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Hypoxia researchers win 2019 Nobel Prize in Medicine
Three scientist friends, working separately, share the prestigious prize.
- Nobel recognizes breakthrough insights into cell's perception and response to changes in oxygen levels.
- Too title oxygen is a problem. Also too much.
- Their research unveiled a genuine "textbook discovery."
The 2019 Nobel Prize in Medicine has just been awarded to three scientists from the U.S. and U.K. working independently on the same problem: How cells sense and adapt to oxygen availability. They've unveiled the series of molecular events that allow cells to assess and respond to changing levels of available oxygen, with implications in the treatment of cancer, heart attacks, strokes, anemia, and other diseases.
According to the Nobel Assembly, these seminal discoveries "revealed one of life's most essential adaptive processes." The Assembly's Randall Johnson says, "Scientists often toss around this phrase 'textbook discovery.' But I'd say this is really essentially a textbook discovery." He envisions the discovery as "something basic biology students will be learning about when they study — at aged 12 or 13 or younger — biology, and learn the fundamental ways cells work."
Three scientists with three questions
Image source: Paramonov Alexander/Shutterstock
The three scientists who received the 5 a.m. call from Stockholm are Gregg Semenza (Johns Hopkins University), Sir Peter Ratcliffe (Oxford University), and William Kaelin, Jr. (Dana-Farber Cancer Institute/Harvard University). The three shared their work informally over the years in an ongoing conversation that moved the whole field of study forward. Each had his own reason for pursuing his research area, and their interests reflect the far-ranging impact of their findings.
Semenza wondered exactly what it was that cancer cells were seeking when they spread to new areas in the body. He suspected it was oxygen.
As a kidney specialist, Ratcliffe was intrigued by the manner in which the kidney regulated the production of a particular hormone, erythropoietin (EPO), which affects the production of red, oxygen-carrying blood cells in response to changes in levels of available oxygen. Others considered this to be a not-very-interesting question, but Ratcliffe was intrigued.
For Kaelin, it was a pursuit of answers behind a rare genetic form of cancer, Von Hippel-Lindau syndrome (VHL disease), known to involve exaggerated production levels of EPO, and an excess of blood vessels. He had a hunch it was something in cells' then-mysterious oxygen-sensing mechanism malfunctioning.
Why this is important
Image source: Daniel Prudek /Shutterstock
Cells need oxygen to live, and Earth's air-breathing organisms have developed ways to ensure their cells get the amount of oxygen they need. At high altitudes, for example, we produce more red blood cells to accommodate the relative scarcity of air and combat the onset of hypoxia. While a lack of oxygen can be deadly, so too can too much — it may be that an excess of oxygen can be exploited by some cancers, among other issues.
Human bodies have developed a couple of ways to monitor and respond to changes in oxygen levels. The carotid body associated with the large vessels on both sides of the neck have unique cells that sense oxygen levels, and, as noted above, the body produces more oxygen-carrying cells to maximize delivery of what O2 there is when there's not enough. Production of these oxygen-carrying cells is triggered by the production of erythropoietin (EPO) — it's this system that the Nobel winners explored.
A technical glimpse into a three-part puzzle
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The research that led to the Nobel-awarded discovery began back in the 1990s when, Semenza started studying the EPO gene to learn how its production was being controlled. He identified a DNA segment near the EPO gene that appeared to be regulating its production in response to hypoxia. Most interestingly, this DNA, also spotted around the same time by Ratcliffe, wasn't only in kidney cells known to produce EPO, but in all cells.
Eventually Semenza discovered a protein complex that binds to the DNA depending on the amount of oxygen available, and named it hypoxia-inducible factor, or HIF. HIF turned out to be a pair of different DNA-binding proteins, HIF-1α and ARNT.
The amount of HIF-1α increases when oxygen levels are low, apparently due to an oxygen-related reduction in the effect of ubiquitin, a peptide that normally would bind with and quickly decay HIF-1α.
As a result of his immersion in Von Hippel-Lindau research, Ratcliffe discovered why a lack of oxygen could dampen ubiquitin's bite: HIF-1α is tagged for destruction by ubiquitin via the VHL gene. (An absence of the VHL gene causes the disease by allowing the presence of too much HIF-1α.)
This implied an unknown interaction between the VHL gene and HIF-1α and Kaelin and Ratcliffe worked it out. They realized that at normal oxygen levels, two hydroxyl groups were added to two locations in HIF-1α. Aided by oxygen-sensitive enzymes, VHL thus binds to HIF-1α and moderates the production of EPO and the number red blood cells. With either too little or too much oxygen, this balance is upset.
