Mini Human Brains Have Been Implanted Into the Brains of Rodents

Researchers have grafted human brain organoids into rodent brains — a breakthrough with great scientific promise and immense ethical significance.

Fast forward to the present. Advances in the development of cerebral organoids — brain structures generated in labs from stems cells, or "brains in a petri dish," as some call them  — have brought about possibilities that never could have been imagined when the debates over in vitro fertilization occurred.

“When the principle of not developing a brain in an in vitro embryo was formulated, the only way it was envisioned that a brain could be developed in vitro was in an embryo, but cerebral organoids show that is obviously no longer true,” Harvard Medical School geneticist John Aach told Seeker. “So, one issue is: How far does the rule against developing brains in embryos apply to isolated brains developing in dishes, and how far should it apply?”

As of this weekend, the issue will even go beyond concerns about brains in a dish. Researchers at Neuroscience 2017, the annual meeting of the Society for Neuroscience, will announce that they have successfully grafted cerebral organoids into rodent brains.

Scientists have transplanted human neural cells into rodent brains for about five decades, so that is nothing novel. The new research, conducted by Fred “Rusty” Gage of the Salk Institute and his team, however, overcame a major barrier in creating functional cerebral brain organoids: giving them a blood supply so that they could essentially live and function on their own.

As Gage and his team write in the abstract for their upcoming presentation: “Here we describe the generation of vascularized, and electrophysiologically active, human cerebral organoids by transplantation of organoids grown in vitro to an adult mouse brain.”

“Engrafted mice were viable, and exhibit long and high survival rates,” Gage and his colleagues continued. “Moreover, histological and immunostaining analysis revealed intact grafts with mature neurons, and extensive axonal trajectories from the implant to multiple regions of the host mouse brain.”

Teams behind twenty other papers at Neuroscience 2017, which will take place at the Washington DC Convention Center, will also announce achievements with organoids, including grafting human brain tissue onto rodent brains.

For example, researchers from the University of Nebraska Medical Center will announce they have identified a treatment target for Down syndrome based on “chimeric mouse brain models” containing both rodent and human brain tissues.  

Yet another research team, led by Han-Chiao Isaac Chen of the University of Pennsylvania’s Perelman School of Medicine, will announce they too have grafted human cerebral organoids into rodent brains in order to develop cell replacement therapies for lost brain tissue and to restore neurological functions.

“Our findings show that human cerebral organoids survive at least 2 months after transplantation in immunosuppressed rats, grow projections into the host brain, and may integrate into the visual network,” Chen and his team write.

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The long-term goals of this and the other related studies are hard to dispute. They may include restoring sight to the blind, eliminating disorders such as Down syndrome, erasing the devastating effects of Alzheimer’s and Parkinson’s, and much more.

Hongjun Song is a neuroscientist at Johns Hopkins School of Medicine. His team has been using human brain organoids to identify mechanisms and treatment strategies for brain tumors and other brain disorders. Song and his colleagues have also made significant progress toward finding an antiviral drug against Zika infection, which can damage fetal brains.

Song explained to Seeker that he and other research teams are able to make brain region-specific organoids with “better reproducibility” and can start to use them to understand “basic mechanisms of brain development and brain disorders.”

He thinks it is theoretically possible to generate any structure of the human brain, but at present, scientists have reliably created forebrain (cortex), midbrain, and hypothalamus organoids.

Asked if brain organoids can think or exhibit other mental states, Song said, “I think it is an interesting question that we do not know the answer for at this moment, simply because we are not sure what constitutes consciousness.”

“We know that some brain organoids can mature and exhibit neuronal activity, and even patterns of neuronal activity,” he continued. “But currently brain organoids exhibit properties resembling properties of an early fetal brain up to the first and second trimester. As science and technology evolve, we need to revisit the question.”

Jonathan Kimmelman, an associate professor in the Biomedical Ethics Unit at McGill University, said there are two major ethical issues now at play concerning human brain organoids. The first, he said, relates to the welfare of animals.

“Introducing modifications to the nonhuman animal brain — whether through genetic modification, transplantation of cells, or transplantation of organoids — has the potential to alter an animal’s brain function,” he explained. “This can give rise to phenomena that are not typical for the species of the animal, and those phenomena can result in either greater suffering, or different behavioral needs that need to be addressed to minimize suffering.”

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For example, he said that a modification that causes heightened fear and anxiety in an animal has obvious potential to increase its suffering.

Josephine Johnston, director of research at the Hastings Center in New York, echoed this concern.

“I think that modifying animals to make them more human — or in some way more sentient, intelligent, conscious — whatever that means, etc. — raises animal welfare concerns and questions about the consequences of these changes for the animal’s moral status,” Johnston told Seeker.

Kimmelman said the second primary issue of concern over cerebral brain organoids is the prospect of animals acquiring human-like mental capacities or sentience.

“At this point in research, we are talking ‘science fiction’ and it is almost inconceivable in the context of rodent experiments,” he said. “Nevertheless, one would need to be extremely restrictive about authorizing — and allowing to continue — any experiment that has the prospect of conferring human-like mental capacities.”

Janet Rossant, a senior scientist in the developmental and stem cell biology program at the Hospital for Sick Children in Toronto, Canada, said steps should be put in place to try to restrict unwanted contributions to tissues other than the ones required for experiments.

Aach pointed out yet another dilemma that he and other researchers are facing in terms of advancing research on cerebral organoids.

He said the closer an organoid models an actual organ, the better the related knowledge will be. For example, if a research group wishes to study the human liver via a liver organoid, the organoid should have the same kinds of cells in the same formation as an actual liver.

“But while for organs like the liver, the goal of making accurate liver organoids doesn’t raise special ethical concerns, matters stand differently for the brain, because the more accurately you can make a cerebral organoid model of the brain, the more you have to ask whether you are experimenting on something that can experience pain or think — and we have strong moral reservations about doing experiments that could cause pain or distress,” Aach said.

But, there’s even a still harder question to consider, he added.

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Aach said prohibiting development of a brain in an embryo was motivated by the idea that embryonic brains normally develop into mature brains that can support the kinds of thought and consciousness that we eventually experience as children and adults.

“We don’t really have any clear conception of what might happen in brains that don’t develop in these normal ways,” he said. “But one thing we know from organoid research is that development in a dish can be very plastic and take tracks that are very unlike what happens normally. So, we have to start asking: Just what happens if normal brain development might be needed to support levels of thought or consciousness that we’d be concerned about if we let them develop in a cerebral organoid?”

“Just because a cerebral organoid might not develop exactly like a normal embryonic brain, doesn’t mean that all the ethical concerns we might have about brains developing in a dish go away,” he said.

As cerebral organoid research advances, such as the breakthroughs that will be announced at the upcoming Neuroscience 2017, so, too, do ethical considerations.

“As technologies evolve,” Song said, “we should have discussions concerning the potential implications of such research, including ethical issues.”

Aach and others are therefore calling upon leading scientists, as well as leaders in other non-scientific fields, to organize a set of inquiries into the questions of where and how the boundaries might be set for cerebral organoid research.

Aach believes it is too early to formulate specific guidelines or to define specific boundaries concerning such studies, but that day is coming — perhaps sooner than we might think.

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