Nobel Vesicles

Nobel season is here once more. Has it really been a year?
Last year, The Nobel Prize in Physiology or Medicine was shared by Sir John Gurdon at Cambridge, and Shinya Yamanaka, a Japanese researcher with labs in Kyoto and San Francisco, for their work on cell reprogramming.
This year, The Karolinska Institute in Stockholm announced the winners: James E. Rothman,; Randy W. Schekman, and Dr. Thomas C. Südhof, on 07 October 2013 "for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells". Their basic research solved the mystery of how cells, which are factories producing molecules, organize a system to transport the molecules within cells and export them outside.
In laymans term, each cell is a factory that produces and exports molecules. Cells move molecules around using tiny membrane-enclosed packages called vesicles. In a large and busy port, systems are required to ensure that the correct cargo is shipped to the correct destination at the right time. The cell, with its different compartments called organelles, faces a similar problem: cells produce molecules such as hormones, neurotransmitters, cytokines and enzymes that have to be delivered to other places inside the cell, or exported out of the cell, at exactly the right moment. Timing and location are crucial. Miniature bubble-like vesicles, surrounded by membranes, shuttle the cargo between organelles or fuse with the outer membrane of the cell and release their cargo to the outside. This is of major importance, as it triggers nerve activation in the case of transmitter substances, or controls metabolism in the case of hormones. For instance, insulin is manufactured and released into the blood and signaling molecules called neurotransmitters are sent from one nerve cell to another. These molecules are transported around the cell in small packages called vesicles.  How do these vesicles know where and when to deliver their cargo?
This year’s Nobel Laureates, who will share the $1.2 million prize, discovered how cells get those vesicles to their intended destination at the intended time.
Randy Schekman, Cell biologist at the University of California, Berkeley was fascinated by how the cell organizes its transport system and in the 1970s decided to study its genetic basis by using yeast as a model system. In a genetic screen, he identified yeast Saccharomyces cerevisiae cells with defective transport machinery, giving rise to a situation resembling a poorly planned public transport system. Vesicles piled up in certain parts of the cell. He found that the cause of this congestion was genetic and went on to identify the mutated genes. Schekman  developed a genetic screen of the yeast to determine the genes that regulate vesicle trafficking. With this information, he identified 23 key genes, which can be divided into three classes that control vesicles at the Golgi complex, the endoplasmic reticulum, or the cell surface.

James Rothman a cell biologist at Yale University was also intrigued by the nature of the cell´s transport system. When studying vesicle transport in mammalian cells in the 1980s and 1990s, Rothman discovered that a protein complex known as  SNARE (soluble N-ethylmaleimide-sensitive factor-activating protein receptor) enables vesicles to dock and fuse with their target membranes. In the fusion process, proteins on the vesicles and target membranes bind to each other like the two sides of a zipper.  These proteins had already been discovered by others, but their function was unknown. Rothman determined that these proteins interact with high specificity: The SNARE protein on a particular target membrane is able to interact with only one or a few vesicle SNARE proteins. The fact that there are many such proteins and that they bind only in specific combinations ensures that cargo is delivered to a precise location. The same principle operates inside the cell and when a vesicle binds to the cell´s outer membrane to release its contents. Thus, Rothman unravelled protein machinery that allows vesicles to fuse with their targets to permit transfer of cargo.
It turned out that some of the genes Schekman had discovered in yeast coded for proteins corresponding to those Rothman identified in mammals, revealing an ancient evolutionary origin of the transport system. Collectively, they mapped critical components of the cell´s transport machinery

Dr. Thomas Südhof, a biochemist at Stanford University, was interested in how nerve cells communicate with one another in the brain. The signalling molecules, neurotransmitters, are released from vesicles that fuse with the outer membrane of nerve cells by using the machinery discovered by Rothman and Schekman. But these vesicles are only allowed to release their contents when the nerve cell signals to its neighbours. How is this release controlled in such a precise manner? Calcium  ions were known to be involved in this process and in the 1990s, Südhof searched for calcium sensitive proteins in nerve cells. He identified molecular machinery that responds to an influx of calcium ions and directs neighbour proteins rapidly to bind vesicles to the outer membrane of the nerve cell. He discovered how calcium regulates neurotransmitter release and that two proteins—complexin and synaptotagmin-1—are key players in calcium-mediated vesicle fusion. Synaptotagmin-1 acts as a calcium sensor during synaptic fusion. Complexin acts as a clamp during synaptic fusion to make sure that regulated exocytosis occurs instead of the vesicle simply being incorporated into the cell membrane. The zipper opens up and signal substances are released. Südhof´s discovery explained how temporal precision is achieved and how vesicles´ contents can be released on command. Südhof also identified the genes that are responsible for controlling the timing of vesicle fusion, particularly those involved in the release of neurotransmitters
The three Nobel Laureates have discovered a fundamental process in cell physiology. Through their discoveries, Rothman, Schekman and Südhof have revealed the exquisitely precise control system for the transport and delivery of cellular cargo. Vesicle transport and fusion operate, with the same general principles, in organisms as different as yeast and man. The system is critical for a variety of physiological processes in which vesicle fusion must be controlled, ranging from signalling in the brain to release of hormones and immune cytokines. Glitches in vesicle transport occur in a variety of diseases including a number of neurological and immunological disorders, as well as in diabetes. . Mutations in genes associated with the protein machinery are involved in specific diseases. For example, mutations in one of the genes are involved in certain forms of epilepsy. Thus, they have revolutionised understanding of how cells are organised which is fundamental to huge number of diseases. Without this wonderfully precise organization, the cell would lapse into chaos.

