Researchers at the Case Western Reserve University School of Medicine have identified a new target in development of Alzheimer’s disease (AD) that could lead to therapies focused on treating the neurodegenerative condition early in its progression.
The discovery helps bolster a promising approach to AD research: finding and manipulating processes earlier in the disease’s development with hopes of slowing its advance.
“This is a missing part of the puzzle,” said Xin Qi, a professor in the Department of Physiology and Biophysics at the School of Medicine and lead researcher of the study, just published in the journal Science Advances. “We’ve discovered a pathway that is accessible to detection and potential treatment, prior to much of the disease’s damage and well before clinical symptoms appear.”
First identified more than 100 years ago, AD is an age-related neurodegenerative disorder that is associated with deposits of plaques of amyloid beta protein and tangles of tau protein in the brain, along with progressive nerve cell death. The cause of AD is not known, and the greatest risk factors for developing AD are age, genetics, and a previous traumatic brain injury.
Before the defining pathological characteristics of the disease are in place, the new pathway identified by Case Western Reserve researchers can be targeted by potential therapeutics that aim to mitigate the degeneration of white matter that impairs the normal functions of brain circuitry.
“There is a growing body of evidence in the field that AD develops much earlier than previously thought, most likely decades before our current ability to clinically diagnose the condition,” said study co-author Andrew A. Pieper, the Morley-Mather Chair in Neuropsychiatry in the School of Medicine, Director of the Harrington Discovery Institute Neurotherapeutics Center at University Hospitals.
“Detecting the disease—and potentially treating it—at earlier stages will be critical to our battle against its devastating effects. The new pathway uncovered by Dr. Qi’s laboratory could be targeted for therapy before the disease has progressed to the point of causing cognitive problems,” said Pieper, also a psychiatrist at the Louis Stokes Cleveland VA Medical Center Geriatrics Research Education and Clinical Center (GRECC).
The Drp1 pathway
Researchers found that the pathway—known as Drp1-HK1-NLRP3—plays a key role in disrupting normal function of brain cells that produce the protective white matter sheathing for nerves, known as myelin.
The dysfunction and eventual death of these myelin-producing cells—called oligodendrocytes (OLs)—are well-established early events in AD that lead to cognitive deficits.
The new findings illuminate how OLs start to go awry: the overexpression of a certain protein (Drp1) within the recently discovered pathway.
It’s the hyperactivation of Drp1 protein that triggers inflammation and injury to OLs, culminating in a reduction of myelin—slowing communication in the brain—which leads to the degeneration of white matter and significant cognitive impairment.
What’s next—targeting with therapeutics
A near total degeneration of OLs occurs before common symptoms of AD become apparent in most patients.
As such, researchers hope to target and manipulate the pathway with therapeutics that regulate the expression of Drp1, thereby slowing or reducing damage to myelin-producing OLs.
In fact, Qi’s lab has patented a small molecule, known as a peptide inhibitor, that regulates the expression of Drp1—putting the brakes on degeneration of brain cells.
In the study published by Science Advances, researchers found that eliminating Drp1 expression in mouse models corrected the energy-related defect in OLs associated with the hyperexpression of that protein; this approach also reduced the activation of inflammation OLs, lessened tissue damage at those brain sites and improved cognitive performance.
“Our results show promise that targeting the Drp1-HK1-NLRP3 pathway and reducing the expression of the Drp1 protein could help reduce the downstream cascade of abnormal brain functions associated with the progression of AD,” said Qi, whose lab has studied Drp1 for a decade, mostly in Parkinson’s and Huntington’s diseases.”
“If therapies targeting this pathway can slow, stop or even reverse early stage AD progression, then possibly there can be a reduction or delay to later stage damage and impairments,” Qi said.
Most AD diagnoses are in patients 65 or older, so identifying the disease in younger patients can be difficult. Many patients experience a significant loss in their brain’s white matter—central to cognition, emotion and consciousness—before receiving a diagnosis.
“Identifying how AD unfolds in its earliest processes will help scientists better understand how to focus research into potential solutions for patients,” said Pieper. “The Qi lab’s findings may help in targeting AD earlier, potentially leading to better management of its symptoms and progression.
“There have still been only a very small number of approved medications for AD since its discovery in 1907. While these medicines augment neurotransmission to provide temporary symptomatic benefit, they do nothing to slow disease progression,” said Pieper. “Identification of earlier approaches to treating AD—such as this research—is critical for society as the magnitude of AD is growing explosively with our aging population.”
Researchers validated the discovery of the pathway using mouse models and post-mortem brain samples of AD patients.
Longevity research always reminds me of the parable of blind men and an elephant. A group of blind men, who’ve never seen an elephant before, each touches a different part of the elephant’s body to conceptualize what the animal is like. Because of their limited experience, each person has widely different ideas—and they all believe they’re right.
Aging, thanks to its complexity, is the biomedical equivalent of the elephant. For decades, researchers have focused on one or another “hallmark” of aging, with admirable success. For example, we now know that energy production in aging cells goes haywire. Immune responses ramp up, stewing aging tissue in a soup of inflammatory molecules. Dying cells turn into zombie-like “senescent cells,” where they abdicate their normal functions and instead pump out chemicals that further contribute to inflammation and damage.
Yet how these hallmarks fit together into a whole picture remained a mystery. Now, thanks to a new study published in Nature Metabolism, we’re finally starting to connect the dots. In mice, the study linked up three promising anti-aging pathways—battling senescent cells, inflammation, and wonky energy production in cells—into a cohesive detective story that points to a master culprit that drives aging.
Spoiler: senolytics, the drug that wipes out senescent cells and a darling candidate for prolonging healthspan, may also have powers to rescue energy production in cells.
Let’s meet the players.
From Metabolism to Zombie Cells
Individual cells are like tiny cities with their own power plants to keep them running. One “celebrity” molecular worker in the process of generating energy is nicotinamide adenine dinucleotide (NAD). It’s got a long name, but an even longer history and massive fame.
