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A Breakthrough in the Search for a Cure for ALS Could Change Our Understanding of “Genetic” Diseases
19 October 2015
via Flickr user Global Panorama
[DIGEST: New York Times, Washington Post, Hopkins Medicine]
We like to think that disease is simple. Medical researchers and molecular biologists know better, of course, but that rarely filters out into our broader cultural imagination. The popular press is filled with stories about toxins or disease-causing genes because we want simple answers to complicated questions. If there is a gene for cancer, then it’s easy to explain, right? The gene causes the cancer, just like a gene might give you blue eyes or red hair. Toxins are even simpler: if you get poison in your cells, they might die. Nothing could be easier to understand.
<p><span style="font-weight: 400;">But the latest medical breakthrough concerning </span><a href="http://www.nytimes.com/2015/09/03/opinion/nicholas-kristof-payday-for-ice-bucket-challenges-mocked-slacktivists.html?_r=0" target="_blank"><span style="font-weight: 400;">amyotrophic lateral sclerosis (ALS)</span></a><span style="font-weight: 400;">, a disease that gained attention in 2014 because of the publicity generated by the “</span><a href="https://www.washingtonpost.com/news/to-your-health/wp/2015/08/19/scientists-are-crediting-the-ice-bucket-challenge-for-breakthroughs-in-research/" target="_blank"><span style="font-weight: 400;">ice bucket challenge</span></a><span style="font-weight: 400;">,” can shed some light on the complicated relationships between genetics and disease.</span></p><p><span style="font-weight: 400;">ALS kills the nerve cells that control movement. Over time, muscles get weaker and waste away. It first became well-known in the United States when it affected baseball player </span><a href="https://en.wikipedia.org/wiki/Lou_Gehrig" target="_blank"><span style="font-weight: 400;">Lou Gehrig</span></a><span style="font-weight: 400;">, and as a result it is informally called Lou Gehrig’s Disease. Today, the most famous person living with the disease is physicist </span><a href="https://en.wikipedia.org/wiki/Stephen_Hawking" target="_blank"><span style="font-weight: 400;">Stephen Hawking</span></a><span style="font-weight: 400;">. It can start expressing itself as a simple weakness in the arms and legs, but can lead to loss of all motor skills.</span></p><p><div data-conversation-spotlight=""></div></p><p class="shortcode-media shortcode-media-rebelmouse-image"><img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yMjA0NTYwMi9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTY1NDMyMDM4NX0.UVLqPfR6TpUETasOwxICAFKnaNh3VU7ZTfQ6VjMdQ-8/img.jpg?width=980" id="d29f4" class="rm-shortcode" data-rm-shortcode-id="7ef4e7603e99707b2d991b465e90f800" data-rm-shortcode-name="rebelmouse-image"><small class="image-media media-caption" placeholder="add caption..."><a href="https://assets.rbl.ms/22045602/origin.jpg"></a> Pictured left to right: Lou Gehrig, Stephen Hawking</small></p><p><span style="font-weight: 400;">ALS has confounded scientists and doctors for years. Research found a connection with genetics only in </span><a href="http://www.mayoclinic.org/diseases-conditions/amyotrophic-lateral-sclerosis/basics/risk-factors/con-20024397" target="_blank"><span style="font-weight: 400;">a small percentage of cases</span></a><span style="font-weight: 400;">; most cases appeared randomly. Detailed cellular research has shown that a regulatory protein called TDP-43 </span><a href="http://www.hopkinsmedicine.org/news/media/releases/scientists_report_explanation_for_protein_clumps_in_autopsy_brain_cells_of_als_patients_" target="_blank"><span style="font-weight: 400;">is clumped in the nerve cells of ALS patients</span></a><span style="font-weight: 400;">. This seemed important, but nobody knew whether this “clumping” was a cause or an effect of the disease, or how it might be related to the symptoms.</span></p><p><span style="font-weight: 400;">This is where the researchers at Johns Hopkins University came in. For the first time, they put together a coherent story about exactly what might be happening “behind the scenes” </span></p><p></p><p><span style="font-weight: 400;">to cause the symptoms of ALS, why that cause is related to genetics, and yet is still not the simple “cause-and-effect” relationship that people had hoped. </span></p><p><span style="font-weight: 400;">The researchers who made the discovery </span><a href="https://www.sciencemag.org/content/349/6248/650.abstract#xref-corresp-1-1" target="_blank"><span style="font-weight: 400;">wrote up a scientific paper</span></a><span style="font-weight: 400;"> that is a bit dense if you’re not actually a molecular biologist. To understand the story it tells about ALS, and how its symptoms come about, let’s back up for a moment and review exactly what genes do.