tag:theconversation.com,2011:/global/topics/cell-division-1932/articlesCell division – The Conversation2023-07-20T12:30:22Ztag:theconversation.com,2011:article/2033242023-07-20T12:30:22Z2023-07-20T12:30:22ZZooming across time and space simultaneously with superresolution to understand how cells divide<figure><img src="https://images.theconversation.com/files/531154/original/file-20230609-17-rkdph4.png?ixlib=rb-1.1.0&rect=8%2C0%2C1355%2C1245&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">This image of actin filaments in a cell was taken using a type of superresolution microscopy.</span> <span class="attribution"><a class="source" href="https://flic.kr/p/SNa523">Xiaowei Zhuang, HHMI, Harvard University, and Nature Publishing Group/NIH via Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc-sa/4.0/">CC BY-NC-SA</a></span></figcaption></figure><p><a href="https://www.britannica.com/science/cell-biology/Cell-division-and-growth">Cell division</a>, or the process of how daughter cells emerge from a mother cell, is fundamental to biology. Every cell inherits the same protein and DNA building blocks that make up the cell it originally came from. Yet exactly how these molecular building blocks arrange themselves into new cells has remained a mystery. </p>
<p>Studying cell division requires simultaneously viewing nanometer-scale macromolecules like proteins and DNA all the way up to millimeter-scale populations of cells, and over a time frame that ranges from seconds to weeks. <a href="https://doi.org/10.1002%2F0471142301.ns0201s50">Previous microscopes</a> have been able to capture tiny objects only in short time frames, typically just tens of seconds. There hasn’t been a method that can examine a wide range of size and time scales all at once.</p>
<p>My team <a href="https://scholar.google.com/citations?user=kpr2nocAAAAJ&hl=en">and I</a> at the University of Michigan’s <a href="https://bioplasmonics.org/home.html">Bioplasmonics Group</a> developed a <a href="https://doi.org/10.1038/s41467-023-39624-w">new kind of superresolution imaging</a> that reveals previously unknown features of how cells divide.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/523124/original/file-20230427-24-3i5rey.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Illustration depiecting superresolution over time as an hourglass, where the bottom shows a protein and the top a dividing cell going from unresolved to resolved" src="https://images.theconversation.com/files/523124/original/file-20230427-24-3i5rey.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/523124/original/file-20230427-24-3i5rey.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=450&fit=crop&dpr=1 600w, https://images.theconversation.com/files/523124/original/file-20230427-24-3i5rey.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=450&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/523124/original/file-20230427-24-3i5rey.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=450&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/523124/original/file-20230427-24-3i5rey.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=566&fit=crop&dpr=1 754w, https://images.theconversation.com/files/523124/original/file-20230427-24-3i5rey.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=566&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/523124/original/file-20230427-24-3i5rey.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=566&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">This hourglass depicts the process of superresolution over time, where the bottom shows a protein and the top a dividing cell going from unresolved, at left, to resolved, at right.</span>
<span class="attribution"><span class="source">Somin Lee</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<h2>Advancing superresolution imaging</h2>
<p>It wasn’t possible to view cells at the molecular level until recently with the <a href="https://www.nobelprize.org/prizes/chemistry/2014/press-release/">2014 Nobel Prize-winning</a> development of superresolution. </p>
<p>Traditional light microscopes <a href="https://courses.lumenlearning.com/suny-physics/chapter/27-6-limits-of-resolution-the-rayleigh-criterion/">blur very small objects</a> that are close together in a sample, because light spreads out as it moves through space. With superresolution, fluorescent probes attached to the sample could be switched on and off like twinkling stars on a clear night. By collecting and combining many images of these probes, a superresolution image can bring very small objects into view. Superresolution opened a whole new world in biology, revealing structures as small as 10 nanometers, which is about the size of a protein molecule. </p>
<p>However, the fluorescent probes that this technique relies on can quickly wear out. This limits its use in studying processes that take place over extended periods, such as cell division. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/537565/original/file-20230714-16543-rjw3zm.gif?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="Two blue blobs, one at the bottom left and one at the top right, are separated by pink and blue specks on a black background." src="https://images.theconversation.com/files/537565/original/file-20230714-16543-rjw3zm.gif?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/537565/original/file-20230714-16543-rjw3zm.gif?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=276&fit=crop&dpr=1 600w, https://images.theconversation.com/files/537565/original/file-20230714-16543-rjw3zm.gif?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=276&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/537565/original/file-20230714-16543-rjw3zm.gif?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=276&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/537565/original/file-20230714-16543-rjw3zm.gif?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=347&fit=crop&dpr=1 754w, https://images.theconversation.com/files/537565/original/file-20230714-16543-rjw3zm.gif?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=347&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/537565/original/file-20230714-16543-rjw3zm.gif?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=347&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">This PINE microscopy image shows cells dividing, their nuclei stained blue.</span>
