Technical challenges at the annual meeting of the International Society for Stem Cell Research (ISSCR) meeting led to at least one lively exchange of stem cell jokes in the chat box as the audience waited for talks to resume, including stem cell parental advice: “You can be anything you want when you grow up!”

The diversity of options was reflected throughout the meeting, which included talks on such far-ranging topics as neurological disorders, skin biology, and heart and muscle regeneration.

Still, the use of stem cells seems particularly likely to help along research in certain organs. Brain research, as a whole, has high hopes for the use of stem cells to gain new insights into brain development and disease.

“Hope, hype and hubris” of brain organoid research, as Jeantine Lunshof described it, were on display at a session on the science and ethics of brain organoids, where talks on the utility of organoids ranged from the down-to-earth to what could be called visionary, or wildly speculative. Lunshof is an ethicist at the Wyss Institute and “embedded” in the lab of synthetic biologist George Church, who spoke on big-picture possibilities at the session.

Paola Arlotta, professor and chair of the stem cell and regenerative biology department at Harvard University, gave an overview of what brain organoid research can accomplish that is not accessible with other model systems. There is no way to study early human brain development, and animal brains have significant differences to those of humans, some of them surprisingly basic – the targets of the RNA-binding protein TDP-43, for example, which is implicated in amyotrophic lateral sclerosis (ALS), are species-specific.

Finally, psychiatric and neurodevelopmental diseases “are complex diseases, most of which are related to complex polygenic states… but also in some cases related to single penetrant de novo mutations,” Arlotta noted. Organoids can model those genetic states and investigate both their molecular mechanisms and possible therapeutic options “in a way that we have really never been able to before,” she said.

In 2019, Arlotta’s lab demonstrated that a broad variety of cell types and their relative proportions can be reproduced reliably when brain organoids were generated from different iPS and ES cells. So can their epigenetic state.

Using brain organoids, for example, Arlotta and her colleagues were able to show that compared to isogenic control cells, cells missing one copy of the gene SUV420H1, which codes for an epigenetic enzyme, had increased numbers of deep-layer neurons, and that those cells matured more rapidly “within a specific window of cortical development.” Arlotta called the findings an “extremely powerful example” of the detailed insights that are possible using organoids.

Stanford University assistant professor of psychiatry Sergiu Pasca introduced the audience to the possibilities of studying late fetal and early postnatal development via the use of organoids. While a fair amount is known about the earliest stages of neural development, brain development in the second and third trimesters of gestation, and the early postnatal period, remain less well understood. Pasca’s laboratory has developed organoid systems that have given new insights into those stages, including a paper published in Science earlier in 2020 that demonstrated that they could maintain organoids for nearly two years, and that development of the organoids paralleled the development of tissue, as gleaned from the analysis of six separate databases of human brain tissue.

Using their organoids, the team was able to identify a rapid “wave that we call a corticogenesis wave, that... includes 25% of all the changes in chromatin that we’re seeing in human brain development,” as well as rapid changes around 270 to 280 days in a dish that parallel what is known about the early postnatal period, Pasca said.

An ethical question?

With the possibilities of organoids come sometimes-thorny problems. Patient-specific models might bring useful treatment ideas – or breaches of privacy. And as organoids become more complex, so do the ethics questions surrounding them – including the question of whether it is ethically problematic to create something in a dish that can react to stimuli. 

Amongst the bench scientists, the consensus was that being able to react to stimuli does not in itself make an entity worthy of ethical consideration. Church pointed out that some of the earliest insights into neural transmission were gained by electrical stimulation of frog limbs, which jerked in response.

Karin Jongsma, an assistant professor of medical ethics at the University Medical Center Utrecht, noted that the discussion is complicated by the fact that consciousness is not well defined even in those that possess it beyond the shadow of a doubt, making it hard to know how one would recognize it in a cultured organism.

Lunshof agreed that the ability to respond to stimuli did not, in and of itself, confer ethical status.

“It is clear that even unicellular organisms can have… basal cognition,” she pointed out.

That cognition is not to be confused with what goes for cognition in humans. But microbes in solution will move away from harsh chemicals, and toward nutrients.

In some very basic way, that gives them preferences. But to Lunshof, it does not meet the threshold for ascribing pleasure and pain to them.

“From an ethics point of view… is there any ethics discussion that makes sense?” she asked. “We wipe them away with our 99.9% microbial household killer.”

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