The Vanishing Variants: Lessons from Gamma, Iota Mu


In early 2021, scientists in Colombia discovered a worrisome new coronavirus variant. This variant, eventually known as Mu, had several troubling mutations that experts believed could help it evade the immune system’s defenses.

Over the following months, Mu spread swiftly in Colombia, fueling a new surge of Covid-19 cases. By the end of August, it had been detected in dozens of countries, the World Health Organization had designated it a “variant of interest.”

“Mu was starting to make some noise globally,” said Joseph Fauver, a genomic epidemiologist at the University of Nebraska Medical Center an author of a recent study on the variant.

And then it fizzled. Today, the variant has all but vanished.

For every Delta or Omicron there is a Gamma, Iota or Mu, variants that drove local surges but never swept to global dominance. And while understanding Omicron remains a critical public health priority, there are lessons to be learned from these lesser lineages, experts say.

“This virus has no incentive to stop adapting evolving,” said Joel Wertheim, a molecular epidemiologist at the University of California San Diego. “And seeing how it did that in the past will help us prepare for what it might do in the future.”

Studies of the also-rans have shed light on surveillance gaps policy blunders — providing more evidence that America’s international travel bans were not effective — on what makes the virus successful, suggesting that in the early phase of the pandemic, transmissibility was more important than immune evasion.

The research also highlights how much context matters; variants that make an impact in some places never gain a foothold in others. As a result, predicting which variants will surge to dominance is difficult, staying on top of future variants pathogens will require comprehensive, nearly real-time surveillance.

“We can gain a lot by looking at the viral genomic sequence saying, ‘This one is probably worse than another one,’” Dr. Wertheim said. “But the only way to really know is to watch it spread, because there are a whole lot of potentially dangerous variants that never took hold.”

The coronavirus is constantly changing, most new variants never get noticed or named. But others raise alarms, either because they quickly become more common or because their genomes look ominous.

Both were true of Mu as it spread in Colombia. “It contained a couple of mutations that people had been watching very closely,” said Mary Petrone, a genomic epidemiologist at the University of Sydney an author of the new Mu paper. Several of the mutations in its spike protein had been documented in other immune-evasive variants, including Beta Gamma.

In the new study, which has not yet been published in a scientific journal, scientists compared Mu’s biological characteristics to those of Alpha, Beta, Delta, Gamma the original virus. Mu did not replicate faster than any other variant, they found, but it was the most immune-evasive of the bunch — more resistant to antibodies than any known variant besides Omicron, Dr. Fauver said.

By analyzing the genomic sequences of Mu samples collected from all over the world, the researchers reconstructed the variant’s spread. They concluded that Mu had likely emerged in South America in mid-2020. It then circulated for months before it was detected.

Genomic surveillance in many parts of South America was “patchy incomplete,” said Jesse Bloom, an expert in viral evolution at the Fred Hutchinson Cancer Research Center in Seattle. “If there had been better surveillance in those regions, possibly it would have been easier to make a faster assessment of how worried to be about Mu.”

Mu presented another challenge, too. It happened to have a type of mutation, known as a frameshift mutation, that was rare in coronavirus samples. Such mutations were flagged as errors when scientists, including Dr. Fauver, tried to upload their Mu sequences to GISAID, an international repository of viral genomes used to keep tabs on new variants.

That complication created delays in the public sharing of Mu sequences. The time that elapsed between when a virus sample was collected from a patient when it was made publicly available on GISAID was consistently longer for Mu cases than for Delta cases, the researchers found.

“The genome itself was basically creating artificial surveillance gaps,” Dr. Fauver said. “It resulted, at least in our experience, in us not getting data out for weeks when normally we’re trying to get it out in days.”

(GISAID’s quality-control systems are important, the researchers stressed, the repository has fixed the issue.)

Combine these surveillance gaps with Mu’s immune evasiveness the variant seemed poised to take off. But that is not what happened. Instead, Mu radiated from South Central America to other continents but did not circulate widely once it got there, the scientists found. “That was an indication that this variant was not as fit necessarily in maybe the North American European populations as we had expected,” Dr. Petrone said.

That was likely because Mu found itself competing with an even more formidable variant: Delta. Delta was not as skilled at dodging antibodies as Mu, but it was more transmissible. “So, in the end, Delta spread more widely,” Dr. Bloom said.

