Fact Check: Gain of Function research is still going on.
Giving rats human brain cells, upgrading Omicron to make it more deadly.
Two recent studies seem to represent both the stupidity and hubris of scientists, and makes me think the novels of Michael Crichton should be obligatory reading for microbiologists specialising in genetics.
1. Stupid, Stupid, Stupid: gain of Function making Omicron more deadly.
In this first study, they upgraded Omicron, which causes mild, non-fatal infection, to an Omicron S-carrying virus, which means they added the more virulent Spike protein from the original SARS-COV2 virus, and then they infected humanised ACE2 receptor carrying mice with it.
They found that OmicronS inflicts severe disease with a mortality rate of 80%.
Why on earth would you want to do this? The risks are surely not worth the benefits.
This study came out in October and is still a pre-print, and is called: Role of spike in the pathogenic and antigenic behavior of SARS-CoV-2 BA.1 Omicron
Abstract
The recently identified, globally predominant SARS-CoV-2 Omicron variant (BA.1) is highly transmissible, even in fully vaccinated individuals, and causes attenuated disease compared with other major viral variants recognized to date. The Omicron spike (S) protein, with an unusually large number of mutations, is considered the major driver of these phenotypes. We generated chimeric recombinant SARS-CoV-2 encoding the S gene of Omicron in the backbone of an ancestral SARS-CoV-2 isolate and compared this virus with the naturally circulating Omicron variant. The Omicron S-bearing virus robustly escapes vaccine-induced humoral immunity, mainly due to mutations in the receptor binding motif (RBM), yet unlike naturally occurring Omicron, efficiently replicates in cell lines and primary-like distal lung cells. In K18-hACE2 mice, while Omicron causes mild, non-fatal infection, the Omicron S-carrying virus inflicts severe disease with a mortality rate of 80%. This indicates that while the vaccine escape of Omicron is defined by mutations in S, major determinants of viral pathogenicity reside outside of S.
2. A Horror Story In The Making: Human Brain Cells Transplanted Into Rats
In this study they say that brain cells grown in test tubes are a pretty reasonable way to study human diseases, but it’s not quite the same as studying brain cells in a real brain. So they transplanted about a human brain cells into the brains of newborn rats, and then they watched them grow to see what happened.
Once the rats were old enough they did something called optogenetic stimulation, which is actually a way of controlling brain cells with light; I wonder why they want to do this? The possibilities are endless.
Eventually perhaps they could put some kind of remote control into the rats’ brains. Or into human brains, maybe.
But they obviously haven’t read Jurassic Park, or Prey, or the Andromeda Strain by Michael Crichton. Surely the possibility of research like this going wrong is too great.
Because, the only question worth asking, that the study doesn’t seem to answer, is, did any of the rats get away?
Abstract
Self-organizing neural organoids represent a promising in vitro platform with which to model human development and disease. However, organoids lack the connectivity that exists in vivo, which limits maturation and makes integration with other circuits that control behaviour impossible.
Here we show that human stem cell-derived cortical organoids transplanted into the somatosensory cortex of newborn athymic rats develop mature cell types that integrate into sensory and motivation-related circuits. MRI reveals post-transplantation organoid growth across multiple stem cell lines and animals, whereas single-nucleus profiling shows progression of corticogenesis and the emergence of activity-dependent transcriptional programs. Indeed, transplanted cortical neurons display more complex morphological, synaptic and intrinsic membrane properties than their in vitro counterparts, which enables the discovery of defects in neurons derived from individuals with Timothy syndrome. Anatomical and functional tracings show that transplanted organoids receive thalamocortical and corticocortical inputs, and in vivo recordings of neural activity demonstrate that these inputs can produce sensory responses in human cells. Finally, cortical organoids extend axons throughout the rat brain and their optogenetic activation can drive reward-seeking behaviour. Thus, transplanted human cortical neurons mature and engage host circuits that control behaviour. We anticipate that this approach will be useful for detecting circuit-level phenotypes in patient-derived cells that cannot otherwise be uncovered.
Here are some delightful graphics showing the process:
Revah, O., Gore, F., Kelley, K.W. et al. Maturation and circuit integration of transplanted human cortical organoids. Nature 610, 319–326 (2022). https://doi.org/10.1038/s41586-022-05277-w
Da-Yuan Chen, Devin Kenney, Chue-Vin Chin, Alexander H Tavares, Nazimuddin Khan, Hasahn L Conway, GuanQun Liu, Manish C Choudhary, Hans P Gertje, Aoife K OConnell, Darrell N Kotton, Alexandra Herrmann, Armin Ensser, John H Connor, Markus Bosmann, Jonathan Z Li, Michaela U Gack, Susan C Baker, Robert N Kirchdoerfer, Yachana Kataria, Nicholas A Crossland, Florian Douam, Mohsan Saeed Role of spike in the pathogenic and antigenic behavior of SARS-CoV-2 BA.1 Omicron bioRxiv 2022.10.13.512134; doi: https://doi.org/10.1101/2022.10.13.512134