In all, this daisy-chained sets of research has given us a new insight about our bodies — specifically, of the series of molecular events that constantly help our cells assess and respond to changing levels of oxygen. "Textbook discovery," indeed.
Join Pulitzer Prize-winning reporter and best-selling author Charles Duhigg as he interviews Victoria Montgomery Brown, co-founder and CEO of Big Think, live at 1pm EDT tomorrow.
Richard Feynman once asked a silly question. Two MIT students just answered it.
Here's a fun experiment to try. Go to your pantry and see if you have a box of spaghetti. If you do, take out a noodle. Grab both ends of it and bend it until it breaks in half. How many pieces did it break into? If you got two large pieces and at least one small piece you're not alone.
But science loves a good challenge<p>The mystery remained unsolved until 2005, when French scientists <a href="http://www.lmm.jussieu.fr/~audoly/" target="_blank">Basile Audoly</a> and <a href="http://www.lmm.jussieu.fr/~neukirch/" target="_blank">Sebastien Neukirch </a>won an <a href="https://www.improbable.com/ig/" target="_blank">Ig Nobel Prize</a>, an award given to scientists for real work which is of a less serious nature than the discoveries that win Nobel prizes, for finally determining why this happens. <a href="http://www.lmm.jussieu.fr/spaghetti/audoly_neukirch_fragmentation.pdf" target="_blank">Their paper describing the effect is wonderfully funny to read</a>, as it takes such a banal issue so seriously. </p><p>They demonstrated that when a rod is bent past a certain point, such as when spaghetti is snapped in half by bending it at the ends, a "snapback effect" is created. This causes energy to reverberate from the initial break to other parts of the rod, often leading to a second break elsewhere.</p><p>While this settled the issue of <em>why </em>spaghetti noodles break into three or more pieces, it didn't establish if they always had to break this way. The question of if the snapback could be regulated remained unsettled.</p>
Physicists, being themselves, immediately wanted to try and break pasta into two pieces using this info<p><a href="https://roheiss.wordpress.com/fun/" target="_blank">Ronald Heisser</a> and <a href="https://math.mit.edu/directory/profile.php?pid=1787" target="_blank">Vishal Patil</a>, two graduate students currently at Cornell and MIT respectively, read about Feynman's night of noodle snapping in class and were inspired to try and find what could be done to make sure the pasta always broke in two.</p><p><a href="http://news.mit.edu/2018/mit-mathematicians-solve-age-old-spaghetti-mystery-0813" target="_blank">By placing the noodles in a special machine</a> built for the task and recording the bending with a high-powered camera, the young scientists were able to observe in extreme detail exactly what each change in their snapping method did to the pasta. After breaking more than 500 noodles, they found the solution.</p>
The apparatus the MIT researchers built specifically for the task of snapping hundreds of spaghetti sticks.
(Courtesy of the researchers)
What possible application could this have?<p>The snapback effect is not limited to uncooked pasta noodles and can be applied to rods of all sorts. The discovery of how to cleanly break them in two could be applied to future engineering projects.</p><p>Likewise, knowing how things fragment and fail is always handy to know when you're trying to build things. Carbon Nanotubes, <a href="https://bigthink.com/ideafeed/carbon-nanotube-space-elevator" target="_self">super strong cylinders often hailed as the building material of the future</a>, are also rods which can be better understood thanks to this odd experiment.</p><p>Sometimes big discoveries can be inspired by silly questions. If it hadn't been for Richard Feynman bending noodles seventy years ago, we wouldn't know what we know now about how energy is dispersed through rods and how to control their fracturing. While not all silly questions will lead to such a significant discovery, they can all help us learn.</p>
A study looks at the performance benefits delivered by asthma drugs when they're taken by athletes who don't have asthma.
- One on hand, the most common health condition among Olympic athletes is asthma. On the other, asthmatic athletes regularly outperform their non-asthmatic counterparts.
- A new study assesses the performance-enhancement effects of asthma medication for non-asthmatics.
- The analysis looks at the effects of both allowed and banned asthma medications.
