Image reproduction: Credit: Brivanlou Lab/Rockefeller University

The complete article was first published in Nature ~ March 2018.

Starting with an attempt to repair spinal-cord injuries in 2010, there have been more than a dozen clinical trials of cells created from Embryonic Stem cells (ESC's) to treat Parkinson’s disease and diabetes, among other conditions. Early results suggest that some approaches are working: a long-awaited report this week shows improved vision in two people with age-related macular degeneration, a disease that destroys the sharpness of vision.

In 2006, stem-cell biologist Shinya Yamanaka worked out how to return adult mouse cells to an embryonic-like state - the discovery of Induced Pluripotent Stem Cells (iPS cells). The following year, the same feat was accomplished in human cells. The process offered, in theory, a limitless supply of pluripotent cells genetically matched to a patient — but without the ethical quandaries of cells from unused embryos.

Many predicted that iPS cells would soon displace embryonic stem cells in the research space, but it didn’t happen. The number of ES-cell publications grew rapidly after 2006 and has held pace, at about 2,000 per year since 2012. Part of the reason was that ES cells were the gold standard against which researchers could compare iPS cells. And even today, there are some who doubt the safety of using iPS cells with concerns about cells growing out of control. 

In 2007, Yoshiki Sasai at the RIKEN Centre, Japan, discovered a molecule which could keep ES cells from dying when they were removed from the colonies in which they thrived. The success rate for creating new colonies shot from just 1% to 27%. “It fundamentally changed what you could do,” says cell biologist Malin Parmar at Lund University in Sweden. Parmar, who is using ES cells to derive neurons for a Parkinson’s disease clinical trial, says that such technical advances ushered in “a new golden age” for ES-cell research.

Researchers say that iPS cells still promise even more for disease-in-a-dish studies — namely the ability to grow stem cells from any living person with a suspected genetic condition. 

In 2008, for example, Kevin Eggan at Harvard University in Cambridge, Massachusetts, produced iPS cell lines from people with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). From previous work with ES cells, Eggan knew how to coax pluripotent cells into becoming motor neurons, the brain cells affected by the disease. When he did the same with patient-derived iPS cells, he was able to quickly compare the two types of cell. Cells from patients fired much more than their counterparts from people without the disease. “We took advantage of all the work we had done with ES cells to understand motor neurons,” says Eggan. Now, an anti-seizure medicine that quieted iPS cells made from patients is being tested in humans. Results are expected in the next two months.

In the clinical realm, many have assumed that iPS cells would eventually win out over ES cells. One potential advantage is that they can produce cells and tissues with the same DNA as the patient and thus not cause an immune reaction when transplanted. But for most genetic diseases, iPS cells created from a patient would contain the mutation that causes the problem, and the cells would have to be modified to confer any therapeutic benefit.

Macular degeneration has been a popular target for both ES-cell and iPS cell therapies. There have been at least seven clinical trials, in the United States, the United Kingdom, South Korea, China and Israel. On 19 March, researchers of the London Project to Cure Blindness and the University of California, Santa Barbara, reported the results of a study to implant a patch of cells made from ES cells into the damaged retinas of two individuals. A year after the procedure, the participants regained the ability to read, albeit slowly.

This is clearly a “big step forward” for the field and strongly supports further studies in other parts of the body. Scientists are now working out how best to put the cells into people. Many in the stem-cell field are betting the next big clinical breakthrough for ES cells will come in Parkinson’s disease and half a dozen companies and clinics are gearing up to use ES cells or iPS cells to replace dopamine-producing neurons. Click here to read more...

One crucial question is how far the pluripotent cells should be taken down the road towards maturity before transplanting them. An Australian trial started in 2016 and a Chinese trial begun in 2017 use immature neural precursor cells, which do not produce dopamine. Researchers say the immaturity of the cells will help them to survive transplantation and integrate into their new host’s brain. But leaders of a group of ES- and iPS-cell trials known collectively as GForce-PD say that the more-mature cells they use turn into the desired type of dopamine-producing cell more reliably and are less likely to grow out of control.

Despite their sometimes rocky history, ES cells have proved their value repeatedly. Some researchers have even scaled back their use of animal models because ES cells seem to provide a better path to studying human disease. And ES cells are just as crucial today for better understanding the mechanism of pluripotency and for improving the medical application of any pluripotent cell. 

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