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Drug makes tumors more susceptible to chemo
One compound could help combat drug resistance.
Many chemotherapy drugs kill cancer cells by severely damaging their DNA.
However, some tumors can withstand this damage by relying on a DNA repair pathway that not only allows them to survive, but also introduces mutations that helps cells become resistant to future treatment.
Researchers at MIT and Duke University have now discovered a potential drug compound that can block this repair pathway. "This compound increased cell killing with cisplatin and prevented mutagenesis, which is was what we expected from blocking this pathway," says Graham Walker, the American Cancer Society Research Professor of Biology at MIT, a Howard Hughes Medical Institute Professor, and one of the senior authors of the study.
When they treated mice with this compound along with cisplatin, a DNA-damaging drug, tumors shrank much more than those treated with cisplatin alone. Tumors treated with this combination would be expected not to develop new mutations that could make them drug-resistant.
Cisplatin, which is used as the first treatment option for at least a dozen types of cancer, often successfully destroys tumors, but they frequently grow back following treatment. Drugs that target the mutagenic DNA repair pathway that contributes to this recurrence could help to improve the long-term effectiveness of not only cisplatin but also other chemotherapy drugs that damage DNA, the researchers say.
"We're trying to make the therapy work better, and we also want to make the tumor recurrently sensitive to therapy upon repeated doses," says Michael Hemann, an associate professor of biology, a member of MIT's Koch Institute for Integrative Cancer Research, and a senior author of the study.
Pei Zhou, a professor of biochemistry at Duke University, and Jiyong Hong, a professor of chemistry at Duke, are also senior authors of the paper, which appears in the June 6 issue of Cell. The lead authors of the paper are former Duke graduate student Jessica Wojtaszek, MIT postdoc Nimrat Chatterjee, and Duke research assistant Javaria Najeeb.
Healthy cells have several repair pathways that can accurately remove DNA damage from cells. As cells become cancerous, they sometimes lose one of these accurate DNA repair systems, so they rely heavily on an alternative coping strategy known as translesion synthesis (TLS).
This process, which Walker has been studying in a variety of organisms for many years, relies on specialized TLS DNA polymerases. Unlike the normal DNA polymerases used to replicate DNA, these TLS DNA polymerases can essentially copy over damaged DNA, but the copying they perform is not very accurate. This enables cancer cells to survive treatment with a DNA-damaging agent such as cisplatin, and it leads them to acquire many additional mutations that can make them resistant to further treatment.
"Because these TLS DNA polymerases are really error-prone, they are accountable for nearly all of the mutation that is induced by drugs like cisplatin," Hemann says. "It's very well-established that with these frontline chemotherapies that we use, if they don't cure you, they make you worse."
One of the key TLS DNA polymerases required for translesion synthesis is Rev1, and its primary function is to recruit a second TLS DNA polymerase that consists of a complex of the Rev3 and Rev7 proteins. Walker and Hemann have been searching for ways to disrupt this interaction, in hopes of derailing the repair process.
In a pair of studies published in 2010, the researchers showed that if they used RNA interference to reduce the expression of Rev1, cisplatin treatment became much more effective against lymphoma and lung cancer in mice. While some of the tumors grew back, the new tumors were not resistant to cisplatin and could be killed again with a new round of treatment.
After showing that interfering with translesion synthesis could be beneficial, the researchers set out to find a small-molecule drug that could have the same effect. Led by Zhou, the researchers performed a screen of about 10,000 potential drug compounds and identified one that binds tightly to Rev1, preventing it from interacting with Rev3/Rev7 complex.
The interaction of Rev1 with the Rev7 component of the second TLS DNA polymerase had been considered "undruggable" because it occurs in a very shallow pocket of Rev1, with few features that would be easy for a drug to latch onto. However, to the researchers' surprise, they found a molecule that actually binds to two molecules of Rev1, one at each end, and brings them together to form a complex called a dimer. This dimerized form of Rev1 cannot bind to the Rev3/Rev7 TLS DNA polymerase, so translesion synthesis cannot occur.
Chatterjee tested the compound along with cisplatin in several types of human cancer cells and found that the combination killed many more cells than cisplatin on its own. And, the cells that survived had a greatly reduced ability to generate new mutations.
"Because this novel translesion synthesis inhibitor targets the mutagenic ability of cancer cells to resist therapy, it can potentially address the issue of cancer relapse, where cancers continue to evolve from new mutations and together pose a major challenge in cancer treatment," Chatterjee says.
A powerful combination
Chatterjee then tested the drug combination in mice with human melanoma tumors and found that the tumors shrank much more than tumors treated with cisplatin alone. They now hope that their findings will lead to further research on compounds that could act as translesion synthesis inhibitors to enhance the killing effects of existing chemotherapy drugs.
Zhou's lab at Duke is working on developing variants of the compound that could be developed for possible testing in human patients. Meanwhile, Walker and Hemann are further investigating how the drug compound works, which they believe could help to determine the best way to use it.
"That's a future major objective, to identify in which context this combination therapy is going to work particularly well," Hemann says. "We would hope that our understanding of how these are working and when they're working will coincide with the clinical development of these compounds, so by the time they're used, we'll understand which patients they should be given to."
The research was funded, in part, by an Outstanding Investigator Award from the National Institute of Environmental Health Sciences to Walker, and by grants from the National Cancer Institute, the Stewart Trust, and the Center for Precision Cancer Medicine at MIT.
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How would the ability to genetically customize children change society? Sci-fi author Eugene Clark explores the future on our horizon in Volume I of the "Genetic Pressure" series.
- A new sci-fi book series called "Genetic Pressure" explores the scientific and moral implications of a world with a burgeoning designer baby industry.
- It's currently illegal to implant genetically edited human embryos in most nations, but designer babies may someday become widespread.
- While gene-editing technology could help humans eliminate genetic diseases, some in the scientific community fear it may also usher in a new era of eugenics.
Tribalism and discrimination<p>One question the "Genetic Pressure" series explores: What would tribalism and discrimination look like in a world with designer babies? As designer babies grow up, they could be noticeably different from other people, potentially being smarter, more attractive and healthier. This could breed resentment between the groups—as it does in the series.</p><p>"[Designer babies] slowly find that 'everyone else,' and even their own parents, becomes less and less tolerable," author Eugene Clark told Big Think. "Meanwhile, everyone else slowly feels threatened by the designer babies."</p><p>For example, one character in the series who was born a designer baby faces discrimination and harassment from "normal people"—they call her "soulless" and say she was "made in a factory," a "consumer product." </p><p>Would such divisions emerge in the real world? The answer may depend on who's able to afford designer baby services. If it's only the ultra-wealthy, then it's easy to imagine how being a designer baby could be seen by society as a kind of hyper-privilege, which designer babies would have to reckon with. </p><p>Even if people from all socioeconomic backgrounds can someday afford designer babies, people born designer babies may struggle with tough existential questions: Can they ever take full credit for things they achieve, or were they born with an unfair advantage? To what extent should they spend their lives helping the less fortunate? </p>
Sexuality dilemmas<p>Sexuality presents another set of thorny questions. If a designer baby industry someday allows people to optimize humans for attractiveness, designer babies could grow up to find themselves surrounded by ultra-attractive people. That may not sound like a big problem.</p><p>But consider that, if designer babies someday become the standard way to have children, there'd necessarily be a years-long gap in which only some people are having designer babies. Meanwhile, the rest of society would be having children the old-fashioned way. So, in terms of attractiveness, society could see increasingly apparent disparities in physical appearances between the two groups. "Normal people" could begin to seem increasingly ugly.</p><p>But ultra-attractive people who were born designer babies could face problems, too. One could be the loss of body image. </p><p>When designer babies grow up in the "Genetic Pressure" series, men look like all the other men, and women look like all the other women. This homogeneity of physical appearance occurs because parents of designer babies start following trends, all choosing similar traits for their children: tall, athletic build, olive skin, etc. </p><p>Sure, facial traits remain relatively unique, but everyone's more or less equally attractive. And this causes strange changes to sexual preferences.</p><p>"In a society of sexual equals, they start looking for other differentiators," he said, noting that violet-colored eyes become a rare trait that genetically engineered humans find especially attractive in the series.</p><p>But what about sexual relationships between genetically engineered humans and "normal" people? In the "Genetic Pressure" series, many "normal" people want to have kids with (or at least have sex with) genetically engineered humans. But a minority of engineered humans oppose breeding with "normal" people, and this leads to an ideology that considers engineered humans to be racially supreme. </p>
