Scientific basics of neuronal optogenetics

Optogenetics is a biotechnological method that enables the precise regulation of cellular functions using light (Faltus et al. 2023). This requires the prior genetic modification of cells so that previously light-insensitive cells express light-sensitive ion channels or other membrane transport proteins (Deubner et al. 2019). A major breakthrough occurred with the discovery that channelrhodopsins from algae could be introduced into other organisms’ cells, rendering them responsive to light. The controllability of these genetically altered cells is based on the ability to specifically modulate their natural and dynamic membrane potentials through light stimulation. This process necessitates an external light source. Moreover, using different channelrhodopsins sensitive to various light wavelengths allows the selective control of cellular activity within milliseconds (Neghab et al. 2020).

The further development of basic research through the application of optogenetics should also enable the development of new therapeutic options: The control of muscle cells should improve the effectiveness of prostheses and restore the ability to walk (Gundelach et al. 2020). It should also be possible to treat gastric paralysis using optogenetics (Vogt et al. 2021). Research is being conducted into restoring patients’ vision (Mutter et al. 2017) and hearing (DiGuiseppi and Zuo 2019). New therapeutic approaches are being developed for other neurological diseases such as epilepsy (Bentley et al. 2013), depression (Zawadzki and Adamczyk 2021), Parkinson’s disease (Chen et al. 2015) and Alzheimer’s disease (Etter et al. 2019) by using optogenetics. The application of optogenetics to neuronal cells is referred to as neuronal optogenetics.

Scenarios for development

Human cerebral organoids are three-dimensional structures grown from stem cells that mimic the basic properties of a human brain in vitro (Zagha and Winner 2022, p. 22). They consist of different neuronal cell types and form layered structures similar to the human brain. These organoids make it possible to study complex neuronal networks and their development under controlled laboratory conditions.

The combination of cerebral organoids and neuronal optogenetics opens up new possibilities. Researchers can now control neuronal activity in organoids through the influence of light and thus investigate the development of neuronal networks in a human model. This technique enables research into developmental disorders of the brain and secondary diseases such as autism (Luo et al. 2023) or schizophrenia (Obi-Nagata et al. 2019).

In basic research, neuronal optogenetics is used to understand complex neuronal networks and their role in behaviour. Researchers can specifically activate or inhibit individual neuron populations in animals or cerebral organoids and observe how this influences behaviour. This has led to further insights into the functioning of memory and other cognitive processes (Ehrmann and Pauls 2020; Tovote et al. 2015).

Another potential of using cerebral organoids in combination with neuronal optogenetics is the possibility of reducing animal testing. Animal experiments pose ethical challenges and have scientific limitations. They are controversially discussed and sometimes rejected by various actors. Cerebral organoids allow researchers to observe neuronal development and functioning without having to rely on animal testing. This could not only reduce ethical concerns but also improve the relevance of research findings, as organoids can replicate human brain structure and dynamics more accurately than is possible in animal models (Garciá-Delgado et al. 2022).

Principles of technology assessment

To answer the question of whether a TA of neuronal optogenetics is necessary, tasks of TA will be briefly outlined here. TA is described as a heterogeneous and dynamic research practice (Böschen et al. 2021, p. 21). TA is concerned with the assessment of new technologies in terms of their potential impact (Decker et al. 2018, pp. 12–13). Its aim is to support the shaping of scientific progress through its contributions, with regard to the potentials and risks for current and future society (Böschen et al. 2021, p. 21). It attempts to formulate recommendations for decision-makers and society (Böschen et al. 2021, p. 20). TA is intended to enable decisions on the use or non-use of a technology with reference to existing knowledge (Simonis 2013, p. 12). It does not anticipate these decisions, but provides decision-makers with possible bases for their decisions (Zweck 2013, p. 145). What various TA approaches have in common is that they are committed to the common good (Simonis 2013, p. 12). In this sense, TA is necessarily multidisciplinary, as individual disciplines cannot fulfill the scope of the task (Simonis 2013, p. 13).

TA studies on medical and bio technology are concerned with the efficacy and safety of the technologies in question, the relationship between costs, benefits, quality and use, as well as social consequences, ethical implications and social acceptance. In particular, the development of genetic engineering is the focus of the current TA (Kollek 2021, p. 59).

