Is our brain able to regenerate? And can we harness this regenerative potential during aging or in neurodegenerative conditions? These questions sparked intense controversy within the field of neuroscience for many years.
A new study from the Netherlands Institute for Neuroscience shows why there are conflicting results and proposes a roadmap on how to solve these issues.
The notion of exploiting the regenerative potential of the human brain in aging or neurological diseases represents a particularly attractive alternative to conventional strategies for enhancing or restoring brain function, especially given the current lack of effective therapeutic strategies in neurodegenerative disorders like Alzheimer’s disease.
The question of whether the human brain does possess the ability to regenerate or not has been at the center of a fierce scientific debate for many years and recent studies yielded conflicting results.
A new study from Giorgia Tosoni and Dilara Ayyildiz, under the supervision of Evgenia Salta in the laboratory of Neurogenesis and Neurodegeneration, critically discusses and re-analyzes previously published datasets. How is it possible that we haven’t yet found a clear answer to this mystery?
Previous studies in which dividing cells were labeled in postmortem human brain, showed that new cells can indeed arise throughout adulthood in the hippocampus of our brain, a structure that plays an important role in learning and memory, and is also severely affected in Alzheimer’s disease.
However, other studies contradict these results and cannot detect the generation of new brain cells in this area. Both conceptual and methodological confounders have likely contributed to these seemingly opposing observations. Hence, elucidating the extent of regeneration in the human brain remains a challenge.
New state-of-the-art technologies
Recent advances in single-cell transcriptomics technologies have provided valuable insights into the different cell types found in human brains from deceased donors with different brain diseases.
To date, single-cell transcriptomic technologies have been used to characterize rare cell populations in the human brain. In addition to identifying specific cell types, single-nucleus RNA sequencing can also explore specific gene expression profiles to unravel full the complexity of the cells in the hippocampus.
The advent of single-cell transcriptomics technologies was initially viewed as a panacea to resolving the controversy in the field. However, recent single-cell RNA sequencing studies in human hippocampus yielded conflicting results.
Two studies indeed identified neural stem cells, while a third study failed to detect any neurogenic populations. Are these novel approaches – once again – failing to finally settle the controversy regarding the existence of hippocampal regeneration in humans? Will we eventually be able to overcome the conceptual and technical challenges and reconcile these -seemingly- opposing views and findings?
Technical issues
In this study, the researchers critically discussed and re-analyzed previously published single-cell transcriptomics datasets. They caution that the design, analysis and interpretation of these studies in the adult human hippocampus can be confounded by specific issues, which ask for conceptual, methodological and computational adjustments.
By re-analyzing previously published datasets, a series of specific challenges were probed that require particular attention and would greatly profit from an open discussion in the field.
Giorgia Tosoni: ‘We analyzed previously published single-cell transcriptomic studies and performed a meta-analysis to assess whether adult neurogenic populations can reliably be identified across different species, especially when comparing mice and humans.
‘The neurogenic process in adult mice is very well characterized and the profiles of the different cellular populations involved are known. These are actually the same molecular and cellular signatures that have been widely used in the field to also identify neurogenic cells in the human brain.
‘However, due to several evolutionary adaptations, we would expect the neurogenesis between mice and humans to be different. We checked the markers for every neurogenic cell type and looked at the amount of marker overlap between the two species.’
‘We found very little, if no, overlap between the two, which suggests that the mouse-inferred markers we have been long using may not be suitable for the human brain. We also discovered that such studies require enough statistical power: if regeneration of neuronal cells does happen in the adult human brain, we expect it to be quite rare. Therefore, enough cells would need to be sequenced in order to identify those scarce, presumably neurogenic populations.
“Other parameters are also important, for example the quality of the samples. The interval between the death of the donor and the downstream processing is critical, since the quality of the tissue and of the resulting data drops over time.’
Reproducibility is key
Dilara Ayyildiz: ‘These novel technologies, when appropriately applied, offer a unique opportunity to map hippocampal regeneration in the human brain and explore which cell types and states may be possibly most amenable to therapeutic interventions in aging, neurodegenerative and neuropsychiatric diseases. However, reproducibility and consistency are key.
While doing the analysis we realized that some seemingly small, but otherwise very critical details and parameters in the experimental and computational pipeline, can have a big impact on the results, and hence affect the interpretation of the data.’
