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At the moment, if you want to know if you have Covid-19, you have to stick a swab test up your nose, ship the sample to a lab and then wait. Shipping, testing and returning a result can take hours at best and days at worst — and labs in the UK are already severely backlogged.
This kind of test works, but all that lab time means it’s slow. New tests in development using gene-editing CRISPR have been touted as a potential solution, offering a result in minutes at point of care — or even in your own home.
CRISPR stands for Clustered Regularly Interspaced Palindromic Repeats, but that doesn’t really explain the discovery made by biochemist Jennifer Doudna in 2012. Gene editing was possible but incredibly difficult before she and collaborator Emmanuelle Charpentier discovered a way to program a protein known as Cas9 to act as a cut-and-paste tool to remove or alter bits of DNA.
So when the Covid-19 pandemic hit earlier this year, researchers including Doudna quickly shifted their CRISPR work to addressing the outbreak. She had long been working on applying CRISPR to diagnostics via her lab at Berkeley, as well as companies she co-founded, Caribou Biosciences and Mammoth Biosciences — with the latter now developing a COVID test. “Like a lot of things, the emergence of the pandemic has just accelerated the pace of all that,” she says.
At the moment, the bulk of Covid-19 tests are PCR, or polymerase chain reactions, which convert single-strand samples of viral RNA into double-strand DNA and then amplify it into larger quantities that are easier to spot. “And that’s fine, but it needs specific technology, particular enzymes and heat cycles that can really accurately ramp temperatures up and down very fast,” explains Colin Butter, associate professor at the University of Lincoln.
The CRISPR-based tests in the works from Mammoth and rivals such as Sherlock Biosciences don’t need a lab, a technician or that temperature change. “It doesn’t require all of this technology to ramp the temperature up and down because it’s an isothermal reaction,” Butter says. “It can happen very easily and in a field-based situation.” Plus, they’re much faster, taking as little as 20 minutes, and much cheaper.
The test Mammoth has created uses CRISPR technology, but rather than programming a protein to find a bit of gene to cut out, it detects it. Dubbed DETECTR, the system pairs a Cas12 protein, which normally does the cutting and pasting of gene editing, with an RNA guide that looks like the virus. When introduced to a patient sample, if it finds a match, the protein starts slicing apart not only the RNA that matches but all the RNA it can find, and that includes a reporter RNA that’s been added to the sample.
That’s all put through a flow detection system — akin to a pregnancy test — that has filters to stop the full-length reporter RNAs in one position if there’s no virus or sliced ones in a different position if there is Sars-Cov-2 present, giving a result that can be read from a line on the slip of paper. It all means the test doesn’t need to be sent to a lab for processing and it gives a result that can be read by an untrained person in 20 minutes, Doudna says.
The good news is the test was detailed in a peer-reviewed paper in Nature in April, with Mammoth partnering with GSK to produce tests in May. The lab version was awarded emergency authorisation from the FDA in the US at the end of August. Doudna says tests using this approach will initially be used in labs, but the ultimate goal is a home test, which the company has said could be available by the end of the year. The delay has to do with creating the test format, including how to collect a sample for those of us not accustomed to shoving a swab up our noses.
That’s key as incorrectly taken samples lead to false negatives with Covid-19 tests — if you don’t hit the right spot, you may get an all clear when you are in fact infected. There are hopes that such tests could work with saliva, making the process easier for at home users, but Mammoth’s work with GSK is for a nose swab version. The results of these tests may be as easy to interpret as a home pregnancy test, but getting an accurate sample is much harder than peeing on a stick.
Mammoth isn’t the only company racing to create a CRISPR-based test. Rival CRISPR company Sherlock Biosciences — co-founded with Feng Zhang of Harvard and MIT — was first to win emergency authorisation from the US FDA, and operates in a similar fashion to Mammoth’s DETECTR though uses a different CAS protein. A Cas13 protein is paired with an RNA guide to spot the virus; if it finds a match, it chops up RNA including a reporting strand, and that’s run through a pregnancy-style test with an easy to read result.
