Study calls out the genes that make cancer cells so hard to kill
Researchers from the University of Toronto published a new map of cancer cells' genetic defenses against treatment.
There's a great diversity among cancer cells, though many of them share one unfortunate trait: They're often quite adept at resisting the body's immune system. The immune system's T killer cells can theoretically take out cancer cells, and immunotherapies enhance existing T cells' potency. Still, cancer cells are often impervious to them, can mutate to evade them, and worst of all, can acquire "cancer resistance mutations" that cause the disease to worsen in response to T cells. This is especially true of the cells in solid tumors.
A study from researchers at University of Toronto catalogs the genes in cancer tumors that allow the disease to so effectively resist immunotherapy. Its authors hope that their findings will eventually lead to the development of more successful cancer treatments.
The study is published in the journal Nature.
A moving target
Credit: Marcelo Leal/Unsplash
Speaking to U of T News, lead author of the study molecular geneticist Jason Moffat of the university's Donnelly Centre for Cellular and Biomolecular Research says, "Over the last decade, different forms of immunotherapy have emerged as really potent cancer treatments, but the reality is that they only generate durable responses in a fraction of patients and not for all tumor types."
There can be a significant degree of heterogeneity between cancer cells from human to human, and even within the same person, making the development of therapies maddeningly difficult. Attempting to address potential cancer-cell vulnerabilities across these variations is a life-or-death game of whack-a-mole.
"It's an ongoing battle between the immune system and cancer, where the immune system is trying to find and kill the cancer whereas the cancer's job is to evade that killing," says Moffat.
Mapping the mechanisms
Illustration: genes (red, green, and blue spots within the nuclei of HeLa cells) artificially superimposed on images of multi-well plates.
Credit: National Cancer Institute/Unsplash
Moffat and his colleagues decided to investigate and identify genes within cancer cells that help them defeat treatment. Co-lead author Keith Lawson of Moffat's lab explains that "it's important to not just find genes that can regulate immune evasion in one model of cancer, but what you really want are to find those genes that you can manipulate in cancer cells across many models because those are going to make the best therapeutic targets."
To accomplish this, the researchers, working with scientists at Agios Pharmaceuticals in Cambridge, Massachusetts, first exposed cells from breast, colon, kidney and skin cancer tumors to T cells in lab dishes. This established a baseline of their responses to treatment. Next, using CRISPR, the scientists went through the cells, exhaustively turning off one gene at a time to determine its role in immunotherapy resistance by comparing the cells' response to the T cells compared to their original baseline response.
The team identified 182 "core cancer intrinsic immune evasion genes" that affected the cells' response to T cells. The fact that some of the identified genes were already known to be involved in resistance provided the researchers with some confidence that they were on the right track.
Still, many of the genes they ID'ed had not been previously implicated. "That was really exciting to see because it means that our dataset was very rich in new biological information," says Lawson.
Unfortunately, Moffat's research also makes clear that defeating cancer-cell resistance is not as simple as removing certain genes. It's true that when the team switched off some of the genes they'd identified, the cancer cells became more vulnerable to T cells, but on the other hand, removal of some other genes made the cancer cells more resistant.
There also appear to be relationships between multiple genes that complicate matters.
The team explored the manipulation of the genes that allow cancer cells to engage in autophagy, the process by which cells clear out no-longer useful materials to facilitate speedy recovery from damage. Surprisingly, when the researchers deleted certain genes responsible for cancer cells' autophagy, they found the cells' resistance to T cells increased. Apparently, removing one autophagy gene strengthened another mutated autophagy gene.
"We found this complete inversion of gene dependency," said Moffat. "We did not anticipate this at all. What it shows us is that genetic context — what mutations are present — very much dictates whether the introduction of the second mutation will cause no effect, resistance or sensitivity to therapy."
There remains a long road ahead when it comes to unraveling cancer cells' resistance to immunotherapy. However, this new study presents a new map that can help scientists navigate what comes next.
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While legalization has benefits, a new study suggests it may have one big drawback.
- A new study finds that rates of marijuana use and addiction have gone up in states that have recently legalized the drug.
