One of the hazards of constant bombardment with science or technology announcements heralding something as “breakthrough,” “revolutionary,” “unprecedented,” and the like, is developing superlative fatigue. These results can’t all be great; and they’re not. Sometimes it’s just hype. Sometimes the people involved really do think they’re on to something, but they’re not. Occasionally the superlatives are accurate. It’s hard to know the difference between hype, hubris, and reasonable humility, especially if you’re not a specialist fully knowledgeable of the field’s leading edges (and maybe not even then). Driven by the need for funding, science and marketing hyperbole are kissing cousins these days; an awkward situation, at best.
Unfortunately, with all the noise the quietly important may go unnoticed. When I see this headline: Researchers directly turn mouse skin cells into neurons, skipping iPS stage; it’s likely to go floating past my consciousness without even dragging its feet. There are so many stories these days involving creation of this or that stem cell, or of turning this or that stem cell into some other type of cell. All of them promise to make creation of stem cells easier, or the use of stem cells to replace/repair this or that body cell. Each announcement represents one of a thousand steps, a few of which will certainly lead to important medical procedures, but for now just a lot of ‘attaboys!’ for the scientists toiling on their research agenda.
I bet you’ve already forgotten the ‘Researchers directly turn mouse skin cells into neurons, skipping iPS stage.’ It could be you’re unfamiliar with the abbreviation iPS. It stands for induced Pluripotent Stem cell. Pluripotent stem cells can turn into almost any kind of cell. They’re not as flexible that way as embryonic or totipotent stem cells, but close. When a researcher ‘induces’ a pluripotent stem cell, it means they take a typical ‘adult cell’ – one that has already undergone differentiation to become a specific type of cell, say a skin cell – and one way or another forces it to become a stem cell of the pluripotent variety. Stem cell research is full of attempts to create cells from anything other than embryonic stem cells, largely because of the controversy and ethical uncertainty of using cells from human embryos. The typical approach is: Take a mouse cell, a skin (epithelial) cell, and induce it to become a pluripotent cell. Then take the iPS cell and turn it into another kind of cell, for example, a neuron. This seems logical, since differentiating a pluripotent (or embryonic) stem cell is what these cells are meant to do.
This two phase method, with many steps, is time consuming. What if you could go directly from an adult cell, the skin cell, and turn it into a neuron, without going through the iPS phase? Obviously it would be quicker, but most researchers would say, ‘It doesn’t work that way.’ Ah, but it can.
To make this ‘unprecedented’ transformation, it’s necessary to get down and molecular to alter a few genes. But which genes? This is where the researchers at Stanford University (California, USA) started to earn their grant money. They began with a candidate list of 19 genes in mice, all involved with epigenetic reprogramming or neural development. They altered these genes in a virus (lentivirus) and injected the virus into the skin cells of mice. In just over a month some cells developed properties associated with neurons. Further testing narrowed the genes down to just three, and when these were altered and injected, about 20% of the skin cells from the tail of mice became functional neurons.
This was astonishing in (at least) two respects: The rate of cell differentiation success, 20%, is phenomenally high. Typically only 1-2% of adult cells can be induced to become pluripotent. Second, the speed was also extraordinary, just a week as compared to many weeks for the iPS procedure. Faster, better, cheaper – take all three. As one of the researchers put it:
“We actively and directly induced one cell type to become a completely different cell type,” said Marius Wernig, MD, assistant professor of pathology and a member of Stanford’s Institute for Stem Cell Biology and Regenerative Medicine. “These are fully functional neurons. They can do all the principal things that neurons in the brain do.” That includes making connections with and signaling to other nerve cells — critical functions if the cells are eventually to be used as therapy for Parkinson’s disease or other disorders.
“We were very surprised by both the timing and the efficiency,” said Wernig. “This is much more straightforward than going through iPS cells, and it’s likely to be a very viable alternative.” Quickly making neurons from a specific patient may allow researchers to study particular disease processes such as Parkinson’s in a laboratory dish, or one day to even manufacture cells for therapy.
The research suggests that the pluripotent stage, rather than being a required touchstone for identity-shifting cells, may simply be another possible cellular state. Wernig speculates that finding the right combination of cell-fate-specific genes may trigger a domino effect in the recipient cell, wiping away restrictive DNA modifications and imprinting a new developmental fate on the genomic landscape.
“It may be hard to prove,” said Wernig, “but I no longer think that the induction of iPS cells is a reversal of development. It’s probably more of a direct conversion like what we’re seeing here, from one cell type to another that just happens to be more embryonic-like. This tips our ideas about epigenetic regulation upside down.”
That last line, “…tips our ideas about epigenetic regulation upside down” is the kicker, potentially the initial words of a call to ‘revolution.’ He’s saying, modestly, that stem cell scientists may have it all wrong. In the domain of cell differentiation, any cell can go any which way, it all depends on the genetics, the genetics depend on their expression (epigenetic regulation), and could be added, expression is keyed to both the DNA and the environment.
How serious are the Stanford researchers about their findings? They’ve applied for a patent on the technique.