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Can fruit fly research help improve survival of cancer patients? New anti-cancer strategy — blocking chemicals produced by tumors — could boost life span, health span
The experience of a fruit fly dying from cancer may seem worlds away from that of a human with a life-threatening tumor, yet University of California, Berkeley, researchers are finding commonalities between the two that could lead to ways to prolong the lives of cancer patients.
“It’s a really complementary way of thinking about therapy,” said David Bilder, UC Berkeley professor of molecular and cell biology. “You’re trying to help the host deal with the effects of the tumor, rather than killing the tumor itself.”
Jung Kim, a postdoctoral fellow in Bilder’s lab, recently discovered that tumors in fruit flies release a chemical that compromises the barrier between the bloodstream and the brain, letting the two environments mix — a recipe for disaster in numerous diseases, including infection, trauma and even obesity. In collaboration with the labs of UC Berkeley professors David Raulet and Kaoru Saijo, Kim and Bilder subsequently demonstrated that tumors in mice that release the same chemical, a cytokine called interleukin-6 (IL-6), also make the blood-brain barrier leaky.
More importantly, they were able to extend the lifespan of both fruit flies and mice with malignant tumors by blocking the effect of the cytokine on the barrier.
“The IL-6 cytokine is known to cause inflammation. What’s new here is that this tumor-induced inflammation is actually causing the blood-brain barrier to open. If we interfere with that opening process but leave the tumor alone, then the host can live significantly longer and healthier with the same tumor burden,” Bilder said.
IL-6 plays other important roles in the body, so to benefit cancer patients, scientists would have to find a drug that blocks its action at the blood-brain barrier without altering its effects elsewhere. But such a drug could potentially extend the life span and health span of human cancer patients, he said.
Six years ago, Bilder’s team found that tumors in fruit flies also release a substance that blocks the effects of insulin, providing a potential explanation for the tissue wasting called cachexia that kills one-fifth of all cancer patients. That work is now being explored by numerous labs around the world.
One advantage of helping the host fend off a tumor’s effects on tissues far from the tumor site is that it could potentially reduce or even eliminate the need for toxic drugs typically used to subdue tumors. Such drugs also harm the patient, killing healthy cells as well as cancerous cells.
Beyond these side effects, targeting tumor cells “also selects for resistance in the tumor, because the tumor has genetic variability — a drug-resistant clone arises that will then cause cancer recurrence,” he said. “But if you could target the host cells, they have a stable genome and are not going to gain resistance to these drugs. That’s our goal: to understand the ways that the tumor is affecting the host and attack the host side of the tumor-host dialogue.”
Bilder and his colleagues published their work on IL-6 disruption of the blood-brain barrier last week in the journal Developmental Cell, and he authored a review of the impact that fruit fly research has had on understanding tumor-host interactions that was published last month in the journal Nature Reviews Cancer. Their cachexia work appeared in 2015 in Developmental Cell.
What actually kills cancer patients?
According to Bilder, scientists still are uncertain what causes death in many cancer patients. Cancer of the liver, for example, clearly destroys the function of an organ essential for life. However, other organs, like the skin or the ovaries, are less critical, yet people die from cancer in these sites, too, sometimes very quickly. And though cancers often metastasize to other organs — multiple organ failure is one of the main causes of cancer death listed by doctors — Bilder questions if that’s the whole story.
“Many human cancers are metastatic, but that doesn’t change the basic question: Why does the cancer kill?” he said. “If your tumor metastasized to the lung, are you dying because of lung failure or are you dying from something else?”
For that reason, he works with non-metastatic tumors implanted in fruit flies and mice and looks for systemic effects, not merely the effects on the tumor-containing organ itself.
One systemic effect of cancer is cachexia, the inability to maintain weight, which leads to wasting of muscle even when the patient is receiving intravenous nutrition. While Bilder discovered one possible reason for this — cancers release a chemical that prevents insulin from storing energy in the body — other scientists have found additional substances released by cancers that may also be responsible for tissue wasting.
