What is holding stem cell therapy back?
Cell therapy essentially means using cells as a treatment strategy for injury or disease, predominantly to replace cells that have lost their function or died. Stem cells are an exciting resource for this because they can be made into different types of cells, and the majority of cells that are needed for cell therapy cannot be collected from anywhere else — taking cells from a healthy person to treat a patient is not always feasible or ethical. Because stem cells in theory can be turned into anything, they can be used to replace lost cells, or to provide supportive cells that supply nutrients to encourage natural repair or regrowth. All sounds well, so what is holding stem cell transplant therapy back?
Imagine a machine is missing an integral cog right in its centre, and so can’t function properly. Now imagine taking some cogs that look pretty similar to those that that are missing, throwing them at the machine, and expecting the machine to start working again. This over optimistic approach is somewhat similar to a huge issue with stem cell transplantation. Replacing cells in a complex system by simply injecting them into the sort-of-rough-ish area where other cells have gone missing doesn’t mean that the replacement stem cells will know exactly where to go. Indeed, if they don’t know exactly where to go, it is likely that they won’t know exactly what to do if and when they get there. A good example is in the brain, where the complicated connections between cells are both vast in number and highly specific. Replacing lost cells in this intricately balanced system is not as simple as putting new cells in the general area of cell loss. A lot of work is being done to try and figure out what kinds of signalling molecules and directions are given by neighbouring cells to help encourage the proper integration of transplanted cells.
The transplantation of stem cells is particularly tricky, as it is very well documented that this can result in the formation of a tumour. The very nature of stem cells (that they can self-replicate and divide) mirrors the nature of tumorous cells: They divide uncontrollably. Because of this, most research into stem cell transplants does not actually involve transplanting stem cells into a person, but rather differentiating stem cells into a desired cell type (such as a pancreatic cell or skin cell), and then transplanting these. If a cell has completed its normal process of differentiation, it is much less likely that a tumour will form from it. A caveat of this is that it means we need to absolutely understand the detailed instructions that each kind of cell follows to become whatever it may be, and there are a lot of very specific cells that follow very specific instructions. Deciphering these instructions is a complicated business.
Another issue is host rejection. Many people are aware of the notion of rejection as a possibility after organ transplants, and the concept of “finding a good match” is often documented in films describing transplantation of bone marrow stem cells or organs such as kidneys. Transplant rejection happens because each cell from your body has a sort of barcode on its surface that is recognised by the body’s immune system. These barcodes mean that cells can be identified as “self”; they belong to the person, or “non-self” — the cell is from something (or someone) else, and therefore could be dangerous. This system means that the body can recognise the non-self-barcode on the outside of pathogenic cells such as those that have been hijacked by harmful bacteria, but it also means that cells or organs that are transplanted as a therapy can also be recognised as non-self. If this happens, the body’s immune system tries to get rid of these invaders by eliciting an immune response against them. There are similarities between some people’s barcodes, so if a person with a similar enough pattern is identified (and is willing to donate…) they might be selected as a match. But even this doesn’t guarantee success, and often well matched donor cells don’t manage to sneak past the patient’s immune system undetected. Recognition as non-self doesn’t only mean that the cells don’t integrate and serve their intended purpose, but the immune attack causes the unpleasant symptoms associated with infection which can leave the patient feeling huge discomfort. In autoimmune disease, the immune system fails to recognise the body’s own cells as “self” and so turns on itself, causing some really nasty disorders.
There is hope that the use of induced pluripotent stem cells (iPSCs) might help avoid the issue of immune mediated rejection. As an example of how this might work: A person is missing some very specific brain cells which is causing them to develop dementia. This person then donates a blood sample, a scientist in a lab turns these blood cells into stem cells, subsequently turns these into those very specific missing brain cells, and transplants them back into the same person. Because the blood cell that was used to make the stem cells in the first place came from the individual that is receiving the brain cell transplant, the barcode on these brain cells will be recognised as “self” by the immune system. This kind of transplant may reduce immune activation, meaning that the transplanted cells are much more likely to survive. At this point we need to remember the cog and machine: Just because a cell might be able to serve a function once in the correct place, it doesn’t necessarily mean it knows exactly where to go in order for this to happen. Furthermore, any kind of surgery carries a risk of bacterial infection, and matching barcodes won’t avoid this problem at all.
Stem cells can also be used for experimental purposes, such as modelling a disease in a dish to screen potential drugs. This is an exciting advancement as up until now the majority of experiments completed with cells in a lab were done in cancer cells, which don’t accurately represent a lot of the different cells that exist in the body. Even in this scenario there are limitations. iPSCs are still just cells, and don’t truly represent the intricacies of the network of cells that make up organs and the body. There is a possibility that during the process of making iPSCs genetic mutations can randomly occur in the cell’s DNA, which then affects experimental results. You can imagine how this risk of forming genetic mutations is also problematic when making stem cells to transplant into a person — if the mutation that is formed is dangerous, the transplant could actually be harmful. Stem cells are also very expensive to make and work with in comparison to other kinds of cells, and working with them can be extremely laborious with slow results.
We are excited about the potential of pluripotent stem cells in both research and medicine — but with limitations such as these in mind, it is time to reassess the “wonder-cell” myth that is currently being sold.
