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Michelle Monje, MD, PhD, Named MacArthur ‘Genius’ for Research Into Pediatric Brain Cancers

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Michelle Monje, MD, PhD, has won multiple awards for her pioneering work on rare but devastating pediatric gliomas, including most recently the prestigious MacArthur (“genius”) grant. Sometimes experiments fail, she said, but she's not afraid try to suspend assumptions, to let experimental evidence shape the narrative, rather than try to make her findings fit a preconceived theory.

What a month or so it was for Michelle Monje, MD, PhD.

On September 23, the Howard Hughes Medical Institute announced that Dr. Monje, professor of neurology at Stanford University (and by courtesy, neurosurgery, pathology, psychiatry and pediatrics), was now also an HHMI investigator, due to receive approximately $9 million in funding over the course of seven years.

Five days later, she received a MacArthur Foundation fellowship—popularly known as the MacArthur “genius” award—and with it a no-strings-attached grant of $625,000. And on October 18, she was elected to the National Academy of Medicine. All this for her pioneering research into rare pediatric brain cancers.

For all that, however, it took only a few days before the high-flying physician-scientist was brought down to Earth. Just as she stepped into her mini-van to drive her 13-year-old son to school, he said to her: “Hey genius, you left your coffee cup on top of the car.”

Children, in fact, have been the focus of her life for the past 20 years, ever since she was a medical student tasked with caring for a young girl who had just been diagnosed with a universally fatal brain cancer called diffuse intrinsic pontine glioma (DIPG).

“It's the worst kind of cancer you can imagine,” Dr. Monje told Neurology Today. “It takes away brainstem activity but leaves cognition intact. So kids are aware of what's happening to them as they lose the ability to walk, to play, to speak, to swallow. And yet at the time, 20 years ago, we knew absolutely nothing about the biology of DIPG.”

The experience of caring for the girl until she died a few months later moved Dr. Monje to make a career-changing decision. Even though she had been trained in adult neurology, Dr. Monje pivoted to devote herself to investigating and treating DIPG and other rare brain cancers in children.

“I just couldn't turn away,” she said. “I felt we had to develop tools to understand the biology, the neuroscience,” she said.

That she has done.

During a post-doctoral fellowship, Dr. Monje discovered that DIPG tumors emerge from precursor cells in the myelin-forming glial lineage.

Another major breakthrough occurred in 2009, when she created the first DIPG stem cell line and patient-derived mouse model. That came about after the parents of a 5-year-old boy, Dylan Jewett, agreed to donate a sample of his tumor after his death due to DIPG on January 8, 2009.

Her laboratory continued to generate patient-derived model systems from patients, establishing a robust panel of tumor models and freely sharing them internationally to stimulate DIPG research.

Now able to study the cancer in the laboratory, she found that normal brain activity appeared to drive the growth of brain tumors like DIPG and glioblastoma. She reported these transformative discoveries in papers published in Cell and Nature in 2015 and 2017.

“We found that glial malignancies hijack growth factors secreted in response to neuronal activity,” Dr. Monje said.

In 2019, she was the senior author of a paper in Nature showing that neurons and glioma tumors formed an “electrically coupled network.” The tumors,the paper reported, interacted with neurons “through bona fide AMPA receptor-dependent neuron-glioma synapses.” In a mouse model, the growth of glioma xenographs was inhibited by pharmacologically or genetically blocking the electrochemical signaling between tumors and neurons.

“These cancers synaptically integrate into neurocircuits,” Dr. Monje said. “They don't just take up space in the brain. Their electrochemical communication with neurons actually drives their growth.”

Her research has also shown that, in health, interactions between neurons and myelin-forming glial cells help to fine-tune neural circuits and contribute to learning and memory. Disruption of that myelin plasticity, on the other hand, can contribute to cognitive impairment.

“Certain chemotherapies disrupt myelin plasticity and this is an important—and potentially fixable—contributor to cancer therapy-related cognitive impairment,” Dr. Monje said.

Much of her progress in neuro-oncology, she said, flows from her willingness to be proved wrong in risky experiments.

