Neurotransmitters are endogenous chemicals that enable neurotransmission. It is a type of chemical messenger which transmits signals across a chemical synapse, such as a neuromuscular junction, from one neuron to another "target" neuron, muscle cell, or gland cell. Neurotransmitters are released from synaptic vesicles in synapses into the synaptic cleft, where they are received by neurotransmitter receptors on the target cells. Many neurotransmitters are synthesized from simple and plentiful precursors such as amino acids, which are available from the diet and only require a small number of biosynthetic steps for conversion. Neurotransmitters play a major role in shaping everyday life and functions, their exact numbers are unknown, but more than 200 chemical messengers have been uniquely identified. Neurotransmitters are stored in synaptic vesicles, clustered close to the cell membrane at the axon terminal of the presynaptic neuron. Neurotransmitters are released into and diffuse across the synaptic cleft, where they bind to specific receptors on the membrane of the postsynaptic neuron.
Most neurotransmitters are about the size of a single amino acid. A released neurotransmitter is available in the synaptic cleft for a short time before it is metabolized by enzymes, pulled back into the presynaptic neuron through reuptake, or bound to a postsynaptic receptor. Short-term exposure of the receptor to a neurotransmitter is sufficient for causing a postsynaptic response by way of synaptic transmission. In response to a threshold action potential or graded electrical potential, a neurotransmitter is released at the presynaptic terminal. Low level "baseline" release occurs without electrical stimulation; the released neurotransmitter may move across the synapse to be detected by and bind with receptors in the postsynaptic neuron. Binding of neurotransmitters may influence the postsynaptic neuron in either an inhibitory or excitatory way; this neuron may be connected to many more neurons, if the total of excitatory influences are greater than those of inhibitory influences, the neuron will "fire".
It will create a new action potential at its axon hillock to release neurotransmitters and pass on the information to yet another neighboring neuron. Until the early 20th century, scientists assumed that the majority of synaptic communication in the brain was electrical. However, through the careful histological examinations by Ramón y Cajal, a 20 to 40 nm gap between neurons, known today as the synaptic cleft, was discovered; the presence of such a gap suggested communication via chemical messengers traversing the synaptic cleft, in 1921 German pharmacologist Otto Loewi confirmed that neurons can communicate by releasing chemicals. Through a series of experiments involving the vagus nerves of frogs, Loewi was able to manually slow the heart rate of frogs by controlling the amount of saline solution present around the vagus nerve. Upon completion of this experiment, Loewi asserted that sympathetic regulation of cardiac function can be mediated through changes in chemical concentrations. Furthermore, Otto Loewi is credited with discovering acetylcholine —the first known neurotransmitter.
Some neurons do, communicate via electrical synapses through the use of gap junctions, which allow specific ions to pass directly from one cell to another. There are four main criteria for identifying neurotransmitters: The chemical must be synthesized in the neuron or otherwise be present in it; when the neuron is active, the chemical must produce a response in some target. The same response must be obtained. A mechanism must exist for removing the chemical from its site of activation. However, given advances in pharmacology and chemical neuroanatomy, the term "neurotransmitter" can be applied to chemicals that: Carry messages between neurons via influence on the postsynaptic membrane. Have little or no effect on membrane voltage, but have a common carrying function such as changing the structure of the synapse. Communicate by sending reverse-direction messages that affect the release or reuptake of transmitters; the anatomical localization of neurotransmitters is determined using immunocytochemical techniques, which identify the location of either the transmitter substances themselves, or of the enzymes that are involved in their synthesis.