Regulating designer babies<p>On a policy level, there are many open questions about how governments might legislate a world with designer babies. But it's not totally new territory, considering the West's dark history of eugenics experiments.</p><p>In the 20th century, the U.S. conducted multiple eugenics programs, including immigration restrictions based on genetic inferiority and forced sterilizations. In 1927, for example, the Supreme Court ruled that forcibly sterilizing the mentally handicapped didn't violate the Constitution. Supreme Court Justice Oliver Wendall Holmes wrote, "… three generations of imbeciles are enough." </p><p>After the Holocaust, eugenics programs became increasingly taboo and regulated in the U.S. (though some states continued forced sterilizations <a href="https://www.uvm.edu/~lkaelber/eugenics/" target="_blank">into the 1970s</a>). In recent years, some policymakers and scientists have expressed concerns about how gene-editing technologies could reanimate the eugenics nightmares of the 20th century. </p><p>Currently, the U.S. doesn't explicitly ban human germline genetic editing on the federal level, but a combination of laws effectively render it <a href="https://academic.oup.com/jlb/advance-article/doi/10.1093/jlb/lsaa006/5841599#204481018" target="_blank" rel="noopener noreferrer">illegal to implant a genetically modified embryo</a>. Part of the reason is that scientists still aren't sure of the unintended consequences of new gene-editing technologies. </p><p>But there are also concerns that these technologies could usher in a new era of eugenics. After all, the function of a designer baby industry, like the one in the "Genetic Pressure" series, wouldn't necessarily be limited to eliminating genetic diseases; it could also work to increase the occurrence of "desirable" traits. </p><p>If the industry did that, it'd effectively signal that the <em>opposites of those traits are undesirable. </em>As the International Bioethics Committee <a href="https://academic.oup.com/jlb/advance-article/doi/10.1093/jlb/lsaa006/5841599#204481018" target="_blank" rel="noopener noreferrer">wrote</a>, this would "jeopardize the inherent and therefore equal dignity of all human beings and renew eugenics, disguised as the fulfillment of the wish for a better, improved life."</p><p><em>"Genetic Pressure Volume I: Baby Steps"</em><em> by Eugene Clark is <a href="http://bigth.ink/38VhJn3" target="_blank">available now.</a></em></p>
The father of all giant sea bugs was recently discovered off the coast of Java.
- A new species of isopod with a resemblance to a certain Sith lord was just discovered.
- It is the first known giant isopod from the Indian Ocean.
- The finding extends the list of giant isopods even further.
The ocean depths are home to many creatures that some consider to be unnatural.<img type="lazy-image" data-runner-src="https://assets.rebelmouse.io/eyJhbGciOiJIUzI1NiIsInR5cCI6IkpXVCJ9.eyJpbWFnZSI6Imh0dHBzOi8vYXNzZXRzLnJibC5tcy8yMzU2NzY4My9vcmlnaW4ucG5nIiwiZXhwaXJlc19hdCI6MTYxNTUwMzg0NX0.BTK3zVeXxoduyvXfsvp4QH40_9POsrgca_W5CQpjVtw/img.png?width=980" id="b6fb0" class="rm-shortcode" data-rm-shortcode-id="2739ec50d9f9a3bd0058f937b6d447ac" data-rm-shortcode-name="rebelmouse-image" data-width="1512" data-height="2224" />
What benefit does this find have for science? And is it as evil as it looks?<div class="rm-shortcode" data-media_id="7XqcvwWp" data-player_id="FvQKszTI" data-rm-shortcode-id="8506fcd195866131efb93525ae42dec4"> <div id="botr_7XqcvwWp_FvQKszTI_div" class="jwplayer-media" data-jwplayer-video-src="https://content.jwplatform.com/players/7XqcvwWp-FvQKszTI.js"> <img src="https://cdn.jwplayer.com/thumbs/7XqcvwWp-1920.jpg" class="jwplayer-media-preview" /> </div> <script src="https://content.jwplatform.com/players/7XqcvwWp-FvQKszTI.js"></script> </div> <p>The discovery of a new species is always a cause for celebration in zoology. That this is the discovery of an animal that inhabits the deeps of the sea, one of the least explored areas humans can get to, is the icing on the cake.</p><p>Helen Wong of the National University of Singapore, who co-authored the species' description, explained the importance of the discovery:</p><p>"The identification of this new species is an indication of just how little we know about the oceans. There is certainly more for us to explore in terms of biodiversity in the deep sea of our region." </p><p>The animal's visual similarity to Darth Vader is a result of its compound eyes and the curious shape of its <a href="https://lkcnhm.nus.edu.sg/research/sjades2018/" target="_blank" rel="noopener noreferrer dofollow" style="">head</a>. However, given the location of its discovery, the bottom of the remote seas, it may be associated with all manner of horrifically evil Elder Things and <a href="https://en.wikipedia.org/wiki/Cthulhu" target="_blank" rel="dofollow">Great Old Ones</a>. <em></em></p>
We look back at a year ravaged by a global pandemic, economic downturn, political turmoil and the ever-worsening climate crisis.
