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October 3, 2020
October 2, 2020
MIT researchers find blocking the expressions of the genes XPA and MK2 enhances the tumor-shrinking effects of platinum-based chemotherapies in p53-mutated cancers.
Koch Institute
October 2, 2020
Cancer therapies that target specific molecular defects arising from mutations in tumor cells are currently the focus of much anticancer drug development. However, due to the absence of good targets and to the genetic variation in tumors, platinum-based chemotherapies are still the mainstay in the treatment of many cancers, including those that have a mutated version of the tumor suppressor gene p53. P53 is mutated in a majority of cancers, which enables tumor cells to develop resistance to platinum-based chemotherapies. But these defects can still be exploited to selectively target tumor cells by targeting a second gene to take down the tumor cell, leveraging a phenomenon known as synthetic lethality.
Focused on understanding and targeting cell signaling in cancer, the laboratory of Michael Yaffe, the David H. Koch Professor Science and director of the MIT Center for Precision Cancer Medicine, seeks to identify pathways that are synthetic lethal with each other, and to develop therapeutic strategies that capitalize on that relationship. His group has already identified MK2 as a key signaling pathway in cancer and a partner to p53 in a synthetic lethal combination.
Now, working with a team of fellow researchers at MIT’s Koch Institute for Integrative Cancer Research, Yaffe’s lab added a new target, the gene XPA, to the combination. Appearing in Nature Communications, the work demonstrates the potential of “augmented synthetic lethality,” where depletion of a third gene product enhances a combination of targets already known to show synthetic lethality. Their work not only demonstrates the effectiveness of teaming up cancer targets, but also of the collaborative teamwork for which the Koch Institute is known.
P53 serves two functions: first, to give cells time to repair DNA damage by pausing cell division, and second, to induce cell death if DNA damage is too severe. Platinum-based chemotherapies work by inducing enough DNA damage to initiate the cell’s self-destruct mechanism. In their previous work, the Yaffe lab found that when cancer cells lose p53, they can re-wire their signaling circuitry to recruit MK2 as a backup pathway. However, MK2 only restores the ability to orchestrate DNA damage repair, but not to initiate cell death.
The Yaffe group reasoned that targeting MK2, which is only recruited when p53 function is absent, would be a unique way to create a synthetic lethality that specifically kills p53-defective tumors, by blocking their ability to coordinate DNA repair after chemotherapy. Indeed, the Yaffe Lab was able to show in pre-clinical models of non-small cell lung cancer tumors with mutations in p53, that silencing MK2 in combination with chemotherapy treatment caused the tumors to shrink significantly.
Although promising, MK2 has proven difficult to drug. Attempts to create target-specific, clinically viable small-molecule MK2 inhibitors have so far been unsuccessful. Researchers led by co-lead author Yi Wen Kong, then a postdoc in the Yaffe lab, have been exploring the use of RNA interference (siRNA) to stop expression of the MK2 gene, but siRNA’s tendency to degrade rapidly in the body presents new challenges.
Enter the potential of nanomaterials, and a team of nanotechnology experts in the laboratory of Paula Hammond, the David H. Koch Professor of Engineering, head of the MIT Department of Chemical Engineering, netbet sports betting appand the Yaffe group’s upstairs neighbor. There, Kong found a willing collaborator in then-postdoc Erik Dreaden, whose team had developed a delivery vehicle known as a nanoplex to protect siRNA until it gets to a cancer cell. In studies of non-small cell lung cancer models where mice were given the MK2-targeting nanocomplexes and standard chemotherapy, the combination clearly enhanced tumor cell response to chemotherapy. However, the overall increase in survival was significant, but relatively modest.
Meanwhile, Kong had identified XPA, a key protein involved in another DNA repair pathway called NER, as a potential addition to the MK2-p53 synthetic lethal combination. As with MK2, efforts to target XPA using traditional small-molecule drugs have not yet proven successful, and RNA interference emerged as the team’s tool of choice. The flexible and highly controllable nature of the Hammond group’s nanomaterials assembly technologies allowed Dreaden to incorporate siRNAs against both XPA and MK2 into the nanocomplexes.