To date, there has been no systematic TA of neuronal optogenetics, cerebral organoids or the combination of both techniques, but only individual contributions from various disciplines on research ethics, medical, ethical, legal and social issues. TA in Germany has been carried out on the topics of biomedical innovations and clinical research (Bührlen and Vollmar 2009) and genome editing in humans (Albrecht et al. 2021). Both TAs can be partially related to neuronal optogenetics. The TA carried out for genome editing is analyzed in the next paragraph. The TA on medical innovations and clinical research essentially produced the following results: An important potential of clinical research is the possibility for patients to have access to new treatment methods at an early stage (Bührlen and Vollmar 2009, p. 5). As clinical research can lead to the authorization of new therapies, which could help many people, the question of financial support for such research arises (Bührlen and Vollmar 2009, p. 6). The potential of clinical research is offset by the risks, particularly for study participants, when new medical approaches (such as neuronal optogenetics) are trialled (Bührlen and Vollmar 2009, p. 9). There are special regulations for these new approaches, for example if gene transfer is involved (Bührlen and Vollmar 2009, p. 69). As mentioned above, gene transfer is the basis of neuronal optogenetics. In addition, the TA on medical innovations and clinical research points out that suitable animal models are often difficult to find due to the specificity of human metabolism (Bührlen and Vollmar 2009, p. 73). Here, as also mentioned above, a combination of neuronal optogenetics and organoid technology could minimize the problems.

Technology assessment on genetic engineering

Genetic techniques enable a more accurate and faster diagnosis of various diseases. Genetic tests can identify predisposing factors and create individual risk profiles, enabling more precise and earlier treatment. Genetic engineering also has the potential to individualize medicine to a greater extent. Therapies can be tailored to the genetic make-up of the individual patient, which can lead to more effective treatments with fewer side effects (Nogrady 2020). There are initial clinical successes in gene therapy for diseases such as muscular dystrophy (Salmaninejad et al. 2021). Many drugs are now produced using genetic engineering methods (Stryjewska et al. 2013). Genetic engineering has also played a key role in the development of vaccines, for example against COVID-19 (Wang et al. 2021). Public awareness of these potentials increases the acceptance of genetic engineering (Koralesky et al. 2023).

This also applies to the latest genetic engineering vehicles, e.g., CRISPR/Cas: The acceptance arises against the backdrop of the therapeutic potential (Albrecht et al. 2021, p. 7). As the central controversy, the question of potential germline interventions is discussed (Albrecht et al. 2021, p. 7). The fact that germline interventions are hereditary is particularly controversial in this context (Hardt 2019, p. 2). In the case of neuronal optogenetics, it is somatic interventions that lead to genome editing. Somatic interventions are not the subject of the same social and scientific controversy as germline interventions. Essentially, somatic genetic interventions face technical challenges such as the off-target effects, unclear long-term and side effects and the sufficient production of vectors to be able to offer gene therapies on a sufficient scale (Lang et al. 2019, p. 142). Concrete ethical and social issues here primarily concern the assumption of costs for costly gene therapies and thus fair access to promising therapeutic approaches (Lang et al. 2019, p. 144). Applied to neuronal optogenetics, these questions also need to be clarified.

The health or healing of people is seen here by decision-makers and society as a generalisable value. Against this background, the duty is seen not to jeopardize medical potential that could prevent human suffering and death through over-regulation. People have the right to receive the best possible treatment for their illness. At the same time, however, they also have the right to have their treatment carried out on the basis of a rational cost-benefit analysis.

There may be cases in which technology assessment is seen as urgent by scientists but not by society.

The positive attitude towards the use of genetic engineering in medicine in Germany is primarily driven by the concrete medical benefits. At this point, it must of course be noted that the existence or non-existence of a social controversy does not necessarily determine the necessity of a TA. There may be cases in which TA is seen as urgent by scientists but not by society. Conversely, societal outcry could justify TA, even if the scientific community does not see it that way.

The TA on genome editing in humans shows that social controversies not only provide indications of open questions, but that these questions are discussed within the social controversies. New ethical questions arise above all in relation to germline interventions. With regard to somatic interventions, the established ethical standards, such as autonomy, safety, etc., apply. The genetic intervention in neuronal optogenetics is therefore not the subject of new ethical debates and questions.

