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How research can lead to some extraordinary (and very unlikely) discoveries

Patience required. Shutterstock

When it comes to research, you never really know in which fantastic directions it might take you. A discovery in one research area can, many years later, change the world in another.

In the mid-to-late 1970s, I worked with my team here in Dundee, doing a great deal of research around insulin and diabetes. We made 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. We were interested in processes or reactions in cells – their links to disease or certain conditions often come later.

During the course of this work, we identified an enzyme called GSK3, which plays a key role in regulating the conversion of blood glucose into glycogen, its storage form in the tissues.

When insulin is secreted from the pancreas into the blood, it acts on liver and muscle to switch GSK3 off, and so accelerates the conversion of glucose into glycogen in these tissues. Therefore, it was initially hoped that drugs might be developed that could “switch off” GSK3 activity and therefore be beneficial for the treatment of type 2 diabetes.

But further, fascinating discoveries were made. Subsequent research in many laboratories revealed that GSK3 had many other functions in the body, including in 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” – one of the hallmarks of Alzheimer’s disease. These findings 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 patients, and further trials of this drug in larger numbers of patients are now progressing.

From diabetes to dentistry

At the same time, it also emerged that GSK3 is a key component of a biochemical pathway which leads 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.

GSK3: an unlikely route to healthy teeth. Shutterstock

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 Tideglusib has also passed safety tests, there is a real opportunity now to get this treatment quickly into dental clinics.

The results of this study, published in Scientific Reports, received worldwide media attention. As 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 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 leads 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 after all.

This is an excellent illustration of how it can take years or even decades before the results of fundamental research can be fully exploited. It also shows, once again, the critical importance of long-term support from government and other funders of basic research. Without such support, we’ll never know what we’re missing.

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