Researchers from the University of Toronto published a new map of cancer cells' genetic defenses against treatment.
A moving target<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yNDQzNjQ2Ny9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTY1MDM3OTA0N30.z4u2eaulqRu8cslqqny8t9G7iaHr_DarbDJSFKLdDwI/img.jpg?width=980" id="21b22" class="rm-shortcode" data-rm-shortcode-id="aefbbccdf3bb0d25bf14268ab87a821f" data-rm-shortcode-name="rebelmouse-image" alt="IV drip" />
Credit: Marcelo Leal/Unsplash<p>Speaking to <a href="https://www.utoronto.ca/news/u-t-researchers-identify-genes-enable-cancer-evade-immune-system" target="_blank" rel="noopener noreferrer">U of T News</a>, lead author of the study molecular geneticist <a href="http://www.moleculargenetics.utoronto.ca/faculty/2014/9/30/jason-moffat" target="_blank" rel="noopener noreferrer">Jason Moffat</a> of the university's <a href="https://ccbr.utoronto.ca/donnelly-centre-cellular-and-biomolecular-research" target="_blank" rel="noopener noreferrer">Donnelly Centre for Cellular and Biomolecular Research</a> 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."</p><p>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.</p><p>"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.</p>
Mapping the mechanisms<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yNDQzNjQ3Ni9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTYyMjQ1OTM0MX0.HNtivrlU9VBYxcG9JaWKvPJ5RrBsgqd8Fw6ohfSpfh0/img.jpg?width=980" id="0faa6" class="rm-shortcode" data-rm-shortcode-id="7687cdc5abe93503764c1c0401b65fd4" data-rm-shortcode-name="rebelmouse-image" />
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<p>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."</p><p>To accomplish this, the researchers, working with scientists at <a href="https://www.agios.com" target="_blank">Agios Pharmaceuticals</a> 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.</p><p>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.</p><p>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.</p>
It's complicated<p>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.</p><p>There also appear to be relationships between multiple genes that complicate matters. </p><p>The team explored the manipulation of the genes that allow cancer cells to engage in <a href="https://en.wikipedia.org/wiki/Autophagy" target="_blank">autophagy</a>, 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.</p><p>"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."</p><p>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.</p>
Is CRISPR the solution?
Even as the COVID-19 pandemic cripples the economy and kills hundreds of people each day, there is another epidemic that continues to kill tens of thousands of people each year through opioid drug overdose.
New research shows how Americans feel about genetic engineering, human enhancement and automation.
- A review of Pew Research studies reveals the views of Americans on the role of science in society.
- 4 key questions were asked to gauge feelings on genetic engineering, automation and human enhancement.
- Americans are split in how they view technology and many worry about its growing role.
Watch Elon Musk’s presentation on Neuralink here:<span style="display:block;position:relative;padding-top:56.25%;" class="rm-shortcode" data-rm-shortcode-id="a646a0b439db89b498836659049faf35"><iframe type="lazy-iframe" data-runner-src="https://www.youtube.com/embed/lA77zsJ31nA?rel=0" width="100%" height="auto" frameborder="0" scrolling="no" style="position:absolute;top:0;left:0;width:100%;height:100%;"></iframe></span>
A punishment is handed down for performing shocking research on human embryos.
- In November 2018, a Chinese scientist claimed he'd flouted ethics and the law to edit genes in human embryos.
- Other Chinese scientists call He Jiankui's research "crazy."
- Three gene-modified babies are now living in China, future uncertain.
