Benefits of Using Organoid Intelligence

Organoids allow the partial recreation of organ function and the biological microenvironment, making them highly valuable entities for research [18]. To cite just a few examples, brain organoids facilitate the study of central nervous system conditions such as differences in neurodevelopment, neurodegenerative diseases, the study of primary human glioblastoma, idiopathic autism, developmental neurotoxicity, leukodystrophies, Down syndrome, Timothy syndrome, Alzheimer's disease, schizophrenia, bipolar disorder, microcephaly caused by Zika, Parkinson's disease, Huntington's disease, brain tumors, among other conditions. Organoid models are also used to study memory, learning, the long-term cognitive effects of illicit drugs, and the mechanism of action of certain drugs. They also play an important role in replacing animal models in research [6, 14, 15, 17].

Energy Benefits and Pollution Reduction

The human brain is 106 times more energy economist than modern computers, so biological learning requires less energy than machine learning in artificial intelligence to perform the same activity [15, 21]. A clear example is the Alpha Go system (Google, Deepmind, London, UK) that beat the world champion in Go. This system had to be trained with data from 160,000 games. However, a human being would have to play 5 h a day for 175 years to achieve the equivalent of the data provided by the 160,000 games, so with less data, neuronal activity is capable of performing the same activities as machine learning in artificial intelligence. The large amount of energy required to operate AI-based systems leads to global carbon dioxide pollution, a phenomenon that could be reduced in the future with the use of brain organoids in information processing [15]. This contributes to environmental sustainability [19].

In the search for information, no published academic research was found that analyzed with concise economic figures the cost of technological development of the IO. This limits a comparison with the technological costs generated by the development of AI. This type of analysis would be a good contribution to the scientific literature.

Benefits for Animal Use

Another benefit of working with BOs is that they represent an ethical alternative, contributing to the replacement, reduction, and refinement of the use of animals for research, in accordance with the 3Rs principle [23, 24]. While some authors suggest that the use of organoids could result in reduced animal suffering, greater flexibility in experimentation, lower costs, and more personalized research, others argue that it is too early to talk about complete replacement, as scientific journals still prefer in vivo testing [9].

The Food and Drug Administration has announced the progressive elimination of pharmacological, toxicological, pharmacodynamic and immunological studies in animals, making way for New Approach Methodologies (NAMs) as animal replacement models. According to strategic plans, it is assumed that by 2030, pharmacological tests on animals will be in the minority compared to tests performed with NAMs. The opinion that laboratory animals do not provide a sufficiently efficient model for pharmacological testing is growing, it is said that more than 90% of tests that are safe in animals do not receive FDA approval for application in humans [25].

Included in NAMs are organoids and microphysiological systems. Both seem to provide a better simulation model from the biological point of view. Human organoid brains in terms of human genetic-based studies are more reliable because they come from human stem cells, and may even belong to the patient under study, which contributes to personalized medicine in neurological system diseases such as Alzheimer's, Parkinson's, glioblastomas, Autism, Schizophrenia, just to mention a few examples.

Ethical and Moral Considerations Regarding Work with Brain Organoids and Organoid Intelligence

The authors describe three fundamental lines of bioethical considerations: research, social, and philosophical. The first refers to responsible research and the appropriate use of patients' stem cells. The second relates to the inequality of resources among individuals and the creation of false hopes in future research. The third has to do with human experience and the potential consciousness of organoids [26].

An article by Brett J. Kagan et al. based on the DishBrain system (Cortical Labs, Melbourne, Australia) shows the “learning” capacity of biological neural networks (in vitro) when interacting with the arcade game “Pong” [27].

This led to the emergence of concerns such as the potential consciousness and moral status of brain organoids. Added to this is the possible development of pain sensation, as well as the emergence of Greely's dilemma (since the organoid could suffer due to the conditions that served as the ethical impetus for the start of the research). The above leads to concern for organoid welfare. On the other hand, there is the issue of commercialization and intellectual property, as well as the privacy of the donor of the cell from which the organoid is created. Several questions remain unanswered, such as whether donors retain any rights over the derived organoids and what type of informed consent should be obtained from them. The development of these structures may lead to the creation of human-animal neural chimeras, which enters the ethical debate on implantation in animal models [5, 15, 28, 29].

