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expert reaction to two papers on modelling neural networks in the developing brain

Reported in Nature, two teams of scientists have created three-dimensional cellular models of the human brain to study and modify key aspects of early brain development.

 

Dr James Cusack, Director of Science, Autistica, said:

“This is an exciting development which may shed light on how the brain develops. Research like this may help us to understand conditions such as autism and epilepsy. Stem cells are quite new to autism research and we don’t want to over claim, but it certainly looks like a promising area that may lead to exciting developments further down the line. It is important to bear mind that no single model (including lab-based models such as stem cells, or animal models) is likely to fully explain autism because autism is inherently heterogeneous.”

 

Dr Dean Burnett, Neuroscience and psychiatry lecturer, Cardiff Centre for Medical Education, Cardiff University, said:

“Both of these studies employ innovative and potentially incredibly useful techniques. The ability to recreate neural networks from the various different parts of the brain, to manipulate these networks from the outside with things like light signals and see what happens, or to monitor the consequences of genetic anomalies on the development of such networks in real time, there is great potential here for these methods to expand our understanding of how the brain forms, works and goes wrong.

“However, it’s important to keep such things in context. While useful, the networks formed in the lab cannot hope to match the complexity and power of a fully functioning human brain, any more than you can hope to play Grand Theft Auto on a pocket calculator. A working brain is far more than a single network, and most diseases and disorders go way beyond the anomalous behaviour of small, isolated collections of cells. These are important elements of the process, and understanding them allows us to better understand the whole, like how knowing the alphabet is a key element of writing a novel, but we’re still a very long way from creating exact duplicates of human brains and the eye-wateringly complex processes they do in the lab.”

 

Prof. Paul Matthews, Edmond and Lily Safra Chair, Division of Brain Sciences, Imperial College London, said:

“These reports describe continued advances of the fundamentally important new methods for generation of self-assembled ‘brain organoids’.  This is thrilling science!  Living, microscopic structures resembling tiny areas in the brain have been made to develop in a dish in the laboratory.

“Birney and his colleagues at Stanford use this to better understand what goes wrong in children borne with Timothy syndrome, a rare, severe birth defect.

“Quadrotto and the team at Harvard describe use of similar methods to create light responsive organoids resembling sections of the retina in the eye.

“Together, these studies open up a host of opportunities to better understand how the brain develops, create new models of brain diseases that may be more informative than the current animal models and, with these, to more rapidly develop new drugs.”

 

Prof. Malcolm Macleod, Professor of Neurology and Translational Neurosciences, University of Edinburgh, said:

“These two papers show that it is possible, within a cell culture system, to start to develop more complex non-animal models of how the human brain develops. However, the papers also show some issues with the models (sometimes the system seems to lead to different patterns of cells being represented), and this is one of the issues which will need to be addressed before these systems can enter widespread use.”

 

Dr Selina Wray, Alzheimer’s Research UK Senior Research Fellow, UCL Institute of Neurology, said:

“Our understanding of how the human brain develops and dysfunctions in disease has been greatly enhanced by our ability to generate ‘mini brains’ which can be studied in the lab. These two papers represent important and exciting advances in making models which more accurately reflect the structure and diversity of the human brain and allow human-specific features, such as the movement of neurons through the brain in development, and the maturation of the brain over time, and the formation of neuronal circuits, to be modelled in the lab for the first time.

“This technology will provide researchers with insights into brain development and disease which have not previously been possible.  The fact that the maturation of neurons can be captured is particularly exciting as it broadens the scope of diseases that can be accurately modelled using organdies to include those that manifest later in development.”

 

Dr Francois Guillemot, Group Leader and Head of Division of Molecular Neurobiology, The Francis Crick Institute, said:

Q: Have they provided sufficient evidence that they have done what they say they’ve done?

“These are excellent, thorough studies. The Arlotta paper shows that organoids reach great cellular diversity and that neurons become fully mature and functional with almost no external manipulation of the system. The Pasca paper shows that complex cell migrations can be achieved.”

Q: Is this a fully working brain?

“No, far from it. Organoids contain different tissues looking like bits of real brains and the Arlotta paper shows that one of these tissues is amazingly similar to a human retina – this is really surprising because the starting material is an homogenous cell population (induced pluripotent stem cells) and the self organising properties of these cells and their progeny is truly remarkable.

“However, only some parts of the brains are present in an organoid (and not in all – each organoid is different) and these different parts are all scrambled instead of being properly organised. So we are still very far away from a brain, anatomically speaking. The Pasca paper chooses a different approach that generates much simpler but also more predictable and reproducible structures.

“However the papers show that after very long culture (> 9 months in the Arlotta paper) neurons reach full maturity and they establish functional connections with each other and form what looks like circuits. Again, this is still far from the well-organised circuits found in functioning brains because the positions of the participating neurons, which is crucial for establishment of proper connections, is quite random in organoids instead of being well defined. However this is still a huge progress.

Q: Is it valid to say this is a working model of Timothy syndrome?

“No, the Pasca study only models an early stage of forebrain development, when neurons from one part of the forebrain (subpallium) migrate to another part (cerebral cortex), and they found that this step is defective. However later steps of brain development might also be faulty in Timothy patients. In particular the migration defect is likely to result later on in abnormal circuits because neurons do not reach their correct positions. However the authors haven’t looked at this because neurons do not reach well defined locations anyway in normal organoids, as mentioned above. Therefore even circuits from non-diseased tissues are very different from those in a normal brain.

Q: Does that mean we will soon have working models of other brain disorders – which ones and how useful will this be?

“Yes we will soon have models of many different diseases where cell behaviours (such as migration) can be examined. However we will have to wait longer to probe circuit assembly and function. Organoid models of many neurological disorders are currently being developed, including neurodevelopmental disorders (e.g. autism spectrum disorder, schizophrenia, epilepsy, etc.) and neurodegenerative disorders (e.g. Alzheimer’s disease). The later diseases represent an obvious challenge since the pathologies usually become manifest only after several decades.”

Q: How surprising is this work? Is it a game-changer or another small step?

“As mentioned above, the self-organising capacity of organoids is really surprising. I would not call these studies game changers because previous organoid papers had already hinted at this. However they represent large steps forward. This is after all the first time that human neural circuits can be observed in action!”

Q: Does this mean some research using animals can now be done with this instead?

“No, animal experiments are not obsolete but remain complementary to organoid experiments. The Pasca paper actually performs some experiments using mouse brains. Again, organoids and the circuits they contain are not properly organised. Animal experiments are still indispensable when brain connectivity and circuit function must be studied.”

 

* ‘Assembly of functionally integrated human forebrain spheroids’ by Birey et al. and ‘Cell diversity and network dynamics in photosensitive human brain organoids’ by Quadrato et al. published in Nature  on Wednesday 26th April.

 

Declared interests

Prof. Matthews: “Paul is funded by the Medical Research Council, the National Institutes of Health Research and the EPSRC.  He receives industry support for development of a database tool for multiple sclerosis from Biogen and for imaging from GlaxoSmithKline, who both are developing drugs for neurodegeneration.  He holds stock in GlaxoSmithKline and his institution and he has received honoraria or educational support funds from Biogen, Novartis, Roche, OrbiMed Consulting and Adelphi Communications.”

Prof. Macleod: “I have no conflicts of interest”

Dr Wray: “I receive funding from an NC3R Crack It grant to generate stem cell models of Alzheimer’s disease, which is cosponsored by Eli Lilly and Janssen”

Dr Guillemot: “I have no competing interests.”

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