The human brain is unique in many ways, but perhaps the most obvious difference compared with other primates is its size. How the human brain gets to be so large during development specifically in humans is a question that has long intrigued neuroscientists but until recently was difficult to study. Now, using in vitro models of developing brain tissue called cerebral organoids, or brain organoids, we are examining the cell and molecular mechanisms that drive human brain enlargement.

Using these organoids, we have recently demonstrated the production of cerebrospinal fluid (CSF), just like in the actual developing brain, and we discovered that the CSF of brain organoids is highly similar to actual CSF. Excitingly, we identified a number of growth factors and other secreted factors that may influence the surrounding brain tissue, but exactly how and whether this may be different in humans is still unclear. This PhD project will examine just that, but investigating the effects of these identified growth factors on developing cerebral cortical tissue. The student will generate brain organoids, apply various candidate factors, and different time points and examine the effect on neural stem cells and the production of neurons. The project will also involve comparative studies across different primate and rodent organoids to see if these secreted factors could be responsible for some of the enlargement we see in human organoids and in the human brain in vivo.

This project offers the opportunity to learn cutting edge methods in stem cell biology, neuroscience, next generation sequencing methods like single cell RNA-seq, and cell biology. The student will be integrated in a supportive mid-size lab with other PhD students and postdocs exploring various aspects of evolution and development using exciting imaging methods, electrophysiology, and bioengineering approaches.

References

Benito-Kwiecinski S, Giandomenico SL, Sutcliffe M, Riis ES, Freire-Pritchett P, Kelava I, Wunderlich S, Martin U, Wray G, McDole K, Lancaster MA. (2021) An early cell shape transition drives evolutionary expansion of human forebrain. Cell 19:S0092-8674(21)00239-7.

Pellegrini L, Bonfio C, Chadwick J, Begum F, Skehel M, Lancaster MA. (2020) Human CNS barrier-forming organoids with cerebrospinal fluid production. Science 10;369(6500).

Lancaster MA, Renner M, Martin C-A, Wenzel D, Bicknell LS, Hurles ME, Homfray T, Penninger JM, Jackson AP, Knoblich JA. (2013) Cerebral organoids model human brain development and microcephaly. Nature 501(7467):373-9.