Based on the work of Zakaria S. et al., we conducted an analysis of several national and international organizations and regulatory frameworks that are directly or indirectly related to research involving brain organoids. We selected, in our view, the organization or guideline that presents the most suitable ethical framework for brain organoid research in the United Kingdom, the United States, Australia, the Netherlands, Japan, the European Union, and within international forums. Altogether, these organizations and guidelines could contribute to shaping a global bioethical framework specifically adjusted to research involving brain organoids [30].

In summary, the organizations and guidelines that present the most relevant bioethical frameworks for brain organoid research include:

United Kingdom: The Nuffield Council of Bioethics.

The United States: The National Institutes of Health (NIH).

European Union: The European Group on Ethics in Science and New Technologies (EGE).

International Forums: The Guidelines for Stem Cell Research and Clinical Translation, International Society for Stem Cell Research (ISSCR).

Australia: ISSCR.

Netherlands: Foundation Hubrecht Organoid Biobank (FHOB).

Japan: ISSCR.

A special mention should be made of the ISSCR and its guidelines. Due to their specificity regarding stem cell research and the development of organoids (including brain organoids), as well as their international influence, the ISSCR guidelines serve as a leading ethical reference. Japan and Australia are clear examples where the ISSCR guidelines are used to guide national-level research practices.

In 2023, Lavazza and Zilio coined the term “anticipatory neuroethics” in an article referring to ethical issues related to brain organoids, since to date and to their knowledge, these organoids did not yet show consciousness. However, the term “precaution” is used to refer to the way in which research with this biological material should be conducted, because in some ways they are potentially conscious and will become more complex over time [7, 9, 31,32,33]. Regarding the precautionary principle for working with brain organoids, Boyd JL. and Lipshitz N. consider that it is currently too early to apply this principle, but that it may be necessary in the future [19, 34].

A study conducted by Lavazza and Chinaia, based on interviews with scientists working with brain organoids, revealed important insights into prevailing attitudes. One-third of the invited experts declined to participate, and among those interviewed, the majority expressed skepticism regarding the possibility of organoids ever achieving consciousness. The participants argued that brain organoids should not be assigned moral status, as they lack sensitivity and awareness, and emphasized that there are no fundamental differences between organoids and other biological tissues commonly used in laboratories. They further suggested that current ethical standards for biological research are sufficient and do not require additional layers of regulation for organoid studies [4].

Complementing this perspective, some authors argue that attributing consciousness to organoids represents a mereological fallacy: characteristics of the whole (the human being) cannot be ascribed to its parts (such as the brain or brain organoids). Under this reasoning, the brain alone cannot love, remember, or learn; such capacities emerge only when embedded in the complexity of a whole human body. From this standpoint, much of the current scientific communication surrounding organoids risks “personifying” them, attributing characteristics they do not possess [35].

Other scholars emphasize that whether organoids could ever be considered conscious depends heavily on one’s philosophy of mind. For example, Smart’s Identity Theory and the Hylomorphism Mind–Body Powers Model provide contrasting interpretations, leading to different conclusions about the moral standing of organoids [36]. This highlights the lack of a unified theoretical framework, where philosophical commitments shape divergent ethical evaluations.

In real-world contexts, ethical dilemmas rarely admit black-and-white answers [37]. Bassil K. underscores the importance of responsible scientific communication, advocating for the use of precise technical language to avoid misleading the public. Terms like “mini-brains” may inadvertently suggest human-like capacities, especially for non-specialist audiences, who could incorrectly assume organoids possess higher cognitive or emotional traits [38, 39].

There is nonetheless a growing consensus that organoid research should be subject to restrictions, although the scope of such restrictions remains unsettled. Koplin et al. propose a three-tiered moral framework: (1) non-conscious organoids should be regulated like any other human biological material; (2) organoids with some form of consciousness must be safeguarded against suffering; and (3) advanced organoids with environmental interaction must be carefully monitored for emergent cognitive functions, ensuring they too are protected from harm [5].

