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Posts Tagged ‘Nobel Prize in Physiology and Medicine’


Nobel Prize in Medicine – 2015

Larry H Bernstein, MD, FCAP, Curator

LPBI

 

Nobel Prize in Medicine Awarded for Drugs to Battle Malaria and Other Tropical Diseases

  • The Nobel Prize in medicine was awarded today to three scientists from the U.S., Japan, and China, for discovering drugs to fight malaria and other tropical diseases that affect hundreds of millions of people annually.

http://www.genengnews.com/gen-news-highlights/nobel-prize-in-medicine-awarded-for-drugs-to-battle-malaria-tropical-diseases/81251819/

The prize was awarded by the Nobel judges in Stockholm to William Campbell, Ph.D., who was born in Ireland and became a U.S. citizen in 1962, Satoshi Omura, Ph.D., of Japan, and Youyou Tu, the first-ever Chinese medicine laureate.

Dr. Campbell was associated with the Merck Institute for Therapeutic Research from 1957 to 1990, and from 1984 to 1990 he was senior scientist and director for assay research and development.

Dr. Campbell, 85, is currently a research fellow emeritus at Drew University in Madison, NJ. Dr. Omura, 80, is a professor emeritus at Kitasato University in Japan and is from the central prefecture of Yamanashi. Ms. Tu, 84, is chief professor at the China Academy of Traditional Chinese Medicine.

Nobel prize recipients Dr. Campbell and Dr. Omura were cited for discovering avermectin, derivatives of which have helped lower the incidence of river blindness and lymphatic filariasis. These two diseases are caused by parasitic worms that affect millions of people in Africa and Asia.

Ms. Tu, who won the Lasker Award in 2011, was inspired by traditional Chinese remedies to find an alternative treatment for the ailing first line therapies for malaria, quinine and chloroquine. Ms. Tu poured through ancient texts searching for herbal malaria tinctures and came upon an example that utilized the Chinese sweet wormwood plant, Artemisia annua. From this plant she was able to extract the active compound for the antimalarial drug called artemisinin—currently the first line of defense given in malarial endemic regions that have seen resistance to other commonly used drugs, such as chloroquine. Artemisinin has greatly aided in reducing the mortality rates of malaria, a parasitic disease spread by mosquitos that affects close to 50% of the world’s population.

Efforts to eradicate the black fly date back decades. Merck developed Mectizan (ivermectin), a drug to treat river blindness, which kills the worm’s larvae and prevents the adult worms from reproducing. In 1987, Dr. P. Roy Vagelos, the chairman of Merck reportedly decided to make Mectizan available without charge because those who need it the most could not afford to pay for it.

The oral medication ivermectin paralyzes and sterilizes the parasitic worm that causes the illness.

The disease is spread by bites of the black fly, which breeds in fast-flowing rivers. The worm can live in the human body for many years and it can grow to two feet in length, producing millions of larvae. Infected people suffer severe itching, skin nodules, and a variety of eye lesions, and in extreme cases blindness.

“The two discoveries have provided humankind with powerful new means to combat these debilitating diseases that affect hundreds of millions of people annually,” said the Nobel Committee in a statement. “The consequences in terms of improved human health and reduced suffering are immensurable.”

 

 

 

Nobel Prize Predictions See Honors for Gene Editing Technology

By Julie Steenhuysen

http://www.medscape.com/viewarticle/851475?

Scientists selected as “Citation Laureates” rank in the top 1% of citations in their research areas.

“That is a signpost that the research wielded a lot of impact,” said Christopher King, an analyst with IP&S who helped select the winners.

Among the predicted winners for the Nobel Prize in Chemistry are Emmanuelle Charpentier of Helmholtz Center for Infection Research in Germany and Jennifer Doudna of the University of California, Berkeley. They were picked for their development of the CRISPR-Cas9 method for genome editing.

The technique has taken biology by storm, igniting fierce patent battles between start-up companies and universities, and touching off ethical debates over its potential for editing human embryos.

Missing from the list is Feng Zhang, a researcher at the MIT-Harvard Broad Institute, who owns a broad U.S. patent on the technology, which is the subject of a legal battle. King said he was aware of Zhang’s claims on the technology, but noted that his scientific citations did not rise to the level of a nomination.

Other contenders for the chemistry prize, which will be awarded on Oct. 7 in Stockholm, include John Goodenough of the University of Texas Austin, and Stanley Whittingham of Binghamton University in New York for research leading to the development of the lithium-ion battery.

Also in contention is Carolyn Bertozzi of Stanford University for her contributions to “bioorthogonal chemistry,” which refers to chemical reactions in live cells and organisms. Bertozzi’s lab is using the process to develop smart probes for medical imaging.

For the Nobel in medicine, to be announced Oct. 5, Thomson Reuters picked Kazutoshi Mori of Kyoto University and Peter Walter of the University of California, San Francisco. They showed that a mechanism known as the unfolded protein response acts as a “quality control system” inside cells, deciding whether damaged cells live or die.

Other contenders include Jeffrey Gordon of Washington University in St. Louis for showing a relationship between diet and metabolism and microbes that live in the human gut.

The group also picked a trio of researchers – Alexander Rudensky of Memorial Sloan Kettering Cancer Center, Dr. Shimon Sakaguchi of Osaka University, and Ethan Shevach of the National Institutes of Health – for discoveries relating to regulatory T cells and the function of Foxp3, a master regulator of these immune cells.

For the prizes in physics and economics, to be announced Oct. 6 and 12 respectively, Thomson Reuters predicts winners from scientists who helped pave the way for making X-ray lasers and work that helped explain the impact of policy decisions on labor markets and consumer demand.

Science enthusiasts can weigh in with their own predictions by taking part in Thomson Reuters’ “People’s Choice” prizes at StateOfInnovation.com.

 

 

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Recent Insights in Drug Development

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

A Better Class of Cancer Drugs
http://www.technologynetworks.com/medchem/news.aspx?ID=183124
An SDSU chemist has developed a technique to identify potential cancer drugs that are less likely to produce side effects.
A class of therapeutic drugs known as protein kinase inhibitors has in the past decade become a powerful weapon in the fight against various life-threatening diseases, including certain types of leukemia, lung cancer, kidney cancer and squamous cell cancer of the head and neck. One problem with these drugs, however, is that they often inhibit many different targets, which can lead to side effects and complications in therapeutic use. A recent study by San Diego State University chemist Jeffrey Gustafson has identified a new technique for improving the selectivity of these drugs and possibly decreasing unwanted side effects in the future.

Why are protein kinase–inhibiting drugs so unpredictable? The answer lies in their molecular makeup.

Many of these drug candidates possess examples of a phenomenon known as atropisomerism. To understand what this is, it’s helpful to understand a bit of the chemistry at work. Molecules can come in different forms that have exactly the same chemical formula and even the same bonds, just arranged differently. The different arrangements are mirror images of each other, with a left-handed and a right-handed arrangement. The molecules’ “handedness” is referred to as chirality. Atropisomerism is a form of chirality that arises when the spatial arrangement has a rotatable bond called an axis of chirality. Picture two non-identical paper snowflakes tethered together by a rigid stick.

Some axes of chirality are rigid, while others can freely spin about their axis. In the latter case, this means that at any given time, you could have one of two different “versions” of the same molecule.

Watershed treatment

As the name suggests, kinase inhibitors interrupt the function of kinases—a particular type of enzyme—and effectively shut down the activity of proteins that contribute to cancer.

“Kinase inhibition has been a watershed for cancer treatment,” said Gustafson, who attended SDSU as an undergraduate before earning his Ph.D. in organic chemistry from Yale University, then working there as a National Institutes of Health poctdoctoral fellow in chemical biology.

“However, it’s really hard to inhibit a single kinase,” he explained. “The majority of compounds identified inhibit not just one but many kinases, and that can lead to a number of side effects.”

