Early in the covid pandemic, testing for the virus was tied to central, certified laboratories that quickly became overwhelmed. During peak viral surges, results often arrived too late to give meaningful information about whether someone should quarantine or return to work. And in parts of the world without access to high-tech labs, people had no way to tell if their cough or fatigue was caused by covid or a bad cold.
But even as the world went into lockdown in the spring of 2020, MIT researchers already had a head start in the race to develop the diagnostic tools needed to help contain the pandemic. Teams that had been focused on Zika, Ebola, and cancer pivoted almost overnight to begin working on fast, low-cost, easy-to-use tests that could take pressure off of backlogged labs, allow for more widespread testing in low-resource areas, and be adapted to include emerging viral variants.
“We need testing technologies that will work in both the developed and developing world,” says James Collins, Termeer Professor of Medical Engineering and Science in MIT’s Institute for Medical Engineering and Science, a professor of biological engineering, and a member of the Broad Institute of MIT and Harvard. “There is a significant global need to get to inexpensive rapid tests while someone is in the infectious state.”
Diagnostic tests that analyze nucleic acids, also called molecular tests, are the gold standard in covid testing because they can precisely and reliably identify the presence of an infectious pathogen by detecting either its unique genetic sequences or substances it makes. The nucleic acid tests most common in the US use reverse transcription polymerase chain reaction (RT-PCR) to amplify genetic material and can detect even tiny amounts of coronavirus RNA. But these PCR tests, as they’re known, require expensive equipment, trained technicians, and multiple steps involving careful handling of liquids, and they take several hours to run.
In comparison, rapid antigen tests are quicker and easier to administer. Rather than looking for nucleic acid, they detect the presence of viral proteins called antigens that are present on the surface of the virus. Such tests, which can be done at home, deliver results quickly, but they tend to be less accurate than PCR tests. People in the very early or late stages of the disease may have a low viral load, meaning there may not be enough telltale protein for the test to pick up, so they could be infected with SARS-CoV-2 but receive negative results from a rapid antigen test—and unwittingly keep spreading the virus.
Until recently, we have had to choose between the accuracy of PCR tests and the speed of antigen tests. But what if we could have both, and at a low cost? Through innovations like wearable tech, convenient home-testing devices, and even entirely new platforms, MIT researchers are developing accurate, cheap covid tests for homes and clinics that provide results in under an hour.
Next-gen covid diagnostics
In 2015, long before coronavirus was making headlines, Omar Abudayyeh ’12, PhD ’18, and Jonathan Gootenberg ’13 made a surprising discovery in the lab that suggested a powerful new use for the gene-editing technique known as CRISPR. (CRISPR is so precise at inserting and deleting DNA that it has been described as using molecular scissors.) Both were doctoral students working in the lab of Feng Zhang, an MIT neuroscience and biological engineering professor, and a core member of the Broad Institute. While looking for new enzymes for CRISPR gene-therapy applications, they discovered a peculiar class of enzymes that can be programmed to search for specific RNA or DNA sequences (from a virus, for example) and, upon finding them, chop them up. However, the enzymes don’t always stop there—in fact, at least in a test tube, they chop up all strands of RNA.
“They become this nucleic acid bomb and start chewing everything up. That’s not great for therapeutics, because it kills cells,” Abudayyeh says. But with a few tweaks, CRISPR proved to be useful as a diagnostic tool.
Building on this discovery, Collins, Zhang, Abudayyeh, and Gootenberg (along with other Broad Institute colleagues, including Pardis Sabeti ’97) published a paper in Science in 2017 describing how CRISPR could be used not just to edit genes, but to detect genetic sequences specific to any disease-causing infectious agent. First, their method called for amplifying as little as a single molecule of DNA or RNA from the genetic material in a sample at a constant temperature (avoiding the alternating temperatures required with PCR). Then instead of using CRISPR to insert or delete DNA, they used a different enzyme, Cas13a, to recognize the amplified materials—including those of bacteria and viruses—and simultaneously activate a fluorescent reporter gene. Abudayyeh and Gootenberg came up with the name Sherlock (Specific High-sensitivity Enzymatic Reporter unLOCKing) to describe the new method, which offers extremely high sensitivity on par with PCR-based diagnostics.