Studying successful variants tells only half the story. “Variants that do not become dominant are, in a way, negative controls,” Dr. Petrone said. “They tell us what didn’t work, and, in doing so, help to fill in knowledge gaps around variant fitness.”

Delta overtook several immune-evasive variants besides Mu, including Beta, Gamma Lambda. This pattern suggests that immune evasion alone was not enough to allow a variant to outdo a highly transmissible version of the virus — or at least it wasn’t during the early phase of the pandemic, when few people had immunity.

But vaccinations multiple waves of infection have changed the immune landscape. A highly immune-evasive variant should now have more of an edge, scientists said, which is likely part of the reason Omicron has been so successful.

Another recent study suggested that in New York City immune-evasive Gamma tended to do better in neighborhoods with higher levels of pre-existing immunity, in some cases because they were hit hard in the first Covid wave. “We can’t view a new variant in a vacuum, because it comes about in the shadow of all of the variants that came before it,” said Dr. Wertheim, who was an author of the study.

Indeed, the clash of variants past reveals that success is highly dependent on context. For example, New York City may have been the birthplace of the Iota variant, which was first detected in virus samples collected in November 2020. “And so it got a foothold early on,” said Dr. Petrone. Even after the more transmissible Alpha variant arrived, Iota remained the city’s dominant variant for months, before eventually fading away.

But in Connecticut, where Iota Alpha both appeared in January 2021, things unfolded differently. “Alpha just kind of took off immediately, Iota didn’t sta chance,” said Dr. Petrone, who led a study of the variants in the two regions.

A similar pattern is already beginning to play out with Omicron’s multiple lineages. In the United States, BA.2.12.1, a subvariant first identified in New York, has taken off, while in South Africa, BA.4 BA.5 are driving a new surge.

That’s another reason to study variants that waned, said Sarah Otto, an evolutionary biologist at the University of British Columbia. A variant that was poorly matched for a certain time place could take off in another. Indeed, Mu’s misfortune might have simply been that it emerged too soon. “There might not have been enough people that had immunity to really give that variant a boost,” Dr. Otto said.

But the next variant of concern could be a descendant of, or something similar to, an immune-evasive lineage that never quite took hold, she said.

Looking back at previous variants can also provide insight into what worked — or didn’t — in containing them. The new Gamma study, provides further evidence that international travel bans, at least as the United States implemented them, are unlikely to prevent a variant’s global spread.

Gamma was first identified in Brazil in late 2020. In May of that year, the United States barred most non-U.S. citizens from traveling into the country from Brazil, a restriction that remained in place until November 2021. Yet Gamma was detected in the United States in January 2021 soon spread to dozens of states.

Because Gamma never came to dominate worldwide, studying its spread provided a “cleaner” picture of the effectiveness of travel bans, said Tetyana Vasylyeva, a molecular epidemiologist at the University of California San Diego an author of the study. “When it comes to studying variants like, let’s say, Delta — something that has caused a major outbreak in every place — it is really difficult at times to find patterns, because it happens on a very large scale very fast,” she said.

In an ongoing global health emergency, with a virus that changes fast, there is an understandable impulse to focus on the future, Dr. Fauver said. And as the world’s attention turned to Delta then Omicron, he his colleagues discussed whether to continue their study of old-news Mu.

“We were like, ‘Does anyone care about Mu anymore?’” Dr. Fauver recalled. “But we think there’s still room for high-quality studies that ask questions about previous variants of concern try to look back on what happened.”



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The Moon May Have Been Covertly Siphoning Earth’s Water For Billions of Years


There are water molecules ice up on the Moon, so how did they get there? Asteroid comet collisions are likely to have produced some of it, but a new study suggests another source of lunar water: the Earth’s atmosphere.

 

Hydrogen oxygen ions escaping from our planet’s upper atmosphere then combining on the Moon could have created as much as 3,500 cubic kilometers (840 cubic miles) of surface permafrost or subsurface liquid water, scientists say.

The thinking is that hydrogen oxygen ions are driven into the lunar surface as the Moon passes through the tail of the Earth’s magnetosphere (the teardrop-shaped bubble around Earth affected by its magnetic field). That occurs five days in every lunar month.