Immunocytochemical techniques have revealed that many transmitters the neuropeptides, are co-localized, that is, one neuron may release more than one transmitter from its synaptic terminal. Various techniques and experiments such as staining and collecting can be used to identify neurotransmitters throughout the central nervous system. There are many different ways. Dividing them into amino acids and monoamines is sufficient for some classification purposes. Major neurotransmitters: Amino acids: glutamate, aspartate, D-serine, γ-aminobutyric acid, glycine Gasotransmitters: nitric oxide, carbon monoxide, hydrogen sulfide Monoamines: dopamine, epinephrine, serotonin Trace amines: phenethylamine, N-methylphenethylamine, tyramine, 3-iodothyronamine, tryptamine, etc. Peptides: oxytocin, substance P, cocaine and amphetamine regulated transcript, opioid peptides Purines: adenosine triphosphate, adenosine Catecholamines: dopamine, epinephrine Others: acetylcholine, etc. In addition, over 50 neuroactive pepti
Transcription is the first step of gene expression, in which a particular segment of DNA is copied into RNA by the enzyme RNA polymerase. Both DNA and RNA are nucleic acids. During transcription, a DNA sequence is read by an RNA polymerase, which produces a complementary, antiparallel RNA strand called a primary transcript. Transcription proceeds in the following general steps: RNA polymerase, together with one or more general transcription factors, binds to promoter DNA. RNA polymerase creates a transcription bubble; this is done by breaking the hydrogen bonds between complementary DNA nucleotides. RNA polymerase adds RNA nucleotides. RNA sugar-phosphate backbone forms with assistance from RNA polymerase to form an RNA strand. Hydrogen bonds of the RNA–DNA helix break, freeing the newly synthesized RNA strand. If the cell has a nucleus, the RNA may be further processed; this may include polyadenylation and splicing. The RNA may exit to the cytoplasm through the nuclear pore complex; the stretch of DNA transcribed into an RNA molecule is called a transcription unit and encodes at least one gene.
If the gene encodes a protein, the transcription produces messenger RNA. Alternatively, the transcribed gene may encode for non-coding RNA such as microRNA, ribosomal RNA, transfer RNA, or enzymatic RNA molecules called ribozymes. Overall, RNA helps synthesize and process proteins. In virology, the term may be used when referring to mRNA synthesis from an RNA molecule. For instance, the genome of a negative-sense single-stranded RNA virus may be template for a positive-sense single-stranded RNA; this is because the positive-sense strand contains the information needed to translate the viral proteins for viral replication afterwards. This process is catalyzed by a viral RNA replicase. A DNA transcription unit encoding for a protein may contain both a coding sequence, which will be translated into the protein, regulatory sequences, which direct and regulate the synthesis of that protein; the regulatory sequence before the coding sequence is called the five prime untranslated region. As opposed to DNA replication, transcription results in an RNA complement that includes the nucleotide uracil in all instances where thymine would have occurred in a DNA complement.
Only one of the two DNA strands serve as a template for transcription. The antisense strand of DNA is read by RNA polymerase from the 3' end to the 5' end during transcription; the complementary RNA is created in the opposite direction, in the 5' → 3' direction, matching the sequence of the sense strand with the exception of switching uracil for thymine. This directionality is because RNA polymerase can only add nucleotides to the 3' end of the growing mRNA chain; this use of only the 3' → 5' DNA strand eliminates the need for the Okazaki fragments that are seen in DNA replication. This removes the need for an RNA primer to initiate RNA synthesis, as is the case in DNA replication; the non-template strand of DNA is called the coding strand, because its sequence is the same as the newly created RNA transcript. This is the strand, used by convention when presenting a DNA sequence. Transcription has some proofreading mechanisms, but they are fewer and less effective than the controls for copying DNA.
As a result, transcription has a lower copying fidelity than DNA replication. Transcription is divided into initiation, promoter escape and termination. Transcription begins with the binding of RNA polymerase, together with one or more general transcription factors, to a specific DNA sequence referred to as a "promoter" to form an RNA polymerase-promoter "closed complex". In the "closed complex" the promoter DNA is still double-stranded. RNA polymerase, assisted by one or more general transcription factors unwinds 14 base pairs of DNA to form an RNA polymerase-promoter "open complex". In the "open complex" the promoter DNA is unwound and single-stranded; the exposed, single-stranded DNA is referred to as the "transcription bubble."RNA polymerase, assisted by one or more general transcription factors selects a transcription start site in the transcription bubble, binds to an initiating NTP and an extending NTP complementary to the transcription start site sequence, catalyzes bond formation to yield an initial RNA product.
