur received the Albert Medal from the Royal Society of Arts in 1882. In 1883 he became foreign member of the Royal Netherlands Academy of Arts and Sciences. On June 8, 1886, the Ottoman Sultan Abdul Hamid II awarded Pasteur with the Order of the Medjidie (I Class) and 10000 Ottoman liras. Pasteur won the Leeuwenhoek Medal from the Royal Netherlands Academy of Arts and Sciences for his contributions to microbiology in 1895.

Pasteur was made a Chevalier of the Legion of Honour in 1853, promoted to Officer in 1863, to Commander in 1868, to Grand Officer in 1878 and made a Grand Cross of the Legion of Honor in 1881.

Legacy

Pasteur's street in Odessa.
Vulitsya Pastera or Pasteur Street in Odessa, Ukraine

In many localities worldwide, streets are named in his honor. For example, in the US: Palo Alto and Irvine, California, Boston and Polk, Florida, adjacent to the University of Texas Health Science Center at San Antonio; Jonquière, Québec; San Salvador de Jujuy and Buenos Aires (Argentina), Great Yarmouth in Norfolk, in the United Kingdom, Jericho and Wulguru in Queensland, (Australia); Phnom Penh in Cambodia; Ho Chi Minh City; Batna in Algeria; Bandung in Indonesia, Tehran in Iran, near the central campus of the Warsaw University in Warsaw, Poland; adjacent to the Odessa State Medical University in Odessa, Ukraine; Milan in Italy and Bucharest, Cluj-Napoca and Timișoara in Romania. The Avenue Pasteur in Saigon, Vietnam, is one of the few streets in that city to retain its French name. Avenue Louis Pasteur in the Longwood Medical and Academic Area in Boston, Massachusetts was named in his honor in the French manner with "Avenue" preceding the name of the dedicatee.

Both the Institute Pasteur and Université Louis Pasteur were named after Pasteur. The schools Lycée Pasteur in Neuilly-sur-Seine, France, and Lycée Louis Pasteur in Calgary, Alberta, Canada, are named after him. In South Africa, the Louis Pasteur Private Hospital in Pretoria, and Life Louis Pasteur Private Hospital, Bloemfontein, are named after him. Louis Pasteur University Hospital in Košice, Slovakia is also named after Pasteur. 

Louis Pasteur University Hospital, Košice, Slovakia
 
A statue of Pasteur is erected at San Rafael High School in San Rafael, California. A bronze bust of him resides on the French Campus of Kaiser Permanente's San Francisco Medical Center in San Francisco. The sculpture was designed by Harriet G. Moore and cast in 1984 by Artworks Foundry.

The UNESCO/Institut Pasteur Medal was created on the centenary of Pasteur's death, and is given every two years in his name, "in recognition of outstanding research contributing to a beneficial impact on human health".

Pasteur Institute

After developing the rabies vaccine, Pasteur proposed an institute for the vaccine. In 1887, fundraising for the Pasteur Institute began, with donations from many countries. The official statute was registered in 1887, stating that the institute's purposes were "the treatment of rabies according to the method developed by M. Pasteur" and "the study of virulent and contagious diseases". The institute was inaugurated on November 14, 1888. He brought together scientists with various specialties. The first five departments were directed by two graduates of the École Normale Supérieure: Émile Duclaux (general microbiology research) and Charles Chamberland (microbe research applied to hygiene), as well as a biologist, Élie Metchnikoff (morphological microbe research) and two physicians, Jacques-Joseph Grancher (rabies) and Émile Roux (technical microbe research). One year after the inauguration of the institute, Roux set up the first course of microbiology ever taught in the world, then entitled Cours de Microbie Technique (Course of microbe research techniques). Since 1891 the Pasteur Institute had been extended to different countries, and currently there are 32 institutes in 29 countries in various parts of the world.

Personal life

Faith and spirituality

His grandson, Louis Pasteur Vallery-Radot, wrote that Pasteur had kept from his Catholic background only a spiritualism without religious practice. However, Catholic observers often said that Pasteur remained an ardent Christian throughout his whole life, and his son-in-law wrote, in a biography of him:
Absolute faith in God and in Eternity, and a conviction that the power for good given to us in this world will be continued beyond it, were feelings which pervaded his whole life; the virtues of the gospel had ever been present to him. Full of respect for the form of religion which had been that of his forefathers, he came simply to it and naturally for spiritual help in these last weeks of his life.
Maurice Vallery-Radot, grandson of the brother of the son-in-law of Pasteur and outspoken Catholic, also holds that Pasteur fundamentally remained Catholic. According to both Pasteur Vallery-Radot and Maurice Vallery-Radot, the following well-known quotation attributed to Pasteur is apocryphal: "The more I know, the more nearly is my faith that of the Breton peasant. Could I but know all I would have the faith of a Breton peasant's wife". According to Maurice Vallery-Radot, the false quotation appeared for the first time shortly after the death of Pasteur. However, despite his belief in God, it has been said that his views were that of a freethinker rather than a Catholic, a spiritual more than a religious man. He was also against mixing science with religion.

