Insulin rises before cells develop resistance, new diabetes research implies

 Researchers at the University of Gothenburg, Sweden, have now presented results that may change our basic view of how type 2 diabetes occurs. Their study indicates that free fatty acids (FFAs) in the blood trigger insulin release even at a normal blood-sugar level, without an overt uncompensated insulin resistance in fat cells. What is more, the researchers demonstrate the connection with obesity: the amount of FFAs largely depends on how many extra kilos of adipose tissue a person carries, but also on how the body adapt to the increased adiposity.

Worldwide, extensive research is underway to clarify exactly what happens in the body as type 2 diabetes progresses, and why obesity is such a huge risk factor for the disease. For almost 50 years, diabetes researchers have been discussing their version of the chicken-or-egg question: Which comes first -- insulin resistance or elevated insulin levels? The dominant hypothesis has long been that the pancreas steps up its insulin production because the cells have already become insulin-resistant, and blood sugar then rises. However, the results now published in the journal EBioMedicine support the opposing idea: that it is the insulin that increases first.

Detailed investigations

The study indicates that high FFA levels in the blood after the overnight fast raise insulin production in the morning. FFAs have long been part of the main research equation for type 2 diabetes, but it is now proposed that they also have another role: in progression of the disease.

For the study, researchers compared metabolism in adipose (fat-storing) tissue among 27 carefully selected research subjects (nine of normal weight, nine with obesity and normal blood sugar, and nine with both obesity and progressed type 2 diabetes). For several days, they underwent extensive examinations in which they had samples taken under varying conditions. The researchers analyzed metabolism and gene expression in the participants' subcutaneous fat, and the levels of blood sugar, insulin, and FFAs in their blood.

FFAs seem to trigger insulin production

The people with obesity but not diabetes proved to have the same, normal blood-sugar levels as the healthy individuals of normal weight.

"Interestingly, the nondiabetics with obesity had elevated levels of both free fatty acids and insulin in their blood, and those levels were similar to or higher than the levels we were able to measure in blood from the participants with both obesity and type 2 diabetes," says Emanuel Fryk, resident doctor specializing in general medicine and doctoral student at Sahlgrenska Academy, University of Gothenburg, who is one of the study's first authors.

In collaboration with researchers at Uppsala University, he observed the same pattern in a population study based on blood samples taken from 500 people after an overnight fast.

"The fact that we saw a link between free fatty acids and insulin there too suggests that the fatty acids are connected with the insulin release, and contribute to increased insulin production on an empty stomach, when blood sugar hasn't risen," says Fryk, who nevertheless points out that the finding needs to be confirmed with more research.

Ongoing research

Free fatty acids are found naturally in the bloodstream and, like glycerol, are a product of the body's fat metabolism. In the subjects, the amount of glycerol released proved to be broadly the same per kilo of body fat, regardless of whether they were of normal weight, had obesity alone, or also had type 2 diabetes.

"Our hypothesis is that the free fatty acids increase in the blood because the adipose tissue can't store the excess energy anymore. We believe, in that case, it could be an early sign of incipient type 2 diabetes. If our findings are confirmed when other research methods are used, there may be a chance that some specific fatty acids could be developed into biomarkers. But that's a long way off," Fryk says.

Lifestyle crucial

Diabetes is one of the most common diseases, with an estimated 500,000 people affected in Sweden. There are also a large number of undetected cases, since many with type 2 diabetes are not yet aware they are ill. Diabetics are at an increased risk for a number of serious conditions, such as cardiovascular disease (which may result in heart attacks and strokes).

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How critical part of lung forms at cellular level

Researchers from Children's Hospital of Philadelphia (CHOP) have determined what happens at a cellular level as the lung alveolus forms and allows newborns to breathe air. Understanding this process gives researchers a better sense of how to develop therapies and potentially regenerate this critical tissue in the event of injury. The findings were published online today by the journal Science.

The lung develops during both embryonic and postnatal stages, during which lung tissue forms and a variety of cell types perform specific roles. During the transition from embryo to newborn is when the alveolar region of the lung refines its primary function of exchanging gas, which includes the critical process of ridding the body of carbon dioxide.

Despite these critical steps involved in the formation of the lung, little is known about what happens at a cellular and genomic level. Not only is the lung alveolar critical, it can also suffer damage caused by pathogens such as influenza and the SARS-CoV2 virus that causes COVID-19. Knowing which cells are involved in the formation of healthy lung tissue at birth may provide a basis for therapies that help regenerate this critical portion of the lung.

