Contribute Try STAT+ Today

In early January 2020, Feng Zhang, a gene-editing researcher at the Broad Institute of MIT and Harvard, started getting emails written in Chinese about a newly identified coronavirus that was spreading in China. Some were from academics he had met, but he also got an unexpected one from the science officer at China’s consulate in New York City.

“Even though you are American and not living in China,” the email said, “this is really a problem that’s important for humanity.” It quoted an old Chinese saying: When one place is in trouble, assistance comes from all quarters.

Zhang, who was born in China and emigrated with his mother to Iowa when he was 11, has the geniality and sweet smile of a corn-fed Midwesterner. He knew little about the novel coronavirus other than what he had read in a New York Times article describing the situation in Wuhan, but the emails “gave me a sense of urgency about the situation,” he told me. Even though Zhang’s specialty is the gene-editing tool known as CRISPR, he turned his attention to finding new ways to defeat the coronavirus.

advertisement

In launching this battle, Zhang would be opening another front in a fierce but fruitful eight-year, cross-country competition with Jennifer Doudna, a biochemist at the University of California, Berkeley.

In 2012, a team led by Doudna and her French research partner, Emmanuelle Charpentier, took lessons from bacteria to glean the essential components of a CRISPR system and how they could be used to cut DNA in specifically targeted locations. Doudna and Zhang, along with Harvard’s George Church and others, then raced to show how it would work in living human cells.

advertisement

In January 2013, Zhang and Church published answers just a few weeks before Doudna did. Ever since then, Doudna and Zhang have been entangled in a complex and bitter battle over patents and prizes.

In October 2020, Doudna and Charpentier won the Nobel Prize in chemistry, but the patent battles are still raging.

When the two sides turned their attention to the coronavirus, though, they raced with similar intensity but this time decided to allow their discoveries to be used openly and without patent licensing for anyone fighting the Covid-19 pandemic.

It is fitting that CRISPR pioneers would lead virus-fighting teams because this gene-editing tool is based on a virus-fighting trick used by bacteria, which have been battling viruses for more than a billion years. In their DNA, bacteria develop clustered regularly interspaced short palindromic repeats, known as CRISPRs, that can remember and then destroy viruses that attack them. In other words, it’s an immune system that can adapt itself to fight each new wave of viruses — just what humans need in an era that has been plagued, as if we were still in the Middle Ages, by repeated viral epidemics.

When Zhang and Doudna turned their attention to Covid-19, they focused on detection technology. As we saw at the start of the pandemic, the U.S. — along with much of the world — failed badly in implementing widespread, frequent, and fast testing to detect who was infected with SARS-CoV-2, the virus that causes Covid-19.

In many countries, it’s possible to walk into a pharmacy and buy a simple, cheap, at-home test that will almost instantly signal a pregnancy. But even now, more than a year after Covid-19 emerged, it’s hard to get such a test for the infection. The standard method of using the polymerase chain reaction (PCR) technique involves complex chemical mixtures and temperature cycling. The teams around Zhang and Doudna began developing an alternative: directly detecting the genetic material of viruses the way bacteria do using a CRISPR system.

It helped that Zhang and Doudna had each formed commercial companies a few years earlier to develop CRISPR as a detection technology. They combined CRISPR-associated proteins, such as Cas12 or Cas13, with the gene-editing tool. When the mixture hit a desired target, it would chop up a “reporter” molecule that emitted a fluorescent signal.

Zhang’s company, founded with his graduate students Omar Abudayyeh and Jonathan Gootenberg, is called Sherlock Biosciences. Doudna launched a similar company, called Mammoth Biosciences, with her graduate students Janice Chen and Lucas Harrington.

After Zhang got get emails about the looming epidemic, he decided to reconfigure Sherlock’s Cas-13 detection tool so it could test for the new coronavirus. He and his team devised a test that took only three steps and could be done in an hour without fancy equipment. All it required was a small device to keep the temperature constant while the genetic material from the samples was amplified through a chemical process that was simpler than PCR. The results could be read using a paper dipstick.

Around the time Zhang began working on his coronavirus test, Chen got a call from a researcher on the Mammoth Biosciences scientific advisory board. “What do you think about developing a CRISPR-based diagnostic to detect the SARS-CoV-2 virus?” the researcher asked. They began work immediately.

