From an observatory high above Chile’s Atacama Desert, astronomers have taken a new look at the oldest light in the universe.
Their observations, plus a bit of cosmic geometry, suggest that the universe is 13.77 billion years old – give or take 40 million years. A Cornell researcher co-authored one of two papers about the findings, which add a fresh twist to an ongoing debate in the astrophysics community.
The new estimate, using data gathered at the National Science Foundation’s Atacama Cosmology Telescope (ACT), matches the one provided by the standard model of the universe, as well as measurements of the same light made by the European Space Agency’s Planck satellite, which measured remnants of the Big Bang from 2009 to ’13.
The research was published Dec. 30 in the Journal of Cosmology and Astroparticle Physics.
In 2019, a research team measuring the movements of galaxies calculated that the universe is hundreds of millions of years younger than the Planck team predicted. That discrepancy suggested a new model for the universe might be needed and sparked concerns that one of the sets of measurements might be incorrect.
“Now we’ve come up with an answer where Planck and ACT agree,” said Simone Aiola, a researcher at the Flatiron Institute’s Center for Computational Astrophysics and first author of one of two papers. “It speaks to the fact that these difficult measurements are reliable.”
If you type into a search engine – “why do men have to wait before having sex again?” – you will very quickly come across Prolactin. This little hormone is thought to be involved in hundreds of physiological processes in the body. Among them is the male post-ejaculatory refractory period. This period begins when a male ejaculates and ends when he recovers his sexual capacity.
If you search a bit more, you’ll see that this theory has even led to the development of so called “treatments”. These promise to shorten the length of a person’s refractory period by reducing their body’s prolactin levels.
Well, here is some bad news for anyone who has bought any such merchandise. A new study in mice by scientists at the Champalimaud Centre for the Unknown in Portugal reveals that prolactin may actually not be the culprit after all. These results were published today (January 4th) in the journal Communications Biology.
Ironically, the research project that ended up refuting the theory, never aimed to do so.
“When we started working on this project, we actually set off to explore the theory”, recalls Susana Lima, the principal investigator who led the study. “Our goal was to investigate in more detail the biological mechanisms by which prolactin might generate the refractory period.”
What is the basis of the theory? According to Lima, it emerged through several lines of evidence.
For one, some studies have shown that prolactin is released around the time of ejaculation in humans and rats. And since the refractory period starts right after ejaculation, prolactin seemed like a good candidate. Also, chronic abnormally high levels of prolactin are associated with decreased sexual drive, anorgasmia and ejaculatory dysfunction. Finally, treatment with drugs that inhibit prolactin release in situations of chronically high prolactin, reverse sexual dysfunction.
“These different results all point towards a central role for prolactin in suppressing male sexual behaviour”, says Lima. “However, a direct link between prolactin and the male post-ejaculatory refractory period was never directly demonstrated. Still, this theory has become so widespread that it now appears in textbooks as well as in the popular press.”
Why Not Prolactin?
How did the team end up discovering that the theory was wrong?
To study the role of prolactin in the male refractory period, Lima and her team performed a series of experiments in mice.
“We chose mice as our model animal because the sequence of sexual behaviour in mice is very similar to that of humans”, explains Susana Valente, the first author of the study. “Also, with mice, we can test different strains that exhibit different sexual performance, which makes the data richer. In this case we used two different strains. One that has a short refractory period, and another that has a long one, lasting several days.”
The team began by checking if prolactin levels also increase during sexual activity in male mice. “We measured the levels during the different stages of sexual behaviour using blood samples. And sure enough, they significantly increased during sexual interaction”, says Valente
Once this aspect was confirmed, the researchers moved forward to investigate the relation between prolactin and the length of the animals’ refractory period.
“Our first manipulation was to artificially increase prolactin levels before the animals became sexually aroused. We specifically made sure that the artificial levels matched those we measured during natural sexual behaviour. If prolactin was indeed the cause of the refractory period, the animals’ sexual activity should have decreased”, Valente explains.
To their surprise, this manipulation had no effect on the sexual behaviour of the mice. “Despite the elevation in prolactin levels, both strains of mice engaged in sexual behaviour normally”, she recalls.
Next, the researchers turned to see if blocking prolactin would have the opposite effect on the refractory period. In other words, if animals without prolactin would be more sexually active. Again, the answer was “No”.