In bacteria, RNA polymerase holoenzyme consists of five subunits: 2 α subunits, 1 β subunit, 1 β' subunit, 1 ω subunit. In bacteria, there is one general RNA transcription factor: sigma. RNA polymerase core enzyme binds to the bacterial general transcription factor sigma to form RNA polymerase holoenzyme and binds to a promoter. In archaea and eukaryotes, RNA polymerase contains subunits homologous to each of the five RNA polymerase subunits in bacteria and contains additional subunits. In archaea and eukaryotes, the functions of the bacterial general transcription factor sigma are performed by multiple general transcription factors that work together. In archaea, there ar
A protein family is a group of evolutionarily-related proteins. In many cases a protein family has a corresponding gene family, in which each gene encodes a corresponding protein with a 1:1 relationship; the term protein family should not be confused with family. Proteins in a family descend from a common ancestor and have similar three-dimensional structures and significant sequence similarity; the most important of these is sequence similarity since it is the strictest indicator of homology and therefore the clearest indicator of common ancestry. There is a well developed framework for evaluating the significance of similarity between a group of sequences using sequence alignment methods. Proteins that do not share a common ancestor are unlikely to show statistically significant sequence similarity, making sequence alignment a powerful tool for identifying the members of protein families. Families are sometimes grouped together into larger clades called superfamilies based on structural and mechanistic similarity if there is no identifiable sequence homology.
Over 60,000 protein families have been defined, although ambiguity in the definition of protein family leads different researchers to wildly varying numbers. As with many biological terms, the use of protein family is somewhat context dependent. To distinguish between these situations, the term protein superfamily is used for distantly related proteins whose relatedness is not detectable by sequence similarity, but only from shared structural features. Other terms such as protein class, group and sub-family have been coined over the years, but all suffer similar ambiguities of usage. A common usage is. Hence a superfamily, such as the PA clan of proteases, has far lower sequence conservation than one of the families it contains, the C04 family, it is unlikely that an exact definition will be agreed and to it is up to the reader to discern how these terms are being used in a particular context.. The concept of protein family was conceived at a time when few protein structures or sequences were known.
Since that time, it was found that many proteins comprise multiple independent structural and functional units or domains. Due to evolutionary shuffling, different domains in a protein have evolved independently; this has led, to a focus on families of protein domains. A number of online resources are devoted to cataloging such domains. Regions of each protein have differing functional constraints. For example, the active site of an enzyme requires certain amino acid residues to be oriented in three dimensions. On the other hand, a protein–protein binding interface may consist of a large surface with constraints on the hydrophobicity or polarity of the amino acid residues. Functionally constrained regions of proteins evolve more than unconstrained regions such as surface loops, giving rise to discernible blocks of conserved sequence when the sequences of a protein family are compared; these blocks are most referred to as motifs, although many other terms are used. Again, a large number of online resources are devoted to cataloging protein motifs.
According to current consensus, protein families arise in two ways. Firstly, the separation of a parent species into two genetically isolated descendent species allows a gene/protein to independently accumulate variations in these two lineages; this results in a family of orthologous proteins with conserved sequence motifs. Secondly, a gene duplication may create a second copy of a gene; because the original gene is still able to perform its function, the duplicated gene is free to diverge and may acquire new functions. Certain gene/protein families in eukaryotes, undergo extreme expansions and contractions in the course of evolution, sometimes in concert with whole genome duplications; this expansion and contraction of protein families is one of the salient features of genome evolution, but its importance and ramifications are unclear. As the total number of sequenced proteins increases and interest expands in proteome analysis, there is an ongoing effort to organize proteins into families and to describe their component domains and motifs.
Reliable identification of protein families is critical to phylogenetic analysis, functional annotation, the exploration of diversity of protein function in a given phylogenetic branch. The Enzyme Function Initiative is using protein families and superfamilies as the basis for development of a sequence/structure-based strategy for large scale functional assignment of enzymes of unknown function; the algorithmic means for establishing protein families on a large scale are based on a notion of similarity. Most of the time the only similarity we have access to is sequence similarity. There are many biological databases that record examples of protein families and allow users to identify if newly identified proteins belong to a known family. Here are a few examples: Pfam - Prot
Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane, controlling the flow of ions across secretory and epithelial cells, regulating cell volume. Ion channels are present in the membranes of all excitable cells. Ion channels are one of the two classes of ionophoric proteins, the other being ion transporters; the study of ion channels involves biophysics, electrophysiology, pharmacology, while using techniques including voltage clamp, patch clamp, immunohistochemistry, X-ray crystallography, RT-PCR. Their classification as molecules is referred to as channelomics. There are two distinctive features of ion channels that differentiate them from other types of ion transporter proteins: The rate of ion transport through the channel is high. Ions pass through channels down their electrochemical gradient, a function of ion concentration and membrane potential, "downhill", without the input of metabolic energy.
