Solving a scientific mystery often requires intense focus on a very specific matter. It’s something Zongchao Jia (Biomedical and Molecular Sciences) knows well as he has been zeroing in on molecules called polyphosphates. 

Recently, his team discovered that polyphosphates can modify proteins – a breakthrough that can have implications for how we treat cancer, cognitive impairments, autoimmune diseases, and other health issues.

You may remember from high school biology classes: ATP, involved in providing energy for living cells, contains triphosphate (a short form of polyphosphate). Polyphosphates are found in almost every living organism, from bacteria and yeast to humans and other long-living animals. They can also be found in non-living things, like minerals, and have a variety of potential uses, such as in water purification, agricultural fertilizers, cement thickening, and as food additives.

With that many applications, it is no surprise that researchers across disciplines have been working on new and innovative ways to use polyphosphates. But Dr. Jia, Canada Research Chair in Structural Biology, and his former PhD student Nolan Neville came across a new possible application almost by accident. 

At the time, they were researching an enzyme named polyphosphatase kinase, responsible for producing polyphosphates in bacteria, and the team’s main goal was to investigate alternative treatments for bacterial infections – ones that didn’t lead to antibiotic resistance. But when looking for a way to block the enzyme from doing its job in the bacteria, the team discovered that the polyphosphates produced by the enzyme could actually do something else – modify certain proteins within the bacteria. Since then, the team has found that polyphosphates can modify many proteins in humans, yeast, and plants.

Proteins have different functions within organisms – for example, they can transport nutrients or drive metabolic processes. Every cell contains in its nucleus the recipe for synthesizing the proteins they need – it is recorded in their DNA and, through processes known as transcription and translation, leads the cell to build chains of proteins’ building blocks, the amino acids.

Dr. Jia's lab is working to help design the antibacterial drugs of the future. Viewed under UV light, the bacterium Pseudomonas aeruginosa's pigment pyocyanin produces blue fluorescence, capturing the swarming motility of the bacterium as they swim away from a drop of culture at the centre of the agar plates. Their research is working to engineer new drugs that inhibit this virulence that contributes to its antibiotic resistance leading to infection. Photo submitted to the Queen's Art of Research photo contest by Nolan Neville entitled "Bacterial Swarming Motility".

Most proteins will reach their final composition and form through these processes. However, in some cases, they undergo further modifications that may cause changes not only to their structure, but also to their function in the organism. Scientists call this phenomenon a post-translational modification. In the diminutive environment of a cell, it’s a big deal.

“Single phosphate modification, also known as phosphorylation, has been known and studied for decades. But this new discovery, polyphosphate modification, opened new research possibilities for us,” says Dr. Jia.

Polyphosphates have been reported to play a role in health conditions such as blood clotting, cancer, and neurodevelopmental disorders. Think of them as a new type of molecular switches – like the switches used to lights on and off. However, the specific mechanisms through which this happens remain unclear.

Once researchers can clarify these mechanisms, new potential applications may be revealed. 

“We may be looking at ways to either block or enhance polyphosphate modification, according to the problem we are trying to solve,” Dr. Jia says.

After publishing a series of eight research papers (and counting), Dr. Jia and team are particularly excited about two proteins that can be modified through polyphosphate modification. The first one is associated with cognitive impairments observed in Down syndrome and other conditions like autism spectrum disorders and Alzheimer’s. The second protein plays a dual role in cancer: depending on the cellular context, it may cause cells to grow and divide, or it can do the exact opposite and act as a tumor suppressor. The same protein can have implications for autoimmune diseases such as type 1 diabetes and rheumatoid arthritis.

There is still a long way to go before the research can be translated into new medical treatments. However, discoveries like this stress the importance of foundational science. 

“Our study highlights the importance of exploring unconventional mechanisms to unravel complex biological processes and advance biomedical research,” Dr. Jia says.