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CRISPR Could Be the Future of Disease Diagnosis

The biotechnology tool best known for gene editing is being used to develop portable, at-home tests for infectious disease and even cancer. It could change how medicine is done.

TToday when you get sick, you need to make an appointment to see your doctor. That might take a few days, and during that time, maybe you keep going to work because you’re not sure what’s wrong — or maybe you start to feel worse.

When you finally see a doctor — assuming you have insurance — she might make a probable diagnosis based on your symptoms alone, or run a test to see if you have the flu or another common infection. Depending on the test, it could take another few days to get the results back, days that could be lost to illness, before your doctor can finally prescribe a treatment.

But in the near future, new diagnostic tests could make it possible to save time and money by skipping a visit to the doctor altogether. Similar to an at-home pregnancy test, such diagnostics could render a clear positive or negative result within minutes. That result could be sent via an app on your phone to your doctor, who could then immediately write a prescription or suggest a course of care. The tests could even be used in a hospital setting to rapidly determine the specific genetic mutations causing a tumor, or allow people to quickly determine their future genetic risk of certain kinds of cancer.

These are the ideas driving Mammoth Biosciences and Sherlock Biosciences, two startups that are both developing paper tests that use CRISPR — a breakthrough technology best known as a gene-editing tool — to rapidly diagnose disease. As the race to treat diseases with CRISPR heats up and the first human clinical trials get underway, there is also potential in employing CRISPR to make fast, portable diagnostics that could be used almost anywhere to detect practically any infection or genetic mutation.

“When you sneeze and have a fever, you want to know what type of illness you’re suffering from,” says Feng Zhang, co-founder of Sherlock Biosciences. Zhang believes that if people could stay home and test themselves, instead of traveling to a doctor’s appointment and getting other people sick, it would represent a major advance in public health.

If this sounds familiar — a one-stop, instant diagnostic that could be run at a pharmacy or even at home — it’s because it is similar to the vision expounded by Elizabeth Holmes, founder of the now-disgraced biotech firm Theranos. Theranos — which at one point was valued at $10 billion — shut down in 2018 after Holmes and former president Ramesh “Sunny” Balwani were indicted on wire fraud and conspiracy charges. Though the Palo Alto-based company touted its blood-testing technology as a breakthrough, it never published any peer-reviewed scientific papers to back up its claims. Holmes herself was a Stanford dropout with little actual scientific expertise.

The researchers behind Mammoth and Sherlock’s technology, on the other hand, helped bring CRISPR — arguably one of the most important scientific advances of the 21st century — into being. Zhang is a scientist at the Broad Institute of MIT and Harvard who pioneered the use of CRISPR, while Mammoth Biosciences was co-founded by Jennifer Doudna of the University of California, Berkeley, who also lays claim to inventing CRISPR. (A third scientist, Emanuelle Charpentier of the Max Planck Institute for Infection Policy, is also credited as an inventor of CRISPR, though she is not involved in either company.) The two companies have already published a handful of peer-reviewed papers on the technology underlying their diagnostics and have tried out the tests on patient samples.

Now, the companies’ founders say they want their testing strips to be available in CVS and Walgreens so that anyone could purchase a test without having to go to a doctor’s office. They also want to take their cheap, paper-based tests to developing countries to use during epidemics and outbreaks. There, CRISPR-based tests that require little additional equipment could rapidly confirm cases of Zika, Ebola, or dengue fever, and help healthcare workers triage the patients most in need of care. In the United States and elsewhere, such tests could also be used to spot drug-resistant infections to help doctors decide what antibiotics or other drugs patients should receive.

The power of CRISPR is its ability to cut DNA with relative ease, by using two key molecules: a protein, typically Cas9, that acts like a pair of molecular scissors, and a guide RNA that helps Cas9 get to the right place in the genome. Once it arrives at its target, Cas9 cuts the specific spot in the genome it’s programmed to cut.

That ability has made CRISPR a promising approach to fixing the genetic errors that can cause disease. As a diagnostic tool, however, CRISPR works a bit differently. It also uses a guide RNA, but instead of being paired with Cas9, it’s combined with a different protein within the Cas family — Cas12, Cas13 or Cas14 — that cuts its target but also shreds up nearby DNA or RNA. This would be problematic if you were trying to edit genes, but for a diagnostic test, this property essentially acts as a signal-booster. Attached to the CRISPR system is a so-called reporter molecule, which releases a fluorescent signal if CRISPR hits its target. On paper tests dipped into a patient sample — blood, urine, or saliva — this shows up as a line on the testing strip, similar to a result on a pregnancy test.

