In May this year, I wrote a blog about the wonderful work that economist Esther Duflo of MIT has done in an effort to alleviate poverty in developing countries. I’m happy to hear that Duflo and two of her research peers have been awarded the 2019 Nobel Prize in Economic Science, a well deserved recognition for showing the way in turning the “dismal science” into a useful science.

Bio of the Economics Laureates

Abhijit Banerjee: born 1961 in Mumbai, India. Ph.D. 1988 from Harvard University, Cambridge, USA. Ford Foundation International Professor of Economics at Massachusetts Institute of Technology, Cambridge, USA.

Esther Duflo, born 1972 in Paris, France. Ph.D. 1999 from Massachusetts Institute of Technology, Cambridge, USA. Abdul Latif Jameel Professor of Poverty Alleviation and Development Economics at Massachusetts Institute of Technology, Cambridge, USA.

Michael Kremer, born 1964. Ph.D. 1992 from Harvard University, Cambridge, USA. Gates Professor of Developing Societies at Harvard University, Cambridge, USA.

Read the Economics Nobel Prize press release here: https://www.nobelprize.org/prizes/economic-sciences/2019/press-release/

****

The 2019 Nobel Prize in Medicine or Physiology

If I were to caption this year’s Nobel Prize in Medicine, it would be “life-saving science”, for this is what the scientists sharing this year’s prize have achieved – by unlocking the mystery of how cells sense and adapt to changing oxygen levels, thereby opening the door to the development of new drugs to treat a wide range of life-threatening diseases that degrades the natural cellular level of oxygen. Below is a summary of the stunning achievements of Americans William G. Kaelin Jr. Gregg L. Semenza and Briton, Sir Peter J. Ratcliffe.

Decoding Oxygen Sensing in Cells

We do not see them at work, much less think about them. There are nearly 40 trillion cells in the human body, all working tirelessly and invisibly to perform the daily miracle called life. Oxygen is central to the health of each cell. Too little or too much oxygen can lead to cell damage and in severe cases, death.

Cells are uniquely equipped to sense and respond to changing oxygen levels in a life-preserving manner, most of the time. Trouble occurs when this machinery malfunctions. For example, patients with chronic renal failure often suffer from severe anemia due to decreased levels of oxygen in kidney cells. Those who suffer from turmors also experience low cellular oxygen levels as rapid tumor growth rapidly depletes oxygen levels inside the tumor. And as is well known, stroke and heart attacks are often associated to inadequate oxygen to the brain and heart. Clearly, understanding how cells function with regards to oxygen sensing is central to the development of drugs for treating a variety of diseases. Thanks to the work of Kaelin Jr., Ratcliffe and Semenza, we now have a much better understanding of how cells regulate gene expression in response to varying levels of oxygen.

The Key Discoveries
It turns out the cell’s oxygen-sensing machinery relies on feedback loops and involve a cast of characters such as genes, proteins, hormones and enzymes. Here’s the complex way they work together.

The HIF Protein Complex and the EPO Hormone

The crucial molecule in the loop that matches cell physiology to oxygen availability is a protein complex called hypoxia-inducible factor (HIF). (hypoxia is a condition of low oxygen levels in the blood going into the tissues). HIF actually consists of two proteins, now known as HIF-1 alpha and ARNT. ARNT is always present in a cell, but the level of HIF-1 alpha depends on the amount of oxygen present. When oxygen levels are high, cells contain very little HIF-1 alpha. When oxygen levels are low, the amount of HIF-1 alpha increases.

HIF-1α works in partnership with a hormone called erythropoietin, or EPO. EPO triggers erythropoiesis, the process that generates red blood corpuscles. These are the cells that carry oxygen in the bloodstream. In the 1990s, Semenza, who was working at John Hopkins University, found that HIF-1 alpha regulates oxygen levels by binding to or detaching from a stretch of DNA within the EPO gene.

The VHL Protein Complex

What then regulates HIF? This was Dr. Kaelin’s contribution. It was he who discovered that HIF actually consists of two proteins, HIF-1 alpha and ARNT. Kaelin also found that another protein, VHL, regulates how levels of HIF in a cell are controlled by oxygen levels. 

VHL is short for von Hippel-Lindau’s disease, a genetic disease that exposes families with the genetic mutations to increased risk of certain cancers. While researching on the VHL disease, Kaelin discovered that a non-functional VHL-encoding gene caused many HIF-regulated genes to go into overdrive—which is the underlying cause of the tumours in question (recall that high HIF-1 alpha means low oxygen level). When the VHL gene was reintroduced in cancer cells, normal levels were restored. This was an important clue indicating that VHL-HIF interaction is part of the cell’s oxygen-sensing machinery.

The pieces of the puzzle were then put together by Sir Peter Ratcliffe who works at Oxford University. His experiments confirmed that VHL and HIF-1 alpha interact with one another, mediated through certain enzymes called proteasomes, and that this interaction makes HIF-1 alpha susceptible to degradation.

As I said earlier, the research of Kaelin, Ratcliffe and Semenza and scores of other scientists working in this area, is paving the way for the much hoped-for drug discoveries. Randall Johnson, a member of the Nobel Assembly, adds that the work of the laureates is a “textbook discovery” of seminal importance, something that students would start learning at the most basic levels of biology education.

Press Release of the 2019 Nobel Prize in Physiology or Medicine: https://www.nobelprize.org/prizes/medicine/2019/press-release/