University of Glasgow scientists have discovered fluorescent jellyfish proteins can assist in speeding up the  medical development of vital new treatments

 

JELLYFISH have helped biologists at the University of Glasgow make a breakthrough that could rapidly increase the speed of drug development. In a collaboration with US mathematicians and physicists, the Glasgow team have used a green fluorescent protein from jellyfish to help them track changes in cells.

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.

HeraldScotland:

By using the fluorescent jellyfish protein, the study has found a more accurate way of assessing the actions of medicines

 

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.