Within two weeks, the Mammoth team had reconfigured its CRISPR-based tool to detect SARS-CoV-2. It was similar in many ways to the Sherlock process. All that was necessary was a heating block, the reagents, and paper flow strips to give a readout of the results.

Like the Sherlock team, the Mammoth team decided to put what they had devised into the public domain, to be shared freely.

Chen and Harrington rushed to prepare a paper with the details of the Mammoth test. But Zhang and colleagues got there first.

On Feb. 14, well before most of the U.S. had focused on the novel coronavirus, Zhang’s lab posted a white paper describing the test and inviting any lab to use or adapt the process freely. Once it was up, Zhang tweeted, “Today we are sharing a research protocol for SHERLOCK-based Covid-19 #coronavirus detection, and hope it will help others who are working to combat the outbreak.”

Chen and Harrington got that news via the Slack channel they were using to collaborate on their paper. Someone had posted Zhang’s tweet about his team’s white paper.

“We were like, ‘Oh, shoot'” Chen recalls of that Friday afternoon.

But after a few minutes, they realized that having both papers appear was a good thing. They appended a postscript to the paper they were about to publish: “While we were preparing this whitepaper, another protocol for SARS-CoV-2 detection using CRISPR diagnostics (SHERLOCK, v.20200214) was published,” it said. They then included a useful chart comparing the workflows of the two techniques.

Zhang was gracious, though it was easy for him to be since he had beaten the Mammoth team by a day. “Check out the resource provided by Mammoth,” he tweeted, including a link to the Mammoth white paper. “Glad that scientists are working together and sharing openly. #coronavirus.”

That tweet reflected a welcome new trend in the CRISPR world. The passionate competition for patents and prizes had led to secrecy about research and the formation of competing CRISPR companies. But the urgency that Doudna and Zhang and their colleagues felt about defeating the coronavirus pushed them to be more open and willing to share their work. Yet competition was still an important — and useful — part of the equation. There continued to be a race between Doudna’s team and Zhang’s to publish papers and make advances on the new Covid-19 tests. “I’m not going to sugarcoat it,” Doudna told me. “There’s definitely competition going on. It makes people feel an urgency to move ahead or, if they don’t, other people are going to get to something first.”

But coronavirus made the rivalry less cutthroat because patents were not a paramount concern. “The awesomely good thing about this terrible situation is that all the intellectual property questions have been put aside, and everyone’s really intent on just finding solutions,” said Chen. “People are focused on getting something out there that works, rather than on the business aspect of it.”

The ultimate goal for both teams is to create CRISPR-based coronavirus tests that would be like a home pregnancy test: cheap, disposable, fast, and simple, something you could buy at the corner drugstore and use in the privacy of your home.

Harrington and Chen of the Mammoth team unveiled their concept for such a device in May 2020 and announced a partnership with the London-based multinational pharmaceutical company GlaxoSmithKline to manufacture it. It would provide accurate results in 20 minutes and require no special equipment.

That same month, Zhang’s lab developed a way to simplify the Sherlock system into a process that required just a single-step reaction. The only equipment necessary was a pot to keep the system heated at a steady 140 degrees Fahrenheit. Zhang’s team named it STOP, for Sherlock Testing in One Pot.

“Let me show you what it will look like,” Zhang said to me with his boyish enthusiasm as he shares slides and renderings on a Zoom call. “You just put a nasal or saliva sample into this cartridge, slide it into the device, break one blister to release a solution that will extract the virus RNA, and then break another blister that will release some freeze-dried CRISPR for a reaction in the amplification chamber.”

Both Sherlock and Mammoth have the same vision of making it easy to reprogram their devices to detect any new virus that comes along. “The beauty of CRISPR is that once you have the platform, then it’s just a matter of reconfiguring your chemistry to detect a different virus,” Chen explained. “It can be used for the next pandemic or any virus. It can also be used against any bacteria or anything that has a genetic sequence, even cancer.”

Sherlock Biosciences received emergency use authorization for its test in May 2020; Mammoth received its authorization in late August of that year. Both companies hope that by the end of 2021 they will have simple at-home tests ready for the market.

