Why do we need brain organoids?
Over eight million people were living with Parkinson’s disease in 2019, with over one million new cases annually; a number that continues to rise. The immense physical and emotional burden patients and carers face has driven the search for different lab-based approaches that directly tackle the complexities of the human brain head-on.
The human brain comprises many different cell types that interact to form elegant structures involved in essential tasks, from electrical signaling to dopamine release and thought itself. This cellular and structural complexity makes it challenging to investigate neurological disorders with animals or traditional cell models, like neurons grown flat in a dish, especially when testing potential therapeutic compounds.
While these approaches remain powerful tools for investigating many human disorders, they often fail to recreate the constellation of cell types, structures, and symptoms present in the human brain. “It’s not very accurate to model Parkinson’s disease using animal models because, often, they don’t recapitulate the symptoms that humans have,” explains Sònia Sabaté Soler, Ph.D. neurobiology and project manager at OrganoTherapeutics, a spin-off company from the laboratory of Professor Jens Schwamborn at the Luxembourg Centre for Systems Biomedicine, the University of Luxembourg.
However, it’s now possible to overcome the hurdles faced with traditional methods thanks to advances in brain organoid technology, where the intricate structures and cell-to-cell interactions seen in the human brain can be recreated in miniature.
What’s in a brain organoid?
Early studies allowed brain organoids to grow without being pushed to resemble a particular region. But as different neurodegenerative disorders affect different brain regions, researchers began to develop techniques to instruct brain organoids to resemble specific areas, such as the forebrain, hindbrain, and, in the case of Professor Schwamborn and colleagues, the midbrain. “Since the midbrain is the area of the brain that’s most affected by Parkinson’s disease, midbrain organoids are a great system to recreate Parkinson’s disease in a human model,” highlights Sabaté Soler.
“Since the midbrain is the area of the brain that’s most affected by Parkinson’s disease, midbrain organoids are a great system to recreate Parkinson’s disease in a human model”
The midbrain organoids made by Professor Schwamborn and colleagues include cell types such as microglia, astrocytes, and large numbers of dopaminergic neurons that are not always present in other regions. Importantly, the selective death of these dopaminergic neurons in the midbrain of Parkinson’s disease patients contributes to motor deficiencies faced by patients.
Scientists have now used these models of specific brain regions to provide insights into the molecular changes occurring in conditions like autism, Alzheimer’s disease, Parkinson’s disease, and glioblastoma.
A personalized approach for broad insights
As with many other neurological disorders, Parkinson’s disease varies from person to person, so the advantages of the midbrain organoid system also stem from the personalized nature of the approach. For instance, OrganoTherapeutics mostly works on genetic mutations that lead to Parkinson’s disease.
As Sabaté Soler explains, patients with the same mutation often have similar symptoms. But similar symptoms can also occur in patients with other, unrelated mutations, providing a complex picture of the disease. By modeling the effects of different mutations with midbrain organoids in the lab, broad phenotypic insights can be gained from many individuals to eventually help classify patients who might or might not respond to particular therapeutics.
Sabaté Soler highlights that the process starts with a simple skin biopsy sample from any healthy individual or Parkinson’s disease patient. The scientists then ‘reprogram’ these skin cells into cells that can turn into any other cell in the body called induced pluripotent stem cells (iPSCs). A subsequent reprogramming step then instructs these iPSCs to become brain cells similar to those present at the beginning of brain development. Researchers use a combination of different chemical compounds and supplementation of the cell culture media to do this. Finally, a scaffold is added to these cells to encourage them to make a 3D ball of cells no larger than two millimeters. This personalized approach means that the resulting midbrain organoids are genetically identical to the initial donor.
Exciting opportunities for novel treatments
Once grown, these midbrain organoids drive Parkinson’s disease research by replicating healthy brain development or disease pathology, as Sabaté Soler explains: “You can compare healthy and Parkinson’s disease midbrain organoids to see which cells are degenerating, what is happening with these cells, and how other cells in the brain react to this at the cellular and molecular level.” The researchers can also treat the midbrain organoids with potential therapeutic compounds to detect any molecular effects of the drug on cells or how they function. These changes are investigated under a microscope or with next-generation sequencing-based approaches to see which cell types or genes are affected.
“You can compare healthy and Parkinson’s disease midbrain organoids to see which cells are degenerating, what is happening with these cells, and how other cells in the brain react to this at the cellular and molecular level.”
Currently, most therapeutics aim to balance neurotransmitters with dopamine analogs because dopamine-producing neurons are already degenerated in Parkinson’s disease patients. However, this approach only treats the symptoms of Parkinson’s disease and doesn’t address the root cause of many aspects of motor and non-motor problems faced by patients due to neuron loss. In the future, it might be possible to study and even treat this neuronal degeneration before the onset of symptoms. “Our idea is to, at some point, treat Parkinson’s disease much earlier to try to avoid this neurodegeneration and to try to give patients a longer and better quality of life,” says Sabaté Soler.
The challenges ahead
An increasing number of disorders are now known to involve the communication between multiple organs like the gut and the brain. While organoids are arguably the closest we have come to replicating human physiology in the lab, they lack the interactions or cellular components like blood vessels necessary to inform on the whole system. “You cannot compare an organoid to a full organ because you’re lacking the communication with other organs,” says Sabaté Soler. As gut and vasculature issues are linked to neurological disease, new models including these aspects will be important in the near future.
Researchers are now turning to ‘assembloids’ where different organoid models are combined to create mini systems that recreate combinations of organs like the gut-brain axis or the blood-brain barrier. “If you can connect many organs, you can more accurately recapitulate disorders and therefore more accurately treat or find therapeutics,” emphasizes Sabaté Soler.
“If you can connect many organs, you can more accurately recapitulate disorders and therefore more accurately treat or find therapeutics.”
Luxembourg’s thriving life sciences ecosystem
Despite its small geographical area, Luxembourg packs a punch with its life sciences ecosystem and the support given to start-ups.
For now, OrganoTherapeutics is the only organoid-focused company in Luxembourg. As a consequence, it received help from the University of Luxembourg and the Luxembourg Center for Systems Biomedicine to get started, says Sabaté Soler.
While this means that OrganoTherapeutics’ collaborations within Luxembourg are largely with public entities, their collaborations extend to the USA and Japan, reflecting a global mindset that is commonplace in the Luxembourg life sciences ecosystem.
* Photo: An immunofluorescence image of a midbrain organoid. Dopaminergic neurons important in Parkinson’s disease shown in green. Image courtesy of OrganoTherapeutics.
