Organoids — tissue cultures that roughly replicate the functions of an organ — allow researchers to observe how cells behave in tissues in vitro, in the lab. This is particularly helpful when it comes to investigating the brain and the conditions that affect it. But what are some of the ethical challenges?

One of the greatest breakthroughs that have occurred in the past decade has been the ability to influence adult stem cells to differentiate to create certain cell types.

After conception, the cells that make up an embryo are totipotent, and can turn into any cell type the body requires in order to develop a full human. “Embryonic cells within the first couple of cell divisions after fertilization are the only cells that are totipotent,” explains New York State Stem Cell Science.

This property narrows throughout development and as a human ages, but the body retains some stem cells throughout its life.

Adults have stem cells in their bone marrow, which allow them to create many types of blood cells. This is known as multipotency, which is crucial to allowing the immune system to stage a response to infection, for example.

While they are able to differentiate into many different cell types, multipotent stem cells are not able to differentiate into all the different cells types that form the adult body.

Stem cell research and organ models

Being able to harness the ability to control the destiny of a stem cell has allowed researchers to investigate the minutiae of how our cells work in the lab, and arguably more ethically and practically than can be done in humans or animal models.

Much research has been done into exactly how to turn one type of cell into another one, and is ongoing. Already blood and skin cells can be taken from a person and exposed to certain chemicals and media that allow them to regain their pluripotency, the ability to develop into any cell type.

Called induced pluripotent stem cells, researchers are currently pursuing two main lines of work using this approach. They have created embryo models using fibroblasts, a type of cell found in the skin, for example. Recently created embryo models have allowed researchers to observe the beginning of organogenesis in the laboratory.

Organoids are particularly useful when they can be used to create models of organs or tissues which cannot be easily replicated any other way. The brain is an example of this being highly risky and difficult to biopsy in comparison to the skin, for example.

The other line of work involves the creation of organ or tissue models known as organoids. These allow scientists to investigate how certain cell types function, and can even be used to model whole organs.

In fact, the first cerebral organoid was made from induced pluripotent stem cells from a patient with microcephaly, where the size of the brain is reduced.

Researchers working with Dr. Madeline Lancaster used this model to discover that premature neuronal differentiation was likely to be the cause behind the reduced size of the brain they had observed in the patient, and published the results in Nature.

This finding showed for the first time that brain cells could be created from induced pluripotent stem cells, and could provide insight into the way the brain functioned and the mechanisms underpinning disease.

Recent developments

Since these initial organoids were developed, the complexity of the brain organoids created and the information that has been gleaned from them has increased. Researchers have been able to observe that induced pluripotent stem cells are able to self-organize into structures similar to those that exist in animals and humans.

Brain organoids created from induced pluripotent stem cells allowed to mature for 60 days formed optic cups, or indentations where eyes would form, a paper published in Cell Stem Cell outlined last year.

Similarly, a study published in Nature last year demonstrated cellular changes in cortical organoids after 250-300 days in vitro (approximately 9 months), that mimicked those observed in newborns.

The ability to model fetal brain development in the laboratorty has also allowed for greater clarity to be obtained about the impact of different drugs on brain development in utero.

The sodium valproate scandal is a worldwide scandal that saw pregnant women who had epilepsy receiving a drug to treat it that caused serious learning disabilities in the children they had who were exposed to the drug in the womb.

Recently, a study published in PLOS Biology used human cell-derived organoids to show that the drug caused accelerated aging and death in neuroepithelial cells of the brain, explaining some of the symptoms seen in affected children.

Others are hopeful that organoids could be used to model diseases. They were used to investigate the effect of SARS-CoV-2, the virus that causes COVID-19, on the brain to gain insight into its effects during initial infection and beyond, and some research has been done to model Alzhiemer’s, schizophrenia, and autism.