Billions are at risk of missing out on the digital leap forward, as growing disparities challenge the social fabric.
Image: Global Risks Report 2021<h3>Widespread effects</h3><p>"The immediate human and economic costs of COVID-19 are severe," the report says. "They threaten to scale back years of progress on reducing global poverty and inequality and further damage social cohesion and global cooperation."</p><p>For those reasons, the pandemic demonstrates why infectious diseases hits the top of the impact list. Not only has COVID-19 led to widespread loss of life, it is holding back economic development in some of the poorest parts of the world, while amplifying wealth inequalities across the globe.</p><p>At the same time, there are concerns the fight against the pandemic is taking resources away from other critical health challenges - including a <a href="https://www.weforum.org/agenda/2020/09/charts-covid19-malnutrition-educaion-mental-health-children-world/" target="_blank" rel="noopener noreferrer">disruption to measles vaccination programmes</a>.</p>
A new study explains how a chaotic region just outside a black hole's event horizon might provide a virtually endless supply of energy.
- In 1969, the physicist Roger Penrose first proposed a way in which it might be possible to extract energy from a black hole.
- A new study builds upon similar ideas to describe how chaotic magnetic activity in the ergosphere of a black hole may produce vast amounts of energy, which could potentially be harvested.
- The findings suggest that, in the very distant future, it may be possible for a civilization to survive by harnessing the energy of a black hole rather than a star.
The ergosphere<p>The ergosphere is a region just outside a black hole's event horizon, the boundary of a black hole beyond which nothing, not even light, can escape. But light and matter just outside the event horizon, in the ergosphere, would also be affected by the immense gravity of the black hole. Objects in this zone would spin in the same direction as the black hole at incredibly fast speeds, similar to objects floating around the center of a whirlpool.</p><p>The Penrose process states, in simple terms, that an object could enter the ergosphere and break into two pieces. One piece would head toward the event horizon, swallowed by the black hole. But if the other piece managed to escape the ergosphere, it could emerge with more energy than it entered with.</p><p>The movie "Interstellar" provides an example of the Penrose process. Facing a fuel shortage on a deep-space mission, the crew makes a last-ditch effort to return home by entering the ergosphere of a blackhole, ditching part of their spacecraft, and "slingshotting" away from the black hole with vast amounts of energy.</p><p>In a recent study published in the American Physical Society's <a href="https://journals.aps.org/prd/abstract/10.1103/PhysRevD.103.023014" target="_blank" style="">Physical Review D</a><em>, </em>physicists Luca Comisso and Felipe A. Asenjo used similar ideas to describe another way energy could be extracted from a black hole. The idea centers on the magnetic fields of black holes.</p><p style="margin-left: 20px;">"Black holes are commonly surrounded by a hot 'soup' of plasma particles that carry a magnetic field," Comisso, a research scientist at Columbia University and lead study author, told <a href="https://news.columbia.edu/energy-particles-magnetic-fields-black-holes" target="_blank" rel="noopener noreferrer">Columbia News</a>.</p>
Event Horizon Telescope Collaboration<p>While there might not be immediate applications for the theory, it could help scientists better understand and observe black holes. On an abstract level, the findings may expand the limits of what scientists imagine is possible in deep space.</p><p style="margin-left: 20px;">"Thousands or millions of years from now, humanity might be able to survive around a black hole without harnessing energy from stars," Comisso said. "It is essentially a technological problem. If we look at the physics, there is nothing that prevents it."</p>
A popular and longstanding wave of thought in psychology and psychotherapy is that diagnosis is not relevant for practitioners in those fields.