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Scientists streamline stem cells to treat macular degeneration

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Age-related macular degeneration affects the macula resulting in a blurriness in the central part of visual field

As we age, so do our eyes. Most commonly, this involves changes to vision and new glasses, but there are more severe forms of age-related eye problems.

One of these is age-related macular degeneration, which affects the macula — the back part of the eye that gives people sharp vision and the ability to distinguish details.

The result is a blurriness in the central part of visual field.

The macula is part of the eye’s retina, which is the light-sensitive tissue mostly composed of the eye’s visual cells: cone and rod photoreceptor cells.

The retina also contains a layer called the retinal pigment epithelium (RPE), which has several important functions, including light absorption, cleaning up cellular waste, and keeping the other cells of the eye healthy.

The cells of the RPE also nourish and maintain the eye’s photoreceptor cells, which is why one of the most promising treatment strategies for age-related macular degeneration is to replace ageing, degenerating RPE cells with new ones grown from human embryonic stem cells.

Scientist have proposed several methods for converting stem cells into RPE, but there is still a gap in knowledge of how cells respond to these stimuli over time.

For example, some protocols take a few months while others can take up to a year. And yet, scientists are not clear as to what exactly happens over that period of time.

Mixed cell populations

“None of the differentiation protocols proposed for clinical trials have been scrutinised over time at the single-cell level – we know they can make retinal pigment cells, but how cells evolve to that state remains a mystery,” said Dr Gioele La Manno, a researcher with EPFL’s Life Sciences Independent Research (ELISIR) programme.

“Overall, the field has been so focused on the product of differentiation, that the path undertaken has been sometimes overlooked,” he added.

“For the field to move forward, it is important to understand aspects of the dynamics of what happens in these protocols.

“The path to maturity could be as important as the end state, for example for the safety of treatment or for improving cell purity and reducing production time.”

Tracking stem cells

La Manno has now led a study with Professor Fredrik Lanner at the Karolinska Institutet in Sweden profiling a protocol for differentiating human embryonic stem cells into RPE cells that is actually intended for clinical use.

Their work shows that the protocol can develop safe and efficient pluripotent stem cell-based therapies for age-related macular degeneration.

The study is published and featured on this month’s cover of the journal Stem Cell Reports.

“Standard methods such as quantitative PCR and bulk RNA-seq capture the average expression of RNAs from large populations of cells,” said Alex Lederer, a doctoral student at EPFL and one of the study’s lead authors.

“In mixed-cell populations, these measurements may obscure critical differences between individual cells that are important for knowing if the process is unfolding correctly.”

Instead, the researchers used a technique called single-cell RNA sequencing (scRNA-seq), which can detect all the active genes in an individual cell at a given time.

Intermediate states

Using scRNA-seq, the researchers were able to study the entire gene expression profile of individual human embryonic stem cells throughout the differentiation protocol, which takes a total of 60 days.

This allowed them to map out all the transient states within a population as they grew into retinal pigment cells, but also to optimise the protocol and suppress the growth of non-RPE cells, thus preventing the formation of contaminant cell populations.

“The aim is to prevent mixed cell populations at the time of transplantation, and to make sure the cells at the endpoint are similar to original RPE cells from a patient’s eye,” said Lederer.

What they found was that on the way to becoming RPE cells, stem cells go through a process very similar to early embryonic development.

During this, the cell culture took up a ‘rostral embryo patterning’, the process that develops the embryo’s neural tube, which will go on to become its brain and sensory systems for vision, hearing, and taste.

After this patterning, the stem cells began to mature into RPE cells.

Eye-to-eye

But the point of the differentiation protocol is to generate a pure population of RPE cells that can be implanted in patients’ retinas to slow down macular degeneration.

So the team transplanted their population of cells that had been monitored with scRNA-seq into the sub-retinal space of two female New Zealand white albino rabbits, which are what scientists in the field refer to as a ‘large-eyed animal model’.

The operation was carried out following approval by the Northern Stockholm Animal Experimental Ethics Committee.

The work showed that the protocol not only produces a pure RPE cell population but that those cells can continue maturing even after they have been transplanted in the subretinal space.

“Our work shows that the differentiation protocol can develop safe and efficient pluripotent stem cell-based therapies for age-related macular degeneration,” said Dr Fredrik Lanner, who is currently making sure the protocol can be soon used in clinics.

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On a mission to show that hearing loss is not inevitable

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The world’s largest investigation into the effectiveness of hearing training kicks off this week – as part of a movement to prove that hearing loss is not an inevitable part of ageing.

