Among the most intriguing areas of neuroscience research is the use of brain organoids. An Italian-led study has developed a 3D brain organoid model, representing a step forward in understanding the human brain and tackling conditions that originate in the earliest stages of life.
The use of brain organoids is one of the most promising approaches in the study of the human brain. In particular, there is significant interest in better understanding the cerebral cortex, which is regarded as the most complex and advanced structure, as well as the pinnacle of brain evolution.
The cortex is the critical neural structure underlying higher brain functions and intellect, accounting for roughly 70% of our brain mass, as explained by neuroscientist Patricia Goldman-Rakic in the article “Cerebral Cortex Has Come of Age,” published by Oxford University Press.
It is estimated to have an average surface area of two square metres and to contain 16 billion neurons [source: National Library of Medicine]. The cortex plays a crucial role in governing the cognitive abilities that define humanity, including motor, perceptual, sensory, and memory functions, as well as higher-order functions such as language, consciousness, and logical reasoning.
Beyond aiming to understand the features and activities of the brain and cortex, the research seeks to develop targeted treatments for mental health conditions and brain disorders specific to humans.
A recent study has pioneered a new three-dimensional brain organoid model. According to the researchers involved, this advancement will enhance understanding of brain development and related disorders, particularly those with origins in early developmental stages. Among these conditions is autism, a prevalent disorder, with approximately one in a hundred children affected by autism spectrum disorders [source: World Health Organization].
TAKEAWAYS
Cerebral cortex and brain organoids: the role of italian research
Italian researchers are actively contributing to international efforts in studying the cerebral cortex, with two recent publications highlighting their work. One study has introduced a new cortical surface model that allows for uniform sampling, based on high-quality structural scans (publicly available) of 1,031 brains, 25 times more than existing cortical models.
Maria Ida Gobbini, from the Department of Medical and Surgical Sciences at the University of Bologna and the Neuroimaging Laboratory at the IRCCS Institute of Neurological Sciences of Bologna, contributed to this research. The findings were presented in the article “A cortical surface template for human neuroscience“, published in Nature Methods.
Another recent study, conducted by researchers from the University of Milano-Bicocca, Human Technopole, and the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) in Vienna, focused on brain organoids. These are in vitro culture systems, three-dimensional models derived from pluripotent stem cells that replicate the developmental processes and organization of the human brain.
Often referred to, albeit inaccurately, as “mini-brains“, brain organoids enable the creation of a 3D brain model in vitro that is physiologically relevant for studying neurological development and related pathological processes in the human nervous system. They have significant applications in the study of human brain development and neurological disorders, such as autism.
The new model is detailed in the study “A polarized FGF8 source specifies frontotemporal signatures in spatially oriented cell populations of cortical assembloids“, recently published in Nature Methods.
The international team, with a strong Italian presence, worked on these organoid technologies to investigate human brain development, addressing fundamental questions about how the human cortex reaches its large size and the origins of brain diseases. Leading the research group is Veronica Krenn, holder of the Human Technopole Early Career Fellowship at Milano-Bicocca. We spoke with her to discuss the team’s work and the future prospects it opens up.
Dr. Krenn, your research focuses on creating a 3D brain organoid model aimed at replicating the key aspects of the antero-posterior polarity of the human cerebral cortex in vitro. Why is this aspect so crucial?

First of all, it’s important to understand that organoids are cellular models entirely developed in the lab, offering the enormous advantage of providing access to human tissue. In the case of brain organoids, they allow us to study aspects of the human brain that would be otherwise unfeasible with animal models. Their accessibility, due to the fact that they can be cultured for scientific purposes, enables us to combine them with other technologies and conduct various research activities. This opportunity is particularly valuable because brain organoids are highly simplified prototypes of what an early-stage developing brain might be like. They replicate some aspects quite well, such as the presence of neural stem cells and cortical neurons, while others are less faithfully reproduced.
One of the aspects that could not be comprehensively replicated until our research concerned the antero-posterior polarity. The cortex is a crucial part of the human brain that has significantly expanded over the course of evolution, developing more notably in humans to support different and high-level functions. For instance, think of language, writing, the ability to use tools, or play a musical instrument, just to name a few examples.
What were the key points of your research?
We know that the process leading to functional separation in the human cortex begins at the earliest stages of development, with the definition of distinct regions. Even in the initial phases of cerebral cortex development, domains form and organize according to a specific arrangement. This is referred to as antero-posterior polarity, an organization that encompasses a frontal zone, a posterior zone, and lateral parts as well. This aspect is crucial because it underpins our functional capabilities. It’s also known that this mapping is orchestrated by specific signals known as morphogens, which are produced in a controlled manner. These signals then diffuse through the tissue and indicate to the cells which types of areas they belong to. To understand this early development, we focused on recreating the antero-posterior map using brain organoids, concentrating specifically on the controlled action of these morphogens, which is a very complex aspect. We succeeded thanks to a key insight: generating cell aggregates capable of producing a specific signal known as FGF8. Once we understood that the signal was being produced, the next step was to integrate it with the organoid to create a prolonged source of signalling, allowing for the definition of various areas over time. Another crucial aspect of our research involved the structure of cortical organoids. Traditional organoids are spherical in shape; we noticed that when using these, the signal acted uniformly. The system worked, but it wasn’t able to specify the areas in distinct ways. This led to a second important insight, creating elongated organoids. This allowed the signal to act over a greater distance, and by developing an elongated structure, the signal was perceived differently: stronger at the front and weaker at the back. It was observed that the cells formed in this manner exhibited different characteristics depending on the zone, much like in the human cerebral cortex.
