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Methods to Detect Viruses Get a Boost, Thanks to the COVID-19 Response

The COVID-19 pandemic has jumpstarted innovations in viral detection technologies from electrical-based assays to saliva sampling.
The post Methods to Detect Viruses Get a Boost, Thanks to the COVID-19 Response appeared first on GEN – Genetic Engineering.



Scientific progress has kept an unprecedented pace over the last year and a half. This is perhaps most evident in the near-miraculous development of several highly effective COVID-19 vaccines in under a year. In addition, innovation in viral detection methods has been accelerated by the pandemic response.

Although the gold standard for COVID-19 diagnostic testing—the reverse-transcription polymerase chain reaction (RT-PCR) assay—is already mature and highly optimized, its ancillaries in viral testing are still subject to improvement. Moreover, several such ancillaries are relevant not only to RT-PCR, but also to alternative assay technologies, such as those relying on next-generation sequencing (NGS).

Efforts to improve COVID-19 testing include, but are not limited to, the following activities:

1. decreasing the time needed to run a test, thereby providing results more quickly;

2. increasing the number of samples that can be run at one time;

3. maintaining high levels of sensitivity and specificity while making tests quicker and higher in throughput;

4. democratizing and reducing the costs of testing;

5. enhancing ease of use to enable at-home tests; and

6. multiplexing to allow testing for COVID-19 and other respiratory pathogens simultaneously.

As much of the world enters a new phase of the pandemic, with the ebb and flow of case counts being influenced by factors such as vaccination rates and emerging variants, testing will continue to be a critical component of the public health response.

Swabs are out, saliva is in

Most people who have had a COVID-19 test are familiar with the watery-eye-inducing, nose-tickling, swab-swirling method of sample collection. But this method has serious limitations. For example, it typically requires that the nasal swab be performed by a trained person, it permits variability in the amount of sample that is collected, and it depends on an adequate supply of swabs. To avoid these limitations (and others), researchers have sought alternative sampling methods. Some researchers, such as Anne Wyllie, PhD, associate research scientist, Epidemiology of Microbial Diseases, Yale School of Public Health, see promise in saliva.

Anne Wyllie, PhD
Yale School of Public Health

Saliva is currently not a traditional sample type for clinical diagnoses, Wyllie notes, though it was frequently used in the early 1900s. “The advances that we have made through validation and optimization of saliva for SARS-CoV-2 detection,” she explains, “have highlighted the potential for alternative—and more tolerable—options than the traditional nasopharyngeal swab.”

But saliva samples cannot be simply swapped out for nasopharyngeal samples without other considerations. Saliva is a different sample than a swab, explains Wyllie. And the method used must be suitable for the sample. You wouldn’t apply a method that works for swabs to a urine, blood, or fecal sample and expect it to work, she notes.

Unfortunately, many labs apply a swab-based method to saliva samples. When the tests fail, the labs tend to blame the saliva sample. Wyllie asserts that instead of denigrating saliva testing, we “should be promoting the standardization of saliva testing.” Many methods have used saliva to advantage, and we need to start replicating those successes rather than allowing labs that don’t use saliva properly to fuel further doubt.

Many American labs are currently using saliva. Last year, Wyllie’s group, working with Nathan Grubaugh, PhD, associate professor at Yale School of Public Health, launched the SalivaDirect test. More recently, in April, New York’s Mount Sinai Health System announced the launch of the Mount Sinai COVID-19 PCR Saliva Testing program. In May, the Mount Sinai Health System and the Pershing Square Foundation announced the expansion of a saliva-based COVID-19 testing program in New York City public schools.

SalivaDirect, a COVID-19 diagnostic test developed by researchers at the Yale School of Public Health, processes saliva samples, which can be obtained less invasively than nasal swabs. Having received Emergency Use Authorization from the FDA in August, SalivaDirect has been adopted by some labs across the country. The efficacy of SalivaDirect was evaluated in the SWISH (Surveillance With Improved Screening and Health) study, which included NBA players and staff.

Some companies are trying to move saliva testing into the home. A startup called Vatic has put lateral flow technology at the center of its KnowNow antigen tests. Although the tests currently need to be administered by a trained healthcare professional, Vatic is exploring tests that could be performed in the home.

