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How to make a mouse from scratch: a few drops of blood, one pinch of salt, and a drop of vinegar…

3 February 2014
Appeared in BioNews 740

This is not a witch's recipe for a powerful potion. It is virtually how a group of Japanese scientists have generated new mice. The remarkable finding, published in Nature last week, proved again that true greatness lies in simplicity (1,2).

From plant biology, we know that exposing a piece of carrot to the right environment can produce a new plant. The researchers, from the Riken Center for Developmental Biology in Japan, asked what would happen with mammalian cells exposed to various environmental stimuli. Could some environmental cues turn on genes involved in 'stemness' and change cellular fate as they do in plants? To find that out, Haruko Obokata and her colleagues isolated white blood cells from one-week-old genetically engineered mouse pups.

These mice had an extra gene that could help the scientists monitor cell response: an Oct-4 promoter that controlled expression of a green fluorescent protein. Oct-4 is a pluripotent stem cell marker, which, if activated by cues from the environment, would lead to the fluorescent protein being expressed and cells turning green.

More than 60 years ago, developmental biologists demonstrated that exposure to saline solutions and 'sublethal' conditions such as high acidity can induce neural differentiation in the salamander (3-6). Following that lead, the decision was to focus on perturbations of physiological pH.

The results were stunning. Keeping the blood cells in a medium with acidic pH in a range of 5.4 to 5.8 for only 30 minutes changed them so profoundly that they adopted characteristics of embryonic stem cells and could be used to construct an entire mouse embryo.

They called the phenomenon 'stimulus triggered acquisition of pluripotency' (STAP). Even though they could be used to generate an animal, the cells could not be maintained infinitely in culture as embryonic stem cells (ESCs) or induced pluripotent stem cells (iPSCs) can. Supplementing the culture medium with the right combination of hormones and growth factors overcame the problem. Depending on the supplement, the STAP cells could turn into ESC-like cells or proliferative stem cells with similar characteristics to trophoblasts, cells that will give rise to the placenta. Such plasticity indicated that they represent a unique state of pluripotency, closer to the all-encompassing totipotency of a fertilised egg than either ESCs or iPSCs.

It is not that brief exposure to low pH had such an effect only on white blood cells. Bone marrow, brain, lung, and liver cells all reacted identically. We have to keep in mind that all the cells were isolated from young pups, which are more pliable than adult cells. We do not yet know the extent to which ageing can affect this phenomenon, if at all. If ageing slows down or attenuates cell response to low pH, finding out why and how at the molecular level, can provide insight in the ageing process, which may be a game-changer in the future.

Whether human cells respond in a similar way to comparable environmental cues remains to be shown. I am sure that the group is working on this and I would not be surprised if they succeed even within this calendar year.

The approach is indeed revolutionary. It will fundamentally changethe way scientists perceive the interplay of environment and genome. However, as attractive as it sounds, it does not change how stem cell research is translated into clinical use. It does not bring stem cell-based therapy closer; it only makes manufacturing somewhat cheaper. We will need to use the same precautions for the cells generated in this way as for the cells isolated from embryos or reprogrammed with a standard method.

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