Discovered in 1906, NAD is a molecule that’s critical for helping the cell’s energy factory, the mitochondria, churn out energy. NAD is a finicky worker that appears on demand—the cell will make more if it needs more; otherwise, extra molecules are destroyed (harsh, I know). As we age, our cells start losing NAD. Without the critical worker, the mitochondria factory goes out of whack, which in turn knocks the cell’s normal metabolism into dysfunction.
At least, that’s the story in mice. Although yet unproven for slowing aging or age-related disorders in humans, NAD boosters are already making a splash in the supplement world, raising even more need to understand how and why NAD levels drop as we age.
Giving NAD a run for its anti-aging fame are senolytics, a group of chemicals that destroy senescent “zombie” cells. These frail, beat-up cells are oddities: rather than dying from DNA damage, they turn to the dark side, staying alive but leaking an inflammatory cesspool of molecules called SASP (senescence associated secretory phenotype) that “spread” harm to their neighbors.
A previous study in ancient mice, the equivalent of a 90-year-old human, found that wiping out these zombie cells with two simple drugs increased their lifespan by nearly 40 percent. Others using a genetic “kill switch” in mice found that destroyingjust half of zombie cells helped the mice live 20 percent longer, while having healthier kidneys, stronger hearts, luscious fur, and perkier energy levels. Similar to NAD supplements, pharmaceutical companies are investigating over a dozen potential senolytics in a race to bring one to market.
But what if we can combine the two?
A Hub for Aging
The new study, led by aging detectives Drs. Judith Campisi and Eric Verdin at the Buck Institute for Research on Aging in Novato, California, asked if we can connect the line between NAD and zombie cells, like suspects on an evidence board.
Their “lightbulb” clue was a third molecule of interest, highlighted in a 2016 study. Meet CD38, a molecule that plays double roles as an aging culprit. It wreaks havoc as an immune molecule to boost inflammation, while chewing up and destroying NAD. If CD38 is a new drug flooding the streets, then the team’s goal is to hunt down where it came from.
Using tissue from both mice and humans, the team traced CD38 to a type of immune cells. These cells, called M1 macrophages (literally, “big eaters”) are well known to increase inflammation in the body and cause DNA damage with age. When comparing fat tissue isolated from young and old mice, the team realized that these over-hyper immune cells pump out CD38 like crazy as the cells age—which, in turn, breaks down the good-for-you molecule, NAD.
One mystery in aging, explained Verdin, is whether NAD levels drop because of a faucet problem—our ability to make NAD—or leaky sink problem, where aging cells break down NAD too fast. “Our data suggests that, at least in some cases, the issue stems from the leaky sink,” he said.
The Zombie Connection
Here’s the evidence so far: aging triggers a type of immune cells to pump out CD38, a nasty chemical from immune cells that eats up NAD. But why? More importantly, how can we stop it?
In an unexpected twist of events, the connection seemed to be zombie cells.
Remember, zombie cells leave a chemical evidence trace of inflammatory chemicals called SASP. They also change their “molecular look” so it’s possible to tease them out from a sea of healthy cells (think zombies versus humans in any zombie movie). In fatty tissue from aged mice, the team identified zombie cells and found that their “toxic waste” massively increased the amount of CD38 floating around. Going back to the drug analogy, if CD38 is a drug, then the specific immune cells are the manufacturers pumping it out to eat up NAD and wreck the cell’s energy production. Here, zombie cells are the drug kingpin, and their SASP molecules direct immune cells to make more CD38.
Frozen in Time
If zombie cells are the kingpin, then getting rid of them should reduce the inflammatory CD38 “drug,” and in turn, preserve good guy NAD. To test it out, the team used a genetically engineered mouse, which allows scientists to identify zombie cells and selectively kill them off.
The team injected the mice with a drug that damaged their DNA. This mimics aging, in the sense that it increased zombie cells and CD38. Killing zombie cells lowered CD38 levels—like clearing a drug off the streets—and preserved NAD.
“We are very excited to link two phenomena which have been separately associated with aging and age-related disease,” said Verdin.
For now, zombie cells seem to be a master-level culprit that drives inflammation, decreases NAD levels, and breaks the cell’s energy production. This suggests that senolytics, which selectively kills off zombie cells, could as a secondary effect also increase NAD—something we didn’t know previously.
To Verdin, however, that doesn’t mean NAD supplements are useless or that senolytics are the one-and-only silver bullet against aging. “Ultimately I think supplementation will be part of the equation, but filling the sink without dealing with the leak will be insufficient to address the problem,” he said. In other words, for NAD supplementation to better work, we may need to also use senolytics to decrease zombie cells and CD38 levels, thus “plugging the leak.”
If all this makes your head spin—yup, same here! Our bodies run multiple “aging programs,” and we’ve just begun linking all these disparate culprits together. But the rewards could be great for creating therapies that slow or even reverse aging. After all, if we can find several masters that drive aging, why go after the little guys when you can target the boss?
Over the last several months we’ve gotten very used to communicating via video chat. Zoom, FaceTime, Google Hangouts, and the like have not only replaced most in-person business meetings, they’ve acted as a stand-in for gatherings between friends and reunions between relatives. Just a few short years ago, many of us would have found it strange to think we’d be spending so much time talking to people “face-to-face” while sitting right in our own homes.
Now there’s a new technology looming on the horizon that may one day replace video calls with an even stranger-to-contemplate, more futuristic tool: real-time, full-body holograms.
Picture this: you’re sitting in your living room having a cup of coffee when the phone-booth-size box in the corner dings, alerting you that you have an incoming call. You accept it, and within seconds your best friend (or your partner, your grandmother, your boss) appears in the box—in the form of millions of points of light engineered to look and sound exactly like the real person. And the real person is on the other end of the line, talking to you in real time as their holographic likeness moves around the box—you can see their gestures, body language, and facial expression just as if they were really there with you.
