Artwork by Matthew Kurnia
This article was originally published in The Oxford Scientist Hilary Term 2022 edition, Regeneration.
‘The next great advance in medical care will not be a magical pill, it will be a miraculous cell called the mesenchymal stem cell’.
Speaking at a TEDx event in Ashland, Oregon in 2019, American physician Dr Neil Neimark sang the praises of stem cell therapies and their great potential for treating disease. He is not alone in his optimism. Over the last few years, the number of studies investigating the ability of stem cells to treat notoriously difficult conditions has skyrocketed, with nearly 13,000 papers published in 2021 alone. Their promise is particularly great for degenerative diseases, where drugs typically fail to reverse decades of accumulated damage.
One such condition is Alzheimer’s disease. As the most common form of dementia, Alzheimer’s is estimated to affect over 50 million people worldwide. Although at first patients present only mild memory problems, this progressive neurodegenerative condition rapidly produces severe cognitive deficits. Eventually, patients lose their ability to walk, talk and look after themselves. Moreover, with a continually aging global population, the number of people living with Alzheimer’s is expected to surpass 150 million by 2030, making it an intensifying global health crisis.
From Alois Alzheimer’s initial description of Alzheimer’s disease in 1907 as a “peculiar disease of the cerebral cortex”, our understanding of its causes has grown enormously. We now know that the condition starts long before symptoms appear with the accumulation of toxic amyloid beta molecules which form sticky deposits called plaques on neurons in the brain. In the early stages of the disease, these plaques are particularly prevalent in the hippocampus, a region associated with learning and memory. They also cause further harmful processes, including neuroinflammation and the aggregation of intracellular proteins known as tau tangles. These changes lead to the loss of synapses (the junctions between neurons via which they communicate), the neurons themselves and eventually large portions of brain tissue. This loss of neurons is ultimately what produces the decline in memory and cognitive function experienced by patients.
Despite this knowledge, the development of treatments for Alzheimer’s has stagnated. Until last year, the only drugs available for Alzheimer’s patients merely improved the symptoms of the disease in its early stages and had no effect on patient life expectancy. Although there was much excitement in 2021 when the United States Food and Drug Administration approved the use of Aducanumab, the first drug to target amyloid plaques, long-term effectiveness remains undetermined.
There are currently no approved therapies that tackle neuronal loss in Alzheimer’s disease. This is where stem cells may be the ideal solution.
Stem cells are undifferentiated cells found throughout life. They have two incredible characteristics: their ability to self-renew, meaning they can indefinitely produce more undifferentiated cells, and their capacity to differentiate into various mature cell types. In the right environment, stem cells can become highly specialised, producing everything from cardiac muscle cells in the heart to neurons in the brain. Thus, this power could be harnessed to treat Alzheimer’s disease by regenerating the neurons that have been lost.
Several different approaches to stem cell therapy have been trialled in animal models of Alzheimer’s so far. Embryonic stem cells come from the cluster of cells which develops in the days following egg fertilisation. These cells can differentiate into any cell in the human body, including specialised neurons.
Researchers have shown that implanting human embryonic stem cell-derived neurons into the relevant regions of the brain of a mouse model of Alzheimer’s disease could improve memory and learning performance. They have also been successfully applied in other neurodegenerative conditions including macular degeneration (an age-related breakdown of part of the retina).
Mesenchymal stem cells, the cells Dr Neimark so vehemently advocates for, are produced later in development and are found in abundance in umbilical cord blood, as well as in adult bone marrow and fat. These cells can produce most adult cell types and have an enormous advantage over other stem cells – they can be harvested and readministered to the same person; a process termed autologous transplantation. Mesenchymal stem cells have been successfully implanted into the brains of mice with Alzheimer’s pathology, where they were able to reduce amyloid plaques, tau tangles and inflammatory markers, as well as improve spatial memory.