"Extensive morphological changes properly shape the alveolar niche, but prior to this study, the research community was unsure as to the extent of cellular signaling involved to promote its proper architecture," said first author Jarod A. Zepp, PhD, a research faculty member of the Division of Pulmonary and Sleep Medicine at CHOP and an Assistant Professor at the Perelman School of Medicine at the University of Pennsylvania. "Recent advances in technology allowed us to assess the intracellular communication that drives the generation of this critical portion of the lung."

The study team used a multimodal approach to investigate intercellular relationships that drive the formation of the alveolus. They discovered that alveolar type 1 (AT1) epithelial cells, which form the outer layer of the alveolus tissue, represent a signaling hub that coordinates cell development, especially during the transition to air breathing. They also traced the lineage of AT1 cells and show that they align with myofibroblasts, which are a special cell type involved in tissue remodeling. Finally, the researchers also demonstrated that AT1-restricted ligands, or secreted binding molecules, are required to form these myofibroblasts and the alveolus.

"Our study reveals the complexity of the cell-types and their extensive communication with one another as they form this critical part of the lung," Zepp said. "The recent COVID-19 pandemic has provided the research community with an increased appreciation of the intercellular communication that helps form the alveolar structure and maintain its function and provides us with vital clues on how we might be able to repair damaged tissue at a cellular level."

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Squids: Sophisticated skin

 Squids have long been a source of fascination for humans, providing the stuff of legend, superstition and myth. And it's no wonder -- their odd appearances and strange intelligence, their mastery of the open ocean can inspire awe in those who see them.

Legends aside, squids continue to intrigue people today -- people like UC Santa Barbara professor Daniel Morse -- for much the same, albeit more scientific, reasons. Having evolved for hundreds of millions of years to hunt, communicate, evade predators and mate in the vast, often featureless expanses of open water, squids have developed some of the most sophisticated skin in the animal kingdom.

"For centuries, people have been amazed at the ability of squids to change the color and patterns of their skin -- which they do beautifully -- for camoflage and underwater communication, signaling to one another and to other species to keep away, or as attraction for mating and other kinds of signaling," said Morse, a Distinguished Professor Emeritus of Biochemistry and Molecular Genetics.

Like their cephalopod cousins the octopus and cuttlefish, squids have specialized pigment-filled cells called chromatophores that expand to expose them to light, resulting in various shades of pigmentary color. Of particular interest to Morse, however, is the squids' ability to shimmer and flicker, reflecting different colors and breaking light over their skin. It's an effect that is thought to mimic the dappled light of the upper ocean -- the only feature in an otherwise stark seascape. By understanding how squids manage to fade themselves into even the plainest of backgrounds -- or stand out -- it may be possible to produce materials with the same, light tuning properties for a variety of applications.

Morse has been working to unlock the secret of squid skin for the last decade, and with support from the Army Research Office and research published in the journal Applied Physics Letters, he and co-author Esther Taxon come even closer to unraveling the complex mechanisms that underlie squid skin.

An Elegant Mechanism

"What we've discovered is that not only is the squid able to tune the color of the light that's reflected, but also its brightness," Morse said. Research had thus far has established that certain proteins called reflectins were responsible for iridescence, but the squid's ability to tune the brightness of the reflected light was still something of a mystery, he said.

Previous research by Morse had uncovered structures and mechanisms by which iridocytes -- light-reflecting cells -- in the opalescent inshore squid's (Doryteuthis opalescens) skin can take on virtually every color of the rainbow. It happens with the cell membrane, where it folds into nanoscale accordion-like structures called lamellae, forming tiny, subwavelength-wide exterior grooves.

"Those tiny groove structures are like the ones we see on the engraved side of a compact disc," Morse said. The color reflected depends on the width of the groove, which corresponds to certain light wavelengths (colors). In the squid's iridocytes, these lamellae have the added feature of being able to shapeshift, widening and narrowing those grooves through the actions of a remarkably finely tuned "osmotic motor" driven by reflectin proteins condensing or spreading apart inside the lamellae.

While materials systems containing reflectin proteins were able to approximate the iridescent color changes squid were capable of, attempts to replicate the ability to intensify brightness of these reflections always came up short, according to the researchers, who reasoned that something had to be coupled to the reflectins in squid skin, amplifying their effect.

That something turned out to be the very membrane enclosing the reflectins -- the lamellae, the same structures responsible for the grooves that split light into its constituent colors.