Kong and Dreaden tested these dual-targeted nanocomplexes against established tumors in an immunocompetent, aggressive lung cancer model developed in collaboration between the laboratories of professor of biology Michael Hemann and Koch Institute Director Tyler Jacks. They let the tumors grow even larger before treatment than they had in their previous study, thus raising the bar for therapeutic intervention.
Tumors in mice treated with the dual-targeted nanocomplexes and chemotherapy were reduced by up to 20-fold over chemotherapy alone, and similarly improved over single-target nanocomplexes and chemotherapy. Mice treated with this regimen survived three times longer than with chemotherapy alone, and much longer than mice receiving nanocomplexes targeting MK2 or XPA alone.
Overall, these data demonstrate that identification and therapeutic targeting of augmented synthetic lethal relationships — in this case between p53, MK2 and XPA — can produce a safe and highly effective cancer therapy by re-wiring multiple DNA damage response pathways, the systemic inhibition of which may otherwise be toxic.
The nanocomplexes are modular and can be adapted to carry other siRNA combinations or for use against other cancers in which this augmented synthetic lethality combination is relevant. Beyond application in lung cancer, the researchers — including Kong, who is now a research scientist at the Koch Institute, and Dreaden, who is now an assistant professor at Georgia Tech and Emory School of Medicine — are working to test this strategy for use against ovarian and other cancers.
Additional collaborations and contributions were made to this project by the laboratories of Koch Institute members Stephen Lippard and Omer Yilmaz, the Eisen and Chang Career Development Professor.
This work was supported in part by a Mazumdar-Shaw International Oncology Fellowship, a postdoctoral fellowship from the S. Leslie Misrock (1949) Frontier Fund for Cancer Nanotechnology, and by the Charles and Marjorie Holloway Foundation, the Ovarian Cancer Research Foundation, and the Breast Cancer Alliance.
Molecular biologist and professor emerita advocates for more inclusive science and advises how to get there.
Raleigh McElvery | Department of Biology
September 30, 2020
Over the course of her exceptional career, Amgen Professor of Biology Emerita Nancy Hopkins has overturned assumptions and defied expectations at the lab bench and beyond. After arriving at MIT in 1973, she set to work mapping RNA tumor virus genes, before switching her focus and pioneering zebrafish as a model system to probe vertebrate development and cancer.
Her experiences in male-dominated fields and institutions led her to catalyze an investigation that evolved into the groundbreaking 1999 public report on the status of women at MIT. These findings spurred nine universities, including MIT, to establish an ongoing effort to improve gender equity. A recent documentary, “Picture a Scientist,” chronicles this watershed report and spotlights researchers like Hopkins who champion underrepresented voices. She sat down to discuss what has changed for women in academia in the last two decades — and what hasn’t.
netbet online sports betting How has the situation for women in science evolved since the landmark 1999 report?
A: It’s hard today to remember just how radical the 1999 report was at the time. I read it now and think, ‘What was so radical about that?’
The report documented that women joined the faculty believing that only greater family responsibilities might impede their success relative to male colleagues. But, as they progressed through tenure, many were marginalized and undervalued. Data showed this resulted in women having fewer institutional resources and rewards for their research, and in their exclusion from important professional opportunities. When the study began, only 8% of the science faculty were women.
Former MIT Dean of Science Robert Birgeneau addressed inequities on a case-by-case basis, adjusting salaries, space, and resources. He recruited women aggressively, quickly increasing the number of women School of Science faculty by 50%.
When the report became public, the overwhelming public reaction made clear that it described problems that were epidemic among women in science, technology, engineering, and mathematics (STEM). Former MIT President Chuck Vest and Provost Bob Brown addressed gender bias for all of MIT and “institutionalized” solutions. They established committees in the five MIT schools to ensure that inequities were promptly addressed NetBet live casinoand hiring policies were fair; rewrote family leave policies with input from women faculty; built day care facilities on campus; and recruited women faculty to high-level administrative positions.
