Cancer Therapy by Immune checkpoint

 

                              Cancer kills millions of people every year and is one of humanity’s greatest health challenges. By stimulating the inherent ability of our immune system to attack tumor cells 2018 Nobel Laureates   James P. Allison and Tasuku Honjo  have established an entirely new principle for cancer therapy.

James P. Allison studied a known protein that functions as a brake on the immune system. He realized the potential of releasing the brake and thereby unleashing our immune cells to attack tumors. He then developed this concept into a brand new approach for treating patients.

                         In parallel, Tasuku Honjo discovered a protein on immune cells and, after careful exploration of its function, eventually revealed that it also operates as a brake, but with a different mechanism of action. Therapies based on his discovery proved to be strikingly effective in the fight against cancer.

                              Allison and Honjo showed how different strategies for inhibiting the brakes on the immune system can be used in the treatment of cancer. The seminal discoveries by the two Laureates constitute a landmark in our fight against cancer.

                                    Cancer comprises many different diseases, all characterized by uncontrolled proliferation of abnormal cells with capacity for spread to healthy organs and tissues. A number of therapeutic approaches are available for cancer treatment, including surgery, radiation, and other strategies, some of which have been awarded previous Nobel Prizes. These include methods for hormone treatment for prostate cancer (Huggins, 1966), chemotherapy (Elion and Hitchings, 1988), and bone marrow transplantation for leukemia (Thomas 1990). However, advanced cancer remains immensely difficult to treat, and novel therapeutic strategies are desperately needed.

                          In the late 19th century and beginning of the 20th century the concept emerged that activation of the immune system might be a strategy for attacking tumor cells. Attempts were made to infect patients with bacteria to activate the defense. These efforts only had modest effects, but a variant of this strategy is used today in the treatment of bladder cancer. It was realized that more knowledge was needed. Many scientists engaged in intense basic research and uncovered fundamental mechanisms regulating immunity and also showed how the immune system can recognize cancer cells. Despite remarkable scientific progress, attempts to develop generalizable new strategies against cancer proved difficult.

Accelerators and brakes in our immune system

                                                The fundamental property of our immune system is the ability to discriminate “self” from “non-self” so that invading bacteria, viruses and other dangers can be attacked and eliminated. T cells, a type of white blood cell, are key players in this defense. T cells were shown to have receptors that bind to structures recognized as non-self and such interactions trigger the immune system to engage in defense. But additional proteins acting as T-cell accelerators are also required to trigger a full-blown immune response. Many scientists contributed to this important basic research and identified other proteins that function as brakes on the T cells, inhibiting immune activation. This intricate balance between accelerators and brakes is essential for tight control. It ensures that the immune system is sufficiently engaged in attack against foreign microorganisms while avoiding the excessive activation that can lead to autoimmune destruction of healthy cells and tissues.

A new principle for immune therapy

                                        During the 1990s, in his laboratory at the University of California, Berkeley, James P. Allison studied the T-cell protein CTLA-4. He was one of several scientists who had made the observation that CTLA-4 functions as a brake on T cells. Other research teams exploited the mechanism as a target in the treatment of autoimmune disease. Allison, however, had an entirely different idea. He had already developed an antibody that could bind to CTLA-4 and block its function . He now set out to investigate if CTLA-4 blockade could disengage the T-cell brake and unleash the immune system to attack cancer cells.

                  The results were spectacular. Mice with cancer had been cured by treatment with the antibodies that inhibit the brake and unlock antitumor T-cell activity. Despite little interest from the pharmaceutical industry, Allison continued his intense efforts to develop the strategy into a therapy for humans. Promising results soon emerged from several groups, and in 2010 an important clinical study showed striking effects in patients with advanced melanoma, a type of skin cancer. In several patients signs of remaining cancer disappeared. Such remarkable results had never been seen before in this patient group.

Discovery of PD-1 and its importance for cancer therapy

                                              In 1992, a few years before Allison’s discovery, Tasuku Honjo discovered PD-1, another protein expressed on the surface of T-cells. Determined to unravel its role, he meticulously explored its function in a series of elegant experiments performed over many years in his laboratory at Kyoto University. The results showed that PD-1, similar to CTLA-4, functions as a T-cell brake, but operates by a different mechanism. In animal experiments, PD-1 blockade was also shown to be a promising strategy in the fight against cancer, as demonstrated by Honjo and other groups. This paved the way for utilizing PD-1 as a target in the treatment of patients. Clinical development ensued, and in 2012 a key study demonstrated clear efficacy in the treatment of patients with different types of cancer. Results were dramatic, leading to long-term remission and possible cure in several patients with metastatic cancer, a condition that had previously been considered essentially untreatable.

Immune checkpoint therapy for cancer today and in the future

                                      After the initial studies showing the effects of CTLA-4 and PD-1 blockade, the clinical development has been dramatic. We now know that the treatment, often referred to as “immune checkpoint therapy”, has fundamentally changed the outcome for certain groups of patients with advanced cancer. Similar to other cancer therapies, adverse side effects are seen, which can be serious and even life threatening. They are caused by an overactive immune response leading to autoimmune reactions, but are usually manageable. Intense continuing research is focused on elucidating mechanisms of action, with the aim of improving therapies and reducing side effects.

                                          Of the two treatment strategies, checkpoint therapy against PD-1 has proven more effective and positive results are being observed in several types of cancer, including lung cancer, renal cancer, lymphoma and melanoma. New clinical studies indicate that combination therapy, targeting both CTLA-4 and PD-1, can be even more effective, as demonstrated in patients with melanoma. Thus, Allison and Honjo have inspired efforts to combine different strategies to release the brakes on the immune system with the aim of eliminating tumor cells even more efficiently. A large number of checkpoint therapy trials are currently underway against most types of cancer, and new checkpoint proteins are being tested as targets.

