Peril, promise in induced stem cells
"Science, in the very act of solving problems, creates more ," wrote
educator Abraham Flexner, the father of the modern medical school.
Courtesy of Yoon-Young Jang
Induced stem cells (upper left) spontaneously grew into gut cells (upper right), blood precursor cells (lower left) and nerve cell precursors (lower right) in a recent study.
Courtesy of Yoon-Young Jang
Induced stem cells (upper left) spontaneously grew into gut cells (upper right), blood precursor cells (lower left) and nerve cell precursors (lower right) in a recent study.
No fool, Flexner. Consider the latest problems that medical researchers face with one scientific solution — induced stem cells.
Stem cells, of course, are the predecessors to every type of tissue in the body, growing into everything from your hair to your toes. Induced stem cells are found only in research labs, however. They are made from the patient's ordinary, everyday cells turned into this special kind of tissue-replacing stem cell.
As such, induced stem cells "hold great promise for regenerative medicine," begins a just-released
Nature journal study headed by Yang Xu of the University of California,
San Diego. