Lipopolysaccharide and humans

LPS is bad stuff. But for humans, LPS is far worse.

We humans, it turns out, are unique in a very specific way. Immune system receptors for various things are called toll-like receptors (TLRs). There are quite a few of them, TLRs 1-13.

In most animals, each TLR is paired with a Siglec. Siglecs aren’t numbered for the TLR that they work with. But TLR4, the one for LPS, is normally controlled by Siglec 13.

Each TLR turns the immune system on. The Siglecs damp the TLR response if it gets too high. They don’t work 100%. If they did, no animal would die of sepsis. But they make several thousand-fold difference.

We humans don’t have a working copy of Siglec-13. We haven’t had it for a long, long time, because Neanderthals didn’t have them either. We split with Neanderthals around 1 million years ago. That’s 83,000 grandma’s in the past.

The LPS LD50 for a 25 gram mouse is 150 micrograms. That is 150 millionths of a gram. Not very much, but it works out to around 6 milligrams per kilogram. (1 kg = 2.2 pounds).

If humans had working Siglec-13, we would have an LD50 of around 420 milligrams, based on 6 milligrams per kilogram. But instead, the LD50 for humans is… 300 micrograms.

That’s right. It takes just double the dose of LPS to kill a 25 gram mouse as it does to kill a 70,000 gram man.

That’s why, for injection into a human being, it is even more important to have ultra-clean plasmid preps. And the price for a prep for a human clinical trial reflects the level of cleanliness. Instead of $10,000 or so, human clinical trial material costs around $700,000.

Yes, some of that is “what the traffic will bear.” Some of that is regulatory cost. But it’s also because you just can’t make a mistake.

Well, technically, you can make a mistake and use things like Enbrel, steroids and rapamycin to save the life of a test subject. And anyone doing human clinical trials better have those on hand, along with a well defined protocol for following patients just in case. It should never happen, but that’s always true.

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