thescientist--2020-11-19--Mosquitos in Asia and the Americas More Susceptible to Zika Virus

ABOVE : Females of the globally invasive ( right ) and African ( left ) subspecies of the mosquito Aedes aegypti GREG MURRAY , LOUIS LAMBRECHTS According to the World Health Organization , Zika virus was first isolated from an infected monkey in Uganda in 1947 , but there have only been sporadic cases across the African continent since .
In contrast , thousands of people in the Americas and Asia were infected in multiple outbreaks since 2007 .
During the worst , in 2016 , the virus spread to more than 60 countries and was implicated in some 5,000 @ @ @ @ @ @ @ which a baby ’ s head is much smaller than expected .
The authors of a study published today ( November 19 ) in Science offer a possible explanation for the devastation Zika has caused outside of African countries .
They show that the subspecies of the mosquito vector , Aedes aegypti , that lives in close proximity with people in the tropical urban areas of Asia and the Americas is more likely to both contract and transmit the Zika virus than the subspecies more prevalent in Africa .
“ It ’ s @ @ @ @ @ @ @ populations differ in their susceptibility to human disease-causing virus , ” says Jeffrey Powell , a mosquito geneticist at Yale University who was not involved in the study .
Aedes aegypti formosus ( Aaf ) lives in both forests and urban settings in sub-Saharan Africa and takes blood meals from a variety of vertebrates , including people .
Aedes aegypti aegypti ( Aaa ) , which is thought to have evolved from a shared ancestor , preferentially bites and lives alongside people—often in urban settings where females lay eggs in containers , such @ @ @ @ @ @ @ have shown that the two subspecies can be distinguished based on their genomes and can interbreed .
Aaa is present in some coastal African countries , but invaded other parts of the world starting in the 1500s when international trade flourished .
Nowadays , the subspecies lives on every continent but Antarctica and is the primary vector for the viruses that cause dengue , yellow fever , and Zika , which can cause rashes , muscle pain , mild fever , and , in severe cases , microcephaly and other problems in developing @ @ @ @ @ @ @ mosquitoes and their interactions with viruses at the Institut Pasteur in Paris , and his team started to focus on Zika virus several years ago .
They were interested in why Zika virus is not a problem to the same extent everywhere in the world and whether or not Aaa mosquito evolution affected its ability to transmit viruses .
While it was clear that this subspecies had adapted to live with humans , he says , it wasn ’ t known if “ this adaptation to the domestic environment was accompanied by a @ @ @ @ @ @ @ the virus.
” The researchers fed each of eight groups of mosquitoes originally collected from Africa , the Americas , and Asia blood meals spiked with one of six strains of Zika virus .
They determined the mosquitoes gathered from the Americas and Asia required a lower viral titer to become infected than did the insects from Africa .
Then , they measured the susceptibility of eight mosquito populations collected from across Africa to two Zika virus strains .
The insects from coastal Senegal , where the Aaa and Aaf subspecies are likely @ @ @ @ @ @ @ of virus in an artificial blood meal to become infected .
The authors also showed that the Aaa subspecies was more susceptible than the African subspecies to a Zika infection after feeding on an infected animal—in this case , a mouse .
Aaa mosquitoes were also more likely than their counterparts to have live virus in their saliva after infection , meaning that Aaa is not only more susceptible to virus infection , but also prone to subsequently transmit the Zika virus when feeding on a person .
Finally , Lambrechts and colleagues @ @ @ @ @ @ @ that a gene or genes located on the second mosquito chromosome are likely to contribute to the difference in Zika susceptibility between the two strains .
The authors make a robust link between the mosquito “ domestication process and .
.
.
what that allowed , in terms of the emergence and then subsequent pandemic spread of Zika virus across the Americas , ” says Moritz Kraemer , an infectious disease researcher at the University of Oxford who was not involved in the work .
“ They ’ re answering some of these @ @ @ @ @ @ @ higher in the Americas and in parts of Asia than it is in many parts of Africa.
” “ There may be other explanations , ” Lambrechts says , but the differences in susceptibility between these two subspecies may contribute to the lack of major outbreaks in Africa .
Another possibility to consider , though not a mutually exclusive hypothesis , says Powell , is that genetic changes in the virus allowed it to specialize and become more infective in the populations of mosquitoes outside of Africa .
“ These viruses are RNA-based @ @ @ @ @ @ @ rates , and they have very short generation times , so they can adapt very rapidly , ” he adds .
“ Between the mosquito and the virus , the virus has the advantage of being able to evolve much faster.
” The authors accounted for the possible influence of viral genetic variation by considering a panel of seven Zika virus strains , says Lambrechts .
“ The African mosquitoes were less susceptible to Zika virus infection than the non-African ones regardless of the virus strain .
Thus , our conclusions about the @ @ @ @ @ @ @ subspecies transcend the genetic diversity of viruses.
” That said , he acknowledges that there could be a contribution from both the mosquito diversity and the virus diversity side .
His group recently showed in a preprint that there is natural variation in transmissibility and pathogenicity between Zika virus strains from different places .

ABOVE: Females of the globally invasive (right) and African (left) subspecies of the mosquito Aedes aegypti
GREG MURRAY, LOUIS LAMBRECHTS
According to the World Health Organization, Zika virus was first isolated from an infected monkey in Uganda in 1947, but there have only been sporadic cases across the African continent since. In contrast, thousands of people in the Americas and Asia were infected in multiple outbreaks since 2007. During the worst, in 2016, the virus spread to more than 60 countries and was implicated in some 5,000 cases of microcephaly—a severe birth defect in which a baby’s head is much smaller than expected.
The authors of a study published today (November 19) in Science offer a possible explanation for the devastation Zika has caused outside of African countries. They show that the subspecies of the mosquito vector, Aedes aegypti, that lives in close proximity with people in the tropical urban areas of Asia and the Americas is more likely to both contract and transmit the Zika virus than the subspecies more prevalent in Africa.
“It’s the first really convincing demonstration that these populations differ in their susceptibility to human disease-causing virus,” says Jeffrey Powell, a mosquito geneticist at Yale University who was not involved in the study.
Aedes aegypti formosus (Aaf) lives in both forests and urban settings in sub-Saharan Africa and takes blood meals from a variety of vertebrates, including people. Aedes aegypti aegypti (Aaa), which is thought to have evolved from a shared ancestor, preferentially bites and lives alongside people—often in urban settings where females lay eggs in containers, such as buckets and old tires. Comparisons have shown that the two subspecies can be distinguished based on their genomes and can interbreed.
Aaa is present in some coastal African countries, but invaded other parts of the world starting in the 1500s when international trade flourished. Nowadays, the subspecies lives on every continent but Antarctica and is the primary vector for the viruses that cause dengue, yellow fever, and Zika, which can cause rashes, muscle pain, mild fever, and, in severe cases, microcephaly and other problems in developing fetuses.
Louis Lambrechts, who studies mosquitoes and their interactions with viruses at the Institut Pasteur in Paris, and his team started to focus on Zika virus several years ago. They were interested in why Zika virus is not a problem to the same extent everywhere in the world and whether or not Aaa mosquito evolution affected its ability to transmit viruses. While it was clear that this subspecies had adapted to live with humans, he says, it wasn’t known if “this adaptation to the domestic environment was accompanied by a change in its intrinsic ability to acquire the virus.”
The researchers fed each of eight groups of mosquitoes originally collected from Africa, the Americas, and Asia blood meals spiked with one of six strains of Zika virus. They determined the mosquitoes gathered from the Americas and Asia required a lower viral titer to become infected than did the insects from Africa. Then, they measured the susceptibility of eight mosquito populations collected from across Africa to two Zika virus strains. The insects from coastal Senegal, where the Aaa and Aaf subspecies are likely to mix, needed the lowest dose of virus in an artificial blood meal to become infected.
The authors also showed that the Aaa subspecies was more susceptible than the African subspecies to a Zika infection after feeding on an infected animal—in this case, a mouse. Aaa mosquitoes were also more likely than their counterparts to have live virus in their saliva after infection, meaning that Aaa is not only more susceptible to virus infection, but also prone to subsequently transmit the Zika virus when feeding on a person.
Finally, Lambrechts and colleagues crossed African and non-African mosquitoes and showed that a gene or genes located on the second mosquito chromosome are likely to contribute to the difference in Zika susceptibility between the two strains.
The authors make a robust link between the mosquito “domestication process and . . . what that allowed, in terms of the emergence and then subsequent pandemic spread of Zika virus across the Americas,” says Moritz Kraemer, an infectious disease researcher at the University of Oxford who was not involved in the work. “They’re answering some of these questions as to why transmission is much higher in the Americas and in parts of Asia than it is in many parts of Africa.”
“There may be other explanations,” Lambrechts says, but the differences in susceptibility between these two subspecies may contribute to the lack of major outbreaks in Africa.
Another possibility to consider, though not a mutually exclusive hypothesis, says Powell, is that genetic changes in the virus allowed it to specialize and become more infective in the populations of mosquitoes outside of Africa. “These viruses are RNA-based viruses. They have very high mutation rates, and they have very short generation times, so they can adapt very rapidly,” he adds. “Between the mosquito and the virus, the virus has the advantage of being able to evolve much faster.”
The authors accounted for the possible influence of viral genetic variation by considering a panel of seven Zika virus strains, says Lambrechts. “The African mosquitoes were less susceptible to Zika virus infection than the non-African ones regardless of the virus strain. Thus, our conclusions about the differential Zika virus susceptibility of Aedes aegypti subspecies transcend the genetic diversity of viruses.”
That said, he acknowledges that there could be a contribution from both the mosquito diversity and the virus diversity side. His group recently showed in a preprint that there is natural variation in transmissibility and pathogenicity between Zika virus strains from different places.
F. Aubry et al., “Enhanced Zika virus susceptibility of globally invasive Aedes aegypti populations,” Science, doi:10.1126/science.abd3663, 2020.


thescientist--2020-11-19--Giant Viruses Can Integrate into the Genomes of Their Hosts