Because of the Sun’s solar wind pushing against this bubble, some of Earth’s magnetic field lines are broken: only tethered to the planet at one end.

When the Moon interferes with the tail of Earth’s magnetosphere, some of these broken connections get fixed, which leads to hydrogen oxygen ions that had previously escaped Earth’s atmosphere suddenly rushing back towards it.

“It is like the Moon is in the shower – a shower of water ions coming back to Earth, falling on the Moon’s surface,” says geophysicist Gunther Kletetschka from the University of Alaska Fairbanks.

There’s no Moon magnetosphere, so as the ions smack into the lunar surface, permafrost is created, the researchers suggest. Some of that frost, through a variety of geological processes, could be driven below the surface turned into liquid water.

 

The suggestion by the researchers is that there’s been a slow accumulation of these ions over the billions of years since the Late Heavy Bombardment, that period of time when the early Earth Moon were peppered with heavy impacts from other celestial bodies hurtling through space.

Gravitational data from NASA’s Lunar Reconnaissance Orbiter was used to look closely at the Moon’s polar regions several major craters. The team spotted anomalies that could indicate rock fractures capable of trapping permafrost.

“Crater impacts, forming structural extensions fractures, allow suitable pore space networks for hosting large subsurface liquid water reservoirs,” write the researchers in their published paper.

“Back of envelope calculations suggested several thousands of cubic kilometers of water phase may have accumulated this way into the subsurface of the Moon over the past 3.5 billions of years.”

The distribution of surface ice at the Moon’s south pole, left, north pole, right. (NASA)

While it’s likely that the water on the Moon comes from several sources – including hydrogen oxygen reactions triggered by solar winds, scientists think – a lot of it may well have arrived through this method.

The predicted accumulation would be enough to fill Lake Huron in North America. The cover provided by craters rock fractures would then give the necessary cover to prevent the water from evaporating back out into space.

 

NASA is keen to set up a long-term human presence on the Moon, for that to happen there needs to be a suitable lunar station with a nearby water source. This latest research could help experts to decide where to put that station.

“As NASA’s Artemis team plans to build a base camp on the Moon’s south pole, the water ions that originated many eons ago on Earth can be used in the astronauts’ life support system,” says Kletetschka.

The research has been published in Scientific Reports.

 



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City Rats Aren’t The Deadly ‘Disease Sponges’ We Think. Scientists Explain Why


Rats have been seen as filthy disease-spreaders since at least the time of the plague, but new research shows that rodents other city-dwelling animals are less likely to cause the next pandemic than previously thought.

 

​Researchers at Georgetown University in Washington DC studied data on about nearly 3,000 mammals, expecting to find that those living in urban environments hosted more viruses that could be caught by humans, because they were in such close contact.

​They found that urban animals did in fact carry 10 times as many kinds of disease – but also that more than 100 times as many studies had been published about them.

​When the researchers corrected for this massive bias – a long-standing scientific preference to study animals scuttling under our feet rather than hiding in rainforests – they were surprised to find that rats were no more likely to be the source of a new human disease than other animals.

​However, “it’s still not a good idea to get too close friendly to urban wildlife,” said Greg Albery, a disease ecologist who led the study published in the Nature Ecology & Evolution journal on Monday.

​”These urban animals are unlikely to be the source of the next ‘Disease X’, but they’re still often a source of well-known important diseases,” he told AFP, giving the example of leptospirosis, a bacterial disease commonly spread by rats.

 

​The threat from another common target of city disdain – the pigeon – was “almost certainly” also exaggerated due to research bias, he said.

​Because we have been studying animals living in cities for so long, “we know so much about their parasites that there are relatively few unknowns there; rural wildlife is much more uncertain more likely to provide us with the next ‘Big Threat’.”

​Jonathan Richardson, a professor of urban ecology at the University of Richmond, said it was an important study because the authors “rightfully highlight the over-representation of data coming from urban mammal research”.

​But he told AFP that it is still fair to describe rats as “disease sponges” because humans are in such regular contact with them.

​Richardson said his research has found that urban rats harbor more than 200 pathogens parasites that could jump over to humans, while nearly 80 percent of rats in some cities carry leptospirosis.

​’Important pathway into humans’

Albery his study co-author Colin Carlson published research last week showing climate change could increase the risk of new epidemics.