<span class="attribution"><a class="source" href="https://doi.org/10.1038/s41467-023-39624-w">Somin Lee/Nature Communications</a>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>My research team and I have a developed a solution we call <a href="https://doi.org/10.1038/s41467-023-39624-w">PINE nanoscopy</a>. Instead of absorbing light as traditional fluorescent probes do, the probes we use scatter the light so they do not break down with repeated light exposure.</p>
<p>To resolve very small objects that are close together, we built filters made of thin layers of polymers and liquid crystals that allow for detection of scattered light, which triggers the probes to switch on and off. This allowed us to see nanometer-scale details of cells that would otherwise be blurred by traditional microscopes.</p>
<p>Remarkably, we found that these nanometer-scale details could be viewed for very long periods – over 250 hours. These details would typically be lost over time with traditional superresolution methods.</p>
<h2>Shedding new light on cell division</h2>
<p>We then applied our method to study how molecular building blocks organize in cell division. </p>
<p>We focused on a <a href="https://www.britannica.com/science/actin">protein called actin</a> that helps maintain cell structure, among many other functions. Actin is shaped like branching filaments, each about 7 nanometers (millionths of a millimeter) in diameter, that link together to span thousands of nanometers. Using PINE nanoscopy, we attached scattering probes to actin to visually follow human cells as they divided.</p>
<p>We made three observations on how actin building blocks organize during cell division. First, these molecular building blocks expand to increase their connections to their neighbors. Second, they also draw closer to their neighbors to increase their points of contact. And third, the resulting networks tend to contract when the actin molecules are more connected to one another and expand when they are less connected to one another.</p>
<p>Based on these findings, we were able to <a href="https://doi.org/10.1038/s41467-023-39624-w">discover new information</a> about the process of cell division. We found that interactions between actin building blocks sync up with the contraction and expansion of the whole cell during division. In other words, the behavior of the actin molecules is connected to the behavior of the cell: The cell contracts when the actin expands, and it expands when the actin contracts.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/J2_wdNT4KyM?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">Superresolution microscopy won the 2014 Nobel Prize in chemistry.</span></figcaption>
</figure>
<h2>Uncovering disease with superresolution</h2>
<p>We plan to use our method to study how other molecular building blocks organize into tissues and organs. Like cells, tissues and organs are <a href="https://courses.lumenlearning.com/wm-biology2/chapter/levels-of-organization-of-living-things/">organized in a hierarchy</a> that can be examined from a scale of small to large. Examining the dynamic and complex process of how protein building blocks interact with one another to form larger structures could advance the future creation of new replacement tissues and organs, such as skin grafts. </p>
<p>We also plan to use our imaging technique to study how protein building blocks become disorganized in disease. Proteins organize into cells, cells organize into tissues and tissues organize into organs. A very small change in building blocks can <a href="https://www.ncbi.nlm.nih.gov/books/NBK9963/">disturb this organization</a>, with effects that can lead to diseases like cancer. Our technique could potentially help researchers visualize and, in turn, better understand how molecular defects in tissues and organs may develop into disease.</p><img src="https://counter.theconversation.com/content/203324/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Somin Lee receives funding from the Air Force of Scientific Research (AFOSR) and National Science Foundation (NSF). </span></em></p>Superresolution microscopy allowed researchers to view cells at the molecular level. Improvements on the technique can help study the building blocks of complex cell processes over time.Somin Lee, Assistant Professor of Electrical & Computer Engineering, Biomedical Engineering, University of MichiganLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1699132022-05-31T12:12:43Z2022-05-31T12:12:43ZWhat are HeLa cells? A cancer biologist explains<figure><img src="https://images.theconversation.com/files/465571/original/file-20220526-14-aez4rh.jpg?ixlib=rb-1.1.0&rect=0%2C0%2C1022%2C771&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Cancer-causing viruses like HPV can cause cells to divide indefinitely and, in the case of Henrietta Lacks, become immortal.</span> <span class="attribution"><a class="source" href="https://flic.kr/p/A5Q7L1">Tom Deerinck/NIH via Flickr</a>, <a class="license" href="http://creativecommons.org/licenses/by-nc/4.0/">CC BY-NC</a></span></figcaption></figure><p>In an amazing twist of fate, the aggressive cervical cancer tumor that killed <a href="https://www.npr.org/2010/02/02/123232331/henrietta-lacks-a-donors-immortal-legacy">Henrietta Lacks</a>, a 31-year old African American mother, became an <a href="https://osp.od.nih.gov/scientific-sharing/hela-cells-timeline/">essential tool</a> that helped the biomedical field flourish in the 20th century. As a <a href="https://www.researchgate.net/scientific-contributions/Ivan-Martinez-2109620653">cancer researcher</a> who uses HeLa cells in my everyday work, even I sometimes find it hard to believe. </p>
<p>On Aug. 1, 2023, over 70 years after doctors took Lacks’ cells without her consent or knowledge, her family <a href="https://apnews.com/article/henrietta-lacks-hela-cells-thermo-fisher-scientific-bfba4a6c10396efa34c9b79a544f0729">reached a settlement</a> with biotech company Thermo Fisher. Lacks’ descendants had sued the company in 2021 for making billions of dollars off her cells. The family has not been previously been compensated.</p>