The closest approximation to this that you may have heard about was when a holographic version of the late Tupac Shakur performed at Coachella in 2012. The hologram was simultaneously highly detailed—the lines of Tupac’s washboard abs were clearly defined and visible—and somewhat blurry; after the opening “scene,” in which the hologram stood still, it was hard to see any of Tupac’s facial features.
The Tupac hologram was created by events tech company AV Concepts and Hollywood special effects studio Digital Domain, and reportedly cost at least $100,000. It seems holograms don’t come cheap; the afore-mentioned hologram box is currently going for $60,000.
The box is called an Epic HoloPortl, and it’s made by PORTL, a company whose founder was inspired by Tupac’s hologram; after seeing the 2012 performance, David Nussbaum quickly bought the patents for the technology that made it possible, and has been working on turning the tech into something useful, fun, and scalable ever since.
The Epic has high-resolution transparent LCD screens embedded into its interior walls. The person on the other end—the one appearing as a hologram, that is—just needs to have a camera and be standing against a white background. A camera on the Epic shows the sender the room and people he or she is being beamed to, essentially just like a Zoom call.
Last month PORTL raised $3 million in funding, led by Silicon Valley venture capitalist Tim Draper. Nussbaum says he’s sold a hundred Epics, has pre-orders “in excess of a thousand,” and dozens of the devices have already been delivered, with clients including malls, airports, and movie theaters (all places that aren’t very frequented today—but here’s hoping they’ll make a comeback when the pandemic subsides).
In fact, PORTL may not have gotten this funding if it weren’t for the pandemic; Nussbaum told TechCrunch that Draper pushed him to expand his vision for the company and its technology when the virus hit, likely anticipating that people will want new ways to communicate from a distance.
Few can afford to shell out $60k for a hologram booth, though (not to mention having space for a 7-foot-tall by 5-foot-wide by 2-foot-deep box), and Nussbaum knows it; his next project is to build a smaller, cheaper version of the Epic.
Even at a tenth of the current cost, the tech likely wouldn’t see widespread adoption by people wanting their own personal hologram portal at home. But there are many possible use cases beyond person-to-person communication.
Any venue or event that would typically hire famous people to appear in person—be they celebrities, academics, religious figures, or business leaders—could beam a hologram of those people in instead. The implications may be most significant for education and business; Nussbaum believes the CEOs of the not-too-distant future will conduct their meetings via hologram. “You can now make that very important personal emotional contact with people that you need to talk to without actually having to leave your office,” he said.
Whether this is true remains to be seen. Many of us have experienced Zoom fatigue over the course of the pandemic, becoming acutely aware that while it’s better than nothing, it’s also nothing like being in a room with someone in person; there’s only so much you can get from a face and voice on a screen.
Will a face and voice on a three-dimensional, life-sized hologram be better? Stay tuned to find out.
Driving along Reykjavik’s windswept roads on a cold March morning, Kári Stefánsson turned up the radio. The World Health Organization had just announced that an estimated 3.4% of people infected with SARS-CoV-2 would die — a shockingly high fatality rate, some 30 times larger than that for seasonal influenza.
There was a problem with that estimate, however: it was based on reported cases of COVID-19, rather than all cases, including mild and asymptomatic infections. “I couldn’t figure out how they could calculate it out without knowing the spread of the virus,” recalls Stefánsson, who is the founder and chief executive of deCODE genetics, a human-genomics company in Reykjavik. He became convinced that making sense of the epidemic, and protecting the people of Iceland from it, would require a sweeping scientific response.
When Stefánsson arrived at work, he phoned the leadership of Amgen, the US pharmaceutical company that owns deCODE, and asked whether he could offer deCODE’s resources to track the spread of the virus, which had landed on Icelandic shores only six days earlier. “The response I got from them was, ‘For heaven’s sake, do that,’” says Stefánsson.
Over the ensuing nine months, deCODE and Iceland’s Directorate of Health, the government agency that oversees health-care services, worked hand-in-hand, sharing ideas, data, laboratory space and staff. The high-powered partnership, coupled with Iceland’s diminutive size, has put the country in the enviable position of knowing practically every move the virus has made. The teams have tracked the health of every person who has tested positive for SARS-CoV-2, sequenced the genetic material of each viral isolate and screened more than half of the island’s 368,000 residents for infection.
Late nights analysing the resulting data trove led to some of the earliest insights about how the coronavirus spreads through a population. The data showed, for example, that almost half of infected people are asymptomatic, that children are much less likely to become sick than adults and that the most common symptoms of mild COVID-19 are muscle aches, headaches and a cough — not fever. “Scientific activities have been a huge part of the entire process,” says Runolfur Palsson, director of internal-medicine services at Landspitali — The National University Hospital of Iceland. Researchers at deCODE and the hospital worked day in and day out to gather and interpret the data.
Their achievements aren’t merely academic. Iceland’s science has been credited with preventing deaths — the country reports fewer than 7 per 100,000 people, compared with around 80 per 100,000 in the United States and the United Kingdom. It has also managed to prevent outbreaks while keeping its borders open, welcoming tourists from 45 countries since mid-June. The partnership again kicked into high gear in September, when a second large wave of infections threatened the nation.
COVID-19 is not the first pandemic to reach Iceland’s shores: in October 1918, two ships carrying pandemic influenza docked in Reykjavik’s downtown harbour. Within six weeks, two-thirds of the capital city’s inhabitants were infected1.
A century later, the Icelandic government was better prepared, enacting a national pandemic preparedness plan at the beginning of January, two months before COVID-19 arrived. “We decided from the beginning we would use isolation, quarantine and contact tracing,” says Þórólfur Guðnason, chief epidemiologist at the Directorate of Health. As part of that plan, the microbiology laboratory at the university hospital began testing citizens in early February.