ABOVE : Scientists have found evidence that giant viruses integrate their genomes into that of their hosts , such as this species of Chlorella , a single-celled green algae .
©ISTOCK.COM , SINHYU In the ultimate game of genetic hide and seek , scientists at Virginia Tech have identified several instances in which they found giant virus genomes embedded—some in their entirety—in the genomes of their hosts .
The results , published today ( November 18 ) in Nature , suggest that such integration by giant viruses may be more common than previously believed and that these viruses are likely @ @ @ @ @ @ @ eukaryotes .
“ We always assumed that [ giant viruses ] that can integrate into host genomes were not common , ” Karen Weynberg , a virologist at the University of Queensland in Australia who was not involved in the work , tells The Scientist .
“ Now they ’ ve shown that these viruses are able to integrate on a much wider scope than we ever really perceived .
It ’ s going to be groundbreaking , and I think people will be looking more into where these viruses are popping up.
@ @ @ @ @ @ @ they tend to be about 10 times larger than the average virus , have challenged traditional ideas in virology since their discovery in 2003 .
In addition to their unusually large size , their genomes sometimes include genetic contributions from bacteria and eukaryotes , including metabolic genes .
Because of this , “ they don ’ t necessarily look viral ” at the genomic level , says Frank Aylward , a virologist at Virginia Tech and a coauthor of the study .
Towards the beginning of his postdoc in Aylward ’ s lab @ @ @ @ @ @ @ searching for a handful of giant virus marker genes in all genomes accessible through the National Center for Biotechnology Information ’ s many databases—an exploratory exercise to see what came back .
While most of the genes appeared in genomes labeled as viruses , Moniruzzaman says he was surprised by how many of these giant virus genes appeared in genomes labeled as belonging to microscopic marine phytoplankton .
Aylward and Moniruzzaman first thought they might be picking up contamination .
But when they looked more closely , they noticed genetic signals suggesting parts @ @ @ @ @ @ @ the genomes of their hosts .
Following up on this hypothesis , the team went looking for systematic evidence of this integration in 65 publicly available green algae genomes , some of which are known to be hosts to giant viruses .
Moniruzzaman and his colleagues developed a bioinformatics tool , called ViralRecall , to identify regions in algal genomes suspected of having a viral origin based on several cues .
For example , they used the tool to scan for certain viral hallmark genes , clear demarcations between the two genomes , @ @ @ @ @ @ @ and the presence of noncoding introns and large duplications within the integrated viral sequences thought to be caused by the host ’ s molecular machinery .
The researchers identified 18 examples of “ giant endogenous viral elements ” ( GEVEs ) within a dozen host genomes , meaning that some hosts had more than one of these GEVEs integrated into their genetic code .
In some cases , the viral contributions were fragmented , representing only a small fraction of the virus genome .
But in two samples , the entire viral genome @ @ @ @ @ @ @ the phytoplankton , making up as much as 10 percent of the host ’ s genes .
Overall , these GEVEs contributed between 78 and 1,782 genes .
“ This essentially opens up a large conduit of horizontal gene transfer from viruses into eukaryotes , ” Aylward says .
“ All sorts of possibilities open up once you see these huge cases of endogenization.
” Using a phylogenetic analysis , Moniruzzaman was able to trace the GEVEs back to members of the Phycodnaviridae and Mimiviridae families , two diverse groups that have informed @ @ @ @ @ @ @ viruses .
The first discovery alerting scientists to their existence , for example , was of a mimivirus isolated from a cooling tower in England .
Taken together , the results suggest that endogenization by giant viruses may be more common than previously thought .
“ The idea that they built this new tool and then saw so many cases of this , even with just that first , somewhat limited scan , is pretty surprising , ” says Nels Elde , an evolutionary geneticist at the University of Utah who was not @ @ @ @ @ @ @ They ’ ve built a somewhat circumstantial case , but with several lines of complementary evidence that look pretty strong.
” Elde urges caution in accepting the team ’ s analysis of duplications in the integrated viral genome as evidence of endogenization .
Previous work , including his own on poxviruses ( whose status as a giant virus is debated ) , has shown that viruses are capable of carrying out rapid , large-scale gene duplications themselves without a host .
In the paper , the authors stress that they found many more @ @ @ @ @ @ @ comparisons .
A next step could involve looking more broadly across the tree of life .
Scientists are unsure exactly how many different organisms these viruses can infect , but the green algae targeted in this study , in the phylum Chlorophyta , share a common ancestor with modern land plants .
Another step , both Weynberg and Elde say , should be studies into whether these introduced viral genes bring functional changes to the hosts .
Roughly 10 percent of the human genome , for example , is thought to be derived @ @ @ @ @ @ @ their genes have been coopted in reproduction and brain function .
“ I like the fact that this paper really focuses on the influence of viruses in shaping their hosts ’ genomes that then spills into the evolution of the host as well , ” Weynberg says .
“ Once these viruses become integrated into host genomes and persist across generations , it starts to confer benefits as well .
That really highlights this intimacy that viruses have with their hosts .
”

ABOVE: Scientists have found evidence that giant viruses integrate their genomes into that of their hosts, such as this species of Chlorella, a single-celled green algae.
©ISTOCK.COM, SINHYU
In the ultimate game of genetic hide and seek, scientists at Virginia Tech have identified several instances in which they found giant virus genomes embedded—some in their entirety—in the genomes of their hosts. The results, published today (November 18) in Nature, suggest that such integration by giant viruses may be more common than previously believed and that these viruses are likely an underappreciated source of genetic diversity in eukaryotes.
“We always assumed that [giant viruses] that can integrate into host genomes were not common,” Karen Weynberg, a virologist at the University of Queensland in Australia who was not involved in the work, tells The Scientist. “Now they’ve shown that these viruses are able to integrate on a much wider scope than we ever really perceived. It’s going to be groundbreaking, and I think people will be looking more into where these viruses are popping up.”
Giant viruses, so named because they tend to be about 10 times larger than the average virus, have challenged traditional ideas in virology since their discovery in 2003. In addition to their unusually large size, their genomes sometimes include genetic contributions from bacteria and eukaryotes, including metabolic genes. Because of this, “they don’t necessarily look viral” at the genomic level, says Frank Aylward, a virologist at Virginia Tech and a coauthor of the study.
See “New Giant Viruses Break Records”
Towards the beginning of his postdoc in Aylward’s lab, Mohammad “Monir” Moniruzzaman went searching for a handful of giant virus marker genes in all genomes accessible through the National Center for Biotechnology Information’s many databases—an exploratory exercise to see what came back. While most of the genes appeared in genomes labeled as viruses, Moniruzzaman says he was surprised by how many of these giant virus genes appeared in genomes labeled as belonging to microscopic marine phytoplankton.
Aylward and Moniruzzaman first thought they might be picking up contamination. But when they looked more closely, they noticed genetic signals suggesting parts of the viruses had been incorporated into the genomes of their hosts. Following up on this hypothesis, the team went looking for systematic evidence of this integration in 65 publicly available green algae genomes, some of which are known to be hosts to giant viruses.
The giant virus Ostreococcus tauri virus (OtV-1) infects its host Ostreococcus tauri, the smallest known free-living eukaryote. The arrow points to the attachment site for host cell absorption. karen weynberg
Moniruzzaman and his colleagues developed a bioinformatics tool, called ViralRecall, to identify regions in algal genomes suspected of having a viral origin based on several cues. For example, they used the tool to scan for certain viral hallmark genes, clear demarcations between the two genomes, shared genes between virus and host, and the presence of noncoding introns and large duplications within the integrated viral sequences thought to be caused by the host’s molecular machinery.
The researchers identified 18 examples of “giant endogenous viral elements” (GEVEs) within a dozen host genomes, meaning that some hosts had more than one of these GEVEs integrated into their genetic code. In some cases, the viral contributions were fragmented, representing only a small fraction of the virus genome. But in two samples, the entire viral genome appears to have made the jump into the phytoplankton, making up as much as 10 percent of the host’s genes. Overall, these GEVEs contributed between 78 and 1,782 genes.
“This essentially opens up a large conduit of horizontal gene transfer from viruses into eukaryotes,” Aylward says. “All sorts of possibilities open up once you see these huge cases of endogenization.”
Using a phylogenetic analysis, Moniruzzaman was able to trace the GEVEs back to members of the Phycodnaviridae and Mimiviridae families, two diverse groups that have informed much of what is known about giant viruses. The first discovery alerting scientists to their existence, for example, was of a mimivirus isolated from a cooling tower in England.
Taken together, the results suggest that endogenization by giant viruses may be more common than previously thought. “The idea that they built this new tool and then saw so many cases of this, even with just that first, somewhat limited scan, is pretty surprising,” says Nels Elde, an evolutionary geneticist at the University of Utah who was not involved in the current work. “They’ve built a somewhat circumstantial case, but with several lines of complementary evidence that look pretty strong.”
Elde urges caution in accepting the team’s analysis of duplications in the integrated viral genome as evidence of endogenization. Previous work, including his own on poxviruses (whose status as a giant virus is debated), has shown that viruses are capable of carrying out rapid, large-scale gene duplications themselves without a host. In the paper, the authors stress that they found many more duplications in endogenized viruses than in free-living comparisons.
A next step could involve looking more broadly across the tree of life. Scientists are unsure exactly how many different organisms these viruses can infect, but the green algae targeted in this study, in the phylum Chlorophyta, share a common ancestor with modern land plants.
Another step, both Weynberg and Elde say, should be studies into whether these introduced viral genes bring functional changes to the hosts. Roughly 10 percent of the human genome, for example, is thought to be derived from endogenous retroviruses, and some of their genes have been coopted in reproduction and brain function.
“I like the fact that this paper really focuses on the influence of viruses in shaping their hosts’ genomes that then spills into the evolution of the host as well,” Weynberg says. “Once these viruses become integrated into host genomes and persist across generations, it starts to confer benefits as well. That really highlights this intimacy that viruses have with their hosts.”
See “Viruses Reconsidered”


thescientist--2020-11-20--Alzheimer's-Linked Mutation Causes Blockages in Neurons