- The problem was most severe for those over age of 26, with cases of addiction rising by a third.
- The findings complicate the debate around legalization.
Cannabis Use Disorder, is that when you get so high you can’t figure out how to smoke anymore?<div class="rm-shortcode" data-media_id="hfrVfwoH" data-player_id="FvQKszTI" data-rm-shortcode-id="0e62d9cb9c0a2361f81e9b5278706614"> <div id="botr_hfrVfwoH_FvQKszTI_div" class="jwplayer-media" data-jwplayer-video-src="https://content.jwplatform.com/players/hfrVfwoH-FvQKszTI.js"> <img src="https://cdn.jwplayer.com/thumbs/hfrVfwoH-1920.jpg" class="jwplayer-media-preview" /> </div> <script src="https://content.jwplatform.com/players/hfrVfwoH-FvQKszTI.js"></script> </div> <p><a href="https://www.ncbi.nlm.nih.gov/books/NBK538131/" target="_blank">Cannabis use disorder</a>, also known as CUD or cannabis/marijuana addiction, is a psychological disorder described in DSM 5 as "the continued use of cannabis despite clinically significant impairment." This includes people being unable to cut down on their usage despite wanting to, those who often use it despite finding it severely impairs their ability to function, or those who are putting themselves in danger to secure access to the drug.</p><p>While an understanding that marijuana can be addictive has existed for some time, and the image of the pothead who smokes so much they can hardly function is prevalent in our society, the effects of legalization on addiction rates have somehow gone understudied until now. Importantly, previous studies had failed to consider usage rates amongst populations over the age of 25.</p><p>In the new study, published in <a href="https://jamanetwork.com/journals/jamapsychiatry/article-abstract/2755276?utm_campaign=articlePDF%26utm_medium%3darticlePDFlink%26utm_source%3darticlePDF%26utm_content%3djamapsychiatry.2019.3254" target="_blank">JAMA Psychiatry</a>, focused on self-reported data on monthly drug use in four states where marijuana is now legal, Colorado, Washington, Alaska, and Oregon, from both before and after the drug was legalized in each state and compared it to others which have not yet legalized.</p><p>The data gave insights into the drug use habits of the respondents and specifically gave information about if they had smoked at all in the last month, the frequency of their drug use, and if they had ever had issues with how much they were using drugs.The researchers ultimately considered the responses of 505,796 individuals.</p><p>The increase in cannabis usage they found was <a href="https://www.newsweek.com/cannabis-use-disorder-rising-us-states-where-weed-legal-1471170" target="_blank">considerable</a>. The number of respondents over the age of 26 who claimed to have used the drug in the last month went up by 23% compared with their counterparts in states that have yet to legalize. Abuse of the drug by this group rose by 37%. </p><p>Teen usage rose by 25%, and addiction rates rose as well. This increase was small, though, and the authors have suggested it may be due to an unknown factor. The rate of usage or abuse for respondents between the ages of 18 and 25 did not increase at all. </p><p>After breaking the results down by demographics, the primary finding held; adults over the age of 26 are using marijuana more often when it is legalized, and they are starting to use it too much.</p>
The grain of salt<p>As in any study where findings are self-reported, the exact numbers you see here should be taken with a grain of salt. They could be slightly higher or lower. As this study relies on people self-reporting their usage of a drug that is still illegal in many places, it is very possible that the apparent spike in addiction rates is caused by more accurate reporting, as people who live in an area where pot is still illegal may be less likely to report smoking it every day.</p><p>And it should be repeated a thousand times over that correlation and causation are not the same thing. There could be some unknown factor causing these increases in each case. </p><p>Despite these qualifications, the study is still useful in giving us a general sense of what may happen in states that have yet to legalize. </p>
