Christ Leemans
Research
Currently, multiple gene therapies are tested in patient trials and some have already been approved for clinical use. Gene therapy is also applied in severe combined immunodeficiency (SCID). Herein, hematopoietic stem cells from the bone marrow are transduced with viral vectors, thereby inserting a gene that replaces the defective gene into the host DNA. After transplantation into the patient, a fully competent immune system can be regenerated from these transduced cells.
Accurate computational analysis is needed to monitor safety and efficacy during these trial,. I focus on two methods: integration site analysis (ISA) and T-Cell Receptor diversity analysis (TCR). For a healthy immune response, a diverse repertoire of immune cells is required to deal with all kinds of pathogen. ISA monitors clonal contribution of stem cells to their offspring of by measuring abundance and location of viral insertion sites. Because viral vectors all insert randomly at different locations, immune cells with the viral vector inserted at the same location originated from the same stem cell. Therefore, the presence of many different insertion sites, all in low abundance, indicates that many different cells contribute to the immune cell populations. On the other hand, having high frequency of a single or just a few insertion sites could indicate clonal dominance, which can be an early stage of carcinogenesis. Leukemia development through insertional mutagenesis is a known side-effect of the earlier viral gene vectors and therefore requires careful monitoring. TCR sequencing analyses on the other hand, can be used to assess how diverse the T-cell repertoire is after treatment.
Curriculum Vitae
After completing my Bachelor’s degree in Biomedical Sciences at Maastricht University, I moved to Wageningen University to follow a Master’s degree program in bioinformatics. During this Master, I came into contact with Harmen Bussemaker, professor at Columbia University, where I did an internship on prediction of protein-DNA binding specificity. After this internship, I returned to the Netherlands and moved to Amsterdam for my PhD studies at the Division of Gene Regulation of the NKI-AVL under supervision of prof. Bas van Steensel. Here, I worked on a system measuring thousands of gene reporters integrated in parallel (TRIP). This reporter system uses insertional mutagenesis similar to gene therapy, but instead of insertions with curative genes, reporters are inserted in the genome to measure local chromatin effects on gene expression and double-stranded DNA break repair.
