Joseph Jebelli is a Neuroscience PhD Candidate at University College London (UCL). His research involves studying the cellular and molecular mechanisms of neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease.
New research suggests that human embryonic stem cells, which are experimentally manipulated to develop into mature neurons to model brain diseases, may in fact more closely represent foetal brain cells than those seen in the ageing brains of disease sufferers.
Over the past 20 years, scientists have been exploring the potential of stem cells to provide therapeutic intervention in a variety of brain disorders, such as Alzheimer’s disease, Parkinson’s, and stroke.
The aims are twofold: 1. to harness them as a cellular transplantation therapy, effectively replacing the cells lost in disease, and 2. to generate particular types of neurons in isolation, and to examine what causes them to die in the brain in the first place. At present, the latter is a more realistic goal.
Indeed, the ability to provide researchers with accurate cellular models of disease is crucial as nearly all the current knowledge on neurological disorders has been gathered from post-mortem brain tissue. Although insights have been gleaned from such samples, they fail to illuminate how a disease progresses and develops.
This is a major problem, as disease models that only represent the end-stage of a condition, such as Parkinson’s disease, greatly confound the challenges of early diagnosis and the search for effective therapeutic intervention. What’s more, post-mortem samples may exhibit aspects of pathology not related to the condition under scrutiny, making it difficult to winnow the real disease culprits from the natural process of decay.
Thus, the power of stem cells to faithfully recapitulate disease mechanisms, as they evolve, and in defined cells populations, is one of the greatest boons to medical research in the last one hundred years.
“Stem cells are going to be an incredibly important tool for us to be using to understand brain disorders over the next ten or fifteen years,”
Professor John Hardy, a geneticist from University College London (UCL), and the most cited Alzheimer’s disease researcher in the UK.
“At the moment we’re just trying to make cells, but I think we’re moving towards trying to make whole pieces of brain tissue so that we can also study the interactions between brain cells in stem cell derived material.”
But whilst stem cell technology has offered an unprecedented opportunity to gain insights into the underlying causes of neurological disease, there has been widespread concern over whether they can be considered true replicas of the cells found in the brain of a fully grown adult.
On this basis, a collaboration of scientists from several of the top research institutes in the United Kingdom have employed state of the art genetic sequencing technology to comprehensively map and compare the genomes of stem cell-derived neurons to naturally occurring neurons from the foetal and mature human brain.
To their surprise, the genetic maturity of the neurons was more equivalent to foetal, and not adult, brain tissue. As the cells both looked and behaved like normal neurons, it is now thought that the underlying genetic age of a cell may be more significant than their functional characteristics seen when viewing them down a microscope.
Joint lead author, Dr Patrick Lewis, a postdoctoral researcher specialising in Parkinson’s disease at UCL, said the results shouldn’t have come as a surprise.
“It was difficult to know what to expect, as a study like this hadn’t been attempted before. In a way, perhaps we shouldn’t have been surprised by the results, given that embryonic stem cells derive (by definition) from an embryonic source.”
In the stem cell community, a major upshot of these findings is to now develop ways of accelerating the maturation of these neurons, to more closely resemble their adult counterparts. The hope is that this will lead to more clinically relevant disease models, but exactly how it might be achieved is still an enigma.
Dr Rickie Patani, lead author and postdoctoral clinical research associate from Cambridge University, said the key may lie in changing the environment in which the cells are grown.
“One example would be by introducing supporting cells (‘glia’) that are normally present around nerve cells in the body – indeed there is some evidence to suggest that a group of these supportive cells, called astrocytes, can accelerate the acquisition of electrical properties within nerve cells if they are grown together in close proximity.”
“Such manoeuvres may act by simply changing the chemical signals around growing nerve cells, suggesting that we may eventually be able to achieve accelerated maturation by introducing a single defined chemical into these cell culture systems.”
All in all, what appears to be unequivocally accelerating is the pace and potential of stem cell research into a wide variety of devastating brain disorders.