Trailblazing. Visionary. Highly innovative.
Those are the words the National Institutes of Health use to describe their High-Risk, High-Reward Research program, which provides grants to scientists who are pushing the boundaries of biomedical science.
One of the most coveted of those awards, the NIH Director’s Early Independence Award, is given to exceptional junior investigators — and one of the 2022 winners, who completed her residency just the previous year, is Yun Rose Li, M.D., Ph. D., City of Hope assistant professor in the Departments of Radiation Oncology and Cancer Genetics and Epigenetics. She also holds a joint appointment in the Division of Quantitative Medicine and Systems Biology at the Translational Genomics Research Institute.
Her grant proposal — which received the highest possible impact score — reaped a $1.98 million grant to further her groundbreaking work over the next five years.
Li uses modern technological approaches such as multiomic sequencing — which analyzes genomes as well as other complex biological molecules — and the genetic modification of single human induced pluripotent stem cells to shed light on questions about the origins of cancer that science has not yet been able to answer.
We caught up with her the night before she flew off to Europe to give a presentation on her work at the ESMO Molecular Analysis for Precision Oncology Congress in Amsterdam, and asked her how it felt to receive such an honor so early in her career.
“I was shocked to be selected for this award and given the opportunity to do exciting science that can shape the future of cancer research,” she said. “I’m also really humbled to know that many accomplished researchers are invested in my growth and potential as a physician-scientist.”
She also wanted to emphasize that the award is not just about an individual’s research, but about the institution that supports the work.
The award is, in part, granted for innovation and scientific vision to junior investigators doing high risk, high reward science, and also to the institution for its leadership and investment in providing them with the resources they need to succeed.
Li is clearly grateful for the support she’s received from City of Hope, which recruited her and facilitated the development of this grant proposal while she was still a resident at the University of California San Francisco.
The Upside of Stress
Like the best villains, oxidative stress isn’t all bad. It is a natural physiological molecule that can be important in many biological processes essential for life. For example, it plays a key role in cell signaling, which allows cells to communicate, It also helps immune cells kill bacteria and other toxic agents. But too much oxidative stress is one of the factors that can contribute to cancer.
“There’s been a huge focus on mutations that cause cancer — but the majority of cells with mutations do not become malignant,” she said. “My interest is in understanding how oxidative stress may cause such cells to develop into tumors, possibly through mechanisms that are more complex than can be detected at the level of the genome.”
Specifically, Li believes that the mechanisms through which oxidative stress contributes to cancer risk and normal tissue toxicity is related to how it modifies the ability of the cell to regulate how proteins are expressed.
It’s well known that various lifestyle factors — obesity, certain dietary choices such as a high fat and red meat, and exposure to irritating agents like smoke — as well as conditions like autoimmune diseases can increase the risk of cancer. But Li is taking a deeper dive into the question, using a multidisciplinary approach to identify molecular biomarkers and the mechanisms that drive how oxidative stress acts on cancer-predisposed cells.
“I spent many years training as a molecular biologist, but for my Ph.D. degree I specialized in genomics and computational biology — and in my lab I married them,” she said. “Some people focus mostly on wet lab, others on dry lab, and a few rare birds like myself and trainees in my lab are passionate about combining the two.”
These approaches require both advanced molecular techniques, such as genetic modification and single cell isolation, as well as big data analysis to better understand the patterns of mutations related to oxidative stress that may ultimately lead some cells to transform to cancer cells.
New Approach to Radiation
“Oxidative stress has a critical role in radiation therapy – a yin and yang,” said Li. “It works as a cancer killing agent — but can also cause toxicity and even secondary cancers.”
As both a research scientist and radiation oncologist, part of her research involves manipulating oxidative stress to improve the outcomes of her patients. Finding the right balance is key.
One technique that has shown some success in reducing oxidative stress is dietary modification, such as through short-term or intermittent fasting, which cycles periods of no food with normal eating. The technique has been shown to be safe and improve the health of patients with metabolic diseases like diabetes and obesity.
Recently, fasting has been studied as a way to improve cancer treatment outcomes in vitro, in animals and in humans receiving chemotherapy. One of these studies, led by City of Hope medical oncologist Tanya Dorff, M.D., a collaborator and mentor of Li, showed that a very low-calorie or “fasting-mimic” diet during chemotherapy could reduce toxicity without sacrificing its effectiveness.
This study inspired Li to ask whether such an intervention could improve radiotherapy outcomes. She will soon launch a first-of-kind study using intermittent fasting during radiation treatment for patients with locally advanced colorectal, prostate and cervical cancers.
The patients will be randomized, with half receiving close lifestyle and nutritional coaching during treatment and the other half a recommended form of intermittent fasting for five days a week while receiving radiation, with a break for weekends, when they will be able to eat normally.
If you are interested in taking part in this trial, contact research associate Benjamin Mercier at firstname.lastname@example.org or Li directly at email@example.com.
All Work... and a Little Play
When Li isn’t working in the lab or seeing patients, she tries to stay active physically and mentally.
“I think doing something that’s seemingly irrelevant to medicine or science is actually critical to being successful as a physician-scientist,” she said. “There are all kinds of struggles we face in the lab and in the clinic, so it’s important to be able to put things down when the going gets tough and do something you love. It really reminds me of why I am doing what I do.”
She writes poetry, plays the piano, loves the outdoors, and is also an avid traveler who’s snowboarded in Switzerland and windsurfed in Sardinia.
These days she has been fortunate to blend her love for travel with science, having given talks and chaired meetings in such faraway places as Korea, Australia and Germany. Li also sees these as unique opportunities to inspire and mentor young scientists, and took part in a young oncologist mentoring panel at the ESMO meeting.
“I love to see new places and different cultures, and I also get to meet with scientists and trainees from all over the world who are full of exciting ideas,” she said. “Collaborating with people around the world is really how we think about science now, and it exponentially accelerates what we can do to create a brighter and better future for our cancer patients.”