Today, we realize that the MIT report elucidated two underappreciated forms of bias: “institutional bias” resulting from a system designed for a man with a wife at home; and “unconscious or implicit gender bias.” Voluminous research by psychologists has documented the latter, showing that identical work is undervalued if people believe it was done by a woman. Refusal to acknowledge unconscious gender bias today is akin to denying the world is round.
Q: What do you hope people will take away from the “Picture a Scientist” film?
A: I hope people will better understand why women are underrepresented in science, and women of color particularly so. The film does a terrific job of portraying the range of destructive behaviors that collectively explain the question, “Why so few?” The movie also focuses on the courage it takes for young women scientists to expose these problems.
I hope people will agree that, despite all the progress for women in my generation, as the bombshell report from the National Academy of Sciences documented in 2018, sexual harassment and gender discrimination persist and still require constant attention. It remains a challenge to identify, attract, and retain the best STEM talent. And, as the movie points out, it’s critical to do so.
The producers have received an unprecedented number of requests to show the documentary in institutes, universities, and companies, confirming that underrepresentation remains a widespread and pressing issue.
Q: Where do we go from here? How can academia better support underrepresented groups in science moving forward?
A: People often say you have to “change the culture,” but what does that really mean? You have to do what MIT did: look at the data; make corrections, including policy changes if necessary; continue to track the data to see if the policies work; and repeat as needed. Second, as the National Academies report points out, you must reward administrators who create a diverse workplace. Top talent is distributed among diverse groups. You can only be the best by being diverse.
But how do you change the behavior of individual faculty? Years ago, President Vest told me, “Nancy, anything I can measure I can fix, but I don’t know how to fix marginalization.” His comment was prescient. We’re pretty good at fixing things we can measure. But not at retraining our own unconscious biases: preference for working with people who look just like us; and unexamined, biased assumptions about people different from us. But psychologists tell us all we have to do is ‘change the world and our biases will change along with it.’ Furthermore, they now have methods to measure change in our biases.
I championed this cause because I believe being a scientist is the greatest job there is. I want anyone with this passion to be able to be a scientist. I’m grateful I got to see change first hand. I just wish the change was faster, so young women like Jane Willenbring and Raychelle Burks in the movie can just be scientists.
September 28, 2020
Prize recognizes contributions to biomedical research made by immigrant scientists.
Raleigh McElvery | Sandi Miller | Department of Biology | Department of Physics
September 25, 2020
Associate professor of physics and biology Ibrahim Cissé, professor of biology and Whitehead Institute Director Ruth Lehmann, and Andria and Paul Heafy Whitehead Fellow Silvi Rouskin have been awarded 2021 Vilcek Prizes. The Vilcek Foundation was established in 2000 by Jan and Marica Vilcek, who emigrated from the former Czechoslovakia. Their prizes honor the outstanding contributions of immigrants in the sciences and the arts. Prizewinners will be honored in an April ceremony.
“The 2021 awards celebrate the diversity of immigrant contributions to biomedical research, to filmmaking, and to society,” Vilcek Foundation President Rick Kinsel said in a press release. “In recognizing foreign-born scientists and dynamic leaders in the arts and in public service, we seek to expand the public dialogue about the intellectual value and artistic diversity that immigration provides the United States.”
Ibrahim Cissé
A faculty member in the departments of Physics and Biology, Ibrahim Cissé received the Vilcek Prize for Creative Promise in Biomedical Science for using super-resolution biological imaging to directly visualize the dynamic nature of gene expression in living cells.
Born in Niger, Cissé assumed he would be a lawyer like his father, but he soon became inspired by the science he saw in American films. His high school did not have a laboratory, so he completed high school two years early, enrolled in an English as a Second Language program at the University of North Carolina at Wilmington, and enrolled in Durham Technical Community College before transferring to North Carolina Central University, a historically Black college that was notable for its undergraduate science and mathematics research programs.