<p>Lacks’ cervical cancer cells, called “HeLa” after the first two letters of her first and last name, <a href="https://www.science.org/content/article/art-culture-developing-cell-lines">are immortal</a>, continuing to divide when most cells would die. This ability to survive through endless generations of cells is what makes them invaluable for scientists conducting experiments on human cells.</p>
<h2>Why HeLa cells matter</h2>
<p>Before HeLa cells, scientists wanted a way to grow and study human cells in the lab to conduct studies that are impossible to do in a living person. When Lacks’ cervical cancer cells were <a href="https://osp.od.nih.gov/scientific-sharing/hela-cells-landing/">successfully grown in a petri dish in 1951</a>, scientists now had a source of cost-effective and easy-to-use cells that expanded their ability to conduct research. From <a href="https://doi.org/10.1084/jem.97.5.695">polio</a> and <a href="https://doi.org/10.1016/j.cell.2020.07.024">COVID-19 vaccines</a> to <a href="https://doi.org/10.1002/jcp.22917">cancer research</a> and <a href="https://doi.org/10.1534/g3.113.005777">sequencing the human genome</a>, HeLa cells have played an enormous role in many scientific discoveries and advancements.</p>
<p>Henrietta Lacks’ story is also an <a href="https://www.wgbh.org/news/local-news/2022/05/17/thermo-fisher-seeks-dismissal-of-henrietta-lacks-familys-lawsuit-regarding-sale-of-her-cells">ongoing bioethics case</a>, because these cells were taken from her during a routine cervical cancer biopsy and were then given to researchers without her consent, as was <a href="https://doi.org/10.1146%2Fannurev-genom-083115-022536">common practice</a> at the time. The Lacks family has <a href="https://www.washingtonpost.com/local/legal-issues/henrietta-lacks-family-sues-company/2021/10/04/810ffa6c-2531-11ec-8831-a31e7b3de188_story.html">long attempted legal action</a> against companies they say have unfairly benefited from Henrietta’s cells. A <a href="https://www.npr.org/2010/02/02/123232331/henrietta-lacks-a-donors-immortal-legacy">2010 book</a> by journalist Rebecca Skloot details how HeLa cells affected both science and the Lacks family.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/T3kR2dMCfOM?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">The Lacks family wasn’t aware that Henrietta’s cells had been harvested until Rolling Stone magazine journalist Michael Rogers contacted them two decades after her death.</span></figcaption>
</figure>
<p>But how did Lacks’ cells become immortal?</p>
<p>Lacks didn’t know that cells in her cervix were infected with a virus that causes one of the most common sexually transmitted diseases: <a href="https://www.cdc.gov/std/hpv/default.htm">human papillomavirus</a>, or HPV. There are more than 150 different types of HPVs, but only a small group are known to cause <a href="https://www.cancer.gov/about-cancer/causes-prevention/risk/infectious-agents/hpv-and-cancer">cervical cancer</a>. In fact, <a href="https://doi.org/10.1002/(SICI)1096-9896(199909)189:1%3C12::AID-PATH431%3E3.0.CO;2-F">99.7% of cervical cancers</a> are HPV positive. Fortunately, most people infected with high-risk HPVs are able to clear out the virus before it becomes cancerous. <a href="https://www.cdc.gov/vaccines/vpd/hpv/public/index.html">HPV vaccinations</a> can prevent over 90% of HPV-related cancers. But <a href="https://www.cdc.gov/cancer/hpv/basic_info/index.htm">10% of people</a> with HPV infections on their cervix develop cancer. Sadly, Henrietta was one of the unlucky ones.</p>
<p>Her misfortune has helped elucidate how HPV works. Since the <a href="https://www.nobelprize.org/prizes/medicine/2008/hausen/facts/">Nobel Prize-winning</a> 1976 discovery of <a href="http://www.ncbi.nlm.nih.gov/pubmed/175942">HPV’s essential role</a> in cervical cancer, many scientists, including me, have been investigating how HPV <a href="https://www.ncbi.nlm.nih.gov/books/NBK9929/">causes cancer</a>.</p>
<figure>
<iframe width="440" height="260" src="https://www.youtube.com/embed/SPezZ6qKGFw?wmode=transparent&start=0" frameborder="0" allowfullscreen=""></iframe>
<figcaption><span class="caption">While some types of HPV cause warts on the skin, certain high-risk ones can cause cancer.</span></figcaption>
</figure>
<h2>Two proteins</h2>
<p>It turns out that the virus’ cancer-causing ability is linked to two proteins it produces. These viral proteins can <a href="https://pubmed.ncbi.nlm.nih.gov/1322242/">target and destroy</a> two major human proteins that protect against cancer, <a href="https://doi.org/10.1038/s41598-019-40094-8">p53 and retinoblastoma (Rb)</a>. P53 and Rb act as sentinels making sure cells don’t accumulate harmful genetic mutations and stop dividing after a set number of cycles. My research has focused on how HPV proteins interact with <a href="https://doi.org/10.1038/s41598-019-40094-8">tumor-suppressing</a> <a href="https://doi.org/10.1073/pnas.1017346108">proteins</a> in different types of human cells, including HeLa.</p>
<p>Most cells divide around <a href="https://doi.org/10.1016/0014-4827(65)90211-9">40 to 60 times</a> before they become too old to function properly and are naturally killed off. But HPV can allow cells to divide forever, because they attack the sentinels keeping uncontrolled division in check. After Lacks was infected with <a href="https://doi.org/10.1128/JVI.01747-15">HPV 18</a>, the second-most-common high-risk type of the virus, her cervical cells lost the ability to produce these sentinels. Without growth checks in place, her cells were able to divide indefinitely and became “immortal” – living on to this day both in test tubes and the <a href="https://www.immunology.org/hela-cells-1951">70,000 studies</a> they’ve made possible.</p>
