thescientist--2020-12-07--AI-Assisted Cough Tracking Could Help Detect the Next Pandemic

When Joe Brew worked for the Florida Department of Health as an epidemiologist for two years starting in 2013 , he helped with syndromic surveillance , meaning he had the arduous job of reviewing the symptoms of patients coming into the emergency departments from all across the state .
The goal of such work : to detect an abnormal spike of symptoms in an area that may indicate there ’ s a public health concern .
Public health authorities worldwide continue to use this type of surveillance .
The outbreak of a novel pathogen in Wuhan , China in late @ @ @ @ @ @ @ part detected by a large uptick of patients coming to the hospital with symptoms of a respiratory infection , with unknown etiology .
But Brew says this system fails to prevent the transmission of a virus like SARS-CoV-2 because by the time patients arrive at the hospital , they have likely already been infectious for a matter of days .
COVID-19 tests , too , often fail to return a result in time for patients to properly isolate while they ’ re infectious .
This realization led Brew to turn to a device @ @ @ @ @ @ @ provide public health authorities with real-time symptomatic data from the community .
Brew and several colleagues founded Hyfe , a free phone application that uses artificial intelligence to detect and track users ’ coughs , a hallmark of many respiratory conditions including COVID-19 .
“ The way you beat COVID is by acting fast—by being ahead of it , ” says Brew , who is now the CEO of Hyfe .
“ Those places that very quickly identified clusters and outbreaks were able to shut things down and basically control the pandemic even @ @ @ @ @ @ @ curious to monitor their cough frequency trends , say , if they have a respiratory condition or want to share these data with loved ones or medical professionals , can download Hyfe onto their smartphones .
When the application hears a loud , abrupt noise , such as a cough , it captures that approximately half-second snippet of sound and converts it into a 3-D image called a spectrogram that represents the pitch and intensity of the sound over time .
The spectrogram is then processed through a machine learning algorithm known as @ @ @ @ @ @ @ been trained on a dataset of more than 270,000 sounds—a cough , laugh , grunt , burp , or a fork hitting a plate , for example—that two human listeners have labeled as a cough or not a cough that help the algorithm determine whether the abrupt noise was , indeed , a cough .
The app also learns an individual ’ s unique cough , so if the app detects another person ’ s cough that significantly deviates from their previous coughs , it won ’ t log it .
Brew and @ @ @ @ @ @ @ this concept into the field to see if they can detect an outbreak of an infectious respiratory pathogen .
Their pilot project will examine the cough data at a community-wide level in a small municipality on the outskirts of Pamplona , Spain .
“ There ’ s a lot of people thinking about diagnostics , but everyone is thinking individually , ” ISGlobal Barcelona Institute for Global Health epidemiologist Carlos Chaccour , who is leading the study , tells The Scientist .
“ But so far , the community perspective has not been @ @ @ @ @ @ @ could be many non–infectious disease causes for a cough—air quality , asthma , allergies , fumes from cooking , to name a few—he says the lack of specificity is a feature not a bug .
In the case of wastewater surveillance , which is another tool for public health officials to use to indirectly detect and monitor the spread of infectious disease , “ you ’ re already looking for the virus , and you ’ re already in an epidemic situation , ” he says , whereas Hyfe could , in theory @ @ @ @ @ @ @ novel disease before it progresses to that point .
Chaccour and his team have enrolled more than 60 people in the community so far and aim for as many as 500 to test the concept .
As part of the study , participants grant researchers access to their hospital records and their Hyfe data to determine if a rise from a baseline level of coughing among the participants correlates to more diagnoses of respiratory conditions , including COVID-19 .
If Hyfe can successfully demonstrate that its detection of a higher community incidence in @ @ @ @ @ @ @ clinic , Chaccour says , he envisions users could then view a heat map of anonymized data showing which communities have the highest prevalence of coughing—a tool that could come in handy for public health officials but also people hoping to understand the risk of infection in a community .
Cough has long been a symptom that physicians record , yet the method for monitoring it is typically limited to a self-report during a clinic visit .
Previous research suggests that patients often underreport how much they cough , which has led epidemiologists @ @ @ @ @ @ @ is untapped potential in using cough data .
Alyn Morice , who is the head of respiratory medicine at Hull York Medical School in the UK and specializes in the diagnosis and treatment of cough , says that patients answering questionnaires are entirely unreliable .
He ’ s even seen patients fabricate data from peak flow meters , portable devices that patients use at home to measure how efficiently air flows through their lungs .
“ The great thing about this cough monitoring is it will be passive—the patient won ’ t actually @ @ @ @ @ @ @ says .
University of Washington infectious disease expert Peter Small , who is the senior director of Global Health Technologies and is not involved with Hyfe , tells The Scientist he is optimistic about this new frontier of technology , particularly in the context of eradicating tuberculosis .
“ Patients seek care very late in the disease and part of that is because we , as a society , tend to ignore cough in adults , ” he says .
With the help of AI-assisted cough tracking , he envisions a world in @ @ @ @ @ @ @ a higher rate than normal for , say , two weeks would receive a text notifying them of their symptoms with directions to a public clinic that can test them for tuberculosis .
Even in patients with a confirmed TB diagnosis , Small says , the technology could show patients ’ recovery progress .
“ I ’ ve been around a lot of TB patients and it ’ s a very disconcerting diagnosis , ” he says .
“ Even though it ’ s almost always curable , it ’ s psychologically difficult @ @ @ @ @ @ @ that their cough is getting better can help with their spirits.
” The Hyfe group is not the only one working to integrate cough into a more effective public health tool .
Morice , for instance , developed an alert system using cough tracking through an external monitor users wear around their necks for impending chronic obstructive pulmonary disease ( COPD ) exacerbations—severe episodes that can often lead to hospitalization .
His research team detected 45 percent of these flare-ups an average of four days prior to diagnosis , according to data they @ @ @ @ @ @ @ Respiratory Society virtual conference .
With early intervention , patients who take steroids or bronchodilators can prevent or lessen the severity of these exacerbations , Morice says .
“ If you ’ re able to prevent hospital admissions in these folks , it ’ s much better for the patient but it ’ s also much better for the health economy because [ treating the ] exacerbation is an expensive thing , ” he says .
An MIT group tried to develop a tool to determine if it ’ s possible to identify @ @ @ @ @ @ @ more than 70,000 forced-cough audio samples , of which 2,660 were submitted by people with COVID-19 , through a machine learning algorithm , which they claim accurately identifies 98.5 percent of coughs from people who were confirmed to have COVID-19 , including 100 percent of forced coughs from those who were asymptomatic , according to their paper published in October in IEEE Journal of Engineering in Medicine and Biology .
In other endeavors , researchers are soliciting healthy and COVID-19–infected individuals to help train their AI models to eventually allow users to understand @ @ @ @ @ @ @ their cough .
These projects include a Bill and Melinda Gates Foundation–funded initiative , Cough Against Covid , at the Wadhwani Institute for Artificial Intelligence in Mumbai , the University of Cambridge ’ s COVID-19 Sounds project , and the Coughvid project at the Swiss Federal Institute of Technology Lausanne .
Morice remains skeptical of apps that claim they can diagnose users ’ coughs : “ Frankly , I don ’ t believe them .
You can tell a wet cough from a dry cough , but that ’ s about it from @ @ @ @ @ @ @ the MIT study declined requests for an interview to discuss their work .
Brew says he not only wants to better understand the acoustic signature of different ailments , but also track the diurnal pattern of cough—do people with COVID-19 , for example , tend to cough more during a certain part of the day or night ?
“ When do they begin coughing ?
Does a change in cough frequency indicate a certain prognosis ?
” Brew asks .
“ These are super basic questions that no one really knows [ the @ @ @ @ @ @ @ More than 40 countries and 21 US states and territories use official state-sponsored COVID-19 applications that aid contact tracers in stemming the spread of the virus .
Despite the promise of these apps , few people in the US have downloaded them , in part because users worry about handing over their detailed location history to their government , says Chaccour .
Any app monitoring cough would also require permission to record audio through users ’ smartphones and , in Hyfe ’ s case , track their location to measure cough at a @ @ @ @ @ @ @ to reassure users that the app would only record roughly half-second snippets following an abrupt noise .
Still , he says he thinks there needs to be some value offered back to the user .
One idea is to design a dashboard of users ’ personal data akin to what Fitbit does with step counts .
“ Nobody cared about step counts 15 years ago until Fitbit made it trendy , ” he says .
To Chaccour , if the technology proves useful , the end goal is not to provide it to @ @ @ @ @ @ @ such as Apple or Google , which can integrate it into their phone operating systems .
He ’ s noticed that in Spain , people aren ’ t very trustful of the official government COVID-19 app , but they don ’ t mind their phones listening for users to summon the voice assistant or tracking how much they ’ ve slept .
Brew says he thinks the present moment is a perfect opportunity to roll out the technology .
People care about public health and “ cough counting would have been interesting in @ @ @ @ @ @ @ some five billion humans carrying a microphone with them at all times every day , everywhere .
”