On 28 February, a man returning from a skiing holiday in northeastern Italy tested positive for the virus. Within a week, the number of cases had climbed from 1 to 47, the opening notes of a coming crescendo. As health-care workers began ordering hundreds of tests per day, one of the hospital’s machines for isolating and purifying RNA broke from overuse. “We were not able to cope with all the specimens coming in,” recalls Karl Kristinsson, the university hospital’s chief of microbiology.
By 13 March, deCODE had begun screening the general public and was able to quickly take over much of the hospital’s testing. The company repurposed a large phenotyping centre that it had been using to study the genetics of Icelanders for more than two decades into a COVID-19 testing centre. “It almost looked like these 24 years preceding COVID-19 had just been a training session,” says Stefánsson. “We dove into this full force.”
The company has the staff and machinery to sequence 4,000 whole human genomes per week as part of its regular research activities, says Stefánsson. Throughout the spring, it would set that aside to devote its analytical and sequencing heft to the pandemic response.
deCODE’s main activity has been COVID-19 screening, including open invitations to the general population. Today, any resident with even the mildest symptom can sign up to be tested. Residents sign up online using dedicated COVID software built by deCODE programmers. At a testing centre, they show a barcode from their phone to automatically print a label for a swab sample. Once taken, the sample is sent to a laboratory at deCODE’s headquarters that is run jointly by the university hospital and deCODE and operates from 6 a.m. to 10 p.m. Results are always available within 24 hours, but are often ready in just 4 to 6. “We now have the capacity for about 5,000 samples per day,” says Kristinsson. As a whole, the collaborators have so far screened 55% of the country’s population.
If the test is negative, the person receives an all-clear text. If the test is positive, it triggers two chains of action: one at the hospital and one at the lab.
At the hospital, the individual is registered in a centralized database and enrolled in a tele-health monitoring service at a COVID outpatient clinic for a 14-day isolation period. They will receive frequent phone calls from a nurse or physician who documents their medical and social history, and runs through a standardized checklist of 19 symptoms. All the data are logged in a national electronic medical record system. A team of clinician-scientists at the hospital created the collection system in mid-March with science in mind. “We decided to document clinical findings in a structured way that would be useful for research purposes,” says Palsson.
In the lab, each sample is tested for the amount of virus it contains, which has been used as an indicator for contagiousness and severity of illness. And the full RNA genome of the virus is sequenced to determine the strain of the virus and track its origin.
The same approach could work in other countries that have suitable resources, such as the United States, where all the methods deCODE is currently using were developed, says Stefánsson. In fact, early in the pandemic, many US labs pivoted to offer coronavirus testing, but were stymied by regulatory and administrative obstacles, which critics attribute to a lack of federal leadership. “This was a wonderful opportunity for academia in the United States to show its worth, and it didn’t,” Stefánsson says. “I was surprised.”
Researchers at deCODE, the university hospital and the Directorate of Health began analysing the wealth of data in early March, and quickly published several early results. “Once we started to generate data, we couldn’t resist the temptation to begin to try to pull something cohesive out of it,” says Stefánsson.
Iceland’s COVID-19 results are limited by the fact that cases are occurring in a small and genetically homogeneous population compared with other countries, notes Palsson. But in some cases, that small sample size is also a strength, because it has led to detailed, population-wide data.
In early spring, most of the world’s COVID-19 studies focused on individuals with moderate or severe disease. By testing the general population in Iceland, deCODE was able to track the virus in people with mild or no symptoms. Of 9,199 people recruited for population screening between 13 March and 4 April, 13.3% tested positive for coronavirus. Of that infected group, 43% reported no symptoms at the time of testing2. “This study was the first to provide high-quality evidence that COVID-19 infections are frequently asymptomatic,” says Jade Benjamin-Chung, an epidemiologist at the University of California, Berkeley, who used the Iceland data to estimate rates of SARS-CoV-2 infection in the United States3. “It was the only study we were aware of at the time that conducted population-based testing in a large sample.”
A smaller population study, carried out in an Italian town, came to similar results on asymptomatic infection months later. When a 78-year-old man died in the northern Italian town of Vo’, Italy’s first COVID-19 death, the region’s governor locked the town down and ordered that its 3,300 citizens be tested. After the initial round of government testing, Andrea Crisanti, head of microbiology at the University of Padua in Italy, asked the local government whether his team could run a second round of testing. “Then we could measure the effect of the lockdown and the efficiency of contact tracing,” says Crisanti, who is currently on leave from Imperial College London. The local government agreed. On the basis of the results of the two rounds of testing, the researchers found that lockdown and isolation reduced transmission by 98%, and — in line with Iceland’s results — that 43% of the infections across the two tests were asymptomatic4.
In addition to tracking asymptomatic infections, the researchers in Iceland concluded that children under 10 were about half as likely to test positive as people aged 10 and older — a finding confirmed in Crisanti’s study of Vo’, as well as studies in the United Kingdom5 and United States6. Additionally, the deCODE team analysed the viral genetic material of every positive case, and used that fingerprint to track where each strain of the virus came from and how it spread. Most of the initial cases, the researchers found, were imported from popular skiing destinations, whereas later transmission occurred mainly locally, within families (see ‘Iceland’s three COVID waves’).
That genetic-tracing approach, called molecular epidemiology, was similarly applied in New Zealand to good effect. In March, New Zealand’s government implemented a stringent countrywide lockdown aimed at eliminating the virus. “Essentially, the New Zealand population more or less stayed at home for 7 weeks. After that, we emerged into a virus-free country,” says Michael Baker, a public-health researcher at the University of Otago in Wellington. That’s a feat for a country of 5 million people, more than 13 times larger than Iceland.
Genetic analysis of the first New Zealand wave, from March to May, showed that the strict lockdown began working right away. The rate of transmission — the number of people infected by each person with the virus — dropped from 7 to 0.2 in the first week in the largest cluster7. Sequencing data also showed that an August outbreak in Auckland, the source of which remains unknown, was from a single lineage, reassuring public-health authorities that there had only been one breach. “Genomics has played a vital role in tracking the re-emergence of COVID-19 in New Zealand,” says Jemma Geoghegan, a microbiologist at Otago who co-led the project with Joep de Ligt at the Institute of Environmental Science and Research in Porirua.