<p><em>This article was updated to note the Lacks family’s settlement with Thermo Fisher on Aug. 1, 2023.</em></p><img src="https://counter.theconversation.com/content/169913/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Ivan Martinez receives funding from the National Institute of Health (NIH), the American Cancer Society (ACS), and the National Science Foundation (NSF).</span></em></p>The immortal cancer cells of Henrietta Lacks revolutionized the fields of science, medicine and bioethics. And they still survive today, more than 70 years after her death.Ivan Martinez, Associate Professor of Microbiology, Immunology and Cell Biology, West Virginia UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/1159562019-04-25T10:44:17Z2019-04-25T10:44:17ZDNA as you’ve never seen it before, thanks to a new nanotechnology imaging method<figure><img src="https://images.theconversation.com/files/270811/original/file-20190424-121241-96r4oz.jpeg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A map of DNA with the double helix colored blue, the landmarks in green, and the start points for copying the molecule in red.</span> <span class="attribution"><span class="source">David Gilbert/Kyle Klein</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span></figcaption></figure><figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/270766/original/file-20190424-121245-q8ktd0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/270766/original/file-20190424-121245-q8ktd0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/270766/original/file-20190424-121245-q8ktd0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=609&fit=crop&dpr=1 600w, https://images.theconversation.com/files/270766/original/file-20190424-121245-q8ktd0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=609&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/270766/original/file-20190424-121245-q8ktd0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=609&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/270766/original/file-20190424-121245-q8ktd0.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=766&fit=crop&dpr=1 754w, https://images.theconversation.com/files/270766/original/file-20190424-121245-q8ktd0.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=766&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/270766/original/file-20190424-121245-q8ktd0.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=766&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The first revealing image of DNA taken using X-ray diffraction.</span>
<span class="attribution"><a class="source" href="http://www-project.slac.stanford.edu/wis/images/photo_51.jpg">Raymond Gosling/King's College London</a></span>
</figcaption>
</figure>
<figure class="align-right zoomable">
<a href="https://images.theconversation.com/files/270851/original/file-20190424-121254-1uxir8t.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/270851/original/file-20190424-121254-1uxir8t.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/270851/original/file-20190424-121254-1uxir8t.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=1115&fit=crop&dpr=1 600w, https://images.theconversation.com/files/270851/original/file-20190424-121254-1uxir8t.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=1115&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/270851/original/file-20190424-121254-1uxir8t.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=1115&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/270851/original/file-20190424-121254-1uxir8t.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=1401&fit=crop&dpr=1 754w, https://images.theconversation.com/files/270851/original/file-20190424-121254-1uxir8t.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=1401&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/270851/original/file-20190424-121254-1uxir8t.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=1401&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">The helical DNA staircase. The building blocks of DNA, or bases, lie horizontally between the two spiraling strands.</span>
<span class="attribution"><a class="source" href="https://upload.wikimedia.org/wikipedia/commons/d/db/DNA_orbit_animated_static_thumb.png">Richard Wheeler</a>, <a class="license" href="http://creativecommons.org/licenses/by-sa/4.0/">CC BY-SA</a></span>
</figcaption>
</figure>
<p>For biologists everywhere, April 25 is auspicious. It is <a href="https://www.genome.gov/dna-day">DNA Day</a> and commemorates the date in 1953 when scientists <a href="https://doi.org/10.1038/171737a0">Francis Crick</a>, <a href="https://doi.org/10.1038/171740a0">Rosalind Franklin</a>, <a href="https://doi.org/10.1038/171737a0">James Watson</a> and <a href="https://doi.org/10.1038/171738a0">Maurice Wilkins</a> published seminal scientific papers describing the helical structure of the DNA molecule. In 2003, April 25 was used to announce the completion of the <a href="https://www.genome.gov/human-genome-project">Human Genome Project</a>. Now annual festivities on this day celebrate the molecule of life with new discoveries. What better time to provide a new picture of DNA.</p>
<p>I am DNA DAVE (or at least my license plate since 1984 says so), and one of the things <a href="http://gilbertlab.bio.fsu.edu">my lab</a> likes to do is to “see” DNA. We take images of DNA so that we can directly measure things that are difficult to quantify using indirect methods that usually involve sequencing the four chemical units of DNA, called bases. </p>
<p>For example, I would like to know where on each chromosome the process of DNA replication begins. Error-free duplication of DNA is essential for producing healthy cells. When this process is incomplete or disrupted, the result can cause cancer and other diseases.</p>
<p>In our image that familiar double helix staircase is not visible because this perspective is zoomed out – like looking at the map of a country versus a city. Also each of these molecules is equivalent to 50,000 turns of the helical staircase – a substantial segment of a human chromosome. </p>
<h2>Making a map of DNA</h2>
<figure class="align-left zoomable">