Following graduation, he spent a summer at Princeton University working in condensed matter physics. There, Cissé was confronted by physics professor Paul Chaikin with a question about elliptical geometry and particle density, using M&M’s candies. Cissé’s creative problem-solving enabled him and his fellow researchers to develop experiments for observing and quantifying their results, and they coauthored a paper that was published in Science magazine.
For graduate studies, he was at the University of Illinois at Urbana-Champaign, and earned a PhD under NetBet sportthe supervision of single-molecule biophysicist Taekjip Ha, who was leading research in high-resolution, single-biomolecule imaging technology. Cissé’s interest in using physics to understand the physical processes in biology led him to a post-doctoral fellowship at École Normale Supérieure Paris. He showed that RNA polymerase II, a critical protein in gene expression, forms fleeting (“transient”) clusters with similar molecules in order to transcribe DNA into RNA. He joined the Howard Hughes Medical Institute’s Janelia Research Campus as a research specialist in the Transcription Imaging Consortium, before joining the MIT Department of Physics in 2014, and was recently granted tenure and a joint appointment in biology.
The Cissé Laboratory focuses on the development of high-resolution microscopy techniques to examine the behavior of single biomolecules in living cells, and his own research focuses on the process by which DNA gets decoded into RNA. His Time-Correlated Photoactivated Localization Microscopy (tcPALM) technique of imaging was able to peer inside living cells to study the dynamics of protein clusters. This discovery has led to breakthroughs in viewing the clustering and droplet-like behavior of RNA polymerase II during RNA transcription. In an interview with MIT News, he stated, “It’s becoming clearer that physics may be just as important as biology for understanding how cells work.”
Other national and international awards include the Young Fluorescence Investigator Award from the American Biophysical Society, the Pew Biomedical Scholars, and the National Institute of Health Director’s New Innovator Award. He is a Next Einstein Forum fellow and was listed in Science News’ Scientists to Watch.
Ruth Lehmann
Professor of biology and director of Whitehead Institute for Biomedical Research Ruth Lehmann received the Vilcek Prize in Biomedical Science. As a developmental and cell biologist, she investigates the biology of germ cells, which give rise to sperm and eggs.
The daughter of a teacher and an engineer, Lehmann was captivated by science from a young age. She grew up in Cologne, Germany, and majored in biology as an undergraduate at the University of Tübingen. Her Fulbright Fellowship in 1977 brought her to the University of Washington in Seattle, and served as the catalyst that spurred her career using fruit flies to understand germ cell biology. She went on to train with renowned fruit fly geneticists Gerold Schubiger and Jose Campos-Ortega, learning classical developmental biology and electron microscopy techniques. She then performed her doctoral research with future Nobel laureate Christiane Nüsslein-Volhard at the Max Planck Institute for Developmental Genetics. There, Lehmann probed the maternal genes that influence fruit fly embryo development — studies that ignited her fervor for germ cell research. Later, as a postdoc at the Medical Research Council Laboratory of Molecular Biology in Cambridge, England, she worked with Michael Wilcox and Peter Lawrence to pinpoint the molecules that control the fate of these vital cells.
Lehmann arrived at MIT in 1988, where she served as a professor and member of the Whitehead Institute for eight years. “Being an immigrant in the United States was exhilarating,” she says, “because of the openness to new ideas and the encouragement to take risks and be creative.”
She was recruited to the Skirball Institute at New York University (NYU), where she was appointed as the institute’s director, as well as the director of the Helen and Martin Kimmel Center for Stem Cell Biology, and chair of the Department of Cell Biology at NYU’s Langone Medical Center.
Lehmann returned to MIT this summer to launch the Lehmann Lab and become director of the Whitehead Institute in July.
Although she began her career focused on the formation and maintenance of germ cells, Lehmann has since revealed key insights into their migration — and more recently into mitochondrial inheritance. Her influential work regarding the development and behavior of these essential cells has also enriched related fields including stem cell biology, lipid biology, and DNA repair.
“It means so much to me to be recognized as an immigrant and a researcher,” says Lehmann. “In these days, immigrants don’t feel as welcomed as I did when I came to this country. For me, coming to the U.S. meant to be given a chance to live the dream of being a scientist. This allowed me to explore the fascinating biology of the germ line together with a group of incredibly talented trainees and staff, many of them immigrants themselves, and I share this wonderful recognition with them.”