Two years later, Collins, Zhang, Sabeti, Gootenberg, and Abudayyeh teamed up with other colleagues to cofound Sherlock Biosciences, a biotech company focused on applying this technology to offer fast, accurate diagnostics, ideally without the expensive lab equipment and skill needed for PCR tests. The company began designing rapid tests to detect sexually transmitted diseases such as chlamydia and gonorrhea, and even tumor cell mutations. Meanwhile, Abudayyeh and Gootenberg (who earned spots on MIT Technology Review’s list of 35 Innovators under 35 in 2019 and 2021) became MIT McGovern Institute fellows and established the AbuGoot Lab there in 2019 to develop medical diagnostics and therapeutics through molecular and cellular engineering.
As covid began making its way around the world in late January 2020, Abudayyeh, Gootenberg, and Zhang turned their attention to rapid covid testing. Continuing their longstanding collaboration, they spent two weeks experimenting in the lab to find new enzymes and primers that would allow them to adapt their CRISPR-based Sherlock test to detect SARS-CoV-2. They developed a test that uses two guide-RNA sequences that target signature viral RNA sequences specific to SARS-CoV-2 and, upon finding them, generate a signal that can be detected with either a fluorescent reader or a lateral flow strip test. By May 2020, Sherlock Biosciences had received emergency use authorization from the FDA for its Sherlock-based covid test—the first FDA approval involving CRISPR. Although the Sherlock covid test could be used only in specially certified labs, it only required one hour for results. And its sensitivity was on par with the gold-standard RT-PCR tests.
Zhang, Abudayyeh, Gootenberg, and others also developed STOPCovid, a rapid, inexpensive, and scalable diagnostic test for the virus that they freely shared for research purposes in May 2020. They redesigned the CRISPR diagnostic test to work with fewer steps so that it could be run in doctors’ offices and clinics—away from a certified lab.
STOPCovid eliminates the need to open test tubes while running the test, which could contaminate samples, and simplifies the extraction process by incorporating magnetic beads that bind to and help concentrate viral RNA after it is extracted from the virus. It also reduces the isothermal amplification process used in the original Sherlock test from two steps to one. If the N gene of the SARS-CoV-2 genome is present in a sample, an enzyme (AapCas12b) senses its amplified sequences and produces a fluorescent reporter signal. When the fluorescent signal reaches a certain threshold, the test is considered positive.
Although the STOPCovid test is slightly simpler than the original Sherlock test, it is not FDA-approved. And it still relies on the use of lab equipment such as hot water baths or PCR machines that may not be available to all users, Abudayyeh says.
Collins and his lab have also built upon the original Sherlock technology to create a minimally instrumented Sherlock test, or miSherlock, capable of producing covid-19 test results in about an hour using saliva samples. It can extract, purify, and concentrate RNA for three different viral variants: alpha (B.1.1.7), B.1.351 (beta), and gamma (P.1).
While most CRISPR-based diagnostics rely on a workflow that involves multiple liquid-handling steps using equipment such as pipettes, heating blocks, and centrifugal machines, miSherlock is a self-contained system. All the CRISPR-based chemistry takes place in one chamber, and this “one-pot Sherlock” device makes it possible to move CRISPR testing into a doctor’s office or even a home.
With miSherlock, a critical preprocessing step allows for the test to be saliva-based. Saliva tends to have a slightly higher viral load than mucus in nasal passages, but it contains enzymes that destroy RNA. In the miSherlock test, a user provides 4 milliliters of saliva, which goes into a prep chamber where those enzymes are inactivated by heat and two chemical reagents. Next, the saliva passes through a membrane that extracts and concentrates the viral RNA. Then a one-pot Sherlock reaction is initiated as the device punctures sealed water packets to activate freeze-dried CRISPR/Cas components, amplifying the concentrated viral RNA and producing a telltale fluorescent signal if SARS-CoV-2 or one of three variants is present. The researchers described this technology in Science Advances in August 2021.
“Our miSherlock technology only costs a few dollars, it can be 3D-printed, and it can provide an analysis of saliva samples in under an hour,” Collins says. “We’re positioning this as a point-of-care version of the earlier work with Sherlock.”
Collins has another idea for cheap rapid tests, and it involves a familiar component: the face mask. His lab is working on a single-use disposable sensor that can be inserted inside a face mask to test the wearer’s covid status.