"Evolution has so exquisitely optimized not only the color tuning, but the tuning of the brightness using the same material, the same protein and the same mechanism," Morse said.

Light at the Speed of Thought

It all starts with a signal, a neuronal pulse from the squid's brain.

"Reflectins are normally very strongly positively charged," Morse said of the iridescent proteins, which, when not activated, look like a string of beads. Their same charge means they repel each other.

But that can change when a neural signal causes the reflectins to bind negatively charged phosphate groups that neutralize the positive charge. Without the repulsion keeping the proteins in their disordered state they fold and attract each other, accumulating into fewer, larger aggregations in the lamellae.

These aggregations exert osmotic pressure on the lamellae, a semipermeable membrane built to withstand only so much pressure created by the clumping reflectins before releasing water outside the cell.

"Water gets squished out of the accordion-like structure, and that collapses the accordion so the thickness in spacing between the folds gets reduced, and that's like bringing the grooves of a compact disc closer together," Morse explained. "So the light that's reflected can shift progressively from red to green to blue."

At the same time, the membrane's collapse concentrates the reflectins, causing an increase in their refractive index, amplifying brightness. Osmotic pressure, the motor that drives these tunings of optical properties, couples the lamellae tightly to the reflectins in a highly calibrated relationship that optimizes the output (color and brightness) to the input (neural signal). Wipe away the neural signal and the physics reverses, Morse said.

"It's a very clever, indirect way of changing color and brightness by controlling the physical behavior of what's called a colligative property -- the osmotic pressure, something that's not immediately obvious, but it reveals the intricacy of the evolutionary process, the millennia of mutation and natural selections that have honed and optimized these processes together."

Tunable-Brightness Thin-Films

The presence of a membrane may be the vital link for the development of bioinspired thin films with the optical tuning capacity of the opalescent inshore squid.

"This discovery of the key role the membrane plays in tuning the brightness of reflectance has intriguing implications for the design of future buihybrid materials and coatings with tunable optical properties that could protect soldiers and their equipment," said Stephanie McElhinny, a program manager at the the Army Research Office, an element of the U.S. Army Combat Capabilities Development Command's Army Research Laboratory.

According to the researchers, "This evolutionarily honed, efficient coupling of reflectin of its osmotic amplifier is closely analogous to the impedance matched coupling of activator-transducer-amplifier networks in well-engineered electronic, magnetic, mechanical and acoustic systems." In this case the activator would be the neuronal signal, while the reflectins acts as transducers and the osmotically controlled membranes serve as the amplifiers.

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Scientists sketch aged star system using over a century of observations

 Astronomers have painted their best picture yet of an RV Tauri variable, a rare type of stellar binary where two stars -- one approaching the end of its life -- orbit within a sprawling disk of dust. Their 130-year dataset spans the widest range of light yet collected for one of these systems, from radio to X-rays.

"There are only about 300 known RV Tauri variables in the Milky Way galaxy," said Laura Vega, a recent doctoral recipient at Vanderbilt University in Nashville, Tennessee. "We focused our study on the second brightest, named U Monocerotis, which is now the first of these systems from which X-rays have been detected."

A paper describing the findings, led by Vega, was published in The Astrophysical Journal.

The system, called U Mon for short, lies around 3,600 light-years away in the constellation Monoceros. Its two stars circle each other about every six and a half years on an orbit tipped about 75 degrees from our perspective.

The primary star, an elderly yellow supergiant, has around twice the Sun's mass but has billowed to 100 times the Sun's size. A tug of war between pressure and temperature in its atmosphere causes it to regularly expand and contract, and these pulsations create predictable brightness changes with alternating deep and shallow dips in light -- a hallmark of RV Tauri systems. Scientists know less about the companion star, but they think it's of similar mass and much younger than the primary.

The cool disk around both stars is composed of gas and dust ejected by the primary star as it evolved. Using radio observations from the Submillimeter Array on Maunakea, Hawai'i, Vega's team estimated that the disk is around 51 billion miles (82 billion kilometers) across. The binary orbits inside a central gap that the scientists think is comparable to the distance between the two stars at their maximum separation, when they're about 540 million miles (870 million kilometers) apart.

When the stars are farthest from each other, they're roughly aligned with our line of sight. The disk partially obscures the primary and creates another predictable fluctuation in the system's light. Vega and her colleagues think this is when one or both stars interact with the disk's inner edge, siphoning off streams of gas and dust. They suggest that the companion star funnels the gas into its own disk, which heats up and generates an X-ray-emitting outflow of gas. This model could explain X-rays detected in 2016 by the European Space Agency's XMM-Newton satellite.