It’s a promising technology, but as yet the Sherlock and Mammoth tests are only designed to work in labs and only approved via that emergency authorisation to be used in lab settings. Until an at-home or point of care version is created and approved, this doesn’t solve the current bottlenecks created by shipping to a lab for processing. While Doudna believes a point of care test will be available this year, the fact neither company has been approved for home tests shows more work remains.
Even if such tests do work, the fact they’re not yet ready could put them out of the running in the longer term. “Sometimes things get overtaken by events,” says Butter. “And now PCR testing is being ramped up finally, and there are point of care tests coming out, so how useful it would generally be may be a technology adoption issue.”
If such CRISPR tests do work, they could potentially check for multiple illnesses, letting someone with the sniffles find out if they have Covid-19, influenza, or both — a feature that will become increasingly important as the pandemic stretches into flu season. “That’s very much an immediate need that’s emerging, to be able to distinguish between different types of infections,” Doudna says. Again, the tests approved so far are just for Covid-19, and further development and authorisation will be required before dual influenza-coronavirus tests are on pharmacy shelves, though it could be nothing more than two tests, one for each disease, in the same box.
There’s another benefit to developing CRISPR diagnostics: Doudna says that if a Sars-Cov-2 test works, it should work on other viruses, meaning all the frantic effort to create these diagnostic tools will be of benefit in the next pandemic, whenever it lands. “We can use it to detect coronavirus, but we can also easily change it to recognise other kinds of viruses,” she says.
There are other ways CRISPR is helping the battle against this coronavirus now. Rupert Beale is a researcher at the Francis Crick Institute, where he’s using CRISPR to better understand how Sars-CoV-2 operates and spreads.
In February, the researcher and his lab started looking at which genes were necessary for Sars-CoV-2 replication. “Broadly speaking, what you do is knock out all of the genes in the genome using CRISPR,” he says. That lets researchers see whether knocking out a gene helps a virus replicate or prevents it from replicating.
The aim is to study aspects of the virus’ life cycle and compare it to other seasonal coronaviruses. That could help understand transmission dynamics, he says, or the potential host range, by looking at, say, pangolin proteins. “We’re really keen to understand how it is that Sars-CoV-2 causes inflammation, and how it relates to the way in which it hijacks certain cellular pathways,” he adds. All of this could be done with different techniques than CRISPR, he adds, but this is easier and faster.
In the future, CRISPR technologies could be used for treatments. Researchers at Stanford University were working on ways to use CRISPR to fight influenza, but pivoted to coronavirus when the pandemic hit, pairing a virus-killing enzyme with guide RNA in an effort to meddle with genetic code in SARS-COV-2, in the hopes of preventing it from replicating.
The problem is delivery, as it’s no small task to get a CRISPR system inside a human body: the various component parts are simply too big to access their target cells, so smaller variants are being sought, as are edited versions that are cut down to a more manageable size and delivery systems that carry the system to the right location. “The challenge of using CRISPR as a treatment for a viral infection such as the coronavirus is that it’s hard to see how we would deliver it into the cells of an infected patient,” Doudna says. “That’s just a fundamental challenge for the whole field of gene editing: how do we deliver CRISPR into cells and tissues.”
The Stanford researchers are working with the Molecular Foundry at Berkley on a potential delivery system using synthetic molecules called lipitoids to carry the necessary systems into the lungs where Sars-CoV-2 lives, but until that daunting challenge is solved, CRISPR won’t likely be useful as a cure for Covid-19.
Doudna believes that’s a long way off. But that’s the silver lining to the carnage of Covid-19: the pressure of a pandemic has accelerated science by focusing the efforts of researchers. “I think a few months ago we couldn’t have imagined how fast it’s now moving,” says Doudna.
For Covid-19, the faster pace of CRISPR diagnostic development and regulatory approval could give us at-home tests that don’t need to be sent away to the lab — giving us an answer in minutes if we’re infected, letting us get back to work, travel, and whatever else we’re missing in lockdown. But in the meantime, we’ll have to wait for our swabs to come back from the lab.
Jennifer Doudna will be one of the speakers at WIRED Health:Tech on September 22 – an event exploring the health trends accelerated by Covid-19. Speakers include Heidi Larson, director and founder of The Vaccine Confidence Project, and scientist and author Eric Topol. Tickets start at only £40 + VAT. Book your tickets here.
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