</span></p><h4><strong>Our cryptic genetic code</strong></h4><p><span style="font-weight: 400;">Genes are bits of DNA that our cells use to make proteins. Of course, in the bigger picture we always hear about genes controlling traits: from height and eye color to IQ and personality. But at the fundamental level, these traits come about because our cells produce different types of proteins. The proteins lead to different structures forming in our cells, which in turn can give rise to characteristics of our physical body ranging from the pigment of our skin to the speed of our metabolism, or even the the structure and operation of our brain.</span></p><p><span style="font-weight: 400;">But saying that “DNA is used to produce proteins” is a lot like saying that a blueprint is used to make a house: there are a lot of very complicated steps that need to happen to get from one to the other. DNA is used as kind of a “template” to make RNA strands that travel out into the cell to make the proteins. But not every part of the DNA is useful: when the RNA strand is first made, the important parts are mixed in with “introns” (or segments that shouldn’t be used), and “cryptic exons” (segments that are only supposed to be used some of the time).</span></p><p class="shortcode-media shortcode-media-rebelmouse-image"><img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yMjA0NTYwMy9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTY1NjY3MTM0Mn0.KjI-kgNB5HSGeccvCLM5bCkOVptmRFWUdCGKqiC_1bk/img.jpg?width=980" id="988b5" class="rm-shortcode" data-rm-shortcode-id="d796f6d0ec9ef83a6fc8d32a202854ec" data-rm-shortcode-name="rebelmouse-image"><small class="image-media media-caption" placeholder="add caption..."><a href="https://assets.rbl.ms/22045605/origin.jpg"></a> via Flickr user <a href="https://www.flickr.com/photos/kyz/3340435836/in/photolist-66bBcj-EV6Tu-4rKYZk-4adoJP-6DCAiL-7JQMHY-beGnKg-87woEB-5cenX-bUqM6a-2DW2N-7xrrvu-hhtxEE-4UaQAV-4gqRir-8DHjAj-bquTfb-7i92zp-4pfQWn-9qs76r-agtx9X-9epzdb-4pfQVz-5zpAR-5hvXRf-p6YGQ-4gy5Wc-f9JLE-fQgpE6-foepqv-6QXuSD-hY8WDp-7KZrSc-79LmGq-o1vXDw-8wJacK-8wMarU-5JfKCZ-667tcX-hpj6y6-4HiqxP-hLqAjY-6Nxxbs-e5grRc-C7G5s-4i7Wsj-9H1YHE-4ySHZE-5SMzkY-atptQC" target="_blank">Stuart Caie</a></small></p><p><span style="font-weight: 400;">This strand (called “pre-messenger RNA”) has to go through a complicated chemical “cut and paste” process before it is ready to go make proteins. Your cell has to snip out the important parts of the RNA code, remove any segments that shouldn’t be involved in making the protein, and piece the important bits back together. When that process is done, the result is messenger RNA that is ready to create proteins. (If you’re really curious about learning more about this process, check out chapter 29 in the excellent textbook </span><i><span style="font-weight: 400;">Biochemistry, Third Edition </span></i><span style="font-weight: 400;">by Reginald Garrett and Charles Grisham.)</span></p><p><span style="font-weight: 400;">This level of detail may make your head spin, but this process is important because the protein identified as related to ALS, protein TDP-43, plays a critical role in the cut-and-paste process that is going on in the nucleus of the cell. You can think of TDP-43 as a kind of stencil that attaches itself to the pre-messenger RNA, indicating where the “cutting” needs to </span></p><p></p><p><span style="font-weight: 400;">be done in order to remove the unneeded DNA segments and pick out the parts that are supposed to be used to make the protein.</span></p><p><span style="font-weight: 400;">As you can imagine, when TDP-43 isn’t functioning properly, this copy-and-paste procedure can go very wrong. When not enough TDP-43 is available, it can lead to copying errors, and cryptic exons being activated in the final strand of RNA when they should not be.</span></p><p><span style="font-weight: 400;">What happens when cryptic exons that ought to have been suppressed by TDP-43 are not suppressed? The final products, the proteins, come out deformed. The cell cannot use them properly and ends up getting sick. If enough dysfunctional proteins are created, the cell will die.</span></p><p class="shortcode-media shortcode-media-rebelmouse-image"><img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yMjA0NTYwNC9vcmlnaW4ucG5nIiwiZXhwaXJlc19hdCI6MTY0OTAyODc2MH0.J8xBV_KlHcjli-dBwM_XDkKl4DiBXLpD67emwWeyivY/img.png?width=980" id="a2a9e" class="rm-shortcode" data-rm-shortcode-id="47919d11cfc978141ab551e02549c325" data-rm-shortcode-name="rebelmouse-image"><small class="image-media media-caption" placeholder="add caption..."