Photo by Ron Wurzer
Dr. Sue Biggins’ favorite part about her job is what she gets to do tomorrow.
The Fred Hutchinson Cancer Research Center biologist’s workdays are full of questions, sometimes enlightening, occasionally frustrating — but always new, and never dull.
The constant novelty first drew Biggins to lab research. As a college student, she was planning to become a doctor until she did an internship at Merck the summer after her junior year. She fell in love with the research, withdrew all her medical school applications and went to graduate school instead to pursue a doctorate in molecular biology — and the research bug definitely stuck.
“That’s what I tell my kids when they ask me what I do,” said Biggins, a mother of two. “Every day there’s some new problem to think about or something exciting that … you realized that you didn’t know. It’s cool to have a job where you constantly realize what we don’t know and then try to figure out ways to learn about that.”
That freedom to define what is scientifically unknown — and to design the experiments that will let her and her laboratory teammates chip away at those mysteries — helps motivate Biggins in her pursuit to answer one very difficult question: namely, how mother cells correctly segregate their genetic content to each daughter cell during mitosis, or cell division.
And it’s one of the reasons she’s so excited about her new appointment as an investigator of the Howard Hughes Medical Institute, the prestigious nonprofit founded in 1953 by aviation and film tycoon Howard Hughes. Unlike the National Institutes of Health and many research foundations that provide funding to support specific research projects, HHMI provides unlimited support over five-year terms for researchers it deems talented and creative. Her five-year term will begin in September.
So for Biggins, that means her tomorrows are now full of even more possibilities.
'What would have the highest impact?’
Biggins remembers two workdays 10 years ago that would change the course of her career, opening new doors she never expected.
She started her lab at Fred Hutch 15 years ago using genetic techniques, her area of expertise, to better understand how cells shuffle their chromosomes precisely to the next cellular generation. Cracking that mystery is important not only to comprehend how cells function at a basic level but to understand the biology behind many diseases; cells that end up with the wrong number of chromosomes due to mistakes in this process are a hallmark of cancer, certain genetic birth defects and many miscarriages.
Biggins soon realized that if she and her colleagues were going to reach the rich level of knowledge she aspired to, they’d have to take a different, very risky approach. She and her team study the kinetochore, a complex molecular machine that mediates how chromosomes uncouple from their identical partner and sort themselves, nearly perfectly every time, to each of the two daughter cells during every cell division. She knew to truly grasp how the kinetochore works, she’d have to pull the machine out of cells and study it in a pure state, unhindered by its cellular milieu.
Biggins was waiting for the right time and the right person to help her tackle that major scientific feat. And then, five years after she’d joined the Fred Hutch faculty, she had a conversation with Dr. Bungo Akiyoshi, at the time a student in the Fred Hutch and University of Washington’s joint Molecular and Cellular Biology graduate program. Akiyoshi wanted to discuss carrying out his doctoral work in her lab.
“I went through a bunch of projects with him, and then he said, which I thought was really interesting, ‘What project would have the highest impact?’” Biggins said. “So I just threw it out there: ‘If you want to do something really high impact, you could purify the kinetochore.’”
Akiyoshi’s question about how he could best advance the research field seems intuitive, Biggins said, but it was an unusual question, especially from someone so early in his career.
“It seems like what you should be thinking about, but no one asks that,” she said.
The two scientists talked more about the project, and Akiyoshi asked for some time to think about it.
“The next day, he comes in, he just looks at me and said, ‘I will purify the kinetochore,’” said Biggins, remembering her former student’s no-nonsense way of speaking. “That night I was driving home and I thought, ‘What have I done?’ … I had that moment of, ‘I really don’t know how the hell to do this, now that I’ve convinced someone to do it.’”
Isolating such a large molecular assemblage — the kinetochore is made up of hundreds of individual proteins — required biochemical expertise that she and Akiyoshi didn’t possess at the time. But Biggins didn’t let her doubts slow her down for long. She knew Akiyoshi had the drive to attempt this tough work, and she enlisted her colleague and laboratory neighbor, Dr. Toshio Tsukiyama, to train them on the biochemistry techniques.