ABOVE: © ISTOCK.COM,
ERGIN YALCIN
When Joe Brew worked for the Florida Department of Health as an epidemiologist for two years starting in 2013, he helped with syndromic surveillance, meaning he had the arduous job of reviewing the symptoms of patients coming into the emergency departments from all across the state. The goal of such work: to detect an abnormal spike of symptoms in an area that may indicate there’s a public health concern.
Public health authorities worldwide continue to use this type of surveillance. The outbreak of a novel pathogen in Wuhan, China in late 2019, for instance, was in part detected by a large uptick of patients coming to the hospital with symptoms of a respiratory infection, with unknown etiology. But Brew says this system fails to prevent the transmission of a virus like SARS-CoV-2 because by the time patients arrive at the hospital, they have likely already been infectious for a matter of days. COVID-19 tests, too, often fail to return a result in time for patients to properly isolate while they’re infectious.
This realization led Brew to turn to a device that billions have in their pockets—a smartphone—to provide public health authorities with real-time symptomatic data from the community. Brew and several colleagues founded Hyfe, a free phone application that uses artificial intelligence to detect and track users’ coughs, a hallmark of many respiratory conditions including COVID-19.
Cough has long been a symptom that physicians record, yet the method for monitoring it is typically limited to a self-report during a clinic visit.
“The way you beat COVID is by acting fast—by being ahead of it,” says Brew, who is now the CEO of Hyfe. “Those places that very quickly identified clusters and outbreaks were able to shut things down and basically control the pandemic even without a vaccine.”
People who are curious to monitor their cough frequency trends, say, if they have a respiratory condition or want to share these data with loved ones or medical professionals, can download Hyfe onto their smartphones. When the application hears a loud, abrupt noise, such as a cough, it captures that approximately half-second snippet of sound and converts it into a 3-D image called a spectrogram that represents the pitch and intensity of the sound over time. The spectrogram is then processed through a machine learning algorithm known as a convolutional neural network, which has been trained on a dataset of more than 270,000 sounds—a cough, laugh, grunt, burp, or a fork hitting a plate, for example—that two human listeners have labeled as a cough or not a cough that help the algorithm determine whether the abrupt noise was, indeed, a cough. The app also learns an individual’s unique cough, so if the app detects another person’s cough that significantly deviates from their previous coughs, it won’t log it.
Brew and a team of scientists aim to take this concept into the field to see if they can detect an outbreak of an infectious respiratory pathogen. Their pilot project will examine the cough data at a community-wide level in a small municipality on the outskirts of Pamplona, Spain.
A spectrogram, which is a visual representation of audio frequency and intensity over time, that shows an archetypical cough. Hyfe converts snippets of users’ suspected coughs into these images and processes them through a machine learning algorithm to determine whether the sound is a cough. HYFE
“There’s a lot of people thinking about diagnostics, but everyone is thinking individually,” ISGlobal Barcelona Institute for Global Health epidemiologist Carlos Chaccour, who is leading the study, tells The Scientist. “But so far, the community perspective has not been pursued.”
While Brew admits that there could be many non–infectious disease causes for a cough—air quality, asthma, allergies, fumes from cooking, to name a few—he says the lack of specificity is a feature not a bug. In the case of wastewater surveillance, which is another tool for public health officials to use to indirectly detect and monitor the spread of infectious disease, “you’re already looking for the virus, and you’re already in an epidemic situation,” he says, whereas Hyfe could, in theory, detect a surprise flare-up from an novel disease before it progresses to that point.
The great thing about this cough monitoring is it will be passive—the patient won’t actually have to do anything. —Alyn Morice, Hull York Medical School
Chaccour and his team have enrolled more than 60 people in the community so far and aim for as many as 500 to test the concept. As part of the study, participants grant researchers access to their hospital records and their Hyfe data to determine if a rise from a baseline level of coughing among the participants correlates to more diagnoses of respiratory conditions, including COVID-19.
If Hyfe can successfully demonstrate that its detection of a higher community incidence in coughing precedes more respiratory diagnoses in the clinic, Chaccour says, he envisions users could then view a heat map of anonymized data showing which communities have the highest prevalence of coughing—a tool that could come in handy for public health officials but also people hoping to understand the risk of infection in a community.
A missed opportunity
Cough has long been a symptom that physicians record, yet the method for monitoring it is typically limited to a self-report during a clinic visit. Previous research suggests that patients often underreport how much they cough, which has led epidemiologists such as Brew to think that there is untapped potential in using cough data.
Alyn Morice, who is the head of respiratory medicine at Hull York Medical School in the UK and specializes in the diagnosis and treatment of cough, says that patients answering questionnaires are entirely unreliable. He’s even seen patients fabricate data from peak flow meters, portable devices that patients use at home to measure how efficiently air flows through their lungs.
“The great thing about this cough monitoring is it will be passive—the patient won’t actually have to do anything,” he says.
University of Washington infectious disease expert Peter Small, who has advised Hyfe and provided seed funding to the firm when he was the senior health director of global health technologies at Global Good, tells The Scientist he is optimistic about this new frontier of technology, particularly in the context of eradicating tuberculosis. “Patients seek care very late in the disease and part of that is because we, as a society, tend to ignore cough in adults,” he says.
With the help of AI-assisted cough tracking, he envisions a world in which users who have been coughing at a higher rate than normal for, say, two weeks would receive a text notifying them of their symptoms with directions to a public clinic that can test them for tuberculosis.
Even in patients with a confirmed TB diagnosis, Small says, the technology could show patients’ recovery progress. “I’ve been around a lot of TB patients and it’s a very disconcerting diagnosis,” he says. “Even though it’s almost always curable, it’s psychologically difficult on patients, and having objective evidence that their cough is getting better can help with their spirits.”
Cough counting would have been interesting in 1990, but right now we have some five billion humans carrying a microphone with them at all times every day, everywhere. —Joe Brew, Hyfe
The Hyfe group is not the only one working to integrate cough into a more effective public health tool. Morice, for instance, developed an alert system using cough tracking through an external monitor users wear around their necks for impending chronic obstructive pulmonary disease (COPD) exacerbations—severe episodes that can often lead to hospitalization. His research team detected 45 percent of these flare-ups an average of four days prior to diagnosis, according to data they presented at this year’s European Respiratory Society virtual conference. With early intervention, patients who take steroids or bronchodilators can prevent or lessen the severity of these exacerbations, Morice says.
“If you’re able to prevent hospital admissions in these folks, it’s much better for the patient but it’s also much better for the health economy because [treating the] exacerbation is an expensive thing,” he says.
An MIT group tried to develop a tool to determine if it’s possible to identify a COVID-19–specific cough. The researchers processed more than 70,000 forced-cough audio samples, of which 2,660 were submitted by people with COVID-19, through a machine learning algorithm, which they claim accurately identifies 98.5 percent of coughs from people who were confirmed to have COVID-19, including 100 percent of forced coughs from those who were asymptomatic, according to their paper published in October in IEEE Journal of Engineering in Medicine and Biology.
In other endeavors, researchers are soliciting healthy and COVID-19–infected individuals to help train their AI models to eventually allow users to understand if they have the virus based on their cough. These projects include a Bill and Melinda Gates Foundation–funded initiative, Cough Against Covid, at the Wadhwani Institute for Artificial Intelligence in Mumbai, the University of Cambridge’s COVID-19 Sounds project, and the Coughvid project at the Swiss Federal Institute of Technology Lausanne.
Morice remains skeptical of apps that claim they can diagnose users’ coughs: “Frankly, I don’t believe them. You can tell a wet cough from a dry cough, but that’s about it from the cough sounds.” Several coauthors of the MIT study declined requests for an interview to discuss their work.
Brew says he not only wants to better understand the acoustic signature of different ailments, but also track the diurnal pattern of cough—do people with COVID-19, for example, tend to cough more during a certain part of the day or night? “When do they begin coughing? Does a change in cough frequency indicate a certain prognosis?” Brew asks. “These are super basic questions that no one really knows [the answer to] at this point.”
Privacy concerns of recording audio
More than 40 countries and 21 US states and territories use official state-sponsored COVID-19 applications that aid contact tracers in stemming the spread of the virus. Despite the promise of these apps, few people in the US have downloaded them, in part because users worry about handing over their detailed location history to their government, says Chaccour.
Any app monitoring cough would also require permission to record audio through users’ smartphones and, in Hyfe’s case, track their location to measure cough at a community level. Brew says he hopes to reassure users that the app would only record roughly half-second snippets following an abrupt noise. Still, he says he thinks there needs to be some value offered back to the user. One idea is to design a dashboard of users’ personal data akin to what Fitbit does with step counts. “Nobody cared about step counts 15 years ago until Fitbit made it trendy,” he says.
To Chaccour, if the technology proves useful, the end goal is not to provide it to governments, but perhaps to third-party companies such as Apple or Google, which can integrate it into their phone operating systems. He’s noticed that in Spain, people aren’t very trustful of the official government COVID-19 app, but they don’t mind their phones listening for users to summon the voice assistant or tracking how much they’ve slept.
Brew says he thinks the present moment is a perfect opportunity to roll out the technology. People care about public health and “cough counting would have been interesting in 1990, but right now we have some five billion humans carrying a microphone with them at all times every day, everywhere.”
Correction (December 9): The article has been updated to note Peter Small's relationships to Hyfe. The Scientist regrets the error.