Neural stem cells are highly specialised and are only found in a few places in the adult brain, predominantly in the hippocampus. Although these cells have a much narrower developmental capacity, they can differentiate into different types of neurons as well as astrocytes, the support cells of the brain. Given their location in the memory-storing region of the brain and their natural propensity for producing neurons, neural stem cells are great targets for Alzheimer’s therapies. So far, studies have shown that their transplantation into the brains of rodents has increased new neuron formation and improved brain function. Moreover, these transplanted cells release signalling molecules and growth factors that can stimulate the renewal of existing cells in the brain, in essence helping damaged tissue to repair itself.
Despite these early successes, stem cell approaches remain complex and have faced major controversy. Firstly, the innate ability of stem cells to self-renew and differentiate can lead to the formation of cancers where they are implanted. This is a particular problem with embryonic stem cells, which by nature divide exponentially, wreaking havoc if their differentiation is not controlled. Moreover, the immune system tends to reject foreign implanted cells, meaning the body will likely try and destroy the therapy before it has had time to take effect.
Then, of course, there are ethical concerns, especially regarding the use of embryonic stem cells. Some human rights groups and devout Christians are opposed to the use of embryonic stem cells as they come from fertilised eggs. If life begins at conception, the harvesting of stem cells is preventing that embryo from becoming a life, and the Bible teaches ‘thou shalt not kill’.
Even major funding bodies like the Alzheimer’s Society do not financially support studies on embryonic stem cell therapies, citing patient objections for this decision. However, other religions take a different stance—embryonic stem cells are harvested before many Muslim scholars believe human life begins and thus ‘research on human embryonic stem cells is permissible if they are obtained from in vitro fertilisation and are not viable’ (Supreme Council of Health in Qatar). However, the alternative, mesenchymal stem cells, have also faced controversy. Although adults can consent to the donation of their own stem cells, their collection from umbilical cord blood has angered many. The ethical dilemma is clear.
Due to their highly complicated nature and the debates about their use, there have only been a handful of clinical trials of stem cell therapies in Alzheimer’s disease. In 2015, a study of nine patients with mild Alzheimer’s disease reported that a single infusion of umbilical cord blood stem cells into the hippocampi was safe and produced no severe adverse effects after two years. In 2019, this was extended to three intravenous infusions of stem cells, but this trial is yet to publish its results. However, the safety of these approaches was questioned in 2019 when a study of 21 subjects given nine infusions of autologous stem cells (collected from fat tissue) reported side effects of cancer, pulmonary embolisms and severe fatigue. Nonetheless, ongoing trials are hopeful of their ability to optimise implantation methods and minimise experience of negative side effects.
One way to tackle these issues could be to compare Alzheimer’s to Parkinson’s disease, where stem cell therapies have advanced and are now being tested more broadly. Here, stem cells are specifically differentiated into dopamine neurons to replace those lost to the disease. Nevertheless, these comparisons highlight an overarching concern that, like the drugs currently used to treat Alzheimer’s and Parkinson’s, stem cells are still unlikely to cure the neurodegenerative condition. Describing a patient who received stem cell therapy over 20 years ago, Parkinson’s researcher Dr Jeff Bronstein says, ‘he was a successful patient, but the disease keeps progressing.’ Dr Bronstein believes the mistake people make is that they look at stem cell transplantation as disease-modifying therapy. ‘It’s not. It has the potential to improve disease symptoms, but it can’t alter the course of disease’.
Nonetheless, many still have hope for the regenerative power of stem cells. According to Dr Tilo Kunath, a biologist at the University of Edinburgh, stem cell therapies ‘will have some teething problems at the beginning, as any new therapy would’, but he hopes for a future where improved implantation techniques could revolutionise the treatment of degenerative conditions. It is clear that much more research is needed into stem cell therapies before their true usefulness can be ascertained. However, what will likely be an even greater challenge is the gaining of public trust concerning these strange but powerful cells.