Under normal circumstances, antibodies recognize things that (in molecular terms) are big, like parts of bacteria and viruses that invade our bodies. That's largely because of the way that antibodies are selected for during an immune response. But by playing a bit of a trick on the immune system, it's possible to generate antibodies that attach to smaller molecules, ones that contain only a few dozen atoms. This has been used to do things like create antibodies that act like catalysts for chemical reactions.

The ability to create antibodies that specifically bind to small molecules has raised hopes that they'll prove useful for a very challenging medical problem, namely drug addiction. Antibodies that latch on to drugs could keep them away from their sites of action in the brain, blocking any rewarding high. So far, the results haven't been as promising as the idea, but a new vaccine against heroin appears to do better specifically because it's designed to work with how the drug is processed by the body.

The immune system is able to produce many antibodies that recognize the pathogens it is currently facing for a simple reason: antibody-producing cells can sense when their antibodies are sticking to something. This process works because these cells stick a lot of antibodies on their surface. When they stick to an invader like a virus, it creates a cluster of antibodies in the same area on the cell's surface, all of them stuck to a single virus. This clustering is enough to trigger a signal that tells the cell that its antibody is working.

Small molecules can't do that. Since they're small, only one antibody can stick to them at a time, so there's no clustering, and the cells that produce the relevant antibody remain quiet. (Immunologists, please forgive me for the simplifications I made there.)

The trick to avoiding this is to link lots of the same molecule to the surface of a big protein. Multiple molecules linked to the same protein get recognized by antibodies, which now cluster as a result. A lot of antibodies get made.

Researchers who tried this process with heroin, shown above, tended to hook it up so that the complex, three-dimensional part of the structure that's off on the right was accessible. Since it's chemically distinctive, it should be easy to generate antibodies that are specific to it. So researchers hooked up the heroin to a protein using one of the sites at left, where two CH 3 's hang off the molecule (these, plus the neighboring oxygens, constitute an "acetyl group"). The antibodies were generated; it's just that they weren't especially effective. A slight increase in the dose of heroin, and the antibodies were swamped.

Looking at the biology of heroin, however, a team from the Scripps Institute figured out they were going about it wrong. Normally, in a matter of minutes, the body starts removing the two acetyl groups anyway. When both are gone, the result is morphine, which is the active form of the drug. It's thought that the full heroin molecule crosses into the brain before being converted into morphine.

The researchers hooked the drug up to a protein using a bond near the three-dimensional part, keeping both of the acetyl groups accessible. In their terminology, the vaccine was "dynamic" in that it would undergo all the chemical transformations that heroin does, allowing antibodies to be generated to each of the intermediate molecules.

This approach seemed to do the trick. By various assays, it appears that more of the heroin is retained in the blood rather than transiting into the brain. Rats needed a much higher dose of heroin—over six times higher—to feel its pain-numbing effects, and antibodies generated to morphine alone were much less effective.

The most intriguing test, however, involved rats that had been allowed to self-dose with heroin, which was accompanied by a blinking light. After an extended withdrawal, the rats would go right back to self-medicating if they were given a single dose of heroin or shown the blinking light. Once they were treated to raise the dynamic antibodies, however, the dose of heroin would no longer set off a bout of drug-taking (though the blinking light still would). The antibodies appeared to block the drug efficiently enough that it no longer registered in the brains of these rats.

This isn't an easy or simple solution. Vaccinating the rats required three doses within a month, and the rats still could get a hit off the drug—it just took a lot more of it. In human societies, addicts requiring a lot more of a drug can be a recipe for serious problems. But for those enrolled in supervised treatment programs, it could make a significant difference in keeping a momentary lapse from becoming a full relapse.

PNAS, 2013. DOI: 10.1073/pnas.1219159110 (About DOIs).