Michelle Ward received her B.Sc. and M.Sc. degrees from the University of Cape Town in South Africa. Her M.Sc. research aimed to find a novel therapeutic target in cervical cancer, the second most common form of cancer in women in South Africa. She identified the aberrant expression of the LAP2 gene in cervical cancer tissue compared to normal tissue, and established that the up-regulation is also evident in cancer cell lines compared to normal cervical fibroblasts, thereby allowing for mechanistic follow-up studies.
After studying the regulation of a single gene, she became interested in understanding the general ‘rules’ governing the regulation of transcription genome-wide. For her Ph.D., she therefore joined Dr. Duncan Odom’s group at the Cancer Research UK-Cambridge Institute at the University of Cambridge as a Commonwealth Doctoral Scholar to learn genomic approaches for investigating global gene regulation. These approaches allowed her to gain insight into the evolution of CTCF binding sites, Her Ph.D. thesis investigated the regulatory potential of transposable elements (TEs) in mammalian genomes. In particular, she showed that primate-specific TEs are aberrantly activated on human chromosome 21 in a mouse model of Down syndrome. This work suggests that TEs can drive evolutionary novelty during the divergence between humans and mice, and that TEs contain intrinsic regulatory potential that can be revealed in specific contexts.
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Michelle Ward received her B.Sc. and M.Sc. degrees from the University of Cape Town in South Africa. Her M.Sc. research aimed to find a novel therapeutic target in cervical cancer, the second most common form of cancer in women in South Africa. She identified the aberrant expression of the LAP2 gene in cervical cancer tissue compared to normal tissue, and established that the up-regulation is also evident in cancer cell lines compared to normal cervical fibroblasts, thereby allowing for mechanistic follow-up studies.
After studying the regulation of a single gene, she became interested in understanding the general ‘rules’ governing the regulation of transcription genome-wide. For her Ph.D., she therefore joined Dr. Duncan Odom’s group at the Cancer Research UK-Cambridge Institute at the University of Cambridge as a Commonwealth Doctoral Scholar to learn genomic approaches for investigating global gene regulation. These approaches allowed her to gain insight into the evolution of CTCF binding sites, Her Ph.D. thesis investigated the regulatory potential of transposable elements (TEs) in mammalian genomes. In particular, she showed that primate-specific TEs are aberrantly activated on human chromosome 21 in a mouse model of Down syndrome. This work suggests that TEs can drive evolutionary novelty during the divergence between humans and mice, and that TEs contain intrinsic regulatory potential that can be revealed in specific contexts.
To lay the groundwork for an independent research position investigating the context-dependent regulation of the genome using induced pluripotent stem cells (iPSCs), she joined the group of Prof. Yoav Gilad at the University of Chicago as an EMBO Long-Term Postdoctoral Fellow. Using functional genomics approaches in iPSCs from humans and chimpanzees, she showed that the majority of TEs are similarly silenced in the two species, and that differences in TE silencing do not contribute to inter-species gene expression differences. These findings are in contrast to the common notion that TEs are major sources of regulatory innovation and evolutionary novelty. She also used similar approaches to gain insight into phenotypic differences in the manifestation of cardiovascular disease (CVD) between humans and chimpanzees, by differentiating cardiomyocytes in both species, and subjecting these cells to hypoxia, a consequence of ischemia prevalent in CVD in humans. She showed that conserved response genes are depleted for genes, which show variability in their expression across individuals (eQTLs), hinting that there is less tolerance for variability in genes that respond to stress. This suggests that steady-state eQTL studies may not give immediate insight into disease phenotypes.
Dr. Ward was recruited to join the University of Texas Medical Branch at Galveston as an Assistant Professor and First-Time Tenure Track CPRIT Scholar in 2020. She plans to use her expertise in cancer biology, functional genomics, and iPSC technology over the next five years to gain genetic and mechanistic insight into susceptibility to chemotherapeutic agent-induced cardiotoxicity.
Breast cancer is the most common cancer diagnosed in women. With improvements in diagnosis and treatment strategies, five-year survival rates are as high as 90%. Breast cancer survivors are now more likely to suffer from secondary conditions such as cardiovascular disease, than tumor recurrence. This is partly due to the cardiotoxic side effects of widely used chemotherapeutic agents such as Doxorubicin, which associates with adverse effects on the heart in ~8% of patients. It is not known what distinguishes women who suffer from cardiotoxic side effects from those who do not. The mechanistic basis behind these inter-individual differences is even less clear.
There are 68 drugs approved for the treatment of breast cancer. Being able to predict adverse drug reactions in each individual could help inform on appropriate patient treatment. Using iPSCs from healthy individuals with available genotypes, the Ward Lab will generate iPSC-derived cardiomyocytes to study the molecular response to a panel of drugs used in the treatment of breast cancer. These projects will lead to insight into predicting which chemotherapeutic agents are likely to induce cardiotoxic side effects in a patient based on an individual’s genotype, and will allow better informed treatment strategies. This framework to understand the basis of chemotherapeutic agent-induced cytotoxicities, can be extended to other susceptible cell types such as neurons.
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