Will saliva testing be routine in the future? “I think it has amazing potential,” says Wyllie. It could change diagnostics in low-resource settings, she adds, and it could also provide a powerful screening tool for other diseases.

No PCR? No problem

Since the start of the pandemic, many labs have found a new utility for their previously developed technology in detecting viruses. For example, the lab led by Jussi Hepojoki, PhD, at the University of Helsinki built a COVID-19 test on a method the lab had previously developed, a method known as time-resolved Förster resonance energy transfer (TR-FRET). The method has been used for rapid homogeneous “mix and read” immunoassays to detect antibodies.

FRET occurs when two fluorophores (a donor and an acceptor) come in close proximity to each other. When that happens, the donor transfers energy to the acceptor, causing a photon to be emitted. In the COVID-19 assay, antibodies against the nucleoprotein (anti-NP) of the virus and antibodies against the spike protein of the SARS-CoV-2 virus, each labeled with a fluorophore, are mixed together with the clinical sample.

Data analyses provided by the Johns Hopkins Coronavirus Resource Center indicate that in the United States, the number of COVID-19 tests performed has varied tremendously over time. The decrease in the number of tests performed since January 2021 is likely due to the rise in vaccinations. However, because testing is of critical importance in stopping chains of transmission during a pandemic, the COVID-19 testing drop off may lead to a lack of critical information for epidemiologists and public health officials. [Johns Hopkins Coronavirus Resource Center]

The antigen-based test has been shown to detect SARS-CoV-2 rapidly—in 10 minutes—and is estimated to be capable of analyzing as many as 500 samples in an hour. This method appeared in the journal mBio, in an article titled, “A Generic, Scalable, and Rapid Time-Resolved Förster Resonance Energy Transfer-Based Assay for Antigen Detection—SARS-CoV-2 as a Proof of Concept.” The article’s authors note that although SARS-CoV-2 was used to demonstrate proof of concept for the test, the principle could be applicable to test across a wide variety of infectious and perhaps also noninfectious diseases.

Sequencing samples with standards

NGS-based testing has taken a back seat to the RT-PCR test for COVID-19 diagnostics. However, innovative sequencing-based methods show promise for future testing. Last October, researchers at UCLA and Octant brought the genomic toolbox to SARS-CoV-2 testing by introducing SwabSeq. Combining NGS of pooled samples with sample-specific barcoding and standards, the test has been shown to work on nasal and saliva samples—without the need for RNA extraction.

SwabSeq adds a synthetic RNA standard to every sample. The standard’s sequence is nearly identical to the target in the virus genome, but different enough that it can be distinguished by sequencing. The detection of SARS-CoV-2 is based on the ratio of sequencing reads of the virus to those of the standard. This process eliminates error: if there is synthetic RNA but no SARS-CoV-2 RNA, the COVID-19 test is deemed to have worked (and to have provided a negative result); if there is no synthetic RNA or SARS-CoV-2 RNA, the test is deemed to have failed.

With SwabSeq, it is possible to test thousands of samples in a single run. In July, SwabSeq’s high-throughput nature was described in Nature Biomedical Engineering, in a paper entitled, “Massively scaled-up testing for SARS-CoV-2 RNA via next-generation sequencing of pooled and barcoded nasal and saliva samples.” According to this paper, SwabSeq was used to perform 80,000 tests, with sensitivity and specificity comparable to (or better than) RT-PCR.

CRISPR gets electric

Researchers at the Wyss Institute at Harvard Medical School have innovated more than one way to detect COVID-19 over the past year. For example, a program to create wearable sensors, by embedding synthetic biology reactions into fabrics, produced a facemask that detects SARS-CoV-2 using CRISPR-based SHERLOCK (Specific High-Sensitivity Reporter unLOCKing) technology. The technology can work with any facemask to identify the virus in a person’s breath with high accuracy.

