The Stem Cell Debate: Is it Over?

By Katherine Bassil

Image courtesy of Flickr

In 2006, Yamanaka revolutionized the use of stem cells in research by revealing that adult mature cells can be reprogrammed to their precursor pluripotent state (Takahashi & Yamanaka, 2006). A pluripotent stem cell is a cell characterized by the ability to differentiate into each and every cell of our body (Gage, 2000). This discovery not only opened up new doors to regenerative and personalized medicine (Chun, Byun, & Lee, 2011; Hirschi, Li, & Roy, 2014), but it also overcame the numerous controversies that accompanied the use of embryonic stem (ES) cells for research purposes. For instance, one of the controversies raised by the public and scholars was that human life, at every stage of development, has dignity and as such requires rights and protections (Marwick, 2001). Thus, the use of biological material from embryos violates these rights, and the research findings gathered from this practice does not overrule basic human dignity. With a decline in the use of ES cells in research, the use of induced-pluripotent stem (iPS) cells opened up avenues for developing both two- and three-dimensional (2D and 3D, respectively) cultures that model human tissues and organs for both fundamental and translational research (Huch & Koo, 2015). While the developments in this field are still in an early phase, they are expected to grow significantly in the nearby future, thereby triggering a series of ethical questions of their own.

Organoids of the liver, kidney, intestine, thyroid and other organs are currently grown in-vitro in 3D cultures and are characterized by a less complex architecture and physiology than human adult organs (Lavazza & Massimini, 2018), but are more complex than 2D cultures (Lavazza & Massimini, 2018). However, brain organoids seem to carry the most controversies and ethical issues (Qian, Nguyen, Jacob, Song, & Ming, 2017). First, due to their increasingly complex nature when compared to 2D cultures, and second, that we as humans identify ourselves the most with our brain and attribute all of our actions, thoughts and behavior to our brains. iPS-derived neurons and brain organoids are now increasingly being used in laboratories across the world and are constantly proving to outperform previous models, such as post-mortem tissue, which only capture the disease at its end stages; biopsies, which are invasive (Marchetto, Brennand, Boyer, & Gage, 2011); or even animal models, which can have poor translation to the bedside (Denayer, Stöhr, & Van Roy, 2014). 

An inner ear organoid

Image courtesy of Flickr

Studies looking into neurological disorders like microcephaly (Lancaster et al., 2013), neurodegenerative diseases like Alzheimer’s disease (Tong, Izquierdo, & Raashid, 2017), and psychiatric disorders like major depressive disorder (Licinio & Wong, 2016), typically differentiate adult mature cells into iPS cells and then into (several types of) neurons, with the aim of developing brain organoids to model both biological and behavioral diseases of the brain (Soliman, Aboharb, Zeltner, & Studer, 2017) in a controlled environment. Gaining further understanding of underlying disease mechanisms, screening for drugs, and potentially proposing meaningful therapies are all practices under progress that are performed today in neuroscientific research with iPS-derived neurons (Marchetto & Gage, 2012). This technology is unique in inferring disease mechanisms specific to an individual before, during and even after onset of the disease, hence capturing critical developmental stages of a certain disorder (Marchetto et al., 2011). To some, stem cell technology is the future of medicine.

While the model itself carries several technical challenges, including reductionist tendencies, the validity of the model, variability between cell lines, heterogeneity of the cell population, underlying genetic abnormalities,  and more (Marchetto & Gage, 2012), the points discussed here will cover the unspoken ethics. Independent of the ethical challenges carried by the use of ES cells in research, using iPS cells to create brain organoids holds its own ethical issues that necessitate further discussion. 

Sentience

Ethicists are often judged for committing science-fiction prototyping (Baron, Halvorsen, & Cornea, 2017). This term implies investigating the implications of future technologies in relation to public opinion by using a fictional story. This strategy is often used to involve the public in setting up policies in research and other sectors. In the brain organoid discussion, this entails “consciousness in a dish.” But, before taking a leap into consciousness (which we do not have a single clear definition of or an objective way of measuring) (Moses, 2018), let us question whether brain organoids can be (or will one day be) considered sentient entities. Recently, advances in technology have allowed scientists to generate cerebral and neural tissue organoids with highly specialized nociceptive neurons (Boisvert et al., 2015) usually responsible for the sensation of pain, sensory interneurons (Gupta et al., 2018) involved in the relay of information, and networks of living human neurons with mature firing patterns (Camp & Treutlein, 2017). Additionally, scientists have been successful in growing brain organoids with a maturity compared to a 5-week-old fetus (Watanabe et al., 2017). Similar practices have called for ethical concerns from both biological (Greely, Cho, Hogle, & Satz, 2007) and non-biological perspectives (Ashrafian, 2017), with increasing probability of giving rise to neuronal entities with potentially “conscious-like” states. 