Getting the full picture
This summer at the university hospital, Palsson’s team used the clinical data to investigate8 the full spectrum of disease caused by SARS-CoV-2. The most common symptoms among the 1,797 people who tested positive between 31 January and 30 April were muscle aches, headache and a non-productive cough — not fever, a symptom listed in both the US Centers for Disease Control and the World Health Organization case definitions for COVID-19. When used to guide testing, those definitions are likely to miss some symptomatic people, says Palsson. “Hopefully others will come to a similar conclusion and that will result in changes in the criteria,” he says.
The results from Palsson’s team led to direct medical intervention in Iceland: individuals showing any sign of a common cold or aches are now encouraged to get tested, and the hospital categorizes new patients into one of three stages according to their symptoms, which dictates their level of care.
The most recent study from Iceland focused on a major COVID-19 question: how long does immunity to SARS-CoV-2 last? deCODE’s team found that anti-SARS-CoV-2 antibodies remained high in the blood of 91% of infected people for 4 months after diagnosis9, running counter to earlier results suggesting that antibodies decline quickly after infection10,11. It is possible that the conflicting results represent two waves of antibodies. In an editorial accompanying the paper12, Galit Alter at Harvard Medical School in Boston, Massachusetts, and Robert Seder at the US National Institutes of Health’s Vaccine Research Center in Bethesda, Maryland, suggest that a first wave is generated by short-lived plasma cells in response to acute infection, then a second wave, produced by longer-lived cells, bestows lasting immunity.
And finally, Stefánsson was able to pin down the elusive statistic that first intrigued him — the infection fatality ratio (IFR), or the proportion of infected people who die from the disease. Since the beginning of the pandemic, IFR estimates have ranged from less than 0.1% to a whopping 25%, depending on the size of the study and the age of the population. A growing number of studies are converging at about 0.5 to 1%. In Iceland, where the median age is 37 — relatively young compared with other wealthy nations — and patients have access to good health care, Stefánsson’s team found it to be 0.3%.
On 15 June, Iceland opened its borders to non-essential visitors from 31 European nations. A month later, on 16 July, the country also lifted restrictions on visitors from 12 more countries, including Canada, New Zealand and South Korea. The opening gave a boost to the struggling tourism industry, although numbers of visitors remained low, with about 75–80% fewer summer tourists than in 2019, according to the Icelandic Tourist Board.
Then, on 10 August, a pair of tourists at Reykjavik airport tested positive for SARS-CoV-2, ignored regulations and went into town. That incursion led to a small bump of cases in August centred on two pubs and a fitness centre visited by the tourists. Then, in mid-September, the number of infections increased abruptly, from 1 to 55 in a week. “This one clone of virus was able to spread around and cause lurking infections all over, especially in Reykjavik, and all of a sudden, we saw this increase,” says Guðnason. “It’s evidence of how difficult the virus is to contain.”
By October, coronavirus was more widespread in the community than it had been in the first wave, peaking at 291 infections per day. On 17 October, the number of active infections finally began to decline, which researchers attribute to widespread testing, tracing and quarantine procedures, as well as fresh government restrictions and emphasis on mask wearing. “Hopefully we can start relaxing our restrictions soon,” says Guðnason.
Despite the outbreak, the country continues to keep its borders open to tourists from some countries, although entry requirements are now stricter. Travellers must either self-quarantine for 14 days after arrival or participate in two screening tests: one on arrival, followed by five days of quarantine, then a second test. This method has led to the discovery that 20% of people who test negative in the first round will test positive in the second, notes Guðnason. That is a high number, but seems consistent with other analyses13. The new requirement is likely to have caught many strains of virus that would have otherwise entered the country.
Unlike New Zealand, which closed its borders, elimination was never supported in Iceland for fears that the country would go bankrupt without tourism. So it is possible that new cases will continue to arise, says Guðnason. Furthermore, he and others think the current outbreak might be in large part due to pandemic fatigue, as people disregard health precautions after months of being careful. “I think we’re going to be dealing with the virus, trying to suppress it as much as possible, until we get the vaccine,” he says.
And research continues in any and every spare hour. Palsson’s team is planning to analyse the effect of viral loads on patient outcomes and viral transmission, and to use contact-tracing data to tease out the risk factors for a super-spreading event. “We’ve had households where almost everybody gets infected, then other places where people carry the infection and stay in the workplace and nobody gets infected,” says Palsson. “It’s very difficult to understand.”
At deCODE, Stefánsson and his colleagues are investigating cellular immune responses and whether people with COVID-19 who are very sick produce antibodies directed against their own tissues. And together, the deCODE and university-hospital teams are collaborating on the long-term effects of COVID and how genetics affects susceptibility and responses to the disease.
“We’ve been committed for a long time to take everything we learn about human disease and publish it,” says Stefánsson. “There is no way in which we would have not utilized the opportunity.”
A research team has discovered that Dlgap2, a gene that helps facilitate communication between neurons in the nervous system, is associated with the degree of memory loss in mice and risk for Alzheimer’s dementia in humans. When studying post-mortem human brain tissue, the researchers also discovered low levels of Dlgap2 in people experiencing ‘poorer cognitive health’ and ‘faster cognitive decline’ prior to death.
A gene known for helping facilitate communication between neurons in the nervous system has been discovered to be connected with Alzheimer’s dementia and cognitive decline, according to a national research team led by The Jackson Laboratory and University of Maine.
Catherine Kaczorowski, associate professor and Evnin family chair in Alzheimer’s research at The Jackson Laboratory (JAX), and adjunct professor with the UMaine Graduate School of Biomedical Science and Engineering (GSBSE), spearheaded a study to pinpoint the genetic mechanisms that affect resistance or vulnerability to weakening cognition and dementias, such as Alzheimer’s.
