Genetics and the skeleton

27 June 2016

“Some people may think I’m unfocused,” says Dr Kathryn Cheah, and while the vast range that her research covers may seem to attest to that, her success in the field and myriad incredible discoveries she’s helped bring to light would not have been possible without the focus and curiosity of a true scientist.

Dr Cheah studies, for the most part, skeletal diseases, and the genetic causes of those diseases. From severe disorders causing malformations or even lethal mutations, to less severe disorders like dwarfism or just the normal degeneration of skeletal tissue that comes with aging, the genetic roots of these disorders can be the same.

Intervertebral disk degeneration is the gradual wearing down and degeneration of the intervertebral disks of the spine, resulting in chronic pain, from manageably mild to severe.

Working together with orthopaedic surgeons and other skeletal biologists, Dr Cheah put together a larger scale program combining genetics and functional studies, taking skeletal MRIs from 3,500 people. Through that program, which began in 2000, Dr Cheah and her team were able to identify three of four genes that contribute to the development of disk degeneration.

A new understanding of dwarfism

Dr Cheah also made a discovery connecting a stress response with chondrodysplasial dwarfism. This discovery has strong implications, as it changes what was generally accepted as the root cause of dwarfism.

While it was once thought that a mutated gene leads to the creation of a protein which is exported to the extra cellular matrix, leading to a weakened ECM. However, this discovery showed that the effects of the mutation are also exacerbated by the production of the protein itself, which causes a stress response in the cell. The stress response results in a change in the cell’s differentiation protocol, causing the disorder.

As we now have knowledge of molecules that can be used to treat stress, this discovery opens up a whole range of possible treatment options. If stress can lead to the affected phenotype, then that provides a new target for treatment.

This program also led to new insights into the development of bone cells themselves. It was once believed that cartilage cells, or chondrocytes, die and are then replaced by osteoblasts, or bone cells. However, it was found that chondrocytes are actually able to convert themselves into osteoblasts, a discovery with huge and wide reaching implications.

While 3,500 individuals may be a large sample size for a rare disease, when looking at disorders like disk degeneration (which affects virtually everyone eventually to some degree) it isn’t that large of a group. However, working in collaboration with teams in Finland, Japan, and the UK, a larger sample sized can be assessed.

Unique about this program is the benefit of its long scale. Now, years since the original MRI scans, the same patients can be tested again to confirm whether the speculated genetic associations with diseases can be confirmed. Few research groups in the world have access to such a large sample with the added benefit of being able to compare disk degeneration from the original MRI to the current one, providing insight both into the effects of aging and the scope with which to verify speculations about the effects of certain mutations.

Changes outside the genome

In addition to genetic mutations, epigenetic changes also have strong effects on the progression of disease. Dr Cheah is currently investigating histone modifications that could identify enhancers or regulatory elements that could lend themselves to the development of diseases.

Gene expression, genetic variation, chromatin architecture changes, all these variables present the opportunity for errors or changes eventually leading to disease and with that, opportunities for treatment and understanding of variation rules that affect a person’s disk degeneration. While now in a more investigative phase, the analysis of this large body of information can eventually lead to treatment options.

But that’s just at the molecular level. At the cellular level, the origin of the cell types also reveals a lot. The notochord is present in all chordates, and is an important part of development. It provides a site for muscular attachment, is a precursor to the vertebrae, and is the originator of the nucleus pulposus, the gel-like core of the vertebra. In short, it’s a primitive backbone, but also patterns the tissues and cells around it for differentiation and embryo development.

These nucleus pulposus cells have many vacuoles, a hallmark of their origin as notochords. As we age, our cells look less and less like their notochord precursors. In dogs, it was shown that those dogs with more cells that maintain their notochord-like features suffer from less degeneration, and those that have fewer notochord-like cells degenerate faster, and with an earlier onset. In short, these notochord-like cells keep the disks healthy, acting like a progenitor or stem cell.

By isolating these cells or differentiating embryonic stem cells towards notochord-like cells, they can be investigated, possibly providing insight into what causes their degeneration and how to prevent it. However, these cells are tricky in that it is very difficult to grow the cells in culture. To remedy this, Dr Cheah and her team are working on scaffolds upon which to grow these fickle cells. While still in the early stages as far as treatment development goes, a thorough understanding of the biology of these disk cells is necessary in order to identify targets for treatment. In theory, by growing these cells on a scaffold from a patient’s own deliberately differentiated stem cells the many possible problems of transplantation can be avoided.

A common factor

While her research does cover many diseases and their even more multiple root causes, one thread running through Dr Cheah’s work is SOX9. SOX9 is a transcription factor that plays an important role in sex differentiation during development, but also affects many other genetic processes throughout the body.

While SOX9 mutations can be lethal, some variations also lead to skeletal mutations, as it regulates some factors that lead to bone formation. An incredibly versatile transcription factor, the SOX family also affects inner ear development. Studying campomelic dysplasia, Dr Cheah found that those affected, if they survive, also have inner ear issues, deafness and difficulty balancing among other things.

Dr Cheah learned of these effects of SOX2 accidentally, after developing the Yellow Submarine mouse, a transgenic mouse with mutations leading to (among other things) deafness, balance issues, and yellow fur. Looking for what regulates the collagen 2 gene, Dr Cheah found that errors in SOX2 lead to a lack of sensing-type cells in the inner ear, which are usually responsible for both hearing and maintaining balance. Without the essential inner ear cells that maintain balance, the Yellow Submarine mice are unable to swim properly, hence the name Submarine.

After tracking down the source of these mutations, Dr Cheah learned that in engineering these transgenic mice, her team had disrupted an enhancer that regulated SOX2 expression in the ear.

The scope of Dr Cheah’s research an profundity of incredible discoveries is quite self evident. Confronted with all her findings and contributions to the scientific world, one couldn’t possibly find her unfocused, as she says of herself. If anything, this lack of focus has led to an impressive breadth of revelations into the incredibly complex world of our genetic machinery.

Kathryn Song Eng CHEAH is Chair Professor of Biochemistry at The University of Hong Kong and an internationally renowned expert on understanding gene regulation and function and how mutations cause disease, with an emphasis on the skeletal system and the inner ear. She is the Principal Investigator and Director of an Hong Kong University Grants Council Area of Excellence Programme “Developmental Genomics & Skeletal Disease’ an 8 year multidisciplinary programme involving scientists and clinicians combining molecular, biochemical, cellular, developmental and in vivo models with genomic, genetic and clinical studies, to address key issues in skeletal biology. In the area of public service, she served on the Biology and Medicine Panel of the Research Grants Council of Hong Kong for 6 years. She is the founding President of Hong Kong Society for Developmental Biology and was the President of the International Society for Matrix Biology 2006-2008. She actively promotes public understanding of science in the region. 

To view Dr Cheah's personal Croucher profile, please click here.