What will the next steps be?
There are at least two: improving the model and starting to use it right away. Firstly, what we have developed so far is a rough map, an approximate model. While we have managed to establish an antero-posterior polarity, there are actually many nuances involved. The next phase of our work will focus on optimising the level of resolution to get as close as possible to replicating the real model. The second step involves using the model and the information it provides to determine whether the process centred around the formation of the polarity axis could be useful for studying diseases, particularly neurodevelopmental disorders that emerge in the earliest stages of life. This broad spectrum includes conditions diagnosed in early childhood and even in adulthood: autism, attention deficit hyperactivity disorder (ADHD), language disorders, dyslexia, dysgraphia, and dysorthography. While there is a genetic component at play, it remains unclear whether these alterations are linked to issues with polarisation. In our research, using the model we developed, we identified one of the key factors involved in creating this cortical map: the FGFR3 gene, mutations of which cause a skeletal disorder known as achondroplasia. We focused on this gene because it showed a clear polarisation in our organoid model. However, we found many other genes with similar patterns, also associated with various diseases, suggesting they might play a role in this process. We aim to study and leverage the model by combining it with genetic modifications to explore whether these very early alterations at the polarisation axis level could partially explain the functional relationships observed in patients with such conditions.
Your research seeks to clarify some of the processes related to the human brain, which has long been studied. How much do we currently understand about its functioning, and what is the level of knowledge we have?
Extensive research continues on the human brain, and at the same time, new technologies have emerged that allow us to associate brain activities with various aspects of human life, from health status to emotional state. This provides us with valuable insights into the brain’s plasticity and complexity. However, for a long time, there were no experimental models available for genetic manipulation. Since 2013, with the advent of organoids and similar technologies, we can now study these early life stages in vitro with much greater detail. These stages are crucial not only because they lay the foundation for the future – helping us understand what will eventually become the adult brain – but also because they can offer information and insights into the logic of this process, which can then be applied to understand the development of certain diseases, especially neurodegenerative conditions.
Is there a possibility that research on brain organoids could lead to the development of replacement cells for the cerebral cortex?
Yes, this approach to cell therapy, specifically in terms of cell replacement, is already being explored. One area where this technology is being applied is in Parkinson’s disease, where the use of neural stem cells is being trialed with the aim of restoring functions lost due to neurodegeneration. Naturally, before any form of therapy can be implemented, extensive work is needed to standardise protocols and precisely characterise the activities involved in a potential treatment. It is also necessary to deepen our understanding of this and similar conditions. In any case, organoids are not just a source of study and knowledge but also a potential source of cells that could be utilised. The potential is certainly there, but the path forward remains a long one.
Regarding ethical considerations, what restrictions have been established for research on organoids?
If we are talking about privacy, it is a fundamental requirement. The cells used in the laboratory are anonymised, meaning we do not know the identity of the donors and would never be able to trace any sensitive information. An ethical question arises around “how far can we go in studying and applying these organoids?” From our perspective, we are working with extremely early developmental stages, where the neurons produced are very minimally active. That said, there could be potential in the future to achieve a more advanced level of maturation. However, we are talking about a collection of cells that lack self-awareness and any consciousness of the world. They respond to biochemical stimuli, but not in a behavioural sense; they are essentially just a mass of cells. Thus, I believe the most appropriate classification would be as non-sentient models. The focus of my lab is on understanding how neurons are generated, but there is also an effort to use these models to study how neurons communicate with one another and what rules govern their communication. Significant work is being done in this direction as well. Many labs are developing various techniques involving the use of chips, robotics, or artificial intelligence approaches. Essentially, researchers from different fields are trying to uncover these communication rules. However, they still remain a mystery.
Is there, then, the idea of using these types of cells for the development of future neuromorphic computers?
I think it’s quite a remote possibility. I can imagine the concept of capturing signals generated by neurons and somehow using them to instruct a machine, but as a neuroscientist, even we don’t fully understand what these signals represent. We might be able to define them chemically, but translating them into a specific task is beyond our current capabilities.
What will be the future impact of research on brain organoids?
The hope is that one day we will be able to rely on targeted therapies for individual patients, thanks to organoid models constructed in the laboratory. This means not only contributing to therapeutic advancements but also making a significant impact on personalised medicine. Today, certain conditions are classified under a single name, yet they actually encompass a variety of very different clinical presentations. We need to reach a level of precision that allows for targeted treatment for each patient.
Glimpses of future
The new 3D brain organoid model offers valuable insights into the human brain and related disorders, providing a technology capable of delving into gene-disease mechanisms and understanding how risk factors contributing to mental health conditions might disrupt these essential processes. However, while significant, this is only an initial step toward more effective understanding and treatment of the body’s most complex organ.
