Massachusetts Institute of Technology, Cambridge, USA
Esther Duflo
Massachusetts Institute of Technology, Cambridge, USA
Michael Kremer
Harvard University, Cambridge, USA
“for their experimental approach to alleviating global poverty”
Their research is helping us fight poverty
The research conducted by this year’s Laureates has considerably improved our ability to fight global poverty. In just two decades, their new experiment-based approach has transformed development economics, which is now a flourishing field of research.
Despite recent dramatic improvements, one of humanity’s most urgent issues is the reduction of global poverty, in all its forms. More than 700 million people still subsist on extremely low incomes. Every year, around five million children under the age of five still die of diseases that could often have been prevented or cured with inexpensive treatments. Half of the world’s children still leave school without basic literacy and numeracy skills.
This year’s Laureates have introduced a new approach to obtaining reliable answers about the best ways to fight global poverty. In brief, it involves dividing this issue into smaller, more manageable, questions – for example, the most effective interventions for improving educational outcomes or child health. They have shown that these smaller, more precise, questions are often best answered via carefully designed experiments among the people who are most affected.
In the mid-1990s, Michael Kremer and his colleagues demonstrated how powerful this approach can be, using field experiments to test a range of interventions that could improve school results in western Kenya.
Abhijit Banerjee and Esther Duflo, often with Michael Kremer, soon performed similar studies of other issues and in other countries. Their experimental research methods now entirely dominate development economics.
The Laureates’ research findings – and those of the researchers following in their footsteps – have dramatically improved our ability to fight poverty in practice. As a direct result of one of their studies, more than five million Indian children have benefitted from effective programmes of remedial tutoring in schools. Another example is the heavy subsidies for preventive healthcare that have been introduced in many countries.
These are just two examples of how this new research has already helped to alleviate global poverty. It also has great potential to further improve the lives of the worst-off people around the world.
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 in New York, USA. Ph.D. 1992 from Harvard University, Cambridge, USA. Gates Professor of Developing Societies at Harvard University, Cambridge, USA.
The Prize amount:9 million Swedish krona, to be shared equally between the Laureates
Further information:http://www.kva.se and http://www.nobelprize.org
Experts: Jakob Svensson, +46 70 177 67 17, jakob.svensson@iies.su.se, Torsten Persson, +46 79 313 39 04, torsten.persson@iies.su.se, members of the Committee for the Prize in Economic Sciences in memory of Alfred Nobel
The Royal Swedish Academy of Sciences, founded in 1739, is an independent organisation whose overall objective is to promote the sciences and strengthen their influence in society. The Academy takes special responsibility for the natural sciences and mathematics, but endeavours to promote the exchange of ideas between various disciplines.
Nobel Prize® is a registered trademark of the Nobel Foundation.
The Norwegian Nobel Committee has decided to award the Nobel Peace Prize for 2019 to Ethiopian Prime Minister Abiy Ahmed Ali for his efforts to achieve peace and international cooperation, and in particular for his decisive initiative to resolve the border conflict with neighbouring Eritrea. The prize is also meant to recognise all the stakeholders working for peace and reconciliation in Ethiopia and in the East and Northeast African regions.
When Abiy Ahmed became Prime Minister in April 2018, he made it clear that he wished to resume peace talks with Eritrea. In close cooperation with Isaias Afwerki, the President of Eritrea, Abiy Ahmed quickly worked out the principles of a peace agreement to end the long “no peace, no war” stalemate between the two countries. These principles are set out in the declarations that Prime Minister Abiy and President Afwerki signed in Asmara and Jeddah last July and September. An important premise for the breakthrough was Abiy Ahmed’s unconditional willingness to accept the arbitration ruling of an international boundary commission in 2002.
Peace does not arise from the actions of one party alone. When Prime Minister Abiy reached out his hand, President Afwerki grasped it, and helped to formalise the peace process between the two countries. The Norwegian Nobel Committee hopes the peace agreement will help to bring about positive change for the entire populations of Ethiopia and Eritrea.
In Ethiopia, even if much work remains, Abiy Ahmed has initiated important reforms that give many citizens hope for a better life and a brighter future. He spent his first 100 days as Prime Minister lifting the country’s state of emergency, granting amnesty to thousands of political prisoners, discontinuing media censorship, legalising outlawed opposition groups, dismissing military and civilian leaders who were suspected of corruption, and significantly increasing the influence of women in Ethiopian political and community life. He has also pledged to strengthen democracy by holding free and fair elections.
In the wake of the peace process with Eritrea, Prime Minister Abiy has engaged in other peace and reconciliation processes in East and Northeast Africa. In September 2018 he and his government contributed actively to the normalisation of diplomatic relations between Eritrea and Djibouti after many years of political hostility. Additionally, Abiy Ahmed has sought to mediate between Kenya and Somalia in their protracted conflict over rights to a disputed marine area. There is now hope for a resolution to this conflict. In Sudan, the military regime and the opposition have returned to the negotiating table. On the 17th of August, they released a joint draft of a new constitution intended to secure a peaceful transition to civil rule in the country. Prime Minister Abiy played a key role in the process that led to the agreement.
