Nobel Laureates in Physiology or Medicine

Karl Landsteiner for his discovery of human blood groups

1930

Karl Landsteiner

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He is noted for having first distinguished the main blood groups in 1900, having developed the modern system of classification of blood groups from his identification of the presence of agglutinins in the blood, and having identified, with Alexander S. Wiener, the Rhesus factor in 1937, thus enabling physicians to transfuse blood without endangering the patients life.

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Figure 1 Blood type (or blood group) is determined, in part, by the ABO blood group antigens present on red blood cells. (Picture Blood Type, Wikipedia)

In 1900 Karl Landsteiner found out that the blood of two people under contact agglutinates, and in 1901 he found that this effect was due to contact of blood with blood serum. As a result he succeeded in identifying the three blood groups A, B and O. He also found out that blood transfusion between persons with the same blood group did not lead to the destruction of blood cells, whereas this occurred between persons of different blood groups.

Based on his findings, in 1907 the first successful blood transfusion was performed by Reuben Ottenberg at Mount Sinai Hospital in New York. Today it is well known that persons with blood group AB can accept donations of the other blood groups (universal recipients), and that persons with blood group O (universal donors) can donate to all other groups. It is due to the fact that persons with AB do not form antibodies against either A or B. Further, the immune systems of persons with blood group O, because their blood possesses neither characteristic A nor B, do not refuse the donation. In 1930, Landsteiner was awarded the Nobel Prize in Physiology or Medicine in recognition of these achievements.

Sir Alexander Fleming, Ernst Boris Chain and Sir Howard Walter Florey for the discovery of penicillin and its curative effect in various infectious diseases.

1945

Sir Alexander Fleming

Ernst Boris Chain

Howard Walter

One of the best-known discoveries of Sir Alexander Fleming is the antibiotic substance penicillin from the mould Penicillium notatum in 1928, for which he shared the Nobel Prize in Physiology or Medicine in 1945 with Howard Florey and Ernst Boris Chain Accidental discovery "When I woke up just after dawn on September 28, 1928, I certainly didn't plan to revolutionise all medicine by discovering the world's first antibiotic, or bacteria killer," Fleming would later say, "But I suppose that was exactly what I did." By 1928, Fleming was investigating the properties ofstaphylococci. He was already well-known from his earlier work, and had developed a reputation as a brilliant researcher, but his laboratory was often untidy. On 3 September 1928, Fleming returned to his laboratory having spent August on holiday with his family. Before leaving, he had stacked all his cultures of staphylococci on a bench in a corner of his laboratory. On returning, Fleming noticed that one culture was contaminated with a fungus, and that the colonies of staphylococci that had immediately surrounded it had been destroyed, whereas other colonies farther away were normal. Fleming showed the contaminated culture to his former assistant Merlin Price, who reminded him,"That's how you discoveredlysozyme."Fleming grew the mould in a pure culture and found that it produced a substance that killed a number of diseasecausing bacteria. He identified the mould as being from

He investigated its positive antibacterial effect on many organisms, and noticed that it affected bacteria such as staphylococci and many otherGram-positivepathogens that causescarlet fever,pneumonia,meningitisan ddiphtheria, but nottyphoid feverorparatyphoid fever, which are caused byGramnegativebacteria, for which he was seeking a cure at the time. It also affectedNeisseria gonorrhoeae,which causesgonorrhoeaalthough this bacterium is Gram-negative.

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Figure 2 Miracle cure. (Photo Alexander Fleming, Wikipedia)

Fleming published his discovery in 1929, in the BritishJournal of Experimental Pathology,but little attention was paid to his article. Fleming continued his investigations, but found that cultivating penicillium was quite difficult, and that after having grown the mould, it was even more difficult to isolate the antibiotic agent. Fleming's impression was that because of the problem of producing it in quantity, and because its action appeared to be rather slow, penicillin would not be important in treating infection. Fleming also became convinced that penicillin would not last long enough in the human body (in vivo) to kill bacteria effectively. Many clinical tests were inconclusive, probably because it had been used as a surface antiseptic. In the 1930s, Flemings trials occasionally showed more promise,and he continued, until 1940, to try to interest a chemist skilled enough to further refine usable penicillin. Fleming finally abandoned penicillin, and not long after he did,Howard FloreyandErnst Boris Chainat the Radcliffe Infirmary in Oxford took up researching and mass-producing it, with funds from the U.S. and British governments. They started mass production after the bombing of Pearl Harbor. WhenD-Dayarrived, they had made enough penicillin to treat all the wounded Allied forces.

