Miniature Human Brains Grow for Months When Implanted in Mice Skulls
Miniature Human Brains Grow for Months When Implanted in Mice Skulls
The lab-grown cerebrums are about the size of a lentil
The mice behaved just like others of their kind, as far as scientists could tell, and they also looked the same—except for the human mini brain that had been implanted into each rodent’s own cortex, made visible by a little clear cover replacing part of their skull.
The report on Monday by scientists at the Salk Institute is the first publication describing the successful implant of human cerebral organoids into the brains of another species, with the host brain supplying the lentil-sized mini cerebrums with enough blood and nutrients to keep them alive and developing for months. It won’t be the last, as scientists use the approach to understand human brain development and test whether the tiny entities might one day serve as cortical repair kits, replacing regions of the brain that have been injured or failed to develop normally.
It’s “an important technical advance,” said neuroscientist Michal Stachowiak of the State University of New York, Buffalo, who created human cerebral organoids to study schizophrenia, and “an important initial step toward using organoids in regenerative medicine.”
When the Salk researchers briefly described their experiments last November at the annual meeting of the Society for Neuroscience, bioethicists raised questions about what implants of human brain organoids would do to mice’s intelligence, consciousness, and even their identity as mice. The published paper, in Nature Biotechnology, fills in details about how successfully the human organoid integrated into the mouse brain and addresses one of those concerns: At least in the tests the scientists ran, the mice with human brain organoids seemed no different, and no smarter, than standard lab mice.
Since the first human brain organoids were created from stem cells in 2013, scientists have gotten them to form structures like those in the brains of fetuses, to sprout dozens of different kinds of brain cells, and to develop abnormalities like those causing neurological diseases such as Timothy syndrome. Researchers hope the organoids will be better than lab animals or cells growing in culture at revealing how the human brain develops, both normally and when things go awry, and identify potential therapeutic or genome-editing targets.
The basic recipe takes human stem cells, makes them differentiate into brain cells, and lets them grow into entities a few millimeters across that mimic the structure, cell populations, and even the electrical activity of the full-blown version.
But the verisimilitude of human brain organoids has been limited: Once they grow more than a few millimeters across, oxygen and nutrients can’t get to their innermost cells. “In our hands, the organoids stop growing around five weeks,” said Salk’s Fred Gage, who led the study. “It’s a function of size rather than time. We see some cell death even in the edge of the organoids starting at 10 weeks, which becomes really dramatic over time. This is an obvious hurdle for longtime study” if the goal is to follow brain development for longer than a trimester or two prenatally, the stage at which the current crop of brain organoids start to wither. Implanting human brain organoids in a mouse brain gives them everything they need to grow and develop.
The Salk team therefore took human brain organoids that had been growing in lab dishes for 31 to 50 days and implanted them into mouse brains (more than 200 so far) from which they had removed a tiny bit of tissue to make room. Because the human cells had been genetically engineered to express green fluorescent protein, the tiny blobs showed up in brilliant lime through the transparent window that the scientists glued into the mice’s skull.
Miniature Human Brains Grow for Months When Implanted in Mice Skulls
The lab-grown cerebrums are about the size of a lentil
The mice behaved just like others of their kind, as far as scientists could tell, and they also looked the same—except for the human mini brain that had been implanted into each rodent’s own cortex, made visible by a little clear cover replacing part of their skull.
The report on Monday by scientists at the Salk Institute is the first publication describing the successful implant of human cerebral organoids into the brains of another species, with the host brain supplying the lentil-sized mini cerebrums with enough blood and nutrients to keep them alive and developing for months. It won’t be the last, as scientists use the approach to understand human brain development and test whether the tiny entities might one day serve as cortical repair kits, replacing regions of the brain that have been injured or failed to develop normally.
It’s “an important technical advance,” said neuroscientist Michal Stachowiak of the State University of New York, Buffalo, who created human cerebral organoids to study schizophrenia, and “an important initial step toward using organoids in regenerative medicine.”
When the Salk researchers briefly described their experiments last November at the annual meeting of the Society for Neuroscience, bioethicists raised questions about what implants of human brain organoids would do to mice’s intelligence, consciousness, and even their identity as mice. The published paper, in Nature Biotechnology, fills in details about how successfully the human organoid integrated into the mouse brain and addresses one of those concerns: At least in the tests the scientists ran, the mice with human brain organoids seemed no different, and no smarter, than standard lab mice.
Since the first human brain organoids were created from stem cells in 2013, scientists have gotten them to form structures like those in the brains of fetuses, to sprout dozens of different kinds of brain cells, and to develop abnormalities like those causing neurological diseases such as Timothy syndrome. Researchers hope the organoids will be better than lab animals or cells growing in culture at revealing how the human brain develops, both normally and when things go awry, and identify potential therapeutic or genome-editing targets.
The basic recipe takes human stem cells, makes them differentiate into brain cells, and lets them grow into entities a few millimeters across that mimic the structure, cell populations, and even the electrical activity of the full-blown version.
But the verisimilitude of human brain organoids has been limited: Once they grow more than a few millimeters across, oxygen and nutrients can’t get to their innermost cells. “In our hands, the organoids stop growing around five weeks,” said Salk’s Fred Gage, who led the study. “It’s a function of size rather than time. We see some cell death even in the edge of the organoids starting at 10 weeks, which becomes really dramatic over time. This is an obvious hurdle for longtime study” if the goal is to follow brain development for longer than a trimester or two prenatally, the stage at which the current crop of brain organoids start to wither. Implanting human brain organoids in a mouse brain gives them everything they need to grow and develop.
The Salk team therefore took human brain organoids that had been growing in lab dishes for 31 to 50 days and implanted them into mouse brains (more than 200 so far) from which they had removed a tiny bit of tissue to make room. Because the human cells had been genetically engineered to express green fluorescent protein, the tiny blobs showed up in brilliant lime through the transparent window that the scientists glued into the mice’s skull.