Figure: Upper left: Activation of T cells requires that the T-cell receptor binds to structures on other immune cells recognized as ”non-self”. A protein functioning as a T-cell accelerator is also required for T cell activation. CTLA- 4 functions as a brake on T cells that inhibits the function of the accelerator. Lower left: Antibodies (green) against CTLA-4 block the function of the brake leading to activation of T cells and attack on cancer cells.Upper right: PD-1 is another T-cell brake that inhibits T-cell activation. Lower right: Antibodies against PD-1 inhibit the function of the brake leading to activation of T cells and highly efficient attack on cancer cells.

James P. Allison was born 1948 in Alice, Texas, USA. He received his PhD in 1973 at the University of Texas, Austin. From 1974-1977 he was a postdoctoral fellow at the Scripps Clinic and Research Foundation, La Jolla, California. From 1977-1984 he was a faculty member at University of Texas System Cancer Center, Smithville, Texas; from 1985-2004 at University of California, Berkeley and from 2004-2012 at Memorial Sloan-Kettering Cancer Center, New York. From 1997-2012 he was an Investigator at the Howard Hughes Medical Institute. Since 2012 he has been Professor at University of Texas MD Anderson Cancer Center, Houston, Texas and is affiliated with the Parker Institute for Cancer Immunotherapy.

Tasuku Honjo was born in 1942 in Kyoto, Japan. In 1966 he became an MD, and from 1971-1974 he was a research fellow in USA at Carnegie Institution of Washington, Baltimore and at the National Institutes of Health, Bethesda, Maryland. He received his PhD in 1975 at Kyoto University. From 1974-1979 he was a faculty member at Tokyo University and from 1979-1984 at Osaka University. Since 1984 he has been Professor at Kyoto University. He was a Faculty Dean from 1996-2000 and from 2002-2004 at Kyoto University.

How Oxygen levels affect cellular metabolism

 

                Animals need oxygen for the conversion of food into useful energy. The fundamental importance of oxygen has been understood for centuries, but how cells adapt to changes in levels of oxygen has long been unknown.

William G. Kaelin Jr., Sir Peter J. Ratcliffe and Gregg L. Semenza discovered how cells can sense and adapt to changing oxygen availability. They identified molecular machinery that regulates the activity of genes in response to varying levels of oxygen.

The seminal discoveries by 2019 Nobel Laureates revealed the mechanism for one of life’s most essential adaptive processes. They established the basis for our understanding of how oxygen levels affect cellular metabolism and physiological function. Their discoveries have also paved the way for promising new strategies to fight anemia, cancer and many other diseases.

Oxygen at center stage

                        Oxygen, with the formula O₂, makes up about one fifth of Earth’s atmosphere. Oxygen is essential for animal life: it is used by the mitochondria present in virtually all animal cells in order to convert food into useful energy. Otto Warburg, the recipient of the 1931 Nobel Prize in Physiology or Medicine, revealed that this conversion is an enzymatic process.

During evolution, mechanisms developed to ensure a sufficient supply of oxygen to tissues and cells. The carotid body, adjacent to large blood vessels on both sides of the neck, contains specialized cells that sense the blood’s oxygen levels. The 1938 Nobel Prize in Physiology or Medicine to Corneille Heymans awarded discoveries showing how blood oxygen sensing via the carotid body controls our respiratory rate by communicating directly with the brain.

HIF (Hypoxia Inducible Factor)

In addition to the carotid body-controlled rapid adaptation to low oxygen levels (hypoxia), there are other fundamental physiological adaptations. A key physiological response to hypoxia is the rise in levels of the hormone erythropoietin (EPO), which leads to increased production of red blood cells (erythropoiesis). The importance of hormonal control of erythropoiesis was already known at the beginning of the 20th century, but how this process was itself controlled by O₂ remained a mystery.

Gregg Semenza studied the EPO gene and how it is regulated by varying oxygen levels. By using gene-modified mice, specific DNA segments located next to the EPO gene were shown to mediate the response to hypoxia. Sir Peter Ratcliffe also studied O₂-dependent regulation of the EPO gene, and both research groups found that the oxygen sensing mechanism was present in virtually all tissues, not only in the kidney cells where EPO is normally produced. These were important findings showing that the mechanism was general and functional in many different cell types.

Semenza wished to identify the cellular components mediating this response. In cultured liver cells he discovered a protein complex that binds to the identified DNA segment in an oxygen-dependent manner. He called this complex the hypoxia-inducible factor (HIF) . Extensive efforts to purify the HIF complex began, and in 1995, Semenza was able to publish some of his key findings, including identification of the genes encoding HIF. HIF was found to consist of two different DNA-binding proteins, so called transcription factors, now named HIF-1α and ARNT. Now the researchers could begin solving the puzzle, allowing them to understand which additional components were involved and how the machinery works.

                                     Erythropoietin (EPO)

Erythropoietin (EPO) is a hormone produced primarily by the kidneys, with small amounts made by the liver. EPO plays a key role in the production of red blood cells (RBCs), which carry oxygen from the lungs to the rest of the body.

      The body uses a dynamic feedback system to help maintain sufficient oxygen levels and a relatively stable number of RBCs in the blood.

·         Erythropoietin is produced and released into the blood by the kidneys in response to low blood oxygen levels (hypoxemia). The amount of erythropoietin released depends on how low the oxygen level is and the ability of the kidneys to produce erythropoietin.

·         EPO is carried to the bone marrow, where it stimulates production of red blood cells. The hormone is active for a short period of time and then eliminated from the body in the urine.

·         As oxygen levels in the blood rise to normal or near normal levels, the kidneys slow production of EPO.

