By Joyce Dall'Acqua Peterson
It’s a fact of life: As we age, mutations happen. The longer we live, the more genetic changes accumulate in our cells. That’s why the likelihood of developing cancer, including blood cancers, increases the older we get.
The condition is called CHIP, for clonal hematopoiesis of indeterminate potential, and if you’ve already attended your 25th high school reunion, you may have it.
“It’s estimated now that everyone over the age of 50 — and maybe even 40 — is carrying stem cells with these mutations,” Trowbridge says. “And that puts them at higher risk of developing blood cancers, such as lymphoma and leukemia, and also cardiovascular disease and atherosclerosis.”
That sounds scary, Trowbridge says, “but actually, most people can carry these mutations and live out a normal life span without any problems in their blood or immune systems.” The very name of the condition contains the term “indeterminate potential,” she notes, “and the name implies we don’t really yet know for any particular person how risky it is.”
Trowbridge’s lab is looking at new approaches to extend the production of healthy cells in the bone marrow during aging, and to prevent the progression of CHIP to aging-related blood cancers and other disorders.
For this work, the Leukemia and Lymphoma Society has recently awarded Trowbridge a five-year Career Development Scholar Award, earmarked for rising stars in the blood cancer research field.
Trowbridge’s work caught the attention of gerontologist Esther Koch. Koch has been active with the LLS for nearly two decades, starting when her mother, Harryette Esther Koch, received a diagnosis of leukemia that would ultimately prove fatal.
“Trowbridge’s aging-related research is personal to me in a number of ways,” Esther Koch says. “We already know that age is a risk factor for developing blood cancer. Most people don’t know that 90% of all cancers are diagnosed in patients 45 years and older, and that blood cancers combined are the third leading cancer killer of Americans.”
Harryette Koch was diagnosed with her first cancer in her early 50s, Esther Koch relates, and with chronic lymphocytic leukemia, her fourth of five cancers, at 78. “As a gerontologist, I know that age is a risk factor for so many diseases. What if Trowbridge’s research unlocks the key not only to who will develop blood cancer as they age, but to aging as a general risk factor for cancer and other chronic diseases?”
Harryette Koch’s illness was a turning point for her only child. Esther Koch, who is a C.P.A. with an M.B.A. from Stanford, had held a series of top corporate management jobs when she became her mother’s primary caregiver. She obtained a master’s degree in gerontology from the University of Southern California and started a consulting company, Encore Management, to help her fellow baby boomers with the many issues associated with caring for an aging parent and their own aging. Esther Koch has served as a delegate to the White House Conference on Aging and is in high demand as a speaker on aging-related topics.
But Esther Koch’s connection with The Jackson Laboratory goes back decades before her mother’s illness. She and JAX President and CEO Edison Liu share a friendship that began at Lowell High School in San Francisco in the late 1960s.
“Ed likes to say I’m his oldest friend,” she says with a laugh. “I would prefer to be known as his most longstanding friend.”
Koch and Liu first met in student government, when they were both class presidents who enjoyed jazz — Liu, a lifelong musician, was in the school’s orchestra and in a jazz band with his brother.
Over the years Esther Koch and Liu stayed connected. “I reached out to him when my mother was diagnosed,” she recalls. “I worried that she wasn’t being treated adequately because she was older, and I thought it was ageism. But Ed, in his kind and compassionate way, made it clear to me that her treatment was appropriate given her age and condition.”
Esther Koch has announced that she is making a donation to JAX to support the Trowbridge lab, “in memory of my mother, and in honor of my dear friend, Edison Liu.”
Liu had started his scientific career studying the oncogenic drivers for different forms of leukemia. He was the first to describe an activated oncogene, ras, in a human preleukemic condition. Between 1991 and 1996, when he was on the faculty of the University of North Carolina at Chapel Hill, Liu was named an LLS Scholar, 30 years before Trowbridge.
Since those early days, Liu expanded his line of investigation to breast cancer biology, molecular epidemiology, functional genomics and systems biology, and advanced not only in scientific prominence, but also to institutional leadership, including at the National Cancer Institute. Before joining JAX as president and CEO in 2012, Liu was president of the Genome Institute of Singapore; on trips home to visit family, he and Koch occasionally met for a chat at the San Francisco Airport.
Liu marvels at the progress in the field of blood cancer research since the beginning of his career. “I started focusing on one gene and its effects in preleukemia and leukemias. Now we know a lot more genes that are drivers, and the challenge is now one of understanding genetic complexity.”
Trowbridge says she is delighted with the gift to her lab “to continue pushing forward in our research into the origins of leukemia. Esther Koch's passion for and long-term support of blood cancer research is inspiring, and we are very fortunate to have made this connection with her.”
Working with a novel mouse that models CHIP, the Trowbridge lab has already shown that an age-related increase in the concentration in the bone marrow environment of pro-inflammatory molecules called cytokines accelerates CHIP expansion and progression.
With age, Trowbridge says, “you have more inflammation in your body systemically, and that's true in your bone marrow as well. And so, one hypothesis is that with aging, this inflammation is changing the environment and giving stem cells with these mutations a growth advantage over the other stem cells. They’re thriving more than the stem cells that don’t carry CHIP mutations.”
Besides studying this mechanism with experiments, the Trowbridge lab will be testing whether inhibiting the inflammatory pathways with drugs can prevent the diseases associated with CHIP. “Can you change the environment so that you can you stop those mutated stem cells from having that selective advantage?” If that turns out to be accurate, she says, “then certain anti-inflammatory drugs might be very useful in reducing the risk of people with CHIP to develop a blood disorder, blood cancer or cardiovascular disease.”
In a paper recently published in the distinguished journal Cell Stem Cell, Trowbridge’s lab showed that declining levels of the hormone IGF1 contributes to overall longevity in middle-aged mice, but also causes aging and decline of blood stem cells, a possible precursor to cancers.
Esther Koch notes that while aging certainly has its biological disadvantages, among them increased cancer risk, long friendships are just one of the benefits of living to middle age and beyond. In fact, at her popular talks on successful aging, she always tells her audiences that “relationships are essential, for both emotional and physical well-being.”
She says she is grateful for her 50-year friendship with Liu, and for his contributions and Trowbridge’s to understanding blood cancers. “I know that if my mother were alive today, she would enthusiastically support my decision to fund JAX research.”