"The XMM observations make U Mon the first RV Tauri variable detected in X-rays," said Kim Weaver, the XMM U.S. project scientist and an astrophysicist at NASA's Goddard Space Flight Center in Greenbelt, Maryland. "It's exciting to see ground- and space-based multiwavelength measurements come together to give us new insights into a long-studied system."

In their analysis of U Mon, Vega's team also incorporated 130 years of visible light observations.

The earliest available measurement of the system, collected on Dec. 25, 1888, came from the archives of the American Association of Variable Star Observers (AAVSO), an international network of amateur and professional astronomers headquartered in Cambridge, Massachusetts. AAVSO provided additional historical measurements ranging from the mid-1940s to the present.

The researchers also used archived images cataloged by the Digital Access to a Sky Century @ Harvard (DASCH), a program at the Harvard College Observatory in Cambridge dedicated to digitizing astronomical images from glass photographic plates made by ground-based telescopes between the 1880s and 1990s.

U Mon's light varies both because the primary star pulsates and because the disk partially obscures it every 6.5 years or so. The combined AAVSO and DASCH data allowed Vega and her colleagues to spot an even longer cycle, where the system's brightness rises and falls about every 60 years. They think a warp or clump in the disk, located about as far from the binary as Neptune is from the Sun, causes this extra variation as it orbits.

Vega completed her analysis of the U Mon system as a NASA Harriett G. Jenkins Predoctoral Fellow, a program funded by the NASA Office of STEM Engagement's Minority University Research and Education Project.

"For her doctoral dissertation, Laura used this historical dataset to detect a characteristic that would otherwise appear only once in an astronomer's career," said co-author Rodolfo Montez Jr., an astrophysicist at the Center for Astrophysics | Harvard & Smithsonian, also in Cambridge. "It's a testament to how our knowledge of the universe builds over time."

Co-author Keivan Stassun, an expert in star formation and Vega's doctoral advisor at Vanderbilt, notes that this evolved system has many features and behaviors in common with newly formed binaries. Both are embedded in disks of gas and dust, pull material from those disks, and produce outflows of gas. And in both cases, the disks can form warps or clumps. In young binaries, those might signal the beginnings of planet formation.

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An unusual creature is coming out of winter's slumber: Here's why scientists are excited

 If you binged on high-calorie snacks and then spent the winter crashed on the couch in a months-long food coma, you'd likely wake up worse for wear. Unless you happen to be a fat-tailed dwarf lemur.

This squirrel-sized primate lives in the forests of Madagascar, where it spends up to seven months each year mostly motionless and chilling, using the minimum energy necessary to withstand the winter. While zonked, it lives off of fat stored in its tail.

Animals that hibernate in the wild rarely do so in zoos and sanctuaries, with their climate controls and year-round access to food. But now our closest hibernating relative has gone into true, deep hibernation in captivity for the first time at the Duke Lemur Center.

"They did not disappoint," said research scientist Marina Blanco, who led the project. "Indeed, our dwarf lemurs hibernated just like their wild kin do in western Madagascar."

The researchers say recreating some of the seasonal fluctuations of the lemurs' native habitat might be good for the well-being of a species hardwired for hibernation, and also may yield insights into metabolic disorders in humans.

"Hibernation is literally in their DNA," Blanco said.

Blanco has studied dwarf lemurs for 15 years in Madagascar, fitting them with tracking collars to locate them when they are hibernating in their tree holes or underground burrows. But what she and others observed in the wild didn't square with how the animals behaved when cared for in captivity.

Captive dwarf lemurs are fed extra during the summer so they can bulk up like they do in the wild, and then they'll hunker down and let their heart rate and temperature drop for short bouts -- a physiological condition known as torpor. But they rarely stay in this suspended state for longer than 24 hours. Which got Blanco to wondering: After years in captivity, do dwarf lemurs still have what it takes to survive seasonal swings like their wild counterparts do? And what can these animals teach us about how to safely put the human body on pause too, slowing the body's processes long enough for, say, life-saving surgery or even space travel?