He's experiments<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yMjI2NTE1Ny9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTYyNjE0MDI2Mn0.pD6za00yORg0ZH6nk0RJLh3SBOzed7uc1oh9yZDe3tc/img.jpg?width=980" id="98186" class="rm-shortcode" data-rm-shortcode-id="5a306efb5afbd1a936315f28134a8417" data-rm-shortcode-name="rebelmouse-image" />
He tells the world
Image source: Anthony Wallace/Getty<p>When He first announced his research in November 2018 at the Second International Summit on Human Genome Editing in Hong Kong, the scientific community was stunned at this deliberate flaunting of scientific consensus and Chinese law. A <a href="https://www.yicai.com/news/100067069.html" target="_blank">statement</a> from 122 Chinese scientists referred to He's work as "crazy" and called it "a huge blow to the global reputation and development of Chinese science."</p><p>He, an associate professor at Southern University of Science and Technology in Shenzhen, China, claimed to have used CRISPR-cas9 in an attempt to provide embryos with immunity to HIV. The DNA in 16 embryos was altered, and 11 of these were used in six implant attempts that eventually led to the successful pregnancy of three infants. </p><p>After the announcement, Julian Savulescu of University of Oxford told <a href="https://www.theguardian.com/science/2018/nov/26/worlds-first-gene-edited-babies-created-in-china-claims-scientist" target="_blank"><em>The Guardian</em></a>, "If true, this experiment is monstrous," adding that, "There are many effective ways to prevent HIV in healthy individuals: for example, protected sex. And there are effective treatments if one does contract it. This experiment exposes healthy normal children to risks of gene editing for no real necessary benefit." While there <em>are</em> <a href="https://www.avert.org/professionals/hiv-around-world/asia-pacific/china" target="_blank">HIV infections in China</a>, there was no indication that the embryos had been infected.</p><p>In his announcement, He claimed to have inserted a mutated form of the CCR5 gene into the embryos' genome, a particular mutation that makes a small number of people immune to HIV. <a href="https://www.theguardian.com/science/2018/nov/26/worlds-first-gene-edited-babies-created-in-china-claims-scientist" target="_blank">According to</a> Kiran Musunuru of University of Pennsylvania, though, the mutation has a nasty downside: People who have it are at higher risk of contracting other, non-HIV viruses, and of dying of the flu. So, while potentially shielding his subjects from HIV, He was, in essence, consigning them to a lifetime of enhanced vulnerability to all sorts of more common infections.</p><p>It's likely, however, that He never actually produced or inserted the CCR5 mutation in any event. Excerpts of He's documentation published in <a href="https://www.technologyreview.com/s/614764/chinas-crispr-babies-read-exclusive-excerpts-he-jiankui-paper/" target="_blank"><em>MIT Technology Review</em></a> suggest that what He created were some new kinds of CCR5 mutations, as well as unintended gene mutations elsewhere in the genome, and the effect of all of these edits are anyone's guess. After reviewing the excerpts, University of California, Berkeley's Fyodor Urnov <a href="https://www.theguardian.com/science/2018/nov/26/worlds-first-gene-edited-babies-created-in-china-claims-scientist" target="_blank">concluded</a> He's claim was "a deliberate falsehood."</p>
What the court said<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yMjI2NTU5NS9vcmlnaW4uanBnIiwiZXhwaXJlc19hdCI6MTY0MzkyOTExM30.W-iOUnHs0lXu59_5Wqq6ACnLouuscxg4dr-ySfS1pjg/img.jpg?width=980" id="03f5e" class="rm-shortcode" data-rm-shortcode-id="0ce199d4f8ebb8abea1a6b9b2341146e" data-rm-shortcode-name="rebelmouse-image" />
He Jiankui and his genetic research team
Image source: VCG/Getty<p>Two of He's colleagues involved in the research were also convicted by the Shenzhen court. According to Chinese news outlet <em>Xinhua</em>, the court found:</p><p style="margin-left: 20px;"><em>"The three accused did not have the proper certification to practice medicine, and in seeking fame and wealth, deliberately violated national regulations in scientific research and medical treatment. They've crossed the bottom line of ethics in scientific research and medical ethics."</em></p><p>The court also ruled that He had forged documents from an ethics review panel.</p><p>The other two researchers found guilty were Zhang Renli, who was sentenced to two years in prison and fined one million yuan (about $143,000), and Qin Jinzhou, whose 18-month sentence came with a two-year reprieve, and a 500,000 yuan ($71,000) fine.</p>
Experts are saying it's a "huge step forward for synthetic biology."
- Until recently, the gene-editing tool CRISPR has only been able to make changes within single genes.
- The new tools allow scientists to cut and splice larger chunks of genetic material.
- The findings will likely have major implications for a variety of research fields, and also allow researchers to create synthetic species that can produce molecules not made by natural organisms.