“If prolactin was indeed necessary for the refectory period, males without prolactin should have regained sexual activity after ejaculation faster than controls”, Valente points out. “But they did not.”
Back To The Drawing Board
Together, Valente and Lima’s results provide strong counter evidence to the theory claiming prolactin triggers the male refractory period. Still, prolactin is undoubtedly a part of male sexual behaviour. What could be its role?
“There are many possibilities”, says Lima. “For instance, there are studies that point towards a role for prolactin in the establishment of parental behaviour. Also, it’s important to note that prolactin dynamics are quite different in male mice and men. In mice, prolactin levels rise during mating. However, in men, prolactin seems to only be released around the time of ejaculation, and only when ejaculation is achieved. So there may be some differences in its role across species.”
So what is the reason males have to wait before round two?
“Our results indicate that prolactin is very unlikely to be the cause”, says Lima. “Now we can move on and try to find out what’s really happening”, she concludes.
People dreaming of travel post-COVID-19 now have some scientific data to support their wanderlust.
A new study in the journal of Tourism Analysis shows frequent travelers are happier with their lives than people who don’t travel at all.
Chun-Chu (Bamboo) Chen, an assistant professor in the School of Hospitality Business Management at Washington State University, conducted a survey to find out why some individuals travel more frequently than others and whether or not travel and tourism experiences have a prolonged effect on happiness and wellness.
The results of his analysis show individuals who pay more attention to tourism-related information and frequently discuss their travel plans with friends are more likely to go on regular vacations than those who aren’t constantly thinking about their next trip. Additionally, participants in the survey who reported regularly traveling at least 75 miles away from home also reported being about 7% happier when asked about their overall well-being than those who reported traveling very rarely or not at all.
“While things like work, family life and friends play a bigger role in overall reports of well-being, the accumulation of travel experiences does appear to have a small yet noticeable effect on self-reported life satisfaction,” Chen said. “It really illustrates the importance of being able to get out of your routine and experience new things.”
Previous studies have examined the stress relief, health and wellness benefits of tourism experiences, but they have tended to examine the effect of a single trip or vacation. Chen’s research takes these previous studies one step further by looking at the sustained benefits of travel over the course of a year.
Participants in the study were asked about the importance of travel in their lives, how much time they spent looking into and planning future vacations, and how many trips they went on over a year. They were also asked about their perceived life satisfaction. Out of the 500 survey participants, a little over half reported going on more than four pleasure trips a year. Only 7% of respondents did not take any vacations.
As travel restrictions due to COVID-19 begin to relax in the future, the research could have important implication for both tourists and the tourism industry. Based on the results of the study, Chen said travel companies, resorts and even airlines could launch social media campaigns, such as creating hashtags about the scientific benefits of vacation, to spark people’s interest in discussing their opinions about travel.
“This research shows the more people talk about and plan vacations the more likely they are to take them,” he said. “If you are like me and chomping at the bit to get out of dodge and see someplace new, this research will hopefully be some additional good motivation to start planning your next vacation.”
Promising applications include underarm pads, insoles and shoe linings; Moisture harvested could power small wearable electronics.
A team of researchers from the National University of Singapore (NUS) has created a novel film that is very effective in evaporating sweat from our skin to keep us cool and comfortable when we exercise, and the moisture harvested from human sweat can be used to power wearable electronic devices such as watches, fitness trackers, and more.
Sweating is a natural process for our body to reduce thermal stress. “Sweat is mostly composed of water. When water is evaporated from the skin surface, it lowers the skin temperature and we feel cooler. In our new invention, we created a novel film that is extremely effective in evaporating sweat from our skin and then absorbing the moisture from sweat. We also take this one step further – by converting the moisture from sweat into energy that could be used to power small wearable devices,” explained research team leader Assistant Professor Tan Swee Ching, who is from the NUS Department of Material Science and Engineering.
The main components of the novel thin film are two hygroscopic chemicals – cobalt chloride and ethanolamine. Besides being extremely moisture-absorbent, this film can rapidly release water when exposed to sunlight, and it can be ‘regenerated’ and reused for more than 100 times.
To make full use of the absorbed sweat, the NUS team has also designed a wearable energy harvesting device comprising eight electrochemical cells (ECs), using the novel film as the electrolyte. Each EC can generate about 0.57 volts of electricity upon absorbing moisture. The overall energy harvested by the device is sufficient to power a light-emitting diode. This proof-of-concept demonstration illustrates the potential of battery-less wearables powered using human sweat.
