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>There's a reason some ideas are left unexplored by industry.

But your argument essentially boils down to "We haven't yet discovered an effective delivery method, therefore this technique will never work".

Isn't that one of the basic problems facing all clinical genetic modification research? Is it unreasonable to assume that this problem could be solved by some future breakthrough, or does it somehow violate the laws of physics? If so, should we then discard all basic science research in this field because there is no clear route to market?

I fully support basic science pursuing crazy ideas. I think this is a very interesting piece of basic science, it's just at an incredibly speculative stage that's unsuitable for clinical investment. Efficient delivery of novel proteins into a cell by genetic methods, nanoparticles, or direct transduction is -the- challenge for a lot of novel ideas. Massive effort is ongoing to find breakthroughs here. The proteins in this study face this challenge, but there are other serious issues as well: - Introducing a large amount of a foreign protein, esp. some with viral domains in them, potentially carries risk of an adverse immune reaction... especially since these proteins might quickly transduce themselves into antigen presenting cells. - Most importantly, for a viral prophylactic, it's not clear that the short persistence of these proteins in the cell really makes for an effective approach to defend against viruses. - If you administer it acutely to try and slow an ongoing infection in a stimulated immune system, I suspect the body would raise antibodies against the proteins, preventing them from being used again.

This is fascinating. How in the world does the body "raise antibodies" that are effective against arbitrary proteins it hasn't seen before? How does this get "remembered" and how does the memory get communicated through the body?

If there's an ELI5 (or, ELI-college-101) I'd be interested to read it.

Very over-simplified: You have a random library of many billions of cells each making a single unique antibody that was created via random combinatorial genetic shuffling early on. The ones that accidentally bind to your own natural proteins are filtered out by killing them before they leave the bone marrow, so the circulating cells remaining form a library that could only bind -foreign- proteins. When one of these foreign-binding-cells in the library actually binds a foreign protein this cell multiplies like crazy and eventually the clones secrete free floating versions of the antibodies that neutralize the protein it detected, some of these clones stick around in the bone marrow to form a long-term memory-library of previously activated antibodies.

There are actually two separate systems: the T cells and B cells. I recommend the very readable Lauren Sompayrac's "How the Immune System Works". Or google/wiki "clonal selection" and "VDJ recombination".

Also google "somatic hypermutation". That multiplication process for B cells is inexact, and introduces mutations into the DNA (and therefore structure) of its children. There's a process which indicates whether any of these new antibodies binds better than the original one, which becomes a new candidate for multiplying.

There's fairly recent technology to sequence these antibodies en masse, which gives you a whole load (~10^6) of these antibody DNA sequences. It's a fascinating and frustrating exercise to try and reconstruct the mutation history and families of related cells from this data.

Is there concern that those long-lived antibody clones become pathological themselves?

Yes and no. Yes in that some of the many billions of combinations of antibody genes can recognize self proteins, which is a problem. However, during maturation of B cells, the immune system has a mechanism for killing of those B cells which would produce anti-self antibodies before they mature. There are times when this fails to work--think Grave's Disease, many forms of lupus, alopecia, etc.

I think in the sense you are asking, though, is that any long-lived plasma cell or memory B cell that is active will probably not change to the extent that they would attack self. I don't know off the top of my head if there are examples of this, but I can't think of any.

> How does this get "remembered" and how does the memory get communicated through the body?


Seems XKCD was on point this week: https://www.xkcd.com/1831/

To be fair, a lot of breakthroughs happen by people outside the field in question applying new ways of thinking to that field.

Sure, these people can be kind of annoying, but I think we lose more than we gain by discouraging cross-pollination between fields of science.

Definitely; I was thinking that earlier while reading this post. On the one hand, you have newcomers who might have an answer no one thought would work, but on the other hand experience nets wisdom that often is more accurate than the newcomer's logic.

It is a tough call to make between what's happened and what's possible.

Douglas Crockford should learn from you and use the term cross-pollination instead of promiscuity. That would have saved him a lot of trouble

alevskaya. we've got a great direct transduction technology. when are you going to test it out?

It's more "We haven't yet discovered an effective delivery method, therefore this technique is in the same place as a hundred other techniques that kill things in cell cultures."

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