The code breaker, p.37
The Code Breaker, page 37
That approval finally came on February 4, and the next day the CDC began sending test kits to state and local labs. The way the test works, or was supposed to work, is that a long swab is inserted into the back of a patient’s nasal passage. The lab uses some of the chemical mixtures in the kit to extract any RNA that is in the mucus. The RNA is then “reverse-transcribed” to turn it into DNA. The DNA strands are amplified into millions of copies using a well-known process called a polymerase chain reaction (PCR), which most college biology students learn how to do.
The PCR process was invented in 1983 by Kary Mullis, a chemist at a biotech company. Driving in his car one night, Mullis crafted a way to tag a sequence of DNA and use enzymes to duplicate it through repeated cycles of heating and cooling known as thermocycling. “Beginning with a single molecule of the DNA, the PCR can generate 100 billion similar molecules in an afternoon,” he wrote.2 These days the process is usually done using a machine the size of a microwave that raises and lowers the temperature of the mixture. If the genetic material of the coronavirus is present in the mucus, the PCR process amplifies it so that it can be detected.
When state health officials received the test kits from the CDC, they set about verifying that they worked by trying them on patient samples that were already known to be positive or negative. “Early on Feb. 8, one of the first CDC test kits arrived in a Federal Express package at a public health laboratory on the east side of Manhattan,” the Washington Post reported. “For hours, lab technicians struggled to verify that the test worked.” When they ran the tests on samples known to contain the virus, they got a positive result. That was good. Unfortunately, when they ran the test on purified water, they also got a positive result. One of the chemical compounds in the CDC test kits was defective. It had been contaminated during the manufacturing process. “Oh, shit,” said Jennifer Rakeman, an assistant commissioner of the city’s health department. “What are we going to do now?”3
Adding to the disgrace was the fact that the World Health Organization had delivered 250,000 diagnostic tests that worked just fine to countries around the world. The U.S. could have gotten some of those tests or replicated them, but it had refused.
A university steps in
The University of Washington, at the epicenter of one of the first COVID outbreaks in the U.S., was the first to rush into this minefield. At the beginning of January, after seeing the reports from China, Alex Greninger, a round-faced young assistant director of the virology lab at the university’s medical center, talked to his boss, Keith Jerome, about developing their own test. “We’re probably going to be wasting some money on this,” Jerome said. “It’s probably not going to come over here. But you’ve got to be ready.”4
Within two weeks, Greninger had a working test, which, under normal regulations, they could use in their own hospital system. But then HHS Secretary Azar issued his emergency declaration, which made regulations more strict. So Greninger submitted a formal application to the FDA for an “Emergency Use Authorization.” It took him close to one hundred hours to fill out all of the forms. Then came an astonishing bureaucratic snafu. He got a response from the FDA on February 20 informing him that, in addition to sending his application electronically, he had to mail in a printed copy along with a copy burned onto a compact disc (remember what those were?) to FDA headquarters in Maryland. In an email he wrote to a friend that day describing the FDA’s bizarre approach, Greninger vented, “Repeat after me, emergency.”
A few days later, the FDA responded by requiring him to do more trials to see if the test he was using inadvertently detected the MERS and SARS viruses, even though they had been dormant for years and he had no samples of those viruses to test. When he called the CDC to see if he could get a sample of the old SARS virus, it refused. “That’s when I thought, ‘Huh, maybe the FDA and the CDC haven’t talked about this at all,’ ” Greninger told reporter Julia Ioffe. “I realized, Oh, wow, this is going to take a while.”5
Others had similar problems. The Mayo Clinic had created a crisis team to deal with the pandemic. Of its fifteen members, five were tasked to deal full time with the FDA’s paperwork requirements. By late February, there were dozens of hospitals and academic labs, including at Stanford and the Broad Institute of MIT and Harvard, that had developed testing capabilities, but none had managed to win FDA authorization.
At that point Anthony Fauci, the National Institutes of Health infectious disease chief who had become a national superstar, stepped in. On February 27, he spoke to HHS Secretary Azar’s chief of staff, Brian Harrison, and urged that the FDA allow universities, hospitals, and private testing services to start using their own tests while waiting for Emergency Use Authorizations. Harrison held a conference call with the relevant agencies and told them, using strong language, that before the end of the meeting they had to come up with such a plan.6
The FDA finally relented on Saturday, February 29, and announced that it would allow non-government labs to use their own tests as they waited to get Emergency Use Authorizations. That Monday, Greninger’s lab tested thirty patients. Within a few weeks, it would be testing more than 2,500 a day.
Eric Lander’s Broad Institute also jumped into the fray. Deborah Hung, the codirector of the Broad’s infectious diseases program, also worked as a physician at Brigham and Women’s Hospital in Boston. On the evening of March 9, when confirmed cases of COVID in the state had risen to forty-one, it struck her how bad the virus was going to be. She called her colleague Stacey Gabriel, the director of the Broad Institute’s genomics sequencing facility, which is a few blocks from the Broad headquarters in a former warehouse that stored beer and popcorn for Fenway Park. Could she turn the lab into a facility for testing for the coronavirus? Gabriel said yes, then called Lander to see if that was okay. Lander was, as always, eager to deploy science in the public interest and rightly proud of the teammates he had assembled who shared that instinct. “The call was kind of irrelevant,” Lander says. “I of course said yes, but she was going to do it anyway, as well she should.” The lab went into full operation on March 24, receiving samples from hospitals across the Boston area.7 With the failure of the Trump administration to carry out widespread testing, university research labs began taking on a role that has normally been performed by the government.