To anticipate potential future scenarios, let’s analyse the impacts of advancements in brain organoid research using the STEPS framework, considering social, technological, economic, political, and sustainability dimensions.
S – SOCIAL: The application of brain organoids and related research provides a promising tool for studying autism spectrum disorders and for understanding and addressing complex neurological and psychiatric conditions such as Alzheimer’s, Parkinson’s, autism, schizophrenia, and epilepsy. Modelling the development of brain disorders in a controlled environment will enable faster drug discovery and advancements in personalised medicine. The organoid approach, more broadly, holds enormous potential for advancing basic research, drug screening, and cell therapy aimed at treating injuries or neurodegenerative conditions. These developments could significantly improve treatment options and quality of life for millions of people. According to a study published this year in The Lancet titled “Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021”, more than three billion people worldwide lived with a neurological condition in 2021. Today, neurological conditions are the leading cause of poor health and disability globally [source: World Health Organization]. This situation highlights a major social disparity. Over 80% of deaths and health losses due to neurological causes occur in low- and middle-income countries, where access to care varies significantly. The same World Health Organization report indicates that high-income countries have up to 70 times more neurologists per 100,000 people compared to low- and middle-income countries. Addressing these inequalities through advancements in research and technology, such as the use of brain organoids, could help close the gap in access to neurological healthcare and improve outcomes for populations worldwide.
T – TECHNOLOGICAL: as Veronica Krenn mentioned, the advancing development of brain organoids is poised to intersect with other highly innovative fields, including electronics, robotics, and artificial intelligence (AI). The potential for growth in these areas is varied and intriguing. An illustrative example is the study “Brain organoid reservoir computing for artificial intelligence“, published in Nature Electronics, which demonstrates the possibility of linking brain organoid tissue to a silicon chip and training the resulting tiny biocomputer with AI. The research team behind this approach suggests that brain-inspired chips have significant potential for the creation of future supercomputers. Combining brain organoids with AI could lead to breakthroughs in understanding neural network functioning, while also inspiring new architectures for computational systems. Such hybrid systems, leveraging biological and digital components, might offer superior processing capabilities, potentially transforming fields like data analysis, robotics, and machine learning. These developments could also pave the way for more sophisticated neuroprosthetics and brain-machine interfaces, pushing the boundaries of human-machine interaction.
E – ECONOMIC: the use of brain organoids could play a crucial role in studying the progression of neurodegenerative diseases, facilitating early diagnosis and prevention, thus reducing the burden on healthcare systems. It is estimated that the total cost of mental health conditions now exceeds 4% of GDP (over 600 billion euros) across the 27 EU countries and the UK [source: Health at a Glance – European Commission]. Globally, around 14% of healthcare spending is linked to neuropsychiatric disorders. In developing countries, approximately 75% of people with mental health issues receive no treatment at all [source: Epicentro – Istituto Superiore di Sanità]. By 2030, the global cost of mental health conditions (and their consequences) is projected to rise to $6 trillion, up from $2.5 trillion in 2010. This will make the cost of poor mental health higher than that of cancer, diabetes, and respiratory disorders combined [source: World Economic Forum]. Brain organoids have the potential to significantly reduce these economic impacts by improving the understanding of mental and neurological conditions, leading to more effective treatments and preventive measures. This, in turn, could help mitigate the escalating costs associated with long-term care and disability, as well as lost productivity, ultimately contributing to a more sustainable healthcare economy.
P – POLITICAL: the future use of organoids will necessitate stringent regulation and standardisation of protocols. It will also be essential to ensure that the sourcing of biomaterials for deriving stem cell lines is conducted in accordance with current ethical standards. Even today, the use of organoids raises ethical concerns. To address these, the European HYBRIDA project has been launched, set to conclude in 2024. The project’s research partners have established operational guidelines for organoids and related technologies, along with a Code of Responsible Conduct for researchers working in this field. This code is currently being implemented by the European Bank for Induced Pluripotent Stem Cells. Additionally, the project team has developed a supplement to the European Code of Conduct for Research Integrity, incorporating the ethical dimensions of organoid-based research and related technologies. These efforts aim to provide a framework for navigating the ethical and legal challenges associated with this rapidly evolving field. Ensuring that ethical standards keep pace with technological advancements will be critical to building public trust and securing support for further research. Policymakers will need to engage with scientists, ethicists, and the public to develop guidelines that both encourage innovation and protect against potential misuse.
S – SUSTAINABILITY: the potential for brain organoids to facilitate personalised and targeted medicine in the future could help avoid escalating costs to healthcare systems, thereby supporting economic sustainability. In addition, there would be positive environmental implications if this approach can significantly reduce the overproduction of pharmaceuticals and the associated disposal of unused medicines, which often end up in wastewater, causing chemical pollution. The presence of pharmaceuticals in the environment is already a global issue. According to a global review commissioned by the German Ministry of the Environment in 2014, out of 713 drugs selected for the study, 631 (or their metabolites/transformation products) were found in concentrations above detectable limits in 71 countries worldwide [source: Agenzia Italiana del Farmaco].