Lehmann’s accolades include membership to the National Academy of Sciences, American Academy of Arts and Sciences, and European Molecular Biology Organization, as well as the Conklin Medal from the Society for Developmental Biology, the Porter Award from the American Society for Cell Biology, and the Lifetime Achievement Award from the German Society for Developmental Biology.
Silvi Rouskin
The Andria and Paul Heafy Whitehead Fellow at the Whitehead Institute, Silvi Rouskin received the Vilcek Prize for Creative Promise in Biomedical Science for developing methods to unravel the shapes of RNA molecules inside cells — aiding the potential development of RNA-based therapeutics.
The daughter of rock musicians in early-1980s communist Bulgaria, she grew up fascinated with the geometry of the flora and fauna around her. At 10, she started saving her lunch money to buy a miniature telescope. At 15 she knew that her best chances to study science would be in the United States, and so netbet sports bettingshe joined a student exchange program in Idaho.
“I was not only allowed but encouraged to question my superiors,” she recalls. “I felt free to speak my mind, and often debated with my teachers.” Rouskin completed her GED and studied physics and biochemistry at the Florida Institute of Technology at 16.
As a staff research associate in the laboratory of Joseph DeRisi at the University of California at San Francisco, Rouskin first began studying RNA, using microarrays to detect and track viral infection. She opted to stay at UCSF to pursue her PhD in biochemistry and molecular biology.
She joined the Whitehead Institute in 2015, and established the Rouskin Lab to focus on the structure of RNA molecules, including viruses, and to determine how structure influences RNA processing and gene expression in HIV-1 and other viruses. Most recently, Rouskin uncovered the higher-order structure of the RNA genome of SARS-CoV2 — the virus that causes Covid-19 — in infected cells at high resolution.
“The goal of my own lab has been to perform basic RNA research with clear therapeutic applications and a particular focus on the vulnerabilities of RNA viruses,” says Rouskin. “I want my research to matter for medicine, and so I always approach my research with a cognizance of how my work can directly benefit people.”
Rouskin has also received the Harold M. Weintraub Graduate Student Award for outstanding achievements in biological sciences and the Burroughs Wellcome Fund Career Award at the Scientific Interface.
Eva Frederick | Whitehead Institute
September 24, 2020
Type 1 diabetes is an autoimmune disease that occurs when T-cells in the immune system attack the body’s own insulin-producing cells, called beta cells, in the pancreas. Usually diagnosed in children and young adults, type 1 diabetes accounts for around five percent of all diabetes cases.
The underlying biology of type 1 diabetes is tricky to study for a number of reasons. For one thing, by the time a person begins to show symptoms, their T-cells have already been destroying beta cells for a long period — months or even years. Also, the initial trigger for the disease is often unclear; a number of beta cell proteins can set off the immune response.
In a study published Sept. 22 in Cell Reports Medicine, researchers in the lab of Whitehead Institute Founding Member Rudolf Jaenisch demonstrate a new experimental system for more precisely studying the mechanisms of type 1 diabetes, focusing on how a person’s beta cells respond to an attack from their own immune system. In doing so, they reveal features of the disease that could be targets for future therapeutics.
“Here our question was, let’s say the T cells get activated; what happens next from the perspective of beta cells? Could we find some potential intervention opportunities?” said Haiting Ma, a postdoctoral associate in Jaenisch’s lab and the first author of the study.
Ma, working with Jaenisch, also a professor of biology at MIT, and Jacob Jeppesen, Novo Nordisk’s Head of Diabetes and Metabolism Biology, took a synthetic biology approach to achieve this goal.
The researchers engineered a system by inducing human pluripotent stem cells to differentiate into functional pancreatic beta cells, and added a model antigen called CD19 to these cells using CRISPR techniques. They established that these cells functioned as insulin-producing beta cells by implanting them in diabetic mice; upon receiving the cells, the mice experienced an improvement in glucose levels.
