Doing ‘Mighty Things’ with Mathematical Modeling
Georg Luebeck, Computational Biologist and Molecular Clockmaker
As a trained physicist, he could have ended up designing rockets for Boeing, shaping young minds at a university, or making any number of other scientific contributions.
Instead, “by a stroke of luck,” Dr. Georg Luebeck wound up at Fred Hutchinson Cancer Center, where for the last 30-plus years, his mathematical models of biological processes like cancer initiation and growth have helped everyone from uranium miners at risk for lung cancer to astronauts facing the effects of galactic cosmic radiation.
“It’s coming up to 32 years. Or is it 33?” Luebeck said of his time at the Hutch. “So much of the research and the methods and the technologies have changed. We didn’t have the genome then. We didn’t understand so many things. Now we have affordable, whole-genome sequencing and array technologies to interrogate genomes down to the single-cell level.”
Now, too, there is much more data — clouds full of it — and an even greater need to make sure it’s all interpreted in ways that make sense. That’s where Luebeck’s mathematical modeling of multi-stage carcinogenesis comes in.
“It’s important to have an intellectual context in which you can explain your data,” he said. “To me, that’s a model. If you don’t have that, you can easily be led astray and misinterpret the data.”
Digging into biology and biostatistics
Born and raised in Germany, Luebeck earned his doctorate in theoretical physics at the University of Washington and went on to do postdoctoral work at the Neils Bohr Institute for Astronomy, Physics and Geophysics in Copenhagen before returning to Seattle and joining the Hutch. There, he worked under now-retired Dr. Suresh Moolgavkar.
Luebeck still remembers meeting his mentor-to-be during that first job interview.
“He had an intimidating piling system, not a filing system, and he pulled out two research papers from a huge stack and suggested my reading them,” Luebeck said. “At first glance, it was all gobbledygook.”
Biology, genetics and biostatistics were new to him then, but Luebeck wasted no time digging in. He soon was able to assist his mentor Moolgavkar and began working in lung cancer with former Hutch radiation biophysicist Dr. Stanley Curtis, investigating the association between lung cancer and radon exposure.
“There was a public health concern of radon in homes and in the population of uranium miners,” he said. ”What was surprising to us was that radon, which emits ionizing alpha particles, was much less of a ‘cancer initiator’ — a long-held dogma — and much more of a ‘cancer promotor,’ increasing the growth of bad lesions.”
He and Moolgavkar used data from several studies to develop new lung cancer risk models. The approach they used “assumed a series of biological processes that we modeled computationally and mathematically,” he said. “It was a new way of modeling risks from environmental exposures such as radon.”
Soon, Luebeck and Moolgavkar were joined by others across the world interested in radiation carcinogenesis, in particular modeling cancer risks among A-bomb survivors.
“It became clear that the biological cancer models we developed had wider applications including cancer sites such as colon, pancreas and esophagus,” he said.
It was this work, trying to understand how long it takes for cancers and their precursors to develop, that he first became interested in the concept of tissue aging.
“The idea that tissue aging somehow also plays a role in the initiation of a cancer was something that clicked with me,” he said.
Molecular clockmaker
Luebeck and his colleagues were able to bring mathematical models to this area, he said, by looking at the age of the tissue and backtracking to when a cancer and its precursor first arose.
“We were able to use statistical approaches to turn this information into a molecular clock,” he said. “When you find an adenoma in colon screening, the question has always been, ‘Is this going on to cancer? How old is it?’ Colorectal cancers presumably arise in adenoma, a polyp, but when did the adenoma (the one that makes the cancer) first arise? When should we screen? That’s the question that’s hard to investigate. There’s no epidemiology for that. However, cancer modeling can do this.”
Luebeck created a cancer model that showed that a founder premalignant cell that goes on to become cancerous can actually develop in the first decade of life.
The paper, published in 2019 in the journal Cancer Research, found that precancerous lesions ”can persist for decades before becoming cancerous,” data that suggests that “early dietary and lifestyle interventions may be more effective than later changes in reducing colorectal cancer incidence,” the authors wrote.
Can that information somehow be used to improve colon screening?
“We could start thinking about chemoprevention [taking cancer-preventive drugs], starting to screen people earlier, and having better instruments, more sensitive assays, that detect the precursors in which malignancies arise,” he said.
Modeling paths to esophageal cancer
Luebeck’s modeling and molecular clocks are considered for use in other cancers, such as esophageal cancer.
Over the last ten years, in collaboration with Fred Hutch physician-scientist Dr. Bill Grady and former graduate student Kit Curtius (now at UC San Diego), Luebeck created a DNA methylation clock for esophageal cancers that arise as a result of the condition Barrett’s esophagus, or BE.
“People have looked at smoking, alcohol, BMI, how often you have reflux symptoms, etc.,” he said. “They’ve stratified the risk by age, sex, race and all of that. But the critical information nobody was able to provide was: How long has this tissue been in place?”
"The idea that tissue aging somehow also plays a role in the initiation of a cancer was something that clicked with me.”
BE starts with injury to the tissue by acid reflux, or the more severe condition, gastroesophageal reflux disease, commonly known as GERD. But many people don’t know if they have BE, because it’s basically asymptomatic.
“Reflux or bile juices cause erosion in the lower esophagus and the tissue can turn into metaplasia [sometimes a precursor to cancer],” he said. “Roughly half the people who get esophageal cancers never had GERD symptoms.”
Only a fraction of people with BE actually go on to develop esophageal adenocarcinoma or EAC (about 5%). So those who are diagnosed with it are at risk of overdiagnosis and possibly overtreatment, while some of those who are not may develop EAC without a chance of an intervention.
Working with Curtius and his long-term Hutch collaborator Dr. Bill Hazelton, Luebeck developed a multiscale modeling framework, or molecular clock model, that plots the natural history of how GERD can progress to Barrett’s esophagus and eventually esophageal cancer. The results were published in 2016 and 2017.
“Does age really matter as a risk factor for cancer? The answer is yes,” he said. “There’s a clear correlation between age and cancer risk. The older the tissue is, the more stem cell divisions and the higher the number of mutational events that lead to cancer. Time is of essence.”
Since many people who develop EAC have no symptoms from Barrett’s esophagus, and since the U.S. Preventive Services Task Force doesn’t currently offer any kind of screening guidelines for it, Luebeck also hopes this work will enable clinicians to find a way to identify those at risk.
Perseverance and teamwork
Luebeck’s desire to continue clocking cancer — and collaborate with others at the Hutch determined to do the same — have kept him intrigued and engaged for more than three decades, years in which he’s seen “mind-boggling” progress in cancer research and technology.
“For me, the most enjoyable thing is the interaction with other people at the Hutch, the collaborations,” he said. “The brainstorming, just being exposed to ideas and the teamwork that comes from it. People have different strengths — in computer modeling or computer programming or in the medical field or genetics — we bring all these together.”
The result? Sky’s the limit.
“NASA is now requesting input into understanding the cancer risk from galactic radiation,” he said. “Why? Because we want to go to Mars. I find it all very exciting. Did you see [NASA rover] Perseverance land on Mars? ‘Dare do a mighty thing’: That was the message written on the parachute. I think that’s a great motto — even in cancer research.”
— By Diane Mapes, May 2, 2021
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