The Overlooked Link Between Two of This Year’s Nobel Prizes

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Article</title><path fill="currentColor" d="M2.1 0h45.8v50L25.5 37.5 2.1 50V0z"></path></svg> <div class='h6t uppercase kern ml1 mv0 theme__text'> Read Later </div> </button> <div class='q-tooltip hidden force-mobile-placement w-32 ml-n16 -top-10'> <div class='q-tooltip-content'> <div class='q-tooltip-arrow -bottom-3'></div> <div class='q-tooltip-inner py-1 pl-1' role='tooltip'> <div class='h6t relative z1 uppercase kern--w mx025'> <span class='small no-wrap'>Read Later</span> </div> </div> </div> </div> </div> </li> </ul> <div class='nav__local__progress absolute fit-b fit-l fit-r z1 theme__accent'> <span class='block' style='transform: translateX(-100%);' data-role='content-progress-bar'></span> </div> </div> </div> <div id='postBody' class='theme__background-background theme__text'> <section class='post__title__wrapper relative '> <section class='outer fill-h relative outer--content '> <div class='mha container--s'> <div class='header-spacer'></div> <div class='post__title pv1 scale1 mha'> <div class='scale0'> <div class='mb1 pb025 mt0 h6t post__title__kicker '> <a class="kicker theme__accent theme__text-hover uppercase" href="/abstractions/">Abstractions blog</a> </div> <h1 class='post__title__title mv025 noe theme__text' >The Overlooked Link Between Two of This Year’s Nobel Prizes</h1> <div class='post__title__author-date h5 mt1'> <div class='byline relative flex flex-items-start merriweather mv025 mr1 gray3 h6t theme__text-hover'> <em class='byline__by gray4 mr075'>By </em> <a href='https://www.quantamagazine.org/authors/veronique-greenwood/'> <span class='byline__author uppercase kern light small'>Veronique Greenwood</span> </a> </div> <p class="h6 mv1 pv025 o6"><em>November 27, 2017</em></p> </div> <div class='post__title__meta flex flex-wrap flex-items-start'> <div class='post__title__excerpt wysiwyg p italic mb1 mt025 pr2 o4 theme__text ' > To better understand the molecules described by the latest prize in medicine, we will need the technique recognized by the latest prize in chemistry. </div> <div class='post__title__actions h5 mt025 flex-auto flex flex-items-center'> <div class='comments-button mr05 flex flex-items-center theme__accent-hover h5 theme__accent' data-name='comment-bubble' > <a href='#comments' class='flex flex-items-center pangram'> <svg viewbox='0 0 50 50' enable-background='new 0 0 50 50' xmlns='http://www.w3.org/2000/svg' class=''><title>Comment</title><path fill='currentColor' d='M9.4 4.2h31.2c8.6 0 9.4 7 9.4 15.6s-.7 15.6-9.4 15.6h-2.2l-.9 9.4-18.8-9.4H9.4c-8.6 0-9.4-7-9.4-15.6S.7 4.2 9.4 4.2z'></path></svg> <div> <span class='comments-button__count ml075 small mbold disqus-comment-count' data-disqus-identifier='53294 https://www.quantamagazine.org/?p=53294'></span> </div> </a> </div> <span class='o-divider mh075 relative'></span> <div class='relative'> <button class='bookmark-button mh05 flex flex-items-center theme__accent-hover ' data-toggle-hover='tooltip' data-id='53294' data-active-class='' aria-expanded='false'> <svg class="icon" viewbox="0 0 50 50" enable-background="new 0 0 50 50" xmlns="http://www.w3.org/2000/svg"><title>Save Article</title><path fill="currentColor" d="M2.1 0h45.8v50L25.5 37.5 2.1 50V0z"></path></svg> </button> <div class='q-tooltip hidden force-mobile-placement w-32 ml-n16 -top-10'> <div class='q-tooltip-content'> <div class='q-tooltip-arrow -bottom-3'></div> <div class='q-tooltip-inner py-1 pl-1' role='tooltip'> <div class='h6t relative z1 uppercase kern--w mx025'> <span class='small no-wrap'>Read Later</span> </div> </div> </div> </div> </div> </div> </div> </div> </div> </div> </section> </section> <figure class='leading-0 w-full my-0 mx-auto flex items-center justify-center flex-col max-w-img-large py-0 px-0 l:px-0 l:mb-20'> <div class='w-full flex justify-center max-w-mod-large m:max-w-unset image--module s:flex-col s:m-auto'> <div class='w-auto mr-2 last:mr-0 s:m-0 s:flex s:flex-col flex-1'> <img width="2600" height="1460" src="https://www.quantamagazine.org/wp-content/uploads/2017/11/ColdClock_1300Lede.jpg" class="mb-6 w-full