Photo by Robert Hood / Fred Hutch News Service
Every scientist runs into it at some point: that moment when there’s a new discovery to pursue but instead of funding, there are only fumes.
For Dr. Jason Bielas, that moment came in the summer of 2015. A Fred Hutchinson Cancer Research Center geneticist who develops novel technologies and studies cancer mutations, Bielas had just launched CypherSeq, a promising method to more accurately pinpoint genetic mutations. Bielas believes the technology will not only help researchers understand how environmental agents — think cigarette smoke, air pollution — cause cancer, but can also be used to detect cancers much earlier.
It’s one of many new research tools that the entrepreneurial scientist helped develop since coming to Fred Hutch in 2008.
“We follow the biology,” Bielas said of the work done in his lab. “And because of that we’re a little more diverse than you otherwise would be.”
Because his team members often start their progress toward answering difficult scientific questions with the development of new methods, their work “more often than not reveals new insights into biology that exceed the scope of the hypothesis being tested, driving us down new and exciting pathways of discovery,” Bielas said.
One such insight involved cells’ powerhouses — mitochondria — specialized parts of the cell that have their own genes which influence aging, tumor growth and cancer metastasis. Bielas looked at the DNA of mitochondria and discovered something unexpected: unlike cellular DNA, which erupts with mutations within tumor tissue, mitochondrial DNA in cancer cells actually has fewer mutations than normal.
“So that started all of this mitochondrial work,” Bielas said. “We wanted to know one, why is this happening and two, how can we exploit it to advance treatment and increase patient survival.”
But funding for novel and unexpected findings isn’t always forthcoming, especially in a climate in which only the top 7 percent or so grants submitted to the National Institutes of Health are given a green light.
“It was extremely difficult,” Bielas said. “You need to provide extensive preliminary data, essentially almost have the grant completed, before the reviewers believe and fund it.”
The research ‘valley of death’
Enter the Washington Research Foundation, a 36-year-old nonprofit that supports groundbreaking research commercialization in the life sciences, physical sciences and information sciences. WRF provides small grants for student research, prototype development and fellowships, as well as larger multi-year grants that fund teams of scientists in various areas of research. Since 1981, they’ve awarded $73 million in grants to research institutes across Washington state and earned $507 million in licensing revenue for the University of Washington.
Seattle resident Sally Narodick for more than a decade had served on the WRF board. When she stepped down in early 2015, the organization decided to honor her with an impressive retirement gift: a $100,000 contribution in her name to a nonprofit research institution of her choice.
A former Fred Hutch board chair and member, Narodick immediately chose the Hutch as the grant recipient.
Photo courtesy of the Washington Research Foundation
“We’ve never done this before, but Sally had such an incredibly positive impact on WRF,” said Beth Etscheid, WRF’s director of research commercialization, who worked with Narodick to find just the right grant recipient. “She’s very keen financially and is also a really thoughtful, forward-thinking individual. She is a very mentoring person — and the Hutch is her passion.”
Narodick wasn’t “looking for somebody who had a hugely long track record,” Etscheid said. Instead, she wanted to find a younger researcher, someone with promise, someone who might be able to leverage the $100,000 grant into a more ambitious project.
Narodick reached out to a handful of Fred Hutch leaders, including molecular biologist Dr. Mark Groudine, who at the time was the Hutch’s acting executive vice president and deputy director (Groudine is currently special adviser to the president and director, Dr. Gary Gilliland) to ask for recommendations. One name kept cropping up: Jason Bielas.
Bielas’ work had already earned him several early-career awards and grants, but he’d used this money on specific targeted projects. With no new funding, the scientist found himself entering what many translational researchers call the “valley of death,” that period in which basic discoveries can stagnate before being translated into new therapies because there’s no money to make them happen.
Fred Hutch file
“Jason is an exceptionally creative scientist and had developed some very innovative methods,” said Groudine of the translational researcher. “The problem was he couldn’t get funding for his work. It was way ahead of the field.”
Narodick and her husband weren’t in what she called the “major-givers category,” but her many years as Hutch board chair had taught her how to maximize the power of philanthropy.
“When I was given the tremendous privilege of choosing the recipient of this very generous grant from WRF, I wanted to support a promising, upcoming scientist,” Narodick said. “I wanted to support a project that the leadership team at the Hutch felt had enormous potential to improve outcomes and save lives. I know there are projects that need early funding to accumulate enough milestones to get major research grants. That was what I was looking for. We did due diligence on Jason and were quite confident we had our answer.”
Etscheid, too, was captivated by Bielas and his vision.
“He’s a remarkable young man,” she said. “It’s so much fun to talk to someone with that kind of positive energy, creativity and an interest in so many things. The breadth of his research interests and his passion to help cancer patients made him a compelling choice for this WRF grant.”
Exploring a mitochondrial mystery
At the time, Bielas was still intent on pursuing the questions raised by his work in mitochondrial DNA.
In 2012, he and his team had published findings showing that mitochondrial DNA mutations drop dramatically in colon cancer. This is in contrast to the nuclear genome, the DNA we usually think of when we refer to the “human genome,” which is typically riddled with genetic errors in cancer cells.