Many kinase inhibitors possess axes of chirality that are freely spinning. The problem is that because you can’t control which “arrangement” of the molecule is present at a given time, the unwanted version could have unintended consequences.

In practice, this means that when medicinal chemists discover a promising kinase inhibitor that exists as two interchanging arrangements, they actually have two different inhibitors. Each one can have quite different biological effects, and it’s difficult to know which version of the molecule actually targets the right protein.

“I think this has really been under-recognized in the field,” Gustafson said. “The field needs strategies to weed out these side effects.”

Applying the brakes

So that’s what Gustafson did in a recently published study. He and his colleagues synthesized atropisomeric compounds known to target a particular family of kinases known as tyrosine kinases. To some of these compounds, the researchers added a single chlorine atom which effectively served as a brake to keep the atropisomer from spinning around, locking the molecule into either a right-handed or a left-handed version.

When the researchers screened both the modified and unmodified versions against their target kinases, they found major differences in which kinases the different versions inhibited. The unmodified compound was like a shotgun blast, inhibiting a broad range of kinases. But the locked-in right-handed and left-handed versions were choosier.

“Just by locking them into one or another atropisomeric configuration, not only were they more selective, but they  inhibited different kinases,” Gustafson explained.

If drug makers incorporated this technique into their early drug discovery process, he said, it would help identify which version of an atropisomeric compound actually targets the kinase they want to target, cutting the potential for side effects and helping to usher drugs past strict regulatory hurdles and into the hands of waiting patients.

 

Inroads Against Leukaemia
http://www.technologynetworks.com/medchem/news.aspx?ID=183594

 

Potential for halting disease in molecule isolated from sea sponges.
A molecule isolated from sea sponges and later synthesized in the lab can halt the growth of cancerous cells and could open the door to a new treatment for leukemia, according to a team of Harvard researchers and other collaborators led by Matthew Shair, a professor of chemistry and chemical biology.

“Once we learned this molecule, named cortistatin A, was very potent and selective in terms of inhibiting the growth of AML [acute myeloid leukemia] cells, we tested it in mouse models of AML and found that it was as efficacious as any other molecule we had seen, without having deleterious effects,” Shair said. “This suggests we have identified a promising new therapeutic approach.”

It’s one that could be available to test in patients relatively soon.

“We synthesized cortistatin A and we are working to develop novel therapeutics based on it by optimizing its drug-like properties,” Shair said. “Given the dearth of effective treatments for AML, we recognize the importance of advancing it toward clinical trials as quickly as possible.”

The drug-development process generally takes years, but Shair’s lab is very close to having what is known as a development candidate that could be taken into late-stage preclinical development and then clinical trials. An industrial partner will be needed to push the technology along that path and toward regulatory approval. Harvard’s Office of Technology Development (OTD) is engaged in advanced discussions to that end.

The molecule works, Shair explained, by inhibiting a pair of nearly identical kinases, called CDK8 and CDK19, that his research indicates play a key role in the growth of AML cells.

The kinases operate as part of a poorly understood, massive structure in the nucleus of cells called the mediator complex, which acts as a bridge between transcription factors and transcriptional machinery. Inhibiting these two specific kinases, Shair and colleagues found, doesn’t shut down all transcription, but instead has gene-specific effects.

“We treated AML cells with cortistatin A and measured the effects on gene expression,” Shair said. “One of the first surprises was that it’s affecting a very small number of genes — we thought it might be in the thousands, but it’s in the low hundreds.”

When Shair, Henry Pelish, a senior research associate in chemistry and chemical biology, and then-Ph.D. student Brian Liau looked closely at which genes were affected, they discovered many were associated with DNA regulatory elements known as “super-enhancers.”

“Humans have about 220 different types of cells in their body — they all have the same genome, but they have to form things like skin and bone and liver cells,” Shair explained. “In all cells, there are a relatively small number of DNA regulatory elements, called super-enhancers. These super-enhancers drive high expression of genes, many of which dictate cellular identity. A big part of cancer is a situation where that identity is lost, and the cells become poorly differentiated and are stuck in an almost stem-cell-like state.”

While a few potential cancer treatments have attacked the disease by down-regulating such cellular identity genes, Shair and colleagues were surprised to find that their molecule actually turned up the activity of those genes in AML cells.

“Before this paper, the thought was that cancer is ramping these genes up, keeping the cells in a hyper-proliferative state and affecting cell growth in that way,” Shair said. “But our molecule is saying that’s one part of the story, and in addition cancer is keeping the dosage of these genes in a narrow range. If it’s too low, the cells die. If they are pushed too high, as with cortistatin A, they return to their normal identity and stop growing.”

Shair’s lab became interested in the molecule several years ago, shortly after it was first isolated and described by other researchers. Early studies suggested it appeared to inhibit just a handful of kinases.

“We tested approximately 400 kinases, and found that it inhibits only CDK8 and CDK19 in cells, which makes it among the most selective kinase inhibitors identified to date,” Shair said. “Having compounds that precisely hit a specific target, like cortistatin A, can help reduce side effects and increase efficacy. In a way, it shatters a dogma because we thought it wasn’t possible for a molecule to be this selective and bind in a site common to all 500 human kinases, but this molecule does it, and it does it because of its 3-D structure. What’s interesting is that most kinase-inhibitor drugs do not have this type of 3-D structure. Nature is telling us that one way to achieve this level of specificity is to make molecules more like cortistatin A.”

Shair’s team successfully synthesized the molecule, which helped them study how it worked and why it affected the growth of a very specific type of cell. Later on, with funding and drug-development expertise provided by Harvard’s Blavatnik Biomedical Accelerator, Shair’s lab created a range of new molecules that may be better suited to clinical application.

“It’s a complex process to make [cortistatin A] — 32 chemical steps,” said Shair. “But we have been able to find less complex structures that act just like the natural compound, with better drug-like properties, and they can be made on a large scale and in about half as many steps.”

“Over the course of several years, we have watched this research progress from an intriguing discovery to a highly promising development candidate,” said Isaac Kohlberg, senior associate provost and chief technology development officer. “The latest results are a real testament to Matt’s ingenuity and dedication to addressing a very tough disease.”

While there is still much work to be done — in particular, to better understand how CDK8 and CDK19 regulate gene expression — the early results have been dramatic.

“This is the kind of thing you do science for,” Shair said, “the idea that once every 10 or 20 years you might find something this interesting, that sheds new light on important, difficult problems. This gives us an opportunity to generate a new understanding of cancer and also develop new therapeutics to treat it. We’re very excited and curious to see where it goes.”

 

Seeking A Better Way To Design Drugs

http://www.technologynetworks.com/medchem/news.aspx?ID=183338

NIH funds research at Worcester Polytechnic Institute to advance a new chemical process for more effective drug development and manufacturing.
The National Institutes of Health (NIH) has awarded $346,000 to Worcester Polytechnic Institute (WPI) for a three-year research project to advance development of a chemical process that could significantly improve the ability to design new pharmaceuticals and streamline the manufacturing of existing drugs.

Led by Marion Emmert, PhD, assistant professor of chemistry and biochemistry at WPI, the research program involves early-stage technology developed in her lab that may yield a more efficient and predictable method of bonding a vital class of structures called aromatic and benzylic amines to a drug molecule.

“Seven of the top 10 pharmaceuticals in use today have these substructures, because they are so effective at creating a biologically active compound,” Emmert said. “The current processes used to add these groups are indirect and not very efficient. So we asked ourselves, can we do it better? ”

For a drug to do its job in the body it must interact with a specific biological target and produce a therapeutic effect. First, the drug needs to physically attach or “bind” to the target, which is a specific part of a cell, protein, or molecule. As a result, designing a new drug is like crafting a three-dimensional jigsaw puzzle piece that fits precisely into an existing biological structure in the body. Aromatic and benzylic amines add properties to the drug that help it bind more efficiently to these biological structures.