Possibilities and challenges of neuronal optogenetics

The therapeutic potential of neuronal optogenetics appears to be rich. These must continue to be researched by medical, health economic, ethical and other disciplines. As there are also questions regarding the financing of research by the public sector, the social potentials must be weighed up against the social risks through TA.

Neuronal optogenetics raises questions that are fundamentally aimed at different specialist disciplines. A comprehensive evaluation of neuronal optogenetics and sufficient information for various decision-makers requires the systematic consolidation of the results and assessments of the various disciplines involved through TA.

It is necessary to clarify these questions promptly. Neuronal optogenetics is developing rapidly. This is demonstrated by the founding of the Else Kröner Fresenius Centre for Optogenetic Therapies in Göttingen (Germany) in 2024 (UMG 2024), where potential therapeutic possibilities of neuronal optogenetics intended for translation into clinical application are being researched. The German Federal Ministry of Education and Research has been funding the interdisciplinary ELSA (Ethical, Legal and Social Aspects) project NeurOPTICS since 2023, which deals with the ethical and legal issues of neuronal optogenetics. This shows, that political decision-makers have already become aware of the topic. It is now up to TA to assess a possible approach to the technology on the basis of existing knowledge and to communicate these assessments to the various decision-makers and social groups. ELSA studies can be seen as an indication of the need for TA. While ELSA studies examine the ethical, legal and social aspects of a new technology and thus define the field against the background of great uncertainties about the development of new technologies, more comprehensive TA follows. This is because ELSA research provides important reflections that can later be incorporated into TA. In turn, TA can provide empirical analyses that can enrich an assessment through ELSA research. However, while ELSA research is anchored in scientific ethics and the governance of research, TA pursues the goal of assessing the opportunities and risks and utilizing the results for policy advice and decision-making processes. To this end, TA expands the disciplinary field of ELSA studies.

Basic research and therapeutic innovations

Neuronal optogenetics promises progress in basic research and possible therapeutic approaches. Research into and potential cures for various neurological diseases can be seen as a key potential of the technology. Against this background, neuronal optogenetics can be seen as a ‘disruptive technology’, as it has the potential to open up new avenues in medicine and possibly replace other therapeutic approaches, such as psychotropic drugs or for the treatment of deafness, blindness or neurological diseases, whose application is based on existing experience of benefits and risks. It must be clarified whether the risk-benefit balance of neuronal optogenetics is different from that of known therapeutic approaches.

Regulatory challenges

It is not entirely clear whether the regulatory conditions in Germany are sufficient or whether there is a need to adjust the regulatory conditions (Bührlen and Vollmar 2009, p. 81). Within the field of law, questions relating to neuronal optogenetics are already being considered. Compared to other treatment methods, optogenetics has the special legal feature that the combination of genetic modification and light stimulation requires a medicinal product (usually a gene therapy product) and a medical device (the light source). In Germany, different legal requirements apply to medicinal products and medical devices, e.g., for authorization, safety/performance requirements and clinical trials (Faltus et al. 2023).

Ethical and social challenges

In the context of neural optogenetics, TA could be relevant as this technology intervenes deeply in the human brain and thus in the understanding of identity and consciousness. TA may be necessary to ensure that the development and application of this technology is in line with social values (common good). The NEST (New and Emerging Science and Technology) ethics (Swierstra and Rip 2007, p. 7) could be applicable here, because questions of identity and consciousness concern the fundamental self-understanding of humans and thus have a meta-ethical point of reference. In NEST ethics, meta-ethical questions of technical determinism and human authorship are just as much up for discussion as questions about dual-use or misuse scenarios of the technologies in question and the possible effects of the technologies on moral and ethical judgements (Swierstra and Rip 2007, p. 7).

As mentioned in the literature, optogenetic therapy for depression or trauma could result in both desirable and undesirable changes to the patient’s personality (Zawadzki and Adamczyk 2021). This is essentially nothing new, as other neurotherapies can also have undesirable side effects. However, in order for the optogenetic procedure to be justifiable, the relationship between costs and benefits, e.g., for patients, which neuronal optogenetics harbours, must be clarified. And it must be taken into account that technologies can always have unintended and unwanted side effects that are not yet known at the time of their assessment.