The research project aims to attract a minimum of 10,000 participants to better understand how hearing training impacts auditory processing skills like speech comprehension and the ability to locate where sounds are coming from.

Researchers are interested in the impact of hearing training on users who start training with different hearing ability levels, as well as training adherence in groups with different attitudes to smartphone technology.

Their aim is to find new ways to deliver and improve auditory training at scale and for a wider range of hearing skills; and to measure factors which influence training engagement.

The research is led by health tech firm Eargym. Co-founder Andy Shanks says:  Contrary to popular belief, hearing loss is not an inevitable consequence of ageing. We can take steps to improve and protect our hearing throughout our lives, yet preventative measures like hearing training have traditionally been under-researched.

“Our data shows the transformative impact hearing training can have on our ability to process sounds. Now, we want to deepen and widen our research and use our platform to make hearing training even more effective and accessible. Imagine improving and maintaining your hearing by up to 20% or more: it could make a big difference to the lives of so many people.”

The games on the Eargym app include a “busy barista” exercise, where users must discern speech over a cafe’s bustling background noise; and a “sound seeking” exercise, where users make their way through forests, jungles and oceans to locate the sources of different sounds. Each game is designed to be immersive and to help users practise specific auditory processing skills regularly.

Eargym was set up by former NHS CEO Amanda Philpott and DJ Andy Shanks in 2020, after they were both diagnosed with hearing loss. Amanda has moderate age related hearing loss, whilst Andy has “notch” or noise-induced hearing loss due to DJ-ing. Both found hearing loss isolating and it impacted their ability to socialise and communicate. They created eargym to empower others to better understand their hearing health and take proactive steps to protect it.

Hearing loss currently affects 18 million adults in the UK, with around one billion young people at risk of developing hearing loss due to increased use of headphones. Hearing loss is closely associated with increased dementia risk. Despite this, people wait an average ten years before seeking help for hearing loss.

Eargym plans to publish the findings of its research in early 2025.

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Interview: Exploring electrical stimulation for Parkinson’s disease

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The STEPS II study is investigating functional electrical stimulation (FES) in people with Parkinson’s disease to help improve their walking. Dr Paul Taylor, co-founder and Clinical Director of Odstock Medical Ltd (OML), spoke to Agetech World to tell us more.

Bradykinesia – slowness of movement which can lead to difficulty walking – affects many people living with Parkinson’s disease. The symptom can cause Parkinson’s patients to walk or move slowly, increasing the risk of falls, leading to a reduced quality of life and an increased dependence on others. 

Funded by the National Institute for Health and Care Research, sponsored by Salisbury NHS Foundation Trust, and managed by the University of Plymouth’s Peninsula Clinical Trials Unit, the STEPS II study is exploring the use of an FES device in Parkinson’s patients to help improve bradykinesia. 

The FES device, which has been pioneered by Salisbury researchers as a drop foot treatment for stroke and MS patients, is attached to the patient’s leg and produces small electrical impulses that improve movement.

“If you have Bradykinesia you’re moving slowly. The predominant treatment for Parkinson’s is medication and these can be very effective, but they have the problem of not working all the time,” explains Taylor, co-founder of Odstock Medical Ltd, a company owned by Salisbury NHS Foundation Trust.

”The effects of the drugs will wear off and after a period of time they become less effective, so, there’s a need for improvement.”

Taylor explains that deep brain stimulators are currently available, however, they are very invasive, expensive and can be risky. 

“We’re trying to do something which is a bit simpler and cheaper, which may possibly be able to help people at an earlier stage of Parkinson’s,” Taylor says.

“We’re stimulating the common peroneal nerve, which is the nerve that goes down the leg to the muscles, using a device called a drop foot stimulator. The device is commonly used for stroke and multiple sclerosis.”

A small feasibility study has already been conducted, which showed that FES can help patients walk faster and reduce some symptoms of Parkinson’s. 

In the STEPS II study, researchers hope to confirm the long-term effects of FES on walking speed and daily life with 234 participants at sites across Salisbury, Birmingham, Prestwick, Leeds, Swansea and Carlisle.

Taylor continues: “Our original idea was that we could use electrical stimulation to overcome freezing – which is the effect where people with Parkinson’s will stop walking, particularly when they come to doorways or very narrow areas. It’s to do with the processing of information from the outside world. 

“We wanted to see if we could use electrical stimulation to overcome that freezing and, to a certain extent, we did find that is the case for some patients, but more commonly and with a greater number of patients FES affected bradykinesia – speeding up their movement and helping with more effective walking.”