s:mb-4" alt="Frozen clock photo" decoding="async" fetchpriority="high" srcset="https://www.quantamagazine.org/wp-content/uploads/2017/11/ColdClock_1300Lede.jpg 2600w, https://www.quantamagazine.org/wp-content/uploads/2017/11/ColdClock_1300Lede-520x292.jpg 520w, https://www.quantamagazine.org/wp-content/uploads/2017/11/ColdClock_1300Lede-1720x966.jpg 1720w, https://www.quantamagazine.org/wp-content/uploads/2017/11/ColdClock_1300Lede-768x431.jpg 768w" sizes="(max-width: 2600px) 100vw, 2600px" /> </div> </div> <figcaption class='block my-0 mx-auto w-full'> <section class='py-0 px-12 s:p-0 m:px-16'> <div class='w-full my-0 mx-auto flex flex-col s:mx-5 s:w-full-minus-25 s:max-w-mod-inline m:max-w-mod-inline l:flex-row l:max-w-mod-large justify-end s:mb-4'> <div class='caption wysiwyg h5 theme__anchors--solid fill-h w-auto l:w-140'> <p>Research on circadian clocks and the development of the cryo-electron microscopy technique, both of which were recently honored with Nobel Prizes, have a close connection.</p> </div> <div class='attribution theme__anchors--solid wysiwyg pangram h6 mb1 fill-h text-left w-auto before:block l:before:hidden l:w-half-minus-17 l:text-right l:pl-24'> <p>Photo illustration by Lucy Reading-Ikkanda/Quanta Magazine;<br /> <a href="https://www.shutterstock.com/g/natauskas" target="_blank" rel="noopener noreferrer">Onishchenko Natalya</a> (ice); <a href="https://www.shutterstock.com/g/vadym%20shpontak" target="_blank" rel="noopener noreferrer">Vandame</a> (clock)</p> </div> </div> </section> </figcaption> </figure> <div class='acf-content scale1 mt2'> <h2 class='screen-reader-text'>Introduction</h2> <div class='post__wrapper scale0 show-dropcap'> <div class='mha container--m'> <div class='post__content relative flex flex-items-start flex-justify-between'> <aside class='post__sidebar hide flex flex-justify-center '> <div class='post__sidebar__content'> <div class='post__sidebar__content__inner'> <div class='align-c mb075'> <div class='sidebar__author'> <a class='theme__accent-hover transition--color ' href='https://www.quantamagazine.org/authors/veronique-greenwood/'> <div class='sidebar__author__avatar mha mb1'> <div class='image mx0 relative image--circle '> <div class='image__inner absolute fit-x is-loaded'> <img width="1000" height="1000" src="https://www.quantamagazine.org/wp-content/uploads/2017/04/Greenwood_Nikki.jpg" class="absolute fit-x fill-h fill-v mxa" alt="" decoding="async" srcset="https://www.quantamagazine.org/wp-content/uploads/2017/04/Greenwood_Nikki.jpg 1000w, https://www.quantamagazine.org/wp-content/uploads/2017/04/Greenwood_Nikki-520x520.jpg 520w, https://www.quantamagazine.org/wp-content/uploads/2017/04/Greenwood_Nikki-768x768.jpg 768w, https://www.quantamagazine.org/wp-content/uploads/2017/04/Greenwood_Nikki-160x160.jpg 160w" sizes="(max-width: 1000px) 100vw, 1000px" /> </div> </div> </div> <div class='h3t mv05'> <span class='screen-reader-text'>By </span>Veronique Greenwood </div> <p class="o8 theme__text h5 mt05 mb1"><em>Contributing Writer</em></p> </a> </div> <hr class='mb075 o1'> <p class="h6 mv1 pv025 o6"><em>November 27, 2017</em></p> </div> <form action='https://www.quantamagazine.org/the-overlooked-link-between-two-of-this-years-nobel-prizes-20171127' method='get' class='sidebar__actions'> <hr class='mt075 mb1 o1'> <input type='hidden' id='print' name='print' value='1' /> <button type="submit" class='h6 pangram uppercase mv05 pb1 bold kern flex flex-items-center flex-justify-between sidebar__print transition--color theme__accent-hover'> <small>View PDF/Print Mode</small> <svg class="icon-l theme__accent ml05" viewbox="0 0 50 50" enable-background="new 0 0 50 50"><path fill="currentColor" d="M39.9,27.5h4.9v22.4H0.1V5.1h22.4V10H5v35h35V27.5z M49.8,0.1h-2.4h-1H33.8V5h7.6L20.7,25.8l3.4,3.4L45,8.4v7.7h4.9V2.6L49.8,0.1z"></path></svg> </button> </form> <div class='mt1 pt05 sidebar__tag-wrap'> <a class='sidebar__tag h6 pangram medium inline-block mb0 relative float-left' href='/tag/abstractions-blog'> <span class='absolute fit-x theme__text-background o1'></span> <span class='theme__text theme__accent-hover transition--color relative'>Abstractions blog</span></a> <a