What does this mean for society and drug users?<div class="rm-shortcode" data-media_id="BdVRmwgX" data-player_id="FvQKszTI" data-rm-shortcode-id="d5c2f9e3739c26170f98b48bf07a3444"> <div id="botr_BdVRmwgX_FvQKszTI_div" class="jwplayer-media" data-jwplayer-video-src="https://content.jwplatform.com/players/BdVRmwgX-FvQKszTI.js"> <img src="https://cdn.jwplayer.com/thumbs/BdVRmwgX-1920.jpg" class="jwplayer-media-preview" /> </div> <script src="https://content.jwplatform.com/players/BdVRmwgX-FvQKszTI.js"></script> </div> <p>While claims of "reefer madness" are greatly exaggerated, marijuana has several well established and thoroughly studied side <a href="https://en.wikipedia.org/wiki/Long-term_effects_of_cannabis#Mental_health" target="_blank">effects</a>. While occasional use isn't terribly harmful, addiction can be. Lead author Magdalena Cerdá of New York University explains in the study that heavy marijuana use is associated with "psychological and physical health concerns, lower educational attainment, decline in social class, unemployment, and motor vehicle crashes."</p><p>A substantial increase in the number of people who are addicted to the stuff will incur costs to society down the line. <strong></strong></p><p>Of course, a 37% increase in problematic usage means that the percentage of adults smoking too much went from .9% to 1.23% of the population responding to the survey. This makes it far less prevalent than issues with alcohol, which affected around 6% of all Americans in <a href="https://www.verywellmind.com/prevalence-of-alcoholism-in-the-united-states-67876" target="_blank">2018</a>. </p><p>Recently, Big Think's <a href="https://bigthink.com/u/philip-perry" target="_self">Philip Perry</a> wrote a piece about how <a href="https://bigthink.com/want-to-protect-the-health-of-35-million-americans-legalize-cannabis" target="_self">legalization could improve the health of millions</a> by allowing the government to regulate the purity of commercially sold marijuana. This remains true. However, it must be weighed against the findings of this study, which suggests that at least some of these health gains will be wiped out by increased addiction rates.</p>
What does this mean for legalization efforts?<div class="rm-shortcode" data-media_id="bnPA9J9g" data-player_id="FvQKszTI" data-rm-shortcode-id="429e1d17ba031b02d4e79b4f02f54ab5"> <div id="botr_bnPA9J9g_FvQKszTI_div" class="jwplayer-media" data-jwplayer-video-src="https://content.jwplatform.com/players/bnPA9J9g-FvQKszTI.js"> <img src="https://cdn.jwplayer.com/thumbs/bnPA9J9g-1920.jpg" class="jwplayer-media-preview" /> </div> <script src="https://content.jwplatform.com/players/bnPA9J9g-FvQKszTI.js"></script> </div> <p>The legalization steamroller will undoubtedly keep rolling along. While health concerns are one factor in the debate over marijuana, it is only one of many. In Illinois, where I live, weed will become legal on January 1<sup>st</sup> of 2020. The legalization campaign and <a href="https://www.chicagotribune.com/politics/ct-met-illinois-recreational-marijuana-legislation-20190531-story.html" target="_blank">legislation</a> were more concerned with issues of social justice, the failures of prohibition, and finding a new source of tax revenue (<a href="https://www.chicagotribune.com/news/breaking/ct-illinois-tickets-collection-agencies-20190703-20190711-gyf77w52mbcdxkaxpleeay277a-story.html" target="_blank">since we're half broke</a>) than with matters of potential addiction.</p><p>As Vox <a href="https://www.vox.com/policy-and-politics/2019/11/13/20962924/marijuana-legalization-use-addiction-study" target="_blank">reports</a>, the authors of the study aren't suggesting that legalization shouldn't take place; that is another, broader debate. They merely wish to present the fact that legalization has a particular side effect that we should be aware of.</p><p>While this study is unlikely to change anybody's stance on if weed should be legalized or not, it does show us a critical element to be considered when discussing drug policy. No drug is perfectly safe, and we have reason to believe that legalizing marijuana will mean that more people will have a hard time with it. Let's hope that legalization proponents keep that in mind as they rack up their victories. </p>
Tea and coffee have known health benefits, but now we know they can work together.
Credit: NIKOLAY OSMACHKO from Pexels
- A new study finds drinking large amounts of coffee and tea lowers the risk of death in some adults by nearly two thirds.
- This is the first study to suggest the known benefits of these drinks are additive.
- The findings are great, but only directly apply to certain people.