thescientist--2020-12-06--Genetic Reprogramming Restores Vision in Mice: Study

ABOVE : A mouse ’ s crushed optic nerve , composed of retinal ganglion cell axons ( bright streaks ) , regenerates after researchers injected a virus into the eye that contains genes whose activity dedifferentiates cells into a more youthful state , allowing them to regrow .
YUANCHENG LU/SINCLAIR LAB Loss of visual acuity is a common feature of aging , whether it ’ s from age-related conditions such as glaucoma , an impaired ability for cells to respond to damage , or degeneration .
In an attempt to address these issues with a genetic intervention , scientists reprogrammed @ @ @ @ @ @ @ inducing glaucoma or crushing the optic nerve , and restored visual acuity in healthy , middle-aged mice to that of younger mice by expressing a set of genes known to revert cells to a pluripotent state , according to a study published in Nature Wednesday ( December 2 ) .
The before-and-after genome methylation profiles of treated neurons and the requirement of demethylation enzymes for the success of the treatment indicate that the epigenome may be critical to aging—and to efforts to reverse it .
“ This study is very exciting because it @ @ @ @ @ @ @ rejuvenate neurons .
.
.
and is going to make a difference in the field , ” José-Alain Sahel , who chairs the University of Pittsburgh department of ophthalmology and was not involved with the study , tells The Scientist .
Harvard Medical School geneticist David Sinclair and his colleagues aimed to reset the biological clocks of a group of cells to see if they could rejuvenate injured and aging cells .
They looked to genes that encode transcription factors that de-differentiate cells .
These so-called Yamanaka factors , named after biologist Shinya @ @ @ @ @ @ @ induced pluripotent stem cells ( iPSCs ) .
In a 2016 Cell paper , a different group of scientists had activated these transcription factors in mice with progeria , a condition that causes premature aging , and found that the treatment alleviated symptoms and extended their lifespan by a matter of weeks .
These findings raised the possibility that Yamanaka factors could hold the key to counteract aging .
A risk of using Yamanaka factors in vivo is that dedifferentiation can cause cells to divide rapidly , so researchers in the Cell study @ @ @ @ @ @ @ .
To avoid such out-of-control proliferation , which would risk causing cancerous growth , Sinclair ’ s team eliminated one of the Yamanaka factors from their study—MYC , which is a known oncogene—and fitted the remaining three into an adeno-associated virus and injected it into mice .
The researchers found that the mice didn ’ t develop tumors , even after more than a year .
The next challenge : to see if these transcription factors could successfully revert old and injured neurons back to a more youthful and healthy state .
The @ @ @ @ @ @ @ mice can regrow axons of ocular neurons , unlike older mice .
The team focused on retinal ganglion cells ( RGCs ) , which are neurons whose axons make up the optic nerve and snake their way into the brain , transmitting information from light-sensitive photoreceptors .
Although these cells can regenerate if injured during development , they typically lose their ability to heal within a few days of a mouse ’ s birth .
To test whether adult mice can regain this ability , the researchers crushed the optic nerves of some @ @ @ @ @ @ @ of mice by inserting tiny beads into their eyes , then injected the virus encoding the three transcription factors into all the mice ’ s eyes .
The treatment caused mice to grow new axons from RGCs that reached back into the brain and halted glaucoma progression .
The rodents with glaucoma regained around half of their lost visual acuity , marking the first time that mice with a glaucoma-like condition have restored vision loss .
“ Vision loss from glaucoma was not thought to be recoverable , ” says Sinclair .
“ @ @ @ @ @ @ @ called me at ten o ’ clock at night and told me the news .
It was difficult to believe.
” Many research groups are trying to regenerate new ganglion cells outside the eye to be transplanted back in , says Sahel , but “ this is much better because the cells are already [ in place ] —they just need to regrow and reconnect.
” He notes , however , that the researchers used an acute model of injury , and that it isn ’ t possible to regenerate ganglion cells that @ @ @ @ @ @ @ like to see what happens in a more advanced situation that would mimic what we see in patients that are desperate for regaining vision , ” he says .
In another set of experiments , the researchers injected the virus bearing the genes that encode the three transcription factors into the eyes of healthy , middle-aged ( one-year-old ) mice .
Although they had scored worse on tests of visual acuity than did younger mice before treatment , a month afterward , the one-year-old mice had similar acuity scores to younger ones , @ @ @ @ @ @ @ increase in the number or density of retinal ganglion cells .
Eighteen-month-old mice that received the injection did not show any differences in visual acuity compared with untreated rodents , a result the authors ascribe to an increase in corneal opacity as the mice aged .
University of Edinburgh geneticist Tamir Chandra , who also studies aging and was not involved in this study , says that while these results are interesting , it is unclear to what extent their results are indicative of rejuvenation rather than dedifferentiation .
“ That almost sounds @ @ @ @ @ @ @ ’ s quite important because dedifferentiation always carries the risk of inducing cancer , ” he says .
“ The fact that they didn ’ t induce tumors in the healthy mice is more conceivable in the absence of MYC , but that doesn ’ t mean that if you had a tumor-prone mouse , that you ’ d get the same result.
” Scientists have long looked to the epigenome for clues into understanding disease susceptibility , behavior , and even mental health .
Sinclair has been studying how aging affects the @ @ @ @ @ @ @ study that a loss of epigenetic information over time contributed to aging .
“ If epigenetic loss drives aging , can you recover it , thereby reversing the aging process , and if you do that , do you get the youthful function of a complex tissue back again ?
” he says .
When the researchers looked at DNA methylation patterns of the retinal ganglion cells , they saw that changes caused by injury resembled methylation patterns in the ganglion cells of older mice , and that treatment with the transcription factor–encoding @ @ @ @ @ @ @ did not work in mice that did not have the enzymes necessary to remove methyl groups from DNA , suggesting that the demethylation process plays an important role in rejuvenating the neurons .
“ It ’ s not just that gene A went off with aging and came back on with treatment , ” says Sinclair .
“ There are hundreds and hundreds of genes that went down a certain level and then came back up a proportional level with the programming .
So somehow the cell has recorded not just which genes @ @ @ @ @ @ @ [ to which ] they should be altered.
” Still , Sinclair says , this study doesn ’ t show whether DNA methylation is directly responsible for rejuvenation or if it is more of a bystander .
Both Chandra and Sahel question the paper ’ s general relevance to aging , as the researchers used injury models rather than degeneration models , but they are encouraged by the potential new avenue of treatment .
“ It ’ s already amazing that we are able to ask these questions based on this paper , @ @ @ @ @ @ @ al.
, “ Reprogramming to recover youthful epigenetic information and restore vision , ” Nature , doi:10.1038/s41586-020-2975-4 , 2020 .

