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Stemming the tide of dementia

Dr Rick Livesey once wondered how to ‘build’ a brain that might help shed light on neurodevelopmental disorders, so he and his team went ahead and built one in his lab at the University of Cambridge, UK. Today, he is leading a quiet revolution in the study of Alzheimer’s and other diseases.

A Corkman who is regarded as Ireland’s most recognised stem cell scientist worldwide, Dr Livesey started out studying medicine at University College Cork  (UCC) and now leads the work of the stem cell research centre at the Gurdon Institute in Cambridge.

He is a Faculty member of the Department of Biochemistry and a Fellow of Trinity College, Cambridge. Before starting his research group in Cambridge, he was a Howard Hughes Medical Institute Research Fellow at Harvard Medical School. He obtained his medical degree and PhD from the University of Cambridge.

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Dr Rick Livesey

“The stem cell techniques developed here in Cambridge have revolutionised how we can study diseases like Alzheimer’s,” Dr Livesey told the Medical Independent (MI), in an interview from Cambridge.

The work of the Livesey lab at the Gurdon Institute, named after the 2012 Nobel laureate Prof Sir John Gurdon (who still works at the lab at the age of 82 years), focuses on using human stem cells to study disease, with an eye to advances in drug development, as opposed to the area of transplantation of cells back into patients as a means of treatment.

“The focus of our research in the lab is on how the brain develops and ages, and how changes to this process can cause conditions such as Down syndrome and dementia,” Dr Livesey explains.

The ‘brains’ in Dr Livesey’s models are made up of human cells and have many of the properties of real brains but they cannot learn, do not think and are not sentient, so they are not ‘human’ in that sense.

They are essentially clusters of millions of nerve cells, electrically active and networked to each other. “We use stem cells to make human nerve cells and we make them from people with genetic forms of dementia, which allows us to replay the disease process in the lab over months rather than decades,” Dr Livesey told MI.

“That opens up lots of technical possibilities that allow us to study the nuts and bolts of the disease. You can study all this in a dish —how the disease starts and then progresses and how it affects how nerves communicate with one another. We think that’s an important early stage in the disease. That’s what lies behind the early forgetfulness and mild cognitive impairment stage.

“Long before neurons start dying, they start malfunctioning. You can study this in a dish in a way that you can’t obviously in a human and to a large extent you can’t in animal models. A big problem is that animals don’t reflect the disease, since mice or rats don’t get Alzheimer’s.”

Focus

He hopes that his team’s research will not only shed light on some of the key changes happening in the disease, but also provide a swift and streamlined tool for screening potential new Alzheimer’s treatments and drugs.

“Our initial focus has been on dementia, where we have used stem cells from people with Down syndrome and from patients with familial Alzheimer’s disease to create cell culture models of Alzheimer’s disease pathogenesis in cortical neurons. We are using those models to study Alzheimer’s disease pathogenesis and the efficacy of current therapeutic strategies.”

Dr Livesey did his undergraduate and pre-clinical medical studies in Cork before joining the MB/PhD programme at the University of Cambridge Clinical School. He did his post-doctoral work at the Department of Genetics at Harvard Medical School and started his group at the Gurdon Institute in September 2001.

‘The focus of our research in the lab is on how the brain develops and ages and how changes to this process can cause conditions such as Down syndrome and dementia’

His current research work in Cambridge, which he began about six years ago, emerged partly from his stem cell research in the United States, especially exploring brain stem cells, and much of his team’s work has grown out of that area of study.

“I wondered how you build a brain in the first place, and what happens in neurodevelopmental disorders. What it has shown us is how little we understand about the disease. For example, if we take a form of familial Alzheimer’s disease, where it’s one gene and one mutation that gives people the disease, we still have no clue how this actually really works in the brain and why you can get Alzheimer’s at 40 with this mutation.

“What it allows us to do is to look at the neurons and say ‘here’s what goes wrong’ and that has opened up all sorts of possibilities for us in terms of the fundamental biology of the disease.”

But major breakthroughs may be a long way off, he cautions. “Our understanding of the disease compared to, say, cardiovascular disease is probably 30 to 40 years behind,” Dr Livesey says.

“There was a time in the mid-1970s where it was considered normal for those in middle age to have heart attacks and so on and there wasn’t a lot you could do about it. Fast-forward 40 years and it’s considered highly unusual. Everyone’s healthier and lifestyles have been adjusted. You find people at risk sooner and you control things like blood pressure.

“Statins have transformed everything and that’s kind of where we are with dementia. We don’t understand some of the basic mechanisms that lead to the nerve cells malfunctioning, let alone dying off. That core information is going to lead to therapies in the same way that understanding cholesterol metabolism basically led to statins.”

How long will it take before we catch up on Alzheimer’s?

“It won’t take 40 years, that’s for sure. Biology has moved on so much — we can do things now that were unimaginable five or 10 years ago. But it’s very challenging to put a number on it.

“The UK Prime Minister has made all sorts of promises to try and get drugs into patients for dementia by 2020 or 2025, but that’s very optimistic. The only way you can do that is by re-purposing an existing drug. From scratch, it takes 10 or 15 years to get a new drug into people, so you have to have a certain degree of good fortune that there are existing drugs that you can re-purpose. That’s the challenge.”

Yet, the stem cell revolution is clearly picking up momentum, Dr Livesey notes.

“I was at an amazing [scientific] meeting last year where different possibilities were discussed.  There was a group from Australia talking about how they can make a mini kidney from stem cells. There are also people who can make little bits of lung tissue and even heart tissue from stem cells. Then the question is, how can they do it better and engineer it to a point where it’s functional? That allows you to study it but it also gets you thinking, can you transplant this stuff back?

“It’s an amazing time because of what’s possible. The field [of stem cell research] is moving so fast. It has continued to surprise us in terms of what’s possible. The CRISPR technology, which we all use for editing genes, means you can do things in biology now with a degree of precision that was unheard of.”

In addition to major work on Alzheimer’s, like that being carried out by Dr Livesey, current studies are researching how stem cells may be used to prevent or cure diseases and injuries such as Parkinson’s, type 1 diabetes, heart disease, spinal cord injury, muscular dystrophy, stroke, burns, osteoarthritis, and vision and hearing loss.

Ireland

Dr Livesey’s work is clearly ground-breaking, but here in his native Ireland researchers are worried that the field is restricted and patients may be losing out on new cures and treatments.

To counter this, the Medical Research Charities Group, representing a coalition of more than 30 organisations, called late last year for investment in medical research to be significantly increased.

“Medical research has been pivotal in increasing life expectancy, reducing infant mortality, limiting the toll of infectious diseases and improving outcomes for patients,” said the Group’s Chairman, Mr Philip Watt. 

“Clearly, without significant investment, Irish patients will be left at a serious disadvantage. Patients in very challenging disease areas will have to go abroad if they want to access clinical trials for promising therapies that could make a huge difference to their lives.

“Patients will also be left in the slow lane when it comes to accessing treatments and therapies in the early stages of development. It is simply not right that Irish patients should be treated as second-class [compared] to citizens in other European countries that really are pushing the boundaries and the possibilities of research,” noted Mr Watt.

But in addition to consistent investment, Ireland also needs policy development for such medical research, Dr Stephen Sullivan, Chief Scientific Officer of the Irish Stem Cell Foundation told MI.   

“Cultivating the appropriate environment for researchers such as Dr Livesey takes time and Ireland is unfortunately moving in the wrong direction, having disassembled the Council for Bioethics and the independent Office of the Chief Scientific Advisor in recent years.”

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