That brings us to the question: what are the ethical implications if these neurons are able to feel pain or even sense their environment? In practice, the networks formed are functional networks when cellular activity is measured using molecular and electrophysiological techniques (Goparaju et al., 2017). In most assays, researchers treat the cells with drugs, electric stimulation and other stimuli, expecting the networks to respond in morphological and cellular changes, which is often the case (Soliman et al., 2017). However, the challenge lies in being able to draw the line between what is functional and what is sentient, or capable of integrating information received from the environment and to have a subjective experience of any sort. In order to address this challenge, first a clearer definition of sentience in relation to brain organoids needs to be set. Second, current techniques measuring activity in brain organoids need to either be optimized for greater sensitivity or new technologies need to be utilized for objective measurements of sentience (Lavazza & Massimini, 2018).

Chimerism

The Chimera from Greek mythology

Image courtesy of Wikimedia Commons 

The discussion even covers the notion of chimeras – hybrids of human and animal tissue (Council, 2010). To boost the growth of brain organoids in a way that most resembles in-vivo conditions, scientists are now seeding laboratory animal scaffolds with human brain organoids.  For instance, human brain organoids are transplanted into a mouse brain, where the grafted tissue integrates and makes use of the animal’s vasculature and circulatory system to grow and develop (Choi et al., 2017). That being said, scientists have indeed overcome a practical challenge of growing the organoid in a more “realistic” fashion (Marchetto & Gage, 2012), yet have the moral concerns of chimeras been considered? Some bioethicists have raised their concerns regarding this practice, questioning whether the animals grafted with human brain tissue are capable of greater intelligence than control animals. A recent study, led by a world-renowned neuroscientist Fred H. Gage (Mansour et al., 2018), has refuted those speculations but has not completely denied it. It is clear now more than ever that due to more and more research using increasingly complex human neuronal models, looking into changes in animal abilities, sentience and even species identity needs to be performed to answer this and several related questions. Additionally, the successful integration of human tissue with rodent tissue brings us back to the concept of sentience: has the organoid gained increased sentience now that it is part of a fully functional and viable organism, fully responsive to its environment? 

Moving forward

This breakthrough technology surely favors great advancements in biology by allowing what once seemed impossible and challenging to become a breaking-point in biomedical research. Hence, it is a fallacy to minimize the importance of brain organoids in the progression of neuroscientific research, especially because the prevalence of mental health diseases is on the rise worldwide. Nevertheless, the stem cell debate is unfortunately not over, and it is becoming clearer that the ethical discussions should catch up with the rapid advances in scientific discoveries and applications. A brain organoid with human consciousness is perhaps indeed science-fiction, but ethical assumptions derived from a “conscious-like” entity greatly differ from those of a simple assembly of brain tissue, and in this case a distinction between the two is necessary.

Researchers will need to be aware of and concerned about the ethical issues just as much as the practical challenges, which might change the way brain organoids are manipulated at the bench-side, or even how they are destroyed in the future. The handling of brain organoids bearing moral standing will have to be approached more cautiously, and that constitutes a set of guidelines for their use in research. That being said, the day the level of complexity of these biological entities will be established is the day when limitations on their use in research will be demanded. Researchers will need to collaborate with ethicists to set those necessary boundaries, such as defining a developmental threshold where beyond that point, research using these entities becomes stricter. This might be extended further to forming policies that define their moral and legal status, especially when cases involve living donors (Truog, 2005). This work should not be perceived as a hindrance to scientific progress but as an example of responsible scientific practice, not only in the eyes of the scientific community but also in society. Stem cell research was indeed revolutionized 12 years ago and that is exactly why scientists and ethicists must participate in ensuring this field keeps on striving, both effectively and responsibly.

  _______________

I am a soon to be a Master graduate in fundamental neuroscience at Maastricht University in the Netherlands. I have gained great interest in the ethics of neuroscience (or neuroethics) throughout my studies and have attempted to integrate it in my work where possible. I hope that one day I’ll be able to bridge the fields of neuroscience and neuroethics and hopefully inspire others to see the importance of such an effort. 

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Bassil, K. (2018). The Stem Cell Debate: Is it Over? The Neuroethics Blog. Retrieved on , from http://www.theneuroethicsblog.com/2018/08/the-stem-cell-debate-is-it-over.html