Lower vertebrates have a staggering regenerative capacity when compared to ourselves; newts can regenerate entire limbs, zebrafish are able to regrow fins and some frog species are able to reform tails after amputations. Zebrafish and newts are even capable of regenerating cardiac tissue when heart muscle cells (cardiomyocytes) are removed genetically or the apex of the heart ventricles are resected. As a consequence, much research has been focused on unravelling these, quite literally, superhuman abilities. I thought I’d look at what has been uncovered in the search thus far, and what it means for us feeble homo sapiens.
It’s not like our cells are completely hopeless; there are a number of regenerative therapies on the market already. Carticel, the first FDA approved therapy of this type, takes chondrocytes (cells which produce and form cartilage) expands the population of cells in the lab and then transplants the chondrocytes back into the patient to repair damaged cartilage. A number of similar therapies exist for burn victims and to treat wrinkles (laViv).
It’s likely reprogramming, where cells become less specialised, is what allows these lower vertebrates to carry out seemingly impossible feats of regeneration. In young newts, muscle precursor cells known as satellite cells can be recruited to the limb stump, differentiate into muscle and grow to reform the limb. However, in the adult newt it appears that skeletal muscle fibre cells are recruited to the stump and adopt a more primitive state – they dedifferentiate – and proliferate to form a blastema which then goes on to reform the limb within 90 days.
Humans are now able to ‘reprogram’ our skin cells into cells that can turn into any cell type in the body – these cells are called induced pluripotent stem cells (iPSCs). They exhibit many of the same characteristics as cells in human embryos which give rise to the multitude of different types of cells seen in the adult body. We’ve been able to do this since 2006 when Shinya Yamanaka identified – in Nobel Prize winning work – just 4 transcription factors that are able to change gene expression and revert cells back to a pluripotent state. These factors are called Oct3/4, Sox2, Klf4 and c-Myc and they were real game changers – they allowed researchers to turn back the developmental clock. Researchers can now take a sample of human skin, generate iPSCs and then grow mini-brains from those cells.
I’ve become increasingly fascinated with neurodegeneration – the progressive damage and loss of neurons seen in Alzheimer’s, Parkinson’s, Huntington’s and Amyloid Lateral Sclerosis (ALS) – so fascinated that I’ve just applied for funding for a summer research project investigating a particular gene that is mutated in some cases of ALS. Consequently, I have to talk about how regenerative medicine is attempting to tackle these incredibly complex, and increasingly prevalent, diseases. Researchers took skin cells from healthy individuals, reprogrammed them to iPSCs and then induced them to form the types of neurons that are lost in Parkinson’s; mid-brain dopaminergic neurons. These neurons were then transplanted into macaque monkeys. They found that the transplanted cells survived, and also that they improved neurological and movement scores significantly compared to the monkeys that didn’t receive the iPSC derived neurons.
Where do we go from here? The study I’m talking about was published in August 2017 and there are now a few clinical trials planned to assess the efficacy in humans. There are a number of potential issues with regenerative medicine using stem cells; as stem cells are reprogrammed they begin to look and act more like cancer cells raising the potential for tumour formation. The other key issue is that the personalised approach is hugely expensive. This is why Yamanaka and many others are creating banks of iPSCs so patients can be screened to find the best match.
I feel I should also emphasise that regenerative medicine is not just stem cells. Last year researchers published a paper describing a living ink which utilises bacteria’s diverse metabolic repertoire. Bacteria are embedded into a bioink which is used to print a hydrogel that contains the products of bacterial metabolism, this can then be moulded to create an organ for transplantation or biodegradable plastic.
Regenerative medicine is a field that is growing rapidly and one that may have come at the right time; we are all living longer, and our bodies are paying the price. So, can we be more like newts? Maybe. We’ll just need some 3D printers and induced pluripotent stem cells.