The ongoing search for effective treatments for Alzheimer ’ s disease has focused on aggregates of amyloid-β peptides , which are the hallmark of the disease .
However , efforts to inhibit one of the proteins responsible for producing amyloid-β , called BACE1 , have led to several failed Phase 3 clinical trials .
But researchers aren ’ t giving up hope .
A study published in Science Translational Medicine on November 18 reveals how variants in a gene called GGA3—which are a known risk factor for developing Alzheimer ’ s—alter BACE1 movement through brain cells in culture and in @ @ @ @ @ @ @ BACE1 protein and creates axonal damage similar to that seen in the pre-symptomatic stages of Alzheimer ’ s disease .
This could mean BACE1 inhibitors still have promise as a treatment if used much earlier in the disease process .
“ I think the core message from this paper is that this could be one additional primary pathogenic development that precedes amyloid plaques buildup , ” says Henrik Zetterberg , a neuroscientist at the University of Gothenburg in Sweden who was not involved in the research .
“ What causes amyloid buildup ?
@ @ @ @ @ @ @ That is pretty much unknown .
We have the risk genes , of course , but this paper gives another very interesting piece of the puzzle of what might cause neurodysfunction in Alzheimer ’ s disease and could also cause amyloid buildup.
” Genetic studies have found that rare mutations in GGA3 increase the risk of Alzheimer ’ s disease .
In previous research , the authors of the current study identified the role of the GGA3 protein in transporting BACE1 in non-neuronal cell lines .
BACE1 is a protease responsible for cleaving @ @ @ @ @ @ @ peptides that accumulate into plaques in Alzheimer ’ s .
This new paper is the first demonstration of the consequences of GGA3 dysfunction on BACE1 in cultured neurons and mice .
“ One of the big gaps that we have is taking the genetics , the biochemistry , the pathology , and putting it into a cell biological context .
I think there ’ s a really critical need to understand where in the cell all of this biochemistry takes place , ” says Shawn Ferguson , a cell biologist from Yale University @ @ @ @ @ @ @ .
“ That ’ s where this paper is interesting , because it ’ s focusing on where these proteins may encounter one another , what may regulate the movement of these proteins in the axon , and how all of this could influence the proteolytic processing of APP.
” The researchers found that deletion of the GGA3 gene or mutations found in people reduce the trafficking of BACE1 through the axons .
BACE1 then builds up in the axons , causing them to swell .
This swelling could explain the damage seen @ @ @ @ @ @ @ axonal pathology can be detected in the human brain in the early stage of Alzheimer ’ s disease , ” says lead author Giuseppina Tesco , a neuroscientist at Tufts University .
“ If a patient doesn ’ t have the GGA3 mutation , it ’ s still possible that defects in axonal pathology are caused by other genes .
It is still valuable to know that once you have axonal pathology early , BACE accumulation could be a factor .
So these mechanisms can apply more generally.
” Phase 3 clinical trials @ @ @ @ @ @ @ activity of BACE1 were abandoned , because they often caused side effects that made memory and thinking worse for people with Alzheimer ’ s disease .
It is thought that side effects from BACE1 inhibition result from stopping its other functions in the brain .
In this new study , the researchers found that inhibiting the activity of BACE1 prevented the swelling seen in neurons without any functional GGA3 protein .
Tesco suggests that using a lower dose of BACE1 inhibitors at an early stage of Alzheimer ’ s could be an effective @ @ @ @ @ @ @ disease .
“ The clinical trials that have been conducted , they had a pharmacological inhibition of BACE activity , up to ninety percent in some cases .
So I think that what we learned is that probably we need to inhibit BACE to a lesser extent , ” says Tesco .
The earliest damage to the neurons happens up to 20 years before the appearance of the clinical symptoms of Alzheimer ’ s disease , according to Tesco , so any treatment to prevent this would need to be given over a @ @ @ @ @ @ @ for the benefits of longer , weaker inhibition of BACE1 from studies of a genetic mutation found in the Icelandic population .
The mutation reduces the ability of BACE1 to produce amyloid-β by about 20 percent and lowers the risk of developing Alzheimer ’ s disease .
“ It looks like a small reduction over a very long time seems to be good enough , ” Tesco says .
S. Lomoio et al.
, “ Gga3 deletion and a GGA3 rare variant associated with late onset Alzheimer ’ s disease trigger BACE1 accumulation @ @ @ @ @ @ @ Med , doi:10.1126/scitranslmed.aba1871 , 2020 .

Pharmacological inhibition of BACE prevents the formation of Alzheimer’s disease-like axonal pathology in cultured neurons (top) and in the mouse brain (lower panels). Dr. Selene Lomoio, Tesco Laboratory, Tufts University
The ongoing search for effective treatments for Alzheimer’s disease has focused on aggregates of amyloid-β peptides, which are the hallmark of the disease. However, efforts to inhibit one of the proteins responsible for producing amyloid-β, called BACE1, have led to several failed Phase 3 clinical trials.
But researchers aren’t giving up hope. A study published in Science Translational Medicine on November 18 reveals how variants in a gene called GGA3—which are a known risk factor for developing Alzheimer’s—alter BACE1 movement through brain cells in culture and in mice. This causes the buildup of BACE1 protein and creates axonal damage similar to that seen in the pre-symptomatic stages of Alzheimer’s disease. This could mean BACE1 inhibitors still have promise as a treatment if used much earlier in the disease process.
“I think the core message from this paper is that this could be one additional primary pathogenic development that precedes amyloid plaques buildup,” says Henrik Zetterberg, a neuroscientist at the University of Gothenburg in Sweden who was not involved in the research. “What causes amyloid buildup? What are the primary pathogenic processes? That is pretty much unknown. We have the risk genes, of course, but this paper gives another very interesting piece of the puzzle of what might cause neurodysfunction in Alzheimer’s disease and could also cause amyloid buildup.”
Genetic studies have found that rare mutations in GGA3 increase the risk of Alzheimer’s disease. In previous research, the authors of the current study identified the role of the GGA3 protein in transporting BACE1 in non-neuronal cell lines. BACE1 is a protease responsible for cleaving the protein APP to produce the amyloid-β peptides that accumulate into plaques in Alzheimer’s. This new paper is the first demonstration of the consequences of GGA3 dysfunction on BACE1 in cultured neurons and mice.
“One of the big gaps that we have is taking the genetics, the biochemistry, the pathology, and putting it into a cell biological context. I think there’s a really critical need to understand where in the cell all of this biochemistry takes place,” says Shawn Ferguson, a cell biologist from Yale University who was not involved in the research. “That’s where this paper is interesting, because it’s focusing on where these proteins may encounter one another, what may regulate the movement of these proteins in the axon, and how all of this could influence the proteolytic processing of APP.”
The researchers found that deletion of the GGA3 gene or mutations found in people reduce the trafficking of BACE1 through the axons. BACE1 then builds up in the axons, causing them to swell. This swelling could explain the damage seen in patients’ brains.
“This axonal pathology can be detected in the human brain in the early stage of Alzheimer’s disease,” says lead author Giuseppina Tesco, a neuroscientist at Tufts University.
“If a patient doesn’t have the GGA3 mutation, it’s still possible that defects in axonal pathology are caused by other genes. It is still valuable to know that once you have axonal pathology early, BACE accumulation could be a factor. So these mechanisms can apply more generally.”
Phase 3 clinical trials of several drugs aiming to block the activity of BACE1 were abandoned, because they often caused side effects that made memory and thinking worse for people with Alzheimer’s disease. It is thought that side effects from BACE1 inhibition result from stopping its other functions in the brain.
In this new study, the researchers found that inhibiting the activity of BACE1 prevented the swelling seen in neurons without any functional GGA3 protein. Tesco suggests that using a lower dose of BACE1 inhibitors at an early stage of Alzheimer’s could be an effective approach for slowing the progression of the disease.
“The clinical trials that have been conducted, they had a pharmacological inhibition of BACE activity, up to ninety percent in some cases. So I think that what we learned is that probably we need to inhibit BACE to a lesser extent,” says Tesco.
The earliest damage to the neurons happens up to 20 years before the appearance of the clinical symptoms of Alzheimer’s disease, according to Tesco, so any treatment to prevent this would need to be given over a long period.
There is some evidence for the benefits of longer, weaker inhibition of BACE1 from studies of a genetic mutation found in the Icelandic population. The mutation reduces the ability of BACE1 to produce amyloid-β by about 20 percent and lowers the risk of developing Alzheimer’s disease.
“It looks like a small reduction over a very long time seems to be good enough,” Tesco says.
S. Lomoio et al., “Gga3 deletion and a GGA3 rare variant associated with late onset Alzheimer’s disease trigger BACE1 accumulation in axonal swellings,” Sci Transl Med, doi:10.1126/scitranslmed.aba1871, 2020.


