Brain organoids might be the future of cancer treatment
In 30 years as an oncologist, Dr. Howard Fine estimates he has treated some 20,000 patients with glioblastomas, the most deadly form of brain cancer, “and almost all of them are dead.” Of the 100 new glioblastoma patients he saw last month, “five years from now, only three will be alive,” he said.
During a conversation recently in his office at Weill Cornell Medicine in New York City, Fine rattled off more dismal stats, like the many failed clinical trials of experimental drugs for glioblastoma; like the paltry increase in life expectancy for people with glioblastoma from 12 months in 1990 to 15 today; like the stupid (in hindsight) assumptions about how glioblastomas grow and how to study them in mice. Then Fine, 59, paused for several long seconds.
“My stance as an old man in this field is, someone has to start doing something different,” he said. He thinks the “something different” just might be human micro-brains.
In the barely three years since biologists discovered how to create these “brain organoids,” the lentil-sized structures have taken neuroscience by storm. Starting with a recipe developed by scientists in Austria, researchers from Japan and China to Europe and North America are seeding lab dishes with human stem cells, adding special molecules — many labs, like chili chefs, have their own secret blends — that make the stem cells morph into a variety of brain cells. They then put the dishes into special chambers called bioreactors that keep them warm and in gentle motion reminiscent of a womb, encouraging the cells to form blobs with working neurons and many other features of a full-size human brain.
Most of the researchers making mini-brains hope they will reveal what goes wrong in neurodevelopmental disorders such as autism and epilepsy, in mental illnesses such as schizophrenia, and in neurodegenerative diseases such as Alzheimer’s. Fine is one of the few scientists using organoids to study brain cancer in hopes of personalizing glioblastoma care to an unprecedented degree: by screening drugs in mini versions of cancer patients’ actual brains containing their actual tumor cells.
He had long despaired of oncology’s dirty little open secret: that when scientists transplant bits of human glioblastomas into mouse brains, the standard research approach, the result doesn’t mimic what happens in people. One problem is that the mouse brain is very different from the human brain. Another is that the transplanted bits of tumor act nothing like cancers in actual human brains, Fine and colleagues reported in 2006: Real-life glioblastomas grow and spread and resist treatment because they contain what are called tumor stem cells, but tumor stem cells don’t grow well in the lab, so they don’t get transplanted into those mouse brains.
Glioblastomas in lab dishes and mouse brains are fakes, little Potemkin villages that everyone thought were faithful replicas of human glioblastomas but which, lacking tumor stem cells, were nothing of the kind. In particular, the tumors put into mouse brains are nowhere near as invasive as patients’ glioblastomas, which send out hundreds of invasive tumor cells and deadly little tendrils throughout the brain — and beyond the reach of surgeons.
No wonder what biologists learned from their glioblastoma cell cultures and glioblastoma mice was mostly irrelevant to glioblastomas in actual patients. No wonder experimental compounds that eradicated glioblastomas in mice failed in people.
“The mouse models don’t recapitulate the human disease,” said Ravi Basavappa of the National Institutes of Health, which gave Fine one of its 12 Pioneer Awards for “unusually bold,” high-risk, and potentially high-impact research. “The hope is that [Fine’s organoids] will be a promising path forward.”
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