<a href="https://images.theconversation.com/files/270815/original/file-20190424-121228-9nki4p.png?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/270815/original/file-20190424-121228-9nki4p.png?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/270815/original/file-20190424-121228-9nki4p.png?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=2325&fit=crop&dpr=1 600w, https://images.theconversation.com/files/270815/original/file-20190424-121228-9nki4p.png?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=2325&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/270815/original/file-20190424-121228-9nki4p.png?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=2325&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/270815/original/file-20190424-121228-9nki4p.png?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=2921&fit=crop&dpr=1 754w, https://images.theconversation.com/files/270815/original/file-20190424-121228-9nki4p.png?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=2921&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/270815/original/file-20190424-121228-9nki4p.png?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=2921&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Single strands of DNA are colored blue. Green marks the location of specific landmarks. Red highlights the locations where DNA replication is beginning.</span>
<span class="attribution"><span class="source">David Gilbert/Kyle Klein</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span>
</figcaption>
</figure>
<p>This image, taken with a device called the Bionano Genomics Saphyr imager, features individual DNA molecules – colored in blue, green and red. These strands of DNA have been aligned by threading them through narrow tubes – called nanochannels – that fit only one piece of DNA. As the DNA slips into the tube, the strands straighten. </p>
<p>The whole DNA molecule is colored blue and the green tick marks are landmarks – or specific sequences of DNA that occur on average every 4,500 base pairs. The pattern of landmarks provide a unique fingerprint which tells us where we are along the length of a chromosome. The red fluorescent blips tag the locations where the DNA has begun to replicate. These sites are called “origins of replication” and are where the DNA first unwinds so that the duplication process can start. </p>
<p>Researchers at <a href="https://bionanogenomics.com/">Bionano Genomics</a> in San Diego developed this nanochannel technology to chart regions of chromosomes that were otherwise unmappable, due to tricky genetic sequences that make it difficult to determine the order of the four bases. This device solved the problem by “looking” at the arrangement of sequences on one molecule at a time and is able to read 30 billion base pairs in one hour – the equivalent of 10 human genomes. </p>
<p>My team and that of <a href="https://www.umassmed.edu/rhindlab/">Nick Rhind at the University of Massachusetts</a> recognized that this nanochannel technology would allow us to conduct an experiment never attempted before: map all the locations where DNA replication begins simultaneously on millions of single DNA fibers. </p>
<p>Before a cell can divide into two independent cells, the DNA must make a copy of itself so that each one receives a complete set of chromosomes. To understand how the genetic material is duplicated it is essential to know where along the chromosome the process begins. That has been the greatest challenge to studying how the replication of our own chromosomes takes place and consequently what is going wrong in so many diseases, like cancer, in which replication goes awry. </p>
<h2>DNA replication and cancer</h2>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/270848/original/file-20190424-121262-1iztegm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/270848/original/file-20190424-121262-1iztegm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/270848/original/file-20190424-121262-1iztegm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=283&fit=crop&dpr=1 600w, https://images.theconversation.com/files/270848/original/file-20190424-121262-1iztegm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=283&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/270848/original/file-20190424-121262-1iztegm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=283&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/270848/original/file-20190424-121262-1iztegm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=355&fit=crop&dpr=1 754w, https://images.theconversation.com/files/270848/original/file-20190424-121262-1iztegm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=355&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/270848/original/file-20190424-121262-1iztegm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=355&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Every time a cell divides the DNA double helix must duplicate itself to provide a copy of the genetic instructions to both cells.</span>
<span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/mechanism-dna-replication-one-molecule-produced-759392011?src=z6-3R29O9C2ja3mWxmEeiQ-1-0">Soleil Nordic/Shutterstock.com</a></span>
</figcaption>
</figure>
<p>Origins of replication have been elusive because they occur at many sites on different molecules so we need to look at single DNA molecules to detect them. Although scientists have been able to see single DNA molecules since the early 1960s, we could not tell where in the chromosomes any molecule came from so we could not map anything. </p>
<p>Kyle Klein, <a href="http://gilbertlab.bio.fsu.edu/current.php">a Ph.D. student in my lab</a>, labeled living human stem cells with red fluorescent molecules that marked locations where DNA replication was taking place, which were mapped with the Bionano device. These images were then superimposed onto the blue and green DNA maps of the same DNA molecules. </p>
