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Lectures: 2013 Nobel Prize in Physiology or Medicine

Nobel Prize2013-12-07
Nobel Prize In Physiology Or Medicine (Award Category)#James E. Rothman#Randy W. Schekman#Thomas S. Südhof
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The video discusses the groundbreaking work of Nobel Laureates in Physiology or Medicine on vesicle transport and cellular communication mechanisms, highlighting the importance of understanding protein movement within cells. It covers the discovery of transport vesicles, the role of SNARE proteins in membrane fusion, and the process of neurotransmitter release at synapses. The segment also touches on the history of studying biological processes, the development of modern biochemistry, and the significance of genetic and biochemical approaches in understanding complex biological processes. Additionally, it explores the role of specific proteins in vesicle formation and secretion pathways.

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📊 Transcript
2013 Nobel Laureates in Physiology or Medicine
07:06
James Rothman identified key proteins controlling vesicle fusion and docking.
Randy Scheckman identified important genes in the transport process.
Thomas Sudhof focused on the release of neurotransmitters at synapses and the role of calcium.
Their discoveries have implications for basic science and medical research.
Dr. James Rothman discusses his experience as a Nobel laureate and the significance of the honor.
12:38
He explains the classical work on intracellular transport of proteins, focusing on the journey from the endoplasmic reticulum to different cell destinations.
The key question of how proteins are delivered to the correct location at the appropriate time is examined.
The discovery of transport vesicles is highlighted, revealing the complex mechanisms involved in protein movement within cells.
Importance of Vesicle Fusion in Cellular Transport.
21:45
Vesicles are formed through budding and fusion and are crucial for endocrine and exocrine physiology, nerve signaling, and various biological processes.
Synaptic vesicles store neurotransmitters for rapid information processing in the brain, discovered by Dr. Pilati.
While the physics of membrane fusion is simple, the biology of delivering the right cargo to the right place at the right time is complex.
Dr. Pilati's approach to studying vesicular trafficking and membrane fusion focuses on finding fundamental simplicity amidst complexity.
The speaker discusses his journey as a medical student and his curiosity about cellular complexity.
27:12
Despite warnings, he pursued studying proteins in cell-free reactions, challenging conventional beliefs.
The speaker shares a model he created in the late 1970s resembling current vesicle trafficking diagrams.
The history of studying biological processes in cell-free systems, starting with Eduard Buchner's work, is discussed.
The speaker emphasizes the complexity of scientific discovery and the role of luck and insight in achieving success.
Study on transport reconstitution using VSV glycoprotein.
36:40
Tracking movement of VSV glycoprotein through cellular compartments.
Visualization of transport vesicles and identification of functional carriers.
Discovery of GTP switch mechanism involving ARF and COPI proteins in vesicle formation.
Deeper understanding of vesicle budding and fusion processes in cellular transport.
Role of NSF and SNAP proteins in membrane fusion.
45:30
NSF and SNAP proteins are crucial for fusion reactions in cells but lack specificity.
Specificity in fusion reactions is believed to be provided by membrane receptors, or SNARE proteins.
Isolation of SNARE proteins from brain extracts highlighted their significance in membrane fusion.
High concentration of SNARE receptors in the brain indicates frequent membrane fusion due to constant synaptic activity.
The Snare hypothesis and membrane fusion.
52:30
Snare proteins are crucial in membrane fusion, with v-snare and t-snare proteins assembling to facilitate fusion.
Energy released from protein folding drives bilayer fusion, as shown in experiments with yeast snare genes.
Specific combinations of snare proteins are responsible for encoding the specificity of compartments and enabling fusion.
Nsf disrupts the snare complex, allowing fusion to occur through protein unfolding and energy release.
Membrane fusion process involves snares assembling and zipping to force vesicles into targets.
56:51
Specific proteins regulate membrane fusion, focusing on neurotransmitter release and calcium entry.
Fully zippered snare complex prevents premature release, except for a small section.
Synaptotagmin and complexion play crucial roles in clamping and organizing snares.
Research aims to understand molecular machinery and improve vesicle design with DNA origami; super-resolution optical microscopy advances real-time visualization for cellular organization studies.
Influence of German scientists on the development of modern biochemistry and biological oxidation principles.
01:08:51
Threat to scientific progress during Hitler's rise, leading to emigration of scientists to the US.
Emphasis on the importance of basic research and support for science in the face of challenges.
Dr. Scheckman, a Nobel laureate, presented a lecture on the genetic and biochemical dissection of the secretory pathway.
Global audience's interest and gratitude for the opportunity to share knowledge on a prestigious stage.
Contributions of George Palade and Arthur Kornberg in Cell Biology.
01:10:49
George Palade's research centered on the secretory pathway and molecular movement within cells.
George Palade made key discoveries in protein biosynthesis and cellular structure organization.
Arthur Kornberg's work focused on DNA replication, particularly the enzyme DNA polymerase.
Arthur Kornberg's experiments showed the replication of small chromosomes in a test tube, advancing understanding of cellular processes.
Importance of genetic analysis in understanding complex biological processes.
01:18:20
John Cairns discovered a mutation in E. coli that killed the DNA polymerase enzyme, leading to a defect in DNA repair processes.
Narrator describes his career path from studying DNA replication to focusing on protein secretion in yeast cells.
Exploration of secretion processes using genetics emphasizes the crucial role of vesicles in conveying secreted proteins to the cell surface.
Key highlights from yeast cell mutation research
01:30:55
Mutations affecting cell growth and secretion pathways were discovered through research on yeast cells.
