Building human induced neural circuits to study Parkinson’s disease BRAIN ON A CHIP
Parkinson’s disease
Parkinson’s disease is a progressive brain disorder that affects more than 6 million people worldwide. This includes over 700,000 people in the USA, a num ber expected to increase to 1.2 million by 2030. The disease mainly causes motor symptoms, including tremor and slowness of movement. In addition, it is estimated that 75% of advanced Parkinson’s patients will also develop dementia.
The global economic cost of Parkinson’s is significant. In the USA, the combined direct and indirect cost of Parkinson’s, including treatment, social security payments and lost income, is estimated at around $52 billion every year.
The currently available treatments to control Par kinson’s symptoms, such as the drug L-DOPA or deep brain stimulation, only offer temporary relief and do not affect the course of the disease. Curative treatments against Parkinson’s disease remain one of the world’s largest unmet medical needs.
The challenge
Progress in Parkinson’s disease research is hampered by three major hurdles.
We have very limited access to human brain tissue.
of the dopamine neurons have already died. To un derstand disease progression, we need to have a new diagnostic tool and be able to study the vulnerable brain areas before any damage occurs.
Unlike in oncology or immunology, we do not have access to primary diseased tissue. Human brain tissue is usually only available post-mortem, which provides only a snapshot and often in end stages, when we can no longer observe the processes that have triggered and driven the disease.
We lack reliable, reproducible and patient-specific disease models.
Diagnosis today happens too late, when important brain regions are already irreversibly damaged.
Parkinson’s disease is currently diagnosed based on clinical symptoms, which only appear when 50-60%
In Parkinson’s disease, specific brain networks show abnormal activity, which can only to some extent be modeled by experimental systems. Current research models are valuable but have limitations: preclinical models do not mimic all aspects of human cells and human disease, while patient-derived cellular models usually do not reflect the variety of cell types and functions in the living brain.
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Our solution: creating a brain on a chip
Our aim is for Parkinson’s to be objectively defined by solid molecular criteria, rather than by the clinical criteria that are currently used to diagnose the dis ease. This will mean scientists can develop targeted medical interventions that effectively slow down or even stop the disease based on molecular and genetic pathways. With your support, we aim to create a brain on a chip for Parkinson’s disease. This will be a cellular model that uses patient cells to re-construct the disease-relevant neuronal networks of a living human brain. This is how it works:
samples are available through Stanford Universi ty’s Pacific Udall Center and Alzheimer’s Disease Research Center (ADRC), which house some of the highest-quality Parkinson’s disease cell banks in the USA. Different cell types will be generated using spe cific proteins that guide gene expression (‘transcrip tion factors’). This way, the cells donated by patients can become dopaminergic, cortical or medium spiny neurons.
1 We know that Parkinson’s disease affects specific parts of the brain, notably the striatum, and we know which brain cells are affected: dopaminergic, cortical and medium spiny neurons.
2 We want to re-create these brain cell types from skin biopsies of patients with Parkinson’s. The human
3 Our strategy is unique and distinctive: we plan to induce the differentiation of patient-specific cells at predefined locations step-by-step on a microchip, to grow the specific brain circuits that are affected in Parkinson’s disease.
4 Moreover, the 16.384 electrodes on the chip form a ‘multi-electrode array’ (MEA) and will allow us to measure and manipulate the electrical activity of individual cells in the circuit, which gives us a lot of information about their function.
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5 When we re-create brain cells from the patient skin cells, the cells are ‘re-set’. This gives us the op portunity to look at events that occur before the onset of disease, and to test experimental therapeutics.
6 The system will also make it possible to compare the brain cell networks derived from tissue donated by patients versus healthy people, so that we can find out what exactly goes wrong in the early stages of disease.