They then replicated the autoimmune components of the disease using engineered immune cells called CAR-T cells. CAR-T cells are T-cells tailor-made to attack a certain type of cell; for example, they can be targeted to tumor cells to treat certain types of cancer. For the diabetes model, the researchers engineered the cells to contain receptors for the model antigen CD19.
When the researchers cocultured the synthetic beta cells and CAR-T cells, they found the system worked well to mimic a simplified version of type 1 diabetes: the CAR-T cells attacked the beta cells and caused them to enter the process of cell death. The researchers were also able to implement the strategy in humanized mice.
Using their new experimental system, the researchers were able to identify some interesting factors involved in the beta cells’ response to diabetic conditions. For one thing, they found that the beta cells cranked up production of protective mechanisms such as the protein PDL1. PDL1 is a protein found on non-harmful cells in the body that, in normal circumstances, prevents the immune system from attacking them.
Changes in PDL1 levels had been associated with type 1 diabetes in previous studies. Now, Ma wondered if it was possible to rescue the beta cells from the immune onslaught by inducing the expression of even more of the helpful protein. “We found that we can help beta cells by giving them a higher expression of PDL1,” he said. “When we do this, they can do better in the model.” If validated in human cells, increasing expression of PDL1 could be evaluated as a potential therapeutic method, Ma said.
Another finding concerned the way the cells died after T-cell attack. Ma found that the genes that were being upregulated as the beta cells were under attack were associated not with the usual form of cell death, apoptosis, but with a more inflammatory and violent kind of cell death called pyroptosis.
“The interesting thing about pyroptosis is that it causes the cells to release their contents,” Ma said. “This is in contrast to apoptosis, which is considered to be the main mechanism for autoimmune response. We think that pyroptosis NetBet live casinocould play a role in propelling this autoimmune reaction, because the contents from beta cells include multiple potential antigens. If these are released, they can be picked out by antigen presenting cells and start to crank up this autoimmunity.”
The process of pyroptosis in the context of beta cell autoimmunity could be linked to ER stress in beta cells, a highly secretory cell type. Indeed, an ER stress inducing chemical increased the marker of pyroptosis.
If researchers could find a way to inhibit the process of pyroptosis safely in humans, it could potentially lessen the severity of the autoimmune reaction that is the hallmark of type 1 diabetes. Pyroptosis is mediated by a protein called caspase-4, which can be inhibited in the lab. “If that can be validated in patient beta cells, that could indicate that modulating caspases could also be [a therapeutic mechanism],” Ma said.
Going forward, Ma and Jaenisch plan to investigate the immune mechanisms underlying autoimmunity in humans by using induced pluripotent stem cells from patients with type 1 diabetes. “These cells could be differentiated into immune cells such as T, B, macrophage, and dendritic cells, and we can investigate how they interact with beta cells,” Ma said.
They also plan to keep improving their new experimental system. “This system provides a very robust and tractable synthetic immune response that we can use to study type 1 diabetes,” said Jaenisch. “In the future it could be used to study other autoimmune diseases.”
This study was supported by a generous gift from Liliana and Hillel Bachrach, a collaborative research agreement from Novo Nordisk, and NIH grant 1R01-NS088538 (to R.J.).
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Written by Eva Frederick
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Citation:
Ma, H., Jeppesen, J, and Jaenisch, R. “Human T-cells expressing a CD19 CAR-T receptor provide insights into mechanisms of human CD19 positive cell destruction.” Cell Reports Medicine. Sept 22. https://doi.org/10.1016/j.xcrm.2020.100097
Eva Frederick | Whitehead Institute
September 23, 2020
The essential malaria drug artemisinin acts like a “ticking time bomb” in parasite cells — but in the half a century since the drug was introduced, malaria-causing parasites have slowly grown less and less susceptible to the treatment, threatening attempts at global control over the disease.
