Always, everywhere Gasoreceptor is present
Creators: name: Anbalagan, Savani
Publisher: name: Zenodo
Year: 2024
Subjects: gasoreceptor
gasocrine
oxygen

description:  

Adam Mickiewicz University scientist challenges the 2019 Nobel Prize in Medicine and Physiology discovery regarding oxygen sensing and adaptation in cells. He proposes yet to be discovered oxygen gasoreceptors that function upstream of the proteins in the Nobel Prize discovery.


 

An unexpected inspiration of ideas after attending a couple of lectures on molecular evolution has led a researcher at Adam Mickiewicz University to challenge a widely held dogma on Oxygen sensing in cells.

Oxygen can be considered as fuel for a cell from which electricity is generated. The ideas published in the new study, proposed by Dr. Savani Anbalagan at the Institute of Molecular Biology & Biotechnology, Faculty of Biology, may improve our understanding of how cells directly sense oxygen and shed new light on cellular signaling. His proposal is published in the prestigious American Physiological Society journal.

Ever since the origin of life, gases have played pivotal roles in the evolution of organisms, hence gas-sensing mechanisms must be evolutionarily conserved in organisms from bacteria to humans. One of the essential gases for animal life is oxygen. For many years, researchers have taken great interest in a fundamental question: How do cells respond to stress due to oxygen abundance or limitation?

Cells require oxygen to generate ATP, the fuel of the cells. This conversion occurs in the mitochondria, which are present in virtually all animal cells. Otto Warburg was awarded the Nobel Prize in 1931 for his discovery of the mitochondrial enzymatic process. The discovery of how oxygen sensing by the carotid body and respiration control via the brain led to another Nobel Prize for Corneille Heymans in 1938. The discovery of the structure of protein hemoglobin that transports Oxygen was also awarded an Nobel prize to Max Perutz and John Kendrew in 1962. More recently, the 2019 Nobel Prize in Medicine and Physiology was awarded for how cells recognize oxygen stress to William G. Kaelin Jr., Sir Peter J. Ratcliffe, and Gregg L. Semenza. Their findings have important implications for anemia, cancer, and many other diseases.

But when the 2019 Nobel Prize was announced, Dr. Anbalagan noticed something was amiss, but he could not point it out easily. But all this changed during the two lectures of prof. Zofia Szweykowska-Kulinska recently. The missing piece is his question that will challenge dogmas “If there is a receptor for the gas nitric oxide, what is the receptor for oxygen? How come the 1998 Nobel Prize on another gas, nitric oxide, mentioned the soluble guanylate cyclase, a NO receptor, but the 2019 Nobel Prize did not mention anything about a receptor for oxygen?”. Receptors are evolutionarily conserved proteins that can sense different molecules in a cell and trigger a response. One of the well-studied receptors is the VEGF receptors, which are conserved from Hydra to humans. The discovery of the VEGF receptor led to the discovery of novel plant-derived compounds that can target the VEGF signaling pathway, as well as VEGF receptor-targeting recombinant antibodies to treat cancer patients. Like VEGF receptors, there are many different types of cellular receptors, including RNA-sensing receptors, light-sensing receptors, temperature-sensing receptors, and even a receptor for the gas nitric oxide. With a background in developmental biology and an inquisitive mind, Dr. Anbalagan noticed something that many others had noticed. But unlike others, he simply did not stop asking the question: If there is a receptor for nitric oxide, what is the receptor for oxygen?










“If there is a receptor for the gas, Nitric oxide, Is there a receptor for Oxygen?”






 “For me, this is a bit strange,” Dr. Anbalagan says. “Five Nobel prizes related to two different gases, but only for one gas, a receptor is mentioned. Before my work, others have suggested oxygen as a signaling molecule; some have even identified how bacteria sensory cells in worms can smell oxygen via sensors, yet most studies in mice and humans did not mention anything about oxygen receptors.”

Generally, researchers apply for grants, receive funds, conduct experiments based on careful hypotheses, and analyze the results. However, it is highly challenging for researchers to switch fields or apply for grants on topics where they lack expertise. In such situations, they must collaborate with others who have the necessary expertise. This is the linear path of how science in academia is generally done. What Dr. Anbalagan did is none of those. He simply started by asking, ‘’Is there a cellular receptor for oxygen in bacteria or invertebrates?” Because oxygen-binding receptors must likely be conserved across evolution. So, he hoped that if he could learn about receptors in bacteria, he could probably make educated guesses about them in animals.

"Receptors are proteins that allow a cell to sense. Upon binding a ligand, receptors trigger a signaling response inside the cell. The VEGR receptor is an evolutionary tyrosine kinase." Standing near the door, holding a coffee cup in one hand and a permanent marker in the other, Dr. Anbalagan adds, "If I am the VEGF receptor, if I bind VEGF, the only way I will react is to put a mark on everyone around me and nothing else. Depending on who the other person is, they will do something else when they get that tag. That is how cell signaling receptors and cascades work. But if you look at oxygen receptors in bacteria or even other gas-sensing proteins in humans, they have many signaling domains." He leads us out into the hallway, "Imagine in this hallway, each room is a cell, and in each room, one or a few people are the oxygen receptor. When they bind oxygen, each person will behave differently. One person will make a mark, another person will make a phone call, another person will print a paper, another person will throw out the garbage, another person will open the tap, another person will open the window, and so on. All these people are gas-sensing receptors," Dr. Anbalagan explains as he walks down the corridor. His proposal that gas-sensing receptors have distinct signaling domains has been experimentally demonstrated in numerous organisms. But what was missing was a unifying term for all gas-sensing proteins. Back in his office, he says, "If we want to teach students about gas-sensing proteins, we need a simple term for all these proteins with so many signaling domains. Since no one else had suggested it, I did. I call all these gas-sensing proteins gas receptors. Weren't photoreceptors, thermoreceptors, and mechanoreceptors also first proposed by others, and we teach our students about them?. One of the first gas-sensing receptors to be discovered was the ethylene receptor in plants, which is very important for fruit ripening. Since then, numerous gas-sensing proteins have been discovered for oxygen, carbon monoxide, and nitric oxide. But Dr. Anbalagan's proposal of gas-sensing receptors will also include odorant and pheromone receptors, which also bind to and sense volatile gas molecules.      