thescientist--2020-11-20--The Rise of Cannabis Extraction Labs

The Rise of Cannabis Extraction Labs

For some people , the idea of a cannabis lab stirs up visuals of an illicit facility hidden away in a secret location .
In contrast , modern-day cannabis research facilities focus on extracting key compounds from raw , difficult , unprocessed material .
“ The majority of the business is an agro-chem business , and it 's not super sexy , nor is it exciting .
It 's heavily chemical engineering and agriculturally based chemistry , ” said Jeff Wu , Investor of Chemyx and a cannabis extraction lab investor .
Because of its history of prohibition , cannabis @ @ @ @ @ @ @ charting this new type of chemical extraction are faced with pioneering an entirely new field of chemical engineering .
“ A lot of what we 're doing right now is almost trial and error , where we 're researching with a variety of acids and oxidizers for isomerizations and dehydrogenations for making novel compounds .
But there really has n't even been proper R & D done on this , ” said Wu .
The field of cannabis research is actively evolving as researchers continue to identify and optimize the best method to @ @ @ @ @ @ @ researchers used CO2 extraction because that was a proven method for extracting caffeine from coffee beans .
Later , researchers found that technologies methods using ethanol or butane significantly increased cannabis extraction efficiency and decreased extraction time from days to just 30 minutes .
According to Tully Stroud , Extraction Director at Cannacraft , the lack of both technical expertise and infrastructure causes a high barrier to entry into cannabis research .
As a result , many laboratories find it more cost-effective to source raw cannabis material for their products .
The consistency @ @ @ @ @ @ @ and cookie dough , mixed together and cooled in the refrigerator .
Cannabis researchers are constantly trying to identify the best chemical , the most efficient timing , and the optimal temperature for cannabis extraction , in addition to trying to find the right post-processing tools .
To meet these needs , Wu and his team repurposed Chemyx high-pressure syringe pumps designed for industrial neuroscience and biomedical applications for processing the tacky denseness of raw cannabis extracts .
He called for more basic support tools specifically designed for cannabis processing , extraction , @ @ @ @ @ @ @ compound extraction , researchers are limited in their ability to manipulate those compounds into different versions ( isomers ) , and in their ability to analyze those compounds .
Current tests of cannabis extraction products focus only on measuring its potency or detecting the presence of heavy metals .
Like chemical engineers , cannabis researchers use mass spectrometry , infrared spectrometry , and HPLC to adequately analyze extracted compounds .
However , because of cannabis ’ s novelty , mass spectrometry results for cannabis are often inaccurate .
There are no established chemical @ @ @ @ @ @ @ so many researchers use a variety of standards for potency and cannabis material type .
“ We can send in a sample to three different analytical labs and get back three different results that vary by 15 % , ” said Wu .
When cannabis researchers submit an extracted and crystallized product , many testing facilities report a purity of just 60-70 % .
This is in sharp contrast to the 90-99 % purity expected for a pure crystal of other well-known compounds such as sugar or salt .
“ It 's very @ @ @ @ @ @ @ lack of in-line analytical lab support right now , ” said Wu .
Unlike typical labs , researchers in cannabis extraction labs can not sign a service contract with common lab suppliers due to legal limitations .
Instead , researchers have to purchase their equipment from an intermediary laboratory company .
“ That means we do n't get the best expertise or the best service for our experiments and results done on time , ” said Wu .
Getting results for a chromatograph , which usually takes one day for many labs can @ @ @ @ @ @ @ cannabis service lab .
The culture of secrecy and stereotype that pervades cannabis has also likely impeded its progress .
There are few research labs at academic institutions dedicated to cannabis research and few cannabis specific peer-reviewed journals .
As such , there is a need for more objective information sharing platforms to establish a reliable source of successful methodology and discovery in the field .
However , the culture of secrecy does not just pertain to cannabis-associated stereotypes .
Many cannabis researchers are protective of their hard-won discoveries .
“ Everybody is @ @ @ @ @ @ @ leak out six months later when somebody tells a friend how they 're performing a certain process .
The information sharing peer-review scientific journal style is not there , ” said Wu .
Despite these significant technical and information challenges , researchers , scientists , and investors continue to flock to the cannabis industry , some seeking opportunities in extraction research .
Wu compared the influx to the Gold Rush , as well as the Tech Rush of the late 80s and 90s .
“ The possibilities in the manufacturing space are endless @ @ @ @ @ @ @ re laying the groundwork for a more efficient and scalable supply chain operation while also driving forward on research and development .
This has allowed us to focus on more innovative opportunities that can further the market along.
” The cannabis extraction market extends to both medicinal and recreational purposes .
In California alone , the cannabis sales market is 3.1 billion USD with an estimated growth rate of 23 % .1 In 2018 the global market for cannabis was $ 10.6 billion USD.2 In 2019 , the global market was 17.7 billion @ @ @ @ @ @ @ 18.1 – 32.9 % .2,3 Several estimates project that the market will be 97.35 billion by the end of 2026.2 Many groups in California hold cannabis manufacturing licenses , however , not many are doing extraction work , and less than a third of those are doing it consistently .
“ Many people that get into these businesses , jump right into brand building without really understanding the industry ; or they 're just trying to carve out a name for themselves , ” said Wu .
According to Wu , success is @ @ @ @ @ @ @ rather in establishing a basic supply chain .
He compared it to drinking a bottle of Coca-Cola .
Most consumers know that Coca-Cola contains sugar , but they do not stop to consider how or where that sugar was obtained ; similarly , cannabis extraction products can be used in a variety of products for a number of purposes .
Wu cautioned that there is a large risk , but if researchers can control their risk margins , there is room for substantial success .
Even with the economic crisis associated with the @ @ @ @ @ @ @ extraction .
This is likely to continue for the next decade as cannabis research gains footing with legalization in more locations .
Similar to the Gold Rush and the Tech Rushes , this rush will likely consist of different waves of consolidations and crashes .
“ Right now , I feel like we 're in the early wave , ” said Wu .
“ We just need to build a chip factory .
Let 's not worry about computers or apps yet .
Let 's just build the chip factory and then get @ @ @ @ @ @ @ the basic , “ Cannabis chip factory , ” is in establishing a sound infrastructure .
Currently , there are no dominant cannabis extraction labs , no true operating procedures for extraction , and no reliable distributors .
“ How do you build a computer if there 's no Intel or AMD or CD making hard drives ?
” said Wu , referencing some of the influential companies that helped to shape the development of the computer as we know it today .
“ This is where we 're at right now , @ @ @ @ @ @ @ industry.
” Ultimately , the key to successfully weathering the fluctuating and challenging atmosphere of cannabis research lies in the skillsets and creativity of the people involved .
“ This is a gigantic start-up industry , ” Wu said .
“ With a start-up , it is the strength of the team that will make or break it.
” 1 .
P. McGreevy , “ California now has the biggest legal marijuana market in the world .
Its black market is even bigger , ” Los Angles Times , 2019. https : //www.latimes.com/california/story/2019-08-14/californias-biggest-legal-marijuana-market @ @ @ @ @ @ @ Cannabis/Marihuana Market Size , Share and Industry Analysis By Type ( Flower/Buds and Concentrates ) , By Application ( Medicinal , Recreational ( Edibles and Topicals ) , and Industrial Hemp ) , and Regional Forecast 2019-2026 , ” Fortune Business Insights , 2020. https : //www.fortunebusinessinsights.com/industry-reports/cannabis-marijuana-market-100219 3 .
Grand View Research , “ Legal Marijuana Size , Share & Trends Analysis Report By Marijuana Type ( Medical , Adult Use ) , By Product Type , By Medical Application ( Cancer , Mental Disorders ) , and Segment Forecasts 2020-2027 , ” @ @ @ @ @ @ @ //www.grandviewresearch.com/industry-analysis/legal-marijuana-market This article is brought to you by Chemyx , Inc. Syringe Pumps by Chemyx are used in top-level biomedical , pharmaceutical , chemical , and petrochemical research , offering highly precise , consistent , and reproducible fluidic delivery .
Chemyx pump devices orchestrate the performance of different technologies that make modern research into novel materials , drugs , and energy resources possible .
www.chemyx.com