Purification and stabilisation In 1939, Chain joinedHoward Floreyto investigate natural antibacterial agents produced bymicroorganisms. This led him and Florey to revisit the work ofAlexander Fleming, who had describedpenicillinnine years earlier. Chain and Florey went on to discover penicillin's therapeutic action and its chemical composition. He also theorized the structure of penicillin, which was confirmed byX-ray crystallographydone by Dorothy Hodgkin.

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Figure 3 3D-model of benzylpenicillin. (Picture Alexander Fleming, Wikipedia)

Ernst Boris ChainandEdward Abrahamworked out how to isolate and concentrate penicillin. Abraham was the first to propose the correct structure of penicillin.Shortly after the team published its first results in 1940, Fleming telephonedHoward Florey, Chain's head of department, to say that he would be visiting within the next few days. When Chain heard that he was coming, he remarked,"Good God! I thought he was dead." Norman Heatleysuggested transferring the active ingredient of penicillin back into water by changing its acidity. This produced enough of the drug to begin testing on animals. Florey's research team investigated the large-scale production of the mould and efficient extraction of the active ingredient, succeeding to the point where, by 1945, penicillin production was an industrial process for the Allies in World War II.

Fleming was modest about his part in the development of penicillin, describing his fame as the"Fleming Myth"and he praised Florey and Chain for transforming the laboratory curiosity into a practical drug. Fleming was the first to discover the properties of the active substance, giving him the privilege of naming it: penicillin. He also kept, grew and distributed the original mould for twelve years, and continued until 1940 to try to get help from any chemist who had enough skill to make penicillin. But Sir Henry Harris said in 1998:"Without Fleming, no Chain; without Chain, no Florey; without Florey, no Heatley; without Heatley, no penicillin." Fleming first observed the antibiotic properties of the mould that makes penicillin, but it was Chain and Florey who developed it

Hans Adolf Krebs"for his discovery of the citric acid cycle"and Fritz Albert Lipmann"for his discovery of coenzyme A and its importance for intermediary metabolism".

1953

Hans Adolf

Fritz Albert Lipmann

Krebs is best known for his identification of two important metabolic cycles: theurea cycleand thecitric acid cycle. The latter, the key sequence of metabolic chemical reactions that produces energy in cells, is also known as the Krebs cycleand earned him aNobel Prizein 1953, which he shared withFritz Lipmann. It has long been known that the main components of our foods (proteins, fats, and carbohydrates) are transformed by the living cell into compounds having much smaller molecules. It is a unique property of the cell that simultaneously its own components undergo processes of breaking down and building up which leads to the rejuvenation of the whole organism. The breakdown products from both the food and the cell components are used as building material for the working machinery of the cell. The energy necessary for this construction work is mainly derived from a transformation of a suitable amount of material to carbonic acid and water. That all these processes can take place simultaneously and in an extremely complex manner is due to the very far-reaching structural specialization of the microcosm of the cell. It was Krebs who discovered how these individual reactions are linked to each other in a cyclic process. He brought us a clear understanding of the essential principle of how the released energy is used for the building up processes which take place within the cell.