Like cachexia, breaches in the blood-brain barrier may be another long-distance effect of tumors. In the new study, the researchers found that blocking the activity of IL-6 at the blood-brain barrier increased the lifespan of flies with cancer by 45%. Laboratory mice must be euthanized before they suffer and die from experimental cancer, but the team found that after 21 days, 75% of cancer-carrying mice treated with an IL-6 receptor blocker were alive, versus only 25% of untreated mice with cancer.
“It’s not just the breakdown of the blood-brain barrier that’s killing the animals,” Bilder said. “Flies can live for three or four weeks with a leaky blood-brain barrier, whereas, if they have a tumor, they die almost immediately when the barrier is compromised. So, we think that the tumor is causing something else to happen. Maybe it’s putting something in circulation that then gets through the broken barrier, though it could also be something going the other way, from the brain into the blood.”
Bilder has found additional cancer-produced chemicals in flies that he’s linked to edema — bloating from excess fluid retention — and excess blood clotting, which leads to blocked veins. Both conditions frequently accompany cancer. Other researchers have found tumor-produced fly chemicals linked to anorexia — the loss of appetite — and to immune disfunction, which also are symptoms of many cancers.
Bilder said that studying cancer in fruit flies offers several advantages over cancer models in other animals, such as mice and rats. For one thing, researchers can follow flies right up to the moment of death, in order to determine what actually causes mortality. Ethical concerns prevent researchers from allowing vertebrates to suffer, so research animals are euthanized before they die naturally, preventing a full understanding of the ultimate cause of death. For these animals, tumor size is used as a proxy to assess an animal’s chance of survival.
“We’re incredibly excited about the potential to look directly at survival and life span,” he said. “We think that this is a real blind spot that hasn’t allowed scientists to address questions about how the tumor is actually killing outside of its local growth. That’s not to say that tumor size is misleading, but fruit flies give us a complementary way of looking at what cancer is doing.”
And while most cancer studies in rodents involve just a few dozen animals, fruit fly experiments can involve many hundreds of individuals, which improves the statistical significance of the results. Fruit flies also reproduce quickly and have short natural life spans, allowing quicker studies.
Bilder acknowledges that fruit flies and humans are only distantly related, but in the past, these flies — Drosophila melanogaster — have played a key role in understanding tumor growth factors and oncogenes. Fruit flies now could also be key in understanding cancer’s systemic effects.
“Not only can flies get tumors that resemble human tumors, which we described 20 years ago, but we’re now seeing that the host response has remarkable similarities in cachexia, coagulopathies, immune response, cytokine production, all of these things,” he said. “I think it (the tumor-host response in fruit flies) is a superrich area. Our hope is to bring attention to the field and attract other people to work in it, both from the fly perspective and from the cancer biology and clinician perspective.”
Co-authors of the new paper include UC Berkeley postdoc Hsiu-Chun Chuang, graduate student Natalie Wolf and former doctoral student Christopher Nicolai.The work was supported by the National Institutes of Health (GM090150, GM130388, AI113041, HD092093).
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Early dark energy could resolve cosmology’s two biggest puzzles
A new study by MIT physicists proposes that a mysterious force known as early dark energy could solve two of the biggest puzzles in cosmology and fill in some major gaps in our understanding of how the early universe evolved.
Now, the MIT team has found that both puzzles could be resolved if the early universe had one extra, fleeting ingredient: early dark energy. Dark energy is an unknown form of energy that physicists suspect is driving the expansion of the universe today. Early dark energy is a similar, hypothetical phenomenon that may have made only a brief appearance, influencing the expansion of the universe in its first moments before disappearing entirely.
Some physicists have suspected that early dark energy could be the key to solving the Hubble tension, as the mysterious force could accelerate the early expansion of the universe by an amount that would resolve the measurement mismatch.