Bielas theorized that this decrease in mitochondrial mutation offered a window into how cancer keeps itself alive. Normally, mitochondria produce most of the cells’ energy with oxygen — but cancer cells can bypass that normal mode, using a different method of sustaining themselves that does not rely on the oxygen-dependent mitochondrial energy factories. This is important because in the course of their normal work, mitochondria produce a toxic byproduct that can damage their DNA and eventually drive their host cells to age and die.
“Damage in mitochondria can result in cellular death — apoptosis – the exact thing the cancer cells don’t want,” Bielas said. “By decreasing DNA damaging events, we believe the cancer cells essentially tip the scales to immortality.”
Bielas wondered whether these different observations — that cancer cells change their energy source, that cancer grows and divides unchecked, and that mitochondrial mutations in tumors are suppressed — could be linked. Could mitochondria be a major force in cancer biology? And if so, could scientists devise new therapies aimed at mitochondria that trigger cancer cells to commit suicide and thus halt tumors’ growth?
Bielas and his team delved into some of those questions, slowly gathering evidence. They found that indeed, shifting cells’ energy production away from oxygen-dependent reactions that take place in the mitochondria to the alternate energy production method did reduce mitochondrial DNA mutations.
“By switching their metabolism, cancer cells produce less DNA-damaging compounds and thus the rate at which mitochondrial DNA mutates is lower,” Bielas said. “We showed that metabolism and mutation rate is really correlated.”
The researchers in his lab also found that this shift causes cells to become resistant to chemotherapy, suggesting mitochondria might be resistant to standard chemotherapy.
Bielas hoped to use these findings to predict patients’ treatment response as his work suggested that patients with lower levels of mitochondrial mutations in their tumors might be more likely to develop resistance to chemotherapy.
Finding these patients earlier could allow their clinicians to save them the burden of typical treatment. Instead, the patients would be candidates for new mitochondrial-targeted therapies and drugs.
Image by William (B.J.) Valente of the Bielas Lab / Fred Hutch
A grant at ‘the perfect time’
Unfortunately, Bielas still didn’t have enough data to convince the NIH to fund the project. At least, he didn’t until he got an unexpected email in May 2015 from the Washington Research Foundation, informing him he’d been selected to receive the $100,000 grant.
“We had a few pieces of preliminary data when the grant initially went in [to the NIH],” he said. “We pieced together some money here and there and got a little more preliminary data and we got a score, but not a fundable one. Then the Washington Research Foundation — in honor of Sally — granted us this money and we put it toward the project.”
A year later, Bielas resubmitted a grant proposal to the NIH to test whether cancer therapies directed at mitochondrial DNA could shift the energy production back toward mitochondria and promote suicide in cancer cells.
Last month, Bielas received word that his proposal had finally been funded — to the tune of $2.2 million.
Part of their project aims to “determine through a small biopsy who will respond to therapy — which is very, very important — and identify those who won’t,” Bielas said. “We’re focusing on breast cancer now but it should work across all cancer types.”
Bielas said his newly funded study also has a targeted drug screen component to it.
“We have a few clinically approved drugs that we’re going to test to see if they can re-sensitize the tumors to chemotherapy,” he said. “They’re not currently used in cancer therapy, but according to our underlying hypothesis, we expect that a few of them can be repurposed. Since these drugs are already FDA approved for human use, that makes their potential use and approval for cancer therapy way faster.”
WRF’s Etscheid was delighted that their grant was able to fast forward Bielas’ work and applauded Narodick for her “leap of faith.”
“It ended up being such a happy story,” Etscheid said. “He hadn’t had a sizable grant for some time and needed to get just a little more data. And that’s exactly what he did. We visited him a month or two after he received the $100,000 grant and even in that very short amount of time, he’d already had a major breakthrough on something that had been put on hold because it was unfunded.”
Groudine said the WRF gift was a crucial springboard for Bielas.
“This gift in honor of Sally was a catalyst,” he said. “It permitted him to actually do the work and gain more preliminary data and start nailing this down. This is what you want from philanthropy. … Often the very innovative work isn’t funded by conventional review because it’s considered too risky. This kind of catalytic philanthropic funding is essential for high-risk/high-reward research.”
Bielas agreed that it’s a success story that’s important for researchers — and the general public — to hear.
“It’s all about leveraging,” he said. “Funding goes in cycles and when it’s coming down, you’re letting people go and your projects are slowing down. And then you get this money. It’s a bridge period and we don’t often get that. This just came at the perfect time.”
But of course, Bielas’ motivation is larger than just keeping his laboratory funded.
“We expect that our work will prevent unnecessary overtreatment … and revolutionize treatment regimens by replacing interventions that have life-threatening toxicities with ones that are safe and effective,” he said, and ultimately improve cancer patients’ outcomes, quality of life and survival.”
Diane Mapes is a staff writer at Fred Hutchinson Cancer Research Center. She has written extensively about health issues for NBC News, TODAY, CNN, MSN, Seattle Magazine and other publications. A breast cancer survivor, she blogs at doublewhammied.com and tweets @double_whammied. Email her at firstname.lastname@example.org.
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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