Before the pandemic, the lab was exploring how to use synthetic genetically engineered circuits to create fast, flexible diagnostics. These circuits mimic the logical function of electrical circuits but are built with cell-free, biologically engineered cellular components such as proteins, ribosomes, and nucleic acid. Collins and his team—including Luis Soenksen, PhD ’20, of MIT’s Abdul Latif Jameel Clinic for Machine Learning in Health, and Peter Nguyen, a research scientist at Harvard’s Wyss Institute for Biologically Inspired Engineering—aimed to program them to identify the genetic signatures of specific pathogens.
After figuring out how to print these genetically engineered sensors on paper for Zika tests during the 2015–’16 outbreak in the Americas, his team turned its attention to transforming lab coats. “We were thinking about developing a lab coat of the future that could report on pathogen exposure,” says Collins, who is also affiliated with the Wyss Institute. “We had already discovered that one could freeze-dry cell-free extracts and synthetic gene circuits onto paper, to create paper-based diagnostics. And we did so for Ebola and Zika. But then we also recognized that we could freeze-dry these extracts onto other porous materials, including clothing.”
Collins envisioned coats made of fabric imprinted with genetically engineered sensors capable of detecting a variety of pathogens. But as the pandemic persisted, he and his team realized that the same technology could be used inside face masks. Instead of detecting pathogens from environmental exposure, however, the mask sensors would detect SARS-CoV-2 from the wearer’s respiratory droplets.
The freeze-dried cellular components can remain stable for months. For the face mask application, these components are embedded in a paper mask and encircled by a silicone elastomer ring, which prevents the exhaled sample from escaping the sensor. The wearer pushes a button to inject a small amount of water onto the sensor, and the activated cellular components in the sensor react with the targeted DNA or RNA sequence—if it is present—to induce a color change that signals the presence of the virus.
“It will report out in roughly one hour the infection state of an individual, and it has very high sensitivity and specificity on par with lab-based tests,” Collins says. He is exploring regulatory paths for the face mask concept.
While the current version of the sensor can differentiate between coronavirus variants, Collins and his team are pushing the system to be multifaceted and to detect a variety of other respiratory viruses. The noninvasive device, which continuously monitors for about two hours, will also be affordable. “Probably just a few dollars,” Collins says. “We envision these being something people put on while they go to work or out shopping.”
Abudayyeh and Gootenberg are continuing to push CRISPR-based testing into affordable, rapid diagnostics that anyone can use at home. With Zhang, they cofounded the startup Proof Diagnostics, where they are building on their STOPCovid work, fine-tuning the chemistry steps to untether the test from a laboratory and make it self-contained in a device that can be used in clinics, at workplaces, or at home.
The Proof Diagnostics test requires a nasal swab, and the wand must then be swirled in a cartridge containing a lysis solution filled with tiny magnetic beads that bind to the viral RNA, similar to the STOPCovid test. Once the RNA is converted into DNA and amplified (using a process that doesn’t require temperature changes), the CRISPR AapCas12b enzyme reacts in the presence of the amplified covid DNA, creating a fluorescent signal. A portable device reads the cartridge and indicates a positive test if a fluorescent threshold is reached; users can check the test’s progress through an app. In a prototype version of the test, results took 30 to 40 minutes in cases of low viral detection, Abudayyeh says, but were available in as few as 18 minutes in cases of high viral load.
“It’s fast enough that you are not waiting too long for results, and it’s sensitive enough that you will actually catch the positives, unlike the rapid antigen tests,” Gootenberg says. “One of the thoughts is that we can use tech like this to gather safely again. We need to cross this line to make testing truly meaningful.”
“The main challenge is making the device work with chemistry, and making it work every time,” Abudayyeh says. “Everything matters—what material you have in the cartridge, what gets stuck, when you freeze-dry your reagents, is it rehydrating over time? All these components have so much complexity that it just takes a long time to work through every single bug.”
The tests and device are currently being used for investigational purposes in several point-of-care clinics in Florida, North Carolina, Washington, and Canada. Proof Diagnostics plans to use this investigational data to seek FDA approval.
Assessing immunity and a new test platform
Other MIT researchers are investigating novel platforms that detect either covid or the body’s ability to fight it. Megan McBee ’02, PhD ’07, a program director for the Singapore–MIT Alliance for Research and Technology, or SMART, collaborated on an initiative to transform highly accurate neutralizing antibody (NAb) lab tests into rapid point-of-care tests.