<p><a href="https://www.biorxiv.org/content/10.1101/214841v1">We expect this method to completely transform</a> our understanding of how human chromosomes replicate. Moreover, since most chemotherapy drugs for cancer treatment and most carcinogens – or cancer-causing chemicals – in our environment work by attacking DNA when it replicates, we expect this method to provide a rapid and comprehensive test for how these chemicals disrupt DNA replication. We also hope it reveals how we might alleviate these negative consequences, and how we might develop better and less toxic chemotherapy treatments.</p><img src="https://counter.theconversation.com/content/115956/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>David M. Gilbert receives funding from the NIH (National Institute of General Medical Science, National Genome Research Institute and National Institute of Diabetes and Digestive and Kidney Diseases)</span></em></p>You are probably familiar with graphics depicting the double helix structure of DNA. But have you ever seen a single DNA molecule standing straight?David M. Gilbert, Professor of Molecular Biology, Florida State UniversityLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/959892018-08-30T10:49:40Z2018-08-30T10:49:40ZMath shows how DNA twists, turns and unzips<figure><img src="https://images.theconversation.com/files/233904/original/file-20180828-86138-1y73dsr.png?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">DNA knot as seen under the electron microscope.</span> <span class="attribution"><span class="source">Javier Arsuaga</span>, <a class="license" href="http://creativecommons.org/licenses/by-nd/4.0/">CC BY-ND</a></span></figcaption></figure><p>If you’ve ever seen a picture of a DNA molecule, you probably saw it in its famous B-form: two strands coiling around each other in a right-handed fashion to form a double helix. But did you know that DNA can change its shape?</p>
<p>DNA molecules, which carry the genetic code of an organism, have to be tightly packed to fit inside a cell. However, every few hours, the cell produces a faithful copy of its genome in preparation for cell division. This replication process puts tremendous stress on the DNA and can change its shape in lethal ways.</p>
<p>As a mathematician and a biologist, I am interested in how mathematics can describe the many shapes of DNA, as well as cellular processes like DNA replication. The answers to these questions inspire new mathematics and possibly a better understanding of the molecule of life.</p>
<h2>The shape of DNA</h2>
<p>To understand the mathematics of the shape of DNA, you need to consider both its geometry and its topology. These are related but distinct concepts. </p>
<p>Geometry describes an object at a particular moment in time – frozen rigid in space, like a sculpture. In the cell, the DNA helix coils upon itself, or “supercoils.” The way DNA folds and coils encodes valuable geometric information that can be crucial to <a href="https://doi.org/10.1093/hmg/ddy164">control the way genes are expressed</a>. </p>
<p>Topology describes how an object deforms smoothly, as if made out of clay without making new holes or breaks. For example, imagine a rubber band tumbling around in a whirlpool. As the water swirls, the rubber band twists, stretches and shrinks. All of the shapes adopted by the band as it moves are topologically identical, but geometrically different.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/221240/original/file-20180531-69490-tcfomm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/221240/original/file-20180531-69490-tcfomm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/221240/original/file-20180531-69490-tcfomm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=205&fit=crop&dpr=1 600w, https://images.theconversation.com/files/221240/original/file-20180531-69490-tcfomm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=205&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/221240/original/file-20180531-69490-tcfomm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=205&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/221240/original/file-20180531-69490-tcfomm.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=258&fit=crop&dpr=1 754w, https://images.theconversation.com/files/221240/original/file-20180531-69490-tcfomm.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=258&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/221240/original/file-20180531-69490-tcfomm.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=258&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">These three objects have very different geometries, but are topologically the same – meaning that the objects can be bent or twisted from one shape into another.</span>
<span class="attribution"><span class="source">Mariel Vazquez</span>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>Merely copying DNA creates a large number of shape-related problems, but <a href="http://www.thoughtco.com/dna-replication-3981005">textbook images</a> rarely illustrate this topological conundrum. </p>
<p>During the cell cycle, each chromosome is replicated into two identical copies. In order for that to happen, the DNA helix must unwind, causing stress on the DNA. DNA responds to this stress by supercoiling, just like an old telephone cord. But the cell cannot tolerate too much supercoiling. If DNA contorts too much, the cell will suffer. </p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/234122/original/file-20180829-195325-k3hciw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/234122/original/file-20180829-195325-k3hciw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/234122/original/file-20180829-195325-k3hciw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=281&fit=crop&dpr=1 600w, https://images.theconversation.com/files/234122/original/file-20180829-195325-k3hciw.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=281&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/234122/original/file-20180829-195325-k3hciw.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=281&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/234122/original/file-20180829-195325-k3hciw.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=353&fit=crop&dpr=1 754w, https://images.theconversation.com/files/234122/original/file-20180829-195325-k3hciw.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=353&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/234122/original/file-20180829-195325-k3hciw.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=353&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Sketch of a right handed DNA double helix (left). The opening of the helix, indicated by a triangle, causes the DNA to supercoil (right). A supercoil occurs when the axis of the helix, indicated in purple, coils upon itself.</span>