For some people, the idea of a cannabis lab stirs up visuals of an illicit facility hidden away in a secret location. In contrast, modern-day cannabis research facilities focus on extracting key compounds from raw, difficult, unprocessed material. “The majority of the business is an agro-chem business, and it's not super sexy, nor is it exciting. It's heavily chemical engineering and agriculturally based chemistry,” said Jeff Wu, Investor of Chemyx and a cannabis extraction lab investor.
Because of its history of prohibition, cannabis has been largely unexplored scientifically. Scientists charting this new type of chemical extraction are faced with pioneering an entirely new field of chemical engineering. “A lot of what we're doing right now is almost trial and error, where we're researching with a variety of acids and oxidizers for isomerizations and dehydrogenations for making novel compounds. But there really hasn't even been proper R&D done on this,” said Wu.
The field of cannabis research is actively evolving as researchers continue to identify and optimize the best method to extract cannabis. Initially, many cannabis researchers used CO2 extraction because that was a proven method for extracting caffeine from coffee beans. Later, researchers found that technologies methods using ethanol or butane significantly increased cannabis extraction efficiency and decreased extraction time from days to just 30 minutes.
According to Tully Stroud, Extraction Director at Cannacraft, the lack of both technical expertise and infrastructure causes a high barrier to entry into cannabis research. As a result, many laboratories find it more cost-effective to source raw cannabis material for their products. The consistency of unprocessed raw cannabis is like honey and cookie dough, mixed together and cooled in the refrigerator.
Cannabis researchers are constantly trying to identify the best chemical, the most efficient timing, and the optimal temperature for cannabis extraction, in addition to trying to find the right post-processing tools. To meet these needs, Wu and his team repurposed Chemyx high-pressure syringe pumps designed for industrial neuroscience and biomedical applications for processing the tacky denseness of raw cannabis extracts. He called for more basic support tools specifically designed for cannabis processing, extraction, and analysis.
The Wild West Meets Science
Even with successful cannabis compound extraction, researchers are limited in their ability to manipulate those compounds into different versions (isomers), and in their ability to analyze those compounds. Current tests of cannabis extraction products focus only on measuring its potency or detecting the presence of heavy metals.
Like chemical engineers, cannabis researchers use mass spectrometry, infrared spectrometry, and HPLC to adequately analyze extracted compounds. However, because of cannabis’s novelty, mass spectrometry results for cannabis are often inaccurate. There are no established chemical standards for many novel cannabis compounds, so many researchers use a variety of standards for potency and cannabis material type. “We can send in a sample to three different analytical labs and get back three different results that vary by 15%,” said Wu.
When cannabis researchers submit an extracted and crystallized product, many testing facilities report a purity of just 60-70%. This is in sharp contrast to the 90-99% purity expected for a pure crystal of other well-known compounds such as sugar or salt. “It's very slow and gritty science with a total lack of in-line analytical lab support right now,” said Wu.
Unlike typical labs, researchers in cannabis extraction labs cannot sign a service contract with common lab suppliers due to legal limitations. Instead, researchers have to purchase their equipment from an intermediary laboratory company. “That means we don't get the best expertise or the best service for our experiments and results done on time,” said Wu. Getting results for a chromatograph, which usually takes one day for many labs can take up to four days for a cannabis service lab.
The culture of secrecy and stereotype that pervades cannabis has also likely impeded its progress. There are few research labs at academic institutions dedicated to cannabis research and few cannabis specific peer-reviewed journals. As such, there is a need for more objective information sharing platforms to establish a reliable source of successful methodology and discovery in the field. However, the culture of secrecy does not just pertain to cannabis-associated stereotypes. Many cannabis researchers are protective of their hard-won discoveries. “Everybody is keeping a secret. Then it might leak out six months later when somebody tells a friend how they're performing a certain process. The information sharing peer-review scientific journal style is not there,” said Wu.
Cannabis Rush
Despite these significant technical and information challenges, researchers, scientists, and investors continue to flock to the cannabis industry, some seeking opportunities in extraction research. Wu compared the influx to the Gold Rush, as well as the Tech Rush of the late 80s and 90s.
“The possibilities in the manufacturing space are endless, said Stroud. “We’re laying the groundwork for a more efficient and scalable supply chain operation while also driving forward on research and development. This has allowed us to focus on more innovative opportunities that can further the market along.”
The cannabis extraction market extends to both medicinal and recreational purposes. In California alone, the cannabis sales market is 3.1 billion USD with an estimated growth rate of 23%.1 In 2018 the global market for cannabis was $10.6 billion USD.2 In 2019, the global market was 17.7 billion, with an estimated growth rate of 18.1 – 32.9%.2,3 Several estimates project that the market will be 97.35 billion by the end of 2026.2
Many groups in California hold cannabis manufacturing licenses, however, not many are doing extraction work, and less than a third of those are doing it consistently. “Many people that get into these businesses, jump right into brand building without really understanding the industry; or they're just trying to carve out a name for themselves,” said Wu.
According to Wu, success is not in developing a brand, but rather in establishing a basic supply chain. He compared it to drinking a bottle of Coca-Cola. Most consumers know that Coca-Cola contains sugar, but they do not stop to consider how or where that sugar was obtained; similarly, cannabis extraction products can be used in a variety of products for a number of purposes. Wu cautioned that there is a large risk, but if researchers can control their risk margins, there is room for substantial success.
Even with the economic crisis associated with the coronavirus, money still pours into cannabis extraction. This is likely to continue for the next decade as cannabis research gains footing with legalization in more locations. Similar to the Gold Rush and the Tech Rushes, this rush will likely consist of different waves of consolidations and crashes.
“Right now, I feel like we're in the early wave,” said Wu. “We just need to build a chip factory. Let's not worry about computers or apps yet. Let's just build the chip factory and then get that going.” The key to building the basic, “Cannabis chip factory,” is in establishing a sound infrastructure. Currently, there are no dominant cannabis extraction labs, no true operating procedures for extraction, and no reliable distributors.
“How do you build a computer if there's no Intel or AMD or CD making hard drives?” said Wu, referencing some of the influential companies that helped to shape the development of the computer as we know it today. “This is where we're at right now, just building the basic infrastructure of this industry.”
Ultimately, the key to successfully weathering the fluctuating and challenging atmosphere of cannabis research lies in the skillsets and creativity of the people involved. “This is a gigantic start-up industry,” Wu said. “With a start-up, it is the strength of the team that will make or break it.”
References
1. P. McGreevy, “California now has the biggest legal marijuana market in the world. Its black market is even bigger,” Los Angles Times, 2019. https://www.latimes.com/california/story/2019-08-14/californias-biggest-legal-marijuana-market
2. Fortune Business Insights, “Cannabis/Marihuana Market Size, Share and Industry Analysis By Type (Flower/Buds and Concentrates), By Application (Medicinal, Recreational (Edibles and Topicals), and Industrial Hemp), and Regional Forecast 2019-2026,” Fortune Business Insights, 2020. https://www.fortunebusinessinsights.com/industry-reports/cannabis-marijuana-market-100219
3. Grand View Research, “Legal Marijuana Size, Share & Trends Analysis Report By Marijuana Type (Medical, Adult Use), By Product Type, By Medical Application (Cancer, Mental Disorders), and Segment Forecasts 2020-2027,” Grand View Research, 2020. https://www.grandviewresearch.com/industry-analysis/legal-marijuana-market
Meet the Sponsor:
This article is brought to you by Chemyx, Inc. Syringe Pumps by Chemyx are used in top-level biomedical, pharmaceutical, chemical, and petrochemical research, offering highly precise, consistent, and reproducible fluidic delivery. Chemyx pump devices orchestrate the performance of different technologies that make modern research into novel materials, drugs, and energy resources possible. www.chemyx.com


thescientist--2020-11-23--Immunity to SARS-CoV-2 Lasts at Least Six Months, Data Show

ABOVE : Recovered COVID-19 patients can harbor SARS-CoV-2 ( green ) in the lining of their intestines months after infection .
The residual viral traces might shape the immune response to the virus .
C. GAEBLER ET AL , BIOARXIV , 2020 Immunity to the virus that causes COVID-19 lasts at least six months and might last much longer , according to a preprint posted November 5 on bioRxiv .
Among 87 individuals who had COVID-19 , antibodies to SARS-CoV-2 dwindled after six months but were still detectable , the study ’ s authors found .
A closer look at @ @ @ @ @ @ @ revealed that the antibodies that remained six months after infection were , on average , more potent in neutralizing the virus than were antibodies generated only about a month after infection .
And levels of the memory immune cells that make those more-potent antibodies did not drop off with time , the researchers report .
“ This is fantastic news , ” says immunologist Ziv Shulman of the Weizmann Institute of Science in Israel who wasn ’ t involved in the new work .
“ It was unclear if we make a long-lasting @ @ @ @ @ @ @ The study shows the memory cells are there [ months after infection ] and able to produce high-affinity , virus-neutralizing antibodies.
” The results , which have not yet been peer reviewed , suggest that individuals re-exposed to the virus have a good chance of mounting a quick and effective immune response against it , and they offer a bit of hope for making a long-lasting vaccine , experts say .
In the study , Christian Gaebler , a physician and immunologist at the Rockefeller University in New York City , and colleagues @ @ @ @ @ @ @ antibodies in blood samples taken from 87 volunteers one month and then six roughly months after they ’ d been infected with the virus .
The team specifically measured levels of antibodies called immunoglobulin M ( IgM ) , immunoglobulin G ( IgG ) , and immunoglobulin A ( IgA ) , which are created to neutralize a pathogen .
IgM is usually the first antibody to develop in response to an infection .
IgG is the main type found in the blood , and IgA in the blood helps initiate an inflammatory @ @ @ @ @ @ @ IgM and IgG antibodies reactive to the SARS-CoV-2 spike protein ’ s receptor binding domain ( RBD ) dropped sharply between the two time points , the team found , while IgA levels didn ’ t decline as steeply .
Levels of memory B cells , which generate all of these antibodies when there ’ s a sign of reinfection , remained steady over the course of the study .
The results align with a preprint posted on medRxiv in August that also showed memory B cells to the virus persist after a @ @ @ @ @ @ @ next identified the antibodies present both one month and six months after infection , synthesized them in the lab , and tested their reactivity to the RBD .
Antibodies from six months after infection bound more tightly to the docking component of the virus than did those from shortly after infection .
Those antibodies were also better at neutralizing variants of the SARS-CoV-2 virus .
Those observations indicate that the patients ’ bodies were activating a specific immune system program that generates long-lived memory B cells , which then produce potent antibodies against @ @ @ @ @ @ @ researchers write .
A lack of structures called germinal centers where this production of memory B cells takes place has been tied to severe COVID-19 infection and death .
Curious if the B cells produced the same antibodies a month after infection as six months after infection , Gaebler and colleagues compared the memory B cell receptors ’ genetic sequences and found significant shifts over time .
This observation , combined with the improved potency of antibodies produced by these B cells , indicates the B cells and antibodies evolved in response to @ @ @ @ @ @ @ to see the antibodies had evolved .
That typically happens when a pathogen hides out somewhere in the body or specifically in cells ’ DNA even after symptoms of infections cease—for instance , with HIV .
Saurabh Mehandru , a gastroenterologist at Mount Sinai Hospital , and colleagues had been looking for the SARS-CoV-2 virus in recovered COVID-19 patients ’ intestines and had identified traces of it in the gut .
His group and Gaebler ’ s decided to team up to see if those viral stowaways in the gut could be spurring @ @ @ @ @ @ @ ’ s team took a close look at biopsies from 14 recovered patients infected roughly four months earlier , on average .
At the time of the tissue collection , none of them had a positive PCR result for the virus , yet SARS-CoV-2 RNA was detected in the small intestine of three of the 14 patients , and biopsies from five of the patients contained SARS-CoV-2 N protein .
Electron tomography on one patient ’ s biopsy also revealed SARS-CoV-2 viral particles .
“ If you have the virus persisting in the @ @ @ @ @ @ @ continue to inform the immune system , ” Mehandru , a coauthor of the study , tells The Scientist .
Shiv Pillai , an immunologist at the Ragon Institute of Massachusetts General Hospital , MIT , and Harvard who was not involved in the study , agrees , saying that the study makes a strong case for virus in the gut continuing to prime memory B cells for infection .
The result also suggests that a latent gut infection may explain MIS-C , or multisystem inflammatory syndrome , a rare condition in which @ @ @ @ @ @ @ , such vomiting , diarrhea , and severe abdominal pain , weeks after recovery .
“ This fits with that and says , look , there is a reservoir in the gut for the virus to stay , ” Pillai says .
Mehandru says it is important to emphasize that even though the team found traces of the virus in the gut , there is no evidence that SARS-CoV-2 can be transmitted via stool .
Gaebler says the team is not yet entirely sure if it is the virus in the intestine that @ @ @ @ @ @ @ or if the virus also persists elsewhere in the body and continues to affect the immune system from there .
How long this memory B cell immune response will last past the six-month mark is not yet clear either .
Individuals who were infected with the original SARS virus in 2003 still have memory B cells for that pathogen , so the pattern could be the same for SARS-CoV-2 , Gaebler says .
“ Usually when you see such a memory response , it is quite long lasting.
” A next step , @ @ @ @ @ @ @ blood of individuals who receive a vaccine against the virus for the presence of memory B cells .
“ The immunity data that we see from those vaccines is very encouraging , and seems to resemble the natural infection very closely , which is good news , ” Gaebler says .
“ That might suggest that [ the vaccines ] also lead to the same memory response .
But this would obviously be very , very important to see.
” C. Gaebler et al .
“ Evolution 1 of Antibody Immunity to SARS-CoV-2 @ @ @ @ @ @ @ .