Getting those aromatic and benzylic amines into the structure of a drug, however, is difficult. Traditionally, this requires a specialized chemical bond as precursor in a specific location of the drug’s molecular structure. “The current approach to making those bonds is indirect, requires several lengthy steps, and the outcome is not always precise or efficient,” Emmert said. “Only a small percentage of the bonds can be made in the proper place, and sometimes none at all.”

Emmert’s new approach uses novel reagents and metal catalysts to create a process that can attach amines directly, in the right place, every time. In early proof-of-principle experiments, Emmert has succeeded in making several amine bonds directly in one or two days, whereas the standard process can take two weeks with less accuracy. Over the next three years, with support from the NIH, Emmert’s team will continue to study the new catalytic processes in detail. They will also use the new process to synthesize Asacol, a common drug now in use for ulcerative colitis, and expect to significantly shorten its production.

“Some of our early data are promising, but we have a lot more work to do to understand the basic mechanisms involved in the new processes,” Emmert said. “We also have to adapt the process to molecules that could be used directly for drug development.”

 

Antiparasite Drug Developers Win Nobel

William Campbell, Satoshi Omura, and Youyou Tu have won this year’s Nobel Prize in Physiology or Medicine in recognition of their contributions to antiparasitic drug development.

By Karen Zusi and Tracy Vence | October 5, 2015

http://www.the-scientist.com//?articles.view/articleNo/44159/title/Antiparasite-Drug-Developers-Win-Nobel/

William Campbell, Satoshi Omura, and Youyou Tu have made significant contributions to treatments for river blindness, lymphatic filariasis, and malaria; today (October 5) these three scientists were jointly awarded the 2015 Nobel Prize in Physiology or Medicine in recognition of these advancements.

Tu is being recognized for her discoveries leading to the development of the antimalarial drug artemisinin. Campbell and Omura jointly received the other half of this year’s prize for their separate work leading to the discovery of the drug avermectin, which has been used to develop therapies for river blindness and lymphatic filariasis.

“These discoveries are now more than 30 years old,” David Conway, a professor of biology of the London School of Hygiene & Tropical Medicine, told The Scientist. “[These drugs] are still, today, the best two groups of compounds for antimalarial use, on the one hand, and antinematode worms and filariasis on the other.”

Omura, a Japanese microbiologist at Kitasato University in Tokyo, isolated strains of the soil bacteriaStreptomyces in a search for those with promising antibacterial activity. He eventually narrowed thousands of cultures down to 50.

Now research fellow emeritus at Drew University in New Jersey, Campbell spent much of his career at Merck, where he discovered effective antiparasitic properties in one of Omura’s cultures and purified the relevant compounds into avermectin (later refined into ivermectin).

“Bill Campbell is a wonderful scientist, a wonderful man, and a great mentor for undergraduate students,” said his colleague Roger Knowles, a professor of biology at Drew University. “His ability to speak about disease mechanisms and novel strategies to help [fight] these diseases. . . . that’s been a great boon to students.”

Tu began searching for a novel malaria treatment in the 1960s in traditional herbal medicine. She served as the head of Project 523, a program at the China Academy of Chinese Medical Sciences in Beijing aimed at finding new drugs for malaria. Tu successfully extracted a promising compound from the plant Artemisia annu that was highly effective against the malaria parasite. In recognition of her malaria research, Tu won a Lasker Award in 2011.

 

Optogenetics Advances in Monkeys

Researchers have selectively activated a specific neural pathway to manipulate a primate’s behavior.

By Kerry Grens | October 5, 2015

http://www.the-scientist.com//?articles.view/articleNo/44156/title/Optogenetics-Advances-in-Monkeys/

Scientists have used optogenetics to target a specific neural pathway in the brain of a macaque monkey and alter the animal’s behavior. As the authors reported in Nature Communications last month, such a feat had been accomplished only in rodents before.

Optogenetics relies on the insertion of a gene for a light-sensitive ion channel. When present in neurons, the channel can turn on or off the activity of a neuron, depending on the flavor of the channel. Previous attempts to use optogenetics in nonhuman primates affected brain regions more generally, rather than particular neural circuits. In this case, Masayuki Matsumoto of Kyoto University and colleagues delivered the channel’s gene specifically to one area of the monkey’s brain called the frontal eye field.

They found that not only did the neurons in this region respond to light shone on the brain, but the monkey’s behavior changed as well. The stimulation caused saccades—quick eye movements. “Our findings clearly demonstrate the causal relationship between the signals transmitted through the FEF-SC [frontal eye field-superior colliculus] pathway and saccadic eye movements,” Matsumoto and his colleagues wrote in their report.

“Over the decades, electrical microstimulation and pharmacological manipulation techniques have been used as tools to modulate neuronal activity in various brain regions, permitting investigators to establish causal links between neuronal activity and behaviours,” they continued. “These methodologies, however, cannot selectively target the activity (that is, the transmitted signal) of a particular pathway connecting two regions. The advent of pathway-selective optogenetic approaches has enabled investigators to overcome this issue in rodents and now, as we have demonstrated, in nonhuman primates.”

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Outline of Medical Discoveries between 1880 and 1980

Curator: Larry H Bernstein, MD, FCAP

This is the first of a two part series tracing the developments in medical diagnosis and treatment, and herein, tracing the scientific events of the 19th century that accelerated and created the emergent events that brought together physics, organic and physical chemistry, electronics, computational biology.

Part I. Anatomy and Physiology

The first Nobel Prize in Physiology was awarded to Ivan Pavlov for work on digestion in 1904.  The presentation speech refers to the groundbreaking work of Vesalius and Harvey in his presentation address, citing their passionate pursuit of knowledge.  He credits the work of a young American physician, William Beaumont, who served as the only doctor on Michigan’s Mackinac Island in the French and Indian war in 1822, and who observed the gastric secretion from the gastric fistula of a wounded soldier. (see John Karlawish, Open Wound, University of Michigan Press, 2011). This was the basis for the work by Pavlov on dogs that extends our understanding of the telationship of the central nervous system to the digestive processes.

The Nobel Prize in Physiology or Medicine 1906 was awarded jointly to Camillo Golgi and Santiago Ramón y Cajal “in recognition of their work on the structure of the nervous system”. Golgi first opened the field of neuroanatomy with the silver staining method, and Cajal contributed equally to establishing the foundation for this research of great complexity.

The Nobel Prize in Physiology or Medicine 1909 was awarded to Emil Theodor Kocher for his work on the physiology, pathology, and surgery  of the thyroid gland. It had already been established that the enlargement of the thyroid compresses the trachea, and that complete removal has morbid effects. It was expressed by Kocher in 1883 that removal of the thyroid as a consequence of surgery must leave behind a functioning portion of the gland.

This was later followed by the establishment of a great medical institution Dr. William Worrall Mayo, a frontier doctor, and his two sons, Dr. William J. Mayo and Dr. Charles H. Mayo, Mayo Clinic.

The elder Dr. Mayo emigrated from his native England to the United States in 1846. He became a doctor in 1850. In 1863 he was appointed a surgeon for the enrollment board in southern Minnesota, to examine recruits for the Union Army, and settled in Rochester, Minn. His dedication to medicine became a family tradition when his sons, Drs. William James Mayo and Charles Horace Mayo, joined his practice in 1883 and 1888, respectively.

In 1883, a tornado swept through Rochester leaving in its wake many deaths and injuries. Temporary hospital quarters were set up in offices and hotels. Nuns from the Sisters of St. Francis, a teaching order, were recruited as nurses. The experience inspired Mother Alfred Moes to request that the Drs. Mayo join with the Sisters to build the first general hospital in southeastern Minnesota. The 27-bed Saint Mary’s Hospital opened in 1889 as a result of this partnership.

mayo-brothers

mayo-brothers

As the demand for their services increased, they asked other doctors and basic science researchers to join them in the world’s first private integrated group practice. In 1919, the Mayo brothers dissolved their partnership and turned the clinic’s name and assets, including the bulk of their life savings, to a private, not-for-profit, charitable organization now known as Mayo Foundation. It is worth noting that the Mayo Clinic became a favored place to have thyroid surgery, as its location is in the “goiter belt”.