Given the uncertainty regarding their true capacities, it would be premature to classify brain organoids as either “fully moral” entities comparable to humans or as objects with “no moral status.” Some ethicists propose an intermediate category, analogous to the moral status attributed to non-human animals or fetuses. However, due to the limited understanding of organoid potential, the most accurate designation at present is that of “uncertain moral status” [9].

The following is an analysis of two fundamental theories of consciousness applied to Organoid Intelligence that may help to understand why the most developed brain organoids (BOs) may have an uncertain moral status. If we analyze organoid consciousness from the Global Workspace Theory [26], it could be said that even the most developed brain organoids “are not conscious”, because they are unable to generate attention, defined as selection of relevant information for the passage to the global workspace, hence as these organoids cannot generate attention, the information cannot be selected to become conscious. For in the Global Workspace Theory without attention there is no consciousness.

Taking the Integrated Information Theory [26] as a reference, it can be stated that the most developed cerebral organoids are not conscious yet, but they could be potentially so. Explanation: interneuron connections make the organoid function, causing the information of the system to exceed the information of the independent neurons (partitioned system). However, the limited size of the current organoids and consequently the low number of connections, compared to the human brain makes the value of phi (φ) (defining φ as the degree of integration of information in a system or the information generated by the system as a whole and not present in its parts) very low. Which leads to think that the level of consciousness is null or extremely low for brain organoids according to the Integrated Information Theory.

It can be said that, depending on the theory of consciousness used to evaluate the most developed cerebral organoids, these will have a degree of consciousness or none.

At present, researchers face a major gap: the lack of a clear theoretical framework to assess morally relevant cognitive capacities in human brain organoids, particularly those enhanced through integration with artificial intelligence [40]. Addressing this challenge requires an iterative dialogue between neuroscience and ethics, generating mutual benefits for the advancement of synthetic biological intelligence (SBI). Such collaboration can be envisioned in three progressive stages. First, neuroscience informs ethics by establishing metrics to evaluate complex and potentially morally significant states in organoids. Second, ethics feeds back into neuroscience by signaling when organoids reach developmental thresholds that may carry moral relevance. Finally, a continuous and integrated exchange ensures compliance with the expectations of scientific agencies and global stakeholders [41].

Current evidence suggests that, as of March 2023, brain-based biocomputers have not exhibited properties such as emotional intelligence, sentience, consciousness, or the capacity to suffer [42]. Despite this, the ethical debate surrounding organoid intelligence continues to intensify, given the rapid technological advances. Some scholars highlight the potential role of the World Health Organization (WHO), through its Ethics Review Committee, in establishing an international governance framework capable of guiding research on organoid intelligence in a consistent and harmonized manner [19].

Nevertheless, a global consensus has not yet been reached regarding the regulatory standards that should govern experimentation with brain organoids [7]. Legal and ethical frameworks remain in flux, evolving in response to both the pace of innovation and ongoing philosophical debate [19]. This lack of unified standards underscores the urgency of creating adaptable governance mechanisms that can balance scientific progress with ethical responsibility.

The Future of Organoid Intelligence

Organoid intelligence is an emerging field of research, yet its pioneers have already delineated priority areas for advancement. These include: (1) refining the structural and functional design of brain organoids, (2) enhancing sensory–motor integration, (3) advancing electrophysiological recording and analysis, and (4) optimizing the bidirectional feedback loop between organoids and artificial intelligence systems [14].

Progress in these domains is narrowly linked to the development of enabling technologies such as microfluidics, artificial scaffolds, and blood–brain barrier-on-a-chip models, all of which contribute to improving organoid maturation and physiological relevance [2, 6, 43]. The broader challenge of organoid intelligence lies in leveraging these advances to deepen our understanding of learning processes, human neurobiology, information processing, and the pathogenesis of neurological disorders—while simultaneously reducing the ethical and scientific dependence on studies involving human and non-human animals [42]. It can therefore be stated that, despite their current advances, brain organoids still present a series of limitations and challenges that must be overcome to continue their development.

Limitations and challenges in organoid production:

1.

The process of differentiating induced pluripotent stem cells (iPSCs) into neuroectoderm remains complex and sensitive to multiple variables.

