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Bonus Episode 54 Transcript
Cells & Oxygen Availability | Nobel Special
Kevin Patton: The singer/songwriter Bjork has said, “Singing is like a celebration of oxygen.”
Aileen: Welcome to The A&P Professor, a few minutes to focus on teaching human anatomy and physiology, with host, Kevin Patton.
Kevin Patton: In this special episode, I summarize the 2019 Nobel Prize in Physiology or Medicine.
Kevin Patton: As I mentioned in the intro, this is a special episode. It’s a bonus episode that is being released prior to regular episode number 54. As a matter of fact, it’s coming out prior to the preview of the regular episode 54, so that makes this really special because it’s a pre-preview of the regular episode, and it’s coming out on the same day as what we’re going to cover, and that is the 2019 Nobel Prize in the category of physiology or medicine. I wanted to get this information out to you right away because it’s in the news right now, and our students may be bringing it up, or we may want to be bringing it up to our students to help relate to what’s going on in the news.
Kevin Patton: So I’m going to be sharing with you the press release that was sent out, and this does a really good job of filling in a little bit of the backstory, and it’s arranged in sections, so I’m going to chunk it into segments in this a bonus episode, the same way that they do in the press release. And then, after that, I’m going to come back and briefly discuss how we can use this news in our A&P course. So let’s roll it.
Kevin Patton: Marketing support for this podcast is provided by HAPS, the Human Anatomy and Physiology Society, promoting excellence in the teaching of human anatomy and physiology for over 30 years. Go visit HAPS at theapprofessor.org/HAPS. That’s H-A-P-S.
Kevin Patton: This is from a press release dated October 7, 2019, and it says: The Nobel Assembly at Karolinska Institutet has 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.
Kevin Patton: 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.
Kevin Patton: 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.
Kevin Patton: Oxygen, with the formula O2, makes up about one fifth of the 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 the large blood vessels on both sides of the neck, contains specialized cells that sense the blood 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.
Kevin Patton: In addition to the carotid body=controlled rapid adaptation to low oxygen levels, that is in hypoxia, there are other fundamental physiological adaptations. A key physiological response to hypoxia is the rise in levels of the hormone erythropoietin, or EPO, which leads to increased production of red blood cells. That is 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.
Kevin Patton: 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 oxygen 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.
Kevin Patton: 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, or 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-1 alpha and ARNT. Now the researchers could begin solving the puzzle, allowing them to understand which additional components were involved and how the machinery works.
Kevin Patton: A searchable transcript and a captioned audiogram of this special bonus episode are funded by AAA, the American Association for Anatomy. Find them at anatomy.org.
Kevin Patton: When oxygen levels are high, cells contain very little HIF-1 alpha. However, when oxygen levels are low, the amount of HIF-1 alpha increases so that it can bind to and thus regulate the EPO gene, as well as other genes with HIF-binding DNA segments. Several research groups showed that HIF-1 alpha, which is normally rapidly degraded, is protected from degradation in hypoxia. At normal oxygen levels, a cellular machine called the proteasome, 2004 Nobel Prize in Chemistry to Aaron Ciechanover, Avram Hershko and Irwin Rose, degrades HIF-1 alpha. Under such conditions a small peptide, ubiquitin, is added to the HIF-1 alpha protein. Ubiquitin functions as a tag for proteins destined for degradation in the proteasome. How ubiquitin binds to HIF-1 alpha in an oxygen dependent manner remained a central question.
Kevin Patton: The answer came from an unexpected direction. At about the same time as Semenza and Radcliffe were exploring their regulation of the EPO gene, cancer researcher William Kaelin, Jr was researching an inherited syndrome, Von Hippel-Lindau disease, also called 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. Radcliffe and his research group then made a key discovery demonstrating that VHL can physically interact with HIF-1 alpha and is required for its degradation at normal oxygen levels. This conclusively linked VHL to HIF-1 alpha.
Kevin Patton: 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-1 alpha. The search focused on a specific portion of the HIF-1 alpha protein known to be important for VHL dependent degradation, and both Kaelin and Radcliffe 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-1 alpha. This protein modification, called prolyl hydroxylation, allows VHL to recognize and bind to HIF-1 alpha, and thus explained how normal oxygen levels control rapid HIF-1 alpha degradation with the help of oxygen sensitive enzymes, so-called prolyl hydroxylases. Further research by Radcliffe and others identified the responsible prolyl hydroxylases. It was also shown that the gene activating function of HIF-1 alpha was regulated by oxygen dependent hydroxylation. The Nobel Laureates had now elucidated the oxygen sensing mechanism and had shown how it worked.
Kevin Patton: 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 oxygen sensing machinery. Oxygen sensing has even been shown to be essential during fetal development for controlling normal blood vessel formation and placenta development.
Kevin Patton: Oxygen sensing is central to a large number of diseases. 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.
Kevin Patton: The free distribution of this podcast episode is sponsored by The Master of Science in Human Anatomy and Physiology Instruction. The HAPI degree. I’m on the faculty of this program so I know the incredible value it is for all A&P teachers. Check out this online graduate program at nycc.edu/hapi. That’s H-A-P-I. Or click the link in the show notes or episode page.
Kevin Patton: Yes, these are significant contributions to our scientific knowledge, but what does this have to do with A&P, and maybe more to the point, what does this have to do with teaching A&P?
Kevin Patton: Well, think about how this story has unfolded. It’s all about oxygen use, which is a central core concept of what we do in A&, right? It is a central part of the story that we tell as we tell the story of the human body. And it ties together a number of different plots in this story that you may be covering in your course. For example, erythropoiesis and the role of EPO. The regulation of respiratory ventilation. The fact that every cell has oxygen needs and every cell has multiple regulatory factors that help address those needs as conditions change. I talk about proteasomes when I’m discussing, actually it comes up in several different places, but it’s introduced when I first start talking about the organelles of the cell and which organelles are going to be part of our story. So, proteasomes are part of these discoveries, that part of this story.
