How can we mend a “broken” brain?
Author: Francisco J Molina-Ruiz
We have all dealt with a break-up at one point or another in our lives. Indeed, heartbreak is an unfortunately common part of the human experience. Our familiarity with this kind of situations, along with the influence that movies and TV shows have on the way we perceive the world, have led to the popular belief that nothing is quite as shattering as a broken heart.
However, is that so? Well, the answer is no. Actually, from my (probably not very objective) perspective, a “broken brain” can be much more devastating.
This statement comes as quite obvious when you think of the brain as the most complex organ in the human body. This 1.4-kilogram jelly-like mass of tissue is by far the most powerful supercomputer on the planet, and represents the base of our identity, producing our every thought, action, memory, feeling and experience of the world. The brain is made up of a staggering complex network of 80 billion brain cells, or neurons, each of which functions as a separate computer processor which can connect (with mind-blowing complexity) with thousands or even tens of thousands of others. In other words: your brain is the one thing that you would probably miss the most.
Unfortunately, brains do not always remain in their prime, and neurons can, begin to deteriorate and die at some point. Neurodegenerative diseases, such as the infamous Alzheimer’s disease and Parkinson’s disease, affect millions of people globally, with a significant impact on individuals, families, economies and wider society. Worldwide, around 50 million people have some form of dementia, and there are nearly 10 million new cases every year (according to the World Health organization). These disorders don't just kill, they disable, and conventional drug therapies have not had much success in treating them. Since these conditions are currently incurable, finding ways to mend “broken” brains is one of today’s most urgent unmet medical needs.
As the population continues to age, the world is facing an epidemic of devastating neurodegenerative diseases that take a tremendous economic and emotional toll on families and society.
Nevertheless, how can we, as neuroscientists, possibly tackle this problem? Understanding even the healthy brain is still a colossal challenge for research, arguably the greatest of modern science, let alone how to aid in its repair! The task becomes even harder when considering that until recently, most neuroscientists thought that brains could not heal. It was actually my fellow countryman and neuroanatomist Santiago Ramón y Cajal who first described neurons as “fragile and irreplaceable” in the late 19th century. Brain cells, he stated, “may die” and cannot “be regenerated.” Nonetheless, the Nobel Price awardee then threw down the gauntlet, asserting in 1928 that it was the job of the “science of the future to change, if possible, this harsh decree.”
Santiago Ramon y Cajal, pioneer of bodybuilding and Nobel Prize, proving that life is not about having time, but making time.
Well, almost a century later, the future is now. Luckily for us, the brain is way more adaptive than what transpires from Cajal’s impressions, thanks to a property referred to as neuroplasticity, or the ability of the brain to remodel in response to new information, including injury or degeneration. One of the ways the brain does this is through neurogenesis (the birth of neurons), which is now accepted as a process that occurs normally in the healthy adult brain. This means, contrary to the previous paradigm, that we are not born with a fixed number of neurons. To put it another way, the brain has the ability to self-repair. Be that as it may, Ramón y Cajal was not completely wrong: brain cells’ lack of versatility to generate different cell types and their inability to divide hampers efficient neural regeneration, as evidenced by the relative lack of recovery from brain injury and neurodegenerative disease. Hence, neurogenesis might require a little push from our end before brain repair can be a reality.
Along these lines, two broad strategies for repair have now emerged as some of the many ways we can try to fix a 'broken' brain. On one hand we could try to boost the brain’s own healing mechanisms. To that regard, scientists are exploring how drugs or genetic manipulation can be used to coax native cells into a different set of behaviours, in an attempt to enhance neurogenesis or to “convince “the brain itself to manufacture the new cells it needs. On the other hand, brain damage could be fixed by “filling the gap”, simply replacing lost or damaged cells with foreign cells which are transplanted into the damaged brain area. This latter approach, which is included into the set of therapeutic strategies know as cell therapies, is only made possible thanks to our ability to produce, outside the body, the cells that we need. For which, as we will see later, stem cells are of paramount relevance.
As some of my fellow Early Stage Researchers have pointed out in previous blog posts, stem cells are special cells, which are able to self-renew (meaning they can continuously make new copies of themselves) and differentiate (meaning they can transform into other types of cells). We can harness the potential of stem cells by constraining their differentiation in vitro towards a specific cell type of interest (neurons, in our case). Directed stem cell differentiation was not an easy milestone to achieve, since it requires accurately mimicking what happens during embryonic development. This means that, in order to generate neurons, a detailed and deep understanding of developmental biology and the factors that make a stem cell “decide” to become a neuron is essential.
