Brain organoids provide hope for neurological disease, but should we be testing on them?
There are currently many neurological diseases that scientists are trying to understand in order to test and design treatments. The human brain is a delicate organ however, and studying it without causing harm is a difficult thing to do.
A solution for this problem is provided by stem cells, which can be used to grow brain organoids in the lab – tiny collections of brain cells which organise themselves into structures that resemble parts of the human brain.
Because brain organoids behave in ways similar to real brains, they can be studied without the need to test treatments and therapies on live patients.
Rather than embryonic stem cells, brain organoids are created using human-induced pluripotent stem cells. By causing developed adult cells from a donor to change into stem cells, these cells can then, in turn, be caused to become brain cells, or neurons.
When placed in lab culture, the neurons then self-replicate and grow, and with the help of an artificial, scaffold-like 3-D support structure, begin to spontaneously form into shapes resembling parts of the human brain. Researchers have also now managed to transplant human brain organoids into the brains of mice and rats, where they grow quicker, and survive for longer.
At the time of writing, many types of brain organoid have been created, each modelling a different region of the human brain; the forebrain, cerebellum and the cerebral cortex.
Brain organoids respond to chemicals and pharmaceuticals in the same way as real human brains, and so are already being used to test potential treatments for Alzheimer’s, Parkinson’s disease, the zika virus, and even brain cancer.
But just how similar to brain organoids to real brains, and what are the ethical questions that we should be asking before whilst creating them for this type of research?
Eurostemcell asked Sarah Chan, a bio-ethicist at the Usher Institute of Population Health Sciences and Informatics at the University of Edinburgh.
Can you briefly list/summarise the key areas of ethical debate regarding brain organoids?
One of the first things we might think of when we contemplate brain organoids is that we’re growing little mini brains in a dish. What if they could think and feel? Actually I think that’s something that we don’t need to be concerned about – we’re not at that stage yet with the research. But there are some other interesting ethical questions around brain organoid research. For example, we’re talking about using human cells to produce these organoids. Who did these cells come from, and did they know that this kind of research was being done? And then what are they good for? In other words, is this research worth doing; why is it interesting? I think that there are some really useful therapeutic applications that do make the research worth doing. Then the final question is, what are we going to do with these organoids? Growing them in a dish is one thing, but could we transplant them into humans or into animals, and what would be the consequences of that? These are the sorts of issues that we need to think about.
You mentioned first that it’s easy to imagine a scenario in which brain organoids develop the ability to experience some limited form of perception, or even consciousness. How likely is this to happen, and what would be the ethical implications for research?
It’s easy to imagine, but in fact in practice we are light years away from that “brain in a dish” research. What we’re talking about here are small agglomerations of cells, that are helped to organise themselves in a way that superficially resembles parts of the brain. This means that they are able to respond physiologically and molecularly to drugs or to signals in a similar way to parts of the brain, but they are not brains. They are not capable of the sophisticated higher level sensing, feeling and thinking that we associate with the brain. So I would say that at the stage we’re at, there’s no concern about that at all.
Organoids are grown from human stem cells, donated from adults with their consent. Is the current best practice in ethical consent fit for purpose as this area of research progresses?
One of the challenges that I think we’re going to face here is that as science progresses, we are able to use cells in ways which we perhaps didn’t envisage five or ten or twenty years ago. Stem cells are obviously a hugely valuable resource that we want to continue to use, and yet if I were a donor of tissue I wouldn’t want people to be coming back to me every day to say, “well what about this, and this, and this?” So I think we have to start to understand the use of human tissue in a way that’s not necessarily about individual consent to every possible use, because that would just be burdensome. We need to think more about whether we trust scientists in general. Do we trust them to be doing the right things, to be doing good research that’s going to make lives better with the tissue that we’ve donated. And we need to think not only about whether we trust scientists, but about what scientists need to do in order to be trustworthy.
With that in mind, what type of statements of consent would you like to see brought into use that would encompass those kind of ideas?