Death

In 1868, Pasteur suffered a severe brain stroke that paralyzed the left side of his body, but he recovered. A stroke or uremia in 1894 severely impaired his health. Failing to fully recover, he died on September 28, 1895, near Paris. He was given a state funeral and was buried in the Cathedral of Notre Dame, but his remains were reinterred in the Pasteur Institute in Paris, in a vault covered in depictions of his accomplishments in Byzantine mosaics.

Publications

Pasteur's principal published works are:

French Title Year English Title
Etudes sur le Vin 1866 Studies on Wine
Etudes sur le Vinaigre 1868 Studies on Vinegar
Etudes sur la Maladie des Vers à Soie (2 volumes) 1870 Studies on Silk Worm Disease
Quelques Réflexions sur la Science en France 1871 Some Reflections on Science in France
Etudes sur la Bière 1876 Studies on Beer
Les Microbes organisés, leur rôle dans la Fermentation, la Putréfaction et la Contagion 1878 Microbes organized, their role in fermentation, putrefaction and the Contagion
Discours de Réception de M.L. Pasteur à l'Académie française 1882 Speech by Mr L. Pasteur on reception to the Académie française
Traitement de la Rage 1886 Treatment of Rabies

Steroid

From Wikipedia, the free encyclopedia

Complex chemical diagram
Steroid ring system: The parent ABCD steroid ring system (hydrocarbon framework) is shown with IUPAC-approved ring lettering and atom numbering.

A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes which alter membrane fluidity; and as signaling molecules. Hundreds of steroids are found in plants, animals and fungi. All steroids are manufactured in cells from the sterols lanosterol (opisthokonts) or cycloartenol (plants). Lanosterol and cycloartenol are derived from the cyclization of the triterpene squalene.

The steroid core structure is composed of seventeen carbon atoms, bonded in four "fused" rings: three six-member cyclohexane rings (rings A, B and C in the first illustration) and one five-member cyclopentane ring (the D ring). Steroids vary by the functional groups attached to this four-ring core and by the oxidation state of the rings. Sterols are forms of steroids with a hydroxy group at position three and a skeleton derived from cholestane. Steroids can also be more radically modified, such as by changes to the ring structure, for example, cutting one of the rings. Cutting Ring B produces secosteroids one of which is vitamin D3

Examples include the lipid cholesterol, the sex hormones estradiol and testosterone, and the anti-inflammatory drug dexamethasone.

Filled-in diagram of a steroid
Space-filling representation
Ball-and-stick diagram of the same steroid
Ball-and-stick representation
 
5α-dihydroprogesterone (5α-DHP), a steroid. The shape of the four rings of most steroids is illustrated (carbon atoms in black, oxygens in red and hydrogens in grey). The apolar "slab" of hydrocarbon in the middle (grey, black) and the polar groups at opposing ends (red) are common features of natural steroids. 5α-DHP is an endogenous steroid hormone and a biosynthetic intermediate.

Nomenclature

Chemical diagram
A gonane (steroid nucleus)
 
Chemical diagram
Steroid 5α and 5β stereoisomers
 
Gonane, also known as steran or cyclopentaperhydrophenanthrene, the simplest steroid and the nucleus of all steroids and sterols, is composed of seventeen carbon atoms in carbon-carbon bonds forming four fused rings in a three-dimensional shape. The three cyclohexane rings (A, B, and C in the first illustration) form the skeleton of a perhydro derivative of phenanthrene. The D ring has a cyclopentane structure. When the two methyl groups and eight carbon side chains (at C-17, as shown for cholesterol) are present, the steroid is said to have a cholestane framework. The two common 5α and 5β stereoisomeric forms of steroids exist because of differences in the side of the largely planar ring system where the hydrogen (H) atom at carbon-5 is attached, which results in a change in steroid A-ring conformation. Isomerisation at the C-21 side chain produces a parallel series of compounds, referred to as isosteroids.

