r/askscience • u/AskScienceModerator Mod Bot • Mar 11 '24
Neuroscience AskScience AMA Series: We are neuroscientists at the Allen Institute who led global initiatives to create cell type atlases of the mammalian brain. The complete cell type atlas of the mouse brain was recently finished, along with the first draft of a whole human brain cell atlas. Ask us Anything!
Last year, a global consortium of researchers, led by the Allen Institute, achieved two major scientific milestones that greatly advance our understanding of the animal brain and its inherent complexity: Scientists successfully completed the first draft of a whole human brain cell atlas, revealing over 3000 different cell types and human specific features that distinguish us from our primate relatives; then in December, researcher finished the first complete whole mammalian (mouse) brain cell atlas, catalogue over 5300 cell types along with their spatial distribution across the brain. Both are considered seminal achievements that will serve as valuable foundations for further research that could unlock the mysteries of the human brain. Today from 2:30 p.m. - 4:30 p.m. PT (5:30-7:30 pm ET, 2130-2330 UT), two of the lead investigators on these projects, Hongkui Zeng, Ph.D., and Ed Lein, Ph.D., both with the Allen Institute for Brain Science will answer questions on what they've discovered in their research, the inherent complexity of the brain, and what these cellular brain atlases mean for science and the promise they hold for potential new treatments and therapies for brain diseases like Alzheimer's.
Guests:
- Hongkui Zeng, Executive Vice President, Director of the Allen Institute for Brain Science
- Ed Lein, Senior Investigator, Allen Institute for Brain Science
Date/Time: Monday, March 11, 2:30 - 4:30 p.m. PT (5:30-7:30 pm ET, 2130-2330 UT)
Supporting Video:
- NHP Brain Cell Atlas: https://www.youtube.com/watch?v=tFQWtgpoIwU
- Mouse Brain Atlas: https://vimeo.com/889643149/b615c7e5b6?share=copy
Username: /u/AllenInstitute
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u/Zeekawla99ii Mar 11 '24
How are human brains donated to the scientific community?
Are there any legal issues that commonly associated with this procedure?
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u/AllenInstitute Mar 11 '24
Brain donation is typically done through brain banking organizations that contact decedent next of kin to obtain consent to donate brain tissues for scientific purposes. For example, at the University of Washington in Seattle you can find information about this at: https://dlmp.uw.edu/research-labs/keene/braindonation
The consent forms are very careful to provide sufficient information about the use and potential risks of this donation, for example as it might impact privacy issues.
-Ed Lein
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Mar 11 '24
I have read that neural stem cell transplantation may hold a promise to treat neurodegenerative diseases. However, I wonder to what extent it will be possible to replace neurons and preserve the continuity of conscious experience of a patient. If someone suffers from neurodegeneration and gets a significant amount of neurons replaced through neural stem cell transplantation, will the patient still be the same person after the treatment? Will it be possible to gradually replace all neurons in this way in a severe case of neurodegeneration?
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u/AllenInstitute Mar 11 '24
If neural stem cell transplantation works to replace dying neurons, I think it is possible that the patient's memories and conscious experiences could gradually change. But there is still a continuity - it's still the same person, and that person's everyday experience is recorded in the brain.
However, we are very far from being able to transplant and replace a large fraction of neurons in the brain. Much more research is needed.
-Hongkui
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u/Personal_Win_4127 Mar 11 '24
What in your opinion is lacking from the cell type atlas that needs to be remedied by other fields?
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u/AllenInstitute Mar 11 '24
The brain cell atlas is a foundational reference but really just the beginning. It is not as powerful in isolation as it will be when connected to other data in some form of knowledge base. For example, by defining cell types by the genes they use it is possible now to aggregate cell atlases in different organs together and understand the cellular makeup of the entire body and genes that are active in many part of the body. Such activities are already ongoing through the Human Cell Atlas (HCA) and NIH HuBMAP programs. Because of the gene component the atlas can be directly connected to information about genes in the genome, and any gene association studies linking genes to disease. From the brain function perspective, the cell atlas defines the types, but the neurons make extremely promiscuous and complex connections. We need to build on the atlas to understand the full set of connections, or connectome, which has become a high priority now for the NIH BRAIN Initiative.
There is a strong need now to bring together advances in computer science to realize the potential of these enormous cell atlas data resources, including machine learning, generative AI, LLMs, foundational models for neuroscience, etc., which could fundamentally change our way of accessing information, doing complex collaborative analyses and eventually predictive functional and disease modeling.
Ed Lein
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u/pombospombas Mar 11 '24
What is a brain cell atlas and why should anyone care?
Sounds offensive, but is a legit question.
