I’ve been following the story of stimulus-triggered acquisition of pluripotency (STAP) cells with considerable interest, and there’s a good reason for that: from the very beginning, it contradicted how I’d always thought about cell states, and if it were true, I’d have to rethink a lot of things, which was vexing. But on the other hand, empirical results always trump mental models, so if the results held up, there was no question but that I’d have to go through that uncomfortable process of reorganizing my preconceptions. It would be OK, though, because there’d be a great prize at the end.
Well, it turns out that I don’t have to reboot my brain after all, because now that all the flailing about is over, STAP is a product of sloppiness and fakery, and is dead.
So here’s the controversy, and why I found it vexatious. We want to be able to specify cell states; in particular, we’d love to be able to take any cell from the human body, tickle it with a few specific signals, and see it throw away all of its historical constraints and become a different cell type altogether. In particular, the Holy Grail is to find the right combination of switches to cause any cell to become a pluripotent stem cell — the kind of cell we can then induce to become any other cell type we might need.
We know this can’t be impossible, and is probably even fairly simple, because we know that cells can do this already (well, to some degree; your body accomplishes this task by setting aside reserve populations of stem cells. It’s also likely that some cell types are so tightly locked in by the process of differentiation that their state is not reversible). The idea is that we just need to find the right combination of signals/genes — the right kind of key — and we can unlock the cell, and make it open to additional inductions that will allow us to manipulate it.
We have some idea of the shape of the key. Yamanaka identified four genes, Oct4, Sox2, cMyc, and Klf4, that when activated, switched cells into a pluripotent state, making induced pluripotent stem cells, or iPS cells. It works. The handicap right now is that we only have a kind of brute force method of switching those genes on, and two of them are oncogenic, so it’s as if we’ve got a rather clumsy key that opens the lock, but also damages it in unfortunate ways. The resolution to that problem, though, was learning how to finesse the genes — we need to figure out how to more delicately switch on the necessary genes by a way other than bluntly transfecting cells with copies of the genes that are always on.
Then along came Haruko Obokata, an investigator in Japan who announced that she could induce stem cells with simple, generic stress, such as by exposing them to acid or physically pushing on the cells. It was like saying she didn’t need a specific key, all you needed to do was shake the lock really hard, and it would spontaneously pop open. What, really? That just seems too simple. It would be phenomenally awesome if true, but it seemed unlikely. But then, I remember this one lab I worked in where all the publicly popular drugs, like ketamine, were kept locked in a drawer to which only the PI had a key…but the countertop wasn’t secured to the bench, so if you knew about it, you could just lift the top and get easy access. It was a backdoor to the goodies that was so stupid you couldn’t believe it existed, but it did.
Could it be that cells similarly had a stupid weakness that could be so easily exploited? The short answer is no; read the whole article by David Cyranoski.
But the paper1 that set out the fundamental technique was soon shot full of holes. There was plagiarized text in the article. Figures showed signs of manipulation, and some images were identical or nearly identical to those used later in the same paper and elsewhere to represent different experiments. More damning were genetic analyses that strongly suggested the cells were not what they were purported to be. And although deriving STAP cells was advertised as simple and straightforward, no one has yet been able to repeat the experiment.
Within the space of six months, Obokata was found guilty of misconduct by her institution; well-respected scientists, including RIKEN head Ryoji Noyori, bowed their heads in apology; and both papers were retracted. In the end, the evidence for STAP cells seemed so flimsy that observers began to ask where were the extra precautions and the ‘extraordinary proof’ that had been promised post-Hwang.
It sure would have been nice to have a simple technique for generating stem cells, but I have to confess to being a bit relieved. There’s the vindication of prior thinking and the value of incrementally improving our stem cell protocols, of course, but also, I’d personally rather that it weren’t trivial to switch my cells to a de-differentiated pluripotent state — that’s a recipe for easy cancer generation, too. It is somehow reassuring to think that evolution has shaped multi-cellular organisms to be somewhat resistant to spontaneously going all stem-celly under stress.
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