There's been a seismic sea-change in the creation of drugs

So far only jellyfish proteins have been used but organisms in the marine environment have differently coloured proteins and these could be employed to speed up drug development and efficacy even further.

“One coral has a red one so you could link it to one protein in the cell and a green one to another so you can see both at one time - obviously that can be extended in lots of ways,” said Graeme Milligan, Gardiner Chair of Biochemistry at the University of Glasgow.

“It will allow us to understand why some drug candidates are effective while others are not and can potentially be applied to different classes of proteins that are targets in the treatment of many diseases.”

The research is an example of how science and maths can work together to produce new insights. Biologists have used microscopes for many years to study cells but what has made this project more exciting is the way maths and physics have been used to harvest more data from the images.

“We are using the power of physics in terms of optical imaging and we use the maths to extract the information from the image as we need an algorithm to do this,” said Professor Milligan. “Essentially what we have done is written a computer programme and made that publicly available so that anyone skilled in this type of knowledge can use it.”

Cells are more than just balloon-like structures filled with water and a few proteins and chemicals. They are far more complex and the proteins contained within them can be found in a number of intricate structures.

For a drug to intervene in cells or entire organs that are not behaving normally, it must first bind to specific protein receptors in the cell membranes. Receptors can change their molecular structure in a multitude of ways during binding – and only the right structure will “unlock” the drug’s therapeutic effect.

By using the fluorescent jellyfish protein, the study has found a more accurate way of assessing the actions of medicines. Developed by the Glasgow researchers and a team from the University of Wisconsin-Milwaukee, it reduces the time and labour of finding the protein receptors with the “right” response to drug candidates by several orders of magnitude. Using the new method, it is possible to characterise how each receptor responds differently to various drug candidates.

“What we are showing is that different drugs have different effects and not all are equally effective,” said Professor Milligan. “This way we can see which one is going to work better before we give the drug to the patient and that will save a lot of time and money.”
The team has already applied their method to a member of the G protein-coupled receptor (GPCR) family, a group of proteins that are targeted by a wide range of medicines. The effect of the association between drugs and receptors was shown in a matter of hours, compared to months using current technologies.

The researchers’ method tracks a chemical process called oligomerisation that occurs when a receptor exists as a single subunit, but then shifts to a multi-structure – an oligomer – in the presence of the ligand (drug compound), or vice versa.
Prof Valerica Raicu, UW-Milwaukee professor of physics, said: “We used to think of these receptors as binary. They were either activated by the compound or not. But now we are beginning to understand that, depending on the ligand, the same receptor can produce many different responses.”

The Raicu lab uses fluorescence-based imaging in order to see protein receptors in oligomeric states under various environmental conditions. Using single or two-photon excitation microscopy, the researchers can produce a kind of road map of the various kinds of protein receptor oligomers in the absence or presence of ligands (or drugs) that bind to them.

Researchers image protein-receptor molecules by attaching florescent tags. This way, single molecule protein receptors give off light when they pass under a laser and are excited and those bursts are recorded with a camera. Receptor oligomers give off a more intense burst of light and those are also photographed.
Prof Raicu said: “Now you can graph the intensity and the number of bursts and see how many are associated into oligomers – how big they are – and where they are in the sample. 

“After adding the ligand, you can see whether it promotes association of single molecules of receptor proteins into oligomers, or the breakdown of oligomers into the former.”

The study, “A general method to quantify ligand-driven oligomerisation from fluorescence-based images”, is published in Nature Methods. The study is partly funded by the National Science Foundation (USA), the Medical Research Council and the UWM Research Growth Initiative grants.

Farming out revolutionary new treatments 

How the son of a dairy herdsman became an innovator in bioscience

MILKING cows seems an unlikely basis on which to build a career in science but having to rise at the crack of dawn to head out to the dairy gave Graeme Milligan the drive to pursue a more academic goal.

The son of a herdsman, he was the first in his family to go to university, graduating with first class honours in Biochemistry from the University of Birmingham in 1979 before going on to take a PhD at Nottingham University and then a fellowship at Bethesda in the US.

GUT INSTINCT: Professor Milligan’s studies of gut bacteria have led directly  to new ways of treating conditions such as diabetes.

“I suppose I am somewhat of an outlier in the family as I remain the only one to go to university - most of the others have stuck to dairy farming,” he said. “My mother was keen I should try something else and I was always interested in biology.”
His particular interest in drug design and how medicines work at molecular level has certainly taken him far in his chosen line of work as he is now widely recognised as one of the leading international figures in his field. 

Gardiner Professor of Biochemistry at University of Glasgow, where he has been based since 1986, as well as Dean for Research within the College of Medical, Veterinary and Life Sciences, his studies and ideas have influenced approaches to drug design within the pharmaceutical industry. 

Contributions to how products of bacterial fermentation of dietary fibre in the gut control metabolic and inflammatory status have provided new avenues to tackle obesity, diabetes and inflammatory diseases of the lower gut. Innovative technologies developed in his laboratory have been incorporated into early stage drug discovery pipelines, including an entirely novel approach for treatment of post-operative pain.

Professor Milligan has published more than 500 peer-reviewed articles topics, his research has been cited more than 22,000 times and he is a Thompson Reuters 2014 Highly Cited Researcher. In 2015 he co-founded Caldan Theraeutics with Trond Ulven, Head of Research for Medicinal Chemistry at the  University of Southern Denmark, to develop novel therapeutics for metabolic diseases including Type 2 Diabetes, non-alcoholic steatohepatitis (NASH) and inflammatory diseases.

He was a finalist in the Biosciences and Biotechnology Research Council Innovator of the Year in 2016 and awards for his work include the Poulsson Medal for Pharmacology from the Norwegian Society of Pharmacology and Toxicology, the Ariens Medal from the Dutch Pharmacological Society and the JR Vane Medal for Pharmacology from the British Pharmacological Society. 

He was elected to the Fellowship of the Royal Society of Edinburgh in 1998 and to the Fellowship of the Academy of Medical Sciences in 2016.