2.

A precise protocol is required to achieve that the organoids imitate a specific region of the brain tissue and do not become a small heterogeneous mass with absent cellular subtypes of interest.

3.

The absence of vasculature limits the arrival of oxygen and nutrients, as well as the removal of toxic metabolic by-products; this affects the long-term survival of these entities and limits the size of the organoid.

4.

It is necessary to connect the organoids in interface to obtain an interaction with the environment (organoid intelligence); the challenge is the biocompatibility with the interfaces. These interfaces must be biocompatible, conductive, flexible and biomimetic to cause the least possible damage to the organoids.

5.

The lack of an immune system in the organoid entity distances it from reality, since the nervous system develops in interaction with the microbiome.

6.

The development of microphysiological systems is key to favor the increase in the size of the organoids with which research can be conducted [2, 6, 14, 43].

Another issue to be resolved in the future is the definition of consciousness and the moral status that would be assigned to the more developed brain organoids. One of the fundamental questions are the tests to be performed to determine the degree of consciousness. As a proposal we suggest the following:

1.

Behavioral tests: in the most developed organoids it is possible to perform behavioral tests such as the evaluation of learning, although it would not be appropriate to take learning alone as a parameter of consciousness. Artificial intelligence shows that the phenomenon of learning is possible in the absence of consciousness as such.

2.

Neurophysiological tests: the measurement of neuronal electrical activity by EEG (special electroencephalography for cerebral organoids) would also be an important test, taking into account the frequency, amplitude, synchrony and complexity of the waves. Low frequencies, with high amplitude, synchrony and low complexity correspond to low levels of consciousness. High frequencies, with low amplitude, asynchrony and high complexity correspond to high levels of consciousness.

3.

Theories of consciousness: the Integrated Information Theory could be used to complete the analysis of consciousness in Brain Organoids.

In the future, the improvement of brain organoids in terms of size, vascularization, biocompatibility with their interfaces, and integration with the environment will depend on the overcoming of the previously mentioned limitations.

IO and Multi-Organoid Systems (Organoid-on-a-chip)

Organoid intelligence is not exempt from the possibility of integration into a system, which can include communication and perfusion through channels that favor interaction between several organoids, as well as chemical signals that simulate a more realistic environment than the simple cultivation of an isolated organoid. However, there are limitations to the creation of signaling gradients. Organoids-on-a-chip are part of the NAMs suggested by the FDA for the replacement of experimental animal models.

Tsai YC et al. present a Brain-Organoid-on-a Chip model with multiple layers in which they use four different growth factors that can enter a chamber where the organoid is cultured, by this method they achieved the culture of a brain organoid with its defined anatomical structures emulating the human brain in a dorso-ventral direction [44].

With the Organoid-on-a-chip, the toxicological, pharmadynamic and disease study takes a qualitative leap compared to isolated organoids. Although this technology must continue to be improved.

Responsible Communication

Irresponsible scientific communication can lead to misinformation, generation of false expectations, aversion, among other reactions of the population [38]. Specialized topics in biology, informatics and bioinformatics are fields of knowledge where unfamiliar terms or words are often used that are not understood by the general population. It is a challenge to keep journalistic communication simple, with terms that are understandable to the general public, but at the same time maintain scientific rigor.

To reduce the possibility of misinformation, two alternatives are suggested in this work: 1) The ideal is the training of journalists specialized in science communication or scientists specialized in popularization. People who master both fields of knowledge, i.e., journalism and the natural or exact sciences, are the best people to write the articles or news that will reach the general public. 2) The partnership between scientists and communicators, in order to transmit information on innovations resulting from research in an objective manner, is fundamental in creating a balance of forces with the sensationalist press that covers scientific topics.

One recommendation to prepare the future workforce for responsible OI development and communication is for each organoid research team to establish a partnership with a news media outlet, to which it provides advice through its journalist or communicator representatives. As a second recommendation, information written for the general public should first be approved by both a scientific team and a team comprising members of the general public. This will prevent the information from becoming overly technical, which would prevent it from being understood by the public, while also ensuring that the information remains scientifically rigorous.