Examples of steroid structures are:
In addition to the ring scissions (cleavages), expansions and contractions (cleavage and reclosing to a larger or smaller rings)—all variations in the carbon-carbon bond framework—steroids can also vary:
  • in the bond orders within the rings,
  • in the number of methyl groups attached to the ring (and, when present, on the prominent side chain at C17),
  • in the functional groups attached to the rings and side chain, and
  • in the configuration of groups attached to the rings and chain.
For instance, sterols such as cholesterol and lanosterol have an hydroxyl group attached at position C-3, while testosterone and progesterone have a carbonyl (oxo substituent) at C-3; of these, lanosterol alone has two methyl groups at C-4 and cholesterol (with a C-5 to C-6 double bond) differs from testosterone and progesterone (which have a C-4 to C-5 double bond). 

Chemical diagram
Cholesterol, a prototypical animal sterol. This structural lipid and key steroid biosynthetic precursor.
 
Chemical diagram
5α-cholestane, a common steroid core

Species distribution and function

In eukaryotes, steroids are found in fungi, animals, and plants.

Fungal steroids

Fungal steroids include the ergosterols, which are involved in maintaining the integrity of the fungal cellular membrane. Various antifungal drugs, such as amphotericin B and azole antifungals, utilize this information to kill pathogenic fungi. Fungi can alter their ergosterol content (e.g. through loss of function mutations in the enzymes ERG3 or ERG6, inducing depletion of ergosterol, or mutations that decrease the ergosterol content) to develop resistance to drugs that target ergosterol. Ergosterol is analogous to the cholesterol found in the cellular membranes of animals (including humans), or the phytosterols found in the cellular membranes of plants. All mushrooms contain large quantities of ergosterol, in the range of 10-100's of milligrams per 100 grams of dry weight. Oxygen is necessary for the synthesis of ergosterol in fungi. Ergosterol is responsible for the vitamin D content found in mushrooms; ergosterol is chemically converted into provitamin D2 by exposure to ultraviolet light. Provitamin D2 spontaneously forms vitamin D2. However, not all fungi utilize ergosterol in their cellular membranes; for example, the pathogenic fungal species Pneumocystis jiroveci does not, which has important clinical implications (given the mechanism of action of many antifungal drugs). Using the fungus Saccharomyces cerevisiae as an example, other major steroids include ergosta‐5,7,22,24(28)‐tetraen‐3β‐ol, zymosterol, and lanosterol. S. cerevisiae utilizes 5,6‐dihydroergosterol in place of ergosterol in its cell membrane.

Animal steroids

Animal steroids include compounds of vertebrate and insect origin, the latter including ecdysteroids such as ecdysterone (controlling molting in some species). Vertebrate examples include the steroid hormones and cholesterol; the latter is a structural component of cell membranes which helps determine the fluidity of cell membranes and is a principal constituent of plaque (implicated in atherosclerosis). Steroid hormones include:

Plant steroids

Plant steroids include steroidal alkaloids found in Solanaceae and Melanthiaceae (specially the genus Veratrum), cardiac glycosides, the phytosterols and the brassinosteroids (which include several plant hormones).

Prokaryotes

In prokaryotes, biosynthetic pathways exist for the tetracyclic steroid framework (e.g. in mycobacteria) – where its origin from eukaryotes is conjectured – and the more-common pentacyclic triterpinoid hopanoid framework.

Types

By function

The major classes of steroid hormones, with prominent members and examples of related functions, are:
Additional classes of steroids include:
As well as the following class of secosteroids (open-ring steroids):

By structure

Intact ring system

Steroids can be classified based on their chemical composition. One example of how MeSH performs this classification is available at the Wikipedia MeSH catalog. Examples of this classification include:

Chemical diagram
Cholecalciferol (vitamin D3), an example of a 9,10-secosteroid
 
Chemical diagram
Cyclopamine, an example of a complex C-nor-D-homosteroid
 
Class Example Number of carbon atoms
Cholestanes Cholesterol 27
Cholanes Cholic acid 24
Pregnanes Progesterone 21
Androstanes Testosterone 19
Estranes Estradiol 18

The gonane (steroid nucleus) is the parent 17-carbon tetracyclic hydrocarbon molecule with no alkyl sidechains.

