Fred Hutchinson Cancer Center geneticist Linda Breeden, PhD, recently retired from a career spent untangling the intricacies of the factors that regulate the cell cycle, the series of steps a cell takes to divide into two new cells.
Now a professor emerita, Breeden focused on the factors and DNA elements that turn on the genes needed to jumpstart the cell cycle in resting cells. After making notable contributions to the cell cycle field, Breeden pivoted and began studying how cells stop the cell cycle by entering the dormant state known as quiescence.
“Linda is a hard-core geneticist,” said Steven Hahn, PhD, a colleague of Breeden’s in Fred Hutch’s Basic Sciences Division, who studies the molecular machines, called transcription factors, that transform information in genes into the RNA molecules that serve as protein-making instructions. “She’s very exacting. If she says this is how something works, you know that’s how it works.”
She used genetic strategies to work out the important factors and DNA regions involved in these fundamental cellular processes. Her work revealed key factors that regulate proliferation and dormancy, and shed new light on proteins whose quiescence-specific nature had remained mysterious to scientists focused on how cells gear up to replicate DNA and divide.
“I really enjoyed watching her career,” said Senior Vice President and Basic Sciences Division Director Sue Biggins, PhD, who studies how cells form and regulate the kinetochore, a protein complex that enables them to separate chromosomes after DNA replication. “She was doing all this amazing work on transcription, and then I give her a ton of credit for switching fields.”
After growing up in Spokane, Washington, Breeden received her PhD from the University of Colorado Boulder, studying a stress response strategy bacteria use to adapt to nutrient deprivation. Before taking a faculty position at Fred Hutch, she held postdoctoral positions at CU Boulder and the MRC Lab of Molecular Biology in Cambridge, England.
Cells transiting the cell cycle are a little like cars on a racetrack, circling a pre-programmed lap that moves them through the process of DNA replication and cell division. Cells that make it all the way around may continue onto a new lap or pull off and idle in neutral. Rampant proliferation is a hallmark of cancer, making a deep understanding of the cell cycle and quiescence critical to understanding how tumors work.
To gear up from neutral into drive, cells need to turn on a suite of new genes that will carry them through a lap of the cell cycle. Breeden’s early work focused on the transcriptional control of this process, the transcription factors and DNA elements responsible for activating these genes in yeast.
As a postdoctoral fellow in the MRC Lab, Breeden developed a better way to work out the genes — and by extension, the proteins they encode — involved in the cell cycle.
“She came up with a creative way to systematically identify factors or genes involved in cell cycle-specific transcription,” said Basic Sciences colleague Toshio Tsukiyama, PhD, DVM, whose collaborations with Breeden on quiescence inspired him to devote his team to studying the role that DNA packaging plays in helping cells enter and maintain dormancy. “Until that point, the assay was very tedious. She streamlined it and identified a lot of important genes.”
In particular, Breeden identified two transcription factors, called SWI4 and SWI6, that cooperate to turn on the genes that start the yeast cell cycle. Much of her work on the cell cycle focused on working upstream and downstream from these factors, fleshing out how they are regulated and the events they promote to help cells grow and divide. She worked out the roles various proteins played in processes as varied as DNA replication, cell separation and assembly of the kinetochore, a protein complex that’s necessary for separation of replicated DNA prior to cell division.
“She made some really important contributions to discovering new linkages between gene expression in the cell cycle,” said Brenda Andrews, PhD, a molecular geneticist at the University of Toronto who also focused on how the cell cycle regulates transcription in her early career.
After 20 years of focusing on how yeast cells grow, Breeden switched to studying quiescence, and how cells stop growing and exit the cell-cycle in a way that can be reversed when conditions improve.
As important as the cell cycle is, most cells in our bodies aren’t on this track. But as important as quiescence is, it’s difficult to study in multicellular organisms like mice. Breeden recognized an opportunity to use yeast to better understand this important cell state — but first she had to convince other scientists that yeast cells could enter a distinct quiescent state.
“It was a hard transition. We had established ourselves with log-exponential growth [studies] and we had to prove that no, really, we could do this other aspect of the cell cycle,” said Shawna Miles, Breeden’s longtime lab manager. “Abstractly, it made sense because G0 [quiescence] is just a branch off of G1 [earliest cell cycle stage].”
To dig into quiescence, Breeden capitalized on a strategy that allowed researchers to separate cycling and quiescent yeast cells and study purely quiescent populations. Using this strategy, she and her team were able to reveal factors and mechanisms that govern the transition from an active state to a dormant one.
