Roughly 60% of the 12 million animal experiments in Europe each year involve mice. But despite their undoubted usefulness, mice haven’t been much help in getting successful drugs into patients with brain conditions such as autism, schizophrenia or Alzheimer’s disease. So too have researchers grown 2D human brain cells in a dish. However, human brain tissue comprises many cell types in complex 3D arrangements, necessary for true cell identity and function to emerge.
Researchers are hopeful that lab grown mini-brains – tiny 3D tissues resembling the early human brain – may offer a more promising approach. ‘We first published on them in 2013, but the number of brain organoid papers has since skyrocketed, with 300 just last year,’ says Madeline Lancaster at the Medical Research Council’s Laboratory of Molecular Biology lab in Cambridge, UK.
Lancaster was the first to grow mini-brains – or brain organoids – as a postdoc in the lab of Juergen Knoblich at the Institute of Molecular Biotechnology in Vienna, Austria. The miniature brains comprised parts of the cortex, hippocampus and even retinas, resembling a jumbled-up brain of a human foetus.
‘We were stunned by how similar the events in the organoids were to what happens in a human embryo,’ says Knoblich. To be clear, the brain tissue is not a downsized replicate. Lancaster compares the blobs of tissue to an aircraft disassembled and put back together, with the engine, cockpit and wings in the wrong place.
Growing mini brains to discover what makes us human | Madeline Lancaster. Video: TEDx Talks
‘The plane wouldn’t fly, but you can study each of those components and learn about them. This is the same with brain organoids. They develop features similar to the human brain,’ she explains.
Psilocybin mushrooms have psychedelic properties. Image: Wikimedia Commons
The psychoactive compound in psychedelic ‘magic mushrooms’ could pave the way for new drugs to treat depression, according to a new study. Patients in the study reported that their mood had lifted, they felt less depressed and were less stressed immediately after taking psilocybin. Nearly half (47%) were still benefiting five weeks after discontinuing treatment.
Robin Carhart-Harris and his team at Imperial College London, UK – the Psychedelic Research Group – gave psilocybin to 19 patients suffering from ‘treatment resistant’ depression, who had failed to benefit from other depression therapies. They were given 10mg initially and 25mg one week later.
The Psychedelic Research Group is the first in 40 years to use LSD in research in the UK since the Misuse of Drugs Act 1971. Image: Pixabay
‘Several of our patients described feeling “reset” after the treatment and often used computer analogies,’ said Carhart-Harris. ’Psilocybin may be giving these individuals the temporary kick start they need to break out of their depressive states.’
Functional MRI scans measuring activity and blood flow in the brain showed marked differences after the treatment. There was reduced blood flow to areas of the brain, including the amygdala, which processes emotional responses, such as stress and fear. Another brain network appeared to ‘stabilise’ after treatment.
‘fMRI scans indicate that the communication within a certain prefronto-limbic circuit known to regulate affective responsiveness, is normalised one day after psilocybin treatment,’ said Imperial College psychologist Tobias Buchborn. ‘This normalisation seems specifically related to the feeling of unity experienced during the psilocybin session.’
The trial didn’t include a control/placebo group for comparison. However, the team plans to compare the effects of psilocybin against a leading antidepressant in a six-week trial in 2018.
Scientists used neuroimaging to track the effectiveness of the treatment.
‘These are exciting, but preliminary findings,’ said Mitul Mehta, professor of neuroimaging & psychopharmacology at King’s College London. ‘It is only a single dose of psilocybin, but this was able to reduce symptoms and produce changes in the same brain networks we know are involved in depression. This impressive study provides a clear rationale for longer-term, controlled studies.’
‘Some of the next challenges are to see if the therapeutic effects hold up in larger groups,’ commented Anil Seth, professor of cognitive and computational neuroscience at Sussex University, UK: ‘And to understand more about how the changes in brain activity elicited by psilocybin underpin both the transient changes in conscious experience the drug produces, as well as the more long-lasting effects on depression.’
