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January 30 - April 24, 2022
“Small meetings, where unpublished data and ideas can be shared and everyone helps everyone, can change the world,”
the CRISPR system targeted the DNA of the invading virus.8 That had a holy-cow implication.
if the CRISPR system was aimed at the DNA of viruses, then it could possibly be turned into a gene-editing tool.
“If it could target and cut DNA, it would allow you to fix the cause of a genetic problem.”
“When you do experiments in vivo, you’re never completely sure what’s causing things,” Marraffini concedes. “We cannot look inside a cell and see how things are working.” To understand each component fully, you need to take them out of cells and put them into a test tube, where you control precisely what’s included.
She was forty-four, happily married, with a smart and polite seven-year-old son. Yet despite all of her success, or maybe partly because of it, she was having a mild midlife crisis. “I’d been running an academic research lab for fifteen years, and I started to wonder, ‘Is there more?’ ” she recalls. “I wondered if my work was having an impact in the broader sense.”
she was becoming restless with basic science. She was eager to do more applied science and translational research, which aims at turning fundamental scientific knowledge into therapies that enhance human health.
recombinant DNA technology, which was Stanford biochemist Paul Berg’s discovery of how to splice pieces of DNA from different organisms to create hybrids.
They agreed to work together on the idea, and within four months they had spliced together DNA fragments from different organisms and cloned millions of them, giving birth to the field of biotechnology and launching the genetic engineering revolution.
It had not fully occurred to them that one could patent recombinant DNA processes, which are found in nature.
a new type of company that would make medicines out of engineered genes.
in August 1978, blasted into hypergrowth when it won a bet-the-company race to make a synthetic version of insulin to treat diabetes. Until then, one pound of insulin required eight thousand pounds of pancreas glands ripped from more than twenty-three thousand pigs or cows. Genentech’s success with insulin not only changed the lives of diabetics (and a lot of pigs and cows); it lifted the entire biotechnology industry into orbit.
I once asked Steve Jobs what his best product was, thinking he would say the Macintosh or iPhone. Instead he said that creating great products is important, but what’s even more important is creating a team that can continually make such products.
This transition from player to coach happens in many fields. Writers become editors, engineers become managers. When bench scientists become lab heads their new managerial duties include hiring the right young researchers, mentoring them, going over their results, suggesting new experiments, and offering up the insights that come from having been there.
the role of Cas6 is latching on to the long RNAs made by the CRISPR array and slicing them into the shorter CRISPR RNA snippets, which precisely target the DNA of attacking viruses.
The result was that Cas6 would recognize and cut a very precise place and not mess up other RNA.
“Right now you are punching below your weight. You’re not taking the kinds of projects that a student like you is capable of. Why else do we do science? We do it to go after big questions and take on risks. If you don’t try things, you’re never going to have a breakthrough.”
The camaraderie in the lab was not an accident: in hiring, Doudna placed as much emphasis on making sure someone was a good fit as she did assessing their research accomplishments.
Jinek’s cautionary note, he says, was “one hundred percent accurate,” but that made her lab an exciting place to work for a self-driven person. “She definitely doesn’t hover over you,” says Wilson, who now runs his own Berkeley lab aligned with Doudna’s, “but when she goes over your experiments and results with you, there are times when she will lower her voice a bit, look you right in the eye, lean in, and say, ‘What if you tried…?’ ” Then she would describe a new approach, a new experiment, or even a big new idea, usually involving some new way of deploying RNA.
“She has a knack for asking the right critical big questions when you’re developing your project,”
They were designed to get her researchers to look up from the details and see the big picture. Why are you doing this? she will ask. What’s the point?
Although she takes a hands-off approach during the early stages of a researcher’s project, as it gets close to fruition she engages intensely. “Once something exciting emerges or a real discovery is in the works, she...
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When her lab produced a new discovery, Doudna was tenacious about getting it published. “I’ve discovered that the journal editors favor people who are aggressive or pushy,” she says. “That’s not necessarily my nature, but I have become more aggressive when I feel that journal editors are not appreciating that something we did is really important.”
“Once we understood how the Cas6 protein worked,” she says, “we started to get some ideas on how we might steal it from bacteria and repurpose it for our own uses.”
Doudna says. “I also feel that there is an anti-female undercurrent, and I was worried that if we took venture money, that Rachel might be pushed out as CEO.”
Caribou was an example of this approach. Berkeley, a public university with private philanthropic supporters, housed Doudna’s lab and had a partnership with the federally funded Lawrence Berkeley National Laboratory. The amount of federal grants that went from the National Institutes of Health (NIH) to Berkeley to support Doudna’s research into CRISPR-Cas systems was $1.3 million.
She felt at home in the lab. It was a quiet temple for individual persistence and contemplation.
“I began to see myself as a scientist and not just as a student,” she says. “I wanted to create knowledge, not just learn it.”
“I enjoy the freedom of being on my own, of not depending on partnership,” she says. She hated the phrase “work-life balance” because it implied that work competes with life. Her work in the lab and her “passion for science,” she says, brought her a “happiness that is as fulfilling as any other passion.”
They had also established the essential role of another part of the complex: CRISPR RNAs, known as crRNAs. These are the small snippets of RNA that contain some genetic coding from a virus that had attacked the bacteria in the past. This crRNA guides the Cas enzymes to attack that virus when it tries to invade again. These two elements are the core of the CRISPR system: a small snippet of RNA that acts as a guide and an enzyme that acts as scissors.
It was dubbed a “trans-activating CRISPR RNA,” or tracrRNA, pronounced “tracer-RNA.”
It turns out that tracrRNA performs two important tasks. First, it facilitates the making of the crRNA, the sequence that carries the memory of a virus that previously attacked the bacteria. Then it serves as a handle to latch on to the invading virus so that the crRNA can target the right spot for the Cas9 enzyme to chop.
Charpentier’s little team discovered that the CRISPR-Cas9 system accomplished its viral-defense mission using only three components: tracrRNA, crRNA, and the Cas9 enzyme.