ABOVE: A mouse’s crushed optic nerve, composed of retinal ganglion cell axons (bright streaks), regenerates after researchers injected a virus into the eye that contains genes whose activity dedifferentiates cells into a more youthful state, allowing them to regrow.
YUANCHENG LU/SINCLAIR LAB
Loss of visual acuity is a common feature of aging, whether it’s from age-related conditions such as glaucoma, an impaired ability for cells to respond to damage, or degeneration. In an attempt to address these issues with a genetic intervention, scientists reprogrammed neurons in mouse eyes to regrow after inducing glaucoma or crushing the optic nerve, and restored visual acuity in healthy, middle-aged mice to that of younger mice by expressing a set of genes known to revert cells to a pluripotent state, according to a study published in Nature Wednesday (December 2). The before-and-after genome methylation profiles of treated neurons and the requirement of demethylation enzymes for the success of the treatment indicate that the epigenome may be critical to aging—and to efforts to reverse it.
“This study is very exciting because it’s really proposing an approach to rejuvenate neurons. . . and is going to make a difference in the field,” José-Alain Sahel, who chairs the University of Pittsburgh department of ophthalmology and was not involved with the study, tells The Scientist.
Harvard Medical School geneticist David Sinclair and his colleagues aimed to reset the biological clocks of a group of cells to see if they could rejuvenate injured and aging cells. They looked to genes that encode transcription factors that de-differentiate cells. These so-called Yamanaka factors, named after biologist Shinya Yamanaka, are widely used to generate induced pluripotent stem cells (iPSCs). In a 2016 Cell paper, a different group of scientists had activated these transcription factors in mice with progeria, a condition that causes premature aging, and found that the treatment alleviated symptoms and extended their lifespan by a matter of weeks. These findings raised the possibility that Yamanaka factors could hold the key to counteract aging.
If epigenetic loss drives aging, can you recover it, thereby reversing the aging process, and if you do that, do you get the youthful function of a complex tissue back again? —David Sinclair, Harvard Medical School
A risk of using Yamanaka factors in vivo is that dedifferentiation can cause cells to divide rapidly, so researchers in the Cell study only turned them on in short bursts. To avoid such out-of-control proliferation, which would risk causing cancerous growth, Sinclair’s team eliminated one of the Yamanaka factors from their study—MYC, which is a known oncogene—and fitted the remaining three into an adeno-associated virus and injected it into mice. The researchers found that the mice didn’t develop tumors, even after more than a year. The next challenge: to see if these transcription factors could successfully revert old and injured neurons back to a more youthful and healthy state. The eyes were a logical target because younger mice can regrow axons of ocular neurons, unlike older mice.
The team focused on retinal ganglion cells (RGCs), which are neurons whose axons make up the optic nerve and snake their way into the brain, transmitting information from light-sensitive photoreceptors. Although these cells can regenerate if injured during development, they typically lose their ability to heal within a few days of a mouse’s birth. To test whether adult mice can regain this ability, the researchers crushed the optic nerves of some mice and induced glaucoma in another set of mice by inserting tiny beads into their eyes, then injected the virus encoding the three transcription factors into all the mice’s eyes.
The treatment caused mice to grow new axons from RGCs that reached back into the brain and halted glaucoma progression. The rodents with glaucoma regained around half of their lost visual acuity, marking the first time that mice with a glaucoma-like condition have restored vision loss.
“Vision loss from glaucoma was not thought to be recoverable,” says Sinclair. “Bruce [Ksander, a collaborator] called me at ten o’clock at night and told me the news. It was difficult to believe.”
A mouse with a microbead injected into its eye to induce glaucoma. YUANCHENG LU/SINCLAIR LAB
Many research groups are trying to regenerate new ganglion cells outside the eye to be transplanted back in, says Sahel, but “this is much better because the cells are already [in place]—they just need to regrow and reconnect.” He notes, however, that the researchers used an acute model of injury, and that it isn’t possible to regenerate ganglion cells that have already died. “You would like to see what happens in a more advanced situation that would mimic what we see in patients that are desperate for regaining vision,” he says.
In another set of experiments, the researchers injected the virus bearing the genes that encode the three transcription factors into the eyes of healthy, middle-aged (one-year-old) mice. Although they had scored worse on tests of visual acuity than did younger mice before treatment, a month afterward, the one-year-old mice had similar acuity scores to younger ones, yet the researchers did not find an increase in the number or density of retinal ganglion cells. Eighteen-month-old mice that received the injection did not show any differences in visual acuity compared with untreated rodents, a result the authors ascribe to an increase in corneal opacity as the mice aged.
University of Edinburgh geneticist Tamir Chandra, who also studies aging and was not involved in this study, says that while these results are interesting, it is unclear to what extent their results are indicative of rejuvenation rather than dedifferentiation. “That almost sounds like a semantic question, but it’s quite important because dedifferentiation always carries the risk of inducing cancer,” he says. “The fact that they didn’t induce tumors in the healthy mice is more conceivable in the absence of MYC, but that doesn’t mean that if you had a tumor-prone mouse, that you’d get the same result.”
Epigenetics at work
Scientists have long looked to the epigenome for clues into understanding disease susceptibility, behavior, and even mental health. Sinclair has been studying how aging affects the epigenome and found in a 2008 Cell study that a loss of epigenetic information over time contributed to aging.
“If epigenetic loss drives aging, can you recover it, thereby reversing the aging process, and if you do that, do you get the youthful function of a complex tissue back again?” he says.
When the researchers looked at DNA methylation patterns of the retinal ganglion cells, they saw that changes caused by injury resembled methylation patterns in the ganglion cells of older mice, and that treatment with the transcription factor–encoding virus reversed those changes. The intervention did not work in mice that did not have the enzymes necessary to remove methyl groups from DNA, suggesting that the demethylation process plays an important role in rejuvenating the neurons.
“It’s not just that gene A went off with aging and came back on with treatment,” says Sinclair. “There are hundreds and hundreds of genes that went down a certain level and then came back up a proportional level with the programming. So somehow the cell has recorded not just which genes should be altered, but the level [to which] they should be altered.” Still, Sinclair says, this study doesn’t show whether DNA methylation is directly responsible for rejuvenation or if it is more of a bystander.
Both Chandra and Sahel question the paper’s general relevance to aging, as the researchers used injury models rather than degeneration models, but they are encouraged by the potential new avenue of treatment.
“It’s already amazing that we are able to ask these questions based on this paper,” says Sahel.
Y. Lu et al., “Reprogramming to recover youthful epigenetic information and restore vision,” Nature, doi:10.1038/s41586-020-2975-4, 2020.


thescientist--2020-12-07--Q&A: Tire Rubber Preservative Harms Coho Salmon, Study Suggests

In the 1980s , there were anecdotal reports of something fishy afoot : coho salmon near cities in the Pacific northwest were dying off at higher rates than salmon farther from the city .
Since then , scientists have suspected that urban runoff was to blame , and a study published in Science last week ( December 3 ) supports their hypothesis .
Urban watersheds contain a chemical called 6PPD-quinone , which is a derivative of tire rubber and toxic to coho salmon .
The Scientist spoke with University of Washington chemical engineer Edward Kolodziej , a coauthor of the @ @ @ @ @ @ @ Scientist : Can you tell me a bit about what you were noticing with salmon populations before starting the study ?
Anecdotal reports that urban stormwater killed coho salmon have been around since the 1980s .
Beginning in the 1990s in the Seattle area , much more extensive documentation of these annual mortality phenomena started to occur .
There was a research team led by Jay Davis , Nat Scholz , and Jen McIntyre , who are all coauthors [ of the latest study ] , looking at the toxicology of this phenomena @ @ @ @ @ @ @ for about 20 years now .
I joined in 2014 and employed some sophisticated water quality analyses to better understand the chemical composition of the waters that were killing the coho salmon .
TS : Tell me more about these die-off events .
EK : Salmon are born in fresh water and then coho salmon live in fresh water for maybe a year or so and then they go out to the ocean and come back two or three years later .
They only come back in a relatively short period of time @ @ @ @ @ @ @ reproduce .
After they reproduce , they die , so people are used to seeing dead salmon in the stream because the assumption was , ‘ they ’ ve laid their eggs , they ’ ve died , that ’ s totally natural.
’ What people started to figure out in the 1990s was actually they came back to reproduce and then when it rained , they died .
They could cut them open they were full of eggs , so they hadn ’ t reproduced , and so that ’ s really @ @ @ @ @ @ @ of work went on to understand where it was happening , how much , and if water was related .
TS : Can you describe your process of narrowing down what could be in the water and hurting the salmon ?
EK : We were pairing water quality analyses and toxicology observations together .
And by doing that , we found roadway-derived chemicals in the water , which was very consistent with some of the landscape modeling and the GIS-based statistical analyses .
Those are actually present during time periods when the salmon @ @ @ @ @ @ @ , were showing that among all these different possible sources of chemicals , the only one that killed coho salmon was tire rubber .
If we just soaked tire rubber bits in water , that was very lethal to the coho salmon .
That ’ s a very complex mixture—our instrument sees more than 2,000 chemicals there .
We had to just start separating it apart and isolating it into chemically simpler fractions .
We just started to follow the toxicity as we kept separating and separating and separating .
Eventually , we @ @ @ @ @ @ @ leachate that was highly toxic to the coho salmon .
We could then replicate the phenomena with a pure standard exposure .
TS : I ’ ve never heard of this chemical .
What do we know about it ?
EK : All tires need a number of preservative chemicals in them to make them durable , last longer , and be stronger .
At least since the 1930s , it ’ s been known that ground level ozone—this little concentration of ozone in the air—really degrades tire rubbers .
There ’ s @ @ @ @ @ @ @ designed to soak up the ozone before it can react with the tire rubber .
This antioxidant chemical , 6PPD , was identified in the early-to-mid 1950s .
I ’ m not exactly sure when it became widespread in tire manufacturing , but it ’ s one of the most abundant , if not the most abundant , antioxidant compound added to tires to soak up ozone .
Essentially , what happens is the reaction product—what ’ s present after the ozone reaction—is what we were seeing in the tire leachate and what @ @ @ @ @ @ @ coho salmon .
TS : In the grand scheme of factors that could be affecting fish populations—climate change or other known pollutants , for example—how big a threat does this novel chemical pose ?
EK : I can ’ t answer that cleanly .
It ’ s a big giant question that people devote their entire lives to .
All struggling aquatic organisms often face multiple stressors , multiple threats , multiple difficulties .
For systems where there ’ s roadway runoff contacting habitats that are important for coho salmon , this seems @ @ @ @ @ @ @ Some of the population modeling predicts localized extinction of coho from these exact creeks within 20 or 30 years because of this constant level of mortality in the returning fish .
They just can ’ t sustain their population , and every year it gets smaller and smaller .
TS : In this study , you were focusing on the coho salmon .
Is there indication that other species that interact with the runoff may also die from the tire runoff ?
EK : We do know that in these same watersheds where @ @ @ @ @ @ @ cutthroat trout co-occur , and they don ’ t seem to die from the same storms that kill the coho .
That field data tells us that we can anticipate differences in species sensitivity .
Beyond coho salmon , we just don ’ t know how sensitive other species are , so that ’ s work that requires follow-up study .
TS : What do you hope to do with these data , and do you hope that your study will inspire change in the way tires are produced in the future ?
@ @ @ @ @ @ @ ’ ll be doing is looking at these receiving waters , understanding the dynamics of this compound—how does it persist , what breaks it down , how much of it [ there is ] , what its fate is out in the environment—so we have a lot of work to do just to understand the basic water quality elements of this compound now that we know about it .
Concurrently , I ’ m sure there ’ ll be a bunch of related toxicology studies understanding the biology of these exposures .
We @ @ @ @ @ @ @ can improve problems and solve problems , and I certainly hope that we can have a conversation about chemical ingredients used in consumer products like tires that is linked to this type of work .
I would anticipate people will think about whether or not this chemical is the best choice for the desired attributes in consumer products like tires .
Disposal of used tires is a giant materials-handling issue .
Sustainable products are ones that we can reuse and recycle .
For tires , they ’ re reused in playing fields , @ @ @ @ @ @ @ they ’ re used in building materials .
To better enable sustainable products , we need to consider their end uses and their reuses as well .
Chemical safety is very relevant for the decisions we make with respect to reuse .
Enabling product sustainability comes from making sure everything in those products is environmentally benign and benign for people .
That is an aspect of this finding that I think is important to think about .
TS : What personal significance does this work have for you ?
EK : It ’ @ @ @ @ @ @ @ on .
It ’ s devastating to me , all of my group , and all the people working on this to every single year see adult salmon dying when they return to spawn .
I mean , these are really beautiful fish .
If you went to the store , you might buy these fish .
It ’ s very motivating for all of us to try and understand what it is that ’ s harming these fish because they really are that one percent of salmon which actually make it back @ @ @ @ @ @ @ can ’ t survive our water .
All of my group is very motivated and excited by the prospect that we can improve our management of these important species .
Editor ’ s note : The interview was edited for brevity .