To find out, Duke Lemur Center staff teamed up to build fake tree hollows out of wooden boxes and placed them in the dwarf lemurs' indoor enclosures, as a haven for them to wait out the winter. To mimic the seasonal changes the lemurs experience over the course of the year in Madagascar, the team also gradually adjusted the lights from 12 hours a day to a more "winter-like" 9.5 hours, and lowered the thermostat from 77 degrees Fahrenheit to the low 50s.

The animals were offered food if they were awake and active, and weighed every two weeks, but otherwise they were left to lie.

It worked. In the March 11 issue of the journal Scientific Reports, the researchers show for the first time that fat-tailed dwarf lemurs can hibernate quite well in captivity.

For four months, the eight lemurs in the study spent some 70% of their time in metabolic slow-motion: curled up, cool to the touch, barely moving or breathing for up to 11 days at a stretch, showing little interest in food -- akin to their wild counterparts.

Now that spring is afoot in North Carolina and the temperatures are warming, the lemurs are waking up. Their first physical exams after they emerged showed them to be 22% to 35% lighter than they were at the start but otherwise healthy. Their heart rates are back up from just eight beats per minute to about 200, and their appetites have returned.

"We've been able to replicate their wild conditions well enough to get them to replicate their natural patterns," said Erin Ehmke, who directs research at the center.

Females were the hibernation champs, out-stuporing the males and maintaining more of their winter weight. They need what's left of their fat stores for the months of pregnancy and lactation that typically follow after they wake up, Blanco said.

Study co-author Lydia Greene says the next step is to use non-invasive research techniques such as metabolite analysis and sensors in their enclosures to better understand what dwarf lemurs do to prepare their bodies and eventually bounce back from months of standby mode -- work that could lead to new treatments for heart attacks, strokes, and other life-threatening conditions in humans.

Blanco suspects the impressive energy-saving capabilities of these lemurs may also relate to another trait they possess: longevity. The oldest dwarf lemur on record, Jonas, died at the Duke Lemur Center at the age of 29. The fact that dwarf lemurs live longer than non-hibernating species their size suggests that something intrinsic to their biological machinery may protect against aging.

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Experts recreate a mechanical Cosmos for the world's first computer

 Researchers at UCL have solved a major piece of the puzzle that makes up the ancient Greek astronomical calculator known as the Antikythera Mechanism, a hand-powered mechanical device that was used to predict astronomical events.

Known to many as the world's first analogue computer, the Antikythera Mechanism is the most complex piece of engineering to have survived from the ancient world. The 2,000-year-old device was used to predict the positions of the Sun, Moon and the planets as well as lunar and solar eclipses.

Published in Scientific Reports, the paper from the multidisciplinary UCL Antikythera Research Team reveals a new display of the ancient Greek order of the Universe (Cosmos), within a complex gearing system at the front of the Mechanism.

Lead author Professor Tony Freeth (UCL Mechanical Engineering) explained: "Ours is the first model that conforms to all the physical evidence and matches the descriptions in the scientific inscriptions engraved on the Mechanism itself.

"The Sun, Moon and planets are displayed in an impressive tour de force of ancient Greek brilliance."

The Antikythera Mechanism has generated both fascination and intense controversy since its discovery in a Roman-era shipwreck in 1901 by Greek sponge divers near the small Mediterranean island of Antikythera.

The astronomical calculator is a bronze device that consists of a complex combination of 30 surviving bronze gears used to predict astronomical events, including eclipses, phases of the moon, positions of the planets and even dates of the Olympics.

Whilst great progress has been made over the last century to understand how it worked, studies in 2005 using 3D X-rays and surface imaging enabled researchers to show how the Mechanism predicted eclipses and calculated the variable motion of the Moon.

However, until now, a full understanding of the gearing system at the front of the device has eluded the best efforts of researchers. Only about a third of the Mechanism has survived, and is split into 82 fragments -- creating a daunting challenge for the UCL team.

The biggest surviving fragment, known as Fragment A, displays features of bearings, pillars and a block. Another, known as Fragment D, features an unexplained disk, 63-tooth gear and plate.

Previous research had used X-ray data from 2005 to reveal thousands of text characters hidden inside the fragments, unread for nearly 2,000 years. Inscriptions on the back cover include a description of the cosmos display, with the planets moving on rings and indicated by marker beads. It was this display that the team worked to reconstruct.

Two critical numbers in the X-rays of the front cover, of 462 years and 442 years, accurately represent cycles of Venus and Saturn respectively. When observed from Earth, the planets' cycles sometimes reverse their motions against the stars. Experts must track these variable cycles over long time-periods in order to predict their positions.