This energy is liberated by the oxidation of a 2-carbon compound to carbonic acid and water. This 2-carbon compound is derived from the foodstuffs and is introduced into the Krebs cycle. The nature of this compound and the mechanism of its incorporation were discovered by Fritz Lipmann. In the beginning Krebs was quite alone with his idea, and when he first presented it, it was criticized by many. Krebs' idea was that the mysterious 2carbon compound is added on to a known substance with 4 carbon atoms yielding a 6carbon compound. The 2-carbon compound, bound in this way, is then degraded stepwise to carbonic acid, water, and energy. When this degradation is completed, the 4-carbon compound is again free to react with another 2-carbon molecule, which starts a new period in the oxidation cycle. Krebs could show that the 6-carbon compound formed at the onset of this cycle is citric acid which contains three carboxyl groups. The cycle is therefore also called the tricarboxylic acid cycle.

The Krebs cycle explains two simultaneous processes: the degradation reactions which yield energy, and the building-up processes which use up energy. Out of the chaos of isolated reactions Krebs succeeded in extracting the basic system for the essential pathway of oxidation process within the cell.

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Figure 4 Overview of the citric acid cycle (Picture: Citric

The Krebs cycle explains two simultaneous processes: the degradation reactions which yield energy, and the building-up processes which use up energy. Out of the chaos of isolated reactions Krebs succeeded in extracting the basic system for the essential pathway of oxidation process within the cell. It is necessary to introduce compounds from the outside into the Krebs cycle in order to keep it in operation, because theoretically speaking the integral components are not used up in the process. The principal incorporation takes place through Lipmann's 2-carbon compound. It had been generally assumed that this compound was closely related to acetic acid. It was known that large amounts of acetic acid are formed in the metabolism of the cell. This acid possesses two carbon atoms and could fit well into the mechanism of the Krebs cycle. It seemed quite certain that the 2-carbon compound was acetic acid, but that it was active in some unknown form. Lipmann maintained for several years that acetyl phosphate, a compound formed from acetic acid and phosphoric acid was the active principle.Just when most biochemists became convinced that this compound would not fit into the mechanism of the Krebs cycle, and were ready to abandon the whole idea, Lipmann announced his discovery of coenzyme A. Now suddenly everything fitted perfectly - the last notch of a combination lock fell into its place. Coenzyme A is a compound with a rather small molecule, which, when united with the enzymeprotein, acquires the property of binding acetic acid. Acetic acid is normally quite unreactive but when bound in this way it becomes labile and reactive and represents the previously mystical 2-carbon compound which combines with a 4-carbon compound to form citric acid. A new way for the transmission of energy in the cell was demonstrated by this discovery.

Robert W. Holley, Har Gobind Khorana and Marshall W. Nirenberg"for their interpretation of the genetic code and its function in protein synthesis".

1968

Robert W. Holley

Har Gobind Khorana

Marshall W. Nirenberg

Robert William Holleyshared theNobel Prize in Physiology or Medicinein 1968 (withHar Gobind KhoranaandMarshall Warren Nirenberg) for describing the structure of alaninetransfer RNA, linkingDNAandprotein synthesis. Holley's research onRNAfocused first on isolatingtransfer RNA(tRNA), and later on determining the sequence and structure of alanine tRNA, the molecule that incorporates theamino acidalanineintoproteins. Holley's team of researchers determined the tRNA's structure by using tworibonucleasesto split the tRNA molecule into pieces. Each enzyme split the molecule at location points for specific nucleotides. By a process of "puzzling out" the structure of the pieces split by the two different enzymes, then comparing the pieces from both enzyme splits, the team eventually determined the entire structure of the molecule.

The structure was completed in 1964,and was a key discovery in explaining thesynthesisof proteins frommessenger RNA. It was also the first nucleotide sequence of aribonucleic acidever determined. Holley was awarded the Nobel Prize in Physiology or Medicine in 1968 for

The structure was completed in 1964,and was a key discovery in explaining thesynthesisof proteins frommessenger RNA. It was also the first nucleotide sequence of aribonucleic acidever determined. Holley was awarded the Nobel Prize in Physiology or Medicine in 1968 for this discovery,andHar Gobind KhoranaandMarshall W. Nirenbergwere also awarded the prize that year for contributions to the understanding of protein synthesis. Har Gobind Khorana shared theNobel Prize in Physiology or Medicinein 1968