For the STEPS II study, participants will be randomised into a care as normal group, or a care as normal plus FES group. They will use the stimulator if they are in the FES group for 18 weeks, then the stimulator is taken away, with patients followed up one month later to see if the effects are continued.

Measurements of walking speed and movement will be analysed, along with sensory perception, balance, coordination, muscle strength, as well as secondary effects such as how the device impacts daily living and quality of life.

OML has established clinics around the country with trained therapists where the device will be used if the study is successful. 

“There’s a network of clinics already experienced in using the treatment so we plan to reach those clinics to include Parkinson’s patients in their cohorts,” says Taylor. “Then we’ll work with our contacts to see if we can get it overseas as well.”

OML is currently recruiting participants for the study, to find out more please visit: https://www.plymouth.ac.uk/research/penctu/steps-2 

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Quit Googling to stave off dementia onset, expert urges

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Resisting the temptation to search the web for information that could otherwise be recalled be exercising your brain could help to reduce the risk of dementia.

That is according to Canadian academic Professor Mohamed I. Elmasry who believes simple daily habits such as afternoon naps, memory ‘workouts’ and not reaching for a smartphone can increase the odds of healthy aging.

His new book, iMind: Artificial and Real Intelligence, says the focus has shifted too far away from RI (natural, or real) intelligence in favour of AI (machine, or artificial) intelligence. Elmasry instead calls us to nurture our human mind which, like smartphones, has ‘hardware’, ‘software’ and ‘apps’ but is many times more powerful – and will last much longer with the right care.

Professor Elmasry, an internationally recognised expert in microchip design and AI, was inspired to write the book after the death of his brother-in-law from Alzheimer’s and others very close to him, including his mother, from other forms of dementia.

Although he says that smart devices are ‘getting smarter all the time’, he argues in iMind that none comes close to ‘duplicating the capacity, storage, longevity, energy efficiency, or self-healing capabilities of the original human brain-mind’.

He writes that: “The useful life expectancy for current smartphones is around 10 years, while a healthy brain-mind inside a healthy human body can live for 100 years or longer.

“Your brain-mind is the highest-value asset you have, or will ever have. Increase its potential and longevity by caring for it early in life, keeping it and your body healthy so it can continue to develop.

“Humans can intentionally develop and test their memories by playing ‘brain games,’ or performing daily brain exercises. You can’t exercise your smartphone’s memory to make it last longer or encourage it to perform at a higher level.”

In iMind: Artificial and Real Intelligence Professor Elmasry shares an anecdote about his grandchildren having to use the search engine on their smartphones to name Cuba’s capital—they had just spent a week in the country with their parents.

The story illustrates how young people have come to rely on AI smartphone apps instead of using their real intelligence (RI), he says, adding: “A healthy memory goes hand-in-hand with real intelligence. Our memory simply can’t reach its full potential without RI.”

Published by Routledge, iMind: Artificial and Real Intelligence includes extensive background on the history of microchip design, machine learning and AI and their role in smartphones and other technology.

The book also explains how both AI and human intelligence really work, and how brain function links the mind and memory. It compares the human mind and brain function with that of smartphones, ChatGPT and other AI-based systems.

Drawing on comprehensive existing research, iMind aims to narrow the knowledge gap between real and artificial intelligence, to address the current controversy around AI, and to inspire researchers to find new treatments for Alzheimer’s, other neurodegenerative conditions and cancer.

It argues that current or even planned AI cannot match the capabilities of the human brain-mind for speed, accuracy, storage capacity and other functions. Healthy aging, Professor Elmasry notes, is as important as climate change but doesn’t attract a fraction of the publicity.

He calls for policymakers to adopt a series of key reforms to promote healthy aging. Among such changes, he suggests that bingo halls could transition from their sedentary entertainment function to become active and stimulating learning centers.

As well as napping to refresh our memories and other brain and body functions, he also outlines a series of practical tips to boost brain power and enhance our RI (Real Intelligence).

These include building up ‘associative’ memory – the brain’s ‘dictionary of meaning’ where it attaches new information to what it already knows. Try reading a book aloud, using all of your senses instead of going on autopilot and turning daily encounters into fully-lived experiences.

Other techniques include integrating a day for true rest into the week, reviewing your lifestyle as early as your 20s or 30s, adopting a healthy diet, and eliminating or radically moderating alcohol consumption to reduce the risk of dementia.

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