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Gene Editing

A day with Jennifer Doudna: Trying to keep up with one of the world’s most sought-after scientists

The gene-editing tool CRISPR-Cas9 rerouted Doudna’s career path. What hasn’t changed for the renowned scientist and serial entrepreneur? Living and breathing the science

by Lisa M. Jarvis
March 8, 2020 | APPEARED IN VOLUME 98, ISSUE 9

 

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Credit: Laura Morton Photography
PIONEER Jennifer Doudna in the lobby of her fifth-floor lab at the Innovative Genomics Institute.
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Credit: Laura Morton Photography
PIONEER Jennifer Doudna in the lobby of her fifth-floor lab at the Innovative Genomics Institute.

8:58 a.m. A crowd is starting to gather in the first-floor conference room of the Innovative Genomics Institute (IGI), which sits on the edge of the University of California, Berkeley’s campus. As students, postdoctoral researchers, and staff scientists trickle down from their fifth-floor offices and labs, the rows of chairs in the back of the room and around the conference table fill up.

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As people enter, each one glances over at the central figure in the room, Berkeley biochemist Jennifer Doudna. Although Doudna sits quietly toward the front of the table scanning her open laptop, her presence looms large. Students find their way over to steal a few precious minutes of her time, chatting about projects or papers with an almost reverent tone. Doudna is the executive director of the IGI, an academic initiative run by UC Berkeley and UC San Francisco with the aim of fulfilling the promise of CRISPR, the powerful genome-editing tool that she helped discover.

When the minute hand ticks past the hour, Doudna signals that group meeting should begin. Stragglers are still arriving, but there is so much to cover today. There is so much to cover every day when you’re one of the world’s most sought-after scientists.

In the nearly 8 years since Doudna and her collaborators first published a paper unveiling the gene-editing system CRISPR-Cas9, her life has been moving at a relentless pace. The system, often simply called CRISPR, provides a breathtakingly simple way to precisely snip DNA, then remove a tract of bases and replace it with another. The possibilities for the tool’s use were immediately obvious: to treat or even cure genetic diseases, to reengineer the immune system to fight cancer, to tweak crops to be more efficient or resilient, and even to rewrite the code of life itself.

CRISPR’s scientific impact was of a magnitude rarely seen in science—and its discovery fundamentally changed the course of Doudna’s life and career. She had always been considered a world-class scientist, but after CRISPR, her résumé swelled with new accolades and responsibilities.

To understand how she has evolved as a leader, mentor, and serial entrepreneur, C&EN spent a day with the woman once called the Beyoncé of science. We wanted to give readers a glimpse of how she manages to make it all work—how any scientist who has been catapulted into the realm of celebrity makes it all work. What follows is a snapshot of Doudna’s hectic, fulfilling life.

CRISPR companies

Jennifer Doudna has cofounded five biotech firms that are commercializing gene-editing technology.

Caribou Biosciences

Year formed: 2011

Focus: Off-the-shelf CAR T-cell therapies, gene-edited cell therapies, and engineered gut microbes based on CRISPR-Cas9 technology

Editas Medicinea

Year formed: 2013

Focus: Medicines and engineered cell therapies based on CRISPR-Cas9 technology

Intellia Therapeutics

Year formed: 2014

Focus: Therapeutics based on CRISPR-Cas9 technology

Mammoth Biosciences

Year formed: 2017

Focus: Diagnostics for health, agricultural, and environmental applications based on Cas12, Cas13, and Cas14 technology

Scribe Therapeutics

Year formed: 2019

Focus: Treatments based on CasX technology

a Doudna was part of the original founding team but is no longer connected to Editas.

9:08 a.m.

After Doudna gives some quick updates on the arrival of new equipment and a few other mundane details of lab life, a plant biologist gives the first presentation of group meeting. He updates the room on a project jointly overseen by Doudna and Berkeley colleague Brian Staskawicz to produce gene-edited rice. Next up is a prospective postdoc, here to interview for a position on the team. The graduate student, from the California Institute of Technology, ticks rapidly through slides sprinkled with reaction schemes while explaining a chemical technique called directed evolution.