Enrique Lin Shiao and Jennifer Hamilton
CHAPTER 50 The Berkeley Lab
The volunteer army
When Doudna and her colleagues at Berkeley’s Innovative Genomics Institute decided at their March 13 meeting to focus on building their own coronavirus testing lab, there was a discussion about what technology to use. Should it be the cumbersome but reliable process of amplifying the genetic material from test swabs using a polymerase chain reaction (PCR), as described earlier? Or should they try to invent a new type of test, one that used CRISPR technology to directly detect the RNA of the virus?
They decided to do both, but they would initially scramble to do the first approach. “We need to walk before we run,” Doudna said at the conclusion of the discussion. “Let’s use current technology right away, then we can innovate.”1 By having its own testing lab, the IGI would have the data and patient samples to try out new approaches.
After the meeting, the institute sent out a tweet:
Innovative Genomics Institute @igisci: We are working as hard as possible to establish clinical #COVID19 testing capability at @UCBerkeley campus. We will update this page often to ask for reagents, equipment, and volunteers.
Within two days, more than 860 people had responded and the volunteer list had to be cut off.
* * *
The team that Doudna put together reflected the diversity of her lab and of the biotech field in general. To command the operation, she turned to Fyodor Urnov, a gene-editing wizard who had been leading IGI’s efforts to develop affordable methods to cure sickle-cell anemia.
Born in 1968 in the heart of Moscow, Urnov learned English from his mother, Julia Palievsky, who was a professor, and his father, Dmitry Urnov, a distinguished literary critic and Shakespeare scholar, William Faulkner fan, and biographer of Daniel Defoe. I asked Fyodor whether the coronavirus had led him to ask his father, who now lives near him in Berkeley, about Defoe’s 1722 book, A Journal of the Plague Year. “Yes,” he said, “I’m going to get him to give me and our daughter who lives in Paris a Zoom lecture on the book.”2
Like Doudna, Urnov read Watson’s The Double Helix when he was about thirteen and decided to become a biologist. “Jennifer and I joke about the fact that we both read The Double Helix at about the same age,” he says. “For all of Watson’s shortcomings as a human being, which are substantial, he produced a ripping good yarn that makes the hunt for the mechanisms of life seem very exciting.”
At eighteen, Urnov, a bit of a rebel, was drafted into the Soviet military and his head shaved. “I survived unscathed,” he says, after which he left for the United States. “In August of 1990, I found myself landing in Boston’s Logan Airport, having been accepted to Brown, and a year later my mom got a Fulbright to be a visiting scholar at the University of Virginia.” Soon he was happily pursuing his doctorate at Brown, buried in test tubes. “I realized that I was not going back to Russia.”
Urnov is among those researchers comfortable with having one foot in academia and the other in industry. For sixteen years, while teaching at Berkeley, he was a team leader at Sangamo Therapeutics, which translates scientific discoveries into medical treatments. His Russian roots and literary parentage instilled in him a dramatic flair, which he earnestly combines with a passion for America’s can-do spirit. When he got the assignment from Doudna to lead the lab, he sent around a quote from Tolkien’s Lord of the Rings:
“I wish it need not have happened in my time,” said Frodo.
“So do I,” said Gandalf, “and so do all who live to see such times. But that is not for them to decide. All we have to decide is what to do with the time that is given us.”
One of his two scientific field marshals was Jennifer Hamilton, the Doudna protégée who a year earlier had spent a day teaching me to edit a human gene using CRISPR. She grew up in Seattle, studied biochemistry and genetics at the University of Washington, and then worked as a lab technician while listening to the podcast This Week in Virology. She did her doctorate at Mount Sinai Medical Center in New York, where she turned viruses and virus-like particles into mechanisms for delivering medical treatments, and then joined Doudna’s lab as a postdoc. At the 2019 Cold Spring Harbor conference, Doudna watched proudly when Hamilton presented her research on using virus-like particles to deliver CRISPR-Cas9 gene-editing tools into humans.
When the coronavirus crisis hit in early March, Hamilton told Doudna that she wanted to get involved like people at her University of Washington alma mater were. So Doudna tapped her to lead the technical development of the lab. “It felt like a call to arms,” Hamilton says. “I simply had to say yes.” She never dreamed that her dexterity at optimizing RNA extraction would turn out to be an urgent skill in a global crisis. The real-world deployment also gave her and her fellow academics a taste of the type of project-oriented teamwork that is common in the business world. “It’s the first time that I’ve been a part of a scientific team where so many people with different talents have coalesced around a common goal.”3
Working with Hamilton to get the testing lab running was Enrique Lin Shiao, born and raised in Costa Rica, the son of Taiwanese immigrants who left everything behind to start over in a very new place. The cloning of Dolly the sheep in 1996 sparked his interest in genetics. After high school, he got a scholarship to the Technical University of Munich, where he researched how to fold DNA into different shapes to build nanotech biology tools. From there he went to Cambridge University to study how DNA folding is important for cell function. For his doctorate, he went to the University of Pennsylvania, where he figured out how non-coding regions of our genome, previously described as “junk DNA,” could play a role in disease progression. In other words, like Feng Zhang, Enrique Lin Shiao was a typical American success story from when the nation was a magnet for diverse global talent.