Pluripotent stem cells such as embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) can generate any cell type in the body, but they have their limitations. For instance, they cannot become Optimus Prime.
As of today, two main cell sources with the potential to address Cajal's regenerative vision are being used to produce billions of stem cells which are, in turn, capable of producing every cell type in the body. The first source to be considered was embryonic stem cells (ESC), which are pluripotent; in other words, they can become whatever they want, by differentiating into any type of cell in the body, from heart cells to brain cells. However, ESCs cannot be produced from your own cells, since they must come from embryos. Thus, the source of cells is limited, and ethical questions are raised. More recently, however, another Nobel Prize-awardee (Shinya Yamanaka) offered an alternative by discovering that stem cells with properties similar to ESCs could be made from any cell in the body, by adding specific molecules that send a “cocktail” of signals into the cells. These cells were named induced pluripotent stem cells (iPSCs), which constitute a powerful tool since they possess all the functions of ESCs and can be made from a person´s own cells (including cells such as skin cells, which are abundant and easily accessible). ESCs and iPSCs have the potential to transform the science of brain repair and regenerative medicine by enabling the generation and therapeutic deployment of neurons in a scalable and low-cost manner.
iPSCs made from skin cells of people suffering brain disorders can be used to produce neurons that are transplanted to the damaged area of the brain, in an attempt to replace lost or damaged neurons.
To wrap things up, it is time to address the initial question that I raised in the title of this blog post. Since the discovery of how neurons can be generated from stem cells, there has been a lot of excitement about how this can be used to treat brain diseases. Over the next two decades, we expect that scientists will figure out how to allow the use of stem cells to successfully treat the long list of currently incurable neurodegenerative diseases. However, this goal will not be achieved by a single person. Finding stem cell-based treatments for all of these different problems will require teamwork from people around the world, including scientists, doctors, governments that fund research, patients that are willing to participate in clinical trials, and companies that will help grow large numbers of stem cells. This effort could also use the help of the next generation of young scientists, who can bring new ideas to the field and help push this research forward. Moreover, it is precisely in that context where we, as part of the ASCTN-Training consortium, are working hard to make our contribution to make brain repair a reality.
References and further reading:
Azevedo FA, Carvalho LR, Grinberg LT, Farfel JM, Ferretti RE, Leite RE, Jacob Filho W, Lent R, Herculano-Houzel S. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J Comp Neurol. 2009 Apr 10;513(5):532-41 (doi:10.1002/cne.21974 .
De Gioia R, Biella F, Citterio G, et al. Neural Stem Cell Transplantation for Neurodegenerative Diseases. Int J Mol Sci. 2020;21(9):3103. Published 2020 Apr 28. (doi:10.3390/ijms21093103).
Eriksson, P., Perfilieva, E., Björk-Eriksson, T. et al. Neurogenesis in the adult human hippocampus. Nat Med 4, 1313–1317 (1998) (https://doi.org/10.1038/3305).
Gitler AD, Dhillon P, Shorter J. Neurodegenerative disease: models, mechanisms, and a new hope. Dis Model Mech. 2017;10(5):499-502. (doi:10.1242/dmm.030205).
Henriques D, Moreira R, Schwamborn J, Pereira de Almeida L, Mendonça LS. Successes and Hurdles in Stem Cells Application and Production for Brain Transplantation. Front Neurosci. 2019;13:1194. Published 2019 Nov 19. (doi:10.3389/fnins.2019.01194).
Lindvall O, Björklund A. Cell replacement therapy: helping the brain to repair itself. NeuroRx. 2004;1(4):379-381. (doi:10.1602/neurorx.1.4.379)
Oh Y, Jang J. Directed Differentiation of Pluripotent Stem Cells by Transcription Factors. Mol Cells. 2019;42(3):200-209. (doi:10.14348/molcells.2019.2439).
Quadrato G, Elnaggar MY, Di Giovanni S. Adult neurogenesis in brain repair: cellular plasticity vs. cellular replacement. Front Neurosci. 2014;8:17. Published 2014 Feb 12. (doi:10.3389/fnins.2014.00017).
Ramon y Cajal, S. Degeneration & Regeneration of the Nervous System. Translated by Raoul May (Hafner Publishing, New York, NY, USA, 1959).
Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell. 2006 Aug 25;126(4):663-76 (doi: 10.1016/j.cell.2006.07.024).