Organoid models for understanding and treatment of disease

Organoid models for understanding and treatment of disease

Reported by Jacob Bradbury, CSaP Policy Intern (April-July 2024).

Members of CSaP's Horn Fellowship gathered together at Downing College, Cambridge to explore the exciting area of organoids, biological models that aid the understanding of human development and disease with Professor Madeline Lancaster, MRC Laboratory of Molecular Biology. The Horn Fellows - named in honour of the late Professor Sir Gabriel Horn - are a small group of supporters who are committed to the Centre's mission: to help public policy making address the major challenges of the 21st century.

Introduction to organoids

To begin, Professor Lancaster introduced organoids to the group. Organoids are miniature 3D models of organs that can be grown in the lab and used as models in research. Organoids are made from induced pluripotent stem cells, a type of cell formed by reprogramming normal cells that has the potential to differentiate into specialised cells. Organoid models can be developed of many different organs, but the Lancaster lab specialises in developing brain organoids. Professor Lancaster described how organoids filled a need for new biological models that are more similar to humans and could reduce the failure of drug candidates during clinical trials – referred to as the ‘valley of death’. This was especially important in neuroscience, where about 90% of drug candidates failed in clinical trials.

Professor Lancaster explained how organoids could be used to model both genetic diseases using cells collected from patients’ tissue such as skin, blood, or urine. However, as organoid technologies develop, modelling biological changes due to environmental factors is also possible. Since organoids are grown in the lab over a period of days, organoids are particularly suited to studying processes involved in development. However, organoids can also give us clues about diseases more commonly seen later in life such as neurodegenerative diseases, as even a 9-month-old brain organoid can show signs of Alzheimer’s disease.

A lot of the work in the Lancaster lab focuses on comparing the development of organoids derived from different species. Generally, the developmental process is very closely conserved between species, leading to a common organisation and complexity of brains. However, much of the functional differences between the brain of a species is down to size. Comparing the brain of humans and chimpanzees, Professor Lancaster stated that “If a chimpanzee had a brain that was twice its size it would be sat here having this conversation with us!” Other differences between species could often be explained by the rate of brain development. Generally, the slower the development the more advanced the cognitive ability, as reflected in humans whose brains are not fully developed until their third decade of life. Professor Lancaster also discussed some of the limitations to organoids models. For example, one limitation is the divergence between the models and their organoids after about seven weeks when development of blood vessels among the tissue would begin in humans or animals.

"If a chimpanzee had a brain that was twice its size it would be sat here having this conversation with us!"

Participants asked questions relating to the policy implications of organoids. Professor Lancaster spoke about how organoid models were changing the regulatory landscapes for drug development. For example, the new US Inflation Reduction Act has begun to lay the groundwork for using organoids instead of animal testing before drug candidates enter clinical trials. While Professor Lancaster believed that organoids were unlikely to completely remove the need for animals during drug development, this technology can certainly expedite this process. Professor Lancaster also argued that the UK was a perfect place to undertake organoid research because of its history of stem-cell research and its favourable regulatory environment.

Ethical implications of organoid use

Professor Lancaster discussed the significant differences between brain organoids and animal brains. A primary reason for these differences were due to the lack of development of blood vessels among the tissue which hindered full development. Brain organoids are simple models, they are not exposed to stimuli beyond the petri dish and don’t have any reinforcements to learn in the way that a human brain does. However, despite this simplicity, several studies have shown the ability of organoids to respond to simple electrical stimuli and show a response once the organoids are linked up to muscle tissue via a spinal cord. Professor Lancaster argued that the definition of consciousness was fuzzy, and that even responding to a stimulus was not proof of consciousness, but one step on a scale of cognitive ability usually proportional to the number of functional neurons.

Organoids have about 250,000 neurons which is about the same number as a fly, an organism commonly used for laboratory experiments without requirement for ethical approval. Conversely, a lot of actually conscious humans are suffering, and so Professor Lancaster argued that it was ethically wrong not use organoid models to try to reduce this suffering. What Professor Lancaster was more concerned about was the transplantation of these organoid brains into a live animal. This allows the organoid to become more like an animal brain, developing further and receiving sensory input which raised greater ethical concerns.

Drugs discovery using organoids

Finally, Professor Lancaster discussed how organoid models had been used in the development of treatments. Firstly, there were many examples of organoids being used in screens in drug development. Due to their small size and accuracy in modelling human disease, organoids were excellent tools for drug screening that could deliver highly relevant candidates at scale. Additionally, in the future organoids could potentially be used as the treatment themselves, being transplanted into patients like current organ transplants.

One exciting example of organoid screening during drug development was in personalised medicine for Cystic Fibrosis patients. Intestinal organoids were grown from patient derived stem cells and used to screen possible treatments. Any treatments shown to be effective in the organoid could then be used to improve symptoms in patients. A health policy participant emphasised the need for organoid experts to start speaking to policy makers so that the health system could prepare for these new technologies. Professor Lancaster agreed but warned that currently the development of personalised medicines would be prohibitive to run on a routine basis.

The passing of drugs across the blood brain barrier is a very challenging problem in drug discovery for neurological diseases. Professor Lancaster suggested a different solution may be to deliver drugs into the cerebral spinal fluid where they would then need to pass the cerebral spinal fluid barrier, a much easier challenge. Professor Lancaster’s group had developed a model of this barrier using organoids, and it could be used to screen drugs for their ability to pass this barrier, increasing their likelihood of success.

Professor Lancaster closed by situating organoids as a powerful tool in the research and treatment of human disease that could more closely mimic human disease than existing models and without the ethical implications of experimentation on animals. Overall, organoids were “another tool in the toolbox” for bringing new drugs to market.

Image by Ousa Chea on Unsplash.