However, if your kidneys are damaged and do not produce enough erythropoietin, then too few RBCs are produced and you can becomes anemic. Similarly, if your bone marrow is unable to respond to the stimulation from EPO, then you may become anemic. This can occur with some bone marrow disorders or with chronic diseases, such as rheumatoid arthritis.

If you have a condition that affects the amount of oxygen you breathe in, such as a lung disease, you may produce more EPO to try to compensate for the low oxygen level. People who live at high altitudes may also have higher levels of EPO and so do chronic tobacco smokers.

If you produce too much erythropoietin, which can happen with some benign or malignant kidney tumors and with a variety of other cancers, you may produce too many RBCs (polycythemia or erythrocytosis). This can lead to an increase in the blood’s thickness (viscosity) and sometimes to high blood pressure (hypertension), blood clots (thrombosis), heart attack, or stroke. Rarely, polycythemia is caused by a bone marrow disorder called polycythemia vera, not by increased erythropoietin.

VHL: Von Hippel Lindau

When oxygen levels are high, cells contain very little HIF-1α. However, when oxygen levels are low, the amount of HIF-1α increases so that it can bind to and thus regulate the EPO gene as well as other genes with HIF-binding DNA segments (Figure 1). Several research groups showed that HIF-1α, which is normally rapidly degraded, is protected from degradation in hypoxia. At normal oxygen levels, a cellular machine called the proteasome, recognized by the 2004 Nobel Prize in Chemistry to Aaron Ciechanover, Avram Hershko and Irwin Rose, degrades HIF-1α. Under such conditions a small peptide, ubiquitin, is added to the HIF-1α protein. Ubiquitin functions as a tag for proteins destined for degradation in the proteasome. How ubiquitin binds to HIF-1α in an oxygen-dependent manner remained a central question.

The answer came from an unexpected direction. At about the same time as Semenza and Ratcliffe were exploring the regulation of the EPO gene, cancer researcher William Kaelin, Jr. was researching an inherited syndrome, von Hippel-Lindau’s disease (VHL disease). This genetic disease leads to dramatically increased risk of certain cancers in families with inherited VHL mutations. Kaelin showed that the VHL gene encodes a protein that prevents the onset of cancer. Kaelin also showed that cancer cells lacking a functional VHL gene express abnormally high levels of hypoxia-regulated genes; but that when the VHL gene was reintroduced into cancer cells, normal levels were restored. This was an important clue showing that VHL was somehow involved in controlling responses to hypoxia. Additional clues came from several research groups showing that VHL is part of a complex that labels proteins with ubiquitin, marking them for degradation in the proteasome. Ratcliffe and his research group then made a key discovery: demonstrating that VHL can physically interact with HIF-1α and is required for its degradation at normal oxygen levels. This conclusively linked VHL to HIF-1α.

              Under normal oxygen levels, hydroxyl groups are added at two specific positions in HIF-1α . This protein modification, called prolyl hydroxylation, allows VHL to recognize and bind to HIF-1α and thus explained how normal oxygen levels control rapid HIF-1α degradation with the help of oxygen-sensitive enzymes (so-called prolyl hydroxylases). Further research by Ratcliffe and others identified the responsible prolyl hydroxylases. It was also shown that the gene activating function of HIF-1α was regulated by oxygen-dependent hydroxylation. The Nobel Laureates had now elucidated the oxygen sensing mechanism and had shown how it works.

Figure 1. When oxygen levels are low (hypoxia), HIF-1α is protected from degradation and accumulates in the nucleus, where it associates with ARNT and binds to specific DNA sequences (HRE) in hypoxia-regulated genes (1). At normal oxygen levels, HIF-1α is rapidly degraded by the proteasome (2). Oxygen regulates the degradation process by the addition of hydroxyl groups (OH) to HIF-1α (3). The VHL protein can then recognize and form a complex with HIF-1α leading to its degradation in an oxygen-dependent manner (4).

Oxygen shapes physiology and pathology

Thanks to the groundbreaking work of these Nobel Laureates, we know much more about how different oxygen levels regulate fundamental physiological processes. Oxygen sensing allows cells to adapt their metabolism to low oxygen levels: for example, in our muscles during intense exercise. Other examples of adaptive processes controlled by oxygen sensing include the generation of new blood vessels and the production of red blood cells. Our immune system and many other physiological functions are also fine-tuned by the O₂-sensing machinery. Oxygen sensing has even been shown to be essential during fetal development for controlling normal blood vessel formation and placenta development.

Oxygen sensing is central to a large number of diseases . For example, patients with chronic renal failure often suffer from severe anemia due to decreased EPO expression. EPO is produced by cells in the kidney and is essential for controlling the formation of red blood cells, as explained above. Moreover, the oxygen-regulated machinery has an important role in cancer. In tumors, the oxygen-regulated machinery is utilized to stimulate blood vessel formation and reshape metabolism for effective proliferation of cancer cells. Intense ongoing efforts in academic laboratories and pharmaceutical companies are now focused on developing drugs that can interfere with different disease states by either activating, or blocking, the oxygen-sensing machinery.

Figure 2. The awarded mechanism for oxygen sensing has fundamental importance in physiology, for example for our metabolism, immune response and ability to adapt to exercise. Many pathological processes are also affected. Intensive efforts are ongoing to develop new drugs that can either inhibit or activate the oxygen-regulated machinery for treatment of anemia, cancer and other diseases.

 

Von Hippel-Lindau Syndrome

What is von Hippel-Lindau disease?

Von Hippel-Lindau syndrome (VHL) is a hereditary condition associated with tumors arising in multiple organs. VHL-related tumors include hemangioblastomas, which are blood vessel tumors of the brain, spinal cord, and retina. The retinal tumors are also called retinal angiomas, which can lead to blindness if not treated in a timely manner. People with VHL also have an increased risk of developing clear cell renal cell carcinoma (ccRCC), which is a specific type of kidney cancer, as well as a type of tumor in the pancreas known as pancreatic neuroendocrine tumor (pNET). Tumors of the adrenal gland or pheochromocytoma can also develop, with a small number becoming metastatic, meaning they spread to other parts of the body. 