Patients discovered the advantages to a “pooled resource” of knowledge and skills among doctors. In fact, the group practice concept that the Mayo family originated has influenced the structure and function of medical practice throughout the world.

The Nobel Prize in Physiology or Medicine 1912 was awarded to Alexis Carrel “in recognition of his work on vascular suture and the transplantation of blood vessels and organs”. He demonstrated the technique used to suture together open vessels, and even to transplant whole organs from one animal to another with excellent results.

The Nobel Prize in Physiology or Medicine 1920 was awarded to August Krogh “for his discovery of the capillary motor regulating mechanism”.  Harvey had shown in 1628 that the blood traverses the circulation returning to the heart in one minute. Malpighi showed that blood passes from the artery to the vein by capillaries  in 1661.  Krogh demonstrated by very elegant experiments that the quantity of gas that diffuses across the pulmonary alveoli is the same amount of gas that is released to the alveolar space. The importance of this is that the investigations having the aim to determine the process by which the oxygen requirement of the tissues is satisfied.

The Nobel Prize in Physiology or Medicine 1922 was divided equally between Archibald Vivian Hill “for his discovery relating to the production of heat in the muscle” and Otto Fritz Meyerhof “for his discovery of the fixed relationship between the consumption of oxygen and the metabolism of lactic acid in the muscle”. One need not be a physiologist to recognize that muscular activity is essentially bound up with the development of heat, or even with combustion. AV Hill determined the time relationships of heat production in muscle contraction measured galvanometrically, and Otto Meyerhof determined the oxygen consumption in the production of lactic acid. The muscle is regarded as a machine that converts chemical energy to mechanical energy (tension) with the production of heat. The development of heat entirely fails to appear if the supply of oxygen to the muscle is cut off, while the development of heat during the actual twitch, is independent of the presence of oxygen (consistent with Meyerhof’s glycolysis). The relaxation phase is consistent with oxygen uptake during recovery.

Fletcher and Hopkins had shown earlier that muscle not only forms, but also uses lactic acid in the presence of oxygen. Meyerhof determined by parallel determination of the lactic acid metabolism and the oxygen consumption during the recovery of the muscle, which yielded the result that the oxygen consumption does not account for more than1/3 – 1/4 of the lactic acid formed. When lactic
acid is formed an equivalent amount of glycogen in muscle disappears, and when lactic acid disappears, the quantity of
carbohydrate increases by the difference between lactic acid and quantity used in oxygen consumption.

The Nobel Prize in Physiology or Medicine 1923 was awarded jointly to Frederick Grant Banting and John James Rickard
Macleod “for the discovery of insulin”.  In 1857, Claude Bernard discovered that the liver contains glycogen, which converted to glucose, enters the blood stream (and thereby, the urine). Glycosuria became a starting point for the study of diabetes. It is of interest that he could not produce glycosuria by ligation of the pancreatic duct. But in 1889 Mering and Minkowsky did an operation on dogs that removed the pancreas, resulting in glycosuria, and creating a disease comparable to diabetes in humans. If part of the pancreas was left behind, it failed to produce diabetes. Brown-Sequard had called attention to ductless organs in the 1880s that are glands. These were
endocrine glands secreting hormones. Langerhans had shown in 1869 that the pancreas has glands that have no secretion into the pancreatic ducts, and in the beginning of the 1890s Languese surmised that these glands were involved in diabetes mellitus. Schulze and Ssobolev had shown that ligation of the duct resulted in atrophy of the pancreas sparing the islets. Frederick Banting at this time postulated that trypsin degraded the hormone, and with Best and Collip, under MacLeod’s guidance, Banting pursued his idea, and the effective extract was obtained in 1921, and demonstrated in 1922.

Arch Anat Histol Embryol. 1993-1994;75:151-82.

[History of histology in Strasbourg].

Le Minor JM.

Since the cellular theory was formulated in 1839, the University of Strasbourg has held a pioneer place in histology. This new morphological science has had, since its origin, close relations with physiology, and from 1846 to 1871, an original histophysiological school was organized in Strasbourg. The microscope and the study of tissues were considered as a fundamental approach for the progress of biological and medical knowledge. After the German annexation of Alsace, the scientists from this school participated in the renewal of histology in Nancy, Montpellier, and Paris. In 1872, when the new German university was created, an anatomical institute regrouped all aspects of normal morphology: anatomy, histology, and embryology. This was the case until 1918. In 1919, when the Faculty of Medicine was reorganized after Alsace was restored to France, a specific chair and institute of histology were created. This was the beginning of a school of histophysiology which was internationally renowned in the rise of experimental endocrinology. Great discoveries followed one after another: folliculin in 1924 and demonstration of the duality of ovarian hormones, the prominent place of the anterior part of the hypophysis and the demonstration of prolactin in 1928, thyreostimulin in 1929, then study of the other stimulins. In 1946 a chair and institute of medical biology were created. In 1948, a service of electron microscopy was opened.
P. Bouin (1870-1962), M. Aron (1892-1974), J. Benoit (1896-1982), R. Courrier (1895-1986) et M. Klein (1905-1975), were among the famous scientists who worked in histology in Strasbourg in the
period after the French restoration.
The Nobel Prize in Physiology or Medicine 1947

Bernardo Alberto Houssay

“for his discovery of the part played by the hormone of the anterior pituitary lobe in the metabolism of sugar”

He had already begun studying medicine and, in 1907, before completing his studies, he took up a post in the Department of Physiology. He began here his research on the hypophysis which resulted in his M.D.-thesis (1911), a thesis which earned him a University prize.

In 1919 he became Professor of Physiology in the Medical School at Buenos Aires University. He also organized the Institute of Physiology at the Medical School, making it a center with an international reputation. He remained Professor and Director of the Institute until 1943.  He made a lifelong study of the hypophysis and his most important discovery concerns the role of the anterior lobe of the hypophysis in carbohydrate metabolism and the onset of diabetes.

The Nobel Prize in Physiology or Medicine 1950

Edward Calvin Kendall, Tadeus Reichstein and Philip Showalter Hench

“for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects”

As late as in 1854 the German anatomist, Kölliker, was able to claim in a review of the subject that although the function of the adrenals was still unknown, yet in certain respects great advances had been made. Two quite different parts were now distinguished, an outer part, a fairly firm cortex, and an inner, softer medulla. Kölliker classified the adrenal cortices as ductless glands, which we now call the endocrine organs.

Thomas Addison, the English doctor, observed a rare disease with a fatal course, which was characterized chiefly by anemia, general weakness and fatigue, disturbances in the digestive apparatus, enfeebled heart activity and a peculiar dark pigmentation of the skin. He published a paper 1n 1855, suggesting that this morbid picture made its appearance in persons the greater part of whose adrenals was destroyed. Subsequent experiments in animals showed that removal of the adrenals led to speedy death, the symptoms recalling those known from Addison’s disease.

In 1894 Oliver and Schäfer proved that the injection of a watery extract from the adrenals had extremely pronounced effects. Within a few years adrenaline had been produced from the extract, its composition had been ascertained, and its artificial production accomplished. The more detailed analysis showed effects of the same kind as those resulting on increased activity of the so-called sympathetic nervous system, which innervates internal organs such as the heart and vessels, the intestinal canal, etc.  Attempts to prevent by means of adrenaline the deficiency symptoms following on the removal of the adrenals failed completely. The explanation of this was given when Biedl and others showed that it is the cortex which is of vital importance, not the medulla.