This technological breakthrough was reported in the September print issue of the scientific journal Nano Energy.
Absorbing moisture for personal comfort
Conventional hygroscopic materials such as zeolites and silica gels have low water uptake and bulk solid structures, making them unsuitable for absorbing moisture from sweat evaporation. In comparison, the new moisture-absorbing film developed by NUS researchers takes in 15 times more moisture and do this 6 times faster than conventional materials.
In addition, this innovative film shows a colour change upon absorbing moisture, from blue to purple, and finally pink. This feature can be used an indicator of the degree of moisture absorption.
The NUS team packaged the film into breathable and waterproof polytetrafluoroethylene (PTFE) membranes, which are flexible and commonly used in clothing, and successfully demonstrated the application of the moisture-absorption film for underarm pad, shoe lining and shoe insole.
Asst Prof Tan said, “Underarm sweating is embarrassing and frustrating, and this condition contributes to the growth of bacteria and leads to unpleasant body odour. Accumulation of perspiration in the shoes could give rise to health problems such as blisters, calluses, and fungal infections. Using the underarm pad, shoe lining and shoe insole embedded with the moisture-absorbing film, the moisture from sweat evaporation is rapidly taken in, preventing an accumulation of sweat and provides a dry and cool microclimate for personal comfort.”
“The prototype for the shoe insole was created using 3D printing. The material used is a mixture of soft polymer and hard polymer, thus providing sufficient support and shock absorption,” explained research team co-leader Professor Ding Jun, who is also from the NUS Department of Material Science and Engineering.
The NUS team now hopes to work with companies to incorporate the novel moisture-absorption film into consumer products.
Researchers at Osaka University have developed a technique of attacking cancer cells with lethal alpha rays from within by using a nutrient transporter to deliver radionuclides into malignant tumors.
A cancer-specific L-type amino acid transporter 1 (LAT1) is highly expressed in cancer tissues. Inhibiting the function of LAT1 has been known to have anti-tumor effects, but there has been limited progress in the development of radionuclide therapy agents targeting LAT1. Now, a multidisciplinary research team at Osaka University has established a targeted alpha-therapy with a novel drug targeting LAT1.
The researchers first produced the alpha-ray emitter 211Astatine, no easy task given that Astatine (At) is the rarest naturally occurring element on Earth. Targeted alpha-therapy selectively delivers α-emitters to tumors; the advantage over conventional β-therapy is that alpha decay is highly targeted and the high linear energy transfer causes double-strand breaks to DNA, effectively causing cell death. The short half-life and limited tissue penetration of alpha radiation ensures high therapeutic effects with few side-effects to surrounding normal cells.
Next, to carry the radioisotope into cancer cells, the researchers attached it to α-Methyl-L-tyrosine, which has high affinity for LAT1. This subterfuge exploits the elevated nutrient requirements of rapidly multiplying cancer cells.
“We found that 211At-labeled α-methyl-L-tyrosine (211At-AAMT) had high affinity for LAT1, inhibited tumor cells, and caused DNA double-strand breaks in vitro,” reports Associate Professor Kazuko Kaneda-Nakashima, lead author. “Extending our research, we assessed the accumulation of 211At-AAMT and the role of LAT1 in an experimental mouse model. Further investigations on a human pancreatic cancer cell line showed that 211At-AAMT selectively accumulated in tumors and suppressed growth. At a higher dose, it even inhibited metastasis in the lung of a metastatic melanoma mouse model.”
Professor Atsushi Shinohara, senior author, explains, “We could establish the efficacy of 211Astatine in the treatment of cancer including advanced and metastatic malignancies, as well as the utility of the amino acid transporter LAT1 as a vehicle for radionuclide therapy. As the drug is delivered cancer-specifically it can attack from inside the cell after being taken in as a nutrient.”
Adding to efficacy is dosing convenience. As an injectable short-range radiopharmaceutical, 211At-AAMT may be administered in outpatient clinics, a huge advantage over conventional radiation protocols, and may even be an alternative to surgery in specific cancers. This approach has immense potential to revolutionize radionuclide therapy of not only pancreatic cancer but other malignancies that lack effective treatment including advanced or metastatic disease.