Psychedelics: Lifting the veil | Robin Carhart-Harris | TEDxWarwick Video: TEDx Talks
The trial also backs up the results of an earlier study by Robin Carhart-Harris and coworkers in 2016, which found that psilocybin reduced symptoms in 12 treatment resistant patients, five of whom were no longer classed as depressed three months later. Also in 2016, a trial by other researchers in the US demonstrated that a single dose could alleviate the anxiety and depression of people with advanced cancer for six months or longer.
What is paralysis? Video: Doctors’ Circle
Patients suffering from paralysis can at last look forward to a time when their condition is cured, and they can walk, run or move their damaged limbs again, as recent advancements show the possibility of reversal.
‘The environment has never been better for exploring ways to restore neurological function, including paralysis – in fact, there has been a dramatic escalation of the entire research spectrum aimed at functional neurorestoration,’ says Charles Liu, Director of the University of Southern California Neurorestoration Center.
Paralysis comes in many forms: the paralysis of one limb (monoplegia), one side of the body (hemiplegia), below the waist (paraplegia), and all four limbs below the neck (tetraplegia, or also referred to as quadriplegia).
There are many classifications of paralysis. It can be localised or generalised, and can affect most areas of the body. Image: Pixabay
In an able-bodied person, the brain sends a signal as an electrical impulse, known as an action potential, down the spinal cord to the peripheral nerves, which instruct the muscles to contract and move, whereupon sensors in the muscles and skin send signals back to the brain.
In most paralysis cases, the condition occurs as a result of damage to nerves rather than an injury to the affected area. Strokes are the most common cause of paralysis, followed by spinal cord injuries. Multiple sclerosis, cerebral palsy, polio, head injuries and several other rare diseases can also cause paralysis.
‘Long term, we hope to cure paralysis and make the injured walk,’ explains William Sikkema, a graduate student at Rice University, Houston. The challenge is not only to repair cells but to restore connectivity, too. In collaboration with researchers at Konkuk University in South Korea, the team has already made a paralysed rat walk again.
The addition of graphene nanoribbons restored motor and sensory neuronal signals across the previous nerve gap after 24 hours, with almost perfect motor control recovery after a period of healing. ‘Two weeks later, the rat could walk without losing balance, stand up on his hind limbs and use his forelimbs to feed himself with pellets. No recovery was observed in controls,’ the team reported.
‘After a neuron is cut, it doesn’t know where to grow. So, it either doesn’t grow, or grows in the wrong direction,’ says Sikkema. ‘Our graphene nanoribbons act as a scaffolding track, and it tells the neurons where to grow.’
Rats are a common animal model in paralysis studies, as they share similar structure and functions with humans. Image: Pexels
Spinal cord stimulation
Electrical stimulation of the spinal cord could also provide a big breakthrough, says Chet Moritz, Co-Director of the Center for Sensorimotor Neural Engineering at the University of Washington, US.
‘We’re seeing some really impressive results with spinal cord stimulation where people with complete paralysis, who have been unable to function, have regained control of their limbs. We didn’t expect this. It’s the most exciting thing we’ve seen in the last 20 years,’ he says.
Last year, a team led by Grégoire Courtine at the Swiss Federal Institute of Technology inserted an implant in the brains of paralysed monkeys and another over the spinal cord below the injury. The brain-spine interface worked by capturing leg-moving brain signals, decoded by a computer and sent – bypassing the damaged region – to the second implant, which delivered the signals as electrical impulses to the nerves, causing the leg to move.
Grégoire Courtine talks about his pioneering work on paralysis using electrical stimulation. Video: TED
Within six days, the monkeys had regained the use of their lower limbs and improved even more over time. The success of the experiment has led Courtine to launch a human trial of a spinal implant system.