"The classic astronomy of the first millennium BC originated in Babylon, but nothing in this astronomy suggested how the ancient Greeks found the highly accurate 462-year cycle for Venus and 442-year cycle for Saturn," explained PhD candidate and UCL Antikythera Research Team member Aris Dacanalis.

Using an ancient Greek mathematical method described by the philosopher Parmenides, the UCL team not only explained how the cycles for Venus and Saturn were derived but also managed to recover the cycles of all the other planets, where the evidence was missing.

PhD candidate and team member David Higgon explained: "After considerable struggle, we managed to match the evidence in Fragments A and D to a mechanism for Venus, which exactly models its 462-year planetary period relation, with the 63-tooth gear playing a crucial role."

Professor Freeth added: "The team then created innovative mechanisms for all of the planets that would calculate the new advanced astronomical cycles and minimize the number of gears in the whole system, so that they would fit into the tight spaces available."

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Astronomers have detected a moving supermassive black hole

 Scientists have long theorized that supermassive black holes can wander through space -- but catching them in the act has proven difficult.

Now, researchers at the Center for Astrophysics | Harvard & Smithsonian have identified the clearest case to date of a supermassive black hole in motion. Their results are published today in the Astrophysical Journal.

"We don't expect the majority of supermassive black holes to be moving; they're usually content to just sit around," says Dominic Pesce, an astronomer at the Center for Astrophysics who led the study. "They're just so heavy that it's tough to get them going. Consider how much more difficult it is to kick a bowling ball into motion than it is to kick a soccer ball -- realizing that in this case, the 'bowling ball' is several million times the mass of our Sun. That's going to require a pretty mighty kick."

Pesce and his collaborators have been working to observe this rare occurrence for the last five years by comparing the velocities of supermassive black holes and galaxies.

"We asked: Are the velocities of the black holes the same as the velocities of the galaxies they reside in?" he explains. "We expect them to have the same velocity. If they don't, that implies the black hole has been disturbed."

For their search, the team initially surveyed 10 distant galaxies and the supermassive black holes at their cores. They specifically studied black holes that contained water within their accretion disks -- the spiral structures that spin inward towards the black hole.

As the water orbits around the black hole, it produces a laser-like beam of radio light known as a maser. When studied with a combined network of radio antennas using a technique known as very long baseline interferometry (VLBI), masers can help measure a black hole's velocity very precisely, Pesce says.

The technique helped the team determine that nine of the 10 supermassive black holes were at rest -- but one stood out and seemed to be in motion.

Located 230 million light-years away from Earth, the black hole sits at the center of a galaxy named J0437+2456. Its mass is about three million times that of our Sun.

Using follow-up observations with the Arecibo and Gemini Observatories, the team has now confirmed their initial findings. The supermassive black hole is moving with a speed of about 110,000 miles per hour inside the galaxy J0437+2456.

But what's causing the motion is not known. The team suspects there are two possibilities.

"We may be observing the aftermath of two supermassive black holes merging," says Jim Condon, a radio astronomer at the National Radio Astronomy Observatory who was involved in the study. "The result of such a merger can cause the newborn black hole to recoil, and we may be watching it in the act of recoiling or as it settles down again."

But there's another, perhaps even more exciting possibility: the black hole may be part of a binary system.

"Despite every expectation that they really ought to be out there in some abundance, scientists have had a hard time identifying clear examples of binary supermassive black holes," Pesce says. "What we could be seeing in the galaxy J0437+2456 is one of the black holes in such a pair, with the other remaining hidden to our radio observations because of its lack of maser emission."

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With gene therapy, scientists develop opioid-free solution for chronic pain

A gene therapy for chronic pain could offer a safer, non-addictive alternative to opioids. Researchers at the University of California San Diego developed the new therapy, which works by temporarily repressing a gene involved in sensing pain. It increased pain tolerance in mice, lowered their sensitivity to pain and provided months of pain relief without causing numbness.

The researchers report their findings in a paper published Mar. 10 in Science Translational Medicine.

The gene therapy could be used to treat a broad range of chronic pain conditions, from lower back pain to rare neuropathic pain disorders -- conditions for which opioid painkillers are the current standard of care.

"What we have right now does not work," said first author Ana Moreno, a bioengineering alumna from the UC San Diego Jacobs School of Engineering. Opioids can make people more sensitive to pain over time, leading them to rely on increasingly higher doses. "There's a desperate need for a treatment that's effective, long-lasting and non-addictive."