The development of home testing kits has a potential impact beyond the fight against Covid-19: bringing biology into the home, the way that personal computers in the 1970s brought digital products and services — and an awareness of microchips and software code — into people’s daily lives and consciousness.

Personal computers, and then smartphones, became platforms on which waves of innovators could build neat products. They also helped make the digital revolution into something personal, which caused people to develop some understanding of the technology.

I believe that molecules will be the new microchips. When medical devices come into our homes, it will increase our understanding and appreciation for how molecules work.

When Zhang was growing up, his parents emphasized that he should use his computer as a tool for building things. After his attention turned from microchips to microbes, he wondered why biology did not have the same involvement in people’s daily lives as computers did. There were no simple biology devices or platforms that innovators could build things on or that people could use in their homes. “As I was doing molecular biology experiments, I thought, ‘This is so cool and it’s so robust, but why hasn’t it impacted people’s lives in ways that a software app does?'”

Zhang was still asking that question when he got to graduate school. “Can you think of how we can bring molecular biology into the kitchen or into people’s homes?” he would ask his classmates. As he was working on developing his at-home CRISPR tests for viruses, he realized they could be the way to do that. Home testing kits could become the platform, operating system, and form factor that will allow us to weave the wonders of molecular biology more into our daily lives. Developers and entrepreneurs may someday be able to use CRISPR-based home testing kits as platforms on which to build a variety of biomedical apps: virus detection, disease diagnosis, cancer screening, nutritional analyses, microbiome assessments, and genetic tests.

“We can get people in their homes to check if they have the flu or just a cold,” said Zhang. “If their kids have a sore throat, they can determine if it’s strep throat.”

In the process, it might give us all a deeper appreciation for how molecular biology works. The inner workings of molecules may remain, for most people, as mysterious as those of microchips, but at least we may be a bit more aware of the beauty and power of both.

Before the pandemic, communication and collaboration between academic researchers had become constrained. Universities created large legal teams dedicated to staking claim to each new discovery, no matter how small, and guarding against any information sharing that might jeopardize a patent application.

“They’ve turned every interaction scientists have with each other into an intellectual property transaction,” said Berkeley biologist Michael Eisen. “Everything I get from or send to a colleague at another academic institution involves a complex legal agreement whose purpose is not to promote science but to protect the university’s ability to profit from hypothetical inventions.”

The race to beat Covid-19 has not been run by those rules. Instead, led by Doudna and Zhang, most academic labs declared that their discoveries would be made available to anyone fighting the virus. This allowed greater collaboration between researchers, and even between countries.

Almost all of the scientists I talked to when writing a book on CRISPR and gene editing said that their main motivation was not money, or even glory, but the chance to unlock the mysteries of nature and use those discoveries to make the world a better place. I believe them. And I think that may be one of the most important legacies of the coronavirus pandemic: reminding scientists of the nobility of their mission. It might also imprint these values on a new generation of students who, as they contemplate their careers, may be more likely to pursue scientific research now that they have seen how exciting and important it can be.

Walter Isaacson is a journalist, professor of history at Tulane University, and author. This article is adapted from his forthcoming book, “The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race” (Simon & Schuster, March 9, 2021).

Hear Isaacson talk more about CRISPR on an episode of the “First Opinion Podcast.

Editor’s note: This article was updated to correct the timing of the emergency use authorizations for the Sherlock and Mammoth Covid-19 test kits.

  • This is an extremely promising precedent. Back to the idea of keeping the end-goal in sight—health outcomes—rather than the intermediate focus on commercialization and exclusivity. It also shows that researchers/inventors still retain power and control when they choose to exert it, and that both Doudna and Zhang have learned from their earlier experiences in patent wars. Good for them. Really. And good for the rest of us.

  • I cannot imagine anything more laudable than a spirit of competition combined with cooperation motivated by the desire to solve global health issue. Beyond the immediate importance of this particular example, there should be untold possibilities of ancillary developments redounding to human kind, to molecular biology and to science in general. What Doudna and Zhang decided to do reminds me of Francis Collins’ call earlier (if memory serves – hope I’m correct!) for more open exchange of research data.

Comments are closed.