“I said, ‘Don’t laugh, but I convinced this guy to do this,’” Biggins said.
The project hit several stumbling blocks at first, Biggins said, but by Akiyoshi’s second year in her lab, things were looking up. They’d isolated what they thought were all the kinetochore components from dividing yeast cells and then turned to Biggins’ collaborator, UW biophysicist Dr. Charles Asbury, to test whether that protein slurry could come together in a test tube to work as a machine outside of cells, attaching to and tugging on chromosomes.
And it did.
Biggins credits her collaborators’ expertise and Akiyoshi’s determination and methodical approach for much of their success, but this accomplishment wouldn’t have been possible without Biggins’ intellect and leadership skills, said Dr. Jonathan Cooper, Biggins’ colleague and director of Fred Hutch’s Basic Sciences Division (Biggins is associate director of the division).
“She can see the big picture and get right to the key questions,” Cooper said. “She's an exemplar of the Hutch philosophy of individual thinking and passion for science.”
Biggins also credits the culture of risk-taking that her colleagues embody — that spirit was part of the reason she felt she could try something new and unpredictable, even if she didn’t know where the project would take her, she said.
“I would have never imagined I would be doing biophysics now,” Biggins said.
The next big thing
The research took off quickly from there, Biggins said. With the pure kinetochores in hand, she and her colleagues made several discoveries about the molecular machines, including the somewhat counterintuitive finding that tension makes them work — the harder kinetochores are pulled by the protein tubes that guide chromosomes to daughter cells, the stronger their grip on chromosomes, like tiny locking seat belts.
Her team has also identified many of the protein players involved in chromosome sorting, proteins that could eventually lead to better, more precise cancer therapeutics. If drugs were developed to stop kinetochores from doing their job in diseased cells, that could halt tumor growth.
In collaboration with Asbury, Biggins and her team looked at the mechanics behind meiosis, the special cell division that leads to egg and sperm formation. The scientists found that during the early stages of meiosis in yeast, kinetochores that attach to chromosome pairs are actually fused together. If that kind of fusion occurs in humans as well, it could be a physical failsafe against the cell division errors that can lead to miscarriage or infertility, especially age-related infertility, Biggins said, and could point to potential targets for new fertility therapies.
Biggins has a lot of ideas about what she wants to do next, and the relatively unfettered support from HHMI has spurred even more plans.
She wants to understand what the kinetochore truly looks like in detail by capturing 3-D images of the protein machine. Those structural pictures will help researchers better understand which pieces of the kinetochore attach to other protein machines in the cell or to chromosomes, and how those attachments work. She also wants to understand the checks and balances cells employ to stop cell division when kinetochores make faulty connections.
She wants to know how kinetochores keep their grip on the protein fibers that tow them to the daughter cells as they form — those tiny but strong tubes are continually falling apart at their ends, where the kinetochores bind, but somehow the whole system stays together.
“It’s sort of like you’re trying to stay attached to a rope and somebody is constantly pulling the rope out from under you,” Biggins said, mimicking trying to grab onto a moving object. “We still don’t understand how it is keeping that attachment.”
Ultimately, she wants to study the kinetochore’s role in cells in which chromosome segregation has gone wrong, cancer cells and eggs from older or infertile women. Those larger projects will first require purifying the human kinetochore, which will be a bigger challenge than her team’s work to isolate yeast kinetochores since the human version is even more complicated, Biggins said.
But she’s already started on it — like everything else Biggins and her team do, it will be something new.
“It’s still the idea of every day getting to think about, ‘What’s the next thing I want to learn?’” Biggins said, “and what can we do to get there?”
Rachel Tompa is a former staff writer at Fred Hutchinson Cancer Research Center. She has a Ph.D. in molecular biology from the University of California, San Francisco and a certificate in science writing from the University of California, Santa Cruz. Follow her on Twitter @Rachel_Tompa.
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