‘Accurate reporting is essential for making these single-cell transcriptomics experiments and their analysis reproducible. Once we re-analyzed these previous studies applying common computational pipelines and criteria, we realized that the apparent controversy in the field may in reality be misleading: with our work we propose that there may actually be more that we agree on than previously believed.’
News
New Research Reveals That Your Sense of Smell May Be Smarter Than You Think
A new study published in the Journal of Neuroscience indicates that the sense of smell is significantly influenced by cues from other senses, whereas the senses of sight and hearing are much less affected. A popular [...]
Deadly bacteria show thirst for human blood: the phenomenon of bacterial vampirism
Some of the world's deadliest bacteria seek out and feed on human blood, a newly-discovered phenomenon researchers are calling "bacterial vampirism." A team led by Washington State University researchers has found the bacteria are [...]
Organ Architects: The Remarkable Cells Shaping Our Development
Finding your way through the winding streets of certain cities can be a real challenge without a map. To orient ourselves, we rely on a variety of information, including digital maps on our phones, [...]
Novel hydrogel removes microplastics from water
Microplastics pose a great threat to human health. These tiny plastic debris can enter our bodies through the water we drink and increase the risk of illnesses. They are also an environmental hazard; found [...]
Researchers Discover New Origin of Deep Brain Waves
Understanding hippocampal activity could improve sleep and cognition therapies. Researchers from the University of California, Irvine’s biomedical engineering department have discovered a new origin for two essential brain waves—slow waves and sleep spindles—that are critical for [...]
The Lifelong Cost of Surviving COVID: Scientists Uncover Long-Term Effects
Many of the individuals released to long-term acute care facilities suffered from conditions that lasted for over a year. Researchers at UC San Francisco studied COVID-19 patients in the United States who survived some of the longest and [...]
Previously Unknown Rogue Immune Key to Chronic Viral Infections Discovered
Scientists discovered a previously unidentified rogue immune cell linked to poor antibody responses in chronic viral infections. Australian researchers have discovered a previously unknown rogue immune cell that can cause poor antibody responses in [...]
Nature’s Betrayal: Unmasking Lead Lurking in Herbal Medicine
A case of lead poisoning due to Ayurvedic medicine use demonstrates the importance of patient history in diagnosis and the need for public health collaboration to prevent similar risks. An article in CMAJ (Canadian Medical Association [...]
Frozen in Time: How a DNA Anomaly Misled Scientists for Centuries
An enormous meteor spelled doom for most dinosaurs 65 million years ago. But not all. In the aftermath of the extinction event, birds — technically dinosaurs themselves — flourished. Scientists have spent centuries trying [...]
‘Mini kidneys’ reveal new insights into metabolic defects in polycystic kidney disease
Scientists at Nanyang Technological University, Singapore (NTU Singapore) have successfully grown 'mini kidneys' in the lab and grafted them into live mice, revealing new insights into the metabolic defects and a potential therapy for [...]
Decoding the Origin of Life: Scientists Solve Early Earth RNA Puzzle
Recent research illustrates how RNA molecules’ chemical characteristics might have played a crucial role in the development of complex life forms. How did complex life manage to evolve on the early, inhospitable Earth? Initially, [...]
Improving infectious disease testing with gold nanoparticles
By harnessing the power of composite polymer particles adorned with gold nanoparticles, a group of researchers have delivered a more accurate means of testing for infectious diseases. Details of their research was published in the [...]
New micromaterial releases nanoparticles that selectively destroy cancer cells
Researchers have developed micromaterials made up only of proteins, capable of delivering over an extended period of time nanoparticles that attack specific cancer cells and destroy them. The micromaterials mimic natural secretory granules found [...]
Alzheimer’s Breakthrough: Scientists Make Revolutionary Leap
Dementia is a major health issue worldwide in the 21st century, impacting over 50 million people globally. This figure is expected to soar to 152 million by 2050, as the global population ages. Alzheimer’s disease (AD) [...]
How small RNA molecules regulate viral infections of bacteria
Viruses need hosts. Whether it's measles, the flu or coronavirus, viral pathogens cannot multiply or infect other organisms without the assistance of their hosts' cellular infrastructure. However, humans are not the only ones affected [...]
Computer scientists discover gap in the latest security mechanisms used by some chips
Over the past few years, hardware manufacturers have developed technologies that ought to make it possible for companies and governmental organizations to process sensitive data securely using shared cloud computing resources. Known as confidential [...]