The MIT researchers have now found that early dark energy could also explain the baffling number of bright galaxies that astronomers have observed in the early universe. In their new study, reported in the Monthly Notices of the Royal Astronomical Society, the team modeled the formation of galaxies in the universe’s first few hundred million years. When they incorporated a dark energy component only in that earliest sliver of time, they found the number of galaxies that arose from the primordial environment bloomed to fit astronomers’ observations.
“You have these two looming open-ended puzzles,” says study co-author Rohan Naidu, a postdoc in MIT’s Kavli Institute for Astrophysics and Space Research. “We find that in fact, early dark energy is a very elegant and sparse solution to two of the most pressing problems in cosmology.”
The study’s co-authors include lead author and Kavli postdoc Xuejian (Jacob) Shen, and MIT professor of physics Mark Vogelsberger, along with Michael Boylan-Kolchin at the University of Texas at Austin, and Sandro Tacchella at the University of Cambridge.
Big city lights
Based on standard cosmological and galaxy formation models, the universe should have taken its time spinning up the first galaxies. It would have taken billions of years for primordial gas to coalesce into galaxies as large and bright as the Milky Way.
But in 2023, NASA’s James Webb Space Telescope (JWST) made a startling observation. With an ability to peer farther back in time than any observatory to date, the telescope uncovered a surprising number of bright galaxies as large as the modern Milky Way within the first 500 million years, when the universe was just 3 percent of its current age.
“The bright galaxies that JWST saw would be like seeing a clustering of lights around big cities, whereas theory predicts something like the light around more rural settings like Yellowstone National Park,” Shen says. “And we don’t expect that clustering of light so early on.”
For physicists, the observations imply that there is either something fundamentally wrong with the physics underlying the models or a missing ingredient in the early universe that scientists have not accounted for. The MIT team explored the possibility of the latter, and whether the missing ingredient might be early dark energy.
Physicists have proposed that early dark energy is a sort of antigravitational force that is turned on only at very early times. This force would counteract gravity’s inward pull and accelerate the early expansion of the universe, in a way that would resolve the mismatch in measurements. Early dark energy, therefore, is considered the most likely solution to the Hubble tension.
Galaxy skeleton
The MIT team explored whether early dark energy could also be the key to explaining the unexpected population of large, bright galaxies detected by JWST. In their new study, the physicists considered how early dark energy might affect the early structure of the universe that gave rise to the first galaxies. They focused on the formation of dark matter halos — regions of space where gravity happens to be stronger, and where matter begins to accumulate.
“We believe that dark matter halos are the invisible skeleton of the universe,” Shen explains. “Dark matter structures form first, and then galaxies form within these structures. So, we expect the number of bright galaxies should be proportional to the number of big dark matter halos.”
The team developed an empirical framework for early galaxy formation, which predicts the number, luminosity, and size of galaxies that should form in the early universe, given some measures of “cosmological parameters.” Cosmological parameters are the basic ingredients, or mathematical terms, that describe the evolution of the universe.
Physicists have determined that there are at least six main cosmological parameters, one of which is the Hubble constant — a term that describes the universe’s rate of expansion. Other parameters describe density fluctuations in the primordial soup, immediately after the Big Bang, from which dark matter halos eventually form.
The MIT team reasoned that if early dark energy affects the universe’s early expansion rate, in a way that resolves the Hubble tension, then it could affect the balance of the other cosmological parameters, in a way that might increase the number of bright galaxies that appear at early times. To test their theory, they incorporated a model of early dark energy (the same one that happens to resolve the Hubble tension) into an empirical galaxy formation framework to see how the earliest dark matter structures evolve and give rise to the first galaxies.
“What we show is, the skeletal structure of the early universe is altered in a subtle way where the amplitude of fluctuations goes up, and you get bigger halos, and brighter galaxies that are in place at earlier times, more so than in our more vanilla models,” Naidu says. “It means things were more abundant, and more clustered in the early universe.”
