What are you trying to do with the human brain cells you are working with?
In short, we are trying to model Alzheimer's disease in a dish. Conventionally, researchers have been using animal or cellular models with rare Alzheimer's disease gene mutations to improve our understanding of the disease. That has given us invaluable information, but the mutations only represent about 1% of the Alzheimer's patient population. Here, in the dementia stem cell study I'm working on, we'll be working with samples from 14 Alzheimer's patients who do not have a family history of Alzheimer's disease, comparing the characteristics of their brain cells to their actual clinical symptoms.
Studying living human brain cells in a dish is potentially a game-changer for dementia research. I work on a stem cell study into Alzheimer's disease in which we've developed living brain cells from the blood samples of volunteers who took part in a cohort study. To our knowledge, we're one of the first labs in the world to take this approach - it's an extremely exciting study to work on. - Bryan Ng, postdoctoral researcher in the Wade-Martins lab, University of Oxford
How have you been able to study living human brain cells?
Using a complicated set of techniques involving many different collaborators. Firstly, we took blood cells from 14 Alzheimer's patients from the Deep and Frequent Phenotyping (DFP) study pilot cohort and turned those cells into pluripotent stem cells in a dish. Pluripotent stem cells are 'embryonic' stem cells that can be developed into any type of cell in the body. This process of creating pluripotent stem cells, established by Shinya Yamanaka from Kyoto, Japan, is called 'reprogramming', and it won the Nobel Prize in 2012. We then guide these cells with a carefully designed protocol over 80 days so that they become brain cells.
Once we have these brain cells, we then conduct various experiments and the results could potentially show us how this disease develops in the individual people. We'll then compare these results to these patients' individual clinical tests for interpretation and modelling.
What are the next steps for you?
We are currently at the stage of setting up these experiments. Obviously, COVID-19 does affect our work – however, as soon as we can, we will start the derivation of brain cells for all 14 patients in parallel for various experiments in three collaborating labs in Oxford.
For example, we'll use a high-content automatic imaging microscope called the Opera Phenix for detailed visualisation and quantification of the connections among brain cells. This can then be complemented with real-time measurement of active brain cell firing with a method called multiple-electrode array experiment. We'll compare these results to cognitive tests or brain wave measurements in the clinic. In addition, we are going to go one step further to interrogate the details of our findings with transcriptomics and proteomics – probing every gene expression and protein production respectively in these brain cells. The resulting data can then inform us how the genetic and protein expression profiles of these brain cells relate to the individual patients.
What do you expect to find?
These brain cells derived from the cohort volunteers' blood cells have provided us with an unprecedented opportunity to investigate Alzheimer's disease in a dish in extraordinary detail, while at the same time drawing corresponding information from clinical tests. However, these brain cells are ultimately not the real mature cells in the brains of Alzheimer's patients. We therefore do not expect the brain cells in a dish to mimic exactly the clinical progression of the patients.
Despite the technical challenges we face in this work, we hope to discover certain aspects of these brain cells that do correlate well with the clinical manifestations of these patients. Once we achieve that, even with just a single but reproducible trait, the clinical implication will be extremely significant. We can't experiment on human patients, and clinical trials just for a single drug are costly and require many years of effort. In contrast, with the techniques we're refining, we can experiment on brain cells derived from Alzheimer's patients and we can scale it up to screen many drugs in multiple patient brain cells at one go.
Bryan Ng works on the DPUK-funded experimental medicine study into clinical and cellular features of Alzheimer's disease.
Researchers in Bryan's lab are also working on studies into repurposing existing drugs for dementia research.