“She’s a real scholar,” said Tsukiyama, who recently collaborated with Breeden on a review of the state of quiescence research. “She’s spot on about what’s the most important progress in the field.”
Breeden’s knowledge of the literature is not restricted to the cell cycle, her colleagues said.
“Linda really, really loves science,” said Biggins. “I can’t think of a day that Linda wasn’t in her office with stacks of papers. She was a voracious reader. She would come and ask interesting questions or sometimes she would point out a paper in my field that I hadn’t seen, but she had.”
Breeden’s interests outside science receive the same level of care and attention as her research, colleagues said. She is a wine afficionado who fostered a wine club that many Fred Hutch colleagues joined.
She is also dedicated to the art of cultivating bonsai trees, maintaining ties with a Japanese teacher and starting her own trees using a combination of grafting, air-layering, wiring and carving.
Breeden brings the same dedication to mentorship and support of other researchers. Andrews first connected with Breeden as a postdoc when Breeden was preparing to start her own lab. Both of their postdoctoral labs studied cell cycle regulation of transcription.
“My advisor suggested I give her a call so we could see if we could collaborate instead of competing,” Andrews said. “She was wonderful and supportive. … At the time, it was an extremely competitive field; she was a breath of fresh air: open to sharing information and data.”
Though the two never formally collaborated, they worked on similar problems in parallel and shared ideas and reagents over the years, Andrews said.
Biggins’ lab space has abutted Breeden’s since Biggins arrived at Fred Hutch. Breeden immediately became a mentor and guide.
“Linda was a wonderful mentor,” Biggins said of Breeden, who also sat on her promotion committee. “I could walk into her office and talk to her about anything. She never called me crazy. And she always gave honest feedback.”
Hahn also benefitted from Breeden’s support in his early years at Fred Hutch.
“Linda is a real expert on yeast, and a tremendous resource when I needed help with anything,” he said. “We do baby genetics — she does the real thing.”
Miles and former Breeden Lab members also shared positive experiences.
“She's a wonderful boss,” Miles said. “She really encourages people to go explore science and to get involved in it.”
Breeden has been committed to giving credit where it’s due.
“Even though I don’t have a PhD, I’m first author on a lot of papers,” Miles said. Volunteers and lab aides have also been credited in Breeden’s publications.
Her approach to science and building lab culture still influence her mentees today, they said.
Pramila Tata, PhD, now a consultant at the healthcare development company Indegene, joined Breeden’s lab as a postdoc and then transitioned to staff scientist.
“Now as I take on the role of mentor, I realize how good she was as a mentor,” Tata said. “Each [trainee] has their ups and downs. How she handled that was fantastic. It didn’t really sink in until I found myself in the same position.”
Breeden’s support extended beyond science. Tata, then a new mother, had come to Breeden’s group from New York City and didn’t drive. Breeden gently pointed out how important driving would be if Tata’s infant son had an emergency. She taught Tata to drive.
“At the time I was busy as a young mom. Now I realize she went out of her way to help me,” Tata said. “It’s something I try to do for my reportees.”
Biggins also recalled how Breeden, who also balanced motherhood with top-tier academic work, helped Biggins when she faced the same challenge.
University of Washington cell biologist Julia Sidorova, PhD, worked in Breeden’s lab during a sabbatical during her PhD work, then joined as a postdoctoral fellow. She remembered the diverse and enriching community Breeden fostered in her lab. Every autumn, Breeden, her lab team and her family drove out to Ocean Shores on the Washington coast to dig for clams. They camped on the beach and hunted for razor clams in the dark of night, armed with lanterns and shovels.
“Then we’d cook them. It was really a slice of life — just unforgettable,” she said. “I was coming from Russia. It was my introduction to science in the U.S., and Linda became my cultural ambassador: this is how everything is done.”
Breeden is the mentor who shaped Sidorova as a scientist, she said.
“Her love of science has always inspired me. Her delight at discoveries was just galvanizing. Science was fun,” Sidorova said.
But science can also be hard, and Breeden taught Sidorova that there’s room to emote.
“The next day you just get back to work and do more, better science. That was another lesson that has helped me in the years since: How hard we have to fight sometimes,” Sidorova said. “Nothing is really easy in science, so there’s this level of work to communicate your message, to be heard.”
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a PhD in immunology from the University of Washington, an MA in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at srichar2@fredhutch.org.
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