Jennifer A. Doudna: Game-changing puzzle solver

Jennifer Doudna’s scientific path in life, one could say, began in childhood explorations of the Hawaiian rainforests. When she was seven years old the family moved to Hilo on Hawaii’s Big Island. She was mesmerized by exotic mosses and fungi and wanted to know more about the intricate wonders of nature.

“The Double Helix was eye-opening to me in many ways, and really got me thinking about what a life in science might be like.”

“Growing up in Hawaii was hugely influential,” she said. “Everywhere you go, you are surrounded by life. It’s a big evolutionary laboratory. Because Hawaii is so isolated and volcanic, everything that lives in Hawaii came from somewhere else and was shaped by the islands.”

The introduction to science continued during her early teens when her father, a professor of American literature, gave her a copy of The Double Helix. Jim Watson’s account of the discovery of the structure of DNA made her realize that it was possible to do experiments on what a molecule looks. The insight blew her away. “The Double Helix was eye-opening to me in many ways, and really got me thinking about what a life in science might be like,” she says.

Studies and career

During the mid-80s Jennifer studied biochemistry at Pomona College, California, and then entered Harvard University, where she would earn her PhD. Her interest in RNA was really sparked by working with genetics professor and Nobel Laureate Jack Szostak, an experience that laid the foundation for her work on CRISPR.

“That was really the start of my love of RNA, and it set me on a path that would eventually lead me to CRISPR.”

“He was deeply interested in the origins of life, and he was able to translate a big question like that into experiments we could perform in the lab. We published a series of papers while I was a graduate student that showed that you could develop very simple RNA molecules that could synthesize copies of themselves. That was really the start of my love of RNA, and it set me on a path that would eventually lead me to CRISPR,” said Doudna.

She spent the following years at University of Colorado Boulder and Yale University before moving to UC Berkeley for a joint professorship in Molecular and Cell Biology and Chemistry. In 2006, Doudna was introduced to CRIPSR by her colleague Dr. Jillian Banfield. Banfield suspected it was a type of bacterial immune system, but that was still just a hypothesis at the time. When that was proven shortly afterwards, the big question became how it functioned.

“Because it seemed to use a mechanism similar to RNA interference, that is how I got curious and started working on CRISPR in my own lab,” she said.

A meeting in Puerto Rico

In 2011, another defining event took place in Jennifer’s career. During a microbiology conference in Puerto Rico she met Emmanuelle Charpentier. The passion and excitement that her future collaborator exuded was contagious and Doudna and Charpentier decided to work together on the mysterious Cas9.

 “There was no way to know what was going to become of our collaboration, but when she and I met, and she told me that she was excited that I wanted to work with her on “the mysterious Cas9 enzyme” I remember having a gut feeling that we were going to do something interesting together.”

The discovery

Jennifer and Emmanuelle, along with their colleagues, discovered how bacteria use the CRISPR/Cas 9 system to protect themselves from viruses, and then showed how the defense system could be turned into a “cut and paste” tool for editing gene sequences. They succeeded in recreating the bacteria’s genetic scissors in a test tube and simplifying the scissors’ molecular components so they would be easier to use. In a milestone experiment, they reprogrammed the genetic scissors. In their natural form, the scissors recognize DNA from viruses, but Charpentier and Doudna proved that they could be controlled so that they can cut any DNA molecule at a predetermined site. Where the DNA is cut it is then easy to rewrite the code of life.

“I remember being at home, cooking dinner when the magnitude of what it could mean came over me and I started laughing. It was a joyous feeling.”

The implications of what a genome editing tool like CRISPR/Cas9 could do hit her all at once, said Doudna.

“I won’t claim to have seen everything that was coming, because I’m surprised every day. But I remember being at home, cooking dinner when the magnitude of what it could mean came over me and I started laughing. It was a joyous feeling.”

A game changer

Research at labs all around the world quickly picked up on the discovery and put CRISPR to work. The ease of use is one of the things that makes CRISPR/Cas9 so remarkable, says Doudna, and what has led to such rapid uptake by the research community. Researchers can learn to use it and adapt it to their own area of study in almost no time. The huge potential for medical purposes makes the technique a real game changer.

“We still largely approach medical research as “one disease, one cure,” but genome editing can be a platform technology that allows us to treat whole classes of diseases with quick, minor alterations.”

“There are so many unmet rare genetic diseases and a tool like CRISPR gives us a way to address them by engineering personalized treatments at scale. We still largely approach medical research as “one disease, one cure,” but genome editing can be a platform technology that allows us to treat whole classes of diseases with quick, minor alterations,” said Doudna.

At the same time, she thinks that we may not have found the most remarkable aspect of CRISPR yet. “There is such a diversity of CRISPR systems in nature and we have barely begun to understand the breadth of the tools that will one day be in our tool chest.”

Making it affordable

Currently the biggest challenge with the CRISPR therapy is delivery of gene editors to target tissues, said Doudna. “We know a lot about different disease targets, but in many cases we can’t get the gene editors to those cells in vivo.” This is an area her own lab and several other labs at the Innovative Genomics Institute are focused on, since solving the delivery challenge is key to opening up a world of potential treatments.

Making the therapy affordable for patients is also a main hurdle to cross. Doudna takes Sickle Cell Disease as an example: The current CRISPR-based therapy is extremely promising, but costs over $1 million just to cover basic costs. It needs to be done at special facilities that aren’t available everywhere. Luckily, the things that need to be done do to evolve this therapy into the next generation are also what will decrease the costs, such as faster in vivo therapies, ones that can be done safely anywhere.

“We are consciously trying to bend the cost curve down as quickly as possible to make sure that these therapies can be accessible to all who need them.”