Cleaved, contracted, and expanded rings

Secosteroids (Latin seco, "to cut") are a subclass of steroidal compounds resulting, biosynthetically or conceptually, from scission (cleavage) of parent steroid rings (generally one of the four). Major secosteroid sub-classes are defined by the steroid carbon atoms where this scission has taken place. For instance, the prototypical secosteroid cholecalciferol, vitamin D3 (shown), is in the 9,10-secosteroid subclass and derives from the cleavage of carbon atoms C-9 and C-10 of the steroid B-ring; 5,6-secosteroids and 13,14-steroids are similar.

Norsteroids (nor-, L. norma; "normal" in chemistry, indicating carbon removal) and homosteroids (homo-, Greek homos; "same", indicating carbon addition) are structural subclasses of steroids formed from biosynthetic steps. The former involves enzymic ring expansion-contraction reactions, and the latter is accomplished (biomimetically) or (more frequently) through ring closures of acyclic precursors with more (or fewer) ring atoms than the parent steroid framework.

Combinations of these ring alterations are known in nature. For instance, ewes who graze on corn lily ingest cyclopamine (shown) and veratramine, two of a sub-family of steroids where the C- and D-rings are contracted and expanded respectively via a biosynthetic migration of the original C-13 atom. Ingestion of these C-nor-D-homosteroids results in birth defects in lambs: cyclopia from cyclopamine and leg deformity from veratramine. A further C-nor-D-homosteroid (nakiterpiosin) is excreted by Okinawan cyanobacteriospongesTerpios hoshinota – leading to coral mortality from black coral disease. Nakiterpiosin-type steroids are active against the signaling pathway involving the smoothened and hedgehog proteins, a pathway which is hyperactive in a number of cancers.

Biological significance

Steroids and their metabolites often function as signalling molecules (the most notable examples are steroid hormones), and steroids and phospholipids are components of cell membranes. Steroids such as cholesterol decrease membrane fluidity. Similar to lipids, steroids are highly concentrated energy stores. However, they are not typically sources of energy; in mammals, they are normally metabolized and excreted. 

Steroids play critical roles in a number of disorders, including malignancies like prostate cancer, where steroid production inside and outside the tumor promotes cancer cell aggressiveness.

Biosynthesis and metabolism

Chemical-diagram flow chart
Simplification of the end of the steroid synthesis pathway, where the intermediates isopentenyl pyrophosphate (PP or IPP) and dimethylallyl pyrophosphate (DMAPP) form geranyl pyrophosphate (GPP), squalene and lanosterol (the first steroid in the pathway)
 
The hundreds of steroids found in animals, fungi, and plants are made from lanosterol (in animals and fungi; see examples above) or cycloartenol (in plants). Lanosterol and cycloartenol derive from cyclization of the triterpenoid squalene.

Steroid biosynthesis is an anabolic pathway which produces steroids from simple precursors. A unique biosynthetic pathway is followed in animals (compared to many other organisms), making the pathway a common target for antibiotics and other anti-infection drugs. Steroid metabolism in humans is also the target of cholesterol-lowering drugs, such as statins. 

In humans and other animals the biosynthesis of steroids follows the mevalonate pathway, which uses acetyl-CoA as building blocks for dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP). In subsequent steps DMAPP and IPP join to form geranyl pyrophosphate (GPP), which synthesizes the steroid lanosterol. Modifications of lanosterol into other steroids are classified as steroidogenesis transformations.

Mevalonate pathway

Chemical flow chart
Mevalonate pathway

The mevalonate pathway (also called HMG-CoA reductase pathway) begins with acetyl-CoA and ends with dimethylallyl pyrophosphate (DMAPP) and isopentenyl pyrophosphate (IPP). 

DMAPP and IPP donate isoprene units, which are assembled and modified to form terpenes and isoprenoids (a large class of lipids, which include the carotenoids and form the largest class of plant natural products. Here, the isoprene units are joined to make squalene and folded into a set of rings to make lanosterol. Lanosterol can then be converted into other steroids, such as cholesterol and ergosterol.

Two classes of drugs target the mevalonate pathway: statins (like rosuvastatin), which are used to reduce elevated cholesterol levels, and bisphosphonates (like zoledronate), which are used to treat a number of bone-degenerative diseases.

Steroidogenesis

Chemical-diagram flow chart
Human steroidogenesis, with the major classes of steroid hormones, individual steroids and enzymatic pathways. Changes in molecular structure from a precursor are highlighted in white.

