Stem cells ride research roller coaster
Like roller coaster rides? Strap yourself in — stem cells may be your scientific ticket.
A flurry of stomach-dropping up and down moments all week befell one of the brightest, new attractions in science, induced pluripotent stem cells. Such IPS cells are "induced" by genetic signals to grow from normal adult cells into unspecialized ones that look like they could be coaxed into becoming replacement tissues for transplant patients.
First, the roller coaster rocketed down with news that these cells may be a disappointment for studying or treating diseases. Then, more reports rallied their reputation, all in the space of a few days.
"Basically, we are looking at a lot of confusion," says Harvard stem cell scientist Alexander Meissner. "That's not to say one group is wrong and another is right. We have been making a lot of progress, but everyone is looking at the same problems from different sides."
In 2006, a team led by Kyoto University's Shinya Yamanaka first reported they could "reprogram" mouse skin cells into stem cells by forcing four genes to start busily churning out chemicals that trigger the transformation. A year later, when Yamanaka and a separate team led by Jamie Thomson of the University of Wisconsin reported the same success with human cells, a biological boom was on.
Stem cells are the predecessors to every type of tissue in the body. Since 1998, when Thomson's team reported success in growing human embryonic stem cells, cultivated from a few hundred cells taken from a five- to six-day-old embryo, researchers have pursued growing such cells into replacement tissues. They are called "pluripotent" because they can grow into so many types of tissues. Researchers have long suggested embryonic stem cells have the most potential for treatments because they grow so fast, and because ones cloned from patients would have their same immune system characteristics, preventing the rejection problem that bedevils current transplant organs.
But because the embryos are destroyed in the process of harvesting the embryonic stem cells, a huge political fight over the research erupted over the last decade, with the Bush Administration limiting federal funding of research to less than two dozen lines created before Aug. 9, 2001.
The Obama administration instituted a new policy last year which has led to approval of federal funding for research involving 89 cell colonies, or "lines," as of Thursday, when the National Institutes of Health approved three more. (Of course, the current NIH policy is the subject of a legal fight still playing out and perhaps headed to the Supreme Court, notes stem cell law expert Russell Korobkin, author of Stem Cell Century: Law and Policy for a Breakthrough Technology. But that is a whole 'nother roller coaster ride story.)
Induced stem cells, which were generated from ordinary cells rather than embryos, looked like they would offer an end run around the legal and ethical concerns, not to mention long-running patent disputes dating to 1998. The only catch was that some of the genes involved in transforming normal cells into induced ones also were linked to cancer, not something you would want in your transplant tissues.
But in September, a Cell Stem Cell journal report team led by Derrick Rossi of Children's Hospital Boston unveiled a cancer-gene free method at least 40 times more efficient than old ones to grow the cells. So, things were looking good.
"The big remaining question was whether IPS cells were the same as (embryonic stem) cells, or not," Meissner says. Like blind men describing an elephant, researchers have mostly used mouse cell studies, "with a lot of disagreement," he says, to grope for a full description of induced cells. Embryonic cells, studied for twice as long, and already approved for human transplant treatment experiments by the Food and Drug Administration, have remained the "gold standard" cells for the field, as a result.
The research roller coaster headed downhill early in the week, when the journal Nature released a study of five IPS cell lines and four embryonic cell lines, led by molecular geneticist Joseph Ecker of the Salk Institute in La Jolla, Calif. Instead of being reset to an embryonic state, the induced cells had chromosomes resembling those of the adult cells from which they originated. This suggests induced blood cells retain a "memory" of gene patterns in full-grown blood cells.
Combined with a September Nature paper showing similar memory signatures in mouse IPS cells and Scripps Research Institute researchers last month reporting more cancer genes in IPS cells compared to embryonic ones, things looked bad. "The finding suggests that (induced) cells may not be suitable substitutes for (embryonic) cells in modeling or treating disease," noted Naturescience reporter Elie Dolgin.
But now for the upward curve of the roller coaster, courtesy of Meissner and colleagues in a Cell journal report released Thursday. "What we need is a scorecard," Meissner says. "Some systematic way of looking at all these cells and asking about the overall patterns of how they behave."
So that is what they did. In the study the team created maps of total gene activity among 20 widely-used embryonic cell lines (all on the NIH registry) and 12 induced cell lines. Across the entire genome of the cells, what the team found is that there is a lot of variation in IPS cells, but no more than exists in embryonic ones. "Pretty much, they fall within the range of variation for the (embryonic) cells, with a lot of the variation coming at the same (locations)," Meissner says.
In particular, the scorecard allows researchers to predict which cell lines, embryonic or induced, will most easily grow into desired tissue types, whether blood, bone or brain.
Some confirmation of their results comes in a Nature Biotechnology report led by Gabriella Boulting of the Howard Hughes Medical Institute in Cambridge, Mass., also released Thursday. The paper looked at 16 induced cell lines derived from seven people, some with amyotrophic lateral sclerosis (ALS), or "Lou Gehrig's disease," a progressive loss of brain and spinal cells.
Matching the scorecard's predictions, 13 of the cell lines transformed into brain cell precursors as readily as embryonic cells with similar genetic variability, and three with different variations didn't. "The predictions worked very well," says Meissner, who was not an author on the second paper. "In theory, this will save researchers a lot of time because they can pick the cell line that will differentiate (grow) most readily into the desired kind of cell."
Overall, Meissner sees no reason that induced cells won't eventually supplant embryonic ones in stem cell research. "Of course, it is still early and there are still a lot of cells to look at, so nobody is saying we don't need embryonic cells still," he says.
So, remain seated and keep both hands on the ride. Sounds like the roller coaster trip won't end anytime soon.