Sugar in the diet may be the bête noir of anyone trying to keep their waistline in check. But for scientists, understanding the important complex sugar molecules that our bodies make naturally can tell us much about our immune systems, how our cells communicate with their environment and even how we can detect early signs of disease.
Complex sugars called glycans latch on to around 60 percent of the proteins in our body, and in particular they sugar-coat our cells. "If you are outside a cell looking at the surface, by far the biggest impact would be made by the sugars, - almost all of the cell-surface proteins are covered in sugars," says Professor Pauline Rudd, NIBRT Professor of Glycobiology at UCD.
Sugars have a protective, cushioning role, they help proteins to fold properly in the cell and their bristling ends also mediate specific reactions in the body. Yet despite their importance, they have been something of a poor relation in research, lagging behind more high-profile molecules like DNA and protein. "[Sugars] are much more complicated to analyse," explains Professor Rudd in her office at the UCD Conway Institute, where she and her 12-strong team have been based since they moved from Oxford two years ago. "So the field has been going along quietly in the background for a long time because people have been focused on the genome project and proteins."
But sugars also play a key role: DNA is translated into proteins in the cell, and then the addition of sugars can further refine a protein's function. "It's what enables us to have a relatively small genome because the gene products can be further diversified by post-translational modifications. I think it took a while for people to really understand how significant that could be." And when something goes awry, the results can be serious. "There's a series of congenital disorders of glycosylation where the sugars are grossly disturbed," notes Professor Rudd. "Most of them are lethal in utero but those who survive have very severe problems, usually ocular, motor and intellectual problems. They often don't go through puberty because the pituitary hormones are not properly glycoslyated. These diseases give you an insight into the things that can go wrong and understanding these is the first step towards designing treatment."
Professor Rudd has also looked closely at how sugars allow the immune system to recognise invaders. "The innate immune system involves a lot of sugar recognition because they are on the surfaces of bacteria or parasites," she explains. But it's a fine balance. In the case of some auto-immune conditions, like rheumatoid arthritis, the body's own proteins can become glycosylated in a way that makes it a target for the immune system. "If it goes wrong your proteins can look like a parasite or look like a yeast," she says.
Professor Rudd's team has also developed an interest in sugar changes in cancer. "I went to a meeting with research colleagues and realised that very little progress had been made in cancer diagnostics for a long time," she says. "Sugars are always altered in cancer and so we said we would look at them." Their work showed that when cancer was present, sugars were altered on tumour proteins and some inflammatory proteins, and that the changes could be detected in blood and tissue samples.
Looking for such early "biomarkers" of disease is one area where glycobiology can help to refine current, protein-based approaches, and Professor Rudd's group and collaborators are working on identifying potential sugar indicators for prostate cancer, ovarian and breast cancers. “In our prostate cancer studies with Professor William Watson (UCD) we are targeting a subset of PSA molecules that has altered sugars. We are also collaborating with Professor Dolores Cahill (UCD) to look for markers of ovarian cancer and in our breast cancer study with Professor Joe Duffy from St Vincent's University Hospital we are attempting to find markers that will detect metastasis in advance of those that are used at the moment," says Professor Rudd, who explains they may be picking up changes from the process of a tumour starting to move to other sites in the body. "The markers that come directly from the metastasised tumour won't be able to give you a marker until the metastasis happens and it grows. But the migration from the primary site might initiate information in advance of that event."
The cancer work could also shed light on how sugars can change when cells are grown in culture under different conditions to produce therapeutic drugs, says Professor Rudd, whose work receives funding from Enterprise Ireland and Cancer Research Ireland among others. And commercialising the technologies they develop has been one goal of moving her group from Oxford to the National Institute for Bioprocessing Research and Training, a not-for-profit partnership between UCD, TCD, DCU and IT Sligo. "It's easier here than in Oxford because Ireland has a more direct pipeline from academia to industry," she says.