As with gene editing, the guide RNA can be programmed to look for any sequence of genetic code, such as a virus, a strain of antibiotic-resistant bacteria, or even a genetic mutation associated with cancer. Both Mammoth and Sherlock want to use that versatility to create new tests for conditions that currently can’t be easily diagnosed.

“A lot of people just don’t use diagnostics today,” says Trevor Martin, CEO of Mammoth Biosciences. “They’ll maybe suffer through some disease because they don’t know whether they should go to the doctor or not.” The San Francisco-based company came out of stealth mode in April 2018, and shortly after announced an initial $23 million funding round. A year later, Sherlock Biosciences — which takes its name from its diagnostics platform — launched in Cambridge, Massachusetts with $35 million in financing.

This isn’t the first time these two major centers of CRISPR research have found themselves competing. Since 2015, the Broad Institute and UC Berkeley have been locked in an ongoing and expensive legal dispute over who holds the rights to fundamental CRISPR patents for gene editing. Doudna and Zhang have already co-founded companies to pursue CRISPR-based therapies: Caribou Biosciences and Editas Medicine, respectively. Now, the two CRISPR pioneers will go head to head again in the diagnostic testing space.

If we’re able to develop better diagnostics, patients will benefit. I think the more people that are trying to advance this the better.”

Zhang doesn’t see that as a bad thing, though. (A representative for Doudna said she was not available for an interview for this story.) “There are so many public health and human health problems that need to be addressed,” he says. “So I think there’s space for two, maybe even more companies. If we’re able to develop better diagnostics, patients will benefit. I think the more people that are trying to advance this the better.”

Provided, of course, the tests are effective.

TTrevor Martin became interested in diagnostics when he was finishing his PhD at Stanford in 2016. He was looking for an opportunity to start a company around an idea that could potentially improve the healthcare system, and settled on diagnostics. He read an early paper by Doudna’s group that described using CRISPR to detect RNA, the molecular cousin of DNA. Many viruses that infect humans, like Ebola and measles, have RNA instead of DNA as their genetic material. Doudna and her team realized this ability could be used in disease detection, even as Zhang’s group at the Broad Institute was making similar discoveries.

Martin approached Doudna about starting a company based on her team’s technology, which they eventually dubbed DETECTR. “I originally just cold-emailed her. I had never talked to her before,” he says. Doudna introduced Martin to some of the doctoral students in her lab who were working on DETECTR, and a few months later, the teams joined up to start Mammoth Biosciences.

“I became really enamored with diagnostics because of how unsexy and overlooked the field was,” Martin says. “The diagnostics industry is using technologies that are many decades old.”

Martin is right. One of the chief techniques for infectious disease testing today has been around since the time of Alexander Fleming, the Scottish biologist who discovered the antibiotic penicillin in 1928. Bacterial or viral cells are taken from blood, urine, skin, or another part of the body, and grown in a dish to help identify infectious agents. Called a culture test, results can take anywhere from a few days up to a week or two, because some microbes grow more slowly than others.

With tuberculosis, it can take up to six or eight weeks to get a result. “That’s way too long if you need to get treatment,” says Emily Crawford, a scientist at the Chan-Zuckerberg Biohub who’s working on another CRISPR-based diagnostic tool, dubbed FLASH, that identifies drug-resistant microbes that may be present in body fluids.

Another conventional testing method — enzyme-linked immunosorbent assay, or ELISA — measures antibodies the body produces in response to certain infectious conditions and was developed in the 1970s. It requires a complex lab process and can take several days to get a result.

Then there’s polymerase chain reaction, or PCR, which was invented in the 1980s. It’s a way of making many copies of a specific DNA or RNA segment — say of a virus — essentially amplifying it until it can be detected. But the test needs to be processed on expensive machines that, on average, cost tens of thousands of dollars and require electricity and trained scientists to run. Many hospitals have the equipment and expertise necessary to do these tests, but smaller clinics often need to send patient samples away to companies like LabCorp and Quest Diagnostics.