Osaka University was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan’s leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world, being named Japan’s most innovative university in 2015 (Reuters 2015 Top 100) and one of the most innovative institutions in the world in 2017 (Innovative Universities and the Nature Index Innovation 2017). Now, Osaka University is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.
Mollusks build shells to protect their soft tissues from predators. Nacre, also known as the mother of pearl, has an intricate, highly regular structure that makes it an incredibly strong material. Depending on the species, nacres can reach tens of centimeters in length. No matter the size, each nacre is built from materials deposited by a multitude of single cells at multiple different locations at the same time. How exactly this highly periodic and uniform structure emerges from the initial disorder was unknown until now.
Nacre formation starts uncoordinated with the cells depositing the material simultaneously at different locations. Not surprisingly, the early nacre structure is not very regular. At this point, it is full of defects. “In the very beginning, the layered mineral-organic tissue is full of structural faults that propagate through a number of layers like a helix. In fact, they look like a spiral staircase, having either right-handed or left-handed orientation,” says Dr. Igor Zlotnikov, research group leader at the B CUBE – Center for Molecular Bioengineering at TU Dresden. “The role of these defects in forming such a periodic tissue has never been established. On the other hand, the mature nacre is defect-free, with a regular, uniform structure. How could perfection emerge from such disorder?”
The researchers from the Zlotnikov group collaborated with the European Synchrotron Radiation Facility (ESRF) in Grenoble to take a very detailed look at the internal structure of the early and mature nacre. Using synchrotron-based holographic X-ray nano-tomography the researchers could capture the growth of nacre over time. “Nacre is an extremely fine structure, having organic features below 50 nm in size. Beamline ID16A at the ESRF provided us with an unprecedented capability to visualize nacre in three-dimensions,” explains Dr. Zlotnikov. “The combination of electron dense and highly periodical inorganic platelets with delicate and slender organic interfaces makes nacre a challenging structure to image. Cryogenic imaging helped us to obtain the resolving power we needed,” explains Dr. Pacureanu from the X-ray Nanoprobe group at the ESRF.
The analysis of data was quite a challenge. The researchers developed a segmentation algorithm using neural networks and trained it to separate different layers of nacre. In this way, they were able to follow what happens to the structural defects as nacre grows.
The behavior of structural defects in a growing nacre was surprising. Defects of opposite screw direction were attracted to each other from vast distances. The right-handed and left-handed defects moved through the structure, until they met, and cancelled each other out. These events led to a tissue-wide synchronization. Over time, it allowed the structure to develop into a perfectly regular and defect-free.
Periodic structures similar to nacre are produced by many different animal species. The researchers think that the newly discovered mechanism could drive not only the formation of nacre but also other biogenic structures.
Reference: Maksim Beliaev, Dana Zoellner, Alexandra Pacureanu, Paul Zasklansky, and Igor Zlotnikov: Dynamics of Topological Defects and Structural Synchronization in a Forming Periodic Tissue. Nature Physics (January 2021) doi: 10.1038/s41567-020-01069-z https://www.nature.com/articles/s41567-020-01069-z
Brown fat is that magical tissue that you would want more of. Unlike white fat, which stores calories, brown fat burns energy and scientists hope it may hold the key to new obesity treatments. But it has long been unclear whether people with ample brown fat truly enjoy better health. For one thing, it has been hard to even identify such individuals since brown fat is hidden deep inside the body.
Now, a new study in Nature Medicine offers strong evidence: among over 52,000 participants, those who had detectable brown fat were less likely than their peers to suffer cardiac and metabolic conditions ranging from type 2 diabetes to coronary artery disease, which is the leading cause of death in the United States.
The study, by far the largest of its kind in humans, confirms and expands the health benefits of brown fat suggested by previous studies. “For the first time, it reveals a link to lower risk of certain conditions,” says Paul Cohen, the Albert Resnick, M.D., Assistant Professor and senior attending physician at The Rockefeller University Hospital. “These findings make us more confident about the potential of targeting brown fat for therapeutic benefit.”
A valuable resource
Although brown fat has been studied for decades in newborns and animals, it was only in 2009 that scientists appreciated it can also be also found in some adults, typically around the neck and shoulders. From then on, researchers have scrambled to study the elusive fat cells, which possess the power to burn calories to produce heat in cold conditions.