ABOVE: Recovered COVID-19 patients can harbor SARS-CoV-2 (green) in the lining of their intestines months after infection. The residual viral traces might shape the immune response to the virus.
C. GAEBLER ET AL, BIOARXIV, 2020
Immunity to the virus that causes COVID-19 lasts at least six months and might last much longer, according to a preprint posted November 5 on bioRxiv.
Among 87 individuals who had COVID-19, antibodies to SARS-CoV-2 dwindled after six months but were still detectable, the study’s authors found. A closer look at the samples of six of those patients revealed that the antibodies that remained six months after infection were, on average, more potent in neutralizing the virus than were antibodies generated only about a month after infection. And levels of the memory immune cells that make those more-potent antibodies did not drop off with time, the researchers report.
“This is fantastic news,” says immunologist Ziv Shulman of the Weizmann Institute of Science in Israel who wasn’t involved in the new work. “It was unclear if we make a long-lasting immunological memory against this new coronavirus. The study shows the memory cells are there [months after infection] and able to produce high-affinity, virus-neutralizing antibodies.”
The results, which have not yet been peer reviewed, suggest that individuals re-exposed to the virus have a good chance of mounting a quick and effective immune response against it, and they offer a bit of hope for making a long-lasting vaccine, experts say.
In the study, Christian Gaebler, a physician and immunologist at the Rockefeller University in New York City, and colleagues compared the levels and potency of SARS-CoV-2 antibodies in blood samples taken from 87 volunteers one month and then six roughly months after they’d been infected with the virus. The team specifically measured levels of antibodies called immunoglobulin M (IgM), immunoglobulin G (IgG), and immunoglobulin A (IgA), which are created to neutralize a pathogen. IgM is usually the first antibody to develop in response to an infection. IgG is the main type found in the blood, and IgA in the blood helps initiate an inflammatory reaction to infection.
The levels of IgM and IgG antibodies reactive to the SARS-CoV-2 spike protein’s receptor binding domain (RBD) dropped sharply between the two time points, the team found, while IgA levels didn’t decline as steeply. Levels of memory B cells, which generate all of these antibodies when there’s a sign of reinfection, remained steady over the course of the study. The results align with a preprint posted on medRxiv in August that also showed memory B cells to the virus persist after a mild COVID-19 infection.
Gaebler and colleagues next identified the antibodies present both one month and six months after infection, synthesized them in the lab, and tested their reactivity to the RBD. Antibodies from six months after infection bound more tightly to the docking component of the virus than did those from shortly after infection. Those antibodies were also better at neutralizing variants of the SARS-CoV-2 virus.
Those observations indicate that the patients’ bodies were activating a specific immune system program that generates long-lived memory B cells, which then produce potent antibodies against subsequent exposures to the virus, the researchers write. A lack of structures called germinal centers where this production of memory B cells takes place has been tied to severe COVID-19 infection and death.
Curious if the B cells produced the same antibodies a month after infection as six months after infection, Gaebler and colleagues compared the memory B cell receptors’ genetic sequences and found significant shifts over time. This observation, combined with the improved potency of antibodies produced by these B cells, indicates the B cells and antibodies evolved in response to infection.
Gaebler says he was surprised to see the antibodies had evolved. That typically happens when a pathogen hides out somewhere in the body or specifically in cells’ DNA even after symptoms of infections cease—for instance, with HIV. Saurabh Mehandru, a gastroenterologist at Mount Sinai Hospital, and colleagues had been looking for the SARS-CoV-2 virus in recovered COVID-19 patients’ intestines and had identified traces of it in the gut. His group and Gaebler’s decided to team up to see if those viral stowaways in the gut could be spurring memory B cells’ evolution.
Mehandru’s team took a close look at biopsies from 14 recovered patients infected roughly four months earlier, on average. At the time of the tissue collection, none of them had a positive PCR result for the virus, yet SARS-CoV-2 RNA was detected in the small intestine of three of the 14 patients, and biopsies from five of the patients contained SARS-CoV-2 N protein. Electron tomography on one patient’s biopsy also revealed SARS-CoV-2 viral particles.
“If you have the virus persisting in the intestines, it has the potential to continue to inform the immune system,” Mehandru, a coauthor of the study, tells The Scientist.
Shiv Pillai, an immunologist at the Ragon Institute of Massachusetts General Hospital, MIT, and Harvard who was not involved in the study, agrees, saying that the study makes a strong case for virus in the gut continuing to prime memory B cells for infection. The result also suggests that a latent gut infection may explain MIS-C, or multisystem inflammatory syndrome, a rare condition in which children who contracted SARS-CoV-2 suffer from symptoms, such vomiting, diarrhea, and severe abdominal pain, weeks after recovery. “This fits with that and says, look, there is a reservoir in the gut for the virus to stay,” Pillai says.
Mehandru says it is important to emphasize that even though the team found traces of the virus in the gut, there is no evidence that SARS-CoV-2 can be transmitted via stool.
Gaebler says the team is not yet entirely sure if it is the virus in the intestine that is causing the evolution in immunity, or if the virus also persists elsewhere in the body and continues to affect the immune system from there.
How long this memory B cell immune response will last past the six-month mark is not yet clear either. Individuals who were infected with the original SARS virus in 2003 still have memory B cells for that pathogen, so the pattern could be the same for SARS-CoV-2, Gaebler says. “Usually when you see such a memory response, it is quite long lasting.”
A next step, he says, is to screen the blood of individuals who receive a vaccine against the virus for the presence of memory B cells. “The immunity data that we see from those vaccines is very encouraging, and seems to resemble the natural infection very closely, which is good news,” Gaebler says. “That might suggest that [the vaccines] also lead to the same memory response. But this would obviously be very, very important to see.”
C. Gaebler et al. “Evolution 1 of Antibody Immunity to SARS-CoV-2,” bioRxiv, doi.org/10.1101/2020.11.03.367391, 2020.


thescientist--2020-11-23--Q&A: COVID-19 Infectiousness Peaks Early in Sickness, Study Shows

Since early March , a number of studies have suggested that patients infected with SARS-CoV-2 generally have a long incubation period and are most infectious early on in their sickness , with viral loads dropping off after nine days .
These results have informed guidelines put forth by public health bodies , such as the US Centers for Disease Control and Prevention , which recommend that people isolate for at least 10 days following a positive COVID-19 test .
A meta-analysis published November 19 in The Lancet Microbe reviewed 98 studies on coronaviruses—79 of which focused on SARS-CoV-2 and the @ @ @ @ @ @ @ patients ’ viral loads are highest and could therefore transmit the virus most effectively .
Of the SARS-CoV-2 studies , 73 included hospitalized patients only .
Their report finds that patients with COVID-19 show the highest amount of live virus in the upper respiratory tract within the first five days of showing symptoms , while the highest amount of virus in SARS and MERS is seen during the second week after showing symptoms .
Despite finding high viral RNA loads , no study in the review isolated live virus beyond day nine after @ @ @ @ @ @ @ Scientist spoke with Muge Cevik , a virologist and a clinician at the University of St Andrews and the lead author of the analysis , about the findings .
The Scientist : What inspired you to do this research ?
Muge Cevik : Around April , we were writing a review paper mainly for clinicians .
In writing that paper , we realized that we don ’ t have a good understanding about viral load dynamics and infectiousness periods not only for [ SARS-CoV-2 ] but also for [ SARS-CoV ] and MERS @ @ @ @ @ @ @ , we set up this systematic review and recruited four doctors to work together because systematic reviews are quite a huge task .
At the beginning of the pandemic—I ’ m a clinician as well—we were not sure when to stop isolating patients , when we can safely discharge patients , and when patients stop being infectious .
These have important implications for cases in the community but also cases in the hospital setting .
TS : How did you go about deciding which studies you were going to include in your analysis @ @ @ @ @ @ @ we included papers mainly looking at viral load dynamics .
We wanted to include large studies—that ’ s the reason we excluded case reports or case series with less than five patients because generally [ they ] report atypical , unusual cases , and that ’ s typically those who basically shed virus for a long time .
We didn ’ t want our subjective opinion to influence the results , so specifically we included studies that counted the viral shedding from the time of symptom onset , not from time of hospitalization @ @ @ @ @ @ @ after discharge from hospital , so we didn ’ t know when the symptoms started .
We tried to make it really similar across all studies , and that ’ s the reason our inclusion criteria were really strict .
TS : The scientific community has had inklings in terms of COVID-19 ’ s infectious window , so did the results surprise you at all ?
MC : This study really emphasizes that people are highly infectious really early on , especially seeing peak viral loads around symptom onset to day five .
@ @ @ @ @ @ @ but I think it doesn ’ t align with our ‘ test , trace , isolate ’ practice because in order to prevent onward transmission , testing , on itself , is not enough .
We need to ensure those people who are infectious isolate and their contacts isolate .
In a way , that emphasizes that we need much more prompt testing and prompt results so we can prevent onward transmission .
What happens at the moment is that people seek testing around two or three days after symptom onset , and @ @ @ @ @ @ @ , they ’ re already past the most infectious time period .
Many people struggle to take sick leave without having the test results , so that tells us that we need to change the way we look at ‘ test , trace , and isolate ’ now—maybe symptom onset needs to prompt isolation before testing .
The other aspect is that the majority of studies agree that the infectious virus is not detectable after day nine , and when we put that result with the peak viral load , which happens around @ @ @ @ @ @ @ that people are really infectious in the first week of symptom onset .
At the moment , when patients come into the hospital , they ’ re already around day six or eight after symptom onset because people have pneumonia around day eight after symptom onset , so that tells us that , when people come to hospital with a possible diagnosis of COVID-19 , they may not be as infectious as .
.
.
a case in the community .
TS : Asymptomatic COVID-19 cases have also made it difficult to test @ @ @ @ @ @ @ find among the asymptomatic cases you included in your analysis ?
MC : There were very few studies looking into this , but what we found is that the majority of studies agreed that initial viral loads were similar between symptomatic and asymptomatic people .
When I say asymptomatic , these were studies only recruiting those with no symptoms whatsoever throughout the disease course , not those presymptomatic patients , because we know that if you have peak viral load around symptom onset , that means people can be infectious before symptoms begin @ @ @ @ @ @ @ you know asymptomatic individuals have shorter viral shedding , which means they may be infectious but for a shorter period , and maybe that ’ s a reason that , in contact tracing studies , asymptomatic patients seem to be one-third as infectious as someone with symptoms .
Another study we ’ ve done looks at transmission dynamics in asymptomatic people , and what we found is it generally happens among households .
People have much more opportunity to transmit to each other—it may happen [ over a ] very short period of @ @ @ @ @ @ @ greater ] opportunity to transmit it to [ each other ] .
TS : How does your analysis of SARS-CoV and MERS put the viral load dynamics of SARS-CoV-2 in perspective ?
MC : It shows why SARS-CoV was a bit easier to control in the community because the viral load peak actually occurred in the second week after symptom onset .
.
.
.
It was probably the time when patients were already hospitalized , which is a bit different than COVID-19 , where we ’ re seeing really high viral loads @ @ @ @ @ @ @ really infectious in the community .
Another major difference in SARS-CoV and MERS is that we saw a lot of hospital-based outbreaks—almost sixty percent of all outbreaks were based in the hospital .
We ’ re not seeing that much for SARS-CoV-2 .
These results put these three highly infectious pathogens into context and [ explain ] why we ’ re seeing different patterns and why we ’ re struggling to contain SARS-CoV-2 because it spreads really quickly in the community .
TS : Which of the ‘ test , trace , and @ @ @ @ @ @ @ need to focus on more , based on your research ?
MC : I think the isolation part is the weakest part of our programs .
It ’ s not surprising that we ’ re having difficulty containing the virus because when we look at—and I don ’ t know the numbers in the US—but in the UK only one in five people isolate .
That means even if we do more testing , if people don ’ t or are not able to isolate—this may be [ due to ] their working @ @ @ @ @ @ @ able to prevent onward transmission .
There ’ s been a lot of emphasis on testing but testing on its own is not an intervention .
It needs to be connected to an intervention , especially when it ’ s a respiratory pathogen .
If I ’ m someone that my family is dependent on and if I need to pay my rent , if I ’ m not getting sick leave from my employer—people need to make difficult choices .
I ’ m especially worried about people on zero-hour contract jobs where @ @ @ @ @ @ @ .
When we look at the global figures , countries who supported their citizens—I ’ ve seen a couple of papers from Vermont and New York—have much better isolation numbers .
That emphasizes that we need to do more to support more disadvantaged groups , especially working people , because even when we were in lockdown , we ’ ve seen that there there ’ s been a difference between those areas where [ people are ] still commuting to work versus people who are able to work from home .
We know @ @ @ @ @ @ @ population that are at high risk of acquiring , being exposed to , and transmitting [ the virus ] to their household because of living conditions .
And we know that crowded housing increases the risk of transmission , so I think we need to do more to support immediate isolation .
Supported isolation needs to be a norm .
In any public health intervention , if you support people , they will do what ’ s needed .
Our results emphasize why it ’ s been very difficult over the last few @ @ @ @ @ @ @ could be shortening the isolation period but giving more support to people to isolate during that five-day period when everyone is so infectious .
There ’ s a need to balance risks and benefits but also listen to people—what are their needs and how we can support them .
TS : How might your study help our readers decide what they should and shouldn ’ t be doing , particularly as the holiday season approaches ?
MC : First of all , if you have symptoms , even mild symptoms—COVID-19 does not only @ @ @ @ @ @ @ people have other symptoms like severe muscle aches , fatigue , sore throat , [ loss of taste and smell ] .
These are all early symptoms that tell us it could be COVID-19 , so if you have those symptoms , isolation needs to start promptly .
Especially within the first five days of symptoms , we need to be very , very careful not to interact with high risk and vulnerable contacts—especially elderly people or those with comorbidities .
But again , we can be infectious before having symptoms so that @ @ @ @ @ @ @ careful and behave as if we have the infection and could transmit it to someone else .
M. Cevik et al.
, “ SARS-CoV-2 , SARS-CoV , and MERS-CoV viral load dynamics , duration of viral shedding , and infectiousness : a systematic review and meta-analysis , ” The Lancet Microbe , doi:10.1016/S2666-5247 ( 20 ) 30172-5 , 2020 .
Editor ’ s note : The interview was edited for brevity .