Ion channels are located within the membrane of all excitable cells, of many intracellular organelles. They are described as narrow, water-filled tunnels that allow only ions of a certain size and/or charge to pass through; this characteristic is called selective permeability. The archetypal channel pore is just one or two atoms wide at its narrowest point and is selective for specific species of ion, such as sodium or potassium. However, some channels may be permeable to the passage of more than one type of ion sharing a common charge: positive or negative. Ions move through the segments of the channel pore in single file nearly as as the ions move through free solution. In many ion channels, passage through the pore is governed by a "gate", which may be opened or closed in response to chemical or electrical signals, temperature, or mechanical force. Ion channels are integral membrane proteins formed as assemblies of several individual proteins; such "multi-subunit" assemblies involve a circular arrangement of identical or homologous proteins packed around a water-filled pore through the plane of the membrane or lipid bilayer.
For most voltage-gated ion channels, the pore-forming subunit are called the α subunit, while the auxiliary subunits are denoted β, γ, so on. Because channels underlie the nerve impulse and because "transmitter-activated" channels mediate conduction across the synapses, channels are prominent components of the nervous system. Indeed, numerous toxins that organisms have evolved for shutting down the nervous systems of predators and prey work by modulating ion channel conductance and/or kinetics. In addition, ion channels are key components in a wide variety of biological processes that involve rapid changes in cells, such as cardiac and smooth muscle contraction, epithelial transport of nutrients and ions, T-cell activation and pancreatic beta-cell insulin release. In the search for new drugs, ion channels are a frequent target. There are over 300 types of ion channels just in the cells of the inner ear. Ion channels may be classified by the nature of their gating, the species of ions passing through those gates, the number of gates and localization of proteins.
Further heterogeneity of ion channels arises when channels with different constitutive subunits give rise to a specific kind of current. Absence or mutation of one or more of the contributing types of channel subunits can result in loss of function and underlie neurologic diseases. Ion channels may be classified by i.e. what opens and closes the channels. For example, voltage-gated ion channels open or close depending on the voltage gradient across the plasma membrane, while ligand-gated ion channels open or close depending on binding of ligands to the channel. Voltage-gated ion channels close in response to membrane potential. Voltage-gated sodium channels: This family contains at least 9 members and is responsible for action potential creation and propagation; the pore-forming α subunits are large and consist of four homologous repeat domains each comprising six transmembrane segments for a total of 24 transmembrane segments. The members of this family coassemble with auxiliary β subunits, each spanning the membrane once.
Both α and β subunits are extensively glycosylated. Voltage-gated calcium channels: This family contains 10 members, though these members are known to coassemble with α2δ, β, γ subunits; these channels play an important role in both linking muscle excitation with contraction as well as neuronal excitation with transmitter release. The α subunits have an overall structural resemblance to those of the sodium channels and are large. Cation channels of sperm: This small family of channels referred to as Catsper channels, is related to the two-pore channels and distantly related to TRP channels. Voltage-gated potassium channels: This family contains 40 members, which are further divided into 12 subfamilies; these channels are known for their role in repolarizing the cell membrane following action potentials. The α subunits have six transmembrane segments, homologous to a single domain of the sodium channels. Correspondingly, they assemble; some transient receptor potential channels: This group of channels referred to as
Julius Axelrod was an American biochemist. He won a share of the Nobel Prize in Physiology or Medicine in 1970 along with Bernard Katz and Ulf von Euler; the Nobel Committee honored him for his work on the release and reuptake of catecholamine neurotransmitters, a class of chemicals in the brain that include epinephrine, and, as was discovered, dopamine. Axelrod made major contributions to the understanding of the pineal gland and how it is regulated during the sleep-wake cycle. Axelrod was born in New York City, the son of Jewish immigrants from Poland and Isadore Axelrod, a basket weaver, he received his bachelor's degree in biology from the College of the City of New York in 1933. Axelrod wanted to become a physician, but was rejected from every medical school to which he applied, he worked as a laboratory technician at New York University in 1935 he got a job with the New York City Department of Health and Mental Hygiene testing vitamin supplements added to food. While working at the Department of Health, he attended night school and received his master's in sciences degree from New York University in 1941.