Maybe you should enjoy this article with a cup of coffee or tea.<p> The <a href="https://drc.bmj.com/content/8/1/e001252?T=AU" target="_blank" rel="noopener noreferrer">study</a> involved 4,923 type 2 diabetics living in Japan. The average participant was 66 years old. All of the participants were taken from the rolls of the Fukuoka Diabetes Registry, a study geared at learning about the effects of new treatments and lifestyle changes on the health of diabetics. <br> <br> The participants filled out questionnaires concerning their health, diet, habits, and other factors. Among the questions were two focused on determining how much green tea or coffee, if any, the participants consumed over the course of a week. The health of the participants was recorded for five years. During this time, 309 of the test subjects died from a variety of causes. <br> <br> Subjects who drank more than one cup of tea or coffee per day demonstrated lower odds of dying than those who had none. Those who consumed the most tea and coffee, more than four and two cups a day, respectively, enjoyed the most significant reductions in their risk of death. This level of consumption was associated with a 40 percent lower risk of <a href="https://www.sciencedaily.com/releases/2020/10/201020190129.htm" target="_blank" rel="noopener noreferrer">death</a>. </p><p>Most interestingly, the effects of drinking tea and coffee appear to combine to reduce risk even further. Those who reported drinking two or three cups of tea a day and two or more cups of coffee were 51 percent less likely to die during the study, while those who drank a whopping four or more cups of tea and two or more cups of coffee had a 63 percent lower risk of <a href="https://www.medicalnewstoday.com/articles/diabetes-coffee-and-green-tea-might-reduce-death-risk" target="_blank" rel="noopener noreferrer">death</a>. </p>
So, should I start swimming in a vat of coffee and green tea?<iframe width="730" height="430" src="https://www.youtube.com/embed/LY0E-JQxeoY" frameborder="0" allow="accelerometer; autoplay; clipboard-write; encrypted-media; gyroscope; picture-in-picture" allowfullscreen></iframe><p> Not quite. </p><p> The primary takeaway from this study is that Japanese adults with type 2 diabetes who drink a lot of green tea and/or coffee die less often than similar people who do not. If this effect is caused by something in the drink, lifestyle choices people who drink that much tea all make, or something else remains unknown. The finding must be considered an association at this point. <br> <br> The eye-popping reductions in mortality rates are compared to the risk of death of others in the study. The people who died reported drinking less tea and coffee than those who lived. Unless you have several demographic and conditional similarities to the subjects of this study, you probably won't suddenly be at a two-thirds lower risk of death than your peers because you drink green tea. </p><p> Like all studies that depend on self-reporting, it is also possible that people misstated how much they consumed any one item. The study also did not look into other factors like socioeconomic status or education level, also known to impact death rates and potentially linked to coffee and tea consumption. </p><p> However, it is yet another study in the pile that suggests that <a href="https://www.healthline.com/nutrition/top-13-evidence-based-health-benefits-of-coffee" target="_blank" rel="noopener noreferrer">coffee</a> and <a href="https://www.healthline.com/nutrition/top-10-evidence-based-health-benefits-of-green-tea" target="_blank" rel="noopener noreferrer">green tea</a> are good for you. That much is increasingly <a href="https://www.health.harvard.edu/press_releases/health-benefits-linked-to-drinking-tea" target="_blank" rel="noopener noreferrer">agreed</a><a href="https://www.rush.edu/health-wellness/discover-health/health-benefits-coffee" target="_blank" rel="noopener noreferrer"> upon</a>. This study also suggests the benefits are additive, which is a new development.</p><p><br> So, while it isn't time to start the IV drip of green tea, a cup or two probably won't <a href="https://www.webmd.com/diabetes/news/20201022/coffee-green-tea-might-extend-life-for-folks-with-type-2-diabetes" target="_blank" rel="noopener noreferrer">hurt</a>. </p>
But most city dwellers weren't seeing the science — they were seeing something out of Blade Runner.
On Sept. 9, many West Coast residents looked out their windows and witnessed a post-apocalyptic landscape: silhouetted cars, buildings and people bathed in an overpowering orange light that looked like a jacked-up sunset.