ABOVE: © ISTOCK.COM,
JORDANSIMEONOV
Since early March, a number of studies have suggested that patients infected with SARS-CoV-2 generally have a long incubation period and are most infectious early on in their sickness, with viral loads dropping off after nine days. These results have informed guidelines put forth by public health bodies, such as the US Centers for Disease Control and Prevention, which recommend that people isolate for at least 10 days following a positive COVID-19 test.
A meta-analysis published November 19 in The Lancet Microbe reviewed 98 studies on coronaviruses—79 of which focused on SARS-CoV-2 and the rest on SARS-CoV and MERS-CoV—to determine when patients’ viral loads are highest and could therefore transmit the virus most effectively. Of the SARS-CoV-2 studies, 73 included hospitalized patients only.
Their report finds that patients with COVID-19 show the highest amount of live virus in the upper respiratory tract within the first five days of showing symptoms, while the highest amount of virus in SARS and MERS is seen during the second week after showing symptoms. Despite finding high viral RNA loads, no study in the review isolated live virus beyond day nine after the first symptoms of COVID-19.
The Scientist spoke with Muge Cevik, a virologist and a clinician at the University of St Andrews and the lead author of the analysis, about the findings.
The Scientist: What inspired you to do this research?
Muge Cevik, University of St Andrews MUGE CEVIK
Muge Cevik: Around April, we were writing a review paper mainly for clinicians. In writing that paper, we realized that we don’t have a good understanding about viral load dynamics and infectiousness periods not only for [SARS-CoV-2] but also for [SARS-CoV] and MERS. With my colleague from Glasgow University, we set up this systematic review and recruited four doctors to work together because systematic reviews are quite a huge task. At the beginning of the pandemic—I’m a clinician as well—we were not sure when to stop isolating patients, when we can safely discharge patients, and when patients stop being infectious. These have important implications for cases in the community but also cases in the hospital setting.
TS: How did you go about deciding which studies you were going to include in your analysis?
MC: In our analysis, we included papers mainly looking at viral load dynamics. We wanted to include large studies—that’s the reason we excluded case reports or case series with less than five patients because generally [they] report atypical, unusual cases, and that’s typically those who basically shed virus for a long time.
We didn’t want our subjective opinion to influence the results, so specifically we included studies that counted the viral shedding from the time of symptom onset, not from time of hospitalization, and some studies actually included patients after discharge from hospital, so we didn’t know when the symptoms started. We tried to make it really similar across all studies, and that’s the reason our inclusion criteria were really strict.
TS: The scientific community has had inklings in terms of COVID-19’s infectious window, so did the results surprise you at all?
MC: This study really emphasizes that people are highly infectious really early on, especially seeing peak viral loads around symptom onset to day five. I’m not that surprised, but I think it doesn’t align with our ‘test, trace, isolate’ practice because in order to prevent onward transmission, testing, on itself, is not enough. We need to ensure those people who are infectious isolate and their contacts isolate. In a way, that emphasizes that we need much more prompt testing and prompt results so we can prevent onward transmission. What happens at the moment is that people seek testing around two or three days after symptom onset, and by the time they get test results, they’re already past the most infectious time period. Many people struggle to take sick leave without having the test results, so that tells us that we need to change the way we look at ‘test, trace, and isolate’ now—maybe symptom onset needs to prompt isolation before testing.
There’s been a lot of emphasis on testing, but testing on its own is not an intervention. It needs to be connected to an intervention, especially when it’s a respiratory pathogen.
The other aspect is that the majority of studies agree that the infectious virus is not detectable after day nine, and when we put that result with the peak viral load, which happens around day five, it basically tells us that people are really infectious in the first week of symptom onset. At the moment, when patients come into the hospital, they’re already around day six or eight after symptom onset because people have pneumonia around day eight after symptom onset, so that tells us that, when people come to hospital with a possible diagnosis of COVID-19, they may not be as infectious as . . . a case in the community.
TS: Asymptomatic COVID-19 cases have also made it difficult to test, trace, and isolate—what did you find among the asymptomatic cases you included in your analysis?
MC: There were very few studies looking into this, but what we found is that the majority of studies agreed that initial viral loads were similar between symptomatic and asymptomatic people. When I say asymptomatic, these were studies only recruiting those with no symptoms whatsoever throughout the disease course, not those presymptomatic patients, because we know that if you have peak viral load around symptom onset, that means people can be infectious before symptoms begin. What we found overall is that you know asymptomatic individuals have shorter viral shedding, which means they may be infectious but for a shorter period, and maybe that’s a reason that, in contact tracing studies, asymptomatic patients seem to be one-third as infectious as someone with symptoms. Another study we’ve done looks at transmission dynamics in asymptomatic people, and what we found is it generally happens among households. People have much more opportunity to transmit to each other—it may happen [over a] very short period of time, but they have [a greater] opportunity to transmit it to [each other].
TS: How does your analysis of SARS-CoV and MERS put the viral load dynamics of SARS-CoV-2 in perspective?
MC: It shows why SARS-CoV was a bit easier to control in the community because the viral load peak actually occurred in the second week after symptom onset. . . . It was probably the time when patients were already hospitalized, which is a bit different than COVID-19, where we’re seeing really high viral loads really early on, so people are really infectious in the community. Another major difference in SARS-CoV and MERS is that we saw a lot of hospital-based outbreaks—almost sixty percent of all outbreaks were based in the hospital. We’re not seeing that much for SARS-CoV-2. These results put these three highly infectious pathogens into context and [explain] why we’re seeing different patterns and why we’re struggling to contain SARS-CoV-2 because it spreads really quickly in the community.
TS: Which of the ‘test, trace, and isolate’ protocol do you think we need to focus on more, based on your research?
Our results emphasize why it’s been very difficult over the last few months and how we move forward—maybe it could be shortening the isolation period but giving more support to people to isolate during that five-day period when everyone is so infectious.
MC: I think the isolation part is the weakest part of our programs. It’s not surprising that we’re having difficulty containing the virus because when we look at—and I don’t know the numbers in the US—but in the UK only one in five people isolate. That means even if we do more testing, if people don’t or are not able to isolate—this may be [due to] their working or living conditions—we won’t be able to prevent onward transmission.
There’s been a lot of emphasis on testing but testing on its own is not an intervention. It needs to be connected to an intervention, especially when it’s a respiratory pathogen. If I’m someone that my family is dependent on and if I need to pay my rent, if I’m not getting sick leave from my employer—people need to make difficult choices. I’m especially worried about people on zero-hour contract jobs where there’s no linkage to support. When we look at the global figures, countries who supported their citizens—I’ve seen a couple of papers from Vermont and New York—have much better isolation numbers. That emphasizes that we need to do more to support more disadvantaged groups, especially working people, because even when we were in lockdown, we’ve seen that there there’s been a difference between those areas where [people are] still commuting to work versus people who are able to work from home.
We know that there are certain groups in the population that are at high risk of acquiring, being exposed to, and transmitting [the virus] to their household because of living conditions. And we know that crowded housing increases the risk of transmission, so I think we need to do more to support immediate isolation. Supported isolation needs to be a norm. In any public health intervention, if you support people, they will do what’s needed.
Our results emphasize why it’s been very difficult over the last few months and how we move forward—maybe it could be shortening the isolation period but giving more support to people to isolate during that five-day period when everyone is so infectious. There’s a need to balance risks and benefits but also listen to people—what are their needs and how we can support them.
TS: How might your study help our readers decide what they should and shouldn’t be doing, particularly as the holiday season approaches?
MC: First of all, if you have symptoms, even mild symptoms—COVID-19 does not only present with cough and fever, but people have other symptoms like severe muscle aches, fatigue, sore throat, [loss of taste and smell]. These are all early symptoms that tell us it could be COVID-19, so if you have those symptoms, isolation needs to start promptly. Especially within the first five days of symptoms, we need to be very, very careful not to interact with high risk and vulnerable contacts—especially elderly people or those with comorbidities.
But again, we can be infectious before having symptoms so that tells us that we need to be careful and behave as if we have the infection and could transmit it to someone else.
M. Cevik et al., “SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis,” The Lancet Microbe, doi:10.1016/S2666-5247(20)30172-5, 2020.
Editor’s note: The interview was edited for brevity.