“A priori, I would not have expected the abundance of JWST’s early bright galaxies to have anything to do with early dark energy, but their observation that EDE pushes cosmological parameters in a direction that boosts the early-galaxy abundance is interesting,” says Marc Kamionkowski, professor of theoretical physics at Johns Hopkins University, who was not involved with the study. “I think more work will need to be done to establish a link between early galaxies and EDE, but regardless of how things turn out, it’s a clever — and hopefully ultimately fruitful — thing to try.”
“We demonstrated the potential of early dark energy as a unified solution to the two major issues faced by cosmology. This might be an evidence for its existence if the observational findings of JWST get further consolidated,” Vogelsberger concludes. “In the future, we can incorporate this into large cosmological simulations to see what detailed predictions we get.”
This research was supported, in part, by NASA and the National Science Foundation.
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Plant-derived secondary organic aerosols can act as mediators of plant-plant interactions
A new study published in Science reveals that plant-derived secondary organic aerosols (SOAs) can act as mediators of plant-plant interactions. This research was conducted through the cooperation of chemical ecologists, plant ecophysiologists and atmospheric physicists at the University of Eastern Finland.
The study showed that Scots pine seedlings, when damaged by large pine weevils, release VOCs that activate defences in nearby plants of the same species. Interestingly, the biological activity persisted after VOCs were oxidized to form SOAs. The results indicated that the elemental composition and quantity of SOAs likely determines their biological functions.
“A key novelty of the study is the finding that plants adopt subtly different defence strategies when receiving signals as VOCs or as SOAs, yet they exhibit similar degrees of resistance to herbivore feeding,” said Professor James Blande, head of the Environmental Ecology Research Group. This observation opens up the possibility that plants have sophisticated sensing systems that enable them to tailor their defences to information derived from different types of chemical cue.
“Considering the formation rate of SOAs from their precursor VOCs, their longer lifetime compared to VOCs, and the atmospheric air mass transport, we expect that the ecologically effective distance for interactions mediated by SOAs is longer than that for plant interactions mediated by VOCs,” said Professor Annele Virtanen, head of the Aerosol Physics Research Group. This could be interpreted as plants being able to detect cues representing close versus distant threats from herbivores.
The study is expected to open up a whole new complex research area to environmental ecologists and their collaborators, which could lead to new insights on the chemical cues structuring interactions between plants.
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Folded or cut, this lithium-sulfur battery keeps going
Most rechargeable batteries that power portable devices, such as toys, handheld vacuums and e-bikes, use lithium-ion technology. But these batteries can have short lifetimes and may catch fire when damaged. To address stability and safety issues, researchers reporting in ACS Energy Letters have designed a lithium-sulfur (Li-S) battery that features an improved iron sulfide cathode. One prototype remains highly stable over 300 charge-discharge cycles, and another provides power even after being folded or cut.
The team coated iron sulfide cathodes in different polymers and found in initial electrochemical performance tests that polyacrylic acid (PAA) performed best, retaining the electrode’s discharge capacity after 300 charge-discharge cycles. Next, the researchers incorporated a PAA-coated iron sulfide cathode into a prototype battery design, which also included a carbonate-based electrolyte, a lithium metal foil as an ion source, and a graphite-based anode. They produced and then tested both pouch cell and coin cell battery prototypes.
After more than 100 charge-discharge cycles, Wang and colleagues observed no substantial capacity decay in the pouch cell. Additional experiments showed that the pouch cell still worked after being folded and cut in half. The coin cell retained 72% of its capacity after 300 charge-discharge cycles. They next applied the polymer coating to cathodes made from other metals, creating lithium-molybdenum and lithium-vanadium batteries. These cells also had stable capacity over 300 charge-discharge cycles. Overall, the results indicate that coated cathodes could produce not only safer Li-S batteries with long lifespans, but also efficient batteries with other metal sulfides, according to Wang’s team.
The authors acknowledge funding from the National Natural Science Foundation of China; the Natural Science Foundation of Sichuan, China; and the Beijing National Laboratory for Condensed Matter Physics.
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