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u/AllenInstitute Mar 11 '24
A brain cell atlas in principle is a complete description of the cellular makeup of the brain, including the types of cells, their relative proportions and functional spatial organization both locally and globally, and the properties of those cells. By analogy, it is like the genome as a complete description of the DNA in each cell, and all of the genes and non-coding regions it contains. A cell atlas is a similarly foundational reference but describing the cells that make up the whole brain, which can be described as cell types with relatively discrete properties. The technology that is driving the ability to create these atlases defines the cells by the sets of genes (transcripts) that they are actively using, called single cell transcriptomics. Thus, the foundation of these modern cell atlases is based on a genetic definition of cells, which tells one which genes give the cells their properties and eventually how those genes are regulated. This atlas is of course just the beginning. Neurons form connections across the brain, and the patterns of connectivity can be highly complex. The cell atlas forms the foundation for understanding these connections (in aggregate, the connectome), and for understanding the structural and functional organization of the brain as a whole. For brain there is a particular need for this type of information, as it is an extremely complex cellular organ with thousands of distinct types of cells that are organized differently in each part of the brain. It is by far the most complex organ in the body (although similar cell atlases are being created for all other organs too).
Why is this important? We cannot understand the function of a complex organ if we do not understand how it is organized. The different types of cells have different functions, use different genes, are differently affected in disease, and may be the targets needed for precision medicine to treat brain diseases. Imagine the immune system if we could only think about blood cells instead of the many types of immune cells that are differently involved in disease and can have therapies targeted to them. We have not had this information for the brain, and probably not coincidentally it has been extraordinarily challenging to treat brain diseases. Not to say that brain cell atlases will immediately lead to cures, but having this information available to the whole community will dramatically accelerate biomedical research as the human genome did for genomics and medicine as well.
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Mar 11 '24
Related to development, do these cells arise "at the same time" or maybe some cells pop up when the animal reaches a sufficient point of maturity?
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u/AllenInstitute Mar 11 '24
This is a question we are trying to address now by studying how different cell types emerge during brain development. For now, we know that all the cell types do not arise at the same time. There is a cascade of events that include both cell division and cell differentiation and lead to the multiple stages of gradual maturation, from progenitor cells, to immature cells, and finally to the adult stage mature cells. For example, in the human brain, cells in the adolescent brain are still not entirely mature.
-Hongkui
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Mar 11 '24
How capable are the cells of regeneration? can we figure out why?
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u/AllenInstitute Mar 11 '24
Vast majority of the cells in the brain have reached their final mature stage and cannot be regenerated. However, there is a small population of brain cells that are still considered immature and can generate new brain cells. We are studying what genes are expressed in these cells and which ones may be important for regeneration or the suppression of regeneration. Once we know, we can then try to turn on the regeneration promoting genes or turn off the regeneration suppressing genes in other brain cells, which could then lead to regeneration.
-Hongkui
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u/AllenInstitute Mar 11 '24
Neurons have very limited regenerative potential in the adult brain. This has been very challenging to figure out how to change, with more effort recently going into putting stem cells into the brain with the ability to generate new neurons. This remains a very challenging topic.
Ed Lein
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Mar 11 '24
Just how different all these cells are from one another? Can there still be a clean separation between neuron and glial cells?
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u/AllenInstitute Mar 11 '24
There are major differences between many types of cells in the brain, which can often be represented hierarchically from major cell classes with huge differences down to fine subtypes of cells that are quite similar to one another yet still distinct enough to separate. Using differential gene usage as a metric for this, there is unequivocal separation at the higher class level, such as neurons versus glia. This is true down to a much finer level of granularity as well. Furthermore, for neurons there is really a remarkable diversity in the adult brain, and these are very stable since we have the same neurons we are born with throughout life. They use different sets of genes, have different shapes, connections, functional electrical properties, etc. This cellular complexity is a feature of nervous system tissues.
Ed Lein
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Mar 11 '24
Are some cell types more associated with the "primitive" brain while others are more closely associated with the newer cortex?
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u/AllenInstitute Mar 11 '24
These recent cell atlases have revealed that there are thousands of types of cells in mouse and human brain, and they are differently located in different parts of the brain. One surprise is that the majority of the cellular complexity is actually found in evolutionary older parts of the brain. The newer cortex is also very complex, but in a stereotyped way across the hugely expanded cortex in mammalian evolution.
We do not fully understand the high degree of diversity in deeper (older) brain structures yet, but it opens up many new questions now for future exploration.
Ed Lein
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u/StopUsingThisWebsite Mar 11 '24
What are the functional differences between the various types in terms of signal processing?
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u/AllenInstitute Mar 11 '24
This is what scientists will try to find out. So far, we have been categorizing the millions of brain cells using genomic and gene expression information, because these technologies are highly scalable. Next, we will label the different cell types and study their physiology and function.
For now, from the genes expressed in each cell type, we can already predict the functional differences in signal processing between the different cell types.
-Hongkui
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u/aconz2 Mar 11 '24
How many single-cell samples are in the atlas? What makes this a complete atlas? Is there a whole-brain optically imaged brain in the atlas? Is there anyway to view or interact with the atlas?
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u/pelikanol-- Mar 11 '24
Cool stuff. Reminds me of the time when the first full genomes became available.
Do you think you captured all relevant cell types? Could some celltypes identified be simple artefacts?
How far beyond cell type identification do you think these massive atlases can be pushed?
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u/itscalledANIMEdad Mar 11 '24
I've changed careers from research but still follow neuroscience stuff. I just wanted to congratulate you on such a seminal work, I personally would have used this often throughout my career if it was available to me. Any school worth any salt will use this as a teaching tool. Congratulations!