Six years ago a Japanese scientist found a way trick a skin cell into a type of stem cell. Quite remarkably, these modified cells, called induced pluripotent stem cells (iPSC), were found to be very much like embryonic stem cells, the cells that can become any cell in the body. The work was published in the journal Cell
The iPSC field has exploded; the cells are not exactly like eSC and there are issues still being worked out (e.g. tumor growth), but iPSC are being used, with good success, in animal experiments, including spinal cord injury (see below). iPSC are also an important tool to model numerous diseases and conditions in the lab ( more below).
Shinya Yamanaka was awarded the Nobel Prize for Medicine October 7 for the iPSC discovery. Normally the Nobel committee waits a few years after a research finding to make sure the work stands the test of time. That this came so soon speaks to its significance. Yamanaka, a professor at Kyoto University and affiliated with the Gladstone Institute in San Francisco, believes the time is near for human clinical use.
A second Nobel was awarded Monday to British scientist John Gurden for work he did 50 years ago (the year Yamanaka was born). In a paper “Adult Frogs Derived From the Nuclei of Single Somatic Cells
,” Gurden pioneered what became known as nuclear transfer reprogramming (cloning); he replaced the cell nucleus of a frog egg cell with a nucleus from a mature cell from the intestine of a tadpole. The egg developed into a fully functional tadpole and later yielded adult frogs. This is the same transfer process used to clone Dolly the sheep in 1996, in Scotland.
While iPSC may at first glance seem far afield from cloning, the discoveries are very much part of the same larger stream of cell biology. Yamanaka, to be sure, cites Gurden’s nuclear transfer work as essential to the emergence of his iPSC studies. Together, both scientists changed the way science looks cells that were once thought to have been fated to a specific function. The process of becoming a specialized cell, so it seems, can be rewound and rebooted.
We will get into a bit more on the Nobel prizes and let Yamanaka summarize the biologic currents, but there was another big iPSC story in recent days:
Another team from Japan, also from Kyoto University, coaxed mouse stem cells – including iPSC cells – to make eggs; these lab-made eggs went on to be fully fertile themselves and became normal mouse pups. Mitinori Saitou’s paper, in the journal Science, “Offspring from Oocytes Derived from in Vitro Primordial Germ Cell–Like Cells in Mice
,” showed how his team started with mouse embryonic stem cells and stem cells induced from skin cells; they introduced a cocktail of signaling molecules to transform the stem cells first into egg precursors -- epiblast cells, and then primordial germ cells (PGCs).
Last year the Saitou group showed that the male PGCs could be injected directly into infertile male mice to become viable sperm. The female process was more complicated. From a report “Mouse Stem Cells Lay Eggs
,” in Nature
The researchers isolated embryonic ovary tissue that did not contain sex cells and then added their lab-made PGCs to the dish. The mixture spontaneously formed ovary-like structures, which they transplanted into female mice. After four weeks, the stem-cell-derived PGCs had matured into oocytes. The team fertilized them and transplanted the embryos into foster mothers. The offspring that were produced grew up to be fertile themselves.
What are the implications of this? Developmental biologists are thrilled to learn more about the complexities of the body as it forms, and as it might be reformed. Press reports noted that this mouse work may have implications for humans with infertility issues. Maybe so, down the long hard road of discovery from mice to humans. But ethicists may have a brave new possibility to worry about: parentless offspring and sexless procreation.
Back to the Nobel prize. Here’s how Yamanaka sees the work flow that led to his discoveries, in three steams:
First was Gurdon, in 1962; his stream leads to Ian Wilmut and Dolly. Said Yamanaka, from an essay earlier this year, “Induced Pluripotent Stem Cells: Past, Present, and Future
These successes in somatic cloning demonstrated that even differentiated cells contain all of the genetic information that is required for the development of entire organisms, and that oocytes contain factors that can reprogram somatic cell nuclei.
The second stream was the discovery by William Gehring and his group in Switzerland of “master” transcription factors
. In 1987, such a factor, Antennapedia, was applied to redesign the body plan of Drosophila, a fruit fly: Legs appeared where antennae were suppose to grow. That same year, a mammalian transcription factor, MyoD, was shown by Andrew Lasser, then at Washington University Medical School, to convert fibroblasts into myocytes
. Said Yamanaka:
These results led to the concept of a “master regulator,” a transcription factor that determines and induces the fate of a given lineage. Many researchers began to search for single master regulators for various lineages. The attempts failed, with a few exceptions.
Yamanaka’s third stream of research involves embryonic stem cells, starting in 1981 with mouse cells
and leading to the 1998 discovery by James Thomson of human eSC
Combining the first two streams of research led us to hypothesize that it is a combination of multiple factors in oocytes or ESCs that reprogram somatic cells back into the embryonic state and to design experiments to identify that combination. Using information about the culture conditions that are needed to culture pluripotent cells, we were then able to identify four factors that can generate iPSCs.
The streams keep on flowing, said Yamanaka, who notes that more than 100 reports have been published in the past three years using disease-specific iPSCs. Here are two for spinal cord injury, both from Japan:
"Grafted Human-Induced Pluripotent Stem-Cell–Derived Neurospheres Promote Motor Functional Recovery After Spinal Cord Injury in Mice
;" (9 days post injury grafts of human fibroblasts, functional motor recovery reported compared to non treated; no tumors) and "Therapeutic Potential of Appropriately Evaluated Safe-Induced Pluripotent Stem Cells for Spinal Cord Injury
Although he is not credited as a co-author, Fred Gage, at the Salk Institute, edited the two SCI papers citred. He has his own iPSC work, too. Gage, the former chair of the Reeve Foundation International Research Consortium on Spinal Cord Injury, reported last year that complex neurological disorders such as schizophrenia can be modeled using iPSC. “Modeling Schizophrenia Using Human Induced Pluripotent Stem Cells
In a recent interview Gage told me iPSC biology is emerging as a powerful tool.
Using iPSC we went right into a neurological disease, using a form of autism called Rett syndrome for which there were good animal models and we knew what gene was missing. We were able to recapitulate the phenotype from patients, and we could develop strategies for repairing it.
What was most fascinating is that we took a lot of known psychiatric drugs that function in some people and not others and screened them on our neurons, and we could reverse the symptoms in this dish with some but not all. And so the view has emerged that maybe we can use this strategy to pre-screen people who have a disease for which there are multiple drugs that only work partially. We might also use the same cell models to screen for new drugs and molecules. It’s very exciting, lots of collaboration, and the technology is moving at an enormous pace.