Andrew Ouellette, a Ph.D student at JAX and a GSBSE NIH T32 predoctoral awardee, led the project, along with his mentor Kaczorowski and scientists from across the U.S.
By studying the memory and brain tissue from a large group of genetically diverse mice, the team found that the expression of the gene Dlgap2 is associated with the degree of memory loss in mice and risk for Alzheimer’s dementia in humans. Further research will ascertain how the gene influences dementia and mental function.
Dlgap2, located in the synapses of neurons, serves to anchor critical receptors for signals between neurons required for learning and memory. When studying post-mortem human brain tissue, the team discovered low levels of Dlgap2 in people experiencing “poorer cognitive health” and “faster cognitive decline” prior to death, according to researchers.
The team’s findings were published in the journal Cell Reports.
“The reason why this is so important is because a lot of research around cognitive aging and Alzheimer’s has been hyper-focused on well-known risk genes like APOE and brain pathologies,” Kaczorowski says. “We wanted to give ourselves the option of looking at new things people keep ignoring because they’ve never heard about a gene before.”
Researchers found that Dlgap2 influences the formation of dendritic spines on neurons, which can affect cognitive function. Longer, thinner spines shaped like mushrooms demonstrate higher mental performance than stubbier spines in mice, Ouellette says, and decreased cognition correlates with a loss in dendritic spines.
The study serves as a springboard for additional research into Dlgap2. Ouellette will explore how it influences cognition and how it can be used in therapeutic treatment for memory loss, in part by manipulating the gene with the editing tool CRISPR. Other members of the Kaczorowski lab are studying how to regulate Dlgap2 with pharmaceuticals to help prevent cognitive decline with age.
Scientists relied on Diversity Outbred mice, a population from eight parents created by The Jackson Laboratory to better reflect genetic diversity in humans. The Dlgap2 study involved 437 mice, each one either six, 12 or 18 months old.
“It’s great because you can harness the best parts of a mouse study and human society,” Ouellette says. “Historically, research has been done with inbred mice with similar genetic makeups; same, similar genetic models. But clinically, humans don’t work like that because they’re not genetically identical.”
The team performed quantitative trait loci mapping on the mouse population, examining entire genome sequences to identify genes responsible for varying cognitive function and where they occurred in the sequences. After pinpointing the connection between Dlgap2 and memory decline in mice, researchers evaluated its significance in human mental functionality using genomewide association studies for Alzheimer’s dementia and studying samples of post-mortem brain tissue using imaging, microscopy and other methods.
Kaczorowski says the project relied on information and expertise from all 25 co-authors. For example, Gary Churchill, professor and Karl Gunnar Johansson chair at JAX, Elissa Chesler, professor at JAX, and postdoctoral fellow Niran Hadad provided their expertise in utilizing diversity outbred models and cross-species genomic data integration to the project. Their efforts, she says, emphasizes the importance of teamwork in advancing medical research.
“We’re going to be able to contribute a lot more to human health with team science,” she says.
The GSBSE and The Jackson Laboratory partner to provide cooperative Ph.D. programs that include on-site training at the laboratory in Bar Harbor. The school also partners with other academic and research institutions to provide similar learning experiences. UMaine grants the degrees for these programs.
Kaczorowski says the GSBSE’s biomedical science Ph.D. program gives students hands-on learning opportunities that, like with Ouellette, can help them realize their passion and talents. Researching Dlgap2 with Kaczorowski influenced Ouellette’s Ph.D. dissertation further exploring how the Dlgap2 influences cognition in animals.
“I really like this study because it’s very interdisciplinary,” Ouellette says, adding that it harmonizes biological and computational science. “This study set me on a path that makes me want to be a more interdisciplinary scientist.”
Andrew R. Ouellette, Sarah M. Neuner, Logan Dumitrescu, Laura C. Anderson, Daniel M. Gatti, Emily R. Mahoney, Jason A. Bubier, Gary Churchill, Luanne Peters, Matthew J. Huentelman, Jeremy H. Herskowitz, Hyun-Sik Yang, Alexandra N. Smith, Christiane Reitz, Brian W. Kunkle, Charles C. White, Philip L. De Jager, Julie A. Schneider, David A. Bennett, Nicholas T. Seyfried, Elissa J. Chesler, Niran Hadad, Timothy J. Hohman, Catherine C. Kaczorowski. Cross-Species Analyses Identify Dlgap2 as a Regulator of Age-Related Cognitive Decline and Alzheimer’s Dementia. Cell Reports, 2020; 32 (9): 108091 DOI: 10.1016/j.celrep.2020.108091
University of Maine. “New connection between Alzheimer’s dementia and Dlgap2.” ScienceDaily. ScienceDaily, 23 November 2020. <www.sciencedaily.com/releases/2020/11/201123161040.htm>.
Fast mapping, the ability to rapidly learn an association between two things after very little exposure, is a key tool responsible for the vast repertoire of human language. It’s the reason we can recognize voices from another room and why newborns prefer to listen to their mothers read them The Cat in the Hat over other women. While fast mapping is generally thought of as a human ability, zebra finches can also distinguish dozens of other finches’ vocalizations, doing so with very little exposure and retaining those memories for at least a month, researchers report today (November 13) in Science Advances.
“The reason that this study is groundbreaking is because zebra finches are the very first vocally learning species aside from ourselves with any evidence that fast mapping takes place,” Samantha Carouso-Peck, a behavioral neuroscientist at Cornell University who researches social influences on vocal learning in zebra finches but was not involved in the current work, tells The Scientist.
Prior to the new study, evidence of fast mapping in nonhumans had been suggested for only a single nonhuman species: dogs. Rico the border collie is capable of distinguishing the name of more than 200 individual objects, while another dog named Chaser could discriminate between more than 1,000. Whether this is truly evidence of fast mapping, however, has been debated among scientists who believe that only species capable of language, specifically humans, can be said to truly fast map.
