If you are reading this blog, you already know all about how a huge portion of your genome is parasitic junk DNA (~40-45%), a fraction of which is retroviral junk (ERVs, ~9%). If youre new here… SURPRISE!
Sure, we have a gene here, a promoter there (maybe) that was domesticated for human genome use, but its junk, and that is a good thing. I mean, if our genome was 9% retrovirus and every one of them was active, we would all be dead from the insertional mutagenesis alone.
So your genome and cells have evolved lots of ways to make sure your junk DNA stays junk… but I guess ERVs are like zombies. I mean, theyre dead, buried, portions of their previous genome have rotted beyond recognition… and yet when something has Gone Wrong, the ERV proteins (and some other junk DNA proteins) can rise from the grave.
Well… if junk DNA being expressed is a sign something is wrong… why dont we vaccinated against the junk DNA proteins? What if you get this vaccine today, and kill the, say, the first breast cancer cells, before they ever have a chance to become a full blown tumor?
… Well? Why not?
Because it could be a problem. Almost half your genome is junk. Which means a couple of things:
- Your immune system is trained not to harm ‘self’. The junk is ‘self’. Dang.
- The transcription and translation process is junky too– Lets say there is a really active gene for microglial cells right next to an ERV. By chance, you might make some junk ERV RNA, which goes on to accidentally make some protein. A smidgen of an ERV, by mistake, might not cause any trouble on its own. But if you have a ton of anti-ERV cytotoxic T-cells around, then we have a problem with autoimmunity.
Okay, well, still, the concept is very, very cool– Why dont we at least try?
The potential vaccines candidates:
- LINE1 Open Reading Frame
- HERV-K gag (four versions)
- HERV-K env
Step 1, of course, is to see if these guys are expressed in healthy tissues. You dont want a vaccine to prevent breast cancer lead to an autoimmune reaction that eats your lungs. So they used panels of healthy tissue from humans, macaques, and mice to see if these guys are expressed anywhere.
gastrointestinal tract (tongue, salivary glands, stomach, duodenum, jejunum, ileum, cecum, and colon); endocrine organs (thyroid, pancreas, adrenal, and thyroid); skeletal muscle (gastrocnemius in mice and quadriceps in macaques); cardiovascular system (heart, aorta, and mesenteric arteries); skin; lymphoid organs (tonsil, spleen, lymph node, and thymus); bone marrow; central (cerebrum, including hippocampus and hypothalamus; cerebellum; medulla; pituitary; and spinal cord) and peripheral (sciatic nerve) nervous system; respiratory tract (nasal mucosa, trachea, bronchus, and lung); adipose tissue; urinary tract (urinary bladder and kidney); eye (retina); and liver from both sexes. The reproductive tract tissue list was as follows: female (ovary, uterus, cervix, vagina, and mammary gland) and male (testis, prostate, seminal vesicle, epididymis, and mammary gland).
On the bright side, out of all of those tissues, there wasnt a lot of reactivity in human tissue… but there was some, which means autoimmunity might be an issue.
Again, on the bright side, the results from humans mirrored the results from macaques, meaning vaccine trials in macaques might give us a really good idea of what kinds of side-effects to expect in humans.
Step 2 is working out how you vaccinate someone against a self protein. It can be done, but your immune system really doesnt wanna. They found that once they figured out what the most immunogenic version of the proteins were, a DNA Prime, Ad5 boost was the way to go (sound familiar?).
In macaques, they got a nice broad cytotoxic T-cell response, and the HERV-K Env was able to induce an antibody response. If you prod your immune system enough, in the right way, you can break immune tolerance.
Step 3 is to wait. If your immune system is attacking an organ, you will know it.
Turns out the vaccinated macaques were doing just fine:
Even in animals with the strongest immune responses, the tissues were morphologically normal.
We observed no histological evidence of disease induced by an immune response (vasculitis, glomerulonephritis, or retinitis) or by immune complex formation and/or deposition (vascular, glomerular, and ocular inﬂammation).
In summary, we observed no adverse safety effects from vaccination with ERE.
In fact, the macaques were doing so well, the researchers decided to go ahead and try to infect some of them with SIV to see what happens. The results are in the pipeline for publication right now! (!!!)
To sum it all up, a vaccine against an ERV might actually be a genuinely viable alternative therapy for some kinds of cancers/other diseases/HIV infection.
One mans junk is another mans life saving treatment!