class='sidebar__tag h6 pangram medium inline-block mb0 relative float-left' href='/tag/biology'> <span class='absolute fit-x theme__text-background o1'></span> <span class='theme__text theme__accent-hover transition--color relative'>biology</span></a> <a class='sidebar__tag h6 pangram medium inline-block mb0 relative float-left' href='/tag/chronobiology'> <span class='absolute fit-x theme__text-background o1'></span> <span class='theme__text theme__accent-hover transition--color relative'>chronobiology</span></a> <a class='sidebar__tag h6 pangram medium inline-block mb0 relative float-left' href='/tag/nobel-prize'> <span class='absolute fit-x theme__text-background o1'></span> <span class='theme__text theme__accent-hover transition--color relative'>Nobel Prize</span></a> <a class='sidebar__tag h6 pangram medium inline-block mb0 relative theme__accent w-full' href='/topics'> <span class='absolute fit-x theme__text-background o1'></span> <span class='theme__text-hover transition--color relative'>All topics</span> <svg class='icon ml05' viewbox='0 0 50 50' enable-background='new 0 0 50 50'><path fill='currentColor' d='M50 25l-17.4-8.7v6.5H0v4.4h32.6v6.5'></path></svg> </a> </div> </div> <div class='sidebar__poster'> <a href='https://www.youtube.com/c/QuantaScienceChannel' title='' target='_blank' class=''> <img width="320" height="550" src="https://www.quantamagazine.org/wp-content/uploads/2021/05/Youtube_Article_160.gif" class="fill-h" alt="" decoding="async" /></a> </div> </div> </aside> <section class='outer mha js-router-anchors outer--content'> <div class='flex-auto mha container--xs '> <div class='post__content__section wysiwyg p theme__anchors--underline' data-role='selectable'> <div class='post__content wysiwyg p theme__anchors--underline '> <p>This year, the <a href="https://www.quantamagazine.org/nobel-prize-awarded-for-biological-clock-discoveries-20171002/">Nobel Prizes in Physiology or Medicine</a> and <a href="https://www.quantamagazine.org/supercool-protein-imaging-gets-the-nobel-prize-20171004/">in Chemistry</a> went to researchers working on the study of the circadian clock and the advancement of cryo-electron microscopy (cryo-EM), respectively. What has attracted little comment is that these fields, seemingly disparate, have intersected: Cryo-EM has become one of the most important tools for pushing forward the research on the proteins responsible for the circadian clock.</p> <p>Researchers investigating the circadian clock discovered, decades ago, a protein whose levels rise and fall inside cells in sync with the sun. This protein, we now know, forms a complex with others that regulate the expression of vast swaths of the genome. Such complexes exist in almost every cell in the body of organisms as diverse as fruit flies and people — there’s even a group of cycling proteins in cyanobacteria, though they are completely different in origin. These protein clocks keep physiologies aligned with night and day, so that organisms eat at the right time, tell their cells to divide at the right time and, of course, sleep at the right time. The researchers’ discoveries helped jump-start a field that’s revealing the rhythms at the core of life on Earth.</p> <aside class='post__aside mb2 relative theme__anchors--none post__aside--right hide-on-print abstract-insight'> <div class='abstractions insights'> <div class='relative image mx0'> <img width="520" height="520" src="https://www.quantamagazine.org/wp-content/uploads/2017/04/Abstractions-520x520.png" class="block mxa is-loaded border-gray1 px1" alt="Abstractions logo" decoding="async" srcset="https://www.quantamagazine.org/wp-content/uploads/2017/04/Abstractions-520x520.png 520w, https://www.quantamagazine.org/wp-content/uploads/2017/04/Abstractions-160x160.png 160w" sizes="(max-width: 520px) 100vw, 520px" /> </div> <div class='post__content wysiwyg pangram medium o8 theme__anchors--solid scale4 mt1 mb1'><em>Abstractions</em> navigates promising ideas in science and mathematics. Journey with us and join the conversation.