In the mid-to-late 1970s, working with my team here in Dundee, we were doing a lot of research around insulin and diabetes, making a number of significant breakthroughs in our understanding of how insulin works.
This was fundamental research at the molecular level, examining the processes of proteins and enzymes, how they work in the body and the results that can arise. This kind of work does not necessarily start off being focused on a particular disease – it is the process or reaction in the cell and the understanding of it that we are interested in. The links to disease or certain conditions, as we will see, often come later.
During the course of this work we identified an enzyme called GSK3 which had a key role in regulating the conversion of blood glucose to its storage form in the tissues, called glycogen. Because insulin can drive this effect by reducing the catalytic power of GSK3, it was initially hoped that drugs might be developed that could `switch off’ GSK3 activity and therefore be beneficial for the treatment of Type2 diabetes.
Subsequent research in many laboratories revealed that GSK3 had many other functions in the body, including the attachment of phosphate to a protein in the brain called `Tau’.
When abnormally high levels of phosphate become attached to Tau, they cause it to aggregate and form deposits in the brain called `tangles’, which are one of the hallmarks of Alzheimer’s disease. These findings in turn led to renewed interest in developing drugs that switch off GSK3 in the hope that they would benefit Alzheimer’s patients.
A number of pharmaceutical and biotechnology companies took up this challenge and a drug called Tideglusib was developed by the Spanish biotechnology company Noscira and entered clinical trials for the treatment of Alzheimers and progressive supranuclear palsy, another neurodegenerative disease of the brain. This drug passed Phase I clinical trials indicating that it could be used safely in human patents, and further trials of this drug in larger numbers of patients are now progressing.
At the same time, it has also emerged that GSK3 is a key component of a biochemical pathway leading to the destruction of certain proteins associated with early responses to tissue damage.
This same pathway is activated when teeth are damaged and, in a remarkable development, Paul Sharpe and his colleagues at King’s College London applied low doses of Tideglusib to biodegradable collagen sponges, which were then inserted into tooth cavities. They found that the sponges degraded with time and were replaced by new dentine, the main supporting structure of the tooth.
This could transform the way we treat teeth cavities, making man-made fillings a thing of the past. Since collagen sponges are already available commercially and approved clinically, and as Tideglusib has passed safety tests, there is therefore a real opportunity to get this treatment quickly into dental clinics.
The results of this study were recently published in Nature Scientific Reports and received worldwide media attention. Paul Sharpe commented, “The simplicity of our approach makes it ideal as a clinical dental product for the natural treatment of large cavities, by providing both pulp protection and restoring dentine.”
One of the fascinations of carrying out fundamental research is that one can never predict what it will eventually lead to and how the discoveries may be used to benefit human health and create wealth.
When we discovered GSK3 in the late 1970s the idea that it might revolutionise dentistry would have sounded like science fiction. But here we are, with a line that stretches all the way back to a laboratory in Dundee and also winds towards the treatment of neurogenerative diseases such as Alzheimer’s. And who knows, GSK3 inhibitors might yet turn out to be useful for the treatment of diabetes.
This story is an excellent illustration of how it can take years or even decades before the results of fundamental research reach the stage where it becomes obvious how it can be exploited for the improvement of health and for wealth creations. It shows once again the critical importance of long term Government support for basic research.
By Sir Philip Cohen, Professor of Enzymology, University of Dundee