In 1946, Axelrod took a position working under Bernard Brodie at Goldwater Memorial Hospital. The research experience and mentorship Axelrod received from Brodie would launch him on his research career. Brodie and Axelrod's research focused on. During the 1940s, users of non-aspirin analgesics were developing a blood condition known as methemoglobinemia. Axelrod and Brodie discovered that acetanilide, the main ingredient of these pain-killers, was to blame, they found that one of the metabolites was an analgesic. They recommended that acetaminophen, be used instead. In 1949, Axelrod began work at the National Heart Institute, forerunner of the National Heart and Blood Institute, part of the National Institutes of Health, he examined the mechanisms and effects of caffeine, which led him to an interest in the sympathetic nervous system and its main neurotransmitters and norepinephrine. During this time, Axelrod conducted research on codeine, morphine and ephedrine and performed some of the first experiments on LSD.
Realizing that he could not advance his career without a PhD, he took a leave of absence from the NIH in 1954 to attend George Washington University Medical School. Allowed to submit some of his previous research toward his degree, he graduated one year in 1955. Axelrod returned to the NIH and began some of the key research of his career. Axelrod received his Nobel Prize for his work on the release and storage of the neurotransmitters epinephrine and norepinephrine known as adrenaline and noradrenaline. Working on monoamine oxidase inhibitors in 1957, Axelrod showed that catecholamine neurotransmitters do not stop working after they are released into the synapse. Instead, neurotransmitters are recaptured by the pre-synaptic nerve ending, recycled for transmissions, he theorized that epinephrine is held in tissues in an inactive form and is liberated by the nervous system when needed. This research laid the groundwork for selective serotonin reuptake inhibitors, such as Prozac, which block the reuptake of another neurotransmitter, serotonin.
In 1958, Axelrod discovered and characterized the enzyme catechol-O-methyl transferase, involved in the breakdown of catecholamines. Some of Axelrod's research focused on the pineal gland, he and his colleagues showed that the hormone melatonin is generated from tryptophan, as is the neurotransmitter serotonin. The rates of synthesis and release follows the body's circadian rhythm driven by the suprachiasmatic nucleus within the hypothalamus. Axelrod and colleagues went on to show that melatonin had wide-ranging effects throughout the central nervous system, allowing the pineal gland to function as a biological clock, he was elected a Fellow of the American Academy of Arts and Sciences in 1971. He continued to work at the National Institute of Mental Health at the NIH until his death in 2004. Many of his papers and awards are held at the National Library of Medicine. Axelrod was awarded the Gairdner Foundation International Award in 1967, the Nobel Prize in Physiology or Medicine in 1970, he was elected a Foreign Member of the Royal Society in 1979.
In 1992, he was awarded the Ralph W. Gerard Prize in Neuroscience. Solomon Snyder, Irwin Kopin, Ronald W. Holz, Rudi Schmid, Bruce R Conklin, Ron M Burch, Marty Zatz, Michael Brownstein, Chris Felder, Richard J Wurtman. Axelrod injured his left eye. Although he became an atheist early in life and resented the strict upbringing of his parents’ religion, he identified with Jewish culture and joined several international fights against anti-Semitism, his wife of 53 years, Sally Taub Axelrod, died in 1992. At his death, he was survived by two sons and Alfred, three grandchildren. After receiving the Nobel Prize in 1970, Axelrod used his visibility to advocate several science policy issues. In 1973 U. S. President Richard Nixon created an agency with the specific goal of curing cancer. Axelrod, along with fellow Nobel-laureates Marshall W. Nirenberg and Christian Anfinsen, organized a petition by scientists opposed to the new agency, on the grounds that by focusing on cancer, public funding would not be available for research into other, more solvable, medical problems.