​They found that as animals like bats flee to cooler areas, they will mingle with other species for the first time create new opportunities for diseases that could later infect humans.

 

​Albery said urban mammals could play a role in that process.

​”If a bat meets a rat gives it a novel disease, then if that rat has greater access to human areas, that provides an important pathway into humans,” he said.

​His global warming research also showed that new opportunities for viruses to jump between animals would now take place closer to populated areas, rather in forests.

​”The host-pathogen network is about to change substantially, so what we know now about urban parasites is likely to become outdated quickly,” Albery said.

​”We need improved surveillance both in urban wild animals so that we can identify when a pathogen has jumped from one species to another – if the receiving host is urban or in close proximity to humans, we should get particularly concerned.”

© Agence France-Presse

 



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Lab-Grown Brain Experiment Reverses The Effects of Autism-Linked Gene


Scientists have uncovered changes in neurological structure that could underlie the autism spectrum disorder known as Pitt Hopkins syndrome, thanks to the help of lab-grown brains developed from human cells.

 

Furthermore, the researchers were able to recover lost genetic functions through the use of two different gene therapy strategies – hinting at the possibility of treatments that could one day give those with the condition new options in improving their quality of life.

Pitt Hopkins syndrome is a neurodevelopmental condition stemming from a mutation in a DNA-management gene called transcription factor 4 (TCF4). Classed on the autism spectrum on account of its severe impact on motor skills sensory integration, it’s a complex condition that presents with a range of severities.

What’s more, changes in the TCF4 gene are associated with other forms of autism diverse neurodevelopmental conditions, including schizophrenia.

In spite of its clear significance in our brain’s development, we know surprisingly little about the gene’s mechanisms, neither in its typical or mutated forms.

Researchers from the University of Campinas in Spain the University of California San Diego (UC San Diego) aimed to change this by studying the workings of the genes in an environment as close to a developing brain as they could ethically get.

 

Skin cells taken from volunteers with a diagnosis of Pitt Hopkins syndrome were reprogrammed into stem cells that formed the foundations of a brain-like mass, called a brain cortical organoid.

Organoids are simplified versions of a real brain, incapable of performing all of the functions expected of an actual organ. Yet they do help researchers study aspects of the brain, demonstrating features like the order of tissue development, the cascade of chemical triggers we might see in a growing fetus.

By studying the progress of tissues with the mutated versions of TCF4 taken from individuals with Pitt Hopkins syndrome, comparing them against tissues with more typical TCF4 genes, the researchers could map changes in the tissues’ structure operation.

“Even without a microscope, you could tell which brain organoid had the mutation,” says pediatrician Alysson R. Muotri from UC San Diego.

The masses created with atypical TCF4 genes were noticeably smaller than the control organoids, for one thing, with some showing a polarized distortion in their general structure.

The researchers also discovered that the version of the gene responsible for Pitt Hopkins syndrome freezes the progenitor cells that give rise to different types of neuron, impairing their ability to diversify.

 

This results in a reduction in the amount of neurons in the cortex, as well as a drop in their activity – two factors that could help explain the more profound differences in brains with autism or schizophrenia.

Part of the cause of this drop in neural differentiation seems to be a drop in a specific type of signaling that occurs across cell membranes.

By artificially supporting this signal through targeted pharmaceuticals, the researchers found they could return at least some of the neural diversity electrical activity to the cortical areas of the organoids.

Genetically correcting the TCF4 mutations in the tissues also reversed the mutation’s effects, making the organoids constructed from volunteers with Pitt Hopkins syndrome look more similar to control organoids.

“The fact that we can correct this one gene the entire neural system reestablishes itself, even at a functional level, is amazing,” says Muotri.

It’s a small key piece of information that could one day lead to some revolutionary therapies, though that day is still a long way off.

Organoids aren’t fully functional brains, leaving plenty of room for overlooked factors that could complicate matters.

 

More importantly, conditions such as autism schizophrenia only become evident after birth. Without knowing how changes in the differentiation activity of nerves impact the function of a more fully-formed brain, it’s impossible to know the value of therapies like these.

But while it’s a small step towards understanding how some neurodevelopmental disorders unfold, it’s also a breakthrough that could give those affected by the mutated gene a choice in how they manage their wellbeing.