ABOVE: © ISTOCK.COM,
BILL_DALLY
In the 1980s, there were anecdotal reports of something fishy afoot: coho salmon near cities in the Pacific northwest were dying off at higher rates than salmon farther from the city. Since then, scientists have suspected that urban runoff was to blame, and a study published in Science last week (December 3) supports their hypothesis. Urban watersheds contain a chemical called 6PPD-quinone, which is a derivative of tire rubber and toxic to coho salmon.
The Scientist spoke with University of Washington chemical engineer Edward Kolodziej, a coauthor of the study, about the findings.
The Scientist: Can you tell me a bit about what you were noticing with salmon populations before starting the study?
Edward Kolodziej UNIVERSITY OF WASHINGTON TACOMA
Edward Kolodziej: Anecdotal reports that urban stormwater killed coho salmon have been around since the 1980s. Beginning in the 1990s in the Seattle area, much more extensive documentation of these annual mortality phenomena started to occur. There was a research team led by Jay Davis, Nat Scholz, and Jen McIntyre, who are all coauthors [of the latest study], looking at the toxicology of this phenomena and its incidence out in the field for about 20 years now. I joined in 2014 and employed some sophisticated water quality analyses to better understand the chemical composition of the waters that were killing the coho salmon.
TS: Tell me more about these die-off events.
EK: Salmon are born in fresh water and then coho salmon live in fresh water for maybe a year or so and then they go out to the ocean and come back two or three years later. They only come back in a relatively short period of time in the fall—the adults are returning to reproduce. After they reproduce, they die, so people are used to seeing dead salmon in the stream because the assumption was, ‘they’ve laid their eggs, they’ve died, that’s totally natural.’ What people started to figure out in the 1990s was actually they came back to reproduce and then when it rained, they died. They could cut them open they were full of eggs, so they hadn’t reproduced, and so that’s really where these observations began. A lot of work went on to understand where it was happening, how much, and if water was related.
TS: Can you describe your process of narrowing down what could be in the water and hurting the salmon?
EK: We were pairing water quality analyses and toxicology observations together. And by doing that, we found roadway-derived chemicals in the water, which was very consistent with some of the landscape modeling and the GIS-based statistical analyses. Those are actually present during time periods when the salmon were dying.
Toxicology observations, meanwhile, were showing that among all these different possible sources of chemicals, the only one that killed coho salmon was tire rubber. If we just soaked tire rubber bits in water, that was very lethal to the coho salmon. That’s a very complex mixture—our instrument sees more than 2,000 chemicals there. We had to just start separating it apart and isolating it into chemically simpler fractions. We just started to follow the toxicity as we kept separating and separating and separating. Eventually, we identified a chemical present in the tire leachate that was highly toxic to the coho salmon. We could then replicate the phenomena with a pure standard exposure.
TS: I’ve never heard of this chemical. What do we know about it?
EK: All tires need a number of preservative chemicals in them to make them durable, last longer, and be stronger. At least since the 1930s, it’s been known that ground level ozone—this little concentration of ozone in the air—really degrades tire rubbers. There’s always been compounds in tires that are designed to soak up the ozone before it can react with the tire rubber. This antioxidant chemical, 6PPD, was identified in the early-to-mid 1950s. I’m not exactly sure when it became widespread in tire manufacturing, but it’s one of the most abundant, if not the most abundant, antioxidant compound added to tires to soak up ozone. Essentially, what happens is the reaction product—what’s present after the ozone reaction—is what we were seeing in the tire leachate and what proved to be very toxic to the coho salmon.
Toxicology observations, meanwhile, were showing that among all these different possible sources of chemicals, the only one that killed coho salmon was tire rubber.
TS: In the grand scheme of factors that could be affecting fish populations—climate change or other known pollutants, for example—how big a threat does this novel chemical pose?
EK: I can’t answer that cleanly. It’s a big giant question that people devote their entire lives to. All struggling aquatic organisms often face multiple stressors, multiple threats, multiple difficulties. For systems where there’s roadway runoff contacting habitats that are important for coho salmon, this seems to be pretty important near Seattle. Some of the population modeling predicts localized extinction of coho from these exact creeks within 20 or 30 years because of this constant level of mortality in the returning fish. They just can’t sustain their population, and every year it gets smaller and smaller.
TS: In this study, you were focusing on the coho salmon. Is there indication that other species that interact with the runoff may also die from the tire runoff?
EK: We do know that in these same watersheds where coho salmon die, chum salmon and cutthroat trout co-occur, and they don’t seem to die from the same storms that kill the coho. That field data tells us that we can anticipate differences in species sensitivity. Beyond coho salmon, we just don’t know how sensitive other species are, so that’s work that requires follow-up study.
TS: What do you hope to do with these data, and do you hope that your study will inspire change in the way tires are produced in the future?
EK: Pretty immediately, what we’ll be doing is looking at these receiving waters, understanding the dynamics of this compound—how does it persist, what breaks it down, how much of it [there is], what its fate is out in the environment—so we have a lot of work to do just to understand the basic water quality elements of this compound now that we know about it.
Concurrently, I’m sure there’ll be a bunch of related toxicology studies understanding the biology of these exposures. We work to generate data hoping that we can improve problems and solve problems, and I certainly hope that we can have a conversation about chemical ingredients used in consumer products like tires that is linked to this type of work. I would anticipate people will think about whether or not this chemical is the best choice for the desired attributes in consumer products like tires.
Disposal of used tires is a giant materials-handling issue. Sustainable products are ones that we can reuse and recycle. For tires, they’re reused in playing fields, they’re mixed into asphalt, they’re used in building materials. To better enable sustainable products, we need to consider their end uses and their reuses as well. Chemical safety is very relevant for the decisions we make with respect to reuse. Enabling product sustainability comes from making sure everything in those products is environmentally benign and benign for people. That is an aspect of this finding that I think is important to think about.
TS: What personal significance does this work have for you?
EK: It’s a very motivating problem to work on. It’s devastating to me, all of my group, and all the people working on this to every single year see adult salmon dying when they return to spawn. I mean, these are really beautiful fish. If you went to the store, you might buy these fish. It’s very motivating for all of us to try and understand what it is that’s harming these fish because they really are that one percent of salmon which actually make it back to survive, and then they just can’t survive our water. All of my group is very motivated and excited by the prospect that we can improve our management of these important species.
E.P. Kolodziej et al., “A ubiquitous tire rubber–derived chemical induces acute mortality in coho salmon,” Science, doi:10.1126/science.abd6951, 2020.
Editor’s note: The interview was edited for brevity.


thescientist--2020-12-09--A Greener Recombinant Monoclonal Antibody

ZooMAb® recombinant monoclonal antibodies are a greener choice , with reduced animal involvement and low-waste , ice-free packaging .
To @ @ @ @ @

ZooMAb® recombinant monoclonal antibodies are a greener choice, with reduced animal involvement and low-waste, ice-free packaging. To learn more, visit SigmaAldrich.com/zoomab


thescientist--2020-12-09--Mystery Illness Cluster in India May Be Due to Neurotoxin

Over the weekend , the city of Eluru in southern India was slammed with a mysterious illness that has hospitalized more than 550 people with symptoms including a loss of consciousness , convulsions , seizures , and an unexplained giddiness .
The outbreak is unrelated to the current COVID-19 pandemic , as none of the patients had tested positive for the SARS-CoV-2 virus .
While there are preliminary hypotheses about the cause of the illness , no definitive cause has been named yet .
Beginning on December 5 , hundreds of people around the city began experiencing symptoms .
There @ @ @ @ @ @ @ as the patients lived in various areas around town , had different water sources , were unrelated to one another , and represented a wide range of ages , according to multiple news sources .
The Associated Press reports that the state of Andhra Pradesh , where Eluru is located , has been hit hard by the COVID-19 pandemic , with more than 800,000 cases to date .
However , none of the patients tested positive for that or any other viral disease , including mosquito-borne illnesses such as dengue fever and chikungunya @ @ @ @ @ @ @ Hindustan Times , the All India Institute of Medical Sciences found traces of lead and nickel in blood samples from some of the patients .
While heavy metals can have neurotoxic effects in the human body , there is not yet a clear source .
Waterways , milk , food sources , and other avenues of possible contamination have been tested so far , but no evidence has been found .
“ We have tentatively identified the primary cause of this strange phenomenon , but it is not yet clear what its source @ @ @ @ @ @ @ happened .
For instance , the chemicals were found in the bodies of the patients but not in either water or any other food substance , ” health commissioner Katamaneni Bhaskar tells the Times .
The majority of the patients have been released from the hospital , and the 84 who remain are expected to be discharged soon , according to The Indian Express .
A 45-year-old man is the only fatality among the patients , though he had a heart attack unrelated to his hospitalization .
Health officials from across the country @ @ @ @ @ @ @ Bhaskar tells the Times that he expects investigators will identify it within the next couple of days .