<span class="attribution"><span class="source">Mariel Vazquez</span>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<p>A DNA molecule can be linear – as in the case of human chromosomes – or circular. Examples of circular DNA molecules include bacterial chromosomes and human mitochondrial DNA. If the DNA molecule is circular, then cellular processes such as replication may <a href="http://doi.org/10.1093/nar/gkx1137">tie DNA into knots</a> or <a href="http://doi.org/10.1098/rstb.2003.1363">links</a>, like rings in a keychain. DNA knots and links can <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC146338/?report=reader">cause cells to malfunction</a> or even die.</p>
<h2>Stabilizing DNA</h2>
<p>Consider the bacterium <em>E. coli</em>. Its genetic code is found in one single DNA chromosome. In <em>E. coli</em> and other bacteria, the DNA double helix closes into a circle, like a twisted rubber band. </p>
<p>Replication of the <em>E. coli</em> chromosome can happen in as short as 20 minutes in a test tube. But when a circular chromosome is replicated, the process yields two <a href="https://www.sciencedirect.com/science/article/pii/S0092867400817407">interlinked chromosomes</a>. That is, the new chromosomes form two rings linked through each other. The new chromosomes must unlink before the cell divides into two cells. Otherwise they would either break on the way to their target cell, or one cell would inherit two interlinked copies of one chromosome and the other one would be missing the chromosome altogether. </p>
<p>The cell recruits enzymes to unlink the DNA. Enzymes called topoisomerases and recombinases act as scissors and glue for DNA. They can change the geometry and topology of DNA, thus maintaining a stable genome. In <em>E. coli</em>, topoisomerases work tirelessly during and after replication to maintain healthy levels of supercoiling and to safely unlink the chromosomes.</p>
<figure class="align-center zoomable">
<a href="https://images.theconversation.com/files/234123/original/file-20180829-195304-6v7isk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/234123/original/file-20180829-195304-6v7isk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/234123/original/file-20180829-195304-6v7isk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=227&fit=crop&dpr=1 600w, https://images.theconversation.com/files/234123/original/file-20180829-195304-6v7isk.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=227&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/234123/original/file-20180829-195304-6v7isk.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=227&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/234123/original/file-20180829-195304-6v7isk.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=285&fit=crop&dpr=1 754w, https://images.theconversation.com/files/234123/original/file-20180829-195304-6v7isk.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=285&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/234123/original/file-20180829-195304-6v7isk.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=285&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
<figcaption>
<span class="caption">Replication of a circular DNA molecule. The arrows show the direction of replication (left). The new molecules interlink in this process (right).</span>
<span class="attribution"><span class="source">Mariel Vazquez</span>, <a class="license" href="http://creativecommons.org/licenses/by/4.0/">CC BY</a></span>
</figcaption>
</figure>
<h2>When topoisomerases don’t work</h2>
<p>When topoisomerases don’t work, the cell eventually dies. This makes them good targets for <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3536865/">drug design</a>. But cells have different types of topoisomerases and other enzymes such as recombinases that may be able to come to the rescue. For example, <a href="http://emboj.embopress.org/content/26/19/4228.long">we showed</a> that, in <em>E. coli</em> cells where the topoisomerases in charge of unlinking have been disabled, other enzymes called site-specific recombinases can untie replication links. </p>
<p>Both topoisomerases and site-specific recombinases bind double stranded DNA and can change its shape by introducing breaks. Type II <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418509/">topoisomerases</a> introduce a break along the DNA molecule and transport another piece of DNA through the break before resealing it. <a href="https://www.annualreviews.org/doi/full/10.1146/annurev.biochem.73.011303.073908?url_ver=Z39.88-2003&rfr_id=ori%3Arid%3Acrossref.org&rfr_dat=cr_pub%3Dpubmed">Site-specific recombinases</a> attach to two sites along the DNA, introduce one cut in each, then reconnect the ends. </p>
<p>My lab uses mathematics and computer simulations to understand how these enzymes unlink DNA molecules. While the local action is well understood on a biochemical level, how exactly enzymes simplify the topology of DNA is still a mystery. </p>
<p>In one of our studies, we focused on <a href="http://emboj.embopress.org/content/26/19/4228.long"><em>E. coli</em> cells where the topoisomerases don’t work</a>. <a href="http://www.pnas.org/content/110/52/20906.long">We showed</a> how to untie a replication link in the minimum number of steps. </p>
<p>In general, there can be many unlinking pathways. We use computer simulations to <a href="https://www.nature.com/articles/s41598-017-12172-2">assign probabilities</a> to each pathway. Our work indicates that, in the case of replication links, the simplest pathway is the one that enzymes most likely take.</p>