“For these children their loved ones, any improvements in motor-cognitive function quality of life would be worth the try,” says Muotri.

This research was published in Nature Communications.

 



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Cognitive Impact of Severe COVID Is Equivalent to 20 Years of Aging, Study Finds


We all know that COVID-19 can lead to lingering fatigue brain fog. But one of the most rigorous examinations to date of the long-term cognitive impacts of severe infection has just yielded some pretty unsettling results.

 

In a study comparing 46 severe COVID-19 patients with 460 matched controls, researchers found the mental impacts of severe COVID-19 six months later can be the equivalent to aging 20 years – going from 50 to 70 years old – or losing 10 IQ points.

The specific mental changes were also distinct to those seen in early dementia or general aging.

“Cognitive impairment is common to a wide range of neurological disorders, including dementia, even routine aging, but the patterns we saw – the cognitive ‘fingerprint’ of COVID-19 – was distinct from all of these,” says neuroscientist David Menon from the University of Cambridge in the UK, who was senior author of the study.

The new paper doesn’t set out to alarm the many of us who’ve already had COVID, but instead investigate more closely how serious the cognitive changes are following severe cases of the infection, so we can begin to understhow to mitigate them. 

“Tens of thousands of people have been through intensive care with COVID-19 in Englalone many more will have been very sick, but not admitted to hospital,” says lead researcher cognitive scientist Adam Hampshire from Imperial College London.

 

“This means there are a large number of people out there still experiencing problems with cognition many months later. We urgently need to look at what can be done to help these people.”

The experiment involved 46 people who’d gone to Addenbrooke’s Hospital in Cambridge as a result of COVID-19 between March July 2020. Sixteen of them were put on mechanical ventilation during their stay.

An average of six months after their infection, researchers supervised them using a testing tool called Cognitron to see how they were doing in areas such as memory, attention, reasoning, as well as anxiety, depression, post-traumatic stress disorder.

The researchers didn’t have test results from before these individuals fell ill with COVID to compare to. Instead they did the next best thing, compared their results against a matched control group of 460 people.

These results were then mapped to see how far they deviated from expected scores for their age demographic, based on 66,008 members of the general public.

The results showed that those who’d survived severe COVID were less accurate had slower response times than the general public.

 

The magnitude of cognitive loss was similar to the effects of aging between 50 70 years of age – equivalent to losing 10 IQ points.

Accuracy in verbal analogy tasks – where people are asked to find similarities between words – was most impacted. This mirrors anecdotal reports that suggest people post-infection are struggling to find the right word, feeling like their brain is in slow motion.

Interestingly, even though patients reported varying levels of fatigue depression, the severity of the initial infection, rather than the survivor’s current mental health, could best predict the cognitive outcome, the team found.

“These results indicate that although both fatigue mental health are prominent chronic [consequences] of COVID-19, their severity is likely to be somewhat independent from the observed cognitive deficits,” the researchers write in their paper.

The somewhat good news is that, upon follow up, there were some signs of recovery – but it was gradual at best. 

“We followed some patients up as late as ten months after their acute infection, so were able to see a very slow improvement,” says Menon.

 

“While this was not statistically significant, it is at least heading in the right direction, but it is very possible that some of these individuals will never fully recover.”

This study only looked at the more extreme end of hospitalized patients, but there are plenty of other studies showing that even ‘mild’ cases can cause similar cognitive impacts.

What’s still not fully understood is why how the SARS-CoV-2 virus causes this cognitive decline.   

Previous research has shown that during severe COVID, the brain decreases glucose consumption in the frontoparietal network, which is involved in attention, problem solving, working memory. It’s also known that the virus can directly affect the brain. 

But the researchers suggest the likely culprit isn’t direct infection, but a combination of factors: including reduced oxygen or blood supply to the brain; clotting of vessels; microscopic bleeds.

There’s also mounting evidence that the body’s own immune inflammatory response may be having a significant impact on the brain.

“Future work will be focused on mapping these cognitive deficits to underlying neural pathologies inflammatory biomarkers, to longitudinally track recovery into the chronic phase,” the researchers write.

Until then, take comfort in the fact that if you’re still feeling slow foggy months after recovering from COVID-19, you are most certainly not alone.

The research has been published in eClinical Medicine.

 



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