Salvation and disaster

The groundbreaking CRIPSR/Cas9 findings are a two-sided discovery. The capability of making exact alterations to the human genome has revived discussions of moral concerns. The fact that the technique is so accessible has raised worry over potential misuse. The ethical implications of genome editing have occupied her mind ever since she started working on CRISPR, said Doudna.

“Every powerful technology comes with tradeoffs, and CRISPR is certainly no exception. How we use it is up to us, and I’m really gratified that there has been so much discussion and thinking early on about how we track and regulate the use of gene editing. There have already been examples of people misusing the technology, but those have been minor compared to the vast amount of positive progress in medicine, agriculture, and as a basic research tool.”

Biooptimist

The documentary Human Nature, where Dr Doudna is also interviewed, explores the moral and ethical implications of CRISPR. In one part of the documentary bioethicist Alto Charo makes a division between bio-pessimists and bio-optimists, talking about the belief in progress and arguing that it’s the user that determines the end point, not the tool. Jennifer Doudna definitely falls on the optimist side, she says. However, optimism doesn’t mean naively ignoring reality, she emphasized.

“I founded the Innovative Genomics Institute on a fundamentally optimistic vision of what genomics can do — the work we do every day is to get over the hurdles to make that vision possible.”

“To really deliver on optimistic visions means having a clear understanding of potential downsides, trade-offs, and challenges that need to be overcome. I founded the Innovative Genomics Institute on a fundamentally optimistic vision of what genomics can do — the work we do every day is to get over the hurdles to make that vision possible.”

A curious mindset

For the discovery of one of gene technology’s sharpest tools Jennifer Doudna and Emmanuelle Charpentier received the 2020 Nobel Prize in Chemistry. When Doudna’s Berkely colleague Professor Fyodor Urnov heard about the news at the beginning of October last year, the feeling of happiness and excitement was so overwhelming that he had the sensation of “levitating off his bed”, as well as a feeling of comfort, he said during a Zoom interview.

“This was a rare moment in 2020 when the primary emotion was that the world is fair; exactly the right thing happened. The right discovery was honored and given to exactly the right people.”

“She is the top of her field. To use a sport analogy, we are talking about a world class athlete who has spent her life training for winning, and when a particular challenge came up, she showed us what she was capable of doing.”

He highlighted the fact that Doudna was a well-known scientist before the Nobel Prize and before the CRIPSR discoveries. He talked about her as someone who is unafraid of difficult things, works with a tremendous discipline, pays attention to detail and devotes herself completely.

“This wasn’t an accident that just landed in her lap. She is the top of her field. To use a sport analogy, we are talking about a world class athlete who has spent her life training for winning, and when a particular challenge came up, she showed us what she was capable of doing,” he said.

A central driving force as a scientist is her curiosity. She sees puzzles and wants to solve them, Doudna said. “It’s the application of science that gets most people excited, but my work always starts with trying to answer fundamental questions and overcome barriers.”

“It’s the application of science that gets most people excited, but my work always starts with trying to answer fundamental questions and overcome barriers.”

During our interview Urnov made an analogy to a story about Isaac Newton. When asked about how he discovered the laws of motion, he supposedly answered, “By thinking of them continuously.”

“When you speak with Jennifer about the area of her research passion, the immediate thought that comes to mind is that she is of that Isaac Newton mindset. Someone who has been thinking continuously about it.”

Hoping for change

When this article is written, the inauguration of Joe Biden as the 46^th president of the United States are merely days away. For the past four years, the world has witnessed a dubious attitude from the Trump administration on both the notion of facts and funding for science. A worrying tendency, says Doudna, who emphasizes the need for more communication.

“Over the past three decades that I’ve been a professional scientist, I’ve seen an increasing distrust of science and scientists, particularly in the US.”

“Over the past three decades that I’ve been a professional scientist, I’ve seen an increasing distrust of science and scientists, particularly in the US. It’s troubling. In some ways, the scientific community hurt itself by staying out of politics and letting others be the storytellers. There hasn’t been enough dialogue between the scientists making discoveries that can help solve society’s problems and the leaders responsible for finding — and funding — solutions.”

I ask her what her thoughts and hopes are of what a new administration can bring about for the sake of science. Many things about 2020 have been very challenging but it has also been a prime example of what science can achieve even under the most difficult circumstances, Dr Doudna concludes.

“We’re staring at an unmatched scientific triumph, and I hope we build on this momentum. If we can do this, think of what else we can do to improve people’s lives in ways that they feel every day.”

“Just a year ago, the scientific community knew nothing about SARS-CoV-2, and now we have multiple successful vaccines, rapidly improving diagnostics, therapeutic approaches that have drastically reduced the fatality rate. We’re staring at an unmatched scientific triumph, and I hope we build on this momentum. If we can do this, think of what else we can do to improve people’s lives in ways that they feel every day. This takes funding and the vision to empower scientists on our most pressing challenges, and I hope we will see more of that.”

The importance of role models

The presence of role models and mentors have been important throughout her career. Professor Jack Szostak was one of them. A significant moment she remembers from high school is listening to the lecture of a young female scientist, further inspiring her to pursue a career in biochemistry.

In various interviews Doudna has talked about the importance of highlighting the challenges that women face and the possibility of self-realization. What kind of role model would she like to describe herself as, I asked her, and what advice would she give to future scientists? Her simple hope is that young women will look at her and realize that they can do it too.

“As a young girl, I needed to see that too. I needed to know it was possible for someone who looks like me to be a scientist.”

“As a young girl, I needed to see that too. I needed to know it was possible for someone who looks like me to be a scientist. And even if young women aren’t interested in science as a career, I hope they can learn what I learned early on, which is to go for what you want. If you want a job or a fellowship, the only one that can really get that for you is yourself — go for it.”