The isolation of the cortin proved to be a difficult task, calling for the combined efforts of a number of research workers. Particularly important contributions were made in this field by Wintersteiner and Pfiffner, and also by Edward Kendall at the Mayo Clinic in Rochester, and Tadeus Reichstein in Basel, and their co-workers. As early as in 1934, Kendall and his group succeeded in preparing from cortex extract what was at first assumed to be pure cortin in crystalline form. They found that it contained carbon, hydrogen, and oxygen, and indicated its empirical formula. But that was only a beginning. There was no reason to suspect that the cortin was not homogeneous; as further experiments proved. In reality Kendall and his co-workers had produced a mixture of different substances closely related to one another, and their work represents the early steps in the crystallization of a whole series of cortin substances. There is at least one active cortical substance – the best known of them all, first named Compound E and now called cortisone or cortone – which was isolated at four different laboratories, among them Kendall’s and Reichstein’s.

As all the cortin substances are closely related to one another, Reichstein’s finding implies that, like the sex hormones, they belong to the large and important group of steroids. The D vitamins and the bile acids, like our most important heart remedies, the active substances in Digitalis leaves and Strophanthus seeds, are also intimately associated with the steroids

The six definitely active cortical hormones are characterized, inter alia, by a double bond in the steroid skeleton; if this double bond disappears, inactive substances are obtained. They differ very inconsiderably from each other chemically. They are built up of 21 carbon atoms, but the number of oxygen atoms in the molecule is three, four, or five. The position of the additional oxygen atoms in the molecule was first established by Reichstein and Kendall, and thus a way was opened for semisynthetic production e.g. from the more easily obtainable bile acids or material from a certain species of Strophanthus. This is of particular importance, since the yield from the adrenals is very poor, at most about 1:1,000,000.

Thanks to the work of Kendall and his school, it has emerged that the comparatively inconsiderable dissimilarities in the matter of the structure of the cortical hormones are accompanied by material differences in respect of the effect. Thus some act especially strongly on the metabolism of sugar, others on the salt and fluid balances, and there are also several other differences. This was illustrated when Compound E was first tested. Pfiffner and Wintersteiner, like the Reichstein group, found that the substance had no, or extremely inconsiderable, life-prolonging effects on animals deprived of the adrenals. On the other hand, Ingle, Kendall’s coworker, observed that it stimulated the muscular work of such animals very strongly.

In the April of 1949, Hench, Kendall, Slocumb and Polley published their experiences in respect of the dramatic effects of cortisone in cases of chronic rheumatoid arthritis. A rapid improvement set in, pains and tenderness in the joints abated or disappeared, mobility increased, so that patients who had previously been complete invalids could walk about freely, and their general condition was also favourably affected. Similar results were obtained with a preparation from the anterior lobe of the pituitary, the so-called ACTH (Adreno-Cortico-Tropic Hormone), which, as the name indicates, stimulates the adrenal cortex to increased activity.

The value of a discovery lies not only in the immediate practical results, but equally much in the fact that it points out new lines of research. This is strikingly illustrated by the research during the last few decades into the cortical hormones, which has already led to unexpected and important new results within widely different spheres.

Nobel Prize in Physiology or Medicine 1966

Charles Huggins

Endocrine-Induced Regression of Cancers

The net increment of mass of a cancer is a function of the interaction of the tumor and its soil. Self-control of cancers results from a highly advantageous competition of host with his tumor. There are multiple factors which restrain cancer – enzymatic, nutritional, immunologic, the genotype and others.Prominent among them is the endocrine status, both of tumor and host – the subjects of this discourse.

The second quarter of our century found the biological sciences much pre-occupied with two noble topics :

  • chemistry and physiology of steroids and
  • biochemistry of organo-phosphorus compounds.

The key to the puzzle of the steroid hormones in cancer was the isolation of crystalline estrone by Doisy et al.2 from extracts of urine of pregnant women. In the phosphorus field there were magnificent findings of hexose phosphates, nucleotides, coenzymes and high-energy phosphate intermediates. These wonderful discoveries provided the Zeitgeist for our work.

Through the portal of phosphorus metabolism we entered on a series of interconnected observations in steroid endocrinology. A program was not prepared in advance for this basic physiologic study. The work was fascinating and informative so that it provided its own momentum and served as an end in itself.

The prostatic cell does not die in the absence of testosterone, it merely shrivels. But the hormone-dependent cancer cell is entirely different. It grows in the presence of supporting hormones but it dies in their absence and for this reason it cannot participate in growth cycles.

A remarkable effect of testosterone is the promotion of growth of its target cells during complete deprival of food. Androstane derivatives conferred on the prostate of puppies a selective nutritional advantage during starvation of 3 weeks whereby abundant growth of this gland-occurred while there was serious cell breakdown in most of the tissues of the body.

At first it was vexatious to encounter a dog with a prostatic tumor during a metabolic study but before long such dogs were sought. It was soon observed that orchiectomy or the administration of restricted amounts of phenolic estrogens caused a rapid shrinkage of canine prostatic tumors.

The experiments on canine neoplasia proved relevant to human prostate cancer; there had been no earlier reports indicating any relationship of hormones to this malignant growth.

Kutscher and Wolbergs9 discovered that acid phosphatase is rich in concentration in the prostate of adult human males. Gutman and Gutman10 found that many patients with metastatic prostate cancer have significant increases of acid phosphatase in their blood serum. Cancer of the prostate frequently metastasizes to bone.

Human prostate cancer which had metastasized to bone was studied at first. The activities of acid and alkaline phosphatases in the blood were measured concurrently at frequent intervals. The methods are reproducible and not costly in time or materials; both enzymes were measured in duplicate in a small quantity (0.5 ml) of serum. The level of acid phosphatase indicated activity of the disseminated cancer cells in all metastatic loci. The titer of alkaline phosphatase revealed the function of the osteoblasts as influenced by the presence of the prostatic cancer cells that were their near neighbors. By periodic measurement of the two enzymes one obtains a view of overall activity of the cancer and the reaction of non-malignant cells of the host to the presence of that cancer. Thereby the great but opposing influences of, respectively, the administration or deprival of androgenic hormones upon prostate cancer cells were revealed with precision and simplicity. Orchiectomy or the administration of phenolic estrogens resulted in regression of cancer of the human prostate whereas, in untreated cases, testosterone enhanced the rate of growth of the neoplasm.

The first indication that advanced cancer can be induced to regress was the beneficial effect of oöphorectomy on cancer of the breast of two women. This empirical observation17 of Beatson in 1896 was remarkable since it was made before the concept of hormones had been developed. The beneficial action of removal of ovaries was not understood until steroid hormones had been isolated 4 decades later.

But why does breast cancer thrive in folks who do not possess ovarian function – in men, old women, and females who have had oöphorectomy?

Farrow and Adair observed that benefits of great magnitude frequently follow orchiectomy in mammary cancer in the human male. Thereby, they established that testis function can sustain mammary cancer.

A half century after the classic invention of Beatson it was found out that adrenal function can maintain and promote growth of human mammary cancer. The adrenal factor supporting growth of cancer was identified when it was shown that bilateral adrenalectomy (with glucocorticoids as substitution therapy) can result in profound and prolonged regression of mammary carcinoma in men and women who do not possess gonadal function. In developing the idea of adrenalectomy for treatment of advanced cancer in man we were considerably influenced by the discovery of Woolley et al. that adrenals can evoke cancer of the breast in the mouse.

Mammary cancers induced in the male rat by aromatics were not influenced by orchiectomy and hypophysectomy; by definition, these neoplasms are hormone-independent. In contrast to male rat, most mammary cancers of men wither impressively after deprival of supporting hormones.

The hormone-responsiveness of established mammary cancers induced in female rat by aromatics or ionizing radiation is identical; it was a newly recognized property of experimental breast cancers. Prior to this finding, clinical study of patients with mammary cancer was the only material available for investigation of hormonal-restraint of neoplasms of the breast.

In female rat, many but far from all of the induced mammary cancers vanished after removal of ovaries or the pituitary. In our experiments hypophysectomy was the most efficient of all methods to cure rat’s mammary cancer.