When Dr. Anbalagan was asked why he thought the Nobel laureates missed the discovery of oxygen sensing receptors. "Missed no. But is their discovery partial: Yes, it is. For such a prestigious prize to be given for a half-truth! It puts enormous pressure on researchers who challenge it. Let me explain with an analogy. Let's say we're having a beer in a non-smoking pub at rush hour and someone starts smoking. If the barmaid is busy serving others, she may not see the smoker. But the smoke sensor on the ceiling will immediately detect the smoke and alert the barmaid. Currently, the 2019 Nobel Prize in Oxygen Sensing is awarded for the discovery of the barmaid who responds to the smoke sensor alarm system, not for the smoke sensor on the ceiling. In the case of the 1998 Nobel Prize for nitric oxide, the Nobel Prize was awarded for the smoke sensor. Now we need to know how smoke sensors work, how many there are? What can block its function? Does it only detect smoke or can it detect something else? If oxygen-sensing receptors exist in bacteria, they must also exist in humans. I will not accept someone telling me that we lost oxygen-sensing receptors during evolution because Nobel laureates did not find them! That's like accepting that we know how cells sense VEGF just because we know all about HIF-1 and not about the VEGF receptor that actually binds to VEGF and starts the signaling process!”

  








“It is an even bigger shift in thinking than the discovery of the estrogen receptor, the first nuclear receptor, a non-enzyme receptor!”   






 

Dr. Anbalagan will face severe criticism for talking about oxygen receptors when he has never worked on them. When asked if he could comment on the challenges. "Someone told me an incident about academic monopoly and how I have to be safe and not 'rock the boat'. And here I am saying that the Nobel Prize was given to half-truths! I guess now I am rocking an expensive submarine!" laughs Dr. Anbalagan. "As for my expertise in oxygen receptors? Did anyone ask Darwin if he had ever worked on evolution? Yet we teach his theories everywhere now! What needs to be asked is whether I have worked on receptors before! All my postdoctoral studies were on the role of receptors, even now we have recently published the ligand-receptor atlas using the latest artificial intelligence software. Our atlas was built from scratch here in Poland! Instead of asking me if I am qualified, the question must be asked of the entire scientific community in biology. Are they ready to accept that for a single gas, its gasoreceptors can have so many signaling domains? This is a big step away from the current view of receptors. It is an even bigger shift in thinking than the discovery of the estrogen receptor, the first nuclear receptor, a non-enzyme receptor!”   

Dr. Anbalagan's suggestion that gases such as oxygen have receptors in almost every cell with different signaling domains may open up new ways of studying human disease, developing new drugs, or understanding why most drugs fail in clinical trials. In Eastern countries, breathing exercises are an integral part of practices such as yoga, qigong, and zen meditation. Gases from synthetic materials in workplaces have also been implicated in patients suffering from Sick Building Syndrome, but whether our cells have receptors for such gases is also largely unknown. Recently, researchers in Germany discovered that the well-known greenhouse gas methane is also produced in our cells. However, it is unclear what role methane plays and whether methane-sensing receptors exist.  When asked how to find oxygen receptors in humans? "You have to see how the researchers identified the oxygen receptors DosP or FixL in bacteria. Or even the human NO receptor soluble guanylate cyclase. We need to ask if the Nobel laureates did similar experiments for oxygen. That's where one must start. And one must also stop depending on the fancy techniques to publish in high impact factor journals and start asking the questions that has ‘real’ impact factor!”

Scientific discoveries are usually made through experimentation, but fresh perspectives and theoretical arguments that challenge the status quo can provide new insights, or even move the field in different directions or unite researchers across scientific disciplines. If Dr. Anbalagan’s hypothesis on gasoreceptors is experimentally proven, it is unclear how many books in biology will have to be edited to include all the gasoreceptors. His hypothesis will face harsh criticism and challenges. But he is determined: "Imagine if Copernicus had remained silent and accepted geocentrism and never questioned it. What would we teach our children today? For 25 years, clinical trial after clinical trial, no good drugs have been found to treat Alzheimer's patients. If we still don't know what the oxygen receptor is in our cells, how are we going to find new drugs to treat complex diseases like Alzheimer's or cancer! And the other burning question is, why do gasoreceptors need iron or copper to sense gases?”

Did the Nobel Foundation overlook the oxygen-binding receptors proposed by Dr. Anbalagan? Will biology textbooks undergo a major revision due to the complexity of signaling domains in gasoreceptors? Will gasoreceptors be relevant in the treatment of human diseases such as asthma or allergies, given the increasing air pollution in major cities? Only time holds the answers. Dr. Anbalagan is the recipient of 2 NCN fellowships and has yet to receive his habilitation degree.  

Related manuscript: 

Heme-based oxygen gasoreceptors.Anbalagan S. Am J Physiol Endocrinol Metab. 2024. doi: 10.1152/ajpendo.00004.2024