To test zebra finches’ ability to recognize individual calls, and the number of exposures they need to do so, researchers at the University of California, Berkeley, designed a five-day “learning ladder.” Birds were initially trained on a small set of call data that became increasingly larger over several days.
On the first day of testing, each bird in the training arena went through a series of trials during which they heard brief clips of either a song or a distance call used by birds to locate their group when it is out of sight. These two distinct vocalizations were chosen because they are thought to have the most variation between individuals. Nineteen birds were trained on songs, while another 19 heard only distance calls. The vocalizations were parsed, so that one set led to a food reward, while the other set didn’t.
In the team’s experiments, birds in an arena learned to distinguish between vocalizations that came with a reward (Re Vocalizer) and those that did not (NoRe Vocalizer). When birds recognized a call they had heard before, they allowed the clip to play fully, which activated a food reward. When they did not, they hit a button to skip ahead to the next trial. In this way, scientists were able to show that individual finches can remember an average of 42 other vocalizers.JULIE ELIE, UC BERKELEY
In that first test, each finch only needed to discriminate between two individuals’ vocalizations, one that provided a food reward and one that did not. By pecking a key, the finch would start the sound file. It could then either peck the key again to start a new trial or listen to the entire clip to receive a food reward. Repeating this process over several trials, the finches learned to associate vocalizations that led to a reward from the ones that did not and to quickly skip vocalizations that weren’t rewarding.
Each successive day, sounds from additional individuals were added to the training set. While finches were originally trained to discriminate between one pair of individuals, by day two it jumped to four pairs, and then eight on days three through five, for a total of 16 different individuals’ vocalizations. The researchers began evaluating the finches’ performance only on days four and five, when each bird had been exposed at least once to each possible vocalizer.
To be certain the finches weren’t simply memorizing the sound files, each bird providing the vocalization was recorded 10 different times. “We were pulling randomly from a large library of calls that we have, so the calls were all different every time,” Frederic Theunissen, an auditory scientist at the University of California, Berkeley, tells The Scientist. “Not only are they different vocalizers, but they heard different renditions from the same vocalizer.”
Even with this added layer of complexity, Theunissen says he was “really impressed” by how well the finches performed. All 19 finches trained using song files were able to discriminate between the vocalizers they recognized based on their individual signatures and those they did not, and the same was true for 18 of the finches trained using distance calls.
Beyond their ability to recognize other birds based on their calls, the team was also struck by how quickly the finches were able make the distinctions. The majority of birds could hear as few as 10 exposures to an individual and memorize their signature, while some required fewer than five, strong evidence for fast mapping in the species.
“We didn’t expect the birds to be so good at this,” Theunissen tells The Scientist. “We thought this was going to be interesting, but the fact that the number of vocalizers is so high, and that they can do this so quickly, was really quite astonishing.”
In the study, the team decided to create what Theunissen calls “an impossible task” to test the limits of the finches’ performance. He created a new set of stimuli that included both songs and distance calls from 56 distinct vocalizers. Only four randomly-selected birds went through this mega-task, but on average, they were able to remember 42 individual vocalizers.
A month later, he tested the recall of two of the four birds by running them through the same, 56-vocalizer test and found that they were still able to distinguish between individuals—they had retained their memories of the individual calls. Both the speed of their learning and their retention over time, Theunissen says, “point towards these really remarkable abilities that these birds have in terms of making auditory memories.”
Because these birds are so social, living gregariously in colonies of more than 100 individuals, it isn’t unexpected that zebra finches could discriminate between dozens of individuals, says Sarah Woolley, a neuroethologist at McGill University who studies the neurological basis for social behavior in songbirds. “We’ve always been pretty sure that birds could do that, zebra finches included,” Woolley says. “But no one had really demonstrated it, certainly not to the degree that they do in this paper.”
While the results are “very interesting evidence” that zebra finches are capable of fast mapping, Carouso-Peck says that more work on a larger sampling of birds is needed “before we can make weightier claims about what they’re capable of.” For example, one of the criticisms of the previous work with Rico the border collie is that fast mapping is a tool for learning language, and therefore only species capable of language truly do it. While Carouso-Peck says she doesn’t necessarily agree, as a next step she would like to see if finches are also capable of fast mapping verbally. For example, how many times must young zebra finches hear their father’s song before they can reproduce it for themselves?
“Language is something which we humans tend to hold up as our great crowning achievement, something that we are capable of which absolutely no [other] species is capable of,” Caruso-Peck tells The Scientist. “Over the last few decades, we’ve had to change the goalposts for what is language in order to maintain that high and mighty position.”
K. Yu et al., “High-capacity auditory memory for vocal communication in a social songbird,” Science Advances, doi:10.1126/sciadv.abe0440, 2020.
Dolphins seem to adjust their heart rates as they dive to avoid decompression sickness, also known as the bends, which is caused by sudden changes in pressure.
Human divers must avoid surfacing too quickly as the drop in pressure can force nitrogen bubbles into their airways and cause joint pain or even paralysis.
It was thought that marine mammals such as dolphins didn’t have this problem, says Andreas Fahlman at the Oceanographic Foundation in Valencia, Spain, but researchers have recently been reassessing this idea.
To test it, Fahlman and his colleagues trained captive bottlenose dolphins to take short or long dives on command. They measured the animals’ heart rates using electrocardiography and found that they slow their hearts just before diving underwater.
When preparing for a long dive, the dolphins reduced their heart rate more quickly and to a lower rate than when they were about to take a shorter dive. This conserves more oxygen and reduces decompression sickness by limiting nitrogen intake.
Fahlman says this is probably a conscious rather than automatic response: the dolphins are controlling their heart rate by deflating part of their lungs to let blood or air flow to areas under pressure. “They are controlling how much blood is sent to the lungs and where in the lungs it’s sent to avoid nitrogen uptake,” he says. “They can basically step on and off the gas pedal when they want to.”