Large-scale studies of brown fat, however, have been practically impossible because this tissue shows up only on PET scans, a special type of medical imaging. “These scans are expensive, but more importantly, they use radiation,” says Tobias Becher, the study’s first author and formerly a Clinical Scholar in Cohen’s lab. “We don’t want to subject many healthy people to that.”
A physician-scientist, Becher came up with an alternative. Right across the street from his lab, many thousands of people visit Memorial Sloan Kettering Cancer Center each year to undergo PET scans for cancer evaluation. Becher knew that when radiologists detect brown fat on these scans, they routinely make note of it to make sure it is not mistaken for a tumor. “We realized this could be a valuable resource to get us started with looking at brown fat at a population scale,” Becher says.
In collaboration with Heiko Schoder and Andreas Wibmer at Memorial Sloan Kettering, the researchers reviewed 130,000 PET scans from more than 52,000 patients, and found the presence of brown fat in nearly 10 percent of individuals. (Cohen notes that this figure is likely an underestimate because the patients had been instructed to avoid cold exposure, exercise, and caffeine, all of which are thought to increase brown fat activity).
Several common and chronic diseases were less prevalent among people with detectable brown fat. For example, only 4.6 percent had type 2 diabetes, compared with 9.5 percent of people who did not have detectable brown fat. Similarly, 18.9 percent had abnormal cholesterol, compared to 22.2 percent in those without brown fat.
Moreover, the study revealed three more conditions for which people with brown fat have lower risk: hypertension, congestive heart failure, and coronary artery disease–links that had not been observed in previous studies.
Another surprising finding was that brown fat may mitigate the negative health effects of obesity. In general, obese people have increased risk of heart and metabolic conditions; but the researchers found that among obese people who have brown fat, the prevalence of these conditions was similar to that of non-obese people. “It almost seems like they are protected from the harmful effects of white fat,” Cohen says.
More than an energy burning powerhouse
The actual mechanisms by which brown fat may contribute to better health are still unclear, but there are some clues. For example, brown-fat cells consume glucose in order to burn calories, and it’s possible that this lowers blood glucose levels, a major risk factor for developing diabetes.
The role of brown fat is more mysterious in other conditions like hypertension, which is tightly connected to the hormonal system. “We are considering the possibility that brown fat tissue does more than consume glucose and burn calories, and perhaps actually participates in hormonal signaling to other organs,” Cohen says.
The team plans to further study the biology of brown fat, including by looking for genetic variants that may explain why some people have more of it than others–potential first steps toward developing pharmacological ways to stimulate brown fat activity to treat obesity and related conditions.
“The natural question that everybody has is, ‘What can I do to get more brown fat?'” Cohen says. “We don’t have a good answer to that yet, but it will be an exciting space for scientists to explore in the upcoming years.”
The liver siphons critical immune cells to render immunotherapy ineffective; radiation to the liver may block this process.
Michael Green, M.D., Ph.D., noticed that when his patients had cancer that spread to the liver, they fared poorly – more so than when cancer spread to other parts of the body. Not only that, but transformative immunotherapy treatments had little impact for these patient.
Uncovering the reason and a possible solution, a new study, published in Nature Medicine, finds that tumors in the liver siphon off critical immune cells, rendering immunotherapy ineffective. But coupling immunotherapy with radiotherapy to the liver in mice restored the immune cell function and led to better outcomes.
“Patients with liver metastases receive little benefit from immunotherapy, a treatment that has been a game-changer for many cancers. Our research suggests that we can reverse this resistance using radiation therapy. This has potential to make a real difference in outcomes for these patients,” says Green, assistant professor of radiation oncology at Michigan Medicine and corresponding author on the paper.
A multidisciplinary team from the University of Michigan Rogel Cancer Center looked at data from 718 patients who had received immunotherapy at the center. Patients had a variety of cancer types, including non-small cell lung cancer, melanoma, urothelial cancer and renal cell cancer, which had spread to different organs, including the liver and lungs.
Repeatedly, those with liver metastases had worse responses to immunotherapy. The issue was not just in the liver either: these patients had more cancer throughout their bodies, compared to similar patients whose cancer had spread but not to the liver.
“The liver is initiating a systemic immunosuppressive mechanism. The mechanism happens in the liver, but we see the systemic impact throughout the body,” says corresponding study author Weiping Zou, M.D., Ph.D., Charles B. de Nancrede Professor of Surgery, Pathology, Immunology and Biology at the University of Michigan.