Other features of VHL include: kidney cysts, which are closed sacs usually filled with fluid; pancreatic cysts, epididymal cystadenomas, which are tumors near a man’s testicles; broad ligament cystadenomas, which occur near the fallopian tubes in women; and endolymphatic sac tumors (ELST), which are tumors of the inner ear that may cause hearing loss.

What causes VHL?

VHL is a genetic condition. This means that the risk of developing certain types of tumors and other features of VHL can be passed from generation to generation. The gene associated with VHL is also called VHL. Inheriting a deletion or mutation (alteration) in the VHL gene gives a person an increased risk of developing any of the different signs of VHL explained above, called manifestations. Nearly everyone who has VHL syndrome has an identifiable VHL genetic mutation.

How is VHL inherited?

Normally, every cell has 2 copies of each gene: 1 inherited from the mother and 1 inherited from the father. VHL follows an autosomal dominant inheritance pattern, in which inheriting 1 copy of the altered gene will likely result in a mutation of the second (normal) copy of the gene. This puts the individual at risk for developing cancer.

 

The increase in body size of humans and other vertebrates requires a

 physiological infrastructure to provide adequate delivery of oxygen to tissues

 and cells to maintain oxygen homeostasis. The heart, lungs and the vasculature

 are all part of a highly regulated system that ensures the distribution of the

 precise amount of oxygen needed throughout the mammalian organism.

1. The role of HIF-1
α pathway in cellular adaptation to hypoxic stress

Mammalian cells need to maintain proper oxygen hemostasis in order to execute their aerobic metabolism and energy generation. In cancer, heart diseases, or chronic obstructive pulmonary disorders, the cellular oxygen balance is highly impaired, and cells become hypoxic (having low oxygen (O2) levels). Hypoxia is common in many types of solid tumors, where tumor cells proliferate rapidly and form large solid tumor masses, leading to obstruction and compression of the blood vessels surrounding these masses. These abnormal blood vessels often do not function properly and result in poor O2 supply to the center tumor regions2. Tumor cells in this hypoxic region begin to adapt these low oxygen tension conditions by activating several survival pathways. Activation of HIF-1 transcription factor is the most recognized pathway adopted by hypoxic cells in this harsh microenvironment

 

 

    2. Regulation of HIF-1α pathway

The activity and accumulation of HIF-1α protein were found to be regulated at different levels throughout its life cycle inside the cells. Independently from O2 levels, HIF-1α is constitutively transcribed and synthesized through a series of signaling events involving several growth factors and other signaling molecules. HIF-1α undergoes quick degradation under normoxic conditions and normally has a very short half-life (about 5 min). In contrast, under hypoxic conditions, several pathways have been shown to control HIF-1α stability and transcriptional activity via post-transnational modifications involving hydroxylation, acetylation, ubiquitination, and phosphorylation reactions

 

The Nobel Prize in Medicine 2021

 

The Nobel Prize in Physiology or Medicine 2021

 

The Nobel Assembly at Karolinska Institutet has  decided to award

the 2021 Nobel Prize in Physiology or Medicine

jointly to David Julius and Ardem Patapoutian

for their discoveries of receptors for temperature and touch

 

Our ability to sense heat, cold and touch is essential for survival and underpins our interaction with the world around us. In our daily lives we take these sensations for granted, but how are nerve impulses initiated so that temperature and pressure can be perceived? This question has been solved by this year’s Nobel Prize laureates.

David Julius utilized capsaicin, a pungent compound from chili peppers that induces a burning sensation, to identify a sensor in the nerve endings of the skin that responds to heat. Ardem Patapoutian used pressure-sensitive cells to discover a novel class of sensors that respond to mechanical stimuli in the skin and internal organs. These breakthrough discoveries launched intense research activities leading to a rapid increase in our understanding of how our nervous system senses heat, cold, and mechanical stimuli. The laureates identified critical missing links in our understanding of the complex interplay between our senses and the environment.

 

How do we perceive the world?

 

One of the great mysteries facing humanity is the question of how we sense our environment. The mechanisms underlying our senses have triggered our curiosity for thousands of years, for example, how light is detected by the eyes, how sound waves affect our inner ears, and how different chemical compounds interact with receptors in our nose and mouth generating smell and taste. We also have other ways to perceive the world around us. Imagine walking barefoot across a lawn on a hot summer’s day. You can feel the heat of the sun, the caress of the wind, and the individual blades of grass underneath your feet. These impressions of temperature, touch and movement are essential for our adaptation to the constantly changing surrounding.

In the 17th century, the philosopher René Descartes envisioned threads connecting different parts of the skin with the brain. In this way, a foot touching an open flame would send a mechanical signal to the brain. Discoveries later revealed the existence of specialized sensory neurons that register changes in our environment. Joseph Erlanger and Herbert Gasser received the Nobel Prize in Physiology or Medicine in 1944 for their discovery of different types of sensory nerve fibers that react to distinct stimuli, for example, in the responses to painful and non-painful touch. Since then, it has been demonstrated that nerve cells are highly specialized for detecting and transducing differing types of stimuli, allowing a nuanced perception of our surroundings; for example, our capacity to feel differences in the texture of surfaces through our fingertips, or our ability to discern both pleasing warmth, and painful heat.

Prior to the discoveries of David Julius and Ardem Patapoutian, our understanding of how the nervous system senses and interprets our environment still contained a fundamental unsolved question: how are temperature and mechanical stimuli converted into electrical impulses in the nervous system?

 

The science heats up!