Steroidogenesis is the biological process by which steroids are generated from cholesterol and changed into other steroids. The pathways of steroidogenesis differ among species. The major classes of steroid hormones, as noted above (with their prominent members and functions), are the Progestogen, Corticosteroids (corticoids), Androgens, and Estrogens. Human steroidogenesis of these classes occurs in a number of locations:
  • Progestogens are the precursors of all other human steroids, and all human tissues which produce steroids must first convert cholesterol to pregnenolone. This conversion is the rate-limiting step of steroid synthesis, which occurs inside the mitochondrion of the respective tissue.
  • Cortisol, corticosterone, aldosterone, and testosterone are produced in the adrenal cortex.
  • Estradiol, estrone and progesterone are made primarily in the ovary, estriol in placenta during pregnancy, and testosterone primarily in the testes (some testosterone is also produced in the adrenal cortex).
  • Estradiol is converted from testosterone directly (in males), or via the primary pathway DHEA - androstenedione - estrone and secondarily via testosterone (in females).
  • Stromal cells have been shown to produce steroids in response to signaling produced by androgen-starved prostate cancer cells.
  • Some neurons and glia in the central nervous system (CNS) express the enzymes required for the local synthesis of pregnenolone, progesterone, DHEA and DHEAS, de novo or from peripheral sources.

Alternative pathways

In plants and bacteria, the non-mevalonate pathway uses pyruvate and glyceraldehyde 3-phosphate as substrates.

During diseases pathways otherwise not significant in healthy humans can become utilized. For example, in one form of congenital adrenal hyperplasia a deficiency in the 21-hydroxylase enzymatic pathway leads to an excess of 17α-Hydroxyprogesterone (17-OHP) – this pathological excess of 17-OHP in turn may be converted to dihydrotestosterone (DHT, a potent androgen) through among others 17,20 Lyase (a member of the cytochrome P450 family of enzymes), 5α-Reductase and 3α-Hydroxysteroid dehydrogenase.

Catabolism and excretion

Steroids are primarily oxidized by cytochrome P450 oxidase enzymes, such as CYP3A4. These reactions introduce oxygen into the steroid ring, allowing the cholesterol to be broken up by other enzymes into bile acids. These acids can then be eliminated by secretion from the liver in bile. The expression of the oxidase gene can be upregulated by the steroid sensor PXR when there is a high blood concentration of steroids. Steroid hormones, lacking the side chain of cholesterol and bile acids, are typically hydroxylated at various ring positions or oxidized at the 17 position, conjugated with sulfate or glucuronic acid and excreted in the urine.

Isolation, structure determination, and methods of analysis

Steroid isolation, depending on context, is the isolation of chemical matter required for chemical structure elucidation, derivitzation or degradation chemistry, biological testing, and other research needs (generally milligrams to grams, but often more or the isolation of "analytical quantities" of the substance of interest (where the focus is on identifying and quantifying the substance (for example, in biological tissue or fluid). The amount isolated depends on the analytical method, but is generally less than one microgram. The methods of isolation to achieve the two scales of product are distinct, but include extraction, precipitation, adsorption, chromatography, and crystallization. In both cases, the isolated substance is purified to chemical homogeneity; combined separation and analytical methods, such as LC-MS, are chosen to be "orthogonal"—achieving their separations based on distinct modes of interaction between substance and isolating matrix—to detect a single species in the pure sample. Structure determination refers to the methods to determine the chemical structure of an isolated pure steroid, using an evolving array of chemical and physical methods which have included NMR and small-molecule crystallography. Methods of analysis overlap both of the above areas, emphasizing analytical methods to determining if a steroid is present in a mixture and determining its quantity.

Chemical synthesis

Microbial catabolism of phytosterol side chains yields C-19 steroids, C-22 steroids, and 17-ketosteroids (i.e. precursors to adrenocortical hormones and contraceptives). The addition and modification of functional groups is key when producing the wide variety of medications available within this chemical classification. These modifications are performed using conventional organic synthesis and/or biotransformation techniques.

Precursors

Semisynthesis

The semisynthesis of steroids often begins from precursors such as cholesterol, phytosterols, or sapogenins. The efforts of Syntex, a company involved in the Mexican barbasco trade, used Dioscorea mexicana to produce the sapogenin diosgenin in the early days of the synthetic steroid pharmaceutical industry.

Total synthesis

Some steroidal hormones are economically obtained only by total synthesis from petrochemicals (e.g. 13-alkyl steroids). For example, the pharmaceutical Norgestrel begins from Methoxy-1-tetralone, a petrochemical derived from phenol.

Research awards

A number of Nobel Prizes have been awarded for steroid research, including:

Representation of a Lie group

From Wikipedia, the free encyclopedia https://en.wikipedia.org/wiki/Representation_of_a_Lie_group...