Malignant cells which succumb to hormone-deprival, by definition, are hormone-dependent. The quality of hormone-dependence resides in the tumor cells whereas their growth is determined by the host’s endocrine status.

Both man and the animals can have some of their cancer cells which are hormone-dependent while other neoplastic cells in the same organism are not endocrine-responsive.

The cure of a cancer after hormone-deprival results from death of the cancer cells whereas their normal analogues in the same animal shrivel but survive. It is a basic proposition in endocrine-restraint of malignant disease that cancer cells can differ in a crucial way from ancestral normal cells in response to modification of the hormonal milieu intérieur of the body.

Cancer is not necessarily autonomous and intrinsically self-perpetuating. Its growth can be sustained and propagated by hormonal function in the host which is not unusual in kind or exaggerated in rate but which is operating at normal or even subnormal levels.

The control of cancer by endocrine methods can be described in three propositions:

  • Some types of cancer cells differ in a cardinal way from the cells from which they arose in their response to change in their hormonal environment.
  • Certain cancers are hormone-dependent and these cells die when supporting hormones are eliminated.
  • Certain cancers succumb when large amounts of hormones are administered.

The Nobel Prize in Physiology or Medicine 1971

Earl W. Sutherland, Jr.

“for his discoveries concerning the mechanisms of the action of hormones”

Part II. Vitamins

The Nobel Prize in Physiology or Medicine 1929

Christiaan Eijkman “for his discovery of the antineuritic vitamin”

Sir Frederick Gowland Hopkins “for his discovery of the growth-stimulating vitamins”

When the 20th century began, the prevailing thought about nutrition rested on the importance of energy requirements, as elucidated by  Rubner, Benedict and others, in the United States, that entails the quantitative measurement of the food value of carbohydrates, fats, and proteins. But there was a misconception of the process in its detail. The quantitative studies of the energetics and of respiratory exchange were not sufficient to explain problems that arise as a result of deficiencies of micronutrients in food intake.  The complexity of these nutritional needs as we now view them is indeed astonishing.

There is a need for indispensable organic substances specific in nature and function of which the quantitative supply is so small as to contribute little or nothing to the energy factor in nutrition. These substances, following the suggestion of Casimir Funk, we have agreed to call vitamins.

In 1881, Lunin, and associate of Bungel noted that a diet of milk was not sufficient to sustain the life of mice, even if the caloric nutrients were adequate. The main lesson taken from the findings was concerned with inorganic nutrients had not been determined that would answer the question. A decade later, Socin, in Bunge’s group, concluded that the deficiency was in the quality of protein.  In an important paper by Professor Pekelharing in 1905 published an astonishing paper following on the work in Bungel’s lab. He noted that there is a substance in milk in small quantities that he was unable to identify that is essential for life.  It is noteworthy that Pekelharing records prolonged endeavours towards the isolation of a vitamin.

Eikman’s work came in the 1880s. He did not at first visualize beriberi clearly as a deficiency disease. The view that the cortical substance in rice supplied a need rather than neutralized a poison was soon after put forward by Grijns and ultimately accepted by Professor Eijkman himself.  The prevailing thinking about nutritional requirements was preoccupied by the methods of calorimetry at the turn of the century.  The idea of “deficiency diseases” was obscured as a result. There was no concept of an indispensable portion of the food supply other than calories, proteins and minerals until 1911-1912.  Hopkins was convinced that the science of nutrition had to come to terms with an explanation for scurvy and rickets, and he needed to use the new science of biochemistry, which was ongoing at Cambridge.

In 1906-1907, he carried out studies of feeding rats casein, along the lines of Bungel.s experiments, and he found variability in the results with different casein preparations.  He next washed the casein so that any soluble substance was extracted and the rats died, but if he added the extract they grew.  He also used butter, with results more favorable than casein, and lard, with unfavorable results.  At the same time he was studying polyneuritis in birds, which took up much time.  He know that he had to extract the substance, but was unaware of the fat solubility in 1910. He published his work in 1912. Soon after the publication of his work, and duting WWI, much research was done in US, by Osborn and Mendel at Harvard, and by McCollum at Johns Hopkins, and the vitamins were separated into “water soluble” and “fat soluble”.

The Nobel Prize in Physiology or Medicine 1937

Albert von Szent-Györgyi Nagyrápolt

“for his discoveries in connection with the biological combustion processes, with special reference to vitamin C and the catalysis of fumaric acid”

https://pharmaceuticalintelligence.com/2014/08/18/studies-of-respiration-lead-to-acetyl-coa/

Szent Gyorgyi was a biochemist who worked with Otto Warburg and others, and had a special interest in muscle metabolism. He delineated a portion of the Krebs cycle (Krebs was also associated with Warburg), that which involves the conversion of fumaric acid to succinate.  He also purified vitamin C (ascorbic acid) from paprika in his native region of Hungary. He later turned his interest to cancer research, for which he was honored by the MD Anderson Cancer Center.

The Nobel Prize in Physiology or Medicine 1934

George Hoyt Whipple, George Richards Minot and William Parry Murphy

“for their discoveries concerning liver therapy in cases of anaemia”

The Nobel Prize in Physiology or Medicine 1943

Henrik Carl Peter Dam “for his discovery of vitamin K”

Edward Adelbert Doisy “for his discovery of the chemical nature of vitamin K”

To further his studies of the metabolism of sterols, Dam obtained a Rockefeller Fellowship and worked in Rudolph Schoenheimer’s Laboratory in Freiburg, Germany, during 1932-1933, and later worked with P. Karrer, of Zurich, in 1935. He discovered vitamin K while studying the sterol metabolism of chicks in Copenhagen. When he returned to Denmark after WWII in 1946, Dam’s main research subjects were vitamin K, vitamin E, fats, cholesterol.

Part III.  Microbiology and Plague

The Nobel Prize in Physiology or Medicine 1901

Emil Adolf von Behring

“for his work on serum therapy, especially its application against diphtheria, by which he has opened a new road in the domain of medical science and thereby placed in the hands of the physician a victorious weapon against illness and deaths”

The Nobel Prize in Physiology or Medicine 1902

Ronald Ross

“for his work on malaria, by which he has shown how it enters the organism and thereby has laid the foundation for successful research on this disease and methods of combating it”

The Nobel Prize in Physiology or Medicine 1905

Robert Koch

“for his investigations and discoveries in relation to tuberculosis”

The Nobel Prize in Physiology or Medicine 1908

The Nobel Prize in Physiology or Medicine 1928

Charles Jules Henri Nicolle

“for his work on typhus”

The Nobel Prize in Physiology or Medicine 1939

Gerhard Domagk

“for the discovery of the antibacterial effects of prontosil”

The Nobel Prize in Physiology or Medicine 1945

Sir Alexander Fleming, Ernst Boris Chain and Sir Howard Walter Florey

“for the discovery of penicillin and its curative effect in various infectious diseases”

The Nobel Prize in Physiology or Medicine 1951

Max Theiler

“for his discoveries concerning yellow fever and how to combat it”

The Nobel Prize in Physiology or Medicine 1952

Selman Abraham Waksman

“for his discovery of streptomycin, the first antibiotic effective against tuberculosis”

The Nobel Prize in Physiology or Medicine 1954

John Franklin Enders, Thomas Huckle Weller and Frederick Chapman Robbins

“for their discovery of the ability of poliomyelitis viruses to grow in cultures of various types of tissue”

The Nobel Prize in Physiology or Medicine 1976

Baruch S. Blumberg and D. Carleton Gajdusek

“for their discoveries concerning new mechanisms for the origin and dissemination of infectious diseases”

Part IV.

Ilya Ilyich Mechnikov and Paul Ehrlich

“in recognition of their work on immunity”

The Nobel Prize in Physiology or Medicine 1919

Jules Bordet

“for his discoveries relating to immunity”

The Nobel Prize in Physiology or Medicine 1930 was awarded to Karl Landsteiner “for his discovery of human blood groups”.