“I am okay with failure,” she said. “It can be equally exciting to learn a hypothesis is wrong because that can lead the work in a different and unexpected direction. It's so important to follow the evidence where it takes you.”

With the support from MacArthur and HHMI, Dr. Monje said, “We're going to take some risks in the laboratory. We're going to have to follow hypotheses that are really quite novel. Some of them will be wrong. We may have to pivot and go in a new direction. We don't want to make incremental progress. We want to make important leaps forward.”

Her humility in the face of negative findings, she said, grows directly out of her experience in the clinic.

“There is nothing more humbling than watching a child die from a disease you can't cure despite decades of trying really, really hard,” she said. So, she said, “I try to suspend assumptions, to let experimental evidence shape the narrative, rather than try to make our findings fit a preconceived theory.”

Walter Koroshetz, MD, FAAN, director of the National institute of Neurological Disorders and Stroke, told Neurology Today he was pleased but not surprised by Dr. Monje's latest awards.

“I had the opportunity to work with Dr. Monje when she was a neurology resident and saw firsthand her intelligence, passion for science and compassion, She has no fear and takes on the most difficult problems,” he said. “Trained as an adult neurologist, she pivoted to focus on fatal brain tumors in children and has moved from discoveries in the lab to clinical trials. It is hard to state the degree of difficulty of this task which takes genius but much more. We greatly look forward to her continued contributions to neuroscience and neurology.”

A colleague of hers at Stanford was equally effusive in his praise for Dr. Monje's work. “The MacArthur fellowship is an incredible testimony to her novel work the last two decades approaching these dreadful cancers,” said Paul G. Fisher, MD, FAAN, professor of neurology and pediatrics at Stanford University and chief of division of child neurology at Stanford University and Lucille Packard Children's Hospital.

“Her finding that neural activity can feed back and drive tumor growth further is a game-changer in our thinking about how cells in the brain behave and interact,” Dr. Fisher said. “With her recent work now trying to leverage that observation and derive completely novel therapies for these cancers, we can all see and applaud how extraordinary and dedicated her work has been and continues to be.”

Dr. Monje's achievements also include five children, including four under the age of 14 and a stepson now 25 years old.

“It is absolutely possible to balance motherhood and academic neurology. It just requires extreme multitasking and the willingness to make clear to those you work with what you need,” she said. “I have been very lucky at Stanford in the department of neurology. When I said ‘I can't do that meeting because I have to pick up my kids,’ or ‘I'm going out on maternity leave and I need X, Y and Z,’ they understood. But they wouldn't have known what I needed if I didn't clearly state it. You just have to be really clear what you need to make the balance work. People are unlikely to guess.”

Dr. Monje added that she tries to anticipate what new parents in her laboratory group may need to succeed, and provides support such as hiring research assistants to help trainees during new parenthood.

Her husband, by the way, is Karl Deisseroth, MD, PhD, also of Stanford. During the same week she received news from MacArthur and HHMI, he was named a co-recipient of the Albert Lasker Basic Medical Research Award for his discoveries regarding microbial light-activated ion channels, which in turn allowed him to develop optogenetics.

She and Dr. Deisseroth, however, are not the only ones in the family with remarkable recent achievements. Their son, Cole, who is pursuing an MD and PhD at Baylor, received a prestigious scholarship that same week from the Child Neurology Society.

What's more, Dr. Monje said, “My two middle-schoolers both got straight As on their report cards last week.” But that includes the wisecracking 13-year-old who teased her for being a “genius” just because she left her coffee cup on the roof of the mini-van. Talk about being humbled.

Link Up for More Information

• Venkatesh HS, Morishita W, Geraghty AC, et al. Electrical and synaptic integration of glioma into neural circuits https://www.nature.com/articles/s41586-019-1563-y. Nature 2019;573(7775):539–545.
• Monje M, Borniger JC, D'Silva NJ, et al. Roadmap for the emerging field of cancer neuroscience https://www.sciencedirect.com/science/article/pii/S0092867420303275. Cell 2020;181(2):219–222.