Acid shock for stem cells

Despite inconclusive results, a new technique has reignited interest in the idea that normal cells can rally in response to stress and help repair the body. Elizabeth Finkel reports.

Researchers in Japan claim this mouse embryo’s tissues came from blood cells that turned into stem cells after an acid shock. A “reporter gene” on board the blood cells makes them glow green when they turn into stem cells. – Haruko Obokata/ RIKEN

Not so long ago, it was the Holy Grail. The idea that you could take one of your own skin cells, wind its clock back to a more embryonic state, and create yourself a store of customised stem cells. Pristine and prolific, cells like these could supply whatever you needed to fix your organs: fresh brain, liver or pancreas cells, for instance.

Achieving this trick with human cells seemed devilishly difficult. In 2005 Korean researcher Woo Suk Hwang claimed success by transplanting the nucleus of a skin cell into a human egg, a technique known as “therapeutic cloning” or “somatic cell nuclear transfer” previously shown to work in animals. But his efforts proved fraudulent. Two years later Japanese scientists did it for real using a remarkably straightforward approach – merely by transferring four particular genes into a human skin cell, they created “induced pluripotent stem cells” or iPS cells.

The Japanese papers showed that simply exposing blood cells of newborn mice to a stress like mild acid was enough to reboot them into becoming 'pluripotent'.

But a young Japanese scientist now looks like she has bettered even that trick. In two papers published in January in Nature, Haruko Obokata at the Riken Center for Developmental Biology in Japan and her colleagues startled the world by showing that simply exposing blood cells of newborn mice to a stress like mild acid was enough to reboot them into becoming “pluripotent” – in other words capable of generating any tissue. From 25% to 50% of the blood cells could be converted, a staggering percentage given that the iPS technique often achieves less than 1% conversion of skin or blood cells to pluripotency.

Researchers were amazed. How could this be? The mild acid conditions Obokata used existed in parts of the body like the stomach, but the stomach does not spontaneously give forth to multiple kinds of tissue. Yet researchers were cautiously optimistic. “If it can be applied to human cells, then it’s a huge turn of the dial. Any old lab with vinegar could do it,” said Alan Trounson, President of the California Institute of Regenerative Medicine.

But a couple of weeks later, the research community was singing a different tune. Scientists poring over pictures in the journal noticed that on at least one occasion the same picture had been used twice, but to demonstrate different things. For wizened stem cell researchers that is a warning sign: it was the way some of Hwang’s phony data was first detected.

Unease has also built from another quarter. If the technique is really that easy, then other researchers should be able to make their own acid-douched stem cells. But so far, the web has been filling with reports of people unable to repeat the experiment.

“Some friends of mine have had trouble repeating this protocol,” says James Godwin from the Australian Regenerative Medicine Institute in Melbourne. “It still may be real as sometimes these protocols can be difficult, but it is not looking good if you read some of the blogs.”

As Godwin cautions, failure to reproduce an experiment does not necessarily mean the original findings aren’t real. Sometimes the skills aren’t easy to acquire.

That was not the case with iPS cells. Researchers around the world quickly adopted the technique, which won its inventor Shinya Yamanaka the Nobel Prize in 2012. Clinical trials using these cells to treat Macular Degeneration are due to start in Japan this year.

After being exposed to mild acid for 30 minutes, blood cells known as “CD45 lymphocytes” form clusters of tiny cells that turn out to be pluripotent – capable of forming any tissue. Obokata reported that up to 50% of cells would switch, but others cannot repeat her results. – Haruko Obokata/ RIKEN

But despite the worrisome chatter on the web, there are good reasons to keep an open mind, says Martin Pera, a stem cell pioneer at the University of Melbourne. For one thing, Obokata’s co-authors make for an all-star team. Teruhiko Wakayama was the first to clone mice and Yoshiki Sasai is revered for his ability to sculpt organs from stem cells. Wakayama has also reported being able to reproduce the acid stem cell feat. But alas, not once he had left the Riken lab and Obokata’s careful guidance. Could it be something in the Riken lab’s water? Riken is said to be preparing a detailed recipe that will allow the rest of the world to finally nail the technique.

Whether the technique pans out or not, the new papers have reignited interest in the idea that normal cells can rally in response to stress and help repair the body. There are certainly examples in other species. Cut the top off a carrot, for instance, and the slice will regrow the entire carrot, while salamander cells can change their fate in response to acid treatment. Obokata now claims that ordinary white blood cells can do it too, reverting to an embryonic state in response to a 25 minute dip in mild acid or being slightly squished. When they were injected into a growing mouse embryo, they could contribute to forming any part of an entire new mouse – the essential test for a pluripotent stem cell. In fact they were more pluripotent than cells made by the other approaches, contributing also to the placenta – something that other types of pluripotent stem cells fail at.

For all these reasons researchers are watching this space closely. “The basic science questions are profound and there is the tantalising potential for a fast and easy route to pluripotency,” says Pera.

The Nature report can be found here.

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