A decade ago, before the CRISPR craze, Doudna had a smaller team that ranged from 15 to 25 people. These days, her lab is not only larger, hosting some 35 graduate students and postdocs, but also more diverse—both in the projects it is exploring and in the types of scientists it attracts. Many of the graduate students and postdoctoral fellows are jointly mentored with other professors, and they come from a wide range of backgrounds.

As Doudna’s group has grown, she’s had to significantly change the way she leads her lab. She necessarily attracts students who are more independent, more apt to work with a peer to figure out a problem than to rely on Doudna. And she sees herself as a strategic planner who always has an eye on the bigger picture. Her aim, she says, is to help each team member do the very best work they can do, which often means “trying to get to know them enough that I can say, ‘Gee, you would do really well if you worked on this project’ or ‘Have you thought about this collaboration?’ ”

It helps that Doudna has a mental database—a veritable who’s who of prominent scientists working in disciplines as diverse as biostatistics, clinical oncology, and chemical synthesis—that she pulls from to help her students push a project forward. Throughout the day, she drops in a “Let me connect you to . . .” into nearly every meeting.

“It’s more of a management thing, and I never thought I would love it,” she says of this acquired skill. “Incredible science happens when you get the right person on the right project at the right time. Figuring that out for each person and project in the lab is a constant jigsaw puzzle.”

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Credit: Laura Morton Photography
Pitching to a prospective postdoc

11:07 a.m.

Doudna’s puzzle skills are on full display as she approaches the whiteboard in her next meeting, where she’s interviewing the Caltech chemist upstairs in her lab’s conference room. Although she had been largely quiet during the last hour of the group meeting, letting others pepper the prospective postdoc with questions about directed evolution, she now comes alive. The whiteboard quickly fills with lists and charts as she outlines her vision for a project that the student, if hired, could work on that would open up a new area of science in the lab.

This morning was supposed to be about Doudna interviewing him for a postdoc position, but instead it feels like he’s being pitched to. She’s not just laying out the scope of the project but also ticking off a full team of collaborators: here’s an expert at the IGI who could help with this piece of the project; here’s someone at a separate institution who could help with another aspect; here’s a venture capitalist who might fund the whole thing. The young chemist, who occasionally interjects with a question or an answer, is practically vibrating with excitement. Doudna seems to have made another good match of person and project.

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Credit: Laura Morton Photography
Pitching to a prospective postdoc
 

“My inbox was exploding, and journal editors were calling me. It was just crazy. You could see this tidal wave coming towards you, you know?”

11:37 a.m.

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After gently passing the postdoc candidate on to an assistant, Doudna walks into her office to find two students from the Gladstone Institutes waiting. In 2018, Doudna moved part of her research to Gladstone, a San Francisco–based nonprofit research institution that aims to tackle unsolved diseases. Gladstone’s mission aligned with Doudna’s own, to pinpoint the genetic causes of—and treatments for—diseases.

Space is tight in Doudna’s unexpectedly small office, and the three women huddle around a laptop, any one of them able to reach out and touch the carefully arranged awards, books, and mementos on a nearby shelf without ever having to leave her seat. In this meeting, the conversation is all about using CRISPR to find a novel drug target against an intractable form of cancer. Yet again, Doudna doesn’t just provide guidance on the day-to-day lab work but also offers to introduce the students to two oncology heavyweights who she thinks could help push the project forward.

Before Gladstone, before the various start-ups, way back in the time before CRISPR, Doudna likely wouldn’t have had this type of conversation with students—one so geared toward drug targets and medicines. Fifteen years ago, her research was focused largely on the structure and function of RNA and making fundamental discoveries.

Then, in her early 40s, she hit a crossroads.

“I went through this kind of early midlife crisis about 10 years ago,” Doudna says. She’d been running her lab for about 15 years, and even though she was proud of her research and the people she’d trained, she wondered: “Is that what the next 15 years is going to look like for me? Am I going to get to the end of my career and feel like I did some cool stuff, had some fun, published some papers we’re proud of, but did I really solve any problems?”

Her soul-searching led her to consider medical school or perhaps even business school: a neighbor had started a solar energy company and, as Doudna saw it, seemed invigorated by the challenge.