The idea for such a treatment emerged when Moreno was a Ph.D. student in UC San Diego bioengineering professor Prashant Mali's lab. Mali had been investigating the possibility of applying CRISPR-based gene therapy approaches to rare as well as common human diseases. Moreno's project focused on exploring potential therapeutic avenues. One day, she came across a paper about a genetic mutation that causes humans to feel no pain. This mutation inactivates a protein in pain-transmitting neurons in the spinal cord, called NaV1.7. In individuals lacking functional NaV1.7, sensations like touching something hot or sharp do not register as pain. On the other hand, a gene mutation that leads to overexpression of NaV1.7 causes individuals to feel more pain.

When Moreno read this, it clicked. "By targeting this gene, we could alter the pain phenotype," she said. "What's also cool is that this gene is only involved in pain. There aren't any severe side effects observed with this mutation."

Non-permanent gene therapy

Moreno had been working on gene repression using the CRISPR gene editing tool as part of her dissertation. Specifically, she was working with a version of CRISPR that uses what's called "dead" Cas9, which lacks the ability to cut DNA. Instead, it sticks to a gene target and blocks its expression.

Moreno saw an opportunity to use this approach to repress the gene that codes for NaV1.7. She points out an appeal of this approach: "It's not cutting out any genes, so there are no permanent changes to the genome. You wouldn't want to permanently lose the ability to feel pain," she said. "One of the biggest concerns with CRISPR gene editing is off-target effects. Once you cut DNA, that's it. You can't go back. With dead Cas9, we're not doing something irreversible."

Mali, who is a co-senior author of the study, says that this use of dead Cas9 opens the door to using gene therapy to target common diseases and chronic ailments.

"In some common diseases, the issue is that a gene is being misexpressed. You don't want to completely shut it down," he said. "But if you could turn down the dose of that gene, you could bring it to a level where it is not pathogenic. That is what we are doing here. We don't completely take away the pain phenotype, we dampen it."

Moreno and Mali co-founded the spinoff company Navega Therapeutics to work on translating this gene therapy approach, which they developed at UC San Diego, into the clinic. They teamed up with Tony Yaksh, an expert in pain systems and a professor of anesthesiology and pharmacology at UC San Diego School of Medicine. Yaksh is a scientific advisor to Navega and co-senior author of the study.

Early lab studies

The researchers engineered a CRISPR/dead Cas9 system to target and repress the gene that codes for NaV1.7. They administered spinal injections of their system to mice with inflammatory and chemotherapy-induced pain. These mice displayed higher pain thresholds than mice that did not receive the gene therapy; they were slower to withdraw a paw from painful stimuli (heat, cold or pressure) and spent less time licking or shaking it after being hurt.

The treatment was tested at various timepoints. It was still effective after 44 weeks in the mice with inflammatory pain and 15 weeks in those with chemotherapy-induced pain. The length of duration is still being tested, researchers said, and is expected to be long-lasting. Moreover, the treated mice did not lose sensitivity or display any changes in normal motor function.

To validate their results, the researchers performed the same tests using another gene editing tool called zinc finger proteins. It's an older technique than CRISPR, but it does the same job. Here, the researchers designed zinc fingers that similarly bind to the gene target and block expression of NaV1.7. Spinal injections of the zinc fingers in mice produced the same results as the CRISPR-dead Cas9 system.

"We were excited that both approaches worked," Mali said. "The beauty about zinc finger proteins is that they are built on the scaffold of a human protein. The CRISPR system is a foreign protein that comes from bacteria, so it could cause an immune response. That's why we explored zinc fingers as well, so we have an option that might be more translatable to the clinic."

The researchers say this solution could work for a large number of chronic pain conditions arising from increased expression of NaV1.7, including diabetic polyneuropathy, erythromelalgia, sciatica and osteoarthritis. It could also provide relief for patients undergoing chemotherapy.

And due to its non-permanent effects, this therapeutic platform could address a poorly met need for a large population of patients with long-lasting (weeks to months) but reversible pain conditions, Yaksh said.

"Think of the young athlete or wounded war fighter in which the pain may resolve with wound healing," he said. "We would not want to permanently remove the ability to sense pain in these people, especially if they have a long life expectancy. This CRISPR/dead Cas9 approach offers this population an alternative therapeutic intervention -- that's a major step in the field of pain management."