Stress from noises like sonar or machinery used for oil exploration may interfere with this conscious control of heart rate, says Fahlman, possibly increasing the chances of a dolphin getting the bends. By learning more about dolphins’ physiology, we might be able to find ways to mitigate these problems, he says.
A huge cache of fresh water found beneath the sea floor off the western coast of Hawaii’s Big Island could lift the threat of drought for people living there.
Eric Attias at the University of Hawaii and his colleagues discovered the reservoir, which is contained in porous rock reaching at least 500 metres beneath the sea floor, using an imaging technique similar to an MRI scan.
They used a boat towing a 40-metre-long antenna behind it to generate an electromagnetic field, sending an electric current through the sea and below the sea floor. As seawater is a better conductor than fresh water, the team could distinguish between the two. They found that the reservoir extends at least 4 kilometres from the coast and contains 3.5 cubic kilometres of fresh water.
Most of Hawaii’s fresh water comes from onshore aquifers, which are layers of rock and soil underground that collect water after rainfall. The team believes that this newfound reservoir is replenished by water flowing out of these aquifers.
Climate change has lead to increasing droughts in many places, which could leave some areas without water. In Hawaii, decreased rainfall and the destruction of forests could mean the onshore aquifers eventually dry up.
Not only would the offshore reservoir help relieve drought, it may also be easier to pump from than the onshore aquifers, because the water is under high pressure. Accessing it would also have minimal impact on surrounding ecosystems, says Attias.
Similar caches of water may be located off other volcanic islands, says the team, which could provide a relief for other places threatened by water scarcity due to climate change.
Drinking cocoa may give your brain a major boost of speed and accuracy, according to new research from the University of Birmingham. Study participants who drank cocoa with high levels of flavanols were able to complete complex cognitive tasks much more efficiently.
Flavanols are plant nutrients that are found in tea, grapes, tomatoes, and many other foods, but they are particularly concentrated in the cacao beans that are used to make cocoa. Previous studies have shown that cocoa flavanols can help lower blood pressure, improve blood circulation, and fight cell damage.
The Birmingham team set out to investigate the cognitive effects of cocoa flavanols in young, healthy individuals while focusing on a link between blood oxygenation and cognitive benefits. The researchers used non-invasive brain imaging to measure blood oxygenation levels among individuals who consumed cocoa that contained either high levels of flavanols or no flavanols.
In collaboration with scientists at the University of Illinois, the experts showed that participants who consumed a flavanol-rich drink produced a faster and greater increase in blood oxygenation levels in response to artificially elevated levels of CO2.
Approximately two hours after drinking the cocoa, the volunteers were exposed to air with 5 percent carbon dioxide, which is about 100 times the normal concentration. This is a standard method for challenging brain vasculature to determine how well it responds, said study co-author Professor Gabriele Gratton. He explained that the body typically reacts by increasing blood flow to the brain. “This brings in more oxygen and also allows the brain to eliminate more carbon dioxide.”
The researchers found that most of the individuals had a stronger and faster brain oxygenation response after the consumption of cocoa flavanols. “The levels of maximal oxygenation were more than three times higher in the high-flavanol cocoa versus the low-flavanol cocoa, and the oxygenation response was about one minute faster,” said study lead author Dr. Catarina Rendeiro.
After the carbon dioxide test, the participants were assigned progressively complex cognitive tests, which often required them to manage contradictory or competing demands. During the tests, the researchers found that volunteers who consumed flavanols executed tasks with significantly higher speed and accuracy.
“Our results showed a clear benefit for the participants taking the flavanol-enriched drink – but only when the task became sufficiently complicated,” said Dr. Rendeiro. “We can link this with our results on improved blood oxygenation – if you’re being challenged more, your brain needs improved blood oxygen levels to manage that challenge. It also further suggests that flavanols might be particularly beneficial during cognitively demanding tasks.”
The experts discovered that a small group of four volunteers did not benefit from the flavanol-enriched drink in terms of blood oxygenation levels, and also did not experience any cognitive benefits. These individuals had high levels of brain oxygenation responses at the beginning of the trial that were not influenced by the enriched cocoa.
“Because these four participants already had the highest oxygenation responses at baseline, this may indicate that those who are already quite fit have little room for improvement,” said Dr. Rendeiro. “Overall, the findings suggest that the improvements in vascular activity after exposure to flavanols are connected to the improvement in cognitive function.”
“We used cocoa in our experiment, but flavanols are extremely common in a wide range of fruit and vegetables. By better understanding the cognitive benefits of eating these food groups, as well as the wider cardiovascular benefits, we can offer improved guidance to people about how to make the most of their dietary choices.”
Earless moths have sound-absorbent wings that act as acoustic camouflage from preying bats. The moth wings have an ultrathin layer of scales that absorb sound and could be adapted for noise-cancelling technology.
Marc Holderied at the University of Bristol, UK, and his colleagues projected sound waves at the wings of two species of earless moths (Antheraea pernyi and Dactyloceras Lucina). They found that the sound waves that bounced back from the moth wings were much quieter.
By using an imaging technique called acoustic topography, the team found that these moth wings have a layer of scales that are arranged in a special repeating pattern that absorbs sound across a wide range of frequencies.
“Similar to how stealth bombers are less detectable by enemy radars, the moths have developed a stealth coating against the bat’s sonar,” says Holderied. The moth wings, which are around a tenth of a millimetre thick, absorb the specific sound waves produced by bats.
Bats interpret their surroundings using echolocation: they send out sound waves and when the sound hits an object, an echo is produced. The bats use these echoes to build an image of their environment. Because the earless moths’ wings absorb these sound waves, they remain largely undetected, improving their chances of survival.
Other moths have ultrasensitive ears to hear bats, but the deaf, earless moths rely on this sound-absorbent layer to evade their predators.
Holderied and his team also compared the earless moths with two species of butterflies and found that only the moths had the sound-absorbing quality.