Understanding How Cells Package Their DNA — And Why
Toshi Tsukiyama, Genome Scientist
If you removed the DNA from a human cell, unraveled it and laid it end to end, the whole thing would stretch about 7 feet. Dr. Toshio "Toshi" Tsukiyama has spent his career studying how all that genetic material gets squeezed into a microscopic cell. All told, it would require the combined length of DNA from over 8 million human cells to cover the distance Tsukiyama traveled from the beginning of his career in Japan to starting his own laboratory at Fred Hutch.
While Tsukiyama was studying to be a veterinarian at Obihiro University of Agriculture and Veterinary Medicine in northern Japan, his sister invited him to visit the microbiology lab where she worked. He still remembers how excited the scientists were to be doing their research.
“It looked really interesting. I had never thought about becoming a researcher… but I decided to try joining a lab,” he said.
He recalled how his very first experiment had been a complete failure, despite following the procedures as laid out. His adviser sat down with him and said that in science, it isn’t enough to blindly follow the protocol; it is necessary to understand why each step is performed in order to know when something might go wrong.
“It was at that moment I realized that doing science was very different from anything else I’d done to that point,” he said. In research it’s not enough to memorize and recite facts — success requires critical thinking. Tsukiyama quickly found that he liked this aspect of research more than doing veterinary work. After finishing his vet training, Tsukiyama knew he wanted to focus on science.
“Since then, I’ve never had a moment that I wanted to do anything else,” he said.
He moved to Hiroshima University to complete his Ph.D. While nearing the end of his training, his adviser pushed him to seek out further research opportunities in the United States. In 1992, he journeyed to Bethesda, Maryland, to work at the National Institutes of Health. There Tsukiyama could see several potential directions in which he could take his career. While making up his mind, he recalled reading about the work of Dr. Harold “Hal” Weintraub, then a well-respected and prominent researcher at Fred Hutch. Tsukiyama was particularly excited by Weintraub’s work studying chromatin, the complex of DNA and structural components that help to compact genetic material and regulate its activity. This excitement pushed him to focus his research on better understanding the role that chromatin plays in cell function.
And that role is crucial. In each of our cells is a nucleus, the structure that houses our DNA. If the nucleus of a cell was about the size of a grapefruit, the length of DNA inside it would be about 12 miles long. Our cells rely on chromatin to bundle that incredible span of DNA into a microscopic space.
Cells also rely on DNA packaging to control gene expression. Genes provide our cells’ recipes for building compounds called proteins, which perform many of the functions that make a cell work. But our cells don’t need to make every protein all the time. DNA packaging helps them control which genes are turned on and which are turned off. Despite chromatin’s importance, there are still many unknowns about how it works, which is what keeps Tsukiyama excited about studying it to this day.
“Everything that happens to DNA happens in the context of chromatin,” Tsukiyama said. “Yet there are so many questions that need to be answered.”
When the time came for Tsukiyama to start his own lab he immediately thought about Fred Hutch, recalling the pioneering work that had come out of the center.
“There were a lot of people I knew through their work at the Hutch,” he said. “As soon as I interviewed here, I knew that I wanted to come ... the main focus is the science.”
“There is a ton of things about quiescence that are still unknown … there are a lot of things to do. It’s a pretty exciting time.”
In 1997 Tsukiyama was offered his own lab space in the Basic Sciences Division. “I didn’t even negotiate,” he said. His lab is housed in the Weintraub Building, named after the very researcher that piqued his interest in chromatin
Tsukiyama still remembers his first week at the Hutch. A senior colleague ran over to his lab to show Tsukiyama the results of a successful experiment he’d just run.
“Oh wow, I’m in the right place,” Tsukiyama remembered thinking. “In other places it is hard for principal investigators, particularly senior ones, to have time at the bench … doing actual science.”
Even though Tsukiyama has now led his lab for decades, the lab bench is still the first place to look for him.
Recently his lab’s research has focused on understanding the role that chromatin plays in cellular quiescence. Quiescence is a reversible state in which cells reduce gene expression, limit the proteins that are made to a select few and stop dividing. When cells enter quiescence, their DNA becomes dramatically more condensed than in nonquiescent cells. Until recently, the mechanism underlying these changes was a mystery. Then Tsukiyama and his team discovered that a protein called condensin is a key regulator of both phenomena.
Tsuikyama’s findings improve our understanding of how normal cells function and may also be a step toward improving cancer therapies. Counterintuitively, some cancer cells can enter a dormant, quiescent-like state. This is thought to underlie the reemergence of cancer years after a patient has been declared disease-free. Many anti-cancer drugs target cell division processes and have limited effect on quiescent cancer cells. Improving our knowledge about this process is essential to developing therapies that can target dormant cancer cells to help ensure that patients declared cancer-free stay that way.
“There is a ton of things about quiescence that are still unknown … there are a lot of things to do. It’s a pretty exciting time,” Tsukiyama said.
— By Matthew Ross, Dec. 3, 2019
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