October is one of the most anticipated months for the scientific community as it is when the Nobel Prizes are announced every year. The Nobel Prize celebrates science and makes celebrities of scientists. Last year on October 7th, three scientists- William G. Kaelin Jr., Sir Peter J. Ratcliffe and Gregg L. Semenza, rose to scientific stardom when they won the 2019 Nobel Prize in Physiology or Medicine.
Sensing the change in oxygen levels
The weeks leading up to the announcement are filled with frenzied anticipation, with social media polls and discussions doing the rounds on which topic of research would take away the grand prize. In 2019, it turned out to be something we cannot live without, Oxygen! Oxygen (or O2) is essential for survival as cells use oxygen to convert food into energy inside tiny power stations known as mitochondria. There is oxygen all around us, but its availability can vary depending upon the environmental conditions. If you feel breathless after an intense workout or while scaling a mountain, it’s because your body cannot keep up with increased oxygen demands during exercise and oxygen levels drop at high altitudes. The body has an in-built mechanism that responds to different levels of oxygen and maintains the organism’s homeostasis.
Kaelin, Ratcliffe and Semenza’s work unraveled the molecular mechanism of how cells sense oxygen availability and how they respond through the regulation of downstream genes. Their independent research in the 1990s and early 2000s showed for the first time that the molecular machinery for oxygen sensing is present in every cell of the body. It was already known that the kidney responds to limiting quantities of oxygen (or Hypoxia) by secreting a protein Erythropoietin (EPO). EPO is transported to the bone marrow where it triggers the production of red blood cells (RBC). Increased number of RBCs in the blood thereby compensate for low oxygen in the body.
A momentous journey of independent discoveries
What we know about the mechanism of oxygen sensing today is a result of many years of research by the three scientists that helped solve the puzzle, piece by piece. Semenza started off by looking at the regulation of the EPO gene and discovered the HIF (Hypoxia Inducible Factor) complex as a key regulator of the process. The HIF complex is a heterodimer that consists of two DNA binding proteins – HIF-1α and ARNT (or Aryl Hydrocarbon Receptor Nuclear Translocator).
Kaelin and Ratcliffe started their investigation by examining the upstream events of HIF-1α control and independently identified an unexpected partner, the VHL (von Hippel-Lindau’s disease) gene. Kaelin was working on von Hippel-Lindau’s disease; a genetic syndrome marked by increased susceptibility to certain cancers and found a link between VHL and hypoxia. Their work showed that when oxygen is present in normal levels, HIF-1 α is hydroxylated and is targeted by VHL for protein degradation via the proteasomal pathway. When oxygen levels are low (Hypoxia), the transcription factor HIF-1α is free to move into the nucleus where it binds to ARNT and regulates transcription of target genes that helps the body adapt to low oxygen e.g. genes involved in erythropoiesis, angiogenesis, and metabolism.
Kaelin and Semenza are American citizens, both born in New York in 1957 and 1956, respectively. Kaelin obtained his medical degree from Duke University, Durham, and is a professor at the Harvard Medical School since 2002. Semenza pursued an MD/Ph.D. from the University of Pennsylvania, School of Medicine, Philadelphia, did his postdoctoral research at Johns Hopkins University, Baltimore, where he is a professor since 2003. Ratcliffe is a British citizen born in 1954. He obtained his medical degree from Cambridge University and is currently the Director of Clinical Research at the Francis Crick Institute, London, and the Target Discovery Institute in Oxford and a member of the Ludwig Institute for Cancer Research.
Implications in physiology and pathology
Oxygen sensing has a role in regulating normal physiological functions of the body, such as embryonic development, erythropoiesis, and immunity. The cells’ oxygen-sensing machinery also plays a role in a disease context, such as cancers, wound healing and renal failure. Hypoxic conditions arise in fast-growing cancers, which triggers angiogenesis in the surrounding tissue. Efforts are underway to develop drugs that would intervene in the oxygen-sensing pathway to curb cancer growth. One such drug, Roxadustat, was recently approved in China to treat anemia. The potential for misuse also exists, as some athletes were implicated in using hypoxia-related drugs to enhance their performance through increased blood cell generation.
A detailed picture of the molecular basis of oxygen sensing has opened up new research areas and advanced the never-ending quest to understand how our body works. It also reminds us just how complicated the simple process of breathing in oxygen really is!
Further information:
https://www.nobelprize.org/prizes/medicine/2019/kaelin/lecture/
https://www.nobelprize.org/prizes/medicine/2019/ratcliffe/lecture/
https://www.nobelprize.org/prizes/medicine/2019/semenza/lecture/
Author:
Sumbul Jawed Khan received her Ph. D. in Biological Sciences and Bioengineering from the Indian Institute of Technology Kanpur, where she studied the role of microenvironment in cancer progression and tumor formation. During her post-doctoral research at the University of Illinois at Urbana-Champaign, she investigated the gene regulatory networks that are important for tissue regeneration after damage or wounding. She is committed to science outreach activities and believes it is essential to inspire young people to apply scientific methods to tackle the challenges faced by humanity. As an editor, her aim is to simplify, translate, and excite people about the current advances in science.
Editors:
Saurja Dasgupta is originally from Kolkata, India. He obtained his Ph.D. at the University of Chicago, where he studied the structure, function, and evolution of catalytic RNA. He is currently doing his postdoctoral research at Massachusetts General Hospital, Boston, where he is trying to understand the biochemical milieu that could have given birth to life on earth (and elsewhere) and reconstruct primitive cells. One of his scientific dreams is to observe the spontaneous emergence of Darwinian evolution in a chemical system. When not thinking about science, Saurja pursues his love for the written word through poetry and song-writing (and meditating on Leonard Cohen’s music). His other passions are trying to make science easier to understand, and fighting unreason and pseudoscientific thinking with a mixture of calm compassion and swashbuckling spirit.
Roopsha Sengupta is the Editor-in-Chief at ClubSciWri. She did her Ph.D. at the Institute of Molecular Pathology, Vienna and postdoctoral research at the Gurdon Institute, University of Cambridge, UK, specializing in the field of Epigenetics. During her research, she was involved in many exciting discoveries and had the privilege of working and collaborating with a number of inspiring scientists. As an editor for ClubSciWri, she loves working on a wide range of topics and presenting articles coherently, while nudging authors to give their best.
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