What a mess! Science has a retraction of a 2005 paper, which is always a nasty enough business, but in this case, the authors can’t agree on whether it should be retracted or not. And no one seems to be able to agree on whether the original results were real, and (even if they weren’t) whether the technique the paper describes works anyway. Well.
The original paper (free full text), from two Korean research groups, described a drug target discovery technique with the acronym MAGIC (MAGnetism-based Interaction Capture). It’s a fairly straightforward idea in principle: coat a magnetic nanoparticle with a molecule whose target(s) you’re trying to identify. Now take cell lines whose proteins have had various fluorescent tags put on them, and get the nanoparticles into them. If you then apply a strong magnetic field to the cells, the magnetic particles will be pulled around, and they’ll drag along whichever proteins have associated with your bait molecule. Watch the process under a microscope, and see which fluorescent spots move in which cells.
Papers were published (in both Science and Nature Chemical Biology), patent applications were filed (well, not in that order!), startup money was raised for a company to be called CGK. . .and then troubles began. Word was that the technique wasn’t reproducible. One of the authors (Yong-Weon Yi) asked that his name be removed from the publications, which was rather problematic of him, considering that he was also an inventor on the patent application. Early last year, investigations by the Korean Advanced Institute of Science and Technology came to the disturbing conclusion that the papers “do not contain any scientific truth”, and the journals flagged them.
The Nature Chemical Biology paper was retracted last July, but the Science paper has been a real rugby scrum, as the journal details here. The editorial staff seems to have been unable to reach one of the authors (Neoncheol Jung), and they still don’t know where he is. That’s disconcerting, since he’s still listed as the founding CEO of CGK. A complex legal struggle has erupted between the company and the KAIST about who has commercial rights to the technology, which surely isn’t being helped along by the fact that everyone is disagreeing about whether it works at all, or ever has. Science says that they’ve received parts of the KAIST report, which states that the authors couldn’t produce any notebooks or original data to support any of the experiments in the paper. This is Most Ungood, of course, and on top of that, two of the authors also appear to have stated that the key experiments (where they moved the fluorescent proteins around) were not carried out as the paper says. Meanwhile, everyone involved is now suing everyone else back in Korea for fraud, for defamation, and who knows. The target date for all this to be resolved is somewhere around the crack of doom.
Emerging from the fiery crater, CGK came up with another (very closely related) technique, which they published late last year in JACS. (If nothing else, everyone involved is certainly getting their work into an impressive list of journals. If only the papers wouldn’t keep sliding right back out. . .) That one has stood up so far, but it’s only April. I presume that the editorial staff at JACS asked for all kinds of data in support, but (as this whole affair shows) you can’t necessarily assume that everyone’s doing the job they’re supposed to do.
The new paper, most interestingly, does not reference the previous work at all, which I suppose makes sense on one level. But if you just came across it de novo, you wouldn't realize that people (at the same company!) had already been (supposedly) working on magnetic particle assays in living cells. Looking over this one and comparing it to the original Science paper, one of the biggest differences seems to be how the magnetic particles are made to expose themselves to the cytoplasm. The earlier work mentioned coating the particles with a fusogenic protein (TAT-HA2) that was claimed to help with this process; that step is nowhere to be found in the JACS work. Otherwise, the process looks pretty much identical to me.
Let’s come up for air, then, and ask how well useful these ideas could be, stipulating (deep breath) that they work. Clearly, there’s some utility here. But I have to wonder how useful this protocol will be for general target fishing expeditions. Fluorescent labeling of proteins is indeed one of the wonders of the world (and was the subject of a recent a well-deserved Nobel prize). But not all proteins can be labeled without disturbing their function – and if you don’t know what the protein’s up to in the first place, you’re never sure if you’ve done something to perturb it when you add the glowing parts. There are also a lot of proteins, of course, to put it mildly, and if you don’t have any idea of where to start looking for targets, you still have a major amount of work to do. The cleanest use I can think of for these experiments is verifying (or ruling out) hypotheses for individual proteins.
But that's if it works. And at this point, who knows? I'll be very interested to follow this story, and to see if anyone else picks up this technique and gets it to work. Who's brave enough?