Looking for cleaners for cells full of unprocessed waste
The fats and sugar metabolism of the human cell is one big puzzle. This is what makes lipid storage diseases and diabetes type 2 so complex. Funding from the European Research Council will allow Professor of Bio-Organic Chemistry Hermen Overkleeft to work further on solving this puzzle. This is fundamental research, the application of which is closer than ever.
Glycolipids, a combination of fats and carbohydrates, are an important component of the cell membrane. Together with his Amsterdam colleague Medical Biochemist Hans Aerts of the AMC, with whom he shares the subsidy, Overkleeft has spent more than a decade investigating the metabolism of these molecules. His main line of approach in this research has been the so-called lysosomal storage diseases, of which Gaucher’s disease is the most common example.
Storage diseases have to do with a glycolipid metabolism disorder in the cell. Overkleeft: ‘These diseases involve a genetic defect, as a result of which the enzymes that are responsible for the breakdown of glycolipids become much less active. Consequently, some of the molecules are not sufficiently broken down and the residue accumulates.’ These cells full of unprocessed waste cause a range of physical symptoms. In Gaucher’s disease these vary from general tiredness and pain in the spleen to serious skeleton and blood disorders. There are also storage diseases which cause neurological and psychosocial symptoms.
Overkleeft has developed a number of molecules which prevent the accumulation of these glycolipid remnants by slowing down the glycolipid production. But there are also other options. ‘It might also be possible to create an enzyme which can take over the role of the genetically handicapped enzyme,’ explains the Leiden researcher. ‘Furthermore, we don’t yet know whether the ‘broken’ enzyme fails to do its work properly or whether it reaches its destination in too small quantities. Once we figure this out, other treatments will probably also become possible.’
There is no shortage of ideas for using the subsidy. Not to mention the larger picture: a disturbed fat and sugar metabolism not only plays a crucial role in storage diseases, but also in other diseases, such as diabetes type 2. Overkleeft: ‘Glycolipids form a large, diverse class of molecules. The composition of the different variants in the cell and their function are not entirely clear yet. This is clearly also something we want to know.’
Organic Chemist Overkleeft is happy with his collaboration with Biochemist Aerts: together they can look at how glycolipids react to ‘his’ inhibitors in a biological system. This is not something he can do by himself, because a test tube is a very different thing from a tissue culture. There is no sharp division between the two fields of research. Overkleeft: ‘We spend most of our time trying to understand each other as well as possible. This means partially working in each other’s field. We are not purely complementary, there is a lot of overlap.’ This is therefore fundamental research, which can be tested in practice.
Area of research Bioscience: the science base of health