</div> <div> <hr class='black o8'> <a href='/abstractions/'> <div class='theme__accent mv1 h4t'>See all Abstractions blog</div> </a> </div> </div> </aside> <p>Meanwhile, the chemistry researchers helped push the thresholds of visibility far beyond what most people believed was possible when the electron microscope was invented in 1931. In electron microscopy, thin slices of tissue are coated in metal and then scanned with a beam of electrons. The electrons that bounce back are picked up by sensitive detectors; researchers then generate images of the insides of cells from those processed signals. Using traditional forms of electron microscopy, the cell’s machinery — the ruffled interior of individual mitochondria, the black flecks of ribosomes — comes into focus.</p> <p>Then, among other innovations, microscopy researchers realized that flash-freezing the samples would allow higher resolution imaging than ever before, and that images of separate proteins could be computationally combined to develop structural models. As a result, it’s now possible to resolve individual proteins — in some cases, even down to their atoms.</p> <p>During the announcement of the Nobel Prize in Chemistry, one of the cryo-EM images that the officials flashed up on the screen to illustrate the power of the technology was of a circadian clock — the one in cyanobacteria. <a href="https://www.uu.nl/staff/AJRHeck">Albert Heck</a>, a structural biologist at the University of Utrecht in the Netherlands who recently <a href="http://science.sciencemag.org/content/355/6330/1181">published the structure in <em>Science</em></a> with his colleagues, was surprised and delighted to hear through the grapevine about its moment of glory. “For us it came as a total surprise,” he said. But understanding the structure of circadian clocks — clusters of proteins whose spatial arrangement is still unclear — is exactly the kind of thing that cryo-EM is good for, he noted.</p> <figure class='mb2 mt1 image--shortcode s:mt-0'> <div class='relative image mx0'> <img width="1025" height="484" src="https://www.quantamagazine.org/wp-content/uploads/2017/11/cryo-EM-clock-protein.png" class="block fit-x fill-h fill-v is-loaded mxa" alt="Image of clock protein complex from cryo-em" decoding="async" srcset="https://www.quantamagazine.org/wp-content/uploads/2017/11/cryo-EM-clock-protein.png 1025w, https://www.quantamagazine.org/wp-content/uploads/2017/11/cryo-EM-clock-protein-520x246.png 520w, https://www.quantamagazine.org/wp-content/uploads/2017/11/cryo-EM-clock-protein-768x363.png 768w" sizes="(max-width: 1025px) 100vw, 1025px" /> </div> <figcaption class='image__meta mt1'> <div class='caption wysiwyg h5 theme__anchors--solid fill-h post__aside__caption post__aside__caption--shortcode'> <p>These top (left) and side views of the three-dimensional circadian clock protein complex in cyanobacteria were derived with the cryo-electron microscopy technique that won this year’s Nobel Prize in Chemistry.</p> </div> <div class='attribution theme__anchors--solid wysiwyg pangram h6 mb1 fill-h post__aside__attribution'> <p>J Snijder, JM Schuller, et al., (2017) <strong><a href="https://dx.doi.org/10.1126/science.aag3218" target="_blank" rel="noopener noreferrer"><em>Science</em></a></strong></p> </div> </figcaption> </figure> <p>Other techniques for deducing the 3-D shape of proteins have strict requirements that disqualify clock complexes. For example, crystallography, which involves bouncing radiation off proteins of interest, needs for the proteins to, well, crystallize. Even if you can collect thousands of copies of a protein molecule and compact them into a sample, many proteins don’t line up into neat crystalline structures. Nuclear magnetic resonance imaging, another structural biology tool, is good for looking only at very small proteins or portions of proteins. With cryo-EM, you don’t need quite as much material, nor do you need a crystal, and size isn’t an obstacle. “Larger sizes are sort of ideal for cryo-EM, the bigger almost the better,” Heck said.</p> <p>Moreover, those other techniques pull the proteins out of the context of their positions and configurations in living cells. That limitation generally undercuts our ability to learn what we most want to know about sensitive, changeable proteins, and Heck’s results show that the constraint would be a huge obstacle for imaging studies of clock complexes without cryo-EM.