The immune system produces neutralizing antibodies that render invading pathogens like SARS-CoV-2 incapable of causing an infection. The body can only make these antibodies if it recognizes a specific pathogen through either natural infection or vaccination. But don’t confuse antibodies and antigens.
“The NAb test answers a different question than the more familiar rapid antigen tests,” McBee says. “NAb tests inform whether a person has levels of neutralizing antibodies that are likely high enough to block the virus from infecting them. Rapid antigen tests inform about whether a person is infected with the virus.” NAb tests can detect prior covid infections and determine if someone mounted a sufficient immune response after an infection. They can be used to monitor the antibody response after vaccination and offer insight on a vaccine’s efficacy and durability. They can also help figure out whether prior infections or vaccinations provide immune protection against new covid variants. And knowing the level of immune protection individuals, or populations, have could help guide public health policy.
SMART’s Antimicrobial Resistance Interdisciplinary Research Group, which includes MIT chemical engineer Hadley Sikes (see “Molecular monitor,” p. 26) and collaborators from Nanyang Technological University in Singapore developed a rapid point-of-care NAb test that performs as well as the best available lab-based NAb tests, she says. The vertical-flow paper-based test gives results in 10 minutes.
Using a drop of blood from a finger prick, the test senses complex interactions between the angiotensin-converting enzyme II (ACE2) receptor of a host cell and the receptor-binding domain of the SARS-CoV-2 virus. If NAbs are present, the test can detect disruptions between these two elements within 10 minutes—a vast improvement over the hours or days required for traditional NAb tests. This new platform eliminates the need for the laboratory-based testing, equipment, and personnel all other NAb-based tests require.
“The test can be done anywhere that a basic screening can be done,” McBee says. “But currently, the test requires a specialized, but small, point-of-care reader. Hence, it cannot be done at home, yet.”
The new test can also detect clinically relevant NAb ranges that correspond to vaccination status. It also detected substantially reduced NAbs against the beta, gamma, and delta variants in people who had received the covid-19 vaccine three months earlier. The decline in NAbs against viral variants offers insights into the rise of breakthrough infections among vaccinated people, showing that their level of protection against emerging viral variants may wane depending upon which vaccine they received and possibly how long ago they received it.
SMART, Nanyang Technological University, and a spinoff company from SMART called Thrixen are pursuing the final development, regulatory compliance, and commercialization of their 10-minute NAb test through agencies in Singapore.
Other MIT researchers are looking for entirely new testing platforms. Before the pandemic, chemical engineering professor Michael Strano and his lab had developed carbon nanotube structures wrapped in polymers that could sense a variety of viral proteins. They quickly adapted this platform to identify viral proteins specific to SARS-CoV-2. Because their method doesn’t rely on antibodies or reagents that take a long time to generate and purify, Strano’s team zeroed in on a modified carbon nanotube that could detect these proteins—and they produced a working prototype within about 10 days of starting the project.
Strano’s team had already shown that when carbon nanotubes are encased in different kinds of polymers, they can chemically sense target molecules. Here’s how it works: The carbon nanotubes naturally fluoresce when exposed to laser light waves. The polymers wrapped around these tubes form loops that create a corona-like layer on the tube’s outer surface. Different polymers have different structural loop forms that can trap target molecules—in this case, viral proteins. When the looping polymers have trapped and bound various molecules, that alters the intensity of fluorescence the carbon nanotube gives off—and an optical reader can detect this difference. The approach is known as corona phase molecular recognition.
Most covid tests rely on nasal swabs because the carbohydrate and digestive enzyme molecules of saliva typically interfere with protein detection. But Strano’s team, which includes postdoctoral researcher Sooyeon Cho (recently named an assistant professor at Sungkyunkwan University) and graduate student Xiaojia Jin, SM ’21, found that their technique can detect the SARS-CoV-2 nucleocapsid protein, which encapsulates the viral genome and is essential to viral replication, when it’s dissolved in saliva. Working with InnoTech Precision Medicine, a Boston-based diagnostic developer, they built a prototype that can detect this protein in saliva samples in five minutes.
While we all hoped the pandemic would be over by now, it appears to be transitioning to coexistence and likely will one day join the ranks of other coronaviruses that cause mild, seasonal colds. Until then, MIT researchers are retooling their labs and shifting their focus to address one of the most pressing needs of the covid era: quick, inexpensive tests we can use in hospitals and homes.
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