Powerstations: Mitochondria

Mitochondria are one of a kind organelle present in the cells. Rightly, called the powerstation of the cells which burns the food we eat with oxygen which we breath to form water.  Every heart beat, every word we speak, every body movement is powered by mitochondria. It been proved that mitochondria was once a simple cell by itself. One simple cell was eaten by another simple cell which leads further to a complex life. The multicellularity requires vast amount of energy and this was provided by mitochondria.
Research has shown due to this function of mitochondria, it’s involved in range of cell functions. Even though they are just complex machinery to make ATP, they contain their own circular DNA mtDNA and array of proteins. Mitochondria is a system in itself, lt can sustain itself forming thousands of copies 10 17 in the cytoplasm of the cell.
It has double membrane structure and energy is mostly generated from hydrocarbons i.e. sugars and acids. Pyruvate goes into the mitochondria and it is burned in the cycle called Tricarboxylic Acid cycle (TCA). TCAs only job is to strip hydrogens from hydrocarbon, which it puts on carrier NAD forming NADH2. Then this NADH2 is burned through electron transport chain, where it reduces an atom of oxygen to molecule of water.  This is where respiration comes into picture leading to Aerobic Respiration.
Each of the mitochondria acts as a capacitor which positively charged outside the inner membrane and negatively charged inside. So we have approximately 10 17 charged capacitors due to hydrogen ion gradient present across the inner membrane. And this gradient is used to produce energy rich ATP. Then these energy packets are distributed throughout the cell for its efficient functioning.
But not all the powerhouses are efficient. Some of them start producing less power and more heat. Basically in our body we use food for two purposes: for energy and to maintain the body temperature. How our mitochondria do it, is by using few proton gradients it bypasses ATP synthatase and it short circuits the capacitor. It burns more hydrogen instead of forming ATP. This balancing between heat and ATP production is called coupling efficiency.
Other important side products in mitochondria are the oxygen radical like superoxides and hydroxyl radicals. These radicals induce mutational breaks in DNA. Thus they are damaging to the mitochondria leading to less energy generation and cells tend to malfunction. This triggers the body function to get rid of such cell by apoptosis, which an orchestrated mechanism involving mitochondrial membrane integrity. It’s been observed that each individual are born with certain number of mitochondria in the cell enough till the age of around fifty. Then the downhill starts, as not all cells can sustain so much oxidative damage.
This downhill leads to various age related diseases, neurodegenerative diseases, diabetes, heart diseases, cancer etc. Thus, certainly research on molecular and physiological aspect of mitochondria function would take us near to understanding of aging and all the related diseases.

Gaurdian Angels

TP53 is the  most studied and important genes present in our genome which codes for p53. p53 is one of the three sisters, as they say, along with p63 and p73. All these proteins are the transcription factors which regulate the expression of the required protein appropriate for situation in the cell. But unlike other siblings, p53 has shorter half life because of absence of the stabilizing domain. P53 is tumor suppressor or stress responder, they are ultimate protector of integrity of our somatic genome. Thus it’s a major fidelity factor in the cell. p53 acts as a tumor suppressor, which means that it regulates cell division by keeping cells from growing and dividing too fast or in an uncontrolled way. But it’s not that simple as it sounds, it’s a key player in so many cellular pathways that defining its role gets difficult.
Tumor protein p53 is located in the nucleus of cells throughout the body, where it binds directly to DNA. When the DNA in a cell becomes damaged by agents such as toxic chemicals, radiation, or ultraviolet (UV) rays from sunlight, this protein plays a critical role in determining whether the DNA will be repaired or the damaged cell will self-destruct (undergo apoptosis). If the DNA can be repaired,  p53 activates other genes to fix the damage. If the DNA cannot be repaired, this protein prevents the cell from dividing and signals it to undergo apoptosis. This process prevents cells with mutated or damaged DNA from dividing, which helps prevent the development of tumors. Because  p53 is essential for regulating cell division and preventing tumor formation, it has been rightly nicknamed as the "guardian of the genome."
This family of gene has been conserved for billions of years seen from invertebrates to vertebrates. This conservation is obliviously due to its function and protection against all kind of stress. Thus it becomes an evolutionary advantageous as stress is the thing which all beings should be able to handle without compromising the fidelity of their genome. Thus this family has been incharge of fidelity through billion years of evolutionary history. In this process, p63/73 became germline fedility factor while p53 became a somatic fedility factor.
Huge amount of research is been done in this field giving insight into overall working of this family.  I think this research will open to us to vast realms of therapeutics for range of diseases.

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