The Nobel Prize in Physiology or Medicine 2019 has been awarded jointly to

• William G. Kaelin Jr., Harvard University, Cambridge, MA, USA,
• Sir Peter J. Ratcliffe, John Radcliffe Hospital, Oxford, UK, and
• Gregg L. Semenza, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

“for their discoveries of how cells sense and adapt to oxygen availability.”

 

It has long been unknown how cells adapt to changes in levels of oxygen. The Nobel Laureates discovered that animal cells can sense oxygen and how cells respond to dangerously low oxygen levels (hypoxia). This pathway is an attractive target for the treatment of kidney disease, stroke, cancer, heart disease, and chronic lung disease, among other conditions associated with oxygen imbalance.

Gregg L. Semenza discovered Hypoxia-Inducible Factor 1 (HIF-1). This protein regulates gene expression. William G. Kaelin Jr. and Sir Peter J. Ratcliffe have uncovered the mechanism by which HIF-1 is regulated by oxygen levels. In response to hypoxia, HIF-1 induces the expression of hundreds of genes. These genes orchestrate adaptive responses to hypoxia, including the formation of more blood vessels.

 

William G. Kaelin Jr., born in 1957 in New York, USA, studied math, chemistry, and medicine at Duke University, Durham, NC, USA, where he received his M.D. in 1982. He spent his residency at Johns Hopkins University, Baltimore, MD, USA, and an oncology fellowship at the Dana-Farber Cancer Institute, Boston, MA, USA. He set up his own lab at the Dana-Farber Cancer Institute, Boston, MA, USA, and in 2002, he became a Professor at Harvard Medical School, Boston. He also has served as an Investigator at the Howard Hughes Medical Institute, Chevy Chase, MD, USA, since 1998.

Among other honors, William G. Kaelin Jr. received the Wiley Prize for Biomedical Science in 2014 and the Albert Lasker Award for Basic Medical Research in 2016.

 

Peter J. Ratcliffe, born in 1954 in Lancashire, UK, studied medicine at the University of Cambridge, UK, and St Bartholomew’s Hospital, London, UK. He graduated in 1978 and then went on to study renal medicine at the University of Oxford, UK. In 1989, he obtained a Senior Fellowship from the Wellcome Trust to work on cellular oxygen sensing pathways. He practiced medicine at the John Radcliffe Hospital, Oxford, and has been Full Professor at the University of Oxford since 1996. He also serves as Director of the Target Discovery Institute, University of Oxford, and as Clinical Research Director at the Francis Crick Institute, London.

Peter J. Ratcliffe was knighted in the 2014 New Year Honours for services to clinical medicine. Among other honors, he received the Wiley Prize for Biomedical Science in 2014 and the Albert Lasker Award for Basic Medical Research in 2016.

 

Gregg L. Semenza, born in 1956 in New York, USA, studied biology at Harvard University, Boston, MA, USA. He received his M.D./Ph.D. from the University of Pennsylvania, Philadelphia, USA, in 1984. He did his specialist training in pediatrics at Duke University, Durham, NC, USA, and postdoctoral training at Johns Hopkins University, where he established an independent research group. He became Full Professor at Johns Hopkins University in 1999. Since 2003, he also serves as Director of the Vascular Research Program at the Johns Hopkins Institute for Cell Engineering.

Among other honors, Gregg L. Semenza received the Wiley Prize for Biomedical Science in 2014 and the Albert Lasker Award for Basic Medical Research in 2016

 

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• NobelPrize.org

 

Selected Publications by William G. Kaelin Jr.

• HIFalpha Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O₂ Sensing,
  M. Ivan, K. Kondo, H. Yang, W. Kim, J. Valiando, M. Ohh, A. Salic, J. M. Asara, W. S. Lane, W. G. Kaelin,
  Science 2001, 292, 464–468.
  https://doi.org/10.1126/science.1059817
• Treatment of kidney cancer,
  William G. Kaelin,
  Cancer 2009, 115, 2262–2272.
  https://doi.org/10.1002/cncr.24232

Selected Publications by Sir Peter J. Ratcliffe

• The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis,
  Patrick H. Maxwell, Michael S. Wiesener, Gin-Wen Chang, Steven C. Clifford, Emma C. Vaux, Matthew E. Cockman, Charles C. Wykoff, Christopher W. Pugh, Eamonn R. Maher, Peter J. Ratcliffe,
  Nature 1999, 399, 271–275.
  https://doi.org/10.1038/20459
• Targeting of HIF-alpha to the von Hippel-Lindau Ubiquitylation Complex by O₂-Regulated Prolyl Hydroxylation,
  P. Jaakkola, D. R. Mole, Y.-M. Tian, M. I. Wilson, J. Gielbert, S. J. Gaskell, A. v. Kriegsheim, H. F. Hebestreit, M. Mukherji, C. J. Schofield, P. H. Maxwell, C. W. Pugh, P. J. Ratcliffe,
  Science 2001, 292, 468–472.
  https://doi.org/10.1126/science.1059796

“>Dynamic Combinatorial Chemistry Employing Boronic Acids/Boronate Esters Leads to Potent Oxygenase Inhibitors,
Marina Demetriades, Ivanhoe K. H. Leung, Rasheduzzaman Chowdhury, Mun Chiang Chan, Michael A. McDonough, Kar Kheng Yeoh, Ya-Min Tian, Timothy D. W. Claridge, Peter J. Ratcliffe, Esther C. Y. Woon, Christopher J. Schofield,
Angew. Chem. Int. Ed. 2012, 51, 6672–6675.
https://doi.org/10.1002/anie.201202000

Selected Publications by Gregg L. Semenza

• Hypoxia-inducible nuclear factors bind to an enhancer element located 3′ to the human erythropoietin gene,
  G. L. Semenza, M. K. Nejfelt, S. M. Chi, S. E. Antonarakis,
  Proc. Natl. Acad. Sci. USA 1991, 88, 5680–5684.
  https://doi.org/10.1073/pnas.88.13.5680
• Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O₂ tension,
  G. L. Wang, B. H. Jiang, E. A. Rue, G. L. Semenza,
  Proc. Natl. Acad. Sci. USA 1995, 92, 5510–5514.
  https://doi.org/10.1073/pnas.92.12.5510
• Oxygen homeostasis,
  Gregg L. Semenza,
  Wiley Interdiscip. Rev.: Syst. Biol. Med. 2010, 2, 336–361.
  https://doi.org/10.1002/wsbm.69

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  At normal oxygen levels, HIF-1 is rapidly degraded by a cellular machine called the proteasome, recognized by the 2004 Nobel Prize in Chemistry to Aaron Ciechanover, Avram Hershko, and Irwin Rose. In hypoxia, HIF-1 is protected from degradation.