What she landed on was a leap to industry. In early 2009, Doudna took a leave of absence from Berkeley, walked away from a Howard Hughes Medical Institute (HHMI) grant, and took a job leading discovery research at Genentech.

“I lasted there 2 months,” she says bluntly.

That was all the time it took for Doudna to realize she would never feel comfortable without the scientific freedom afforded by academia. “It was a painful 2 months, but it was really important to do,” she says. It helped her ask herself, “Who am I?”

That waffling might have struck some as a failure. But in reality, the reset laid the foundation for her most monumental discovery. Doudna decided that if she were going to return to academia, she’d do it on her own terms.

Back at Berkeley, her group was thankfully still intact—her industry plan included the eventual migration of the team to Genentech. She decided she’d now spend her time on science that felt fun and interesting. She put aside worries over where the research might lead. And because she’d canceled all her obligations so that she could take the Genentech gig—the travel, the classes, the committees—she was gloriously free to explore.

“It was like being a new assistant professor again,” she recalls. “Every day I would come to work and there was nothing on my calendar, and I’d literally just go into my lab.” This left the door open for CRISPR.

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Credit: Laura Morton Photography
Discussing next-generation gene editors
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Credit: Laura Morton Photography
Discussing next-generation gene editors

1:10 p.m.

Those pre-CRISPR days seem a distant memory as Doudna carries her lunch, a salad, into a conference room for her next series of meetings, focused on the day-to-day logistics of running a big lab. She wrapped up her last meeting by jotting down in the black notebook she takes everywhere a reminder to connect the Gladstone scientists to potential collaborators. A subsequent lunch break that included an interview with this reporter meant little time to eat, so she’s here, salad in hand, now chatting with a trio of researchers about how to transition a staff scientist, whose project funding is winding down, to a different team.

Next up is a line-by-line budget check with Meredith Triplet, her project manager, and Jeanne Powers, a research administrator at Berkeley who tracks a portion of the lab’s finances. They talk through the financial health of the lab and discuss which scientists might be shifted onto new projects to balance funding streams so that they can hire new postdocs. It’s like an intricate game of chess, deciding who should be paid out of which pot of money according to what each grant or funder allows.

Doudna exudes a preternatural calm throughout this constant whorl of activity, an artifact perhaps of her upbringing in the tranquility of Hawaii. Although she might occasionally furrow a brow or ask a pointed question, she largely seems to go through her day with a serene focus on whoever is in front of her. She manages to pivot between appointments and topics without making her audience—a student, an administrator, an investor—feel rushed or pushed aside.

But that serenity belies the intensity of her schedule and the pressures of such a rapid scientific ascent.

Her stratospheric success was born during that period of relative calm after she returned from Genentech, free of academic obligations. She had become interested in exploring the function of CRISPRs. Shorthand for “clustered regularly interspaced short palindromic repeats,” CRISPRs are short stretches of genetic code that echo throughout the genome of a bacterium. They sandwich remnants of DNA from viruses that once infected the bacterium, forming a database of past invaders that helps prokaryotes fend off future ones. At the time, scientists knew that CRISPRs were part of this prokaryote immune system and had identified some of its components, but they were still trying to sort out the details of how it worked.

Doudna’s early experiments, which were initially focused on solving the structure of certain parts of the CRISPR system, took a momentous turn after she ran into French microbiologist Emmanuelle Charpentier at a conference in Puerto Rico in 2011. The story of their meeting and subsequent collaboration has become the stuff of legend, but the short version is that the pair quickly realized the potential for harnessing CRISPR and its partner enzyme Cas9 to cut nearly any gene of their choosing. Cas9 uses CRISPR sequences as a guide to recognize and snip strands of DNA to protect prokaryotes. Their work led to the now-famous 2012 paper that unveiled the tool’s ability to edit bacterial genomes. By that time, Doudna had already helped start a company, Caribou Biosciences, to further explore the tool and license the technology to others.

Another historic twist in the CRISPR story added to the drama of the discovery and stress of the following years: Charpentier and Doudna were scooped by Feng Zhang, a scientist at Broad Institute of MIT and Harvard who was the first to patent CRISPR-Cas9’s ability to edit human genomes. Battle lines were drawn across institutions and CRISPR-related start-ups.