It is also conceivable that people in psychiatric contexts could be treated without their knowledge or consent (Adamczyk and Zawadzki 2020). This could violate their autonomy. The extent to which the potential of neuronal optogenetics differs from other and already known techniques in this respect can also be the subject of TA.

Other risks include possible unforeseen effects on the neuronal network, such as the unintended activation of neighbouring neurons (Le Bras 2021). Long-term safety and stability studies are needed to ensure that these genetic changes do not have negative long-term effects. Neuronal optogenetics could also result in far-reaching social changes, for example through new possibilities in the manipulation of consciousness and behaviour or through the development of therapies that fundamentally change individual and collective experience.

Abuse scenarios are already being discussed in this regard (Zawadzki and Adamczyk 2021). Even if scenarios of super-soldiers controlled by neuronal optogenetics (Adamczyk and Zawadzki 2020) may be nothing more than science fiction, they are still capable of influencing scientific and social debates (Mehnert and Grunwald 2024, p. 282). Hermeneutic TA is particularly important for NEST when evidence-based perspectives on development are still rare and assumptions are made in the debates and then influence them, the empirical content of which cannot yet be sufficiently assessed (Mehnert and Grunwald 2024, p. 288) and it is first necessary to analyze the corresponding assumptions (Mehnert and Grunwald 2024, p. 288). Hermeneutic TA could make important contributions in the case of neuronal optogenetics.

Further social consequences such as discrimination and access barriers could arise and would have to be analyzed by TA. This is also nothing new in principle and has already arisen as a problem in the context of gene therapies. Who decides who may or should be treated? How can it be ensured that optogenetics does not become a technology that exacerbates social inequalities by only being accessible to the wealthy? These questions point to the need for an interdisciplinary assessment by TA.

The technology assessment of neuronal optogenetics

The TA of neuronal optogenetics requires an interdisciplinary risk and benefit assessment. To this end, possible short- and long-term risks must be identified and quantified and the potential medical and social benefits must be demonstrated. Based on this, scenarios (best-case, worst-case, middle ground) must be developed and analyzed by various disciplines. The TA to be carried out must be orientated towards the ‘common good’ and be multi-perspective. This means that acceptable, universalizable social values must be identified, to which the development of technology must conform.

Against this background, ethical issues (interference with autonomy, consent and informed consent), safety concerns (long-term and side effects), social implications (access, justice, misuse, dual use, social impact, social acceptance) and legal aspects (regulation under medical, pharmaceutical and medical product law, liability) can be identified. These points require an interdisciplinary consideration of the technology and its consequences.

New questions through combination with organoid technology

The combination of neuronal optogenetics and organoid technology raises uncharted territory: The moral status of cerebral organoids is the subject of much debate and has by no means been conclusively assessed (Dederer and Hamburger 2022). It can be assumed that the assessment will depend on the further technical development of organoid technology, which is not yet foreseeable.

As already explained above, the use of organoid technology within research into neuronal optogenetics is linked to questions of animal ethics, which are now gaining in importance, as organoid technology is expected to increasingly replace animals while at the same time improving the transferability of results in the case of human cerebral organoids.

The organoid technology raises questions about the legal status of organoids or the potential production of chimeras through the transplantation of human organoids into animals (Faltus et al. 2023).

The combination of neuronal optogenetics with organoid technology could also justify TA. The fact that this combination raises new questions must also be communicated to (political) decision-makers, as many current regulations cannot be easily transferred to these possible applications.

Conclusion

In terms of its character, neuronal optogenetics can be understood as a topic of TA. There are various questions that need to be answered in an interdisciplinary setting. Even if it was possible to show that TA of genetic engineering provides initial indications for an assessment of neuronal optogenetics, it was not possible within the scope of this article to shed light on all the questions raised by neuronal optogenetics.

Answering these questions through TA will enable an interdisciplinary, ethically sound assessment of neural optogenetics that takes into account its social potential. Since genetic engineering and medical innovations in general has been identified as a topic for TA, the question arises as to why this should not be the case with neuronal optogenetics. New technologies rarely raise previously unknown questions. Rather, familiar questions appear in a new light as a result of new technologies and must be asked and answered anew against this background. TA is therefore called upon to address the topic of neuronal optogenetics and to determine the extent to which neuronal optogenetics requires new answers to known questions.