Potential is a sad thing to lose. Have you ever thought that it would be great to return to your childhood, when your options seemed limitless and life hadn’t taken you down increasingly narrow corridors of possibility? Wouldn’t it be great to rewind the clock and have the choice to start over?
While that’s still the stuff of science-fiction, for some cells in your body it may soon be science fact. In one of the most exciting scientific breakthroughs of the year, two groups of scientists have found a way of turning adult human cells back into the stem cells of embryos.
Creating embryonic stem cells
Embryonic stem cells are the embodiment of potential. Armed with a trait called ‘pluripotency‘, they can give rise to every single type of cell and tissue in the body, renewing themselves indefinitely while their daughters take up the mantle of nerves, muscles, blood and more.
For years, stem cells have been touted as the Holy Grail of modern medicine. Within their membranes lies the potential to understand how we develop, test new drugs and most importantly, provide replacement cells to treat Alzheimer’s, Parkinson’s, spinal cord injuries, diabetes, stroke and more.
To fulfil this potential, we need to find a way to produce stem cells with the same genetic material as the patient being treated. There are two ways to achieve this personal touch. The first involves transplanting a nucleus (and the DNA inside) from one person’s cell into an empty egg. Egg turns into embryo, and embryo provides embryonic stem cells. But harvesting these cells destroys the embryo, which steers the technique into an ethical quagmire.
The second method is less controversial – we could reprogram adult cells into their original stem-like state, rather like erasing a person’s CV and school record and have them start again as a fresh-faced child.
As stem cells spawn off new lineages, the DNA of these daughters picks up molecular post-its that dictate how, when and where their genes are to be read. These ‘epigenetic‘ changes commit the cells to increasingly specialised fates and ensures that development is an ordered, timely process. In theory, these changes should be reversible with the right combination of chemicals.
From mice to men
Last year, Shinya Yamanaka and Kazutoshi Takahashi from Kyoto University proved that this could be done in mice. Using just four proteins – Oct4, Sox2, c-Myc and Klf4 – the duo managed to turn cells from connective tissue of their tails into stem cells or, as they called them, ‘induced pluripotent stem (iPS)’ cells.
That experiment fired the starting pistol in a race to duplicate the success in human cells. This week, two groups shot past the finishing line in a photo-finish tie. Yamanaka and Takahashi were in the driving seat of the first group and they showed that the same four proteins could turn adult human cells into iPS cells.
They successfully reprogrammed skin cells from the face of a 36-year-old woman and connective tissue from a 69-year-old man into cells with the same shape and rates of growth as true embryonic stem cells. These iPS cells also had a similar portfolio of genetic activity and similar coats of protein. And just like embryonic stem cells, they had high levels of the telomerase enzyme, which effectively grants them immortality by repairing protective structures on the end of DNA strands.
As a final proof of their ‘stemness’, Takahashi and co. successfully coaxed the induced stem cells into producing neurons and heart muscle cells. When they were transplanted into the sides of mice with weakened immune systems, they formed tumours called teratomas (literally ‘monster tumour’) containing a Frankenstein-like mash-up of different cell types including cartilage, gut lining, muscle, nerves and keratin.
Using c-Myc is a bit of a problem though, as mutant forms are linked to several human cancers and the protein can sometimes cause human embryonic stem cells to die. With this in mind, a second group led by Junying Yu and James Thomson from the Genome Center of Wisconsin searched for a different combination of reprogramming proteins.
They whittled their way through 14 candidates and through a process of elimination hit upon a slightly different quartet – Oct4 and Sox2, like the Japanese group used, and two newcomers, Nanog and Lin28. In similar experiments, they used these proteins to reprogram skin cells from a foetus and from the foreskin of a baby boy. Again, the induced stem cells were superficially and genetically similar to true embryonic stem cells, were rife with telomerase and could produce a wide variety of cell types.
Questions and problems
So far, so promising, but it’s not quite time to hang up the lab coats and start distributing panaceas. The two papers are both breakthroughs in the field, but neither has come up a method that’s feasible for actual clinics.
The biggest drawback of the studies is that both used retroviruses to cut and paste the quartet of genes into the reprogrammed cells. It’s quite a brutish method. The viruses inevitably insert their load in places that disrupt other genes, which could eventually lead to cancer in tissues grown from the resulting cells. Indeed, Yamanaka found that one in five of the mice grown from his induced mouse stem cells eventually developed cancer.
Obviously, that’s unacceptable and stem cell researchers need to find new methods. They could either develop carriers that shuttle the new genes and proteins into the cells without disturbing their DNA, or create small molecules that activate the existing genes without the need for introducing new copies.
There’s also a small but significant question over the identity of the induced stem cells. They may be very similar to their embryonic counterparts, but they aren’t identical. The Japanese group compared 32,000 genes in the two groups of cells and found large differences in activity in over a thousand of these (just under 4%). It will be important to discover the precise nature of these differences.
We’ll also need a better understanding of the method itself. In a case of the technology preceding the science, it isn’t entirely clear how these two sets of four proteins restore an adult cell’s lost potential.
So far, we know that Oct4 and Sox2 work together to activate genes that maintain ‘stemness’, while suppressing genes that chain cells to specific fates. Non-stem cells build up a series of molecular barricades that stops these partners from affecting their target genes, and Takahasi speculates that c-Myc and Klf4 alter the way DNA is packaged to give Oct4 and Sox2 easier passage to their targets.
For the moment, it seems that reprogramming has taken the lead over nucleus transfer as a technique for producing stem cells. It certainly avoids the moral dilemma posed by its rival method by avoiding the need for embryos and donated eggs.
Nonetheless, it would be prudent to remember that these new successes depended on knowledge that we gleaned through research on actual embryonic stem cells. This line of work will also be necessary to help us answer the many unsolved questions posed above. It’s would be premature to dismiss nuclear transfer as an unnecessary technique.
It’s certainly rich to suggest, as George Bush has done, that trying to block this research was actually responsible for driving scientists down the more morally acceptable path of reprogramming. Have a look at Nick Anthis’s post at the Scientific Activist for a more detailed rundown on the American Right’s reaction to these studies.
More on stem cells: Stem cells only grow up properly in the right environment
References: Takahashi, K., Tanabe, K., Ohnuki, M., Narita , M., Ichisaka, T., Tomoda, K., Yamanaka, S. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. . Cell, 131, 1-12.
Yu, J., Vodyanik, M., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J., Tian, S., Jonsdottir, G., Ruotti, V., Nie, J., Thomson, J. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science, , . DOI: 10.1126/science.1151526