 

In the latter part of the 1990’s, David Julius at the University of California, San Francisco, USA, saw the possibility for major advances by analyzing how the chemical compound capsaicin causes the burning sensation we feel when we come into contact with chili peppers. Capsaicin was already known to activate nerve cells causing pain sensations, but how this chemical actually exerted this function was an unsolved riddle. Julius and his co-workers created a library of millions of DNA fragments corresponding to genes that are expressed in the sensory neurons which can react to pain, heat, and touch. Julius and colleagues hypothesized that the library would include a DNA fragment encoding the protein capable of reacting to capsaicin. They expressed individual genes from this collection in cultured cells that normally do not react to capsaicin. After a laborious search, a single gene was identified that was able to make cells capsaicin sensitive. The gene for capsaicin sensing had been found! Further experiments revealed that the identified gene encoded a novel ion channel protein and this newly discovered capsaicin receptor was later named TRPV1. When Julius investigated the protein’s ability to respond to heat, he realized that he had discovered a heat-sensing receptor that is activated at temperatures perceived as painful.

 

The discovery of TRPV1 was a major breakthrough leading the way to the unravelling of additional temperature-sensing receptors. Independently of one another, both David Julius and Ardem Patapoutian used the chemical substance menthol to identify TRPM8, a receptor that was shown to be activated by cold. Additional ion channels related to TRPV1 and TRPM8 were identified and found to be activated by a range of different temperatures. Many laboratories pursued research programs to investigate the roles of these channels in thermal sensation by using genetically manipulated mice that lacked these newly discovered genes. David Julius’ discovery of TRPV1 was the breakthrough that allowed us to understand how differences in temperature can induce electrical signals in the nervous system.

 

Research under pressure!

 

While the mechanisms for temperature sensation were unfolding, it remained unclear how mechanical stimuli could be converted into our senses of touch and pressure. Researchers had previously found mechanical sensors in bacteria, but the mechanisms underlying touch in vertebrates remained unknown. Ardem Patapoutian, working at Scripps Research in La Jolla, California, USA, wished to identify the elusive receptors that are activated by mechanical stimuli.

Patapoutian and his collaborators first identified a cell line that gave off a measurable electric signal when individual cells were poked with a micropipette. It was assumed that the receptor activated by mechanical force is an ion channel and in a next step 72 candidate genes encoding possible receptors were identified. These genes were inactivated one by one to discover the gene responsible for mechanosensitivity in the studied cells. After an arduous search, Patapoutian and his co-workers succeeded in identifying a single gene whose silencing rendered the cells insensitive to poking with the micropipette. A new and entirely unknown mechanosensitive ion channel had been discovered and was given the name Piezo1, after the Greek word for pressure (í; píesi). Through its similarity to Piezo1, a second gene was discovered and named Piezo2. Sensory neurons were found to express high levels of Piezo2 and further studies firmly established that Piezo1 and Piezo2 are ion channels that are directly activated by the exertion of pressure on cell membranes.

 

The breakthrough by Patapoutian led to a series of papers from his and other groups, demonstrating that the Piezo2 ion channel is essential for the sense of touch. Moreover, Piezo2 was shown to play a key role in the critically important sensing of body position and motion, known as proprioception. In further work, Piezo1 and Piezo2 channels have been shown to regulate additional important physiological processes including blood pressure, respiration and urinary bladder control.

 

It all makes sense!

 

The groundbreaking discoveries of the TRPV1, TRPM8 and Piezo channels by this year’s Nobel Prize laureates have allowed us to understand how heat, cold and mechanical force can initiate the nerve impulses that allow us to perceive and adapt to the world around us. The TRP channels are central for our ability to perceive temperature. The Piezo2 channel endows us with the sense of touch and the ability to feel the position and movement of our body parts. TRP and Piezo channels also contribute to numerous additional physiological functions that depend on sensing temperature or mechanical stimuli. Intensive ongoing research originating from this year’s Nobel Prize awarded discoveries focusses on elucidating their functions in a variety of physiological processes. This knowledge is being used to develop treatments for a wide range of disease conditions, including chronic pain .

 

David Julius was born in 1955 in New York, USA. He received a Ph.D. in 1984 from University of California, Berkeley and was a postdoctoral fellow at Columbia University, in New York. David Julius was recruited to the University of California, San Francisco in 1989 where he is now Professor.

Ardem Patapoutian was born in 1967 in Beirut, Lebanon. In his youth, he moved from a war-torn Beirut to Los Angeles, USA and received a Ph.D. in 1996 from California Institute of Technology, Pasadena, USA. He was a postdoctoral fellow at the University of California, San Francisco. Since 2000, he is a scientist at Scripps Research, La Jolla, California where he is now Professor. He is a Howard Hughes Medical Institute Investigator since 2014.

 

प्रोटीनः रक्षा कवच भी एवं वायरस जनित रोगों का द्वारपाल भी

 

प्रोटीन हमारे शरीर के लिए बहुत ही महत्चपूर्ण अवयव है। इसकी कमी,अत्यधिक मात्रा एवं प्रोटीन की संरचना में गड़बड़ी होने पर हमारे शरीर में इसका बहुत बुरा प्रभाव पड़ता है। प्रोटीन जहां हमारे शरीर को स्वस्थ एवं मजबूत बनाने में मदद करता है वहीं इसके अधिक मात्रा का सेवन भी  हमारे शरीर पर बुरा प्रभाव डालता है। प्रोटीन की संरचना में गड़बड़ी आने पर हमारा जीनोम प्रभावित तो होता ही है साथ ही इससे कई प्रकार की बीमारियां भी होती है,जैसे कैंसर,डिसमेंिशया इत्यादि।

