The cartographer of cancer
Paul Mischel’s groundbreaking research is reshaping our understanding of the cancer genome. As he traces both his family narrative and his scientific journey, intersections emerge—on campus, under the specter of cancer, and within a family defined by transformative discoveries.
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Paul Mischel. Photo: Jess Alvarenga
Battles in war and peace
When Nazi Germany annexed their native Austria in 1938, the Mischel family rushed to destroy any documents proving their Jewish heritage. Paul Mischel’s father, Theodore, and uncle, Walter, were 13 and 8, respectively. The family narrowly escaped thanks to a serendipitous discovery: Walter found a document revealing that their maternal grandfather had become an American citizen. Document in hand, they fled to the United States as refugees.
Eighteen-year-old Theodore Mischel was headed to the Battle of the Bulge—the deadliest battle for American forces in World War II—when he came down with the mumps. Reassigned to intelligence, he served as an interpreter for the post-war Dachau concentration camp trials. Having survived at least two close calls with death before his 20th birthday, he went to college on the GI Bill. He became a philosophy professor.
“It was the American Dream,” Paul Mischel says of his father’s trajectory. “He felt the best thing you could do with your life was to become a scholar, and I imbibed that as a child. My favorite place to be was in Dad’s study, surrounded by all those books.”
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Paul Mischel with his father.
When Paul Mischel was 14, his father was diagnosed with stomach cancer. “He died a very painful death,” says Mischel. “I saw him suffer terribly and decided I would dedicate my life to fighting cancer.”
Following the loss of his father, Mischel found a father figure in his uncle.
“With Walter, sometimes it was like my dad was a third person in the room talking with us,” he remembers.
If the name Walter Mischel sounds familiar, it’s for good reason. He was the pioneering Stanford psychologist who studied personality traits and famously developed the so-called marshmallow test, to examine the role of delayed gratification in cultivating self-control.
Although Paul Mischel began his career as a pathologist to “look the enemy in the eye,” he decided to focus on research when he recognized that he could spend his life confronting his adversary without making any strides toward a cure.
“I saw him suffer terribly and decided I would dedicate my life to fighting cancer.”Paul Mischel
Mischel drew on insights from the Cancer Genome Atlas and human genome map to investigate precision medicine for glioblastoma, a highly lethal brain cancer. Central to his investigation was a gene called epidermal growth factor receptor (EGFR), amplified in most glioblastoma patients, prompting uncontrollable cell division.
In theory, patients should have responded to EGFR inhibitors, but they did not.
When Mischel published the results, some scientists speculated that cancer cells differed subtly, making some cells more sensitive to treatment and leading to a process of selection familiar to anyone who studied Gregor Mendel’s pea plants in high school.
However, this explanation troubled Mischel. Many cancer cell divisions would be necessary for such selection to occur. “So you would predict that the process would be pretty slow,” he says. “That’s not what we saw in our data. It happened really fast.”
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Putting ecDNA on the map
Much as we rely on advanced technologies like GPS and cell phones in our everyday lives, scientists rely heavily on gene sequence maps. To understand his data, Mischel needed to stop trusting the existing map and look inside the cell.
Mischel assumed the amplified copies of EGFR would be located on chromosome 7, near the original EGFR gene, but the extra copies were not found on chromosomes. Astonishingly, EGFR was found on extrachromosomal DNA (ecDNA)—mysterious DNA circles free-floating in the nucleus of cells. First observed in the 1970s and studied by Stanford Professor Robert Schimke, ecDNA’s function remained unclear. It was largely forgotten and not shown as distinct from chromosomal DNA on genome maps.
Our former understanding of cancer genetics centered on the chromosome, assuming it was the primary driver of tumor growth. Mischel’s research revealed that ecDNA is a powerful driver for some cancers, allowing it to evade treatments.
When Mischel cultured glioblastoma cells in the laboratory, each original cell gave rise to a colony of cells with varying levels of the EGFR gene: high levels, low levels, and none. According to classical genetics, a cell carrying a few copies of a gene should give rise only to cells similarly carrying a few copies.
Unlike chromosomes, which undergo a symmetrical distribution to daughter cells during division, Mischel found that ecDNA is allocated haphazardly to daughter cells, contributing to rapid changes in a tumor’s genetic makeup.
“It’s absolutely remarkable.Within two cell divisions, they’ve changed their genes. Bacteria do that. That’s why we struggle with antibiotic resistance.”
Mischel points out that, like bacteria, ecDNA has a circular structure—in contrast to the oblong structure of a chromosome, where genes are controlled only by nearby regulators. The circular structure of bacteria and ecDNA enables regulators to control genes even when they are not neighbors, similar to how you could make eye contact with someone else in a circle more easily than someone at the other end of a line. This circular structure enables ecDNA to adapt at a rate that renders some cancers tenaciously resistant to treatment.