<p>Sophisticated mathematical methods can help explain how enzymes unlink DNA. Without mathematical modeling, researchers would be restricted to simplified models suggested by biological experiments.</p><img src="https://counter.theconversation.com/content/95989/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Mariel Vazquez receives funding from the National Science Foundation (CAREER DMS 1519375, DMS 1716987 and DMS 1817156).</span></em></p>Mathematical models can describe the many shapes of DNA, as well as cellular processes like DNA replication.Mariel Vazquez, Professor of Mathematics, University of California, DavisLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/169192013-08-13T05:27:13Z2013-08-13T05:27:13Z‘Mitotic spindles’ could help develop better chemo drugs<figure><img src="https://images.theconversation.com/files/29073/original/9bdwbfy9-1376302663.jpg?ixlib=rb-1.1.0&rect=1%2C0%2C1022%2C683&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">A good yarn: chromosomes are shared out to dividing cells by mitotic spindles.</span> <span class="attribution"><span class="source">Triesquid</span></span></figcaption></figure><p>Cells use a tiny machine called the mitotic spindle to share genetic material equally between cells when they divide. But when this process goes wrong it can lead to cancer. </p>
<p>For many years we’ve been interested in how the spindle divides up genetic material accurately. When a cell divides it must make sure that each daughter cell receives just one copy of each chromosome, which carries DNA to the new cell. Defects in this process can lead to cells having the wrong amount of chromosomes, which can lead to cancer or birth defects.</p>
<p>Anti-cancer drugs have been developed which target the mitotic spindle and destroy dividing cells in tumours. But these drugs have significant side effects. In my lab, we’re trying to understand how the mitotic spindles work in order to develop drugs that are more targeted and have fewer side effects.</p>
<figure class="align-right ">
<img alt="" src="https://images.theconversation.com/files/29083/original/2hntmvff-1376311514.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=237&fit=clip" srcset="https://images.theconversation.com/files/29083/original/2hntmvff-1376311514.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=447&fit=crop&dpr=1 600w, https://images.theconversation.com/files/29083/original/2hntmvff-1376311514.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=447&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/29083/original/2hntmvff-1376311514.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=447&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/29083/original/2hntmvff-1376311514.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=562&fit=crop&dpr=1 754w, https://images.theconversation.com/files/29083/original/2hntmvff-1376311514.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=562&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/29083/original/2hntmvff-1376311514.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=562&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
<figcaption>
<span class="caption">Mitotic spindle: chromosomes in blue, microtubles in green.</span>
<span class="attribution"><span class="source">Wikimedia Commons/Afunguy</span></span>
</figcaption>
</figure>
<p>Chromosomes are allocated by the mitotic spindle, which is made up of many thin filaments called microtubules. These are held together in bundles and these bundles share the chromosomes equally during mitosis.</p>
<p>Colleagues and I at Warwick Medical School have shown <a href="http://bit.ly/1boixL1">in a paper published</a> in The Journal of Cell Biology that a team of three proteins - called the TACC3–ch-TOG–clathrin complex - work to hold the spindle’s microtubules together and stabilise the bundle through a system of “bridges”. Drugs such as Taxol (Paclitaxel) have been used very effectively in chemotherapy because they poison microtubles and inhibit the mitotic spindle. This stops cancer cells from dividing and causes them to die. </p>
<p>However, the disadvantage is that microtubules are needed for many functions in non-cancerous cells. This means that existing treatments don’t discriminate between cancerous and normal cells. So the use of Taxol and others in its family, for example, cause side effects such as nerve damage. If we could target the mitotic spindle proteins, rather than microtubules, we may be able to develop effective anti-cancer drugs with far fewer side effects.</p>
<p>We’ve found that in cancer cells, the amount of the protein complex is either too low or too high. This suggests that these proteins could be targeted for potential anti-cancer therapies in the future.</p>
<p>Our research group, together with Richard Bayliss’ lab at the University of Leicester, have recently described how the proteins in the TACC3–ch-TOG–clathrin complex bind to one another. In turn this led us to understand how the complex binds to microtubules. By taking out the TACC3 protein, the clathrin loses its function and is no longer able to create some of the bridges that bind the microtubles. </p>
<p>It’s important as we can use this information to think of ways to break the complex apart or to prevent it binding microtubules. From this, we may be able to disrupt the function of the protein complex in dividing cells and inhibit the sharing of chromosomes during mitosis, causing the death of cancerous cells. </p>
<p>The research is in the early stages, but we have also discovered that an enzyme called Aurora A kinase controls the assembly of the protein complex. Aurora A is often amplified in tumours and clinical trials into inhibiting its role are already underway into drugs that cause the TACC3-ch-TOG-clathrin complex to fall apart and actually break away from the mitotic spindle altogether. </p>
<p>When treating cancer we still often cause damage in other areas. Understanding and controlling the action of the mitotic spindle could help us to better target treatment by directly shutting down defective cells.</p><img src="https://counter.theconversation.com/content/16919/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Steve Royle is a Senior Fellow for Cancer Research UK which funds his lab at Warwick University.</span></em></p>Cells use a tiny machine called the mitotic spindle to share genetic material equally between cells when they divide. But when this process goes wrong it can lead to cancer. For many years we’ve been interested…Steve Royle, Associate Professor, University of WarwickLicensed as Creative Commons – attribution, no derivatives.