Professor Stefan Bröer from the ANU Research School of Biology. Photo by Stuart Hay.
Can a drug replace surgery?
If you think transporters are just for Star Trek fans, think again. Mel Norris reports.
Obesity is a problem all over the world – it currently affects more than 400 million people and is one of the main risk factors for Type 2 diabetes.
In a couple of years we hope to replace an invasive surgical procedure with a pill.
Five million people die from diabetes each year and it can have complications such as end-stage renal disease.
Losing weight using diet and exercise can be very difficult, however, and many highly obese people turn to gastric bypass surgery, also known as bariatric surgery.
It is a dramatic and effective treatment but also invasive – the stomach is surgically reduced in size and reconnected to the intestine further down so it bypasses a large section of intestine.
The surgery leads to a staggering change in appetite but is expensive and has risks, according to Professor Stefan Bröer from the ANU Research School of Biology.
He is using cell membrane transporters to develop a new treatment for Type 2 diabetes.
“There is clearly a demand for a non-surgical solution and the question is, how can we replicate gastric bypass surgery?” he says.
“In the end, gastric bypass surgery impairs the intestine so it can’t take up these nutrients – can we do this in a different way?”
The intestine is lined with single cells, and these contain protein transporters that act as doors or gates to the body. Transporters sit in the cell membrane, which encloses the cell.
The transporter carries a nutrient across the otherwise impermeable membrane by enclosing a molecule of nutrient on one side of the membrane, and then opening on the other side of the membrane, releasing the nutrient.
Bröer has spent most of his academic life studying these transporters and how nutrients are absorbed.
In 2004 his research group discovered the gene that is mutated in Hartnup disease, a disorder resulting from a transporter mutation that reduces the body’s ability to absorb amino acids. Hartnup disease can cause skin problems and other symptoms, mainly in children, but is treatable with improved nutrition.
After 12 years of research – five to characterise the transporter and seven more to test a mouse model that replicates the disorder – the group discovered that reduced amino acid absorption can be used to improve metabolic disorders, such as Type 2 diabetes and obesity.
If you have diabetes, your fasting levels of glucose are quite high. If a non-diabetic person drinks a sugary drink, their blood sugar rises sharply but returns to normal in a couple of hours. If a person with diabetes takes the same drink, it takes much longer to return to normal and the level is much higher. This is called reduced glucose tolerance.
Mice with the impaired transporter had much better glucose tolerance and, after three months on an unlimited high-fat diet, gained a lot less weight. These mice showed almost all the same physiological effects as the people who underwent gastric bypass surgery.
The challenge now is to find something to block the transporter. “It sounds simple but is actually a difficult procedure,” Bröer says.
His group is currently using high-throughput screening, a process that uses very large libraries of hundreds of thousands of chemical compounds to detect whether some of them can block the transporter.
“At this point we need very sophisticated robotic equipment which used only to be available to the pharmaceutical industry,” he says. “Now we have it at ANU, at The John Curtin School of Medical Research.”
So, when will this new miracle drug be available? Hard to say.
“Many people don’t realise how long it takes,” Bröer says. “It took from 2003 to 2016 to get to compound screening stage, and we still have to do compound optimisation, animal testing and clinical trials.
“In a couple of years we hope to replace an invasive surgical procedure with a pill.”