RESEARCH
Dylan Bergen, PhD
I am interested in how the skeleton (cartilage/bone) is formed on both organismal and cellular levels. The skeleton defines the shape of most organisms, gives protection to vital organs (such as brain, lungs, and heart), and participates in the movement of more complex animals. In bone and cartilage elements, matrix is laid down in a specific way giving these skeletal tissues their specific characteristics (e.g. cartilage is spongy, bone is mineralised). Healthy bone is constantly remodelled (the complete human skeleton is slowly regenerated over ten years) to repair microfractures caused by loading of bone occurring in daily life of an organism. This remodelling process depends on a balanced act of bone building cells (osteoblasts and osteocytes) and bone degrading cells (osteoclasts) to maintain the right amount of bone.
​
The most common disease that affects bone strength is osteoporosis which is diagnosed by assessing bone mineral caused using a Dual-energy X-ray absorptiometry (DXA) scan. Low bone mineral density is the parameter to diagnose osteoporosis, which affects ~50% of women and ~33% of men above the age of 55 (around 3.2 million people in the UK alone). Low bone mineral density is caused by a reduction in bone matrix caused by an altered balance of bone building cells and bone degrading cells. This results in brittle (porous) bones that fracture easily leading to serious, sometimes even life threatening, fractures in the hip, vertebrae, and long bones (ribs, femur etc.). Current pharmacological treatments unfortunately do not fully recover bone mineral density and bone strength.
During my first fellowship after my PhD, I used large human genomic datasets (genome wide association studies, whole exome sequencing) of bone mineral density and bone mass to identify important genetic factors that regulate bone matrix. These novel genetic factors allow better understanding of osteoporosis biology. I aim to find new osteo-anabolic (stimulating bone-building cells called osteoblasts -> bone strength) genetic factors as current treatment options for osteoporosis mainly block osteo-catabolic (bone resorbing cells called osteoclasts -> bone degrading) pathways.
​
Large human genomic datasets of bone mineral density offer a great way to identify new bone mineral density genes however, these strategies produce 100s of potential genes. I am currently concluding my in silico prioritisation pipeline to select the best candidates for studies in the lab. In the Hammond lab I will continue prioritising these candidates using the zebrafish model. This in vivo prioritisation will encompass making mutants using CRISPR/Cas9, in vivo osteoblast imaging, assessing bone mineralisation with micro-CT and bone staining, and assessing candidate gene expression. The zebrafish animal model allows fast screening of in silico prioritised candidate genes from human genomic datasets in a cost-effective way [Bergen et al 2019].
​
Functional studies of candidate genes that show an effect on bone mineral density and bone matrix integrity could therefore become novel drug targets for osteoporosis. I therefore aim to use my scientific interest in the skeleton and extracellular matrix to develop an interdisciplinary pipeline that is composed of in silico and in vivo strategies. This will integrate large genomic studies and functional studies in the lab, to define putative drug targets for osteoporosis.
