Rob Holt

Medical Genetics/Molecular Biology & Biochemistry



T-cells circulating in blood are the key players in your adaptive immune system and are particularly important in recognizing and killing other cells that are infected with viruses, or that carry cancer causing mutations. Because there are a vast number of different infectious agents or cancer causing mutations possible, a vast number of T-cell variants are required to recognize them. The component of the T-cell responsible for this recognition is the T-cell receptor, and the variation required for recognition is generated mainly by shuffling the large number of short DNA segments that comprise T-cell receptor genes. Although the central importance and T-cell receptor in adaptive immunity is well established, the actual number and diversity of T-cells that exist in an individual (ie. the T-cell repertoire), how this changes in response to immune challenge, and how it varies from one individual to the next, remains unknown. We have used the latest DNA sequencing technologies to develop an approach for examining the T-cell repertoire in a given blood sample by directly sequencing T-cell receptor genes. We are using this method to explore T-cell repertoires in healthy individuals, and in instances of immune challenge, such as cancer, infectious disease, vaccination and transplantation. We are also developing novel methods for identifying antigens recognized by T cell receptors.
Metagenomics – Infectious agents in Cancer

A large proportion (at least 15%) of the global cancer burden is attributable to known infectious agents, such as HPV, HBV and H. pylori. It is possible that infectious agents may have a still greater role in cancer etiology, but traditional methods for finding them have limited sensitivity. As an alternative approach we are using deep metagenomic sequencing of tumours to find microbial signatures associated with various types of cancer. Linking of an infectious agent to cancer is useful because is leads to the possibility of prevention and/or intervention by vaccination or antibiotic therapy.
Cancer Genomes

We are using deep sequencing to identify the spectrum of somatic mutations in various cancers, with a particular focus on the identification of mutational epitopes for cancer vaccines.

The causes of disorders such as schizophrenia and bipolar disorder remain unknown. We are using DNA sequence analysis and IP/MS to explore candidate genes for these and other disorders. We also have ongoing projects in the genetics of cognitive evolution, and we are part of the Pleiades Promoter Project ( and related projects, where the aim is to develop synthetic human promoter systems suitable for driving gene expression in specific brain regions of therapeutic interest.
Synthetic Biology

There has been spectacular success reading genetic code. In contrast, progress made in writing genetic code and building genomes has been extremely limited. The new field of synthetic biology explores these possibilities. Our current work in synthetic biology focuses on developing laboratory methods for constructing large DNA molecules, engineering whole microbial genomes and exploring microbial genome interaction.
DNA Sequencing

The Sequencing Group at BCGSC provides an efficient, flexible, reliable high throughput platform to support collaborative research related to human disease, model organisms, and organisms of industrial importance in Canada. Laboratory and informatics technology development is ongoing.