The original ‘aha’ moment for me was when I ran into Hagan Bayley at a 3D printing workshop at Oxford. We started talking over beer while we waited for them to get the projector to work!
I was there to 3D print neurons out of plastic to show my students their size, shape and structure and he was looking for someone to print live 3D neurons with. I was studying subventricular zone cells (SVZ), which are stem cells that continue to make more neurons in the adult brain, one of the exceptions Zoltan referred to earlier. I told him my SVZs were very robust in vitro and could be collected and manipulated, so very soon after we started a few pilot experiments and got a John Fell grant. I’ve been developing the technique to 3D print viable human neural stem cells with the Hagan Lab for a number of years now and we recently published a paper discussing how they yield important insights into human cerebral cortex development - “Lipid-Bilayer-Supported 3D Printing of Human Cerebral Cortex Cells Reveals Developmental Interactions” in Advanced Materials.
However, SVZ cells migrate to the ‘olfactory bulb’ in the brain, which is an ancient part of the brain involved in the sense of smell. I reasoned that we should instead look at the cerebral cortex, which is functionally the most important part of the human brain for regulating who we are as individuals. If you kill your cerebral cortex, you lose your ability to organise your life and to remember, but nobody at the time was recreating the layers of the cerebral cortex. Others have grown cerebral organoids or ‘mini brains’, as Zoltan said, but the cells are all higgledy-piggledy and do not refelect the layered cortical columns necessary for proper cortical functioning.
I realised that we could actually print human neurons from hiPSC in these columnar layered organisations and then use them for two things. One, to better understand human cortical development, as we know a great deal about how the mouse brain develops but relatively little about how human brain cells develop, and make these layered columns. Two, and I have to give a lot of credit to Hagan Bayley for this realisation, was to understand whether we could use these layered cortical columns for functional recovery in conditions such as Alzheimer’s disease, traumatic brain injury or stroke. I also realised that DPAG happens to have one of the world’s experts in the development of the cerebral cortex and that’s Zoltán Molnár!
For the last 30 years I’ve been studying how cerebral cortical neurons are born, migrate and interconnect and how you affect their circuitry if you change their position. I’m interested in the understanding you can generate with this printing: how different proportions of cells self-organise into functional units. Even better if we can then implant these and find they work better than normal unorganised stem cell mixture.
I was initially sceptical, but there are so many limitations to the conventional methods growing organoids, or ‘mini brains’, you have to give another approach a shot, no matter how futuristic.