Researchers at UC San Diego and Navega will next work on optimizing both approaches (CRISPR and zinc fingers) for targeting the human gene that codes for NaV1.7. Trials in non-human primates to test for efficacy and toxicity will follow. Researchers expect to file for an IND and to commence human clinical trials in a couple years.

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Air pollution: The silent killer called PM 2.5

 Millions of people die prematurely every year from diseases and cancer caused by air pollution. The first line of defence against this carnage is ambient air quality standards. Yet, according to researchers from McGill University, over half of the world's population lives without the protection of adequate air quality standards.

Air pollution varies greatly in different parts of the world. But what about the primary weapons against it? To find answers, researchers from McGill University set out to investigate global air quality standards in a study published in the Bulletin of the World Health Organization.

The researchers focused on air pollution called PM2.5 -- responsible for an estimated 4.2 million premature deaths every year globally. This includes over a million deaths in China, over half a million in India, almost 200,000 in Europe, and over 50,000 in the United States.

"In Canada, about 5,900 people die every year from air pollution, according to estimates from Health Canada. Air pollution kills almost as many Canadians every three years as COVID-19 killed to date," says co-author Parisa Ariya, a Professor in the Department of Chemistry at McGill University.

Small but deadly

Among the different types of air pollution, PM2.5 kills the most people worldwide. It consists of particles smaller than approximately 2.5 microns -- so small that billions of them can fit inside a red blood cell.

"We adopted unprecedented measures to protect people from COVID-19, yet we don't do enough to avoid the millions of preventable deaths caused by air pollution every year," says Yevgen Nazarenko, a Research Associate at McGill University who conducted the study with Devendra Pal under the supervision of Professor Ariya.

The researchers found that where there is protection, standards are often much worse than what the World Health Organization considers safe. Many regions with the most air pollution don't even measure PM2.5 air pollution, like the Middle East. They also found that the weakest air quality standards are often violated, particularly in countries like China and India. In contrast, the strictest standards are often met, in places like Canada and Australia.

Surprisingly, the researchers discovered that high population density is not necessarily a barrier to fighting air pollution successfully. Several jurisdictions with densely populated areas were successful in setting and enforcing strict standards. These included Japan, Taiwan, Singapore, El Salvador, Trinidad and Tobago, and the Dominican Republic.

"Our findings show that more than half of the world urgently needs protection in the form of adequate PM2.5 ambient air quality standards. Putting these standards in place everywhere will save countless lives. And where standards are already in place, they should be harmonized globally," says Nazarenko.

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Mapping the best places to plant trees

 Reforestation could help to combat climate change, but whether and where to plant trees is a complex choice with many conflicting factors. To combat this problem, researchers reporting in the journal One Earth on December 18 have created the Reforestation Hub, an interactive map of reforestation opportunity in the United States. The tool will help foresters, legislators, and natural resource agency staff weigh the options while developing strategies to restore lost forests.

"Often the information we need to make informed decisions about where to deploy reforestation already exists, it's just scattered across a lot of different locations," says author Susan Cook-Patton, a Senior Forest Restoration Scientist at the Nature Conservancy. "Not everybody has the computer science experience to delve into the raw data, so we tried to bring this information together to develop a menu of options for reforestation, allowing people to choose what they would like to see in their community, state, or nation."

The culmination of these efforts is the Reforestation Hub, a web-based interactive map that color-codes individual counties by reforestation opportunity or level of potential for successful reforestation. And the results show that there is a great deal of reforestation opportunity in the United States.

"There are up to 51.6 million hectares (about 200,000 square miles) of opportunity to restore forest across the United States after excluding productive cropland and other places where trees are infeasible," she says. "Those additional forested areas could absorb the emissions equivalent to all the personal vehicles in California, Texas, and New York combined."

In addition to quantifying the amount of land that could yield viable forests, the Hub also identifies trends in how this opportunity is distributed throughout the country.

"While there's no single best place to restore forest cover, we did find a particularly high density of opportunity in the Southeastern United States," says Cook-Patton. "This is a region where carbon accumulation rates are high, costs are low, and there is a lot of opportunity to achieve multiple benefits like creating habitats for biodiversity, improving water quality, and climate mitigation."

The map also quantifies the acreage of 10 individual opportunity classes -- or categories based on land ownership and quality. Some of these include pastures, post-burn lands, and floodplains. "The choice to plant trees really depends on what people want out of the landscape, whether it's controlling flood waters, improving urban environments, or recovering forests after a fire," she says.

The researchers hope to create similar maps for other countries, an important next step for combating the global problem of climate change.

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