Axelrod lent his name to several protests against the imprisonment of scientists in the Soviet Union. Dr. Axelrod was a member of the Board of Sponsors of the
Carl Ferdinand Cori
Carl Ferdinand Cori, ForMemRS was a Czech-American biochemist and pharmacologist born in Prague who, together with his wife Gerty Cori and Argentine physiologist Bernardo Houssay, received a Nobel Prize in 1947 for their discovery of how glycogen – a derivative of glucose – is broken down and resynthesized in the body, for use as a store and source of energy. In 2004, both were designated a National Historic Chemical Landmark in recognition of their work that elucidated carbohydrate metabolism. Carl was the son of Carl Isidor Cori, a zoologist, Maria née Lippich, a daughter of the Italian-Bohemian/Austrian physician Ferdinand Lippich; the Cori Family came from the Papal State to the Royal Bohemian Crownland,(Monarchical Austria at the end of the 17th century. Carl Ferdinand's grandfather Eduard Cori was an administrative officer and beekeeper in Brüx, grandmother was Rosina Trinks. Carl Ferdinand's younger sister Margarete Cori was a lecturer of Prague and the wife of the Bohemian geneticist Felix Mainx.
He grew up in Trieste, where his father Carl Isidor was the director of the Marine Biological Station. In late 1914 the Cori family moved to Prague and Carl entered the medical school of Charles University in Prague. While studying there he met Gerty Theresa Radnitz, he was drafted into the Austro-Hungarian Army and served in the ski corps, was transferred to the sanitary corps, for which he set up a laboratory in Trieste. At the end of the war Carl completed his studies, graduating with Gerty in 1920. Carl and Gerty worked together in clinics in Vienna, their only child, married Anne, a daughter of the American constitutional lawyer and anti-feminist Phyllis Schlafly. Carl was invited to Graz to work with Otto Loewi to study the effect of the vagus nerve on the heart. While Carl was in Graz, Gerty remained in Vienna. A year Carl was offered a position at the State Institute for the Study of Malignant Diseases in Buffalo, New York and the Cori's moved to Buffalo. In 1928, they became naturalized citizens of the United States.
While at the Institute the Coris’ research focused on carbohydrate metabolism, leading to the definition of the Cori cycle in 1929. In 1931, Carl accepted a position at the Washington University School of Medicine in St. Louis, Missouri. Carl joined. In St. Louis, the Cori's continued their research on glycogen and glucose and began to describe glycogenolysis and synthesizing the important enzyme glycogen phosphorylase. For these discoveries, they received the Nobel Prize in Physiology or Medicine in 1947. Gerty died in 1957 and Carl married Anne Fitzgerald-Jones in 1960, he stayed on at Washington University until 1966, when he retired as chair of the biochemistry department. He was appointed visiting professor of Biological Chemistry at Harvard University while maintaining a laboratory space at the Massachusetts General Hospital, where he pursued research in genetics. From 1968 to 1983, he collaborated with noted geneticist Salomé Glüecksohn-Waelsch of the Albert Einstein College of Medicine in New York, until the 1980s when illness prevented him from continuing.
In 1976, Carl received the Laurea honoris causa in Medicine from the University of Trieste. Carl shares a star with Gerty on the St. Louis Walk of Fame. In addition to winning the Nobel Prize, Cori won the Albert Lasker Award for Basic Medical Research in 1946 and in 1959, the Austrian Decoration for Science and Art. Cori was elected a Foreign Member of the Royal Society in 1950 and the Carl Cori Endowed Professorship at Washington University is named in his honor held by Colin Nichols
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine, administered by the Nobel Foundation, is awarded yearly for outstanding discoveries in the fields of life sciences and medicine. It is one of five Nobel Prizes established in his will in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite. Nobel was interested in experimental physiology and wanted to establish a prize for scientific progress through laboratory discoveries; the Nobel Prize is presented at an annual ceremony on 10 December, the anniversary of Nobel's death, along with a diploma and a certificate for the monetary award. The front side of the medal displays the same profile of Alfred Nobel depicted on the medals for Physics and Literature; the reverse side is unique to this medal. The most recent Nobel prize was announced by Karolinska Institute on 1 October 2018, has been awarded to American James P. Allison and Japanese Tasuku Honjo – for their discovery of cancer therapy by inhibition of negative immune regulation; as of 2015, 106 Nobel Prizes in Physiology or Medicine have been awarded to 12 women.