          प्रोटीन जहां एंटीजेन के रूप में हमारा प्रतिरोधक क्षमता बढ़ा कर हमें अनेक बिमारियों से बचाता है वहीं यह रिसेप्टर के रूप में वायरस को हमारे शरीर में प्रवेश भी कराता है। वैक्सीन के निर्माण में भी प्रोटीन का इस्तेमाल किया जाता है।

                    देश के 16 शहरों में हुए एक सर्वे के मुताबिक 73% भारतीयों में प्रोटीन की कमी है और 93% लोगों को इसकी जानकारी भी नहीं है। जबकि कोरोना काल में प्रोटीन की ज्यादा जरूरत है। संक्रमण के बाद कमजोर हो चुकी मांसपेशियों और रोगों से लड़ने वाले इम्यून सिस्टम के लिए एक्सपर्ट प्रोटीन लेने की सलाह दे रहे हैं। प्रोटीन की कमी होने पर मरीज थकान, कमजोरी, चलने-फिरने में दिक्कत और अनिद्रा से जूझ रहे हैं।

एक्सपर्ट का कहना है शरीर में हुए डैमेज को रिपेयर करने का काम प्रोटीन ही करता है लेकिन 90% लोग यही नहीं जानते कि रोजाना कितना प्रोटीन लेना चाहिए। इसमें सबसे ज्यादा 95% से अधिक महिलाएं शामिल हैं। नतीजा 71% भारतीयों की मांसपेशियां कमजोर हैं।

प्रोटीन कैसे काम करता है, रोजाना कितना प्रोटीन लेना चाहिए और डाइट में इसकी मात्रा अधिक या कम होने पर क्या फायदे-नुकसान हो सकते हैं।

 

प्रोटीन क्या है और कितना लें

जिस तरह एक बिल्डिंग को तैयार करने के लिए ईंटों का होना जरूरी है, उसी तरह शरीर के लिए प्रोटीन अहम है। इसीलिए इसे बिल्डिंग ब्लॉक्स ऑफ लाइफ भी कहा जाता है। शरीर के विकास के लिए प्रोटीन का होना जरूरी है। ICMR (इंडियन काउंसिल ऑफ मेडिकल रिसर्च) का कहना है कि रोजाना कम से कम 48 ग्राम प्रोटीन लेना जरूरी है, लेकिन भारतीयों के खानपान में प्रोटीन की मात्रा इससे काफी कम है।

औसतन, एक इंसान का जितना वजन होता है, उसे उतने ग्राम प्रोटीन लेना चाहिए। जैसे- आपका वजन 60 किलो है तो रोजाना डाइट में 60 ग्राम प्रोटीन लेना चाहिए।

प्रोटीन कैसे काम करता है, अब इसे समझें

प्रोटीन एक ग्रीक शब्द प्रोटीयोज से मिलकर बना है, जिसका मतलब है प्राइमरी यानी सबसे जरूरी।

 प्रोटीन अमीनो एसिड की छोटी-छोटी चेन से मिलकर बना

 होता है। आसान भाषा में समझें तो यह स्किन और मांसपेशियों में होने वाली टूट-फूट को रिपेयर करता

 है। इंसान के शरीर में एक लाख तरह के प्रोटीन होते

 हैं। इनमें हीमोग्लोबिन, किरेटिन और कोलेजन जैसे प्रोटीन शामिल हैं। जिनका शरीर के अलग-अलग

 हिस्सों से कनेक्शन है।

भारतीयों में प्रोटीन की कमी के 4 बड़े कारण

·       

       भारतीयों की थाली में फैट-स्टार्च अधिक: बीएमजे जर्नल में पब्लिश रिसर्च रिपोर्ट कहती है, भारतीयों की थाली में स्टार्च और फैट अधिक व प्रोटीन     कम होता है। 91% शाकाहारियों में प्रोटीन की कमी देखी गई है।

·         जागरूकता की कमी: ज्यादातर भारतीयों को इसकी जानकारी नहीं रहती कि रोजाना डाइट में कितना प्रोटीन लें। वर्किंग वुमन और हाउसवाइव्स में 70-80% तक प्रोटीन की कमी रहती है।

·         थाली में चावल और गेहूं अधिक: भारतीयों की थाली में चावल और गेहूं अधिक होता है जबकि दालों का प्रयोग कम किया जाता है। एक शाकाहारी इंसान की डाइट में दालों का होना जरूरी है। 2016 में दालों को सुपरफूड घोषित किया गया था।

·         प्रोटीन को लेकर भ्रम: 70% महिलाएं मानती हैं फल और सब्जियों में प्रोटीन होता है। वहीं, 73% शहरी आबादी के मुताबिक  पत्तेदार सब्जियों में प्रोटीन अधिक होता है। ऐसे भ्रम भी प्रोटीन की कमी का कारण बनते हैं।

अब प्रोटीन के फायदे और नुकसान भी जान लीजिए

·         प्रोटीन लेना जरूरी है, क्योंकि यह रोगों से लड़ने वाले इम्यून सिस्टम को मजबूत बनाता है। हड्डियों और मांसपेशियों को स्ट्रॉन्ग बनाने का काम भी यही प्रोटीन करता है। यह हार्मोन का लेवल नहीं बिगड़ने देता। इसके साथ बाल, नाखून और स्किन को सेहतमंद रखता है। गर्भवती और बच्चे को दूध पिलाने वाली महिलाओं के लिए यह बेहद जरूरी है ताकि बच्चे का विकास बेहतर हो सके।

·         एक रिसर्च में साबित भी हुआ है कि यह मेटाबॉलिज्म सुधारकर मोटापा कंट्रोल करता है। साथ ही थकावट दूर करने का भी काम करता है।

