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CHEMICAL DETECTIVE WORK GIVES HOPE TO SEPTICAEMIA SUFFERERS

In an amazing piece of chemical sleuthing published in the leading scientific journal Nature, scientists at the Victor Chang Cardiac Research Institute have discovered a new cause for the potentially deadly low blood pressure characteristic of septicaemia — a finding that provides promise for future treatments of this devastating condition killing  100 Australians each week.

Commonly referred to as blood poisoning, septicaemia affects almost 50 Australians a day, and most are struck down with this life-threatening inflammatory condition while already dangerously sick in a hospital intensive care unit.

Even with powerful antibiotics, and despite modern-day supportive therapies in intensive care settings, septicaemia — a severe generalised infection — has an extraordinarily high fatality rate of more than 25 percent.

In an earlier study reported in Nature Medicine in 2010, Professor Roland Stocker showed a metabolite of the amino acid tryptophan, called kynurenine, causes blood vessels to dilate profoundly during sepsis. This results in the very low blood pressure characteristic of the condition, which, in turn, can cause multi-organ failure and death.

Following up from this observation, Prof Stocker’s team at the Victor Chang Cardiac Research Institute found that, in fact, the culprit that causes blood vessels to dilate was not kynurenine itself, but a precursor of kynurenine. But to identify this precursor took many additional years of research and very detailed and sophisticated chemical detective work.

Now for the first time, Prof Stocker and his team have identified the true nature of the blood vessel dilating substance. They found it to be a previously unknown molecule called cis-WOOH that is made by an enzyme. The enzyme is present in blood vessels only during inflammatory conditions such as sepsis, and it converts tryptophan to cis-WOOH.

Prof Stocker said the finding paved the way for scientists to explore a potential new treatment to arrest the shocking mortality rate of  septicaemia sufferers.

“The death rate is around one in every four cases. It’s frightening,” said Prof Stocker, who has been working on the causes of low blood pressure since the late 1980s, and on this particular breakthrough for almost 10 years.

“Sepsis is a complicated disorder, so our finding is potentially extremely significant. It could also possibly be used to develop treatments for other inflammatory conditions such as certain types of heart disease, neurological disorders like multiple sclerosis, and perhaps even the inflammatory components of cancer.”

But it is an associated discovery – an evolutionary finding - that has Prof Stocker most excited  

During the course of their cis-WOOH experiments, the scientists identified that a molecule called singlet oxygen is required to convert tryptophan to cis-WOOH.

Singlet oxygen was previously thought to only be used in plants and micro-organisms, where it is formed via chemical reactions that require light and oxygen. The discovery now shows singlet oxygen to also be made in mammals, including humans, but without the need for light.

“The finding that singlet oxygen, a highly reactive molecule, can be produced in our body, means it likely has an important function …  otherwise why would evolution have allowed this to happen?” Prof Stocker said. “For me, that is the most exciting part of our work.”

“This pathway is very heavily studied in the context of cancer therapy and inflammatory conditions. So, one of the things we propose, very hypothetically, is that this molecule could potentially kill tumour cells ­– a stretch, but nevertheless an exciting hypothesis

“And our findings now provide the rationale for investigating this novel but potentially far-reaching proposition.”

Victor Chang Cardiac Research Institute Executive Director Professor Bob Graham described the study as “a simply extraordinary piece of beautiful science that is destined to become a landmark —the thing of textbooks”.

“From an evolutionary point of view, discovering that mammals and humans can use singlet oxygen is quite remarkable because no-one has ever shown that before,” Prof Graham said.

“The preservation of singlet oxygen despite millions of years of evolution indicates its profound biological importance.”

Dr Chris Stanley, a lead author of the paper, who works in Prof Stocker’s laboratory, said that while translating the findings into therapies could take some years, having discovered a new biological building block had the potential to lead to breakthroughs we had hitherto not even begun to consider.

The project, Prof Stocker noted, had been “all about endurance and tenacity”, involving many people from multiple institutes, universities and hospitals around Australia and in several other countries over the past decade.

“It spans the gamut of investigative approaches from synthetic chemistry, to analytical chemistry, biochemistry, molecular biology, physiology and then to pre-clinical work, involving an array of technologies – it’s pretty cool, and extremely rewarding, to actually be able to do that”.

The project has been funded in part by grants from NSW Health and the National Health and Medical Research Council, Australia, and involved collaborations with scientists at the University of NSW, Sydney and Monash, as well as universities in Tokyo (Japan), Nanjing (China) and Sao Paulo (Brazil), and also King’s College and the Rayne Institute, London.

The work, entitled “Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation” has been published in Nature (doi:10.1038/s41586-019-0947-3). A copy is available upon request.

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