In 1901, in the course of his serological studies Landsteiner observed that when, under normal physiological conditions, blood serum of a human was added to normal blood of another human the red corpuscles in some cases coalesced into larger or smaller clusters. This observation of Landsteiner was the starting-point of his discovery of the human blood groups. In the following year, i.e. 1901, Landsteiner published his discovery that in man, blood types could be classified into three groups according to their different agglutinating properties. These agglutinating properties were identified more closely by two specific blood-cell structures, which can occur either singly or simultaneously in the same individual.

Landsteiner’s discovery of the blood groups was immediately confirmed but it was a long time before anyone began to realize the great importance of the discovery. The first incentive to pay greater attention to this discovery was provided by von Dungern and Hirszfeld when in 1910 they published their investigations into the hereditary transmission of blood groups. Thereafter the blood groups became the subject of exhaustive studies, on a scale increasing year by year, in more or less all civilized countries. In order to avoid, in the publication of research on this subject, detailed descriptions which would otherwise be necessary – of the four blood groups and their appropriate cell structures, certain short designations for the blood groups and corresponding specific cell structures have been introduced. Thus, one of the two specific cell structures, characterizing the agglutinating properties of human blood is designated by the letter A and another by B, and accordingly we speak of «blood group A» and «blood group B». These two cell structures can also occur simultaneously in the same individual, and this structure as well as the corresponding blood group is described as AB.

The fourth blood-cell structure and the corresponding blood group is known as O, which is intended to indicate that people belonging to this group lack the specific blood characteristics typical of each of the other blood groups. Landsteiner had shown that under normal physiological conditions the blood serum will not agglutinate the erythrocytes of the same individual or those of other individuals with the same structure. Thus, the blood serum of people whose erythrocytes have group structure A will not agglutinate erythrocytes of this structure but it will agglutinate those of group structure B, and where the erythrocytes have group structure B the corresponding serum does not agglutinate these erythrocytes but it does agglutinate those with group structure A. Blood serum of persons whose erythrocytes have structures A as well as B, i.e. who have structure AB, does not agglutinate erythrocytes having structures A, B, or AB. Blood serum of persons belonging to blood group O agglutinates erythrocytes of persons belonging to any of the group.

The group characteristics are handed down in accordance with Mendel’s laws. The characteristics of blood groups A, B, and AB are dominant, and opposing these dominant characteristics are the recessive ones which characterize blood group O. An individual cannot belong to blood group A, B, or AB, unless the specific characteristics of these groups are present in the parents, whereas the recessive characteristics of blood group O can occur if the parents belong to any one of the four groups. If both parents belong to group O, then the children never have the characteristics of A, B, or AB. The children must then likewise belong to blood group O. If one of the parents belongs to group A and the other to group B, then the child may belong to group A or B or it may possess both characteristics and therefore belong to group AB. If one of the parents belongs to group AB and the other to group O, then in accordance with Mendel’s law of segregation the AB characteristic can be segregated and the components can occur as separate characteristics in the children.

Even while he was a student he had begun to do biochemical research and in 1891 he published a paper on the influence of diet on the composition of blood ash. To gain further knowledge of chemistry he spent the next five years in the laboratories of Hantzsch at Zurich, Emil Fischer at Wurzburg, and E. Bamberger at Munich.

In 1896 he became an assistant under Max von Gruber in the Hygiene Institute at Vienna. Even at this time he was interested in the mechanisms of immunity and in the nature of antibodies. From 1898 till 1908 he held the post of assistant in the University Department of Pathological Anatomy in Vienna, the Head of which was Professor A. Weichselbaum, who had discovered the bacterial cause of meningitis, and with Fraenckel had discovered the pneumococcus. Here Landsteiner worked on morbid physiology rather than on morbid anatomy. In this he was encouraged by Weichselbaum, in spite of the criticism of others in this Institute.

Up to the year 1919, after twenty years of work on pathological anatomy, Landsteiner with a number of collaborators had published many papers on his findings in morbid anatomy and on immunology. He discovered new facts about the immunology of syphilis, added to the knowledge of the Wassermann reaction, and discovered the immunological factors which he named haptens (it then became clear that the active substances in the extracts of normal organs used in this reaction were, in fact, haptens). He made fundamental contributions to our knowledge of paroxysmal haemoglobinuria.

He also showed that the cause of poliomyelitis could be transmitted to monkeys by injecting into them material prepared by grinding up the spinal cords of children who had died from this disease, and, lacking in Vienna monkeys for further experiments, he went to the Pasteur Institute in Paris, where monkeys were available. His work there, together with that independently done by Flexner and Lewis, laid the foundations of our knowledge of the cause and immunology of poliomyelitis.

http://www.nobelprize.org/nobel_prizes/medicine/laureates/1930/landsteiner-bio.html

His discovery of the differences and identification of the groups that were alike made it possible for blood transfusions to become a routine procedure.  This paved the way for many other medical procedures that we don’t even think twice about today, such as surgery, blood banks, and transplants.

While in medical school, Landsteiner began experimental work in chemistry, as he was greatly inspired by Ernst Ludwig, one of his professors. After receiving his medical degree, Landsteiner spent the next five years doing advanced research in organic chemistry for Emil Fischer, although medicine remained his chief interest. During 1886-1897, he combined these interests at the Institute of Hygiene at the University of Vienna where he researched immunology and serology. These fields were developing rapidly in the late 1800s as scientists explored numerous physiological changes associated with bacterial infection. Immunology and serology then became Landsteiner’s lifelong focus. Landsteiner was primarily interested in the lack of safety and effectiveness of blood transfusions.

Landsteiner is known as the “melancholy genius” because he was so sad and intense, yet he was so systematic, thorough, and dedicated. He wrote 346 papers during his long career contributing to many areas of scientific knowledge. He is considered the father of Hematology (the study of blood), Immunology (the study of the immune system), Polio research, and Allergy research.

The fundamental contribution of Robert A. Good to the discovery of the crucial role of thymus in mammalian immunity

Domenico Ribatti

Immunology. Nov 2006; 119(3): 291–295.

http://dx.doi.org:/10.1111/j.1365-2567.2006.02484.x

Robert Alan Good was a pioneer in the field of immunodeficiency diseases. He and his colleagues defined the cellular basis and functional consequences of many of the inherited immunodeficiency diseases. His was one of the groups that discovered the pivotal role of the thymus in the immune system development and defined the separate development of the thymus-dependent and bursa-dependent lymphoid cell lineages and their responsibilities in cell-mediated and humoral immunity.

Keywords: bursa of Fabricius, history of medicine, immunology, thymus

Robert A. Good (Fig. 1) began his intellectual and experimental queries related to the thymus in 1952 at the University of Minnesota, initially with paediatric patients. However, his interest in the plasma cell, antibodies and the immune response began in 1944, while still in Medical School at the University of Minnesota in Minneapolis, with his first publication appearing in 1945.

Robert Good

Robert Good

Figure 1

Robert A. Good with two young patients. Source: http://www.robertagoodarchives.com.

Good described a new syndrome that would carry his name: ‘Good syndrome: thymoma with immunodeficiency’.7 The clinical characteristics of Good syndrome are increased susceptibility to bacterial infections by encapsulated organisms and opportunistic viral and fungal infections. Subsequently, Good saw several patients with thymic tumours, which regularly presented with immunodeficiencies, leukopenia, lymphopenia and eosinophylopenia. Plasma cells, however, were not completely absent: the patient was severely hypogammaglobulinaemic rather than agammaglobulinaemic.

The association of thymoma with profound and broadly based immunodeficiency provoked Good’s group to ask what role the thymus plays in immunity.

Good and others found that the patients lacked all of the subsequently described immunoglobulins. These patients were found not to have plasma cells or germinal centres in their haematopoietic and lymphoid tissues. They possessed circulating lymphocytes in normal numbers.

