They walk, they talk; they aren’t growing, but they squawk. They are the senescent cells, the tiny zombies living inside us.
We all have senescent cells in our bodies, which are damaged body cells that don’t grow or divide as normal cells do. Before adulthood, senescence plays an important role in encouraging tissue development; as adults, our cells become senescent when they are damaged through ageing or other more abrupt causes like wounding or toxication. Senescent cells don’t grow or divide, but they use specific proteins to talk to the immune system so that it can recognise and order them to self-destruct – this is one of our body’s ways to refresh tissues and prevent and fight diseases. Unfortunately, senescence is a double-edged sword. If our immune systems can’t clear them out, senescent cells get the chance to accumulate and, worse, turn neighbouring cells senescent and form an army of zombies. Persistent senescent cells can cause prolonged inflammation, tissue damage, and even cancer, so it is best not to have the zombies stay inside us for too long.
Cells rely on proteins for almost every task they do, as well as using them as vocabularies to talk to each other. They only carry out their pre-programmed functions when they receive, or do not receive, certain molecular signals. These functions include apoptosis – the cells’ self-destruct programme which they only execute when things go wrong. However, persistent senescent cells trick this self-destruct system by secreting an abnormally large amount of zombie proteins to suppress apoptosis and keep themselves alive. If we want to take these cells down, we will need to take the zombie proteins out of them.
To do so, we can harness the usual protein degradation pathways that work in all cells. All we need to do is tag the protein of interest with ubiquitin, then cellular mechanisms will kick in and take the tagged protein into protein shredders called proteasomes. The state of the art in this technology now is PROTAC, which combines a tagger enzyme and a selective protein trap into a dual-ended molecule; once our protein of interest binds to the trap, the enzyme will be in close proximity with the protein so that it does the tagging easily. As good as it sounds, the current form of PROTAC has a major pitfall as these molecules are difficult to design and optimise. Also, they are not specific to a particular cell type – if we apply them directly to treating senescence, they will also mess around with our healthy cells.
My project will look into using nanoparticles as a platform to host both components of PROTAC. This approach avoids the need for careful molecular design while keeping the tagger and trap close to each other. Even better, this platform is very versatile in that we can add other stuff to make the nanoparticles target senescent cells only and change the components to tailor them for different senescence-related diseases, like pancreatic cancer or Alzheimer’s. They may be the solution for an actual zombie apocalypse too, but for now, let’s focus on our inner walking dead.
Images were generated using biorender.com and NightCafe.
NanoDTC PhD Student, c2022