“Right now it might take days to get an infectious disease result because of the centralization of testing… Moving that testing closer to the patient can turn that into a matter of minutes.”

So slow are most of the existing tests for infectious disease that, by one estimate, the underlying causes of up to a quarter of pneumonia cases and 30% of fever and sepsis cases are never fully identified. “Right now it might take days to get an infectious disease result because of the centralization of testing,” says Rahul Dhanda, president and CEO of Sherlock Biosciences. “Moving that testing closer to the patient can turn that into a matter of minutes.”

A good diagnostic tool needs to be both sensitive and specific. Sensitivity refers to a test’s ability to correctly identify those with the disease, while specificity is the ability to correctly identify those without the disease. A highly sensitive test means that there are few false negative results, and so fewer cases of disease are missed. A very specific test means that there are few false positives, thus minimizing the wasted treatment and anguish that can result from a misdiagnosis. Rapid nasal swab tests for influenza, which can provide results in 10 to 15 minutes, have been available for years, but they lack sensitivity, missing up to half of flu cases.

Mammoth and Sherlock say they’ve been able to achieve high rates of both sensitivity and specificity, but the companies’ platforms will need to be tested in clinical trials and compared with currently available tests. Neither company has said when they plan to do that.

Accuracy is only one hurdle. To be used widely in developing countries, a diagnostic would also have to be cheap, ideally between $1 to $3 per test, according to Ranga Sampath, chief scientific officer at the Foundation for Innovative New Diagnostics in Geneva, a global health nonprofit. (ELISA tests run about $15 to $20 each.)

Zhang has said that the materials to produce a SHERLOCK test cost less than $1. “When you scale up the production the cost will probably be even lower,” he adds. “That’s one thing that makes this attractive, especially if you want to use it in low-resource settings.” The challenge, he believes, will be manufacturing the materials on a wide scale and distributing tests around the world.

Sampath wonders about that, too. He notes that the majority of patients in low-resource countries are taken care of by healthcare workers in rural clinics, sometimes hundreds of miles away from the nearest city and hospital. “How do you get diagnostics into those settings?” he asks.

That’s a challenge researchers from the Broad Institute are already addressing. A team that’s collaborating with Zhang took the SHERLOCK system to Nigeria to see if it could be used in an active outbreak setting. Last year, a worrying spike in cases of Lassa fever swept across the West African country of Nigeria, which is home to more than 190 million people.

A viral, hemorrhagic fever, Lassa is part of the same family as the deadly Ebola and Marburg viruses, and kills several thousand people in West Africa each year. The diseases present similarly, at least at first, with hemorrhaging, fever, and diarrhea. “People come in and the first thing they have is a fever, which could be malaria, or flu, or something else,” says Kayla Barnes, a fellow at the Harvard School of Public Health and the Broad Institute. That makes it difficult for clinicians to diagnose Lassa off symptoms alone, so patients stand the risk of being misdiagnosed or missed completely, which in turn could further fuel an outbreak. It’s one reason why an accurate and fast diagnostic for Lassa is so desperately needed.

The sooner patients are diagnosed, the sooner they can get supportive care like rehydration, as well as treatment with the antiviral drug ribavirin, and the better chance they’ll have at recovering. So Barnes and her team, along with West African collaborators, are testing out the SHERLOCK system in Nigeria and Sierra Leone to see if they can identify cases as early as possible.

As a first step, they’re using the test in hospitals, but Barnes says the idea is to eventually move to villages and rural areas. (Up until recently, testing for Lassa fever was only available in one hospital in the entire country, though in response to last year’s outbreak the Nigeria Centre for Disease Control is opening up additional diagnostic clinics in other hospitals.) “Where it will make the most difference is in the community setting and getting patients to the hospital in time,” she says. So far, Barnes and her team have been able to identify a handful of patients with Lassa fever that were missed by current testing methods.

The current test for identifying Lassa requires a minimum of five hours under ideal conditions, but realistically, it can take labs in poor-resource areas around a day or two to get results. Using the SHERLOCK system, however, Barnes and her colleagues in Nigeria have been able to reduce that turnaround time to about three hours.

The current test also requires a cold chain — a temperature-controlled supply chain — as well as specialized expertise and an expensive machine powered by electricity. Both are often in short supply — less than 60% of Nigerians have regular access to electricity, a figure that falls even lower in rural areas. The SHERLOCK tests can be freeze-dried and use a small, electric-powered lab instrument to process samples, which Barnes says could be run off a car generator if electricity isn’t available.