ABOVE: © ISTOCK.COM, REDDEES
Over the weekend, the city of Eluru in southern India was slammed with a mysterious illness that has hospitalized more than 550 people with symptoms including a loss of consciousness, convulsions, seizures, and an unexplained giddiness. The outbreak is unrelated to the current COVID-19 pandemic, as none of the patients had tested positive for the SARS-CoV-2 virus. While there are preliminary hypotheses about the cause of the illness, no definitive cause has been named yet.
Beginning on December 5, hundreds of people around the city began experiencing symptoms. There was no common thread between them, as the patients lived in various areas around town, had different water sources, were unrelated to one another, and represented a wide range of ages, according to multiple news sources.
The Associated Press reports that the state of Andhra Pradesh, where Eluru is located, has been hit hard by the COVID-19 pandemic, with more than 800,000 cases to date. However, none of the patients tested positive for that or any other viral disease, including mosquito-borne illnesses such as dengue fever and chikungunya, CNN adds.
According to the Hindustan Times, the All India Institute of Medical Sciences found traces of lead and nickel in blood samples from some of the patients. While heavy metals can have neurotoxic effects in the human body, there is not yet a clear source. Waterways, milk, food sources, and other avenues of possible contamination have been tested so far, but no evidence has been found.
“We have tentatively identified the primary cause of this strange phenomenon, but it is not yet clear what its source is and how and why it has happened. For instance, the chemicals were found in the bodies of the patients but not in either water or any other food substance,” health commissioner Katamaneni Bhaskar tells the Times.
The majority of the patients have been released from the hospital, and the 84 who remain are expected to be discharged soon, according to The Indian Express. A 45-year-old man is the only fatality among the patients, though he had a heart attack unrelated to his hospitalization.
Health officials from across the country continue to search for the culprit. Bhaskar tells the Times that he expects investigators will identify it within the next couple of days.


thescientist--2020-12-10--World's Largest Sand Island Devastated by Wildfire

ABOVE : Fire on K ’ gari-Fraser Island QUEENSLAND FIRE AND EMERGENCY SERVICES Wildfire has scorched around half of Fraser Island , a World Heritage site off the East coast of Australia , after starting from an illegal campfire .
There are concerns that the sand island ’ s unique rainforest ecosystems could be threatened as weather worsens .
Also known as K ’ gari by the local Butchulla people , who hold native title over the island , Fraser Island is the world ’ s largest sand island—76 miles long—but it is also home to rainforests and other ecosystems @ @ @ @ @ @ @ While some of the plant species need fire to regenerate , ecologist Gabriel Conroy of the University of the Sunshine Coast in Queensland says he is worried about the island ’ s fauna , from microbial communities all the way up to the island ’ s distinctive—and sometimes notorious—native dogs known as dingoes , which Conroy studies .
“ They ’ re very adaptable feeders but you ’ re talking about fifty percent of the island ’ s ecosystems and habitat wiped out in one hit , that ’ s significant , ” @ @ @ @ @ @ @ the genetics of the K ’ gari-Fraser Island dingo population , which is protected because the canines are considered the purest strain of dingo in eastern Australia , although they are not threatened or endangered .
He says he doesn ’ t believe the fire will directly impact dingoes but will likely reduce access to food sources .
The fire started in the northern part of the island , in what forest ecologist Grahame Applegate of University of the Sunshine Coast says are mostly so-called Wallum forests containing more fire-tolerant species such as @ @ @ @ @ @ @ rediscovering historical vegetation plots set up across the island ’ s ecosystems decades ago by park authorities to monitor changes in those habitats .
He says the wealth of data on vegetation changes over time from those plots will enable the study of the effect of fire and subsequent regeneration of the flora , if the fire does affect them .
The University of the Sunshine Coast operates a research centre on the island , which is further south of the fire front .
Applegate says he is concerned that hot northerly winds @ @ @ @ @ @ @ the more rainforest-type blackbutt eucalyptus forests , where there are large amounts of fuel to burn .
“ Once you start to get those high fuel loads , then things can change dramatically , ” he says .
Firefighters have been backburning in an effort to protect towns on the island , and water-bombing aircraft are being used to try to bring the fire under control .
The rainforests of southern Queensland have long been thought largely resistant to fire because of the level of moisture in them , says Christine Hosking , @ @ @ @ @ @ @ the University of Queensland .
“ But this is all changing now with climate change : the vegetation is so much hotter and so much drier .
.
.
so things that wouldn ’ t have traditionally burned are burning.
” And while many of K ’ gari-Fraser Island ’ s plant species are fire-adapted , Conroy warns that a fire of this magnitude on an island reduces the opportunities for species to either escape or for post-fire landscapes to be recolonized from nearby populations .
“ Although the northern half of the @ @ @ @ @ @ @ , there may be a pronounced shift in the way these ecosystems look in the future , ” he says .

ABOVE: Fire on K’gari-Fraser Island
QUEENSLAND FIRE AND EMERGENCY SERVICES
Wildfire has scorched around half of Fraser Island, a World Heritage site off the East coast of Australia, after starting from an illegal campfire. There are concerns that the sand island’s unique rainforest ecosystems could be threatened as weather worsens.
Also known as K’gari by the local Butchulla people, who hold native title over the island, Fraser Island is the world’s largest sand island—76 miles long—but it is also home to rainforests and other ecosystems, including numerous freshwater dune lakes.
While some of the plant species need fire to regenerate, ecologist Gabriel Conroy of the University of the Sunshine Coast in Queensland says he is worried about the island’s fauna, from microbial communities all the way up to the island’s distinctive—and sometimes notorious—native dogs known as dingoes, which Conroy studies.
“They’re very adaptable feeders but you’re talking about fifty percent of the island’s ecosystems and habitat wiped out in one hit, that’s significant,” he says. Conroy has been studying the genetics of the K’gari-Fraser Island dingo population, which is protected because the canines are considered the purest strain of dingo in eastern Australia, although they are not threatened or endangered. He says he doesn’t believe the fire will directly impact dingoes but will likely reduce access to food sources.
The fire started in the northern part of the island, in what forest ecologist Grahame Applegate of University of the Sunshine Coast says are mostly so-called Wallum forests containing more fire-tolerant species such as banksias and myrtles. Applegate has been rediscovering historical vegetation plots set up across the island’s ecosystems decades ago by park authorities to monitor changes in those habitats. He says the wealth of data on vegetation changes over time from those plots will enable the study of the effect of fire and subsequent regeneration of the flora, if the fire does affect them. The University of the Sunshine Coast operates a research centre on the island, which is further south of the fire front.
Applegate says he is concerned that hot northerly winds could push the fire south and into the more rainforest-type blackbutt eucalyptus forests, where there are large amounts of fuel to burn. “Once you start to get those high fuel loads, then things can change dramatically,” he says. Firefighters have been backburning in an effort to protect towns on the island, and water-bombing aircraft are being used to try to bring the fire under control.
A dingo (Canis dingo) resting on the foredunes on K’gari (Fraser Island). The iconic K’gari dingo population is lower in genetic diversity and has become genetically differentiated from its mainland counterparts. CODY JAMES
The rainforests of southern Queensland have long been thought largely resistant to fire because of the level of moisture in them, says Christine Hosking, a landscape ecologist and conservation biologist at the University of Queensland. “But this is all changing now with climate change: the vegetation is so much hotter and so much drier . . . so things that wouldn’t have traditionally burned are burning.”
And while many of K’gari-Fraser Island’s plant species are fire-adapted, Conroy warns that a fire of this magnitude on an island reduces the opportunities for fauna to either escape or for post-fire landscapes to be recolonized from nearby populations.
“Although the northern half of the island will bounce back in some capacity, there may be a pronounced shift in the way these ecosystems look in the future,” he says.


thescientist--2020-12-09--Tools for Infectious Disease Research

Tools for Infectious Disease Research

Infectious disease research involves understanding an array of physiological mechanisms , including infection routes , genomic adaptations , and innate @ @ @ @ @ Moreover , potential therapeutic discovery hinges on scientists ' ability to investigate these responses and @ @ @ @ @ .
Download this infographic from 10x Genomics to learn how single cell gene expression screening @ @ @ @ @ , and spatial gene expression profiling uncover the depths of infectious disease .

