February 14, 2017 | by Abe Rosenberg
Markus Müschen, M.D., Ph.D., is driven.
You wouldn't know it at first, noting his calm, soft-spoken manner.
But talk with him for a few minutes, listen to his plans, read a list of his breakthroughs over the past decade, glance at the more than 100 publications of his still-young career, and the passion of his personal mission emerges loud and clear.
Hailed as one of the best researchers of his generation, this quiet man from Germany has joined City of Hope with the singular goal of wiping out acute lymphoblastic leukemia (ALL), the most common form of cancer in children. To achieve this goal, Müschen, the Norman and Sadie Lee Foundation Endowed Professor in Pediatrics, will lead the newly founded Department of Systems Biology, which will leverage the power of computational biology for the discovery of better drugs for children with ALL.
“Cancer is always personal. In particular, if you think about ALL, the most frequent type of cancer in children, and its effect on kids and their parents,” he said. “Childhood cancer is one of the most devastating experiences for any family to go through.
“With all the new information from genetic and computational studies, we have now a real chance to make a difference for children with ALL and their families.”
That enormous potential is a big reason City of Hope recruited Müschen, signaling a new emphasis on pediatric illnesses.
“It's a new direction for us,” said David Horne, Ph.D., vice provost and associate director of Beckman Research Institute of City of Hope. “We have a strong track record in adult leukemia, so extending that ability to pediatric leukemia was the logical next step.”
Acute lymphoblastic leukemia strikes about 3,000 children each year. For most of them there's hope, thanks to advances in radiation, chemotherapy, targeted therapy and stem cell transplants.
“One of the things we'd like to figure out is which children do well with less aggressive chemotherapy,” said Müschen. “Because maybe we can cure them with something less drastic than the aggressive chemo we give everybody else.”
Children who receive intensive chemotherapy often develop lifelong side effects ranging from diabetes to heart, bone and fertility problems. “With our current diagnostic tools, we cannot separate the patients who will do well from those who need aggressive treatment,” he said. “Our goal is to find a reliable diagnostic test that will tell us before the treatment begins”.
That's the kind of practical, patient-centered work that most excites Müschen now, after delving deeply into the biology of leukemia and conducting critical basic research that's fascinated him since his own childhood.
Raised in a medical family – both parents are doctors – Müschen displayed an early curiosity about nature and the way things work. He carried that curiosity through his undergrad studies in Nantes and Paris, then to medical school in Germany where he began to realize that a career in research would take him “beyond the textbooks.”
He established his laboratory in 2001, in Cologne, Germany, at age 28. In 2006, he moved to Children's Hospital Los Angeles, then to University of California, San Francisco, where he's been since 2010 and where many of his groundbreaking achievements took place.
“I really enjoyed my time at UCSF,” he said. “We engaged in high-quality experiments to explain and understand the mechanism of ALL, why some people are cured and some are not.”
Having an opportunity to translate his work into actual human treatments at a facility that specializes in the total process, bench to bedside, appeals to Müschen. At City of Hope he plans to take many of his recent achievements to the next level. Among them:
Leukemia cells need rest, too: Müschen's team has demonstrated that leukemia cells multiply rapidly (“an engine in overdrive,” he said) but not all the time. They periodically revert to a dormant, “quiescent” state. Conventional chemo cannot reach these cells. They linger in the body and may trigger a relapse, even after chemo kills all the “aggressive” cells. The BCL6 molecule is the trigger that sends leukemia cells into their dormant state. Stop BCL6 or eliminate it, and the cancer cells remain vulnerable.
“We've isolated a peptide that acts on BCL6,” said Müschen. “Now, at City of Hope, we'll be able to turn that knowledge into a drug, take it through clinical trials ... because we think this could be the missing link we're looking for.”
Sending leukemia cells into overdrive: In healthy people, white blood cells, or B-lymphocytes, go through a multistep quality-control process as they develop the ability to produce antibodies that ward off disease. Childhood leukemia cells emerge from B-lymphocytes that took a different turn. However, it was only in the past year that Müschen's team found that those cancer-causing B-lymphocytes must also survive a similar quality-control regimen. Stopping that regimen kills the cells.
“We found the signaling system that begins the quality-control process. A simple chemical could theoretically shut it off,” said Müschen. “Now our goal is to test several agents, screen them to find the most effective one with the fewest side effects, and get it manufactured.”
Immunotherapy for childhood leukemia: The CD25 molecule, found on the surface of one of the most aggressive, drug-resistant forms of ALL, works as a buffer, keeping the cancer-cell multiplication process in balance. Turning off the buffer would wreak havoc with that scenario, and the cancer cells would perish.
“We've created an antibody-drug-conjugate that binds to that molecule's receptor,” said Müschen. He hopes to develop his ADC into an effective treatment as rapidly as possible.
Beyond that are still more plans to use targeted therapy to disrupt that “engine in overdrive” and frustrate the cancer-creating machine. As chair of the new department, Müschen will expand his current team of 30 scientists who are each focused on the cause of childhood leukemia. Over the course of 2017, seven new research groups will join the new department to create a major hub for research and innovation in childhood leukemias.
In all these areas, Müschen projects a quiet, matter-of-fact determination to reach the goals he has set.
“He's got a lot of no-nonsense, roll-up-your-sleeves and get-things-done quality,” said Horne. “He knows how to pick a project and see it through. He's a perfect fit for us.”
Müschen, an outdoor enthusiast and avid hiker, is happy to be back in Southern California. But it's the trails blazed by rigorous science, and the many steps that lead to cures, that get him really excited.
“To understand the nature of disease for the greater good,” he said. “To be intellectually challenged, to get to the root cause, but not in isolation. To make a difference in people's lives.
“That's what gets me up, and out of the house every morning.”