As research involving “mini-brains” grown in a petri dish continues to expand, so does ethical debate surrounding the practice, particularly when these brain organoids are transplanted into animals.
One concern is that the transplanted organoids could induce a level of consciousness in host animals, as the models evolve to better resemble the human brain.
Now, a paper published yesterday in the journal Cell Stem Cell has tried to address the dilemma by evaluating the potential risks of creating “humanized” animals – a term the authors say is not helpful – while also considering the potential benefits to progressing in this important area.
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"Due to their ability to mimic certain brain structures and activity, human brain organoids—in animal models—allow us to study neurological diseases and other disorders in previously unimaginable ways," says first author Han-Chiao Isaac Chen, professor of Neurosurgery at the Perelman School of Medicine.
"However, the field is developing quickly, and as we continue down this path, researchers need to contribute to the creation of ethical guidelines grounded in scientific principles that define how to approach their use before and after transplantation in animals.”
An ethical framework is lacking
In the paper, Chen and colleagues clarify the capabilities of the brain organoids and suggest that an ethical framework be developed that better contextualizes their use and what the thresholds should be.
“Such guidelines can help avoid confusion for scientists, especially when communicating with the public, and clearly lay out the benefits of this research, against which any ethical or moral risks can be weighed," says Chen.
The team’s paper was prompted by recent progress made in transplanting brain organoids into rodents, which has led to some serious ethical concerns about whether the scientists are creating part-human or “humanized” animals.
Organoids currently too basic to induce human traits
It should be noticed that lab-grown organoids, which are grown from human pluripotent stem cells, are no larger than the size of a pea. While they can recapitulate human brain architecture and some layers of the human cortex, they are too basic to induce traits such as emotions, consciousness or self-awareness.
They lack the cell types needed for the brain’s supporting microenvironment such as endothelial cells and microglia. They also lack the structural nodes and white matter connections between the brain that are needed for higher brain function.
The fact that they are made up of living human brain cells, though, and can resemble the midbrain, hippocampus and hypothalamus, means scientists can use them to study human brain development, cognitive disorders and the ways in which certain diseases may affect the brain.
The point where people start to get nervous
Anders Sandberg, a researcher at the University of Oxford’s Future of Humanity Institute, who is not affiliated with the paper, says researchers cannot yet create full-sized brains due to the lack of blood vessels, supporting structure, and other elements required to build a fully functioning brain.
However, that is where transplantation into animals becomes useful: “One way of getting around the problem of the lack of blood vessels in a petri dish is to implant them in an animal… but it’s at this point when people start to get a bit nervous,” he says.
The concern is that once human brain cells are transplanted into a non-human animal, that any human-like trait the animal may develop would mean it deserves higher moral consideration and therefore a different set of rules in terms of what should be permitted during experiments.
The term “humanized” is not helpful
Chen and team say that using terms such as “humanized” or “humanization” to describe these animals or the processes involved is not useful from a biological point of view.
Orly Reiner, a molecular geneticist at the Weizmann Institute of Science in Israel, says “these technologies cannot offer human-cell driven brain activity over-riding host-based activity.” In other words, the presence of human cells in an animal’s brain does not mean the brain simply becomes a human one, where a human mind is “trapped” inside an animal’s body.
On the other hand, says Reiner, who was not involved with the paper, a “crucial time point” will arise if “these barriers are crossed.” While it is important to embrace new technologies, she says, this must only be done in parallel with the promotion of “public and ethical discussions to help in defining risks and adding precautions.”
Scientists should exercise ‘additional thought and discussion’
Chen and his team think that although these types of experiments do not need to be limited right now, that could change if researchers start to enhance certain brain functions in chimeric animals, that is, animals endowed with human attributes such as human brain cells.
Scientists will need to be wary of inducing robust levels of consciousness in chimeric animals and stand-alone brain organoids, they warn.
What would be helpful, they add, is identifying any augmentations in biological traits and functions that could raise an animal’s moral status, as this would dictate how and when to use the models in future research.
Chen says there is currently no answer as to which traits, in particular, would warrant concern:
It is something that requires additional thought and discussion in the scientific community working closely with bioethicists and other stakeholders… As we discuss in the paper, it is likely the case that cognitive function is in a higher tier requiring more discussion than basic neurological functions like sensation and vision.”
Ethical considerations must become routine for organoid research
The authors believe that, irrespective of the functional outcome of brain organoid transplantation, the host animal's well-being and other socio-legal matters need to be considered and would need to be a routine part of this ongoing research.
While today's brain organoids and brain organoid hosts do not come close to reaching any level of self-awareness. there is wisdom in understanding the relevant ethical considerations in order to avoid potential pitfalls that may arise as this technology advances."
Han-Chiao Isaac Chen, First Author
Chen, H. I., et al. (2019). Transplantation of Human Brain Organoids: Revisiting the Science and Ethics of Brain Chimeras. Cell Stem Cell. DOI: 10.1016/j.stem.2019.09.002.