Infectious disease research involves understanding an array of physiological mechanisms, including infection routes, genomic adaptations, and innate and adaptive immune responses. Moreover, potential therapeutic discovery hinges on scientists' ability to investigate these responses and measure how interventions affect them.
Download this infographic from 10x Genomics to learn how single cell gene expression screening, single cell protein profiling, and spatial gene expression profiling uncover the depths of infectious disease.


thescientist--2020-12-09--RNA Interference Comes of Age

RNA Interference Comes of Age

ABOVE : A newly approved RNAi-based therapy reduces the overproduction of oxalate among people who have a rare genetic disorder .
The condition leads to kidney stones , which are formed by calcium oxalate crystals such as these , and tissue damage .
© ISTOCK.COM , TOEYTOEY2530 Last month , the US Food and Drug Administration approved lumasiran ( Oxlumo ) , a drug to treat a rare genetic disorder known as primary hyperoxaluria type 1 .
PH1 results in an overproduction of a substance known as oxalate by the liver , which can accumulate in the kidney and urinary @ @ @ @ @ @ @ effects , including kidney stones , widespread organ damage , and end-stage renal disease .
The only cure for PH1 is a liver transplant .
Lumasiran , which was developed by Cambridge , Massachusetts-based Alnylam Pharmaceuticals , is the first drug that reduces oxalate levels in patients , thus reducing the risk of complications later in life .
“ This is really the first treatment that medically can address the underlying effect of this disease , ” says Jeffrey Saland , a pediatric nephrologist at Mount Sinai Hospital in New York and an @ @ @ @ @ @ @ ’ s Phase 3 trials of lumasiran .
It ’ s also only the third drug of its kind to gain regulatory approval .
Lumasiran harnesses a naturally occurring process known as RNA interference ( RNAi ) , which hijacks the production of specific proteins by silencing mRNA , the genetic blueprints for proteins .
The drug reduces the levels of oxalate production in the liver by blocking mRNA that encodes for glycolate oxidase , an enzyme involved in the synthesis of oxalate , with a fragment of double-stranded RNA known as small-interfering @ @ @ @ @ @ @ two Phase 3 clinical trials for lumasiran—ILLUMINATE-A , a multinational , randomized , placebo-controlled trial of 39 patients ages six and older , and ILLUMINATE-B , an open-label study of 16 patients under six years old .
Patients in both trials had functioning kidneys .
In the first trial , they received three monthly injections followed by a maintenance dose every three months , while in the second , dosing regimens were adjusted to patients ’ weights .
After six months of treatment , lumasiran significantly lowered oxalate levels in both studies : @ @ @ @ @ @ @ the drug had a 65 percent reduction of oxalate in their urine on average , compared to a 12 percent reduction among those in the control group .
Patients in the second study exhibited an average of a 71 percent decrease .
No significant changes in kidney function or other clinical outcomes were seen during this period ( aside from early signs of improvement in nephrocalcinosis , the level of calcium deposits in the kidneys ) .
The company plans to continue to monitor patient outcomes in an extended , open label trial @ @ @ @ @ @ @ injection site reactions , which include symptoms such as redness , pain , and swelling .
There are two other FDA-approved RNAi therapies , and both belong to Alnylam .
Patisiran ( Onpattro ) , an RNAi treatment for a rare genetic disorder that causes buildup of the protein transthyretin in the nervous system , known as hereditary transthyretin amyloidosis , was approved in 2018 .
The second drug , givosiran ( Givlaari ) , for acute hepatic porphyria , a rare genetic condition that leads to the buildup of toxic polypyrin molecules @ @ @ @ @ @ @ three drugs are expensive—lumasiran , for example , is priced at $ 493,000 per patient per year , and patients will likely need to take the drug for life to keep oxalate levels low .
It took two decades from the initial discovery of RNAi for the first treatment using this technology to get past regulatory scrutiny , and the field faced numerous obstacles and setbacks along the way .
The approval of a third RNAi therapeutic “ is a huge milestone for the RNAi field , ” says Derek Dykxhoorn , a @ @ @ @ @ @ @ .
“ We ’ ve always seen the potential that this technology had—the ability to harness the cell ’ s own endogenous silencing mechanisms to be able to treat disease—but it ’ s been a long journey from those studies to actually having FDA-approved therapies.
” See “ The Second Coming of RNAi ” More than 20 years ago , biologists Andrew Fire and Craig Mello uncovered the process of RNAi in the roundworm Caenorhabditis elegans—a groundbreaking discovery that earned the pair the 2006 Nobel Prize in Physiology or Medicine .
The finding @ @ @ @ @ @ @ the early 2000s from researchers seeking to use RNAi as a technique for basic science and the development of therapeutics .
Because RNAi could , in theory , target the production of any disease-causing protein—as long as the sequence of the gene encoding it is known—scientists began investigating it as a weapon against a wide range of ailments , including rare genetic disorders , cancer , and infectious diseases .
Despite a deluge of research , the results of early clinical trials were disappointing ; low efficacy and harmful side effects meant treatments @ @ @ @ @ @ @ the first treatments to make it to a Phase 3 clinical trial—an RNAi therapeutic for macular degeneration from the Florida-based company OPKO Health—was shut down in 2009 after disappointing early results .
By 2010 , pharma began to turn away from this technique , with large companies such as Roche , Pfizer , and Merck shuttering their RNAi research programs .
Independent biotech consultant Dirk Haussecker described this period to The Scientist in 2014 as “ the era of doubts and despair.
” The main obstacle the field faced was figuring out how @ @ @ @ @ @ @ in the body at high enough concentrations to be therapeutically relevant , Dykxhoorn says .
A key issue is that siRNAs are readily degraded by enzymes in the bloodstream .
To address this issue , scientists focused on identifying ways of packaging siRNAs .
One of the first effective techniques involved coating them in droplets of fat called lipid nanoparticles ( LNPs ) .
But these LNPs had their limitations , says Phillip Zamore , director of the RNA Institute at the University of Massachusetts School of Medicine and cofounder of Alnylam .
@ @ @ @ @ @ @ that although the LNPs would accumulate in the liver because a lot of blood—which carries the RNAi payload—flows through it , they did not explicitly target that organ .
But what researchers wanted was a highly selective method of delivering the drug to tissues .
Alnylam developed another technique , dubbed GalNac , which involves linking a sugar , N-acetylgalactosamine , to the siRNA .
Receptors on the surface of liver cells recognize N-acetylgalactosamine , enabling the conjugated molecules to reach those cells with a high level of specificity while limiting off-target effects @ @ @ @ @ @ @ , including lumaisran , use this technology , and for that reason treatments for liver-related conditions have been the first to advance clinically .
“ It ’ s clear now that everyone is using some strategy that involves conjugating a ligand to an siRNA to get it to the tissue of interest , ” Zamore says .
“ For liver , it works incredibly well.
” To the liver and beyond With new , effective methods of delivery , the RNAi field began to finally see some successes , namely , Alnylam ’ @ @ @ @ @ @ @ Alnylam ’ s therapeutics is nearing the end of the pipeline : inclisiran , an RNAi treatment for high cholesterol that inhibits the liver ’ s production of PCSK9 , an enzyme involved in cholesterol metabolism .
( Alnylam designed inclisiran , but pharmaceutical giant Novartis has acquired the license for it . )
The regulatory approval of this drug , which the FDA is expected to announce this month , would mark another milestone : RNAi ’ s first success in treating a common condition .
“ I think everyone who follows @ @ @ @ @ @ @ s going to be approved , ” says Judy Lieberman , a professor of pediatrics at Harvard Medical School who studies the use of RNAi in cancer and infectious diseases .
“ The Phase three data are so incredibly strong.
” ( Lieberman is a former member of Alnylam ’ s scientific advisory board . )
Alnylam ’ s successes reveal that RNAi has become a platform technology , Zamore says .
“ We now know it ’ s possible to have a global strategy that can be applied to any disease where @ @ @ @ @ @ @ liver will provide clinical benefit.
” Other biotech companies , such as Dicerna Pharmaceuticals and Arrowhead Pharmaceuticals , also have several RNAi drugs in their pipelines .
Expanding beyond the liver is the next big test .
RNAi therapies with targets outside the liver have yet to make it far in clinical trials , according to Lieberman .
The GalNac technique is specific to liver cells , so in order to get to other organs , researchers need to find methods that can target other tissues in a similar way .
Many groups @ @ @ @ @ @ @ developing and testing various methods of getting siRNA to other tissues , such as attaching antibodies and aptamers that , like GalNac , are recognized by cell-surface receptors that are unique to particular tissues , or by using lipid conjugates that home in on specific tissues .
In addition to several more drugs in the pipeline for liver-related conditions , including other genetic conditions and infectious diseases such as hepatitis B , Alnylam also has therapies in development with targets outside the liver .
Currently , the company is also focused on developing @ @ @ @ @ @ @ nervous system and the eye , says Pritesh Gandhi , vice president and general manager of Alnylam ’ s lumasiran program .
“ There ’ s a lot more to come , ” Gandhi says .
“ This is just the beginning .
”