Identification of temperature-sensitive lethal mutations led to important findings in cell biology.
Mutants exhibited abnormal vesicle accumulation and Golgi apparatus formation.
Experiments mapped mutations to different genes, revealing crucial functions in the secretion pathway.
Enzymes in the cytoplasm catalyze reactions due to substrate presence.
01:33:17
Adding a signal peptide forces the enzyme into the endoplasmic reticulum, hindering its function.
Genetic selection for mutations in the translocation apparatus was explored to compromise the process.
The sex 61 gene was discovered as the translocation channel, showing conservation across different organisms.
Further research identified genes for protein sorting in the Golgi apparatus and vesicle targeting.
Experiment on bacteriophages in 1965 by Bill Wood and Paul Berg showed genetic complementation.
01:40:13
Increase in infectious virus particles was observed over a 30-minute incubation period.
Enzymology and biochemical complementation were highlighted in the study.
Further research in identifying and purifying proteins essential for DNA replication was inspired by this experiment.
David Baker simplified a reaction to measure transport vesicles in vitro, and Chris Kaiser focused on genetic interactions and separate stages in protein flow.
Overview of the process of vesicle formation and purification using differential centrifugation assay.
01:47:19
Importance of sec genes and proteins in vesicle budding and formation.
Discussion on the assembly of COP2 proteins, cargo molecule separation, and vesicle formation.
Role of specific proteins like Sar-1 and Sec-12 in initiating and completing the budding process.
Exploration of the structural details of proteins involved in vesicle formation and molecular interactions during the process.
Roles of cop2 proteins in secretion pathway and plasma membrane assembly.
02:00:47
Sar-1b is involved in packaging lipoproteins, while sec-24 proteins play a role in molecule recognition.
Mutations in sec-24b impact neural tube development in mice, while sec-24a deficiency results in low cholesterol levels.
Sec-23 mutations are associated with anemia and craniofacial dysmorphism.
Biochemical analysis demonstrates how mutations affect coat assembly, highlighting a conserved secretion pathway throughout evolution.
The role of calcium in synaptic transmission.
02:06:55
Three key steps in the process are explained, emphasizing the importance of calcium influx and its rapid action.
Localization of calcium at the active zone is crucial for precise coupling of action potential to neurotransmitter release.
Advancements in molecular understanding of synaptic components over the years are highlighted.
An overview of the molecular framework that explains neurotransmitter release is provided.
Formation of a complex at the active zone of a synapse involving calcium channels, synaptic vesicles, and snare proteins.
02:09:38
Studies from various labs demonstrate the role of snare proteins in membrane fusion and the formation of snare complexes.
Monkeytin identified as a key player in membrane fusion reactions essential for neurotransmitter release.
Recycling of snare complexes involves the action of chaperones.
Mutations in monkeytin linked to epileptic encephalopathy, emphasizing the importance of monkeytin and sm proteins in synaptic transmission.
Role of key proteins in snare complex assembly during the cycle of neurotransmitter release.
02:17:46
Loss of alpha-synuclein or csp alpha in mice leads to neurodegeneration, relevant to Parkinson's disease research.
Reintroduction of synuclein in neurons aids in snare complex assembly, potentially protecting against neurodegenerative conditions.
Study of synaptotagmin as a calcium sensor highlights its importance in fast calcium-triggered neurotransmitter release.
Importance of Complexin in Calcium-Triggered Vesicle Fusion.
02:26:40
Complexin is an essential cofactor for synaptotagmin-triggered calcium-dependent fusion.
Complexin binds to the snare complex and activates synaptotagmin.
Experiments transferring complexin from jellyfish to mouse neurons rescued neurotransmitter release.
The findings highlight the conservation and importance of complexin in vesicle fusion and calcium-triggered release.
Study on mutations in calcium sensor proteins and their effects on neurotransmitter release.
02:32:39
Mutations had opposite effects on calcium binding and neurotransmitter release.
Calcium binding to synaptotagmin triggers neurotransmitter release.
Different synaptotagmins have varying calcium binding abilities, impacting neurotransmitter release.
Specific synaptotagmins identified as calcium sensors for fast release.
The importance of synaptotagmin 10 in calcium-triggered release of igf-1 in neurons.
02:40:41
Knockdown of synaptotagmin 10 leads to impaired igf-1 secretion and smaller neurons with fewer synapses.
Wild-type synaptotagmin 10 can rescue the phenotype, highlighting its significance in neurotransmitter release.
Different synaptic isoforms play distinct roles in vesicle fusion reactions, with complexin identified as an essential cofactor alongside synaptotagmin.
The study provides insights into the mechanisms underlying neurotransmitter release and the specific roles of proteins in this process.
Importance of localized calcium influx in synaptic processes.
02:45:24
Rim protein plays a crucial role in calcium channel localization and vesicle docking.
Absence of Rim protein leads to impairments in vesicle docking and priming.
Experiments demonstrate Rim's specific role at presynaptic terminals in coupling calcium channels and vesicles for fusion.
Rim protein is essential for neurotransmitter release and active zone function at synapses.
Acknowledgment of Collaborators and Nobel Laureates at Science Event.
02:55:32
Gratitude is expressed towards collaborators, students, and postdocs for their dedication to science.
Nobel laureates are thanked for delivering inspiring talks and invited to the stage for applause.
The video segment ends with a mention of a photo session with the laureates.
The head usher takes over to provide housekeeping information.