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Credit: Laura Morton Photography
A model of CRISPR-Cas9, the revolutionary gene-editing system
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Credit: Laura Morton Photography
A model of CRISPR-Cas9, the revolutionary gene-editing system

2:30 p.m.

Doudna ducks into her office with Pattie Altizio, her IGI assistant, to run through her schedule for a trip to Washington, DC, the next week. She’ll be presenting her research to a panel that will decide whether to renew her HHMI grant. The Berkeley scientist might be world renowned, but like everyone in academia, she still has to do the funding hustle.

The pair go over a laminated printout of Doudna’s schedule. Altizio hands one just like it to Doudna each morning so she knows where to be throughout the day. It’s a small but essential piece of a larger infrastructure that helps keep everything in Doudna’s busy life running smoothly.

This organizational framework has been several years in the making. Within 3 years of the initial CRISPR paper, companies had formed, patent battle lines had been drawn, and the size of Doudna’s lab had mushroomed. Invitations and obligations piled up—not just to participate in the usual academic affairs but also to speak about the ethics of the gene-editing tool. During that time, she spoke before Congress, gave a TED Talk, appeared on Time’s list of 100 most influential people, and attended star-studded galas.

After a holiday dinner in December 2012, Doudna says her sister Ellen, who lives in Berkeley, found her sitting on the stairs in her house looking defeated. When her sister asked why she looked so upset, Doudna told her, “We’ve done something extraordinary in the lab, and I should be happy, but I feel like I can’t manage it.”

“I suddenly felt so crushed by the coming weight of everything,” Doudna recalls. “My inbox was exploding, and journal editors were calling me. It was just crazy. You could see this tidal wave coming towards you, you know?”

Doudna’s sister helped her devise a strategy for dealing with it all. Successfully riding that rapidly gathering wave meant hiring someone to tend Doudna’s beloved garden and another to plan meals and help around the house, because, after all, she and her husband, a successful scientist in his own right, had a young son to raise. At work, it meant assembling—over 7 years—a well-oiled team, including Altizio, Triplet, and others to help manage the constantly moving pieces of Doudna’s professional life.

Doudna’s meeting with Altizio miraculously ends 10 min early, giving her a moment to catch up on emails. She retreats to her office and seems to relish those few moments of quiet before shifting gears again.

3:00 p.m.

Doudna is back in the conference room for a meeting with a team working on CasX, a next-generation enzyme that works with CRISPR to snip DNA. This latest gene editor is smaller and potentially more nimble than the original Cas9 and the later-discovered Cas12.

For those keeping track, she started the day with a discussion of gene-edited rice, sat in on a rapid-fire talk that pushed the boundaries of the audience’s understanding of organic synthesis, dove into a deep genetic analysis of a specific cancer in search of a new drug target, spent nearly 2 h on group personnel and fiscal management, and has now landed back in a sweet spot: the chemical and structural intricacies of the next generation of gene editors.

While therapies based on Cas9 are already making their way into patients, much of the Doudna lab’s work currently focuses on finding and understanding better editors—ones that, like CasX, are compact and can more easily slip inside cells while also being more efficient and precise with their cuts to DNA.

Although she is many hours into the day, Doudna is at her most animated and concentrated while discussing CasX. There’s a deep discussion of new data and whether they’re enough to publish a paper. Doudna presses her team to think about what the headline of the journal article could be. What’s the story they want to tell with this work?

The CasX project has already been spun out into a company, Scribe Therapeutics. Like two other start-ups that she has cofounded, Caribou and Mammoth Biosciences, this latest is run by a former lab member who did the firm’s foundational research.

Placing former students at the helm of her start-ups is an intentional choice that began with the first company she cofounded, Caribou. The biotech was, and still is, led by Rachel Haurwitz, Doudna’s former graduate student who did some of the fundamental work that led to today’s CRISPR craze.

So much of what Doudna has learned about entrepreneurship “really grew out of that experience with Rachel,” she says. They had to figure out how to get it funded, what the company’s mission should be, and how to build a team. Now, Doudna says, she’s constantly texting with the former students at her newer start-ups, helping them navigate those same types of issues.