ABOVE: A newly approved RNAi-based therapy reduces the overproduction of oxalate among people who have a rare genetic disorder. The condition leads to kidney stones, which are formed by calcium oxalate crystals such as these, and tissue damage.
© ISTOCK.COM, TOEYTOEY2530
Last month, the US Food and Drug Administration approved lumasiran (Oxlumo), a drug to treat a rare genetic disorder known as primary hyperoxaluria type 1. PH1 results in an overproduction of a substance known as oxalate by the liver, which can accumulate in the kidney and urinary tract and cause a wide range of effects, including kidney stones, widespread organ damage, and end-stage renal disease.
The only cure for PH1 is a liver transplant. Lumasiran, which was developed by Cambridge, Massachusetts-based Alnylam Pharmaceuticals, is the first drug that reduces oxalate levels in patients, thus reducing the risk of complications later in life. “This is really the first treatment that medically can address the underlying effect of this disease,” says Jeffrey Saland, a pediatric nephrologist at Mount Sinai Hospital in New York and an investigator on ILLUMINATE-A, one of Alnylam’s Phase 3 trials of lumasiran. It’s also only the third drug of its kind to gain regulatory approval.
Lumasiran harnesses a naturally occurring process known as RNA interference (RNAi), which hijacks the production of specific proteins by silencing mRNA, the genetic blueprints for proteins. The drug reduces the levels of oxalate production in the liver by blocking mRNA that encodes for glycolate oxidase, an enzyme involved in the synthesis of oxalate, with a fragment of double-stranded RNA known as small-interfering RNA (siRNA).
The regulatory approval of another drug, which the FDA is expected to announce this month, would mark another milestone: RNAi’s first success in treating a common condition.
There were two Phase 3 clinical trials for lumasiran—ILLUMINATE-A, a multinational, randomized, placebo-controlled trial of 39 patients ages six and older, and ILLUMINATE-B, an open-label study of 16 patients under six years old. Patients in both trials had functioning kidneys. In the first trial, they received three monthly injections followed by a maintenance dose every three months, while in the second, dosing regimens were adjusted to patients’ weights.
After six months of treatment, lumasiran significantly lowered oxalate levels in both studies: in the first, patients who received the drug had a 65 percent reduction of oxalate in their urine on average, compared to a 12 percent reduction among those in the control group. Patients in the second study exhibited an average of a 71 percent decrease. No significant changes in kidney function or other clinical outcomes were seen during this period (aside from early signs of improvement in nephrocalcinosis, the level of calcium deposits in the kidneys). The company plans to continue to monitor patient outcomes in an extended, open label trial. The most common side effects were injection site reactions, which include symptoms such as redness, pain, and swelling.
There are two other FDA-approved RNAi therapies, and both belong to Alnylam. Patisiran (Onpattro), an RNAi treatment for a rare genetic disorder that causes buildup of the protein transthyretin in the nervous system, known as hereditary transthyretin amyloidosis, was approved in 2018. The second drug, givosiran (Givlaari), for acute hepatic porphyria, a rare genetic condition that leads to the buildup of toxic polypyrin molecules, received approval in 2019. All three drugs are expensive—lumasiran, for example, is priced at $493,000 per patient per year, and patients will likely need to take the drug for life to keep oxalate levels low.
It took two decades from the initial discovery of RNAi for the first treatment using this technology to get past regulatory scrutiny, and the field faced numerous obstacles and setbacks along the way. The approval of a third RNAi therapeutic “is a huge milestone for the RNAi field,” says Derek Dykxhoorn, a molecular geneticist at the University of Miami. “We’ve always seen the potential that this technology had—the ability to harness the cell’s own endogenous silencing mechanisms to be able to treat disease—but it’s been a long journey from those studies to actually having FDA-approved therapies.”
See “The Second Coming of RNAi”
Boom and bust
More than 20 years ago, biologists Andrew Fire and Craig Mello uncovered the process of RNAi in the roundworm Caenorhabditis elegans—a groundbreaking discovery that earned the pair the 2006 Nobel Prize in Physiology or Medicine. The finding also generated a surge of interest in the early 2000s from researchers seeking to use RNAi as a technique for basic science and the development of therapeutics.
Because RNAi could, in theory, target the production of any disease-causing protein—as long as the sequence of the gene encoding it is known—scientists began investigating it as a weapon against a wide range of ailments, including rare genetic disorders, cancer, and infectious diseases.
Despite a deluge of research, the results of early clinical trials were disappointing; low efficacy and harmful side effects meant treatments failed to progress far. One of the first treatments to make it to a Phase 3 clinical trial—an RNAi therapeutic for macular degeneration from the Florida-based company OPKO Health—was shut down in 2009 after disappointing early results. By 2010, pharma began to turn away from this technique, with large companies such as Roche, Pfizer, and Merck shuttering their RNAi research programs. Independent biotech consultant Dirk Haussecker described this period to The Scientist in 2014 as “the era of doubts and despair.”
RNAi therapies with targets outside the liver have yet to make it far in clinical trials.
The main obstacle the field faced was figuring out how to deliver siRNAs to the right cells in the body at high enough concentrations to be therapeutically relevant, Dykxhoorn says. A key issue is that siRNAs are readily degraded by enzymes in the bloodstream. To address this issue, scientists focused on identifying ways of packaging siRNAs. One of the first effective techniques involved coating them in droplets of fat called lipid nanoparticles (LNPs). But these LNPs had their limitations, says Phillip Zamore, director of the RNA Institute at the University of Massachusetts School of Medicine and cofounder of Alnylam. One drawback, he explains, was that although the LNPs would accumulate in the liver because a lot of blood—which carries the RNAi payload—flows through it, they did not explicitly target that organ. But what researchers wanted was a highly selective method of delivering the drug to tissues.
Alnylam developed another technique, dubbed GalNac, which involves linking a sugar, N-acetylgalactosamine, to the siRNA. Receptors on the surface of liver cells recognize N-acetylgalactosamine, enabling the conjugated molecules to reach those cells with a high level of specificity while limiting off-target effects. Many of Alnylam’s therapeutics, including lumasiran, use this technology, and for that reason treatments for liver-related conditions have been the first to advance clinically. “It’s clear now that everyone is using some strategy that involves conjugating a ligand to an siRNA to get it to the tissue of interest,” Zamore says. “For liver, it works incredibly well.”
See “Oligonucleotide Therapeutics Near Approval”
To the liver and beyond
With new, effective methods of delivery, the RNAi field began to finally see some successes, namely, Alnylam’s three approved drugs. Another of Alnylam’s therapeutics is nearing the end of the pipeline: inclisiran, an RNAi treatment for high cholesterol that inhibits the liver’s production of PCSK9, an enzyme involved in cholesterol metabolism. (Alnylam designed inclisiran, but pharmaceutical giant Novartis has acquired the license for it.) The regulatory approval of this drug, which the FDA is expected to announce this month, would mark another milestone: RNAi’s first success in treating a common condition.
“I think everyone who follows this field is certain that it’s going to be approved,” says Judy Lieberman, a professor of pediatrics at Harvard Medical School who studies the use of RNAi in cancer and infectious diseases. “The Phase three data are so incredibly strong.” (Lieberman is a former member of Alnylam’s scientific advisory board.)
Alnylam’s successes reveal that RNAi has become a platform technology, Zamore says. “We now know it’s possible to have a global strategy that can be applied to any disease where reducing the concentration of something in the liver will provide clinical benefit.” Other biotech companies, such as Dicerna Pharmaceuticals and Arrowhead Pharmaceuticals, also have several RNAi drugs in their pipelines.
Expanding beyond the liver is the next big test. RNAi therapies with targets outside the liver have yet to make it far in clinical trials, according to Lieberman. The GalNac technique is specific to liver cells, so in order to get to other organs, researchers need to find methods that can target other tissues in a similar way. Many groups, including Lieberman’s, are developing and testing various methods of getting siRNA to other tissues, such as attaching antibodies and aptamers that, like GalNac, are recognized by cell-surface receptors that are unique to particular tissues, or by using lipid conjugates that home in on specific tissues.
In addition to several more drugs in the pipeline for liver-related conditions, including other genetic conditions and infectious diseases such as hepatitis B, Alnylam also has therapies in development with targets outside the liver. Currently, the company is also focused on developing RNAi treatments that work in the central nervous system and the eye, says Pritesh Gandhi, vice president and general manager of Alnylam’s lumasiran program.
“There’s a lot more to come,” Gandhi says. “This is just the beginning.”


thescientist--2020-12-09--A Full View of the Immune System

A Full View of the Immune System

Multiomic cytometry combines the power of single-cell RNA sequencing with the profiling ability of flow cytometry .
Using antibodies conjugated @ @ @ @ @ characterize multiple cell surface proteins at once in complex cell suspensions .
Combined with gene @ @ @ @ @ a comprehensive view of immune system complexity with improved single-cell resolution .
Download this infographic @ @ @ @

Multiomic cytometry combines the power of single-cell RNA sequencing with the profiling ability of flow cytometry. Using antibodies conjugated with DNA barcodes, researchers characterize multiple cell surface proteins at once in complex cell suspensions. Combined with gene expression data, immunologists gain a comprehensive view of immune system complexity with improved single-cell resolution.
Download this infographic from 10x Genomics to
Learn how multiomic cytometry demystifies the complex immune system
Discover multiomic cytometry combined with
- Single-cell RNA sequencing
- Cell surface protein detection
- Immune repertoire profiling
- Antigen specificity measurements
- - Cell surface protein detection - Immune repertoire profiling - Antigen specificity measurements Compare multiomic cytometry to other techniques