Identifying the Cellular and Molecular basis of microcephaly and macrocephaly
Yasir Ahmed Syed's research is focused on uncovering the causes of microcephaly and macrocephaly in order to develop more effective treatments. The hope is to transform our understanding of human brain development in efforts towards developing more personalised medicine.
Human microcephaly and macrocephaly refer to neurodevelopmental conditions in which infants heads are markedly smaller or bigger as compared to babies of same age and gender. They are present at birth or can develop postnatally. Infants associated with these disorders are at greater risk for long term morbidity such as behavioural abnormalities, developmental delay, seizures, motor impairment and problems with eyesight and hearing.
What causes the peculiar pattern of brain growth is as yet un know, limiting the effort to develop the effective treatments. Subjects with gene dosage alterations either due to gains or deletions of genetic material at human chromosome 1q21.1 locus are strongly associated with micro or macrocephalus condition. The locus consists of several key genes such as HYDIN2, NOTCH2NL which have been suggested to control the brain size and proliferation efficiency of the neuronal cells. Studying the impact of 1q21.1 deletion and duplication on brain development promises to dissect the cellular pathology and mechanisms associated with aberrant brain development.
We have generated induced pluripotent stem cells from individuals with 1q21.1 deletion or duplication and differentiated them into “cortical organoids” or “mini brains”. As these organoids display an architecture and neural network activity resembling that of human brain tissue, we are using them to identity defects in cortex formation, neural cell proliferation and differentiation.
Additionally, we will perform morphological, electrophysiological analyses and RNA sequencing at both the single cell and population level as to identify the gene networks and biological pathways that characterize abnormal brain development due to mutation at 1q21.1 locus. Finally, we will validate the utility of the organoid model as a drug testing tool using pharmacological as to rescue some of the observed cellular defects.
The outcome holds promise to transform our understanding of human brain development in health and disease and provide novel insights into the mechanisms that underpin aberrant human brain development due to chromosomal aberration. We believe that result will consolidate efforts towards the development of personalised medicine.