In the words of the author and biochemist Isaac Asimov, "The most exciting phrase to hear in science, the one that heralds new discoveries, is not 'Eureka!', but 'That's funny…'"
This is exactly how a search for new treatments against cardiovascular disease led to our scientists finding an on/off switch for genes that control a completely different condition.
It all started with researchers looking into heart disease. In 2004, scientists at our research center in Les Ulis, France, decided to take a creative approach to find medicines that might lower cholesterol. Scientists had already shown that a protein made by the ApoA1 gene could lower cholesterol in the blood. So they wanted to see if they could find a compound that caused the body to make more ApoA1.
The scientists used a sophisticated screening technique that scanned a library of hundreds of thousands of molecules searching for any that increased ApoA1. Remarkably, they found some that did.
The researchers were delighted to find these ‘hits’, but now the work really needed to begin. They needed to understand how these molecules worked.
Bringing in another group of GSK scientists in Stevenage, UK, the team set about doing some different detective work, which ultimately uncovered that these molecules latched onto a protein family called BET. By doing this, the molecules blocked the activity of the BET protein and allowed the cells to make more ApoA1.
What we had discovered was a new unexpected ‘cellular switch’ that could turn certain genes on or off - in this case the APoA1 gene - and, as a result, change the biology of our cells.
This is called an ‘epigenetic’ switch. Epigenetics is a relatively new area of science that is helping to explain why some genes are turned off in people while in others they are turned on and this dysfunction may underlie many human diseases.
What we had discovered was a new unexpected ‘cellular switch’ that could turn certain genes on or off
Using genetically-engineered proteins and cutting-edge 3D crystal models of the BET protein, our scientists could clearly see that the compounds acted to prevent the BET protein from binding to a chemical tag, thereby controlling an epigenetic switch.
Meanwhile, researchers at Dana Farber Cancer Center had identified that patients with a rare very aggressive type of cancer called NUT midline carcinoma (NMC), seemed to have a rearrangement in the genes of one of the BET proteins that created a cancer-causing fusion protein (Brd4-NUT). Fewer than 70 people worldwide have been diagnosed with NMC since 2004 and despite treatment with aggressive chemotherapy, most patients with NMC have a life expectancy of less than 12 months.
The Dana Farber and GSK researchers decided to investigate whether our investigational compound might have an effect on these cancer cells. It transpired that in cancerous cells taken from people with NMC, the BET inhibitors were able to stop them growing in culture dishes and in animals.
In an incredible journey Isaac Asimov would have been proud of, GSK scientists had gone from looking for a treatment for cardiovascular disease - through unlocking a new epigenetic mechanism – to identifying a new approach to alter a different disease process.