7 Finally, based on the individual molecular and functional signatures recorded by the chip, we aim to subdivide Parkinson’s patients into different groups (known as ‘stratification’), and this both for familial (inherited) and non-familial cases. There are more than 20 known familial causes for Parkinson’s, and a drug that may be extremely effective for one variation, may not work for others. This effectiveness would only become clear when tested against the specific variation for which it is suitable – an outcome that could be masked in experiments using unstratified tissue samples.
In brief, with brain on a chip, we aim to provide:
• A reliable, patient-specific model of Parkinson’s disease.
• A map of Parkinson-specific disease signatures for drug screening and patient subgrouping.
• A robust, multimodal recording system to generate, manipulate and measure human cell networks.
The new tool and patient subgroups should allow us to test new, personalized therapeuties. It can also be relevant to other neurodegenerative diseases such as Alzheimer’s and amyotrophic lateral sclerosis (ALS, also known as motor neuron disease or MND).
To catalyze worldwide progress, we intend to share our tool with research groups across the globe.
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A glimpse into the future: 3D human brain reactors
Our first chip serves to gain crucial insights in what goes wrong in different forms of Parkinson’s disease, but we aim to go much further than that.
In a next step, our goal is to develop an even more advanced, 3D version of the chip, by integrating
multiple layers of perforated 2D chips. This would better mimic the brain’s architecture and give us the relevant information needed to develop a more profound understanding of Parkinson’s disease. Our anticipated 3D chip will be compatible with organoids and other cell cultures.
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Current status of the project and outlook
Thanks to the support of the Chan Zuckerberg Initiative and several other philanthropic donations, the project got kickstarted and our team worked hard to successfully develop the first prototype of the 2D brain on a chip.
We developed lab protocols for the generation of the three neuronal cell populations typically involved in the neural circuits affected by Parkinson’s disease (cortical, striatal and ventral midbrain neurons). We managed to grow these cell types via on-chip electroporation from human induced pluripotent stem cells (hiPSCs). To be able to distinguish each cell type in experiments, we applied a genetic labeling system based on fluorescent reporter proteins. Our protocols are made available within the CZI Neurodegeneration Challenge Network (NDCN).
Our first recordings with the MEA chip show that the three Parkinson-relevant cell types grown on the chip are structurally and functionally connected and have normal electrophysiological activity. So far we have been building networks with hiPSCs from
healthy control lines. Later on, we will include cells from patients with familial Parkinson’s, which express disease-causing genetic mutations and risk genes.
We are currently evaluating the technical and biological variability of the neural circuits. We started to define the electrophysiological phenotypes of five genetically characterized subgroups of sporadic Parkinson’s patients, to develop a high-throughput screening platform for patient profiling.
In parallel, we are making the first preliminary design and fabrication of the 3D brain on a chip.
2020
First 2D brain on a chip prototype
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Our roadmap People with Parkinson’s disease Skin cells and induced pluripotent stem cells On-chip differentiation Data analysis and cloud computing Patient subgroups Personalized therapies Data acquisition to define disease signatures Potential biomarkers and drug targets On-chip preclinical trials Brain-on-a-chip team Collaborative effort within scientific community - sharing tools & data 9 Reproducible neural networks on the chip (healthy controls) 3D MEA chip and re-created biological models of PD 2021 2022 2023 2024 Reproducible neural networks on the chip (PD patients) High-throughput screening platform and patient profiling (subgroups)
Our interdisciplinary team of experts
Prof. Dr. Patrik Verstreken (VIB-KU Leuven, Belgium) is director of the VIB Center for Brain & Disease Research. He is the recipient of several prestigious European awards, including Marie Curie Excellence, ERC Starting and ERC Consolidator grants and the international IBRO-Kemali Prize. He obtained his PhD at HHMI/Baylor College of Medicine, Houston and conducted research for nine years in the USA.
Prof. Dr. Birgitt Schuele (Stanford University School of Medicine, USA) is Associate Professor at the Department of Pathology and co-head of the Udall Analytical and ADRC Neuropathology Cores. She completed her Dr. med in Germany, followed by a neurology internship during which she studied the genetics of Parkinson’s disease and dystonia, and a postdoctoral fellowship in human genetics at Stanford University School of Medicine.