Consent for not just human tissue research (what we call biomaterials), but also for data or genetic information is a difficult issue. How do we ensure that people have enough control over the use of their tissues and data, how do we ensure that people are protected. How do we ensure that important science can go ahead, but in an ethical way. Various models have been proposed - one for example is the idea of a blanket consent where you might authorise all forms of research. Another might be to have a general consent but with specific exceptions - where perhaps I just don’t like the idea of my cells being used to grow brain organoids, and I could say that I don’t want that particular application. Another is dynamic consent, where the agreed terms continue to be discussed and negotiated. I think I would like to see a model of broad consent, but with ongoing governance and oversight. So why I don’t necessarily want to be asked about every experiment that is being done with my tissue, I do want to know that the right sort of experiments are being done. That if the wrong sort of experiment were proposed, there would be some mechanism in place by which that could be flagged to me. So perhaps a model of consent by which each individual tissue donor consents but there are checks and balances on what uses that tissue can be put to.
Human therapies with brain organoids is a new field – are researchers currently bound by regulations, and if so on what basis?
One of the main areas of therapeutic application for brain organoid research is to use them as a sort of test-bed for understanding how our bigger, much more complex brains might react in a molecular way to different chemicals and pharmaceuticals. I don’t think that there are many regulatory obstacles in the way of this particular research. I think that we do need to think about the models of health innovation and the way that new products come to market, and I think that particularly in some other areas in stem cell science, for instance when developing cells as they’re appeasing (?) themselves, there are some obstacles. But as far as simply using brain organoids as a research tool to test new therapies, I don’t think that there are big obstacles at the moment.
Human brain organoids are largely grown and studied in-vitro, in dishes. Recently, though, they are also being transplanted into the brains of living mice and rats in order to give them a more favourable environment to grow. Unexpectedly, the human brain cells have been observed sending and receiving signals from the rat’s own neurons. Can you comment on this scenario from an ethical perspective?
The potential use of brain organoids in animals in order to conduct research raises some very interesting issues. What is created when we transplant human cells into an animal is known in scientific terms as a Chimera; a creature that has both human and animal parts. I don’t think that the simple combining of human and animal elements should cause us much concern. But a question that might come up is, would having human neurons implanted in a mouse brain make the mouse think more like a human? There has been some very interesting research done in which mice brains have been implanted with human glial cells, and interestingly, the mice actually became smarter. They performed better on tests of cognitive processing and memory. Of course, that’s still a long way from a mouse that would think like a human, and the scientific consensus is that the superstructure, the architecture, of the mouse brain is such that even if it were populated with a lot of human cells you would still not have a mouse thinking like a human. But certainly it’s interesting to contemplate the idea that we might make animals smarter, through the use of human cells, and what sort of possibilities that might open up for us – to communicate with animals, for them to become more useful to us in our lives, and for them to have better lives in and of themselves. I think that these are really interesting questions to consider.
Where does this fit into the wider debate on animal testing, particularly in the context of animal/human hybrids?
Once we consider the prospect that we might make animals smarter, give them new capacities, give them more interests, we have to start taking more seriously the moral obligations we have towards them as a result of those interests. For example, if you make an animal more capable of experiencing psychological suffering, you have to start taking into account what we owe to that animal with respect to its increased capacities. Now some people have said that this is a reason not to create human-animal chimeras – that the fact that we would make them more capable and then treat them badly is a reason not to create them. I think that’s an argument to treat them better when we do create them. And in fact, human-animal chimeras could prompt us to reconsider our moral attitudes towards other non-human beings. I think the way that we treat non-human animals in research and in other areas, such as agriculture generally leaves a lot to be desired. So if human-animal chimeras could in a sense pave the way for a better and more moral consideration of non-human animals across the board, then that’s a good thing.
Finally, given all these opportunities and challenges, do you think the benefits outweigh the risks of pursuing research with brain organoids?
I think that the benefits of brain organoid research are many, and that the risks are few. We are talking here about cell culture in a dish. So there might be some concerns about bio-safety and so forth, but really I can think of very few risks at this stage for the research. But if we ever start using brain organoids directly in therapy, as a form of tissue transplantation, then we’ll have to think again about the what the risks are of introducing these cells in particular ways. But the way that the research stands, I think that the benefits are tremendous and the risks are really very few.
Review of brain organoids and their application