快讯！2019年诺贝尔生理学或医学奖揭晓！三位科学家获得殊荣！

药时代 2020-09-08

北京时间2019年10月7日，星期一，北京时间下午5时30分，瑞典斯德哥尔摩当地时间7日上午11时30分，瑞典卡罗林斯卡医学院颁布2019年诺贝尔生理学或医学奖获奖名单。

The 2019 Nobel Prize in Physiology or Medicine has been awarded jointly to William G. Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L. Semenza “for their discoveries of how cells sense and adapt to oxygen availability.”

2019年诺贝尔生理学或医学奖被共同授予

William G. Kaelin Jr

Sir Peter J. Ratcliffe

Gregg L. Semenza

以表彰他们对细胞如何感知和适应氧气供应的发现

药时代热烈祝贺三位获奖者！

Press release

2019-10-07

The Nobel Assembly at Karolinska Institutet

has today decided to award

the 2019 Nobel Prize in Physiology or Medicine

jointly to

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 O2remained 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 O2levels 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

Maxwell, P.H., Wiesener, M.S., Chang, G.-W., Clifford, S.C., Vaux, E.C., Cockman, M.E., Wykoff, C.C., Pugh, C.W., Maher, E.R. & Ratcliffe, P.J. (1999). The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature, 399, 271-275

Mircea, I., 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

Jakkola, 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.

Illustrations: © The Nobel Committee for Physiology or Medicine. Illustrator: Mattias Karlén

激动人心的十月份，有人将收到诺贝尔委员会秘书托马斯·佩尔曼（Thomas Perlmann）的电话，从他那里得到令人振奋的消息。收到电话的下一位会是您码？

关注药时代，我们跟踪报道，及时揭晓！

（Photo: Yanan Li）

关于诺贝尔生理学或医学奖的数据

1901年首届诺贝尔生理学或医学奖颁给了德国医学家Emil Adolf von Behring，表彰他研究了白喉的血清疗法。

自1901年以来，诺贝尔生理学或医学奖共颁发了109次。以下年份空缺：1915, 1916, 1917, 1918, 1921, 1925, 1940, 1941 和 1942。
39 次获奖者仅一人
33 次两人分享
37 次三人分享
自1901年到2018年，共216位获奖者。
216位获奖者的平均年龄为58岁。
最年轻的获奖者是Frederick G. Banting, 他在1923年获奖时年仅32岁。

（图片来源：维基百科）

年纪最大的获奖者是Peyton Rous，1966年获奖时87岁高龄。
216位获奖者中，仅有12位女性。其中，只有Barabara McClintock一人独得诺奖。2015年10月5日，中国女科学家屠呦呦和一名日本科学家及一名爱尔兰科学家分享2015年诺贝尔生理学或医学奖，以表彰他们在疟疾治疗研究中取得的成就。屠呦呦由此成为迄今为止第一位获得诺贝尔科学奖项的本土中国科学家、第一位获得诺贝尔生理医学奖的华人科学家，由此实现了中国人在自然科学领域诺贝尔奖零的突破。

（图片来源：诺贝尔奖官网）

最全面统计 | 119年诺贝尔生理医学奖全面盘点：女性12位，最年轻的只有32岁

该奖项中，没有人两次、多次获奖。
夫妻档:
Gerty Cori 和 Carl Cori, 1947年。
May-Britt Moser 和 Edvard I. Moser, 2014年。
父子档:
Hans von Euler-Chelpin (化学奖) 和 Ulf von Euler (医学奖) 。
Arthur Kornberg (医学奖) 和 Roger D. Kornberg (化学奖)。
兄弟档:
Jan Tinbergen (经济学奖) 和 Nikolaas Tinbergen (医学奖)。
一名获得者被当局迫使拒绝接受诺贝尔奖。阿道夫·希特勒禁止三名德国获奖者接受诺贝尔奖，包括获得1939年诺贝尔生理学或医学奖的Gerhard Domagk。另外两位为诺贝尔化学奖获得者，Richard Kuhn (1938) 和 Adolf Butenandt (1939)。三人战后都可获得诺贝尔奖证书和奖牌，但没有奖金。
主要颁发给5个领域，分别是生理学、遗传学、生物化学、代谢学及免疫学
获奖国家前5名依次是美国、英国、德国、法国和瑞典。
移民到美国的获奖者最多，达到22位。
获奖者受教育学校前5名依次是哈佛大学、剑桥大学、哥伦比亚大学、约翰霍普金斯大学、加利福尼亚大学。
获奖者最喜欢的工作单位前5名依次是哈佛大学、洛克菲勒大学、剑桥大学、巴斯德研究所、加利福尼亚大学。
澳大利亚的神经学家Sigmund Freud被提名诺贝尔生理学或医学奖多达32次却终未获奖。

其它奖项具体揭晓时间：

物理学奖（The Nobel Prize in Physics）：最早于斯德哥尔摩时间10月8日11时45分揭晓（北京时间10月8日17时45分）；
化学奖（The Nobel Prize in Chemistry）：最早于斯德哥尔摩时间10月9日11时45分揭晓（北京时间10月9日17时45分）；
文学奖（The Nobel Prize in Literature）：最早于斯德哥尔摩时间10月10日13时00分揭晓（北京时间10月9日19时00分）。瑞典学院将宣布2018年和2019年诺贝尔文学奖。
和平奖（The Nobel Peace Prize）：最早于斯德哥尔摩时间10月11日11时00分揭晓（北京时间10月11日17时00分）；
经济学奖（The Sveriges Riksbank Prize in Economic Sciences in Memory of Alfred Nobel ）：
最早于斯德哥尔摩时间10月14日11时45分揭晓（北京时间10月14日17时45分）。