Courageous questions
Mischel compares the previous chromosome-centric cancer paradigm to the ancient astronomer Ptolemy’s Earth-centric map of the universe. Ptolemy’s map was inaccurate, but his measurements were so precise that his model dominated astronomical thought until Copernicus upended it 1,400 years later, with his heliocentric map.
When a radical idea comes to light, regardless of the evidence, many vehemently resist it. Just ask Galileo.
“In the beginning, it was lonely,” recalls Mischel. “But I learned that it’s never about you, so just remove yourself from the process and ask, ‘What are the data teaching us?’”
Mischel also points to his uncle’s example: As a Stanford psychology professor, Walter Mischel overturned the prevailing paradigm that personality traits are fixed, insisting that experimental data proved they are context-dependent.
“Walter showed me that you could take perceived knowledge in the field and challenge it if it’s wrong,” he says.
Walter Mischel died from pancreatic cancer in 2018. Seven years earlier, troubled by what his research had uncovered, Paul Mischel took a mini-sabbatical in Paris to spend time with his uncle.
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“Walter showed me that you could take perceived knowledge in the field and challenge it if it’s wrong.”Paul Mischel
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Walter Mischel and Paul Mischel.
“We sat in cafes and talked. He made me realize an aspect of being a scientist that people don’t often realize: courage,” says Mischel. “It’s easy to take what you know and keep improving it, but it’s hellishly difficult to take an assumption and say, ‘What if we’re wrong?’ Because then you’re on your own.”
In conversations with his uncle, the importance of maps came into focus for Mischel. He explains: “When you have too much information to handle, you make a map. The problem is that maps become our reality, which becomes a huge issue when we make maps of things we can’t see, like strings of letters that are our DNA.”
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New map, new mindset
Working with Howard Chang, Stanford’s Virginia and D. K. Ludwig Professor of Cancer Research, Mischel showed that ecDNAs form a powerful hub inside a cancer cell, glued together by a crucial protein. Targeting this protein can halt the expression of cancer-causing genes—a groundbreaking discovery that could lead to a new therapy class for many types of cancer.
While the archetype of the solitary genius may still hold sway in the popular imagination, Mischel—now the Fortinet Founders Professor of Pathology at Stanford—insists that scientific research in the 21st century demands collaboration.
“You must bring a set of tools and domains of knowledge that no individual will possess. But collective groups will possess it. It’s a very different mindset from how people have historically done science.”
Mischel was drawn to Stanford by the university’s commitment to such interdisciplinary collaborations, exemplified by Sarafan ChEM-H—a nexus for exploration at the intersections of chemistry and health—and the Innovative Medicines Accelerator (IMA)—an engine for translating scientific breakthroughs into viable treatments. When he made the move, a friend battling glioblastoma reminded him, “Whatever you do, do it fast. People like me don’t have a lot of time.”
Mischel kept his friend’s plea in mind. After validating a promising target for glioblastoma in the lab, he sought to identify a drug that was already FDA-approved, would suppress this target, and could pass the blood-brain barrier. One such drug existed: Prozac.
Analysis of electronic health records revealed that glioblastoma patients treated with Prozac alongside the standard care regimen experienced improved outcomes. Mischel published the results and found his inbox inundated with patient inquiries about a clinical trial.
One problem: Prozac has been off-patent for 30 years, and there’s no financial incentive for pharmaceutical companies to invest in clinical trials for off-patent drugs. But the IMA seeks to address such scenarios, funding projects on the basis of patient need.
“Through the IMA, we are developing a therapy that we hope will reach patients in the near term,” says Mischel. “It illustrates what’s so unique about this ecosystem.”
Beyond the promise of advances in cancer treatment, Mischel is inspired by how ecDNA teaches us about the relationship between the architecture, topology, structure, and fundamental biology of DNA.
“We had reduced DNA to letters when it is much broader—not just letters, but shapes and how they impact function and spatial organization. And we are only just beginning.”
Here Mischel pauses, then returns to his family map, which charts a journey from Austria to the United States, from New York to California, and ultimately to Stanford.
“I think Walter would be thrilled that I’m here,” he adds.
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The opportunity
Mischel was drawn to Stanford by the university’s commitment to fostering interdisciplinary collaborations and achieving real-world impact, exemplified by Sarafan ChEM-H and the Innovative Medicines Accelerator (IMA). An engine for translating scientific breakthroughs into viable treatments, the IMA funds projects on the basis of patient need. “Through the IMA, we are developing a therapy that we hope will reach patients in the near term,” says Mischel. “It illustrates what’s so unique about this ecosystem.”
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