Doudna concedes that some might question the wisdom of putting a then 26-year-old at the helm of her first company, but she says the choice made sense for her own ambitions. Sure, without a seasoned biotech executive taking the reins, the company didn’t raise tens of millions of dollars out of the gate. So Caribou initially moved a bit more slowly than other CRISPR start-ups of that period. “On the other hand, it made us very focused and allowed us to have a lot more control than you typically have,” she says. “We weren’t handing off the keys to the car to somebody who was a professional CEO.”

The decision is also in keeping with Doudna’s broader aspirations for her students. “I’ve worked hard to try to protect them, because there’s always pressure from investors,” she says. “Because I think they should have a chance. I’ll feel a lot of joy if they succeed.”

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Credit: Laura Morton Photography
Running to the next meeting
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Credit: Laura Morton Photography
Running to the next meeting

4:10 p.m.

Doudna’s next appointment has already casually walked by the conference room several times, presumably to get as much time with her as possible. As the CasX crew wraps up, Doudna rushes out into the hallway, giving last notes and guidance to the researchers. As they amble back to the lab, she has already turned to an open laptop resting on a hallway shelf. Without pausing—and looking entirely unruffled—she joins a videoconference that is already underway. The person from outside the last meeting picks up the laptop, and they and one of the CasX researchers walk inside Doudna’s office and go for another hour.

Every day at about 5:30 p.m., Doudna typically texts her husband, fellow Berkeley researcher Jamie Cate, whose lab is on the second floor of the IGI, and they ride home together. Today, around the same time she sends her text, a series of emails from Triplet pop up at the top of her inbox, timed to remind her of tasks she must complete tonight. Before bed, she will need to polish and press Send on a Nature paper, finish the letters of recommendation she’s been deluged with during application season, and go over a review article. Over the weekend, she’ll hone her HHMI presentation and hopefully steal some time with her family.

Although Doudna takes the grueling pace in stride, she also knows some downtime awaits. She will take a sabbatical in 2021, which not coincidentally is the year her son heads off to college. Along with this, she plans to modestly pare back the size of her lab and to set new limits on her time.

“I’m going to make a pretty significant change at that point,” she says. “I really don’t want to do more than one trip a month. And I’m going to be very strict about that.”

Finding balance is still a struggle. When CRISPR hit the scene, the requests for her time were never ending. As her calendar quickly filled, she’d say “next year” and eventually “the year after next” instead of “no” when asked to speak at an event. “There was a time when I was booked out 2½ years in advance. I just literally couldn’t pack anything else in,” she says.

The wonderful part of how suddenly her lab has blossomed, Doudna says, is that she now has plenty of surrogates for those speaking engagements and conferences. She can be more judicious about what she personally agrees to and prioritize events where the impact of her presence might be greatest. To her, that means giving talks not just at major research institutions but also, as she will this spring, to the undergraduates at Carleton College.

It’s clear that being considered the Beyoncé of science has reshaped Doudna’s life. But has it reshaped how she views herself?

She tells a brief anecdote that gets at the heart of the question. The prior weekend she’d been at the Breakthrough Prize gala, a star-studded event in Silicon Valley launched by tech billionaires to highlight amazing feats of science. There, she ran into GlaxoSmithKline’s chief scientific officer, Hal Barron, whom she first met during her brief time at Genentech but has gotten to know better through a 5-year drug discovery pact between GSK, Berkeley, and UCSF. Barron asked her how, exactly, she makes it all work. How does she run a big lab while founding multiple companies? Doudna replied with a quick rundown of her day, describing how the first thing she’d done that morning was read a journal article, and then she’d headed into the lab for a 2 h meeting with a student to power through a paper they were writing. “We’re struggling through some data and going over figures, and it was totally fun,” she told him. Then she ran home, took a shower, pulled on a dress, and drove to Silicon Valley.

Barron, Doudna recalls, seemed shocked that she still manages to get into the nitty-gritty details with her students. But she told him that she thinks of herself, still and always, as a scientist: “I love the science. When I wake up in the morning, that’s the first thing I’m thinking about, and when I go to bed at night, that’s usually the last thing I’m thinking about.”

“I love the science. When I wake up in the morning, that’s the first thing I’m thinking about, and when I go to bed at night, that’s usually the last thing I’m thinking about.”

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