Our team also started a new collaboration with Dr. Cagla Eroglu (Duke University, USA) within the CZI Neurodegeneration Challenge Network to additionally investigate astrocytes in our brain-on-a-chip tool.
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Dr. Dries Braeken (imec, Belgium) received his PhD in Medical Sciences from KU Leuven, in collaboration with imec, in 2009. Since 2017, he has been group leader and R&D manager in the Life Science Technologies department at imec. His research focuses on the development and validation of silicon technologies for cell and tissue interfacing in healthcare applications.
Prof. Dr. Wim Vandenberghe (UZ Leuven, KU Leuven, Belgium) is neurologist and heads the Movement Disorders Clinic in Leuven. Each year, about 1,000 patients with Parkinson’s disease visit his clinic in Leuven for diagnosis and treatment. Previously, he was a visiting research fellow at the University of Chicago, postdoctoral fellow at the University of California at San Francisco (UCSF), and visiting neurologist at the USCF Movement Disorders Clinic. He now leads a research group that investigates the molecular pathogenesis of Parkinson’s disease, aiming to identify new therapeutic targets.
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Watch a video of Dr. Braeken demonstrating brain on a chip
Further reading
• https://www.imec-int.com/en/articles/how-chip-technology-will-decipher-brain-diseases
• Miccoli et al. 2019 (Frontiers in Neuroscience) High-Density Electrical Recording and Impedance Imaging
With a Multi-Modal CMOS Multi-Electrode Array Chip
• Miccoli, Braeken & Li 2018 (Current Pharmaceutical Design) Brain-on-a-chip Devices for Drug Screening and Disease Modeling Applications (review article)
For the latest overview of our
How others describe our impact
Brain on a chip is a transformative, multi-disciplinary and international collaboration to approach next generation experimental research for Parkinson’s disease. This project will give us deeper insight into functional network changes of the brain, that will allow us to develop new therapies.
Dr. J. William Langston
Clinical Professor, Dept. of Neurology & Neurological Sciences, Stanford University
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publications, go to www.missionlucidity.com/publications
We are incredibly grateful to our growing international network of donors, in partnership with nonprofit organization Amici Lovanienses.
A big thank you to everyone who believes in our project, helps us moving forward and participates in this joint effort towards a future without Parkinson’s disease.
amicilovanienses.org
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The brain on a chip has the potential to become a standard research instrument that could open up new avenues that we don’t even know exist today.
Read the full interview
Wim Roelandts engineer, Parkinson’s patient and supporter of the project
About Mission Lucidity
Founded in 2018, Mission Lucidity is a partnership between four research institutes in Leuven, Belgium: imec, KU Leuven, University Hospitals Leuven (UZ Leuven) and VIB.
By leveraging the expertise of engineers, clinicians and scientists, combined with the backing of visionary donors, we aim to develop game-changing, scalable technology platforms and tools for neurodegeneration research. This will give the scientific community at large a unique opportunity to deliver scientific and medical breakthroughs.
Our projects adopt a multi-angle approach: from zooming in on the cellular and intracellular level via technology development at nanoscale, to studying biomarkers and disease mechanisms in humans.
Ultimately, our transformative technologies will allow us to answer longstanding questions and better understand, predict, diagnose and treat neurodegenerative diseases.
Visit www.missionlucidity.com/research to learn more about our projects.
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Vascularized chip-based brain organoids
Towards improved and humanized disease models
Personalized genetic risk profile
Translating individual risk to disease phenotypes and prevention
A human brain on a chip
Re-creating neural circuits to stratify patients and identify new drug targets
Non-invasive transcranial electrical stimulation
Stimulating the brain to preserve cognitive function
Detecting disease by retinal imaging
The eye as a window to the brain: early biomarkers in the retina
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