As a postdoc researcher in Doudna’s lab, Lin Shiao worked on ways to make new gene-editing tools that could cut and paste long DNA sequences. While sheltering at home in March 2020, he was scrolling through his Twitter feed and saw the tweet from his IGI colleagues seeking volunteers for the planned testing lab. “They were asking for experience in RNA extraction and PCR, which are techniques I routinely perform in the lab,” he says. “The next day I got an email from Jennifer asking if I would be interested in co-leading the technical efforts, and I immediately agreed.”4
The lab
The IGI was fortunate that there was a 2,500-square-foot space on the building’s ground floor that was being converted into a gene-editing lab. Doudna’s team began moving in new machines and boxes filled with chemicals to turn the space into a coronavirus testing facility. A lab-building project that normally would take months was done in days.5
They begged and borrowed and commandeered supplies from labs across campus. One day, when they were ready to start an experiment, they realized that they did not have the right plates to run in one of the PCR machines. Lin Shiao and others went through all the labs in the IGI building and then in two nearby buildings until they found some. “Since campus was largely closed, it felt like a giant scavenger hunt,” he says. “Every day felt a bit like a roller coaster, where we discovered a new problem early in the morning, got worried, and then figured it out by the end of the day.”
The lab spent about $550,000 on equipment and supplies.6 One key machine was a contraption to automate the task of extracting the RNA in patient samples. The Hamilton STARlet uses robotic pipettes to suck small amounts from each patient sample and put them onto plates the size of an iPhone with ninety-six little wells. The trays are moved into the chamber of the machine, where each of the samples is doused with reagents to extract the RNA. Using a barcode, the machines keep track of the patient information from each sample, making sure to follow privacy guidelines. It was a new experience for academic researchers. “Usually for bench scientists like ourselves we feel our impact is a bit indirect and it comes in the long term,” Lin Shiao says. “This feels so direct and immediate.”7
Hamilton’s grandfather had been an engineer on the NASA Apollo rocket launches, and one day her team paused to watch a clip someone had posted on their Slack channel from the movie Apollo 13 where the engineers have to figure out how to make a “square peg fit in a round hole” in order to save the astronauts. “Every day we’ve been facing challenges, but we’re solving these problems as they come up because we know that time is short,” Hamilton says. “This experience has made me wonder if this is what it was like for my grandfather working at NASA in the 1960s.” It was a fitting analogy. COVID and CRISPR were helping to make human cells the next frontier.
Doudna had to figure out what legal liability the university might incur by testing outsiders. That was a process that would normally have taken the lawyers weeks of hand-wringing, so Doudna called the president of the University of California system, Janet Napolitano, a former Homeland Security secretary. In twelve hours, Napolitano had given her approval and brought the system’s legal bureaucracy in line. Urnov notes that it was useful to roll out Doudna as a big gun on such occasions. “I jokingly call her the USS Jennifer Doudna,” he says.
With federal testing still in disarray and commercial labs taking more than a week to return results, there was huge demand for Berkeley’s testing. The town’s health officer, Lisa Hernandez, asked Urnov for five thousand tests, some of which would be done on the area’s poor and homeless. The fire chief, David Brannigan, told Urnov that thirty of his firefighters were quarantined because they couldn’t get test results. Doudna and Urnov promised to accommodate them all.
“Thank you, IGI”
The first major challenge for the new lab was making sure that their COVID tests were accurate. Doudna brought a special eye to this task, since she had been an expert at deciphering readouts involving RNA ever since she was a graduate student. As the results came in, researchers would share them on a Zoom screen and then watch online as Doudna leaned forward and looked intensely at the images of inverted blue triangles, green triangles, and squares indicating data points. Sometimes she would just sit and stare, not moving, as others held their breath. “Yes, that looks good,” she said during one session as she pointed a cursor to a part of an RNA detection test. Then her expression changed for all on Zoom to see as she pointed to another place and muttered, “Nope, nope, nope.”
Finally, early in April, she looked at the latest data that Lin Shiao had gathered and pronounced it “awesome.” The tests were ready to go live.
On Monday, April 6, at 8 a.m., a fire department van pulled up to the door of the IGI and an officer named Dori Tieu delivered a box filled with samples. Urnov, wearing white gloves and a blue mask, accepted the Styrofoam cooler as his colleague Dirk Hockemeyer watched. They promised that they would have results the next morning.
As they were making the final preparations to get the lab into operation, Urnov went to get a takeout meal for his parents, who live nearby. When he arrived back at the IGI building, he saw a sheet of paper taped to the big glass door. On it was written, “Thank you, IGI! Sincerely, the people of Berkeley and the World.”