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Figure 5 The interaction of tRNA and mRNA in protein synthesis. (Picture Transfer RNA, Wikipedia)

The structure was completed in 1964,and was a key discovery in explaining thesynthesisof proteins frommessenger RNA. It was also the first nucleotide sequence of aribonucleic acidever determined. Holley was awarded the Nobel Prize in Physiology or Medicine in 1968 for this discovery,andHar Gobind KhoranaandMarshall W. Nirenbergwere also awarded the prize that year for contributions to the understanding of protein synthesis. Har Gobind Khorana shared theNobel Prize in Physiology or Medicinein 1968

By 1959, experiments and analysis such as theAveryMacLeod-McCarty experiment, theHershey-Chase experiment, theWatson-Crick structureand theMeselson-Stahl experimenthad shownDNAto be the molecule of genetic information. It was not known, however, howDNAdirected the expression of proteins, or what roleRNAhad in these processes. Nirenberg teamed up withHeinrich J. Matthaeiat theNational Institutes of Healthto answer these questions. They producedRNAcomprised solely ofuracil, a nucleotidethat only occurs in RNA. They then added this synthetic poly-uracilRNAinto a cell-free extract ofEscherichia coliwhich contained theDNA,RNA,ribosomesand other cellular machinery forproteinsynthesis. They addedDNase, which breaks apart the DNA, so that no additional proteins would be produced other than that from their syntheticRNA. They then added 1 radioactively labeledamino acid, the building blocks of proteins, and 19 unlabeled amino acids to the extract, varying the labeled amino acid in each sample. In the extract containing the radioactively labeledphenylalanine, the resulting protein was alsoradioactive. They realized that they had found thegenetic codefor phenylalanine: UUU (threeuracilbases in a row) on RNA. This was the first step in

Barry J. Marshall and J. Robin Warren"for their discovery of the bacteriumHelicobacter pyloriand its role in gastritis and peptic ulcer disease.

2005

Barry J. Marshall

J. Robin Warren

In 1979, Marshall was appointed as a Registrar in Medicine at theRoyal Perth Hospital. He metRobin Warren, a pathologist interested in gastritis, during internal medicine fellowship training at Royal Perth Hospital in 1981. Together, the pair studied the presence of spiral bacteria in association with gastritis. In 1982, they performed the initial culture ofH. pyloriand developed their hypothesis related to the bacterial cause of peptic ulcer and gastric cancer.

It has been claimed that theH. pyloritheory was ridiculed by the establishment scientists and doctors, who did not believe that any bacteria could live in the acidic environment of the stomach. Marshall has been quoted as saying in 1998 that "everyone was against me, but I knew I was right."

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Figure 6 Helicobacter Pylori

After failed attempts to infect piglets in 1984, Marshall drank aPetri dishcontaining culturedH. pylori, expecting to develop, perhaps years later, an ulcer. He was surprised when, only five days later, he developed gastritis withachlorhydria, i.e., his vomitus had no acid content. Symptoms included vague stomach discomfort, nausea, vomiting andhalitosis(due to the achlorhydria, there was no acid to kill bacteria in the stomach, and their waste products manifested as bad breath). On the fourteenth day of the infection, biopsies of Marshall's stomach did not reveal any bacteria, so spontaneous eradication may have occurred. However, on the insistence of his wife, Marshall took antibiotics immediately after the endoscopy, so there was no way of double-checking the negative result. Interestingly, Marshall did not develop antibodies toH. pylori, suggesting thatinnate immunitycan sometimes eradicate acuteH. pyloriinfection. Marshall's illness and recovery, based on a culture of organisms extracted from a patient, fulfilledKoch's postulatesforH. pyloriand gastritis, but not for peptic ulcer. This experiment was published in 1985 in theMedical Journal of Australia,and is among the most cited articles from the journal. At theUniversity of Western Australia with his colleagueBarry J. Marshall, Warren proved that the bacterium is the cause of stomach ulcers.Warren helped develop a convenient diagnostic test (14C-urea breath-test) for detectingH. pyloriin ulcer patients.

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