In a paper published September 23 in Nature Communications, Whitehead Institute Member Sebastian Lourido and colleagues use genome screening techniques in the related parasite Toxoplasma gondii (T. gondii) to identify genes that affect the parasites’ susceptibility to artemisinin. Two genes stood out in the screen: one that makes the drug more lethal, and another that helps the parasite survive the treatment.
Artemisinin is derived from the extract of sweet wormwood (Artemisia annua), and is usually used against malaria as part of a combination therapy. “Artemisinin kills malaria-causing parasites super fast—it will wipe out 90 percent of parasites within 24 hours,” says former postdoctoral researcher and co-first author Clare Harding, now a research fellow at the University of Glasgow. Once the fast-acting drug clears out the bulk of the parasites—such as Plasmodium falciparum, the culprit in the deadliest forms of malaria—from the bloodstream, the second drug finishes off the stragglers, curing the infection.
“Artemisinin works differently than most antibiotics,” Lourido said. “You can think of it as a sort of bomb that needs to be turned on in order to work.” The molecule required to light the drug’s fuse is called heme. Heme is a small molecule that facilitates several cellular functions, including electron transport and the delivery of oxygen to tissues as a component of hemoglobin. When heme molecules encounter artemisinin, they activate the drug allowing the creation of small, toxic radicals which react with proteins, lipids and metabolites inside the parasite, leading to its death.
Lourido, Harding, and co-first authors Boryana Petrova and Saima Sidik (“We were the ‘Heme Team,’” Harding said) wanted to understand what mechanisms the less susceptible parasites were using to avoid activating the “bomb”. Previously, Lourido and his lab—which focuses on apicomplexan parasites, a group which includes both Toxoplasma gondii and the malaria-causing Plasmodium falciparum—had developed a method to screen the entire genome of T. gondii to discover beneficial and harmful mutations. For a number of reasons, the screen does not work on Plasmodium parasites, but Lourido hypothesized that the related parasites’ genomes were similar enough that the method could prove helpful.
After running the screen, two genes stood out to the researchers as important factors in the parasites’ susceptibility to artemisinin treatment. One, called Tmem14c, seemed to be protecting the parasites: when the gene was disrupted in the screen, the parasites became more susceptible to treatment with artemisinin. The gene is analogous to one in red blood cells that serves as a transporter for heme and its building blocks, shuttling them in and out of the mitochondrion.
“What could be happening here is that, in the absence of Tmem14c, heme, artemisinin’s activator, collects within the mitochondria where it is being synthesized, thereby rendering the mitochondria better at activating that ticking time bomb,” Lourido said. “Having that high concentration of heme in the mitochondria is like having a flame when there is a gas leak.”
The screen also identified one mutation that led to parasites being less sensitive to artemisinin. The mutation affected a gene called DegP2, the product of which interacts NetBet live casinowith several mitochondrial proteins and appears to play a role in heme metabolism. When less DegP2 was present, the cells contained a lower amount of heme, which in turn made it less likely that the parasites would be killed by artemisinin.
Both the findings support other research suggesting that heme metabolism is crucial for artemisinin susceptibility. “It is important to consider the role of heme when combining artemisinin with other therapies,” Lourido said. “You would want to avoid combination therapy that might inadvertently suppress the level of heme within the parasite and thereby reduce susceptibility to antiparasitic agents.”
The project also showed the potential of using the Toxoplasma screening method as a model to study other related parasites. The screen confirmed findings in Toxoplasma that had previously been shown in Plasmodium, suggesting that it could be a valuable tool in studying malaria and other diseases caused by apicomplexan parasites.
“Through the amazing screens and molecular biology that you can do in Toxoplasma, we can really learn a lot about the biology of this diverse group of parasites,” Lourido said. “Defeating malaria is going to take a lot of different and creative approaches, and the fundamental research that we can do in Toxoplasma can in fact inform many of the critical clinical questions we need to answer to control this disease.”
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Written by Eva Frederick
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Harding, C., Sidik, S, and Petrova, B., et al. “Genetic screens reveal a central role for heme metabolism in artemisinin susceptibility.” Nature Communications. DOI: https://doi.org/10.1038/s41467-020-18624-0