While embryonic stem cells can become any cell type in the body, getting them to become the specific cell type a researcher needs is a notoriously tricky business. In an advance online publication by Nature this week, researchers from the University of Washington and Menlo Park, Calif.-based Geron Corp. describe a method for coaxing embryonic stem cells to become cardiac muscle cells, as well as a way to help those cardiac muscle cells survive and help restore heart function after transplantation into infarcted rats.
The research lags behind experiments with adult stem cells; autologous stem cells from several sources are already in clinical trials for cardiac repair. But Thomas Okarma, Geron's CEO, is nevertheless convinced that embryonic stem cells will ultimately prove superior for both scientific and economic reasons.
"We are not at all opposed to research on adult stem cells," he told BioWorld Today, adding that those cells have clearly proven to be useful in some settings. But "it is completely without fundamental rationale" to use stem cells derived from sources like adult bone marrow to try to regenerate heart muscle.
And that lack of rationale, he says, shows in the results of clinical trials using adult stem cells for heart regeneration: most "have shown absolutely no benefit." And in the few studies that do show some benefit, he added, the mechanism is unclear.
In contrast, Okarma said, the work published in Nature "is reconstructing the actual heart muscle, with new heart muscle that works," leading to improvement that is "dramatic, real, and durable."
Okarma believes that the more rapid progress of adult stem cells in the clinic is due to federal policies restricting embryonic stem cell funding, but is at odds with the relative promise of both approaches: "As with global warming, [the Bush administration's] view flies in the face of all the evidence."
Additionally, even if adult stem cells do turn out to be useful for cardiac repair, Okarma believes that they have an equally fundamental problem on the business side: their production cannot be scaled up. For adult stem cells, "we take your bone marrow and give it to your sister," he said. Personalized medicine, yes, but in cell transplants this means that each batch is different from the last.
In contrast, Okarma said, embryonic stem cells "grow like weeds," with one batch able to supply the cells for many patients. "And that," he added, "makes all the difference in terms of cost of goods and quality of product."
The experiments described in Nature began with what could hardly be termed auspicious results. In a paper published in 2005, the same team had demonstrated embryonic stem cells could form heart muscle cells when they were engrafted into healthy rats. But the method did not fare nearly as well when engrafted into what Okarma termed "the noxious environment of an ischemic scar:" the same protocol that had boasted a 90 percent success rate in healthy rats led to engrafted human cells in fewer than 20 percent of cases after rats had been subjected to an infarct - and those engraftments were smaller, and contained other, unwanted cell types besides heart muscle cells.
The researchers attacked this problem with a cocktail of cocktails. They first used a sequence of growth factors to turn human embryonic stem cells into cardiac muscle cells, and then transplanted those cardiac muscle cells into infarcted cells along with a second cocktail to help them engraft and grow.
To get embryonic stem cells to turn into heart muscle cells, the scientists first applied one protein to generate mesendoderm, followed by another to generate heart muscle cells. Treatment with the two substances, followed by purification, enabled the researchers to transplant a mixture that contained on average about 85 percent cardiac muscle cells.
The team then developed a second cocktail to help those cardiac muscle cells make it in the post-infarct heart. Based on the idea that ischemia, apoptosis, and or inflammation were the most likely culprits for killing off the stem cells, the researchers first tried a variety of single-factor treatments aimed at those three mechanisms to prevent cell death. However, none of the methods, when used in isolation prevented cell death, and the scientists concluded that "multiple, parallel processes were contributing to graft cell death, and that blocking one pathway simply led to cell death by another."
Success came through attacking those multiple mechanisms simultaneously. The researchers co-transplanted cells with a cocktail that combined six ingredients, including both matrix proteins to help stem cells anchor themselves and factors aimed at preventing cell death. Cells treated with this mix -which might also be useful for helping other types of stem cells survive and thrive after transplantation — were better able to engraft into infarcted tissue than cells transplanted by themselves. Hearts engrafted with the treated cells also performed better functionally.
The researchers are currently doing follow-up studies in sheep. Okarma said that the advantage of large animal models for cardiac research is twofold: because rats have a much higher heart rate than humans and other larger animals, cardiac research using rats "underestimates the degree of recovery human cells can cause."
Such research also cannot determine the risk of arrhythmia, because human cardiac muscle in a rat is basically always beating as fast as it can. The company is also following the animals long-term to make sure the engraftments are stable. Okarma said if those experiments go well, Geron hopes to be in the clinic with the cells in two to three years.