Kevin Patton: And all of these different things, and those are just a few, there are many themes that are touched upon here, but all of those tie into even broader themes of the stories that we tell, such as the roles of genes in the body. The roles of enzymatic regulation of metabolism. Of course, the really big theme of homeostasis. So, knowing the story of these particular discoveries is useful for our own background because we’re going to be telling different elements of this story, and for us to know that more deeply than the actual story that we’re telling make our story better. And not only that, it gives us some information that we can pull out of our pocket when we need to, to maybe fill gaps in the story or if there are questions about why things in our story are so we can address the students and say, well, there’s more to it than you might imagine. And, for example, there was a Nobel Prize that was awarded for the people that discovered this or that or the other aspect of this.
Kevin Patton: That gets to the idea that this is in the news. So right now, and over the next week or two, this is something that students would have either recently heard about or will be soon hearing about in the mainstream media, and even some of the side stream media are going to be talking about the Nobel Prizes. And whenever we can peak student interest in talking about things that are actually in the regular general news that is part of “real life,” that kind of… it helps satisfy that longing of students to understand how all these things they’re learning in A& P has anything to do with them. And, not only their own bodies and their own understanding of their own biology, but applications in clinical sciences and so on, which is what they’re looking toward as they’re looking toward their health professional career.
Kevin Patton: And Nobel Prizes are among many prizes and citations and acknowledgments of scientific discovery. But the Nobel Prize is culturally significant. Everybody knows about the Nobel Prize. And if they don’t, they should. Just to be culturally aware, and certainly aware of cultural icons within the scientific community. And yes, it’s not the only one. And yes, there are issues about the fact that these don’t always go to a diverse group of Laureates, and so on. Maybe that reflects what’s going on in science or maybe it’s an issue with the prizes themselves, but it also can serve as a point at which we can discuss things. And I’m going to circle back to that in just a second.
Kevin Patton: The Nobel Prize has become one of the touch points that the general public has for science in general and what some of the big ideas in science are. So if you can say that, well, this discovery was awarded a Nobel Prize, then that’s emphasizing that this is important for us to know. And isn’t that useful in teaching anatomy and physiology? To say, it’s not just me that thinks this is important, it’s the Nobel Prize Committee thinks it’s important.
Kevin Patton: It’s for that reason that I always mention the Nobel Prize in my course and I ask students to look at a list of Nobel Prizes that I have, that I use, that lists the Nobel Prizes that have to do with things that we’re going to be looking at in our course. Going all the way back to the beginning of the Nobel Prizes. It’s not just related to the concepts we’re going to be covering and sort of a preview of that, but I also refer back to them as we proceed through this story and say, “Remember when you’re talking about Nobel prizes and we looked at that list, well guess what? Here’s one of those that we looked at. Here’s one that’s on that list.” It helps emphasize the importance of some of those core concepts, when we get to them, as we go through them.
Kevin Patton: Doing it at the beginning of the course, I discuss the Nobel Prizes in the context of what science is, which I do at the very beginning of my course. What is science as a discipline? And how does it work? And how does it work in the context of society, in culture of our time? Or the society and culture of any time in history?
Kevin Patton: I also briefly discuss the patterns and the issues. So remember, I said I’d circle back to this. So yeah, the patterns and the issues. For example, I have them look at the list and ask them, how many of these Nobel Laureates are women? Not very many. I don’t think you have to look at the list to know that. So is that changing as time goes on? Is it getting better? Is it getting worse? That is, more diverse or not more diverse? How many of them are Europeans? That’s another issue that could be discussed, or at least something to point out to make students aware of the questions and the importance of those questions.
Kevin Patton: Another thing we sometimes look at is, are all the major ideas in science addressed? Even the categories themselves, maybe there should be more categories or maybe they should be broader categories. But then of course if you do that, then, since we only have one award given every year in each category, then that might narrow it. If we have too broad a category, then it’s, how often will we get one in biology? Or get one in, specifically, in human anatomy and physiology?
Kevin Patton: These are some things that can be addressed, some things or questions and so on. And I do want to point out that NobelPrize.org, which I’ll have a link to in the show notes and episode page, has a lot of resources. Not only on these discoveries, but all of the discoveries in the history of the Nobel Prizes, and many of those resources, which include videos and images and diagrams and background information, most of those are available free for use in the classroom. I’ll have lots of those links at the show notes and episode page, but a lot of them you can access just by going directly to NobelPrize.org.
Kevin Patton: There are a lot of links in the show notes and at the episode page at theapprofessor.org, in case you want to further explore any of the ideas or look for resources that I mentioned in this podcast, or if you want to visit our sponsors.
Kevin Patton: And there are many ways to stay connected to this podcast and get new episodes as soon as they’re released. Just go to theapprofessor.org/listen to explore the many ways you can do this. And you’re always encouraged to call in with your questions, comments and ideas at the podcast hotline. That’s 1-833-LION-DEN or 1-833-546-6336. Or send a recording or written message to email@example.com. And you can follow this podcast in Twitter, Facebook, or Instagram using the handle @theappprofessor. I’ll see you down the road.
Aileen: The A&P Professor is hosted by Kevin Patton. Professor, blogger and textbook author in human anatomy and physiology.
Kevin Patton: This episode is not meant for use in your eyes.
This podcast is sponsored by the
Human Anatomy & Physiology Society
This podcast is sponsored by the
Master of Science in
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