</p> <p>The image that Heck and his colleagues made of the cyanobacterial clock using cryo-EM shows a trio of proteins delicately grasping one another. They are frozen in time, representing the stage the clock was in when the researchers stopped it. But there are many, many more configurations out there that the team hasn’t captured yet, Heck said. This is the beauty of circadian clocks, and one of the difficulties of getting pictures of them: They morph over time. The three cyanobacterial clock proteins join together in different ratios depending on the hour. Sometimes it’s four of one protein, six of another, and 10 of the third, or any of numerous other permutations. That complicated the cryo-EM process, because the team had to carefully limit the sample to just one of the permutations to get a clear image. But they managed to do it.</p> <div class="related-list"> <aside class="post__aside mb2 relative hide-on-print post__aside--right"> <h2 class="mv0 h5 bold uppercase kern">Related:</h2> <hr class="mt1 o2"> <ol class="post__aside__list theme__anchors--none pt05"> <li class="mv075 flex"> <h3 class="h5t mt0 mb025 medium"> <a class="theme__accent theme__text-hover" href="https://www.quantamagazine.org/nobel-prize-awarded-for-biological-clock-discoveries-20171002/"> <span class="' . $span_class . '">Nobel Prize Awarded for Biological Clock Discoveries</span> </a> </h3> </li> <li class="mv075 flex"> <h3 class="h5t mt0 mb025 medium"> <a class="theme__accent theme__text-hover" href="https://www.quantamagazine.org/supercool-protein-imaging-gets-the-nobel-prize-20171004/"> <span class="' . $span_class . '">Supercool Protein Imaging Gets the Nobel Prize</span> </a> </h3> </li> <li class="mv075 flex"> <h3 class="h5t mt0 mb025 medium"> <a class="theme__accent theme__text-hover" href="https://www.quantamagazine.org/how-the-bodys-trillions-of-clocks-keep-time-20150915/"> <span class="' . $span_class . '">How the Body’s Trillions of Clocks Keep Time</span> </a> </h3> </li> <li class="mv075 flex"> <h3 class="h5t mt0 mb025 medium"> <a class="theme__accent theme__text-hover" href="https://www.quantamagazine.org/how-circadian-clocks-differ-from-sleep-20170217/"> <span class="' . $span_class . '">How Circadian Clocks Differ From Sleep</span> </a> </h3> </li> </ol> </aside> </div> <p>Generating such images of the mammalian clock, which has far more proteins, could be very tricky, Heck said. Getting even the simple clock of cyanobacteria was a labor of six years.</p> <p>Still, in September, the neurobiologist <a href="https://neuro.hms.harvard.edu/people/faculty/charles-weitz">Charles Weitz</a> and his colleagues at Harvard Medical School <a href="https://www.ncbi.nlm.nih.gov/pubmed/28886335">published a study</a> that used electron microscopy on the mammalian clock complex. It revealed tantalizing images of the surface of that complex, but it was only a shadow of what cryo-EM could eventually accomplish. As Weitz explained in an email, for cryo-EM, “successful results would provide both a higher resolution [of the particles] as well as the internal structure … rather than only the external contours.” It’s a research goal that, given how much electron microscopy has advanced, isn’t as far out of reach as it once seemed.</p> </div> </div> </div> </section> <aside class='post__sidebar hide flex flex-justify-center theme__anchors--solid '> <div class='post__sidebar__content'> <div class='post__sidebar__content__inner'> <div class='h3t mt0'> Share this article </div> <div data-id='social-links'> <div class='social-links social-links--share flex flex-justify-between'> <a href='http://www.facebook.com/sharer.php?u=https://www.quantamagazine.org/the-overlooked-link-between-two-of-this-years-nobel-prizes-20171127/' class='social-links__link flex flex-items-center relative' target="_blank" > <div class='icon-button inline-block relative pointer theme__accent-hover-child'> <div class='absolute 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The Overlooked Link Between Two of This Year’s Nobel Prizes | Quanta Magazine