Pawan Jolly, PhD
Pawan Jolly, PhD
Wyss Institute

Another group at the Wyss is working to detect the virus using CRISPR—by converting the standard optical readout to an electrochemical one. This work is being done by Pawan Jolly, PhD, senior staff scientist I, in the lab of Don Ingber, MD, PhD, Wyss’s founding director, and Helena de Puig Guixe, PhD, a postdoctoral fellow in the lab of James J. Collins, PhD, founding core faculty at the Wyss Institute.

Before COVID-19, the team had developed the eRapid technology. At eRapid’s core is a fouling-resistant, affinity-based platform of multiplexed, electrochemical sensors. The proprietary coating is the key, Jolly tells GEN, because it enables detection in complex samples without any sample preparation. In general, the problem with electrochemical sensors is biofouling. If blood is being assayed, there are many molecules that nonspecifically bind to the surface, which makes detection challenging. The eRapid platform prevents the nonspecific binding.

Helena de Puig Guixe, PhD
Helena de Puig Guixe, PhD
Wyss Institute

Since COVID-19, they have been working to develop the eRapid technology to detect nucleic acids, like the genome of SARS-CoV-2. For that, they turned to CRISPR. But CRISPR detection assays are typically an optical readout, performed either by fluorescence or lateral flow assays. Jolly and de Puig Guixe are using electrical current instead. The advantages of a test with an electrochemical readout are that it is cheap and easily miniaturized, that it requires minimal instrumentation, that it is scalable and capable of multiplexing, and that it needs only small volumes.

The CRISPR-based COVID-19 diagnostic harnesses the Cas12a-based detection system, but instead of reading the reporter as a fluorophore, the reporter probe is modified with a tag that is electrochemically active. If the virus is present, the Cas12a enzyme cleaves the reporter, removing the electrochemically active tag, and no signal will be present. In this assay, the absence of reporter indicates the presence of the virus.

Researchers at the Wyss Institute are applying their previously developed electrochemical sensing technology, known as eRapid, to the COVID-19 pandemic. This work involves combining eRapid with a CRISPR-based method of detection. In addition, the eRapid technology is being developed for multiplexed COVID-19 biomarker detection through collaboration with GBS, a subsidiary of The iQ Group Global.

Jolly states that a benefit to this approach is its built-in validation. In other systems, the absence of virus is indicated by the absence of signal. But Jolly notes that a lack of signal could indicate that an assay has failed. The built-in validation in Wyss team’s system ensures that the assay is working because signal is seen even in the absence of the virus. This system has been validated for use on saliva samples for the detection of SARS-CoV-2—work that has been submitted for publication.

The faster the better

The pace of COVID-19 testing has improved over the past 18 months. At the beginning of the pandemic, it was not unusual to wait up to a week for results. More recently, the expected wait time has fallen to 24 hours. Some antigen tests can give a result in minutes. But a new test, developed at the University of Nevada, is even faster, giving a result in just 30 seconds.

The test uses a nanotube-based electrochemical biosensor and is based on technology that Mano Misra, PhD, professor in the Chemical and Materials Engineering Department, previously developed to detect tuberculosis. The biosensor, which incorporates cobalt-functionalized TiO2 nanotubes (Co-TNTs), detects the receptor binding domain of SARS-CoV-2’s spike protein. According to an article in the journal Sensors, the test consists of a one-step, ultra-fast procedure that can be run at low cost.

With recent news of the surges in cases caused by the Delta variant, the need for routine COVID-19 testing is certain to be a staple of public health for some time. The most advanced testing technologies in development are intended to counter the current pandemic. However, they may not be widely implemented before the pandemic wanes. Regardless, they may be ready by the time we face the rise of a new outbreak or pandemic. The ability to have fast and effective testing at the ready—as the first cases of a new infectious disease are reported—could be the difference between a small cluster of cases and a global pandemic.

The post Methods to Detect Viruses Get a Boost, Thanks to the COVID-19 Response appeared first on GEN - Genetic Engineering and Biotechnology News.

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Potential COVID-19 Treatment Found in Llama Antibodies

The need to uncover effective COVID-19 treatments remains imperative, as case counts remain steady eighteen months into the pandemic. Recent findings point to unique antibodies produced by llamas—nanobodies—as a promising treatment. The small, stable,…



A significant milestone in the COVID-19 pandemic was crossed this week. The number of deaths in the United States due to COVID-19—more than 675,000—has surpassed the number of deaths that occurred during the 1918 flu pandemic. In addition, there are still roughly 150,000 new cases every day. Eighteen months into the pandemic, the need for effective treatments against COVID-19 remains as great as ever.