thescientist--2020-11-23--Twist Bioscience and Biotia Announce Research Use Only Availability of First Hybridization Capture-B

Twist Bioscience and Biotia Announce Research Use Only Availability of First Hybridization Capture-Based Next-Generation Sequencing SARS-CoV-2 Assay for Characterization and Surveillance of the Virus

The companies have developed the SARS-CoV-2 Next-Generation Sequencing ( NGS ) Assay , an NGS-based assay for research-use only ( RUO ) .
The SARS-CoV-2 NGS RUO Assay is a highly sensitive nucleic acid hybridization capture-based assay used for the detection , characterization , and environmental monitoring of the SARS-CoV-2 virus .
It utilizes Twist Bioscience ’ s unique ability to rapidly develop virus-specific panels by DNA synthesis and Biotia ’ s comprehensive data analysis software and reporting capabilities .
The SARS-CoV-2 NGS Assay was validated on a NextSeq® sequencer and identifies all SARS-CoV-2 nucleic acid sequences , to allow @ @ @ @ @ @ @ of the virus is changing .
In contrast , a majority of SARS-CoV-2 tests based on polymerase chain reaction ( PCR ) only identify limited genetic markers of the virus .
A recent study compared the performance of three different commercially available NGS library preparation kits confirming that hybridization capture results in more even coverage across all sequences in a sample when compared to PCR-based NGS assays .
In addition , the SARS-CoV-2 NGS Assay reports the full sequence of the virus , enabling improved understanding of mutations , genetic variations and the @ @ @ @ @ @ @ transmitted .
“ While there are many available high-throughput diagnostic tests available for COVID-19 , our solution provides sequence data that enables researchers the ability to sequence and surveil the evolution of mutations in the virus over time and geography , ” said Emily M. Leproust , Ph.D. , CEO and co-founder of Twist Bioscience .
“ Importantly , while many labs are conducting individual sequencing runs for each patient sample , this assay and the accompanying software provide a way to batch about 100 patient samples together , providing actionable information that @ @ @ @ @ @ @ health particularly as we see second and third waves of COVID escalating.
” '' We are fortunate to be in a position where we can devote our time and resources to fight this global pandemic , ” commented Niamh O ’ Hara , Ph.D. , CEO and co-founder of Biotia .
“ This novel and insightful COVID-19 solution is an important step to make NGS-based infectious disease surveillance more widely available and to advance COVID-19 research and control . ''
Biotia presented data from the assay at the Infectious Disease Week ( IDWeek @ @ @ @ @ @ @ genetic mutations not previously described , including 26 in the functionally important spike protein of SARS-CoV-2 .
The end-to-end solution was validated on 120 clinical samples ( 60 positive , 60 negative ) , and confirmed that the SARS-CoV-2 NGS Assay powered by the COVID-DX Software could be used to detect viral RNA in laboratory research settings .
It also provided insight into genetic variants to track transmission , identify risk , and predict outcome and therapeutic response .
[ Nagy-Szakal et al.
, SARS-CoV-2 NGS Assay Powered by Biotia COVID-DX Software , @ @ @ @ @ @ @ both diagnostic methods and vaccine research , ” noted Christopher Mason , Ph.D. , co-founder of Biotia , “ We believe this end-to-end solution brings needed tools into the fight against COVID-19 , as well as pioneering these capture methods for tracking other pathogens in the future.
” The SARS-CoV-2 NGS Assay is an RUO end-to-end solution intended for the quantitative detection of the SARS-CoV-2 virus from nasopharyngeal ( NP ) , oropharyngeal ( OP ) , anterior nasal and mid-turbinate nasal swabs as well as from nasopharyngeal wash/aspirates , nasal aspirates and @ @ @ @ @ @ @ individuals .
The SARS-CoV-2 NGS Assay , which includes Twist Bioscience ’ s SARS-CoV-2 synthetic RNA controls , detects all strains of SARS-CoV-2 in samples with as few as 800 viral copies per milliliter .
The complementary Biotia COVID-DX software provides an RUO report including the presence or absence of SARS-CoV-2 virus , the full sequence of the virus , genetic variants and phylogenetic analysis .
FASTQ files ( sequencing output ) can be generated in laboratories nationwide and submitted to Biotia COVID-DX ( v1.0 ) , a cloud-based software to generate RUO @ @ @ @ @ @ @ software is provided through a unique order number emailed to a researcher that includes credits for each kit purchased .

The companies have developed the SARS-CoV-2 Next-Generation Sequencing (NGS) Assay, an NGS-based assay for research-use only (RUO). The SARS-CoV-2 NGS RUO Assay is a highly sensitive nucleic acid hybridization capture-based assay used for the detection, characterization, and environmental monitoring of the SARS-CoV-2 virus. It utilizes Twist Bioscience’s unique ability to rapidly develop virus-specific panels by DNA synthesis and Biotia’s comprehensive data analysis software and reporting capabilities.
The SARS-CoV-2 NGS Assay was validated on a NextSeq® sequencer and identifies all SARS-CoV-2 nucleic acid sequences, to allow for surveillance of how the genetic sequence of the virus is changing. In contrast, a majority of SARS-CoV-2 tests based on polymerase chain reaction (PCR) only identify limited genetic markers of the virus. A recent study compared the performance of three different commercially available NGS library preparation kits confirming that hybridization capture results in more even coverage across all sequences in a sample when compared to PCR-based NGS assays. In addition, the SARS-CoV-2 NGS Assay reports the full sequence of the virus, enabling improved understanding of mutations, genetic variations and the evolution of the virus as it is transmitted.
“While there are many available high-throughput diagnostic tests available for COVID-19, our solution provides sequence data that enables researchers the ability to sequence and surveil the evolution of mutations in the virus over time and geography,” said Emily M. Leproust, Ph.D., CEO and co-founder of Twist Bioscience. “Importantly, while many labs are conducting individual sequencing runs for each patient sample, this assay and the accompanying software provide a way to batch about 100 patient samples together, providing actionable information that can then be used to inform public health particularly as we see second and third waves of COVID escalating.”
"We are fortunate to be in a position where we can devote our time and resources to fight this global pandemic,” commented Niamh O’Hara, Ph.D., CEO and co-founder of Biotia. “This novel and insightful COVID-19 solution is an important step to make NGS-based infectious disease surveillance more widely available and to advance COVID-19 research and control."
Biotia presented data from the assay at the Infectious Disease Week (IDWeek) 2020 Annual Meeting that identify 124 genetic mutations not previously described, including 26 in the functionally important spike protein of SARS-CoV-2. The end-to-end solution was validated on 120 clinical samples (60 positive, 60 negative), and confirmed that the SARS-CoV-2 NGS Assay powered by the COVID-DX Software could be used to detect viral RNA in laboratory research settings. It also provided insight into genetic variants to track transmission, identify risk, and predict outcome and therapeutic response. [Nagy-Szakal et al., SARS-CoV-2 NGS Assay Powered by Biotia COVID-DX Software, IDWeek 2020]
“This test spans both diagnostic methods and vaccine research,” noted Christopher Mason, Ph.D., co-founder of Biotia, “We believe this end-to-end solution brings needed tools into the fight against COVID-19, as well as pioneering these capture methods for tracking other pathogens in the future.”
About the Solution
The SARS-CoV-2 NGS Assay is an RUO end-to-end solution intended for the quantitative detection of the SARS-CoV-2 virus from nasopharyngeal (NP), oropharyngeal (OP), anterior nasal and mid-turbinate nasal swabs as well as from nasopharyngeal wash/aspirates, nasal aspirates and bronchoalveolar lavage (BAL) specimens from individuals. The SARS-CoV-2 NGS Assay, which includes Twist Bioscience’s SARS-CoV-2 synthetic RNA controls, detects all strains of SARS-CoV-2 in samples with as few as 800 viral copies per milliliter.
The complementary Biotia COVID-DX software provides an RUO report including the presence or absence of SARS-CoV-2 virus, the full sequence of the virus, genetic variants and phylogenetic analysis. FASTQ files (sequencing output) can be generated in laboratories nationwide and submitted to Biotia COVID-DX (v1.0), a cloud-based software to generate RUO reports. Access to the Biotia COVID-DX software is provided through a unique order number emailed to a researcher that includes credits for each kit purchased.