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Cell replacement therapy: restoring brain’s ability to communicate

Author: Brina Stančič


Communication. Exchange of information, ideas, opinions, or emotions. A process by which human beings perceive meanings and reach understandings. With the development of the technology, we have become excessively dependent on constantly being able to share and receive information. In fact, we are so accustomed to it that only in rare occasions do we realize how imperative it is to communicate and how powerless we feel when we cannot do it.


So why is it so important to communicate? Communication is not just the message itself or its transmission. It is a constant flow of information, followed by understanding and feedback from the receiver. It is vital for a simple conversation with your friends or family, for knowledge transmission at school, and for effectiveness and decision making in any kind of workplace. In fact, no organization can function without communication. And the greater the complexity, the more important the communication.

What about communication in the nervous system? If we think about the human body, the highest complexity can be found in the brain. This complex biological network consists of billions of neurons, which need to communicate so that we can function normally. They are highly specialized to convey information, which needs to be transmitted both within the neuron and from one neuron to the next. One way of the latter form is by releasing neurotransmitters (chemical messengers) into spaces between cells (synaptic clefts) until they reach the receptor sites of other neurons, hence their destination. There are more than 100 neurotransmitters described so far, but the one I would like to mention today is dopamine. Dopamine is released by dopaminergic neurons and it is primarily considered as a neurotransmitter that controls the brain reward system. Additionally, it exerts modulatory effects on signals that flow from the cortex to the basal ganglia circuit, which allows the correct execution of voluntary movements.



Neurotransmitters are chemical substances, produced by neurons to transmit the signal across the synaptic cleft to the receiving cell.




And if the communication fails? Communication is a very important skill, yet it is not so straightforward to master it. In fact, lack of communication between the integral parts of any kind of organization leads to miscommunication and mistakes. Similarly, communication gaps in a human body result in diseases. Due to the complexity of the brain, a single lost information represents severe consequences on a much larger scale. One such disease, where a disrupted information flow of a single neuronal type leads to a serious disorder that significantly impairs the quality of patient’s life is Parkinson’s disease (PD). As my fellow Laura has already mentioned, this neurodegenerative disorder is characterized by a progressive death of dopaminergic neurons, which results in the deficit of dopamine. The absence of this modulatory neurotransmitter represents the first domino, which triggers a cascade of functional changes affecting the basal ganglia network and in the long run, the development of the well-known motor symptoms.

In PD, progressive loss of dopaminergic neurons results in depletion of dopamine, which in the long run leads to development of non-motor and motor symptoms.


So how do we close the communication gap? We are trying to combat the disease by treatments that can increase dopamine activity in the brain and slow its onset, such as dopamine agonists, which mimic the effects of dopamine. Since dopamine cannot cross the barrier that protects the brain (the blood brain barrier), another commonly used agent is levodopa (dopamine precursor), which undergoes conversion into dopamine in the brain. While they carry relative benefits and side effects, there are currently no treatments that can slow the progression of the disease.


Can we do it better? If we again think about workers being the building blocks of an organization, the solution that the scientific community has come up with comes as no surprise. When a worker gets sick, someone needs to replace him or her for the time being. Applying the same logic, a few decades ago (in 1987) scientists transplanted fetal midbrain, which contains dopaminergic neurons, into the brain of PD patients. This proof of principle approach resulted in improved clinical symptoms and despite the ethical concerns, it opened the door to new therapeutic strategy, known as the cell replacement therapy.


Since then, the scientific community has done a lot of pre-clinical research, trying to improve and perfection this technique by injecting dopaminergic progenitors (cells that are destined to become dopaminergic neurons but are not there yet) into the brains of animal PD models to replace those that had been destroyed. This field truly blossomed around 10 years ago with the development of the induced pluripotent stem cell technology. This technology, as my fellow Fran has explained in his blog post, allows one’s skin cells to be reverted into pluripotent stem cells, which are a kind of a “blank state cell” that can develop into any type of the cell in the body. This has revolutionized the field, because it offered the possibility for personalized stem cell therapy, in which people might get treated using their own healthy cells, hence eliminating or minimizing the risk of transplant rejection.




Embryonic and induced pluripotent stem cell have the ability to become any type of cell in the human body.





Where do we stand today? As with any ground-breaking technology, the field has encountered several difficulties with translating the basic and pre-clinical research to clinical application. After years of intensive efforts and numerous studies on grafting iPSC-derived dopaminergic progenitors in PD rodent and monkey models, finally the first clinical trials have started in Japan, China and Australia and more are about to follow. These clinical trials have been attempted at advanced PD patients, but when their safety and efficacy are confirmed, the next step is to move to early-stage patients, which can refine the purpose of the treatment from improving severe symptoms to delaying the advanced stage of PD.


The work, performed in the last three decades, has revolutionized the field and has offered hope to 10 million people, who suffer from this debilitating neurodegenerative disorder. There are still challenges that need to be overcome and there is no doubt that the journey ahead of us is long. However, if the scientific community keeps an open mind and if different disciplines learn to work more closely together, we have a bright future ahead of us.



With this thought, I would like to close the cycle and get back to where I started. We need to communicate more. More openly. More efficiently. And only if we do that, will we be able to restore the communication of the brain as well.




References:

1. Man JHK, Groenink L, Caiazzo M. Cell reprogramming approaches in gene- and cell-based therapies for Parkinson’s disease. J Control Release. 2018;286:114-124. doi:10.1016/j.jconrel.2018.07.017

2. Takahashi J. iPS cell-based therapy for Parkinson’s disease: A Kyoto trial. Regen Ther. 2020;13:18-22. doi:10.1016/j.reth.2020.06.002

3. Parmar M, Grealish S. The future of stem cell therapies for Parkinson disease. Nat Rev Neurosci. doi:10.1038/s41583-019-0257-7


Photo credits:

1. https://images.theconversation.com/files/304620/original/file-20191202-79465-1jnlx05.jpg?ixlib=rb 1.1.0&q=45&auto=format&w=1200&h=1200.0&fit=crop

2. https://www.cmmonline.com/wp-content/uploads/2018-08-communication-builds-housekeeping-professionals-detail-1200x627.jpg

3. https://www.observationbaltimore.com/wp-content/uploads/2015/08/ThinkstockPhotos-470840960-300x300.jpg

4. https://image.slidesharecdn.com/thenervoussystem-140406091707-phpapp02/95/the-nervous-system-9-638.jpg?cb=1396775847

5. https://www.parkinsonassociation.org/wp-content/uploads/2019/01/parkinsons_patients_have_less_dopamine-pic.png

6. https://images.fineartamerica.com/images-medium-large-5/1-colourful-dominoes-falling-down-science-photo-library.jpg

7. https://pyimagesearch.com/wp-content/uploads/2019/04/detect_parkinsons_opencv_patient.jpg

8. https://i.pinimg.com/originals/16/1c/b5/161cb5ec8f75fdff891fe53b25673f9b.jpg

9. https://www.5snews.com/wp-content/uploads/2014/05/Hoshin.jpg

10.https://www.open.edu/openlearn/ocw/pluginfile.php/1210041/mod_resource/content/0/mss_1_olhp_786x400.jpg

11. https://encrypted-tbn0.gstatic.com/imagesq=tbn:ANd9GcSWOZpZ20WtcRsAiCbmfJJit RhcKth0_HFwJg&usqp=CAU



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This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 813851.