One possible treatment, neutralizing single domain antibodies (nanobodies), has significant potential. The unique antibody produced by llamas is small, stable, and could possibly be administered as a nasal spray—an important characteristic as the antibody treatments currently in use require administration by infusion in the hospital. Now, new research shows that nanobodies can effectively target the SARS-CoV-2 virus.

The team from the Rosalind Franklin Institute found that short chains of the molecules, which can be produced in large quantities, showed “potent therapeutic efficacy in the Syrian hamster model of COVID-19 and separately, effective prophylaxis.”

This work is published in Nature Communications in the paper, “A potent SARS-CoV-2 neutralizing nanobody shows therapeutic efficacy in the Syrian golden hamster model of COVID-19.

The nanobodies, which bind tightly to the SARS-CoV-2 virus, neutralizing it in cell culture, could provide a cheaper and easier to use alternative to human antibodies taken from patients who have recovered from COVID-19.

“Nanobodies have a number of advantages over human antibodies,” said Ray Owens, PhD, head of protein production at the Rosalind Franklin Institute. “They are cheaper to produce and can be delivered directly to the airways through a nebulizer or nasal spray, so can be self-administered at home rather than needing an injection. This could have benefits in terms of ease of use by patients but it also gets the treatment directly to the site of infection in the respiratory tract.”

Credit: Rosalind Franklin Institute

The research team was able to generate the nanobodies by injecting a portion of the SARS-CoV-2 spike protein into a llama called Fifi, who is part of the antibody production facility at the University of Reading. They were able to purify four nanobodies capable of binding to SARS-CoV-2. Four nanobodies (C5, H3, C1, F2) engineered as homotrimers had pmolar affinity for the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. Crystal structures showed that C5 and H3 overlap the ACE2 epitope, while C1 and F2 bind to a different epitope.

Regarding their effectiveness against variants, the C1, H3, and C5 nanobodies all neutralized the Victoria strain, and the highly transmissible Alpha (B.1.1.7 first identified in Kent, U.K.) strain. In addition, C1 neutralizes the Beta (B.1.35, first identified in South Africa).

When one of the nanobody chains was administered to hamsters infected with SARS-CoV-2, the animals showed a marked reduction in disease, losing far less weight after seven days than those who remained untreated. Hamsters that received the nanobody treatment also had a lower viral load in their lungs and airways after seven days than untreated animals.

“Because we can see every atom of the nanobody bound to the spike, we understand what makes these agents so special,” said James Naismith, PhD, director of the Rosalind Franklin Institute. If successful and approved, nanobodies could provide an important treatment around the world as they are easier to produce than human antibodies and don’t need to be stored in cold storage facilities, added Naismith.

“Having medications that can treat the virus,” noted Naismith, “is still going to be very important, particularly as not all of the world is being vaccinated at the same speed and there remains a risk of new variants capable of bypassing vaccine immunity emerging.”

The researchers also hope the nanobody technology they have developed could form a so-called “platform technology” that can be rapidly adapted to fight other diseases.

The post Potential COVID-19 Treatment Found in Llama Antibodies appeared first on GEN - Genetic Engineering and Biotechnology News.

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China Syndrome? Is Evergrande A Symptom Of Deeper Malaise

China Syndrome? Is Evergrande A Symptom Of Deeper Malaise

Authored by Bill Blain via,

“If that’s true, we are very close to the China Syndrome ”

Evergrande’s imminent default is rocking markets – but few believe…



China Syndrome? Is Evergrande A Symptom Of Deeper Malaise

Authored by Bill Blain via,

“If that’s true, we are very close to the China Syndrome ”

Evergrande’s imminent default is rocking markets – but few believe the collapse of a Chinese property developer could trigger a global financial crisis. What if Evergrande is just a symptom of a deeper malaise within the Chinese economy and its political/business structures? Maybe there is more at stake than we realise? What if Emperor Xi decides he needs a distraction?