While CRISPR-based tests may be simpler than the current alternatives, they will need to work outside a lab or hospital setting to make a difference in developing countries where infectious diseases like malaria and tuberculosis are still common. “CRISPR may be an enabling technology, but I’m not sure it’s going to fundamentally change the game of diagnostics unless we can get it into a format that people can use in their own hands,” says Dan Wattendorf, director of innovative technology solutions at the Bill & Melinda Gates Foundation.

Richer countries like the United States present a different challenge. Bryan Roberts, a partner at the New York-based venture capital firm Venrock who has invested in diagnostics companies, is skeptical about the idea of at-home testing. “Your performance is going to have to be exquisite,” he says. “If you tell a consumer without a healthcare provider around that they have something and they don’t, you’re in trouble. You’ll have to almost never be wrong.”

He’s also not sure there will be a huge market for individual consumers to buy these tests and keep them on hand. Patients are probably more likely to visit their local CVS or Walgreens to get a CRISPR-based test administered by pharmacy staff and obtain an instant readout instead of waiting to get a doctor’s appointment. That way, a healthcare professional could still explain the results to a patient. Roberts says there’s also potential for CRISPR-based tests to replace traditional ones in hospitals — but only if they’re truly faster and cheaper.

MMammoth and Sherlock want to develop tests that can go beyond infectious diseases. Using CRISPR, tests could be programmed to look for specific genetic mutations linked to cancer. Sherlock’s Dhanda didn’t say which specific genetic mutations the company will pursue, but he did note that the company wants to develop such tests for both “at home and at the hospital.”

People can already take a spit test offered by the genetic company Color Genomics for $249 that evaluates 30 different genes for cancer risk. And 23andMe’s Health + Ancestry test provides reports on three mutations in the BRCA1 and BRCA2 genes. These genes are associated with a higher risk of breast and ovarian cancer, but the three variants 23andMe tests for are not the most common ones that appear in the general population; rather, they are among the most studied.

For patients who already have a cancer diagnosis, speedy tests that can detect the genetic mutations at play could help doctors quickly select the right treatment. As more targeted drugs and immunotherapies for cancer come onto the market, genetic testing of tumors is becoming more common, but it’s still expensive and not all insurers cover the procedures. Dhanda argues that his company’s platform could be a cheaper option. “If you’re able to bring those costs down, you’ll be able to increase the number of patients being tested,” he says.

CRISPR could also serve as an early detector for the human papilloma virus, or HPV. Certain strains of HPV can cause cervical cancer, which kills more than 4,000 people in the United States each year. Experts recommend that women get tested for HPV every three years to reduce the risk of developing cervical cancer, but the HPV test currently requires a Pap smear that takes place in a doctor’s office.

Janice Chen, one of Mammoth’s founders and a former graduate student in Doudna’s lab at Berkeley, says a more accessible HPV test could reduce screening barriers, which can include the stigma attached to HPV, ignorance about the connection between the virus and cervical cancer, and lack of health insurance or transportation to a clinic.

Chen and her colleagues programmed DETECTR to look for certain cancer-causing HPV types in patient samples and found that it was almost 100 percent accurate in identifying the correct strains. The turnaround time for an HPV test today is one to three weeks, but DETECTR took less than an hour to run on each patient sample.

That means patients taking the test in a doctor’s office could get a readout during the same visit. If they’re performing the test at home, they could connect with their doctors using an app — an option both companies are working on. Patients would be able to upload a photo of their testing strip and the app would provide a result, and then connect them with their doctor to learn more about their test results or request a prescription.

“I think the real promise of this is that it’s something that can be used by anyone,” Martin says.

“Patients could have more ownership over their own care if diagnostics can be moved to the point of need rather than being based in the hospital.”

That could take years, since both companies will need to convince the U.S. Food and Drug Administration that their tests hold up to currently available ones. If that happens, the bicoastal CRISPR race will take on a new dimension — not merely about how we cure disease, but how we discover it in the first place.

Former staff writer at Medium, where I covered biotech, genetics, and Covid-19 for OneZero, Future Human, Elemental, and the Coronavirus Blog.

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