We may be a long way still from restoring full function, as prior to paralysis, but Moritz is optimistic. Even a modest change, such as the movement of a single finger, can have a dramatic effect on quality of life and independence. ‘In five years, we’ve had dramatic improvement in function,’ he says. ‘It’s an exciting trajectory with tremendous potential.’
In recent years, novel innovation in healthcare and pharmaceuticals have hit the headlines with increasing regularity. Each story promises a better quality of life for patients and a product that will ‘revolutionise’ healthcare as we know it.
However, many of these innovations fail to materialise due to the complexity of the system. Problems with regulation, intellectual property agreements, and manufacturing are just some of the many issues that industry faces when integrating a new product into hospitals and treatment centres.
Stephen Dorrell. Image: NHS Confederation@Flickr
So, do we need rethink our expectations of innovation? Speaking at New Scientist Live in September, Stephen Dorrell, Chair of NHS Confederation and a former Health Secretary, said that as an innate characteristic of humans, innovation will not stop. However, we should be more concerned about the difficulty of making good innovation available everywhere and rethinking what we consider the most efficient way of treating patients, he said.
As the most common type of dementia – affecting one in six over the age of 80 – Alzheimer’s disease needs good innovation. With no known cure, current efforts rely heavily on having a care plan once symptoms appear and medications can only slightly improve symptoms for a time as well as slow down the progression of the disease.
Progress in pharmaceuticals
The Alzheimer’s research community are well versed in the known causes of the disease, with amyloid plaques and tau tangles the most widely accepted causes of the neurodegeneration that leads to Alzheimer’s. As a result, the majority of research and investment in the field is centred around this theory.
Neuro-Bio is a biotechnology start-up that is taking a different approach to making medicines for Alzheimer’s patients. The company is focused on a ‘previously unidentified mechanism’ of the disease that is linked to the development stages of the brain and cell death, and is working on new drug candidates that can stop the peptide involved in this mechanism from functioning improperly in adults.
After a series of setbacks in Alzheimer’s drug development, Prof Margaret Esiri, a neuropathologist at the Nuffield Department of Clinical Sciences, Oxford, said: ‘Neuro-Bio’s approach to the problem of Alzheimer’s disease is novel and scientifically well-founded. It is a good example of the new thinking that is urgently needed in this field’.
Timing it right
However, with an uncertainty for future success in Alzheimer’s pharmaceuticals, researchers interested in the genetic make-up of neurodegenerative diseases are focusing on how early diagnosis can be beneficial to patients.
Alzheimer’s can cause a significant loss of brain matter (right) compared to a healthy brain (left). Image: National Institutes of Health
According to UCL geneticist John Hardy, a loss in brain matter and amyloid build-up begins 15 to 20 years before symptoms start to appear, highlighting the need for preventative measures. This need is not consistent with what is currently available to patients in the UK however, as to qualify for a clinical trial, patients must be in the advanced stages of Alzheimer’s – often exhibiting severe symptoms that can, quite drastically, negatively affect quality of life for the individual.
Scientists at Case Western Reserve University, Ohio, US, may have solved this issue of early diagnosis after developing a machine learning program that outperforms other methods for diagnosing Alzheimer’s disease. The program integrates known disease indicators and symptoms to predict the likelihood of Alzheimer’s onset. Multiple stage comparisons, which includes associated symptoms that are not always present in Alzheimer’s, allow the program to make a more accurate prediction of who is most vulnerable.
Development of such programs could help initiatives such as the 100,000 Genomes Project which aims to provide the NHS with a new genomic medicine service that can offer better diagnosis and more personalised treatments.
Baroness Susan Greenfield. Image: National Assembly for Wales
SCI is running a Public Evening Lecture in London on Wednesday 28 February – The 21st Century mind: Blowing it, expanding it, losing it. The talk will be given by Baroness Susan Greenfield, neuroscientist and CEO of Neuro-bio. It is free to attend, but spaces are limited. Don’t miss out – booking opening soon.