In the mouse and other rodents, immunological depression is profound after thymectomy in neonatal animals, resulting in considerable depression of antibody production, plus deficient transplantation immunity and delayed-type hypersensitivity. Speculation on the reason for immunological failure following neonatal thymectomy has centred on the thymus as a source of cells or humoral factors essential to normal lymphoid development and immunological maturation.

Three independent groups of experiments showed that neonatal thymectomy has a significant effect on immunological reactivity: (i) the studies of Fichtelius et al. in young guinea-pigs showed that the depression of antibody response is slight, but significant; (ii) the experiments of Archer, Good and co-workers in rabbits and mice; and (iii) the studies by Miller at the Chester Beatty Research Institute in London.

Stutman, in Good’s laboratory, demonstrated that non-lymphoid thymomas induced the restoration of immunological functions in neonatally thymectomized mice and that when thymomas were grafted into allogenic hosts, immunological restoration was mediated by lymphoid cells of host type. Comparable results were obtained with free thymus grafts.

Cooper et al. postulated that a lymphoid stem cell population exists that is induced to differentiate along two distinct and separate cell lines related to two central lymphoid organs. In birds this developmental influence is exercised by the thymus and the bursa of Fabricius. Removal of one or both in the early post-hatching period has strikingly different influences on immunological function in the maturing animals. The thymus in the chicken functions exactly as does the thymus of the mouse. It represents the site of differentiation of a population of lymphocytes that subserve largely the functions of cell-mediated immunity.

The athymic children described by Di George, who lacked lymphoid cells in the deep cortical areas of the nodes but not at the peripheral areas, seemed the equivalent of the neonatally thymectomized mice and chickens. These patients had severe deficiencies of small T lymhocytes and profound deficiencies of all cell-mediated immunities, including delayed allergies, deficient allograft immunities and deficiencies in resistance to viruses, fungi and opportunistic infections.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1819567/

The Nobel Prize in Physiology or Medicine 1960

Sir Frank Macfarlane Burnet and Peter Brian Medawar

“for discovery of acquired immunological tolerance”

The Nobel Prize in Physiology or Medicine 1980

Baruj Benacerraf, Jean Dausset and George D. Snell

“for their discoveries concerning genetically determined structures on the cell surface that regulate immunological reactions”

Part V.

Biochemistry and Molecular Biology

The Nobel Prize in Physiology or Medicine 1922

Archibald Vivian Hill

“for his discovery relating to the production of heat in the muscle”

Otto Fritz Meyerhof

“for his discovery of the fixed relationship between the consumption of oxygen and the metabolism of lactic acid in the muscle”

The Nobel Prize in Physiology or Medicine 1931

Otto Heinrich Warburg

“for his discovery of the nature and mode of action of the respiratory enzyme”

https://pharmaceuticalintelligence.com/2012/11/02/otto-warburg-a-giant-of-modern-cellular-biology/

https://pharmaceuticalintelligence.com/2013/11/28/warburg-effect-revisited/

https://pharmaceuticalintelligence.com/2013/03/12/ampk-is-a-negative-regulator-of-the-warburg-effect-and-suppresses-tumor-growth-in-vivo/

https://pharmaceuticalintelligence.com/2012/10/17/is-the-warburg-effect-the-cause-or-the-effect-of-cancer-a-21st-century-view/

The Nobel Prize in Physiology or Medicine 1933

Thomas Hunt Morgan

“for his discoveries concerning the role played by the chromosome in heredity”

The Nobel Prize in Physiology or Medicine 1947

Carl Ferdinand Cori and Gerty Theresa Cori, née Radnitz

“for their discovery of the course of the catalytic conversion of glycogen”

The Nobel Prize in Physiology or Medicine 1953

Hans Adolf Krebs

“for his discovery of the citric acid cycle”

https://pharmaceuticalintelligence.com/2014/10/22/introduction-to-metabolic-pathways/

Fritz Albert Lipmann

“for his discovery of co-enzyme A and its importance for intermediary metabolism”

https://pharmaceuticalintelligence.com/2014/10/22/introduction-to-metabolic-pathways/

https://pharmaceuticalintelligence.com/2014/11/07/summary-of-cell-structure-anatomic-correlates-of-metabolic-function-2/

https://pharmaceuticalintelligence.com/2014/08/18/studies-of-respiration-lead-to-acetyl-coa/

https://pharmaceuticalintelligence.com/2013/01/26/portrait-of-a-great-scientist-and-mentor-nathan-oram-kaplan/

The Nobel Prize in Physiology or Medicine 1955

Axel Hugo Theodor Theorell

“for his discoveries concerning the nature and mode of action of oxidation enzymes”

https://pharmaceuticalintelligence.com/2014/08/18/studies-of-respiration-lead-to-acetyl-coa/

The Nobel Prize in Physiology or Medicine 1958

George Wells Beadle and Edward Lawrie Tatum

“for their discovery that genes act by regulating definite chemical events”

The Nobel Prize in Physiology or Medicine 1959

Severo Ochoa and Arthur Kornberg

“for their discovery of the mechanisms in the biological synthesis of ribonucleic acid and deoxyribonucleic acid”

Joshua Lederberg

“for his discoveries concerning genetic recombination and the organization of the genetic material of bacteria”

The Nobel Prize in Physiology or Medicine 1962

Francis Harry Compton Crick, James Dewey Watson and Maurice Hugh Frederick Wilkins

“for their discoveries concerning the molecular structure of nucleic acids and its significance for information transfer in living material”

The Nobel Prize in Physiology or Medicine 1963

Sir John Carew Eccles, Alan Lloyd Hodgkin and Andrew Fielding Huxley

“for their discoveries concerning the ionic mechanisms involved in excitation and inhibition in the peripheral and central portions of the nerve cell membrane”

The Nobel Prize in Physiology or Medicine 1964

Konrad Bloch and Feodor Lynen

“for their discoveries concerning the mechanism and regulation of the cholesterol and fatty acid metabolism”
https://pharmaceuticalintelligence.com/2014/10/25/oxidation-and-synthesis-of-fatty-acids/

The Nobel Prize in Physiology or Medicine 1965

François Jacob, André Lwoff and Jacques Monod

“for their discoveries concerning genetic control of enzyme and virus synthesis”

https://pharmaceuticalintelligence.com/2014/10/06/isoenzymes-in-cell-metabolic-pathways/

The Nobel Prize in Physiology or Medicine 1967

Ragnar Granit, Haldan Keffer Hartline and George Wald

“for their discoveries concerning the primary physiological and chemical visual processes in the eye”

The Nobel Prize in Physiology or Medicine 1968

Robert W. Holley, Har Gobind Khorana and Marshall W. Nirenberg

“for their interpretation of the genetic code and its function in protein synthesis”

The Nobel Prize in Physiology or Medicine 1969

Max Delbrück, Alfred D. Hershey and Salvador E. Luria

“for their discoveries concerning the replication mechanism and the genetic structure of viruses”

The Nobel Prize in Physiology or Medicine 1970

Sir Bernard Katz, Ulf von Euler and Julius Axelrod

“for their discoveries concerning the humoral transmittors in the nerve terminals and the mechanism for their storage, release and inactivation”

The Nobel Prize in Physiology or Medicine 1972

Gerald M. Edelman and Rodney R. Porter

“for their discoveries concerning the chemical structure of antibodies”

The Nobel Prize in Physiology or Medicine 1974

Albert Claude, Christian de Duve and George E. Palade

“for their discoveries concerning the structural and functional organization of the cell”

The Nobel Prize in Physiology or Medicine 1975

David Baltimore, Renato Dulbecco and Howard Martin Temin

“for their discoveries concerning the interaction between tumour viruses and the genetic material of the cell”
The Nobel Prize in Physiology or Medicine 1977

Rosalyn Yalow

“for the development of radioimmunoassays of peptide hormones”

The Nobel Prize in Physiology or Medicine 1978

Werner Arber, Daniel Nathans and Hamilton O. Smith

“for the discovery of restriction enzymes and their application to problems of molecular genetics”

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