WADA uncertainty<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yMzUzNzU0OS9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTYxMDc4NjUwN30.fFTvRR0yJDLtFhaYiixh5Fa7NK1t1T4CzUM0Yh6KYiA/img.jpg?width=980" id="01b1b" class="rm-shortcode" data-rm-shortcode-id="2fd91a47d91e4d5083449b258a2fd63f" data-rm-shortcode-name="rebelmouse-image" alt="urine sample for drug test" />
Image source: joel bubble ben/Shutterstock<p>When inhaled β-agonists first came out just before the 1972 Olympics, they were immediately banned altogether by the WADA as possible doping substances. Over the years, the WADA has reexamined their use and refined the organization's stance, evidence of the thorniness of finding an equitable position regarding their use. As of January 2020, only three β-agonists are allowed — salbutamol, formoterol, and salmeterol —and only in inhaled form. Oral consumption appears to have a greater effect on performance.</p>
The study<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yMzUzNzU0Ny9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTY1MTIzMDQyMX0.Gk4v-7PCA7NohvJjw12L15p7SumPCY0tLdsSlMrLlGs/img.jpg?width=980" id="d3141" class="rm-shortcode" data-rm-shortcode-id="ebe7b30a315aeffcb4fe739095cf0767" data-rm-shortcode-name="rebelmouse-image" alt="runner at starting position on track" />
Image source: MinDof/Shutterstock<p>Of primary interest to the authors of the study is confirming and measuring the performance improvement to be gained from β-agonists when they're ingested by athletes who don't have asthma.</p><p>The researchers performed a meta-analysis of 34 existing studies documenting 44 randomized trials reporting on 472 participants. The pool of individuals included was broad, encompassing both untrained and elite athletes. In addition, lab tests, as opposed to actual competitions, tracked performance. The authors of the study therefore recommend taking its conclusions with just a grain of salt.</p><p>The effects of both WADA-banned and approved β-agonists were assessed.</p>
Approved β-agonists and non-asthmatic athletes<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yMzUzNzU1MC9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTYxMzkxODk0M30.3RssFwk_tWkHRkEl_tIee02rdq2tLuAePifnngqcIr8/img.jpg?width=980" id="39a99" class="rm-shortcode" data-rm-shortcode-id="b1fe4a580c6d4f8a0fd021d7d6570e2a" data-rm-shortcode-name="rebelmouse-image" alt="vaulter clearing pole" />
Image source: Andrey Yurlov/Shutterstock<p>What the meta-analysis showed is that the currently approved β-agonists didn't significantly improve athletic performance among those without asthma — what very slight benefit they <em>may</em> produce is just enough to prompt the study's authors to write that "it is still uncertain whether approved doses improve anaerobic performance." They note that the tiny effect did increase slightly over multiple weeks of β-agonist intake.</p>
Banned β-agonist and non-asthmatic athletes<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yMzUzNzU1Mi9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTYzNjI3ODU5Mn0.vyoxSE5EYjPGc2ZEbBN8d5F79nSEIiC6TUzTt0ycVqc/img.jpg?width=980" id="de095" class="rm-shortcode" data-rm-shortcode-id="02fdd42dfda8e3665a7b547bb88007ef" data-rm-shortcode-name="rebelmouse-image" alt="swimmer mid stroke" />
Image source: Nejron Photo/Shutterstock<p>The study found that for athletes without asthma, however, the use of currently banned β-agonists did indeed result in enhanced performance. The authors write, "Our meta-analysis shows that β2-agonists improve anaerobic performance by 5%, an improvement that would change the outcome of most athletic competitions."</p><p>That 5 percent is an average: 70-meter sprint performance was improved by 3 percent, while strength performance, MVC (maximal voluntary contraction), was improved by 6 percent.</p><p>The analysis also revealed that different results were produced by different methods of ingestion. The percentages cited above were seen when a β-agonist was ingested orally. The effect was less pronounced when the banned substances were inhaled.</p><p>Given the difference between the results for allowed and banned β-agonists, the study's conclusions suggest that the WADA has it about right, at least in terms of selection of allowable β-agonists, as well as the allowable dosage method.</p>
Takeaway<p>The study, say its authors, "should be of interest to WADA and anyone who is interested in equal opportunities in competitive sports." Its results clearly support vigilance, with the report concluding: "The use of β2-agonists in athletes should be regulated and limited to those with an asthma diagnosis documented with objective tests."</p>
Certain water beetles can escape from frogs after being consumed.
- A Japanese scientist shows that some beetles can wiggle out of frog's butts after being eaten whole.
- The research suggests the beetle can get out in as little as 7 minutes.
- Most of the beetles swallowed in the experiment survived with no complications after being excreted.