Ethiopia is a country of many different languages and peoples. Lately, old ethnic rivalries have flared up. According to international observers, up to three million Ethiopians may be internally displaced. That is in addition to the million or so refugees and asylum seekers from neighbouring countries. As Prime Minister, Abiy Ahmed has sought to promote reconciliation, solidarity and social justice. However, many challenges remain unresolved. Ethnic strife continues to escalate, and we have seen troubling examples of this in recent weeks and months. No doubt some people will think this year’s prize is being awarded too early. The Norwegian Nobel Committee believes it is now that Abiy Ahmed’s efforts deserve recognition and need encouragement.
The Norwegian Nobel Committee hopes that the Nobel Peace Prize will strengthen Prime Minister Abiy in his important work for peace and reconciliation. Ethiopia is Africa’s second most populous country and has East Africa’s largest economy. A peaceful, stable and successful Ethiopia will have many positive side-effects, and will help to strengthen fraternity among nations and peoples in the region. With the provisions of Alfred Nobel’s will firmly in mind, the Norwegian Nobel Committee sees Abiy Ahmed as the person who in the preceding year has done the most to deserve the Nobel Peace Prize for 2019.
The Nobel Prize in Literature for 2018 is awarded to the Polish author Olga Tokarczuk "for a narrative imagination that with encyclopedic passion represents the crossing of boundaries as a form of life."
Nobel Prize in Literature 2019
Peter Handke
The Nobel Prize in Literature for 2019 is awarded to the Austrian author Peter Handke "for an influential work that with linguistic ingenuity has explored the periphery and the specificity of human experience."
William G. Kaelin Jr., Sir Peter J. Ratcliffe and Gregg L. Semenza
for their discoveries of how cells sense and adapt to oxygen availability
SUMMARY
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 this year’s 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 enters the scene
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.
VHL: an unexpected partner
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.
Oxygen sHIFts the balance
Many pieces had fallen into place, but what was still lacking was an understanding of how O2 levels regulate the interaction between VHL and HIF-1α. The search focused on a specific portion of the HIF-1α protein known to be important for VHL-dependent degradation, and both Kaelin and Ratcliffe suspected that the key to O2-sensing resided somewhere in this protein domain. In 2001, in two simultaneously published articles they showed that under normal oxygen levels, hydroxyl groups are added at two specific positions in HIF-1α (Figure 1). 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 (Figure 2). 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.
Key publications
Semenza, G.L, Nejfelt, M.K., Chi, S.M. & Antonarakis, S.E. (1991). Hypoxia-inducible nuclear factors bind to an enhancer element located 3’ to the human erythropoietin gene. Proc Natl Acad Sci USA, 88, 5680-5684
Wang, G.L., Jiang, B.-H., Rue, E.A. & Semenza, G.L. (1995). Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA, 92, 5510-5514
Ivan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J.M., Lane, W.S. & Kaelin Jr., W.G. (2001) HIFa targeted for VHL-mediated destruction by proline hydroxylation: Implications for O2 sensing. Science, 292, 464-468
Jaakkola, P., Mole, D.R., Tian, Y.-M., Wilson, M.I., Gielbert, J., Gaskell, S.J., von Kriegsheim, A., Heberstreit, H.F., Mukherji, M., Schofield, C.J., Maxwell, P.H., Pugh, C.W. & Ratcliffe, P.J. (2001). Targeting of HIF-α to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science, 292, 468-472
William G. Kaelin, Jr. was born in 1957 in New York. He obtained an M.D. from Duke University, Durham. He did his specialist training in internal medicine and oncology at Johns Hopkins University, Baltimore, and at the Dana-Farber Cancer Institute, Boston. He established his own research lab at the Dana-Farber Cancer Institute and became a full professor at Harvard Medical School in 2002. He is an Investigator of the Howard Hughes Medical Institute since 1998.
Sir Peter J. Ratcliffe was born in 1954 in Lancashire, United Kingdom. He studied medicine at Gonville and Caius College at Cambridge University and did his specialist training in nephrology at Oxford. He established an independent research group at Oxford University and became a full professor in 1996. He is the Director of Clinical Research at Francis Crick Institute, London, Director for Target Discovery Institute in Oxford and Member of the Ludwig Institute for Cancer Research.
Gregg L. Semenza was born in 1956 in New York. He obtained his B.A. in Biology from Harvard University, Boston. He received an MD/PhD degree from the University of Pennsylvania, School of Medicine, Philadelphia in 1984 and trained as a specialist in pediatrics at Duke University, Durham. He did postdoctoral training at Johns Hopkins University, Baltimore where he also established an independent research group. He became a full professor at the Johns Hopkins University in 1999 and since 2003 is the Director of the Vascular Research Program at the Johns Hopkins Institute for Cell Engineering.
The Nobel Assembly, consisting of 50 professors at Karolinska Institutet, awards the Nobel Prize in Physiology or Medicine. Its Nobel Committee evaluates the nominations. Since 1901 the Nobel Prize has been awarded to scientists who have made the most important discoveries for the benefit of humankind.
Nobel Prize® is the registered trademark of the Nobel Foundation