><a href="https://assets.rbl.ms/22045604/origin.png"></a> Structure of the TARDBP protein (TDP-43) via <a href="https://commons.wikimedia.org/wiki/File:Protein_TARDBP_PDB_1wf0.png" target="_blank">Wikipedia</a></small></p><p><span style="font-weight: 400;">Over the last decade, there has been a </span><a href="http://nar.oxfordjournals.org/content/34/12/3494.full" target="_blank"><span style="font-weight: 400;">huge amount of research</span></a><span style="font-weight: 400;"> that examines how the improper “activation” of cryptic exons can lead to errors in the production of proteins, which will cause them to be malformed. The new discovery by the team at Johns Hopkins was the discovery of how the “clumping” of TDP-43 in the nerve cells of ALS patients directly relates to their symptoms of muscular degeneration.</span></p><p><span style="font-weight: 400;">According to the summary published </span><a href="http://www.hopkinsmedicine.org/news/media/releases/scientists_report_explanation_for_protein_clumps_in_autopsy_brain_cells_of_als_patients_" target="_blank"><span style="font-weight: 400;">at the Johns Hopkins Medicine website</span></a><span style="font-weight: 400;">, the researchers tested a theory that was fairly straight-forward once you know all the details. In ALS patients, TDP-43 clumps up in the nerve cells. When the TDP-43 is deformed, it can’t perform its function in the transcription process. As a result, the lack of functional TDP-43 results in more activation of cryptic exons, which leads to more errors in the creation of proteins. The build-up of malformed proteins then ends up gradually killing the nerve cells in the muscle.</span></p><p></p><p><span style="font-weight: 400;">It is a brilliant theory, and the first time an actual story could be told to explain the cause-effect relationships that were producing ALS symptoms. Moreover, the researchers have taken the first steps to testing the theory by proposing a treatment. If this story is correct, then if patients can be treated with a substitute protein that performs the same function as TDP-43, suppressing the cryptic exons and improving the transcription process, their symptoms would be alleviated. They tried it, and it worked: they inserted a custom-designed protein into affected cells, and </span><a href="http://www.nytimes.com/2015/09/03/opinion/nicholas-kristof-payday-for-ice-bucket-challenges-mocked-slacktivists.html?_r=0" target="_blank"><span style="font-weight: 400;">the cells returned to normal</span></a><span style="font-weight: 400;">. The next step is to test the therapeutic strategy in animals afflicted by ALS to see if it can halt the symptoms.</span></p><p><span style="font-weight: 400;">Obviously this is a fantastic breakthrough for ALS. Philip Wong, one of the researchers on the project, has also said that </span><a href="http://www.nytimes.com/2015/09/03/opinion/nicholas-kristof-payday-for-ice-bucket-challenges-mocked-slacktivists.html?_r=0" target="_blank"><span style="font-weight: 400;">similar mechanisms may be at work</span></a><span style="font-weight: 400;"> in other age-related degenerative conditions, as well. This could lead to an entire line of research on possible treatments for frontotemporal dementia, inclusion body myositis, and a variety of other neurological and degenerative diseases.</span></p><p><span style="font-weight: 400;">But there is another reason to find the details of this breakthrough interesting: the relationship between genetics and disease, and indeed between genetics and any physical trait or condition. Is ALS genetic? It’s clearly triggered by genetics and the operation of DNA in the body. But it’s also not a simple matter of some genetic “switch” turning on an illness. The connection between genes and physical traits is enormously complex, in ways that most people don’t think about. It is a complicated dance between enzymes and proteins, and “cryptic” strands of DNA that sometimes are turned on and sometimes are turned off, that will alter the outcome of how genes are expressed.</span></p><p><span style="font-weight: 400;">That’s something to think about, the next time you read a science fiction novel or a news story about the “genetic causes” for things. Whether you’re talking about the genetic control of intelligence, illnesses, personality, athletic skills or even X-men superpowers, the story is never as simple as people want it to be.</span></p><p><em>Featured image: ALS Ice Bucket Challenge via Flickr user <a href="https://www.flickr.com/photos/121483302@N02/15081171240/in/photolist-oA8aZT-oYEWMN-ouNtHr-cUPQAw" target="_blank">Global Panorama</a></em></p>
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