The first one was awarded in 1901 to the German physiologist Emil von Behring, for his work on serum therapy and the development of a vaccine against diphtheria. The first woman to receive the Nobel Prize in Physiology or Medicine, Gerty Cori, received it in 1947 for her role in elucidating the metabolism of glucose, important in many aspects of medicine, including treatment of diabetes; some awards have been controversial. This includes one to António Egas Moniz in 1949 for the prefrontal lobotomy, bestowed despite protests from the medical establishment. Other controversies resulted from disagreements over, included in the award; the 1952 prize to Selman Waksman was litigated in court, half the patent rights awarded to his co-discoverer Albert Schatz, not recognized by the prize. The 1962 prize awarded to James D. Watson, Francis Crick and Maurice Wilkins for their work on DNA structure and properties did not acknowledge the contributing work from others, such as Oswald Avery and Rosalind Franklin who had died by the time of the nomination.
Since the Nobel Prize rules forbid nominations of the deceased, longevity is an asset, considering prizes are awarded as long as 50 years after the discovery. Forbidden is awarding any one prize to more than three recipients. In the last half century there has been an increasing tendency for scientists to work as teams, resulting in controversial exclusions. Alfred Nobel was born on 21 October 1833 in Stockholm, into a family of engineers, he was a chemist and inventor who amassed a fortune during his lifetime, most of it from his 355 inventions of which dynamite is the most famous. He was interested in experimental physiology and set up his own labs in France and Italy to conduct experiments in blood transfusions. Keeping abreast of scientific findings, he was generous in his donations to Ivan Pavlov's laboratory in Russia, was optimistic about the progress resulting from scientific discoveries made in laboratories. In 1888, Nobel was surprised to read his own obituary, titled "The merchant of death is dead", in a French newspaper.
As it happened, it was Nobel's brother Ludvig who had died, but Nobel, unhappy with the content of the obituary and concerned that his legacy would reflect poorly on him, was inspired to change his will. In his last will, Nobel requested that his money be used to create a series of prizes for those who confer the "greatest benefit on mankind" in physics, peace, physiology or medicine, literature. Though Nobel wrote several wills during his lifetime, the last was written a little over a year before he died at the age of 63; because his will was contested, it was not approved by the Storting until 26 April 1897. After Nobel's death, the Nobel Foundation was set up to manage the assets of the bequest. In 1900, the Nobel Foundation's newly created statutes were promulgated by Swedish King Oscar II. According to Nobel's will, the Karolinska Institute in Sweden, a medical school and research center, is responsible for the Prize in Physiology or Medicine. Today, the prize is referred to as the Nobel Prize in Medicine.
It was important to Nobel that the prize be awarded for a "discovery" and that it be of "greatest benefit on mankind". Per the provisions of the will, only select persons are eligible to nominate individuals for the award; these include members of academies around the world, professors of medicine in Sweden, Norway and Finland, as well as professors of selected universities and research institutions in other countries. Past Nobel laureates may nominate; until 1977, all professors of Karolinska Institute together decided on the Nobel Prize in Physiology or Medicine. That year, changes in Swedish law forced the Institute to make public any documents pertaining to the Nobel Prize and it was considered necessary to establish a independent body for the Prize work. Therefore, the Nobel Assembly was constituted, it elects the Nobel Committee with 5 members who evaluate the nominees, the Secretary, in charge of the organization, each year 10 adjunct members to assist in the evaluation of candidates. In 1968, a provision was added.
True to its mandate, the Committee has chosen researchers working in the basic sciences over those who have made applied science contributions. Harvey Cushing, a pioneering American neurosurgeon who identified Cushing's syndrome, was not awarded the prize, nor was Sigmund Freud, as his psychoanalysis lacks hypotheses that can be experimentally confirmed; the public expected Jonas Salk or Albert Sabin to receive th