Amid this week's market turbulence, and the overnight headlines, Evergrande dominates thinking this morning. The early headlines say the risk is “easing”. Don’t be fooled. S&P are on the wires saying it’s on the brink of default and is unlikely to get govt support. It’s Asia’s largest junk-bond issuer. Anyone for the last few choc-ices then?

The market view on the coming Evergrande “event” is mixed. Some analysts are dismissing it as an internal “China event”, others reckon there may be some systemic risk but one Government can easily address. There is some speculation about “lessons” to be learnt… There are even China supporters who reckon its proof of robust China capitalism – the right to fail is a positive!

I’ve got a darker perspective.

The massive shifts we’ve seen in China’s political/business public persona over the past few years have been variously ascribed: a reaction to Trump’s protectionism, China taking its place as a leading nation, Xi flexing his military muscle, and now a clampdown on divisive wealthy businesses to promote common prosperity.

What if Evergrande is just a symptom of something much deeper?

That that last 30-years of runaway Chinese growth has resulted in a deepening internal crisis, one that we barely perceive in the west? What if the excesses that have spawned Evergrande and the illusion every Chinese can afford luxury flats and a western standard of living is about to implode? Crashing oriental minor chords!

The looming Chinese property debacle will be fascinating, but it many respects will be similar and yet very different to the multiple market unwinds we’ve seen in the west. How it plays out will have all kinds of implications for growth, speculation and how global investors perceive China in the future. Folk are variously describing it as China’s Lehman Brothers, or the next “Minsky Moment” when speculation ends with a sharp jab of reality to the kidneys.

I’m thinking back to a story I read a few years ago about the Shanghai Auto-fair pre-pandemic. Evergrande New Electric Vehicles had the largest stand and was showing off 11 different EVs. Not one of these were actually available to buy – they were all models of as-yet unproduced cars. The company was valued at billions and yet never sold a single vehicle. This morning, it’s just another worthless business Evergrande is trying to flog. (See this story on Bloomberg TV: China’s Zombie EV Makers.)

The market is asking itself a host of questions about Evergrande’s collapse: How bad will its tsunami of Chinese contagion deluge global markets? When it’s going to happen? What knock-on effects will cascade through markets?

Perhaps the most important question is: Who will be exposed “swimming naked” when the Evergrande tide goes out? Who will be left with the biggest losses? As the company is definitely bust, these losses rather depend on just how China’s authorities respond.

Step back and think about it a moment – try putting these in context:

  • Fundamentally all business is about identifying a consumer need and filling it.

  • Fundamentally, greedy businessmen tend to get carried away because the political-financial system enables them.

  • Fundamentally, it’s just another burst bubble and who cleans up the mess.

  • In Evergrande’s case a thousand flowers of capitalism with Chinese characteristics grew into an unsustainable business – fundamentally no different from debt-fuelled sub-prime mortgages, or CDOs cubed, in the West.

The big difference this time is its China! China has done things… differently. The path China pursued in its recovery and growth since 1980 has not been without… consequences.

Thus far we’ve praised China for its spectacular growth and the creation of valuable companies under the red banner of Chinese capitalism. It is going to be “interesting” to see how the subsequent mess is cleared out. Questions about Moral Hazard are going to be shockingly simple – Government has made it abundantly clear that any wrongdoing by company executives will be punished in the harshest possible way.

More importantly, Chinese politics and business works on a very different playing field to the west. Forget the rule of law or the T&C’s of Evergrande bonds. It easy to dismiss and characterise the way Chinese business works as institutionalised systemic corruption – but it’s a system Ancient Roman Emperors would recognise as a patron/client relationship. Emperor Xi’s clients and his princelings will continue to benefit from his patronage in return for their support at his court, and will be protected in a meltdown. The system Xi presides over will have little motivation to intervene to protect western investors who find themselves caught in the Evergrande fiasco.

Where Xi will have to take notice is outside the rich, wealthy princeling cadre which increasingly owns and runs China. There will be massive implications for wealth/inequality among the Chinese people from a property collapse. With a third of Chinese GDP dependent on the property sector, (and about 4 million jobs at Evergrande), the collapse of one of the biggest players, and the likelihood others will follow is much more than just a systemic risk.

