Should we vaccinate against PGBD5 which codes for a transposase?
post by ChristianKl
Core Pathways of Aging [LW · GW]is background reading that explains why transposons are an issue.
There are two types of transposons. Class I TEs or retrotransposons generally function via reverse transcription, while Class II TEs or DNA transposons encode the protein transposase. I can't think of a good way of attacking retrotransposons which don't produce any proteins.
On the other hand, DNA transposons can be attacked because they need express transposase to copy themselves. When we vaccinate against a particular type of transposase our immune system will start to attack all cells that express the transposase, because cells present fragments of the transposon on their cell wall.
PGBD5 is expressed in the majority of pediatric solid tumors. While a tumor can mutate in a way that shuts off antigen presentation it's possible that PGBD5 gets expressed in the beginning of the lifecycle of pediatric cancer. While we are at it
Given that we don't know whether some cells have valid reasons for expressing PGBD5 it makes sense to not self-vaccinate and wait for clinical trials, but the potential of a cheap way to increase longevity and reduce cancer risk seem to me worth the effort.
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comment by CellBioGuy ·
2021-06-09T20:38:53.233Z · LW(p) · GW(p)
Sounds like something to look for antibodies (or more functionally, T-cells) in the population at large and see if they are correlated with autoimmune diseases, and sounds like something to look for a mouse equivalent of and see what happens when you immunize them against a sometimes-expressed transposase.
They're also never exactly at high levels.
comment by Charlie Steiner ·
2021-06-08T20:08:37.816Z · LW(p) · GW(p)
Aren't most parts of the body expressing transposons? Seems like not the right thing to alert our immune system to.
Not a biologist, but I assumed we'd need to alter lots of cells - either to produce something that interferes with transposons like RNAi, or to break them with direct gene editing.
Replies from: ChristianKl
↑ comment by ChristianKl ·
2021-06-08T20:40:22.062Z · LW(p) · GW(p)
In humans not all genes are expressed at every moment in time. Parts of the DNA are methylated which prevents them from being read. If the gene PGDBD5 stops being methylated it starts cutting DNA randomly. At the beginning this might still be repaired, but sometimes the PGDBD5 gene manages to copy itself and then you get even more of the protein. This dynamic from PGDBD5 alone might be responsible for the majority of children who die due to cancer.
If a transposon is setup in a way that leads to constant copying then that kills of the host lineage. The evolutionary pressure for transposons is to be active enough to copy themselves often enough to not be removed from the lineage while at the same time not copying enough to kill of the lineage.
PGDBD5 does get expressed in some cells of people who don't have any illness symptoms but it's unclear whether the underlying cells are simply disfunction in which case it would be worthwhile to kill them early or whether they have a valid reason.
comment by Elmer of Malmesbury ·
2021-06-14T01:51:38.203Z · LW(p) · GW(p)
I might be misunderstanding this, but it looks like humans would either:
- Suppress T-cells and B-cells that react against transposase at the negative selection step during maturation, making vaccination impossible
- Already be immune to the antigen (maybe that would be possible if the transposon is expressed very rarely, otherwise it would be recipe for auto-immune damage)
Full disclosure: I've forgotten everything about immunology since ~5 minutes after my last immunology exam.Replies from: ChristianKl
↑ comment by ChristianKl ·
2021-06-14T14:47:45.390Z · LW(p) · GW(p)
The fact that we have a lot of autoimmune disorders suggests that the negative selection step isn't perfect.
If you want to vaccinate I think you would start with a peptide that's not identical to a transporase subjection but similar and first give a vaccination dose against that. Then you vaccinate again with a peptide that's more similar and work your way towards transpoase.
Reading more it's likely that PGBD5 actually gets used productive in the brain to increase cell diversity and thus isn't as good of a target.
PGBD5 being upregulated in Alzheimers and in brain tumors makes the PGBD5 Alzheimers link interesting. If PGBD5 gets constantly expressed in train cells and creates a lot of DNA damage, it's plausible that this leads down the line to enough mutations to be a problem and Alzheimers appearing.
Edit: somehow I mistook the link to be about Alzheimers because that's what a googled for. It's instead about sporadic Creutzfeldt-Jakob disease. I however have found another study that does make the link https://doi.org/10.1371%2Fjournal.pmed.1002487
Having been able to predict that link between Alzheimers and PGBD5 ahead of time seems interesting.