·         प्रोटीन की मात्रा जरूरत से ज्यादा लेते हैं, तो कई तरह का खतरा भी बढ़ता है। इसकी अधिक मात्रा बढ़ने लेने पर शरीर इसे बाहर नहीं निकाल पाता इसका सीधा असर किडनी पर पड़ता है। प्रोटीन अधिक लेने पर किडनी फेल और स्टोन होने का खतरा अधिक रहता है। इसके अलावा वजन बढ़ना, सांसों में बदबू आना, कब्ज होने के साथ कैंसर और हृदय रोगों की आशंका भी रहती है।

प्रोटीन के प्रकार

एम प्रोटीन (membrane protein)- एक वायरस के चारों ओर का प्रोटीन होता है जिसको एम प्रोटीन (membrane protein) कहा जाता है। 

 

ई प्रोटीन (Envelope protein)- जेनेटिक मटेरियल के चारों तरफ दो घेरे होते हैं। इनर लेयर को इनवलेप प्रोटीन कहते हैं। आउटर लेयर को एम प्रोटीन  कहते हैं।

स्पाइक प्रोटीन - स्पाइक प्रोटीन कोरोना वायरस का प्रोटीन है जो इंसानी शरीर के एसीई2 रिसेप्टर से जुड़ता है। इस तरह वायरस शरीर में तेजी से फैलता है।

           कोरोना ग्रीक शब्द है जिसका अर्थ है क्राउन। क्राउन के चारों तरफ सूरज की रोशनी की तरह

 किरणें निकली होती हैं। ऐसी ही संरचना कोरोना वायरस की है। कोरोना वायरस की जो ये लाइन बाहर

 की तरफ निकली होती हैं ये स्पाइक प्रोटीन होती हैं। इसी को एस प्रोटीन भी कहा जाता है।

 

स्पाइक प्रोटीन का नुकसान

वायरस वातावरण के अनुसार खुद को बदलता है। वातावरण के अनुसार अपने जेनेटिक स्ट्रक्चर को

 बदलेगा। जब वह अपनी संरचना बदलेगा तो आरएन से प्रोटीन बन रही हैं तो प्रोटीन का स्ट्रक्चर बदल

 जाएगा। जिससे स्पाइक प्रोटीन में म्युटेशन हो जाते हैं। जब म्युटेशन हो जाता है तब वह आरटीपीसीआर

 टेस्ट में भी पकड़ में नहीं आता है। आरटीपीसीआर में प्रोटीन को देखा जाता है  फिर प्रोटीन से आरएनए

  बनाते  हैं। फिर देखते हैं कि ये आरएनए कोरोना वायरस का है या नहीं। अगर वह कोरोना वायरस से

 मैच कर गया तो कोरोना पॉजिटिव हो जाते हैं और मैच नहीं होने पर कोरोना नेगेटिव हो जाते हैं। जब

 म्युटेशन हो जाता है और किट पुरानी है तब कोरोना पकड़ में नहीं आता। वैक्सीन एक स्पाइक प्रोटीन के

 विरुद्ध काम कर रही है तब तक वायरस म्युटेंट हो जाता है जिस वजह से वैक्सीन प्रभावी नहीं रहती।

 

शरीर में स्पाइक प्रोटीन क्या करता है?

स्पाइक प्रोटीन वायरस को शरीर की कोशिका के अंदर प्रवेश करवाता है। इसे डॉक्टर अवधेश शर्मा ने एक

 उदाहरण के तौर पर समझाया। स्पाइक प्रोटीन किसी गेट की चाबी है। तो घर के अंदर जाने के लिए

 चाबी की जरूरत पड़ती है। स्पाइक प्रोटीन चाबी की तरह काम करता है। स्पाइक प्रोटीन जीवित लोगों

 के अंदर वायरस का प्रवेश आसान बना देता है। वायरस में जो कांटे वाले स्ट्रक्चर होते हैं ये स्पाइक प्रोटीन

 मनुष्य की बॉडी में एसीई2 रिसेप्टर होता है। जिसे angiotensin converting enzyme 2 receptor

 (ace2) कहा जाता है। ये एसीई2 रिसेप्टर शरीर के अलग-अलग अंगों में पाए जाते हैं। हृदय की

 कोशिकाओं में] मासपेशियों की कोशिकाओं में] रक्त वाहिकाओं की कोशिकाओं आदि में पाए जाते हैं।

 लेकिन सबसे ज्यादा फेफडो़ं की कोशिकाओं में होते हैं। स्पाइक प्रोटीन एसीई2 रिसेप्टर पर जाकर चिपक

 जाता है। इनसे चिपकर वायरस लिविंग सेल के अंदर एंट्री कर जाता है। शरीर में अंदर जाने के बाद

 वायरस अपनी कॉपी बनाने लग जाता है और तेजी से शरीर में फैलता है।

वायरस क्या होता है?

 

वायरस एक छोटा परजीवी होता है जो खुद को स्वयं से पुनरुत्पादित (reproduce) नहीं कर सकता। यह

 एक ए सेल्युलर स्ट्रक्चर है। वायरस में जेनेटिक मटेरियल होता है।

वायरस में पाया जाने वालाDNA या RNA सिंगल स्ट्रैंडेड और डबल स्ट्रैंडेड हो सकता है।यह वायरस के

 पूरे जीनोम संरचना का आधार होता है। यह सिर्फ कैस्पीड प्रोटीन,एन्जाईम्स और प्रोटीन को मेजबान के

 शरीर में प्रवेश कराता है जहां यह अपने से रेप्लिकेट करता है। वायरस मेजबान के शरीर में श्वसन तंत्र

 और खुले घाव के द्वारा प्रवेश करता है। कुछ वायरस insect के द्वारा भी मानव शरीर में फैलता है जैसे -

 डेंगू। वायरस का एक species से दूसरे species में पहुंचना बहुत ही कम पाया जाता है।

 शरीर में कैसे फैलता है वायरस?