Property is a key metric in the aspirations to wealth of the rising Chinese middle classes. The same smaller Chinese investors and savers will likely prove the largest losers from the property investment schemes they were sucked into. These real losses will rise if hidden bank exposures trigger a domestic banking crisis – which apparently isn’t likely (meaning it is..). There are reports of investor protests in key China cities – putting pressure on the govt to act to mitigate personal losses.

Xi’s clampdown on big tech is painted as the Party’s programme to engineer a more socially-equal economy. He has pinned the blame for rising inequality on “corrupt” business practices and has his cadre’s waving books on Xi thought, mouthing slogans about “common prosperity” and “frugality”. These are going to look increasingly hollow if the middle classes bear the coming Evergrande pain, and the Party Princelings continue to prosper.

The really big risk in China is not that Evergrande is going to default – it’s much bigger. If the Party is seen to fail in its promise to deliver wealth, jobs and prosperity for the masses – then that is very serious. China’s host of failed EV companies, an economy still reliant on exporting other nations tech, and a massively overvalued property sector (that the masses still equate with prosperity) all suggest a much less solid economy than the Party promotes.

If the illusion of a strong economy is unravelling – who knows what happens next, but in Ancient Rome the answer would be simple… Blame someone else, and invade..

This could get very “interesting…” and not in a good way.

Tyler Durden Wed, 09/22/2021 - 08:45

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White House Reporters Have Launched ‘Formal Objection’ About Biden Refusing To Answer Questions

White House Reporters Have Launched ‘Formal Objection’ About Biden Refusing To Answer Questions

Authored by Steve Watson via Summit News,

CBS News reported Tuesday that the press pool of White House reporters have launched a formal objection



White House Reporters Have Launched 'Formal Objection' About Biden Refusing To Answer Questions

Authored by Steve Watson via Summit News,

CBS News reported Tuesday that the press pool of White House reporters have launched a formal objection over the fact that Joe Biden refuses to answer any questions, with reporters routinely being yelled down and physically pushed away by Biden’s handlers.

The revelation came after an embarrassing scene in the Oval Office with British Prime Minister Boris Johnson answering questions, but Biden not being allowed to by aides.


Johnson took the three questions from British reporters

CBS reporter Ed O’Keefe said that “Johnson took 3 questions. White House aides shouted down U.S. attempts to ask questions. I asked Biden about southern border and we couldn’t decipher what he said.”

CBS radio correspondent Steve Portnoy later reported that “The entire editorial component of the US pool went immediately into Jen Psaki’s office to register a formal complaint that no American reporters were recognized for questions in the president’s Oval Office.”

Portnoy, also president of the White House Correspondents Association, added that the complaint also extended to the fact “that wranglers loudly shouted over the president as he seemed to give an answer to Ed O’Keefe’s question about the situation at the Southern Border. Biden’s answer could not be heard over the shouting.”

“Psaki was unaware that the incident has occurred and suggested that she was not  in a position to offer an immediate solution,” Portnoy continued, adding “Your pooler requested a press conference. Psaki suggested the president takes questions several times a week.”

In addition, National Review notes that after Biden’s UN speech yesterday, French reporter Kethevane Gorjestani “was asked by a very startled Australian reporter whether WH wranglers were always so strict about ushering the pool out without questions.”

The pathetic display is a continuation of the way Biden’s handlers have been acting since even before he took office, shooing away reporters, giving Biden strict instructions on who he can take questions from, and even muting his mic when he goes off script.

A week ago, Republican Senator James Risch demanded to know who is in charge of controlling when the President is allowed to be heard, noting during a Senate hearing that “This is a puppeteer act, if you would, and we need to know who’s in charge and who is making the decisions.”

“Somebody in the White House has authority to press the button and stop the president, cut off the president’s speaking ability and sound. Who is that person?” Risch asked.

Tweeting out the video, leftists insisted the claims were ‘bizarre,’ ‘ridiculous’ and ‘absurd’:

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Tyler Durden Wed, 09/22/2021 - 10:15

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