Ethical boundaries

One of the limitations of using organoids for research is that it is observed in vitro. The way an organ might act in a system, in connection with different organs, or when exposed to metabolites in the blood, for example, could be different from how it behaves when cells are isolated in a single tissue.

More recently, researchers placed an organoid derived from human cells inside the brain of a rat, in a study outlined in Nature.

Using neural organoids that had been allowed to self-organize, these were implanted into the somatosensory cortex — which is in the middle of the brain — of newborn rats. The scientists then found that these cortical organoids had grown axons throughout the rat brain, and were able to contribute to reward-seeking behavior in the rat.

This breakthrough suggested that the lab-created cells are recognizable to other tissues in the body and can influence systems.

Combining the cells of animals and humans is not without some ethical considerations. In fact, this has been the focus of a recent project.

The Brainstorm Organoid Project published its first paper in the form of a comment piece outlining the benefits of the project in Nature Neuroscience on October 18, 2022, the week after the aforementioned study was published.

The Project brought together prominent bioethicists as part of the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative of the US National Institutes of Health, which funded the project.

Co-author of the comment piece Dr. Jeantine E Lunshof, head of collaborative ethics at the Wyss Institute for Biologically Inspired Engineering at Harvard University, MA, told Medical News Today in an interview that existing biomedical research and animal welfare guidelines already provide a framework for this type of work to be done ethically.

Pointing to the International Society for Stem Cell Research guidelines published last year, she stated that those do cover the creation of chimeras, where cells of two species are combined.

These hybrids with non-primates are permitted, she explained: “This is very, very strong emphasis on animal welfare in this ISSCR guideline document that also aligns with existing animal welfare and animal research protocols.”

The potential benefits of this research needed to be considered, “though at this moment, we are still at the stage that a lot of fundamental research is necessary. And I think that that really must be emphasized,” she said.

Growing consciousness

On the same day the aforementioned paper was published, a further paper outlining how researchers had managed to “teach” neural cells created using human induced pluripotent stem cells how to play the video game Pong.

This demonstrated the importance of closed-loop structured feedback for learning in human brains, the authors claimed. They also claimed it showed the neurons were capable of self-organizing and demonstrated sentience.

Dr. Brett Kagan, chief scientific officer of the company Cortical Labs, which invented the DishBrain system used to teach the cortical neurons, told MNT in an interview that of course there were ethical considerations around the experiments they did, but they were no different to those needed for thousands of other experiments taking place around the world:

“We are very clear in the paper that sentience is not consciousness […] it’s weird that people struggle with some cells in a dish. They are certainly less complicated than a fly or a bee.”

Prof. Alysson R. Muotri, professor of cellular and molecular medicine at UC San Diego School of Medicine, CA, told MNT in an email that there were various ways of testing to see if organoids had attained consciousness. These were outlined in a comment piece he had co-authored which was published in March 2022 in the journal Seminars in Cell and Developmental Biology.

When asked whether or not the neurons tested by Cortical Labs were conscious, Prof. Muotri said: “It is hard to know for sure. However, there are some tests one can do to see if they respond in a similar way as a conscious brain. For example, you can anesthetize them and see if the brain waves go away.”

He also thought that if organoids are created that are conscious, it is important to regulate them. “Similar to animal models in research that are conscious, we should have a set of rules to grow conscious organoids,” he suggested.

The next steps for the Cortical Labs are to test how the brain organoids perform when exposed to alcohol and whether they will be able to learn while under the influence. However, there is an even bigger proposal from Dr. Kagan which is that the DishBrain system could be used as an information processing system.

“It is worth considering, at least from our perspective, that you don’t need to think about these neurons, brain cells, as only related to human biology and physiology but you can see them as being a very powerful information processing system.”

– Dr. Brett Kagan

In other words, organoids could be used to process information using very little energy. Anybody with any awareness of the huge power consumption required by the big data that modern genomics and informatics throw up, will be aware of how significant this could be.

If he is proved right, it would be yet another boon for organoid development.

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