डॉ0 अवधेश शर्मा का कहना है कि डीएनए और आरएनए दो तरह के वायरस होते हैं।  डीएनए वायरस

 प्रोटीन बनाते हैं और डीएनए से आरएनए बनता है। आरएनए वायरस भी प्रोटीन बनाते हैं। आरएनए से

 सीधा प्रोटीन बन जाता है। वायरस सजीव और निर्जीव दोनों कैटेगरी में आता है। कोई भी वायरस का

 कण जब हमारे शरीर में आता है तो बॉडी की कोशिकाओ में घुसता है। कोशिकाओं के डिविजन को कंट्रोल

 कर लेता है। वायरस कोशिकाओं को अनियंत्रित तरीके से बढ़ाता है। वायरस कोशिकाओं में जाकर अपनी

 कॉपी बनाने लग जाएगा। जिसे वायरल रेप्लीकेशन कहा जाता है। इस तरह से यह वायरस शरीर को

 नुकसान पहुंचाने लगता है। जिनकी इम्युनिटी स्ट्रांग होती है वह वायरस से लड़ लेती है जिनकी नहीं

 होती है वे बीमार पड़ जाते हैं।

कोरोना वायरस आरएनए वायरस है। आरएनए में भी ये सिंगल स्ट्रैंडिड  वायरस है। आमतौर पर कोरोना

 वायरस सिंगल स्ट्रैंडिड आरएनए  वायरस है। जबकि डीएनए वारयस डबल चेन होते हैं।

कोरोना फेफड़ों को ज्यादा क्यों प्रभावित करता है?

डॉ. अवधेश शर्मा का कहना है कि फेफड़ों में एसीई2 रिसेप्टर सबसे ज्यादा होते हैं, इसलिए कोरोना

 वायरस फेफड़ों को ज्यादा प्रभावित करता है। इसके बाद हार्ट और ब्लड वेसेल और किडनी पर असर

 डालता है। छोटे बच्चों में एसीई2 रिसेप्टर का अमाउंट कम होता है। उम्र के साथ एस रिसेप्टर बढ़ते हैं।

 लेकिन छोटे बच्चों में यह कम होता है इसलिए बच्चों पर कोरोना वायरस ज्यादा गंभीर प्रभाव नहीं डालता

 है। जब एसीई रिसेप्टर कम होंगे तो वायरस शरीर में कम प्रवेश करेगा, इसलिए बच्चों में यह ज्यादा

 नुकसानदायक नहीं है। एडल्ट्स में एसीई रिसेप्टर ज्यादा होते हैं इसलिए एडल्ट्स में ज्याद नुकसान पहुंचाता है।

कोविड-19 टीके कैसे काम करते हैं?

इस समय कोविड-19 के बहुत से टीके तैयार किए जा रहे हैं। इनका परीक्षण हो रहा है और साथ ही इन्हें

 मंजूरी मिल रही है। इन सभी का उद्देश्य है शरीर की रोग प्रतिरोधी व्यवस्था को सुरक्षित तरीके से

 कोरोना वायरस की पहचान कर उसे रोकने के लिए प्रशिक्षित करना है। इसके विभिन्न प्रकार निम्न हैः

 

निष्क्रिय विषाणु (इनएक्टिवेटेड) या कमजोर किए गए विषाणु (वीकेंड वायरस) के टीके, ये वायरस के

 एक स्वरूप का उपयोग करते हैं, जिसे निष्क्रिय कर दिया गया हो या कमजोर कर दिया गया हो, ताकि

 वह रोग का कारण नहीं बन सके। लेकिन ऐसी स्थिति में भी यह रोग प्रतिरोधी व्यवस्था को सक्रिय कर देता है।

वायरल वेक्टर टीके, ये अनुवांशिक इंजीनयरिंग के आधार पर तैयार विषाणु का उपयोग करते हैं ताकि

 अनुवांशिक कोड (जैसे कि डीएनए) को ले जाया जा सके और प्रोटीन पैदा किए जा सकें जो रोग प्रतिरोधी क्षमता को प्रोत्साहित करे, लेकिन कोविड-19 का कारण नहीं बने।

एमआरएनए टीके, जिनमें सिंथेटिक या कृत्रिम एमआरएनए होते हैं। यह कोरोना वायरस स्पाइक प्रोटीन

 तैयार करने के लिए उपयोग की गई सूचना है। यह प्रोटीन अकेला कोविड-19 का कारण नहीं बन सकता।

 हमारी कोशिकाएं इस एमआरएनए का उपयोग करती हैं और वायरल प्रोटीन तैयार करती हैं। ये हमारी

 रोग प्रतिरोधी व्यवस्था को एंटीबॉडी तैयार करने के लिए प्रेरित करती हैं, जो वायरस से लड़ता है और

 उसे रोकता है।

प्रोटीन-आधारित टीके

 ये प्रोटीन या प्रोटीन शेल के हानिरहित अंशों का उपयोग कर बनाये जाते हैं   जो रोग प्रतिरोधी क्षमता

 को सक्रिय करने के लिए कोविड-19 की नकल करता है लेकिन कोविड-19 रोग पैदा नहीं करता।

Cell adhesion molecules

The majority of viral receptors identified to date are celnladhesion molecules(CAMs) tha tfunction in cell- to-cell and cell-to-extra cellular matrix adhesion and thus are essential mediators of cellular processes such as development,maintenance of cellular structure, cell signaling, and maintenance and repair of tissues.The broad family of CAM includes selectins, cadherins, integrins, and IgSF members 

Breaking down the door :how viruses overcome multiple locks/receptors

 

Many viruses must utilize multiple receptors. In order to efficiently invade cells. Furthermore, in many cases,viruses utilize cell-type specific receptors, thereby lending additional restrictions to tropism.