SCIENCE FOUNDATION IRELAND: There is a sugar coating on every living cell and scientists are keen to discover ways of using it in early diagnosis and to help make the medicine go down - so maybe Mary Poppins was right after all.
WHEN Julie Andrews told her charges in Mary Poppins that a spoonful of sugar would help the medicine go down, she couldn't possibly have realised how right she was. Not only can sugar help medicine to go down better, it may also hold the key to rapid diagnosis of diseases such as cancer, the creation of more targeted, effective drugs and the development of new generations of health drinks.
These are just a few of the possible outcomes of the research currently being carried out by the Alimentary Glycoscience Research Cluster (AGRC) at NUI Galway.
Glycoscience is mainly concerned with the study of the glycans or sugars that coat every living cell and are involved in the interactions that occur between cells. Sugars are involved in many physiological processes ranging from fertilisation and stem-cell differentiation to tumour metastasis, immune regulation, inflammation and host-pathogen interactions.
"Sugars have become the main molecules in the language of biology," says Prof Lokesh Joshi, the principal investigator. "There has recently been a surge of activity in this area. Researchers used to look at the RNA and DNA of cells to see how they interacted with each other, then they looked at proteins, and then they looked at the fact that every cell is covered in sugar."
The main focus of the AGRC research, funded by Science Foundation Ireland, is the human digestive system. The human gut carries about 10 trillion bacteria, several times the number of cells in the body. Most of these are friendly and help us to stay healthy. The glycan coat of intestinal cells forms a chemical barrier and communication channel between the gut wall and the interior of the body.
Most microbes in the gut, both useful and harmful, interact with this glycan coat. The structures and presentation patterns of the glycans determine whether a beneficial or pathogenic bacterium can colonise the host.
The gut-wall glycans have the ability to change and thereby prevent or encourage the interaction with these bacteria. The AGRC is studying these changes and developing methods, technologies and possible new therapies to control microbial colonisation. The goal is to find ways to keep unwanted bacteria at bay and to encourage useful ones where necessary.
Joshi describes the sugar coating as a "very complex Velcro" that determines which other cells it will bond with. It is this characteristic that lies at the heart of the research. "Our main goal is to look at how bugs in the gut use sugars to find the right home," he says. "And the new technologies we are developing for this can be used in other areas of research as well."
Among the other areas is drug development. Many drugs are made of proteins that are present in the human body in any case and which are manufactured outside of it to be administered in suitable doses to fight particular diseases or conditions. Like other cells these proteins are covered in sugar but, because they have been manufactured outside the human body, it may not always be the right sugar.
"If it is the wrong sugar, it will activate the immune system and our bodies will reject it," Joshi says. "If we are trying to save the patient, activating the immune system in this way is not what we want to do. This causes side-effects and will reduce the efficacy of the drug."
Identifying and manufacturing the protein is the easy part, according to Joshi. "The sugar is the difficult bit. There are two things we can do to help. The first is to take the drug and say whether it has the right sugar or the wrong one. The second is to help put the right sugar on it."
And this is where Mary Poppins comes in. There might be nothing wrong with a medicine itself, just the sugar. If the right sugar is used, the body's immune system will not be activated and the medicine will be allowed to work unimpeded with no unpleasant side-effects.
This is not the only application of the AGRC research. It also has relevance to the diagnosis and treatment of a range of diseases, including cancer. "We have recently been selected by the EU for grant funding for research into the next generation of glycobiomimic and glycosensor tools for the diagnosis of cancer glycobiomarkers," says Joshi. "Cancer cells are just different types of cells, they are still covered in sugar and the same technologies can be used in relation to them."
In this instance, the aim is the detection of cancer. "Take the example of blood cancer," Joshi says. "How do you tell one cell from another? Which cell is a normal blood cell and which is a cancer cell? One way of telling is that the sugar marker is different. We can look at the sugar coating and tell which is which."
This has important applications for the early diagnosis of such diseases. "One thing that we are very keen on is developing rapid diagnostic tests for a range of diseases," adds Joshi. "My goal is a future where people can go to see their GP and give a small blood sample which can be quickly analysed for various diseases, including cancer. The blood would be analysed for the different sugar markers and early and quick diagnosis of a range of conditions would be facilitated without the need for invasive biopsies."
Information as to which structures to look for could be held on something like an SD card or USB key and used by the machine analysing the blood, he says. So if a person was complaining of symptoms that might be indicative of a salmonella-like infection the data for the glycans coating those cells could be fed into the machine, which would quickly analyse the blood for its presence.
The research goes beyond mere diagnosis, however, with treatment also high on the agenda. The most effective cancer treatments are usually the best targeted, the ones which attack cancer cells but not the healthy cells around them. These pharmaceutical "magic bullets" or "smart bombs" are extremely rare, however. So the answer may lie in the sugar markers and the "Velcro" nature of the sugar coating. If a drug can be coated with a sugar that will attach to the coating on a cancer or other specific type of cell, and no other, it can become one of those sought-after magic bullets.
"We make molecular mimics in the lab," he says. "What we are making is gloves for hands. The hands are the sugar coatings on the cells we are looking to attack and the gloves will be attached to the therapeutics. The drug will only attach itself to those hands. This opens up a huge field of infectious diseases to us. Every virus or microbe uses sugar to bind itself to a host - this includes microbes involved in conditions such as MRSA - and our goal is to come up with novel sugars to assist in their treatment."
A further strand of the research team's work involves the development of nutraceutical products derived from the sugars present in milk. "If you look at human mother's milk, it is designed to assist the baby through the activation of its immune system and fight off diseases and pathogens that affect humans," he says. "We are working to identify the sugars in the milk that perform these actions to enable them to be included in products, such as drinks, which people can take to boost their health."
Joshi came to Ireland from the US in 2007 to become the Stokes Professor of Glycosciences and the Bristol Myers-Squibb (BMS) professor at the National Centre for Biomedical Engineering Science at NUI Galway. He was appointed associate director of the Centre for Bioanalytical Sciences, which was funded by €10 million from BMS and the IDA. In 2009 he was awarded a €5.16 million strategic research grant by Science Foundation Ireland to establish the AGRC.
"I think this funding works very well for both the research community and for Ireland," he says. "I was attracted to come here and work because Ireland has the potential to become a regional, if not a global, leader in glycoscience research and this is very exciting."
