“Mental disorders such as schizophrenia affect up to five million people in Africa, and epilepsy is the most widespread neurological condition on the continent. Despite the high numbers, research and funding for these diseases remain limited, and greater global efforts are urgently needed,” said Daniella Rylander Ottosson of the Regenerative Neurophysiology Research Group at Lund University, Sweden. “A common feature of these disorders is the loss or damage of specific neurons in the brain that are essential for communication within the brain’s signalling network. However, the exact changes in these neurons, and how to prevent or reverse them, are still not fully understood − largely due to the difficulty of accessing living human neurons for research.”
Ottosson, who is both a STIAS and Wallenberg Academy Fellow, explained that this is a big field at her university because of the pioneering work done by Arvid Carlsson, a Swedish pharmacologist based at Lund who, along with Paul Greengard and Eric Kandel, was awarded the 2000 Nobel Prize for Physiology or Medicine for his research establishing dopamine as an important neurotransmitter in the brain. Carlsson’s work discovered that Parkinson disease is caused by loss of dopamine cells and this eventually led to pioneering transplantations of dopamine neurons to patients from aborted foetal cells which produced a drastic improvement post-transplant in both survival and regaining movement in Parkinson’s patients.
Ottosson’s particular interest is in epilepsy and schizophrenia. She explained that epilepsy is characterised by recurrent seizures while schizophrenia is characterised by delusions, hallucinations, disturbed thinking and lack of connection with reality. It’s also linked to higher incidence of suicide. Unlike Parkinson’s which generally affects older people, these diseases are found in people of all ages and there are lots of comorbidities with other psychiatric diseases.
“It’s not fully known why there are such high prevalences of these illness but they are both linked to a genetic predisposition as well as social and economic factors,” she said. “In schizophrenia some of the triggers may be more common in lower-income groups but this is not totally clear.”
“All of these diseases are hard to study because the neuronal damage is central and it’s hard to study live human neurons,” she explained. “Neurons can’t regenerate unlike other organs. Once they die, we lose them. They are formed during embryonic development up to adolescence. There are no new ones in adulthood. So, disease or trauma requires outside cell-replacement strategies.”
Foetal cells, stem cells and skin cells
Ottosson explained that although the use of foetal cells proved successful in Carlsson’s work they can’t be used more widely to treat large numbers of patients because of the limited availability of aborted foetuses; the impossibility of standardising the procedure and quality control; high variability in the cells; and, the ethical and social barriers.
Because of this, the work on Parkinson’s has moved on to using stem-cell derived dopaminergic neurons and is currently in clinical trials. “Stem cells can form any other cell and can divide and copy themselves indefinitely which can also be bad, for example, in tumour formation. The results of the current trials will show the effect of putting stem cell-derived dopamine neurons into the brain,” she said.
A technique called neuron reprogramming is another alternative to generate human neurons for cell repair or for studying these diseases in a dish. “This approach allows scientists to take other types of human cells—such as skin cells—and convert them into neurons in the lab by activating specific neuronal genes.”
Ottosson explained that these lab-grown neurons carry the same genetic background as the patient, making it possible to study disease processes and compare them with healthy cells to identify disease mechanism and find new drug targets.
This work is currently being done in cell culture and animal models, and is still far from trials in humans but has potential for patient-specific therapies in the future
Different types of neurons can be produced depending on the genes used and Ottosson’s group is particularly interested in the interneurons – small modulator cells that control the brain-signalling network. An altered brain signalling is the common link across many of these illnesses.
“Signalling is damaged by the loss of these interneurons,” said Ottosson. “They are like conductors making sure the electrical activity in the brain is coordinated and, if they die, the brain circuitry is damaged. We still don’t know exactly what goes wrong and how to prevent it.”
“Epilepsy is one example where the signalling cannot be properly controlled by the conductors. It is like the breaks do not work and this leads to too much signalling − the neurons go crazy”.
“We have been able to reprogram skin cells into interneurons in a dish – in both 2D and 3D cell culture models. The techniques in the lab used include single-cell sequencing for gene expression and electrophysiology – where mini electrodes catch the cells and look for specific firing.”
“Choosing the right genes for reprogramming is a like a needle in a haystack,” she added. “We are choosing genes we know are important for embryonic development when the conductors are formed naturally and trying to find the best combinations of these genes in the lab for reprogramming. Although interneurons are abundant and widely distributed throughout the brain, we need to look at the specific areas of the brain important for these diseases when we experiment in mice.”
“Our hope is to reprogram to interneurons, reconnect them to the brain circuitry and restore signalling and attenuation of disease symptoms. This would allow for patient-specific brain repair. The next step is in animal disease models and eventually in humans.”
“In the future, reprogramming might be done directly inside the brain − transforming supporting brain cells into new neurons − offering a patient-specific therapy where the brain can heal itself.”
Studying living human neurons in a dish might also offer the possibility of finding ways of preventing these diseases in the first place. “Looking at the pathology in a dish is much easier compared to the human brain,” she said.
Why Africa?
Although these research approaches are expanding rapidly in Western countries Ottosson believes there is a need to expand globally, including in Africa. “There is a need for African data, patient samples and a reprogramming research project. There is also a need to build capacity in neuroscience and biotechnology.”
Her STIAS project will explore possibilities for using cell reprogramming to study and treat neurological diseases common in Africa. It will also seek collaborations, such as collecting skin samples from African patients, with the long-term goal of establishing a hub for brain repair, stem-cell research, and education.
The impact of factors like race and ethnicity on these conditions is not fully understood. “Some groups have found pathologies in neurons from cohorts with schizophrenia,” said Ottosson. “But thus far only from cohorts in the Western world and no one has looked specifically at interneurons. I think there could be different risk genes in Sweden and Africa.”
In a few weeks at STIAS she has found there are a lot of neuroscience groups and interesting research going on in the Western Cape with the advantage that many have established links with the clinical side of the work, particularly for neuropsychiatric disorders.
“There are many opportunities for collaboration. This would help to achieve a better understanding of these diseases and contribute to enhancing equity in neuroscience globally.”
“There’s also a need to increase public knowledge and awareness in Africa about these conditions,” she added.
Michelle Galloway: Part-time media officer at STIAS
Photograph: SCPS Photography