It’s been a good week for advocates of stem cell research, both politically and scientifically. On Wednesday, an appellate court allowed the government to continue its funding of human embryonic stem cell studies after a judge halted the grants in August. And on Thursday researchers at Children’s Hospital and the Harvard Stem Cell Institute announced a long-awaited breakthrough that could make it possible to push another type of stem cell into the clinic earlier for human testing to treat disease.
Derrick Rossi and his colleagues announced a major leap forward with induced pluripotent stem (iPS) cells, which don’t come from embryos and can be generated from any type of cell, including skin cells. IPS cells were first created in 2006 by Shinya Yamanaka of Kyoto University, and launched a flurry of excitement in regenerative medicine, since they bypassed the political and moral challenges that face their embryo-derived cousins. IPS cells, scientists believe, can be reprogrammed back to an embryonic-like state similar to that of embryonic stem cells, and then coaxed into becoming any of the tissues in the body, including nerve and muscle, to treat diseases as varied as diabetes and Alzheimer’s.
But Yamanaka’s method had some drawbacks — in order to turn back the clock on the adult cells he used, he needed to insert four genes into the cell’s genome using retroviruses. The very act of jamming such extra genetic material into a cell can trigger it to become cancerous, as scientists have no way of controlling where the genes slip in — if they insert in the middle of a gene that signals the cell to grow, they could turn a healthy cell into a malignant one.
In addition, one of the genes itself was known to cause cancer in animal models. That meant that these iPS-based cells could never be used in human patients, which is what researchers were hoping to do. Plus, the entire technique, while scientifically remarkable, is woefully inefficient. Only about 1 in 1,000 to 1 in 10,000 cells are generally reprogrammed with the method. (More on Time.com: White House ‘Heartened’ By Stem Cell Ruling).
So ever since Yamanaka’s experiment, scientists have been scrambling to find a better way to reprogram cells, by using more benign vehicles to deliver the genes, such as a cold virus or circles of DNA known as plasmids, with some success. They have even turned to chemicals that might do the same job as the genes, but have only been able to replace two of the four so-called Yamanaka factors.
Rossi decided to try a different approach, one that only in retrospect seems so obvious. Genes are stretches of DNA that a cell “reads” by turning the DNA into messenger RNA (mRNA), a differently coded version of the gene that can then be made into proteins such as hormones or enzymes or other compounds that the cell needs to thrive and survive. Instead of introducing genes into the cell, as Yamanaka had, Rossi skipped straight to the RNA step. If he could provide the cells with enough snippets of the right RNA corresponding to the Yamanaka genes, then the cell would still take the RNA and make it into the four factors that Yamanaka had found were essential for reprogramming the cell.
Unfortunately, it turns out that cells have a built-in defense against foreign RNA (viruses, after all, are made up of RNA) so when Rossi’s team first tried the experiment, the cell simply chewed up the added RNA. Some cells even died in the effort.
But the group found a way to attach a stretch of additional RNA code onto the pieces that would make them invisible to the cell’s destructive forces. Once they did that, the cells happily pumped out enough of the factors to reprogram the cells and turn them back into an embryonic-like state. (More on Time.com: Putting More People on Cholesterol-Lowering Drugs Could Save Money).
In fact, the system worked better than Rossi expected. The mRNAs that he made and introduced into the cells resulted in up to a 100-fold increase in efficiency in generating iPS cells. “We noted that we weren’t just getting iPS cells but getting very very high efficiency,” he told reporters during a teleconference. “This was unexpected … but it’s great if you consider that some patients can only offer a limited number of cells for reprogramming.”
The results impressed Douglas Melton, co-director of the Harvard Stem Cell Institute, enough to convince his colleagues overseeing the institute’s iPS facility to switch over to the new technique for making iPS cell lines. “This solves to a large extent the problem of efficiency,” he said during the teleconference. “The technique makes it much faster, and much more user friendly. So we are going to turn over our entire iPS core to this method to efficiently make stem cells from patients with all sorts of different diseases so we can begin drug screening and studying the causes of these diseases.”
In a written response, Yamanaka also expressed optimism about the technique’s potential for generating iPS cells that are safer for human patients. “I think that the method to generate iPSCs, described in the paper, seems promising in inducing clinical-grade iPSCs and would like to have someone in my lab try the protocol.” (More on Time.com: 5 Pregnancy Taboos Explained).
The new strategy could become the basis for a standard way of generating colonies of cells that are turned into healthy versions of diseased tissue that can then be transplanted into patients, says Melton. So far, the new RNA-based iPS cells appear to be more similar to human embryonic stem cells than they are to stem cells made the Yamanaka way. Rossi believes that may be due to the fact that the Yamanaka cells contain viruses, which may affect their ability to reprogram themselves. But it will take additional studies to confirm that the new iPS cells work the same way as human embryonic stem cells, which are currently the gold standard.
Even if they do prove to be safe and viable, Rossi admits that his approach doesn’t mean that the Yamanaka method will become obsolete. For one, Rossi’s technique requires the daily addition, including over the weekend, of a dose of RNA to the cells over a period of two to three weeks, while Yamanaka’s viral method requires a one-time introduction of the virus-containing genes. For certain lab-based studies that won’t involve human patients, he says, the Yamanaka method may be more convenient.
It’s also not clear how long-lived Rossi’s iPS cell lines are, since they have only been around enough to divide a few dozen times. Yamanaka noted that iPS cell lines vary slightly in their ability to turn into different types of cells, and that more studies need to be done before a standard method for making the cells is established. But, he said, “I think this method has the potential for it.”
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