The ethics of in vitro mini-brains and mini-embryos

by Alexey Bersenev on October 10, 2015 · 0 comments

in methods, neural

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I’m trying to avoid ethical and legal issues, surrounding stem cell research, but some of them are really intriguing. Today, I’d like to highlight the discussion about ethical considerations in growing embryo-like structures and “mini-brains” in vitro. Unfortunately, most of the articles, which discuss these issues, are paywalled, so I’m going to quote here a lot.

The recent editorial Do we need an ethics of self-organizing tissue? and commentary What if stem cells turn into embryos in a dish? in Nature Methods are discussing potential ethical issues with growing of human embryos brain organoids in vitro. Both articles acknowledge that it is not right time for legal/ regulatory actions, but we are getting close to it and some researches may entered “gray zone” already:

The theoretical extreme case—a human embryo perfectly engineered from pluripotent stem cells — makes this clear: it is a good research model, but generating or experimenting on such a structure could be argued to be unethical or even illegal, considering that many jurisdictions severely (and often justifiably) limit, and in some cases even prohibit, human embryo research. But the gray zone between an unpatterned clump of cells and this theoretical perfect embryo is more difficult to parse.

Both editorial and commentary articles are citing 2 recent studies, which brought us very close to possibility of recreation of “whole embryo” in vitro. The first study shows a system for self-organization of mouse ES cells into structures (gastruloids), resembling of whole embryo. The second study describes a method for creating of human spacial self-organizing embryonic structure with primitive streak from ES cells. From Pera’s commentary:

The interpretation of the regulatory status of gastruloids and related structures derived from PSCs is also clouded from a legal perspective, because the definition of a human embryo varies across jurisdictions. Some countries do not define the embryo at all in legislation that deals with research into infertility treatment and related topics. Some specifically define an embryo as the product of the union of sperm and egg but leave open the possibility of reconsidering the definition, which many jurisdictions have done in light of advances in human somatic cell nuclear transfer.
In other words, current experimentation and future progress could lead to a situation in which potentially valuable experimentation is held back or compromised owing to a lack of clarity around the legal definition of the human embryo.

As of today, we have one example of regulation, implemented in UK in 1990, which states that it is illegal to keep human embryo-like in vitro structures intact beyond 14 days. Pera says that embryo-like structures, reported by these 2 groups, “could conceivably breach the 14-day rule.” The authors concluded:

We therefore do not think that they require immediate attention from regulators. However, it might be worth anticipating what could follow. For example, it may be possible to provide extra-embryonic tissues typical of the yolk sac and placenta, which could contribute to the patterning of the PSC-derived structures as well as help to nourish and support them. It may even be possible to combine human gastruloids with extra-embryonic cells from animals, so that the chimeric embryos thus created would be essentially human.

Yet another intriguing topic is maturation of human brain tissue in vitro. Madeline Lancaster, in her recent interview said:

I don’t claim to be an expert in bioethics, but there is a solid foundation of research into network formation in model organisms that indicates that neural networks cannot reach maturity without both input, such as sensory input, and output. Thus, without both sensory input and output, such as the ability to interact with the surroundings, organoids will not form mature “thinking” networks. I think we are a very long way off from being able to create such a construct for organoids that would allow both input and output, so my feeling is that this will not be an issue in the immediate future. However, it may be possible in the more distant future and then it will be necessary to revisit the issue at that time.

Even though sensory input/ output systems in vitro have not been described, the progress in brain organoids methodologies is truly amazing! Few studies demonstrated formation of synapses and “connectivity” in stem cell-derived brain organoids. For example, the recent study from Nature Methods showed that maturation of human brain “cortical spheroids” for more than 2 months resembles fetal brain:

Transcriptional analysis and comparison to the developing human brain revealed that hCSs after 2.5 months resembled the mid-fetal prenatal brain (19–24 post-conception weeks, PCW). Cortical neurons were accompanied by a network of nonreactive astrocytes and were synaptically connected.

From NIH release:

“There’s been amazing progress in this field over the past few years,” said Thomas R. Insel, M.D., Director of the NIH’s National Institute of Mental Health, which provided most of the funding for the study. “The cortex spheroids grow to a state in which they express functional connectivity, allowing for modeling and understanding of mental illnesses. They do not even begin to approach the complexity of a whole human brain. But that is not exactly what we need to study disorders of brain circuitry. As we seek advances that promise enormous potential benefits to patients, we are ever mindful of the ethical issues they present.”

Cerebral organoids and shperoids are far from re-creation of complex brain also because researchers intentionally make separated parts of it. From DNA Science blog:

“As scientists, we take processes apart. Cortical development entails specification of one area, then progenitor cells generate the correct cell types, and then the cells must migrate to the right positions. All of this we have seen with the organoids at an unprecedented level of precision. But if you zoom out, it’s not a whole brain. We don’t think an organoid system of that kind will be able to recapitulate the organ,” Dr. Knoblich concluded.

Finally, I’d like to quote Neuroskeptic blog’s reaction on Lancaster’s study from 2013:

… you might decide that there are no ethical concerns, because it’s just a bunch of cells. You might consider the notion of worrying about the morality of neural cultures to be silly. Or – what amounts to the same thing – you might never think about the ethics at all.
Now, as a neurobiologist I would love it if there were no ethical dimensions to this. It would make things a lot easier. But I’m not so sure.
We are our brains. You don’t need a liver, a mouth, or legs to be a human being. So if it were possible to somehow grow a complete human brain – complete with the kind of connections found in normal human brains – I think that brain would be a human being.

The difference between ganglia and mice is the organization of the neurons. This, rather than size, is what really matters. So I’d say it would only be unethical to create a culture with sufficiently developed connections that it crossed some threshold of complexity.

So, self-assembled embryo-like structures as well as matured brain organoids could be considered by someone as “human being”. The discussion has started, because researcher let cells to self-organize to resemble an organ or organism. If “thinking or sensing” mini-brains are still too far from reality, embryo-like structures may be discussed by regulators/ legislators at some jurisdictions right now.

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