Adam Handel

Current Research

During my Clinical Lectureship, I am using functional genomics methods to understand neuroimmunological conditions in collaboration with Prof. Irani. My particular focus is on applying recently developed single cell genomics approaches to immune-mediated diseases of the central nervous system, such as neuromyelitis optica, autoantibody-mediated encephalitis and multiple sclerosis.

Single cell methods are ideally suited for studying the biology of extremely heterogeneous populations of cells, as exemplified by T-cells and B-cells in the case of autoimmunity; these provide read-outs of cellular functions in individual cells rather than averaging over a large number of cells. This will enable me to identify novel mechanisms of disease.

I am also continuing collaborative projects, started during my DPhil, which aim to uncover the epigenomic basis of promiscuous gene expression in the thymus with Prof. Holländer and further explore the use of stem cell-derived systems to model neurological disease with Prof. Cader.

Previous Research

Induced pluripotent stem cells (iPSC) offer a non-invasive method of modelling human neurological disease in a dish. We used single cell transcriptomics to demonstrate that iPSC-derived cortical neurons closely resemble primary human fetal neurons (Fig. 1). However, I found that markers used to allocate neurons to specific layers within the cortex do not work well in these cells. This suggested that, although a powerful model of corticogenesis, care should be taken in interpreting findings from iPSC-derived systems.

Thymic epithelial cells (TEC) act as vital gatekeepers within the adaptive immune system. Thymocytes are screened by TEC to ensure that only those cells that have the potential to bind to foreign proteins but not proteins found naturally within the organism survive selection and to form the peripheral T-cell repertoire. In order for this to take place, TEC must express almost every protein found in any tissue around the body within the confines of the thymus. We applied functional genomics methods to study the function of TEC within the mature thymus and particularly the role of Foxn1, a master regulator of thymic development and function. Our work identified, for the first time, a set of genes directly regulated by Foxn1 that were critical in supporting the normal function of the thymus (Fig. 2).

I have also examined the contribution of genetic and environmental risk factors to multiple sclerosis susceptibility, including the major histocompatibility complex (MHC), vitamin D deficiency, smoking and Epstein-Barr virus. We used functional genomics methods to identify the location of vitamin D receptor binding across the genome and showed that this was closer to variants associated with multiple sclerosis than expected by chance.