The liver is one of the most common site to which cancer metastasizes. It’s known to interfere with immune response in autoimmune diseases, viral infections and organ transplants by suppressing certain critical immune cells.
This was playing out in metastatic cancer as oncologists observed a lack of immune response. Green notes that patients with liver metastases who received chemotherapy or targeted therapies did not have worse outcomes compared to those with other types of metastases. “It’s unique to immunotherapy,” he says.
Looking within the microenvironment of the liver metastases, researchers saw that the tumors were siphoning off the T cells – immune cells that should have been working to attack the cancer. Not only were the T cells being eliminated in the liver, but this was also creating an immune desert throughout the body. As a result, the immune system could not be activated to fight tumors at any sites.
Using mice with liver metastases, researchers delivered radiation therapy directly to the tumors in the liver. This stopped T cell death. With the T cells restored, an immune checkpoint inhibitor was then able to activate the immune system to eliminate the cancer throughout the body, on par with results seen in non-liver metastases.
“It’s always a challenge to identify a novel mechanism of immune suppression and find a way to address it. With these promising results, we are now looking to open clinical trials in this space to better understand the mechanisms at play in human tumors,” Green says.
Reference: Jiali Yu, Michael D. Green, Shasha Li, Yilun Sun, Sara N. Journey, Jae Eun Choi, Syed Monem Rizvi, Angel Qin, Jessica J. Waninger, Xueting Lang, Zoey Chopra, Issam El Naqa, Jiajia Zhou, Yingjie Bian, Long Jiang, Alangoya Tezel, Jeremy Skvarce, Rohan K. Achar, Merna Sitto, Benjamin S. Rosen, Fengyun Su, Sathiya P. Narayanan, Xuhong Cao, Shuang Wei, Wojciech Szeliga, Linda Vatan, Charles Mayo, Meredith A. Morgan, Caitlin A. Schonewolf, Kyle Cuneo, Ilona Kryczek, Vincent T. Ma, Christopher D. Lao, Theodore S. Lawrence, Nithya Ramnath, Fei Wen, Arul M. Chinnaiyan, Marcin Cieslik, Ajjai Alva & Weiping Zou. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nature Medicine, 2021 DOI: 10.1038/s41591-020-1131-x
Brain tumours might arise when tissue does not heal properly– a finding that opens up new ideas about how cancer develops and how to combat it.
The healing process that follows a brain injury could spur tumour growth when new cells generated to replace those lost to the injury are derailed by mutations, Toronto scientists have found. A brain injury can be anything from trauma to infection or stroke.
The findings were made by an interdisciplinary team of researchers from the University of Toronto, The Hospital for Sick Children (SickKids) and the Princess Margaret Cancer Centre who are also on the pan-Canadian Stand Up To Cancer Canada Dream Team that focuses on a common brain cancer known as glioblastoma.
“Our data suggest that the right mutational change in particular cells in the brain could be modified by injury to give rise to a tumour,” says Dr. Peter Dirks, Dream Team leader who is the Head of the Division of Neurosurgery and a Senior Scientist in the Developmental and Stem Cell Biology program at SickKids.
Gary Bader, a professor of molecular genetics in the Donnelly Centre for Cellular and Biomolecular Research at U of T’s Temerty Faculty of Medicine and Dr. Trevor Pugh, Senior Scientist at the Princess Margaret, also led the research which has been published today in the journal Nature Cancer.
The findings could lead to new therapy for glioblastoma patients who currently have limited treatment options with an average lifespan of 15 months after diagnosis.
“Glioblastoma can be thought of as a wound that never stops healing,” says Dirks. “We’re excited about what this tells us about how cancer originates and grows and it opens up entirely new ideas about treatment by focusing on the injury and inflammation response.”
The researchers applied the latest single-cell RNA sequencing and machine learning technologies to map the molecular make-up of the glioblastoma stem cells (GSCs), which Dirks’ team previously showed are responsible for tumour initiation and recurrence after treatment.
They found new subpopulations of GSCs which bear the molecular hallmarks of inflammation and which are comingled with other cancer stem cells inside patients’ tumours. It suggests that some glioblastomas start to form when the normal tissue healing process, which generates new cells to replace those lost to injury, gets derailed by mutations, possibly even many years before patients become symptomatic, Dirks said.
Once a mutant cell becomes engaged in wound healing, it cannot stop multiplying because the normal controls are broken and this spurs tumour growth, according to the study.
“The goal is to identify a drug that will kill the glioblastoma stem cells,” says Bader, whose graduate student Owen Whitley contributed to the computational data analysis “But we first needed to understand the molecular nature of these cells in order to be able to target them more effectively.”
The team collected GSCs from 26 patients’ tumours and expanded them in the lab to obtain sufficient numbers of these rare cells for analysis. Almost 70,000 cells were analyzed by single-cell RNA sequencing which detects what genes are switched on in individual cells, an effort led by Laura Richards, a graduate student in Pugh’s lab.
The data confirmed extensive disease heterogeneity, meaning that each tumour contains multiple subpopulations of molecularly distinct cancer stem cells, making recurrence likely as existing therapy can’t wipe out all the different subclones.
A closer look revealed that each tumour has either of the two distinct molecular states–termed “Developmental” and “Injury Response”– or somewhere on a gradient between the two.
The developmental state is a hallmark of the glioblastoma stem cells and resembles that of the rapidly dividing stem cells in the growing brain before birth.
But the second state came as a surprise. The researchers termed it “Injury Response” because it showed an upregulation of immune pathways and inflammation markers, such as interferon and TNFalpha, which are indicative of wound healing processes.
These immune signatures were only picked up thanks to the new single-cell technology after being missed by older methods for bulk cell measurements.
Meanwhile, experiments led by Stephane Angers’ lab at the Leslie Dan Faculty of Pharmacy established that the two states are vulnerable to different types of gene knock outs, revealing a swathe of therapeutic targets linked to inflammation that had not been previously considered for glioblastoma.
Finally, the relative comingling of the two states was found to be patient-specific, meaning that each tumour was biased either toward the developmental or the injury response end of the gradient. The researchers are now looking to target these biases for tailored therapies.
“We’re now looking for drugs that are effective on different points of this gradient”, says Pugh, who is also the Director of Genomics at the Ontario Institute for Cancer Research. “There’s a real opportunity here for precision medicine– to dissect patients’ tumours at the single cell level and design a drug cocktail that can take out more than one cancer stem cell subclone at the same time.”
The Hospital for Sick Children (SickKids) is recognized as one of the world’s foremost paediatric health-care institutions and is Canada’s leading centre dedicated to advancing children’s health through the integration of patient care, research and education. Founded in 1875 and affiliated with the University of Toronto, SickKids is one of Canada’s most research-intensive hospitals and has generated discoveries that have helped children globally. Its mission is to provide the best in complex and specialized family-centred care; pioneer scientific and clinical advancements; share expertise; foster an academic environment that nurtures health-care professionals; and champion an accessible, comprehensive and sustainable child health system. SickKids is a founding member of Kids Health Alliance, a network of partners working to create a high quality, consistent and coordinated approach to paediatric health care that is centred around children, youth and their families. SickKids is proud of its vision for Healthier Children. A Better World.
About Donnelly Centre for Cellular and Biomolecular Research
The Donnelly Centre for Cellular and Biomolecular Research at the University of Toronto is a globally renowned interdisciplinary research institute where scientists make discoveries to improve human health. Founded in 2005, the Centre currently houses 29 faculty members and over 300 students and postdoctoral trainees in the areas of integrative and systems biology, bioengineering, regenerative medicine and models of disease. Supported by competitive federal, provincial as well as international and nonprofit funding grants, the Donnelly Centre investigators build and apply the latest technologies with innovative and sophisticated platforms in a highly collaborative environment. In 2019, the Centre launched the Accelerator for Donnelly Collaboration, a biotechnology incubator for startups and companies looking to translate the discoveries made in the Centre into tangible medical advances. For more information: https://www.thedonnellycentre.utoronto.ca/.
About Princess Margaret Cancer Centre
Princess Margaret Cancer Centre has achieved an international reputation as a global leader in the fight against cancer and delivering personalized cancer medicine. The Princess Margaret, one of the top five international cancer research centres, is a member of the University Health Network, which also includes Toronto General Hospital, Toronto Western Hospital, Toronto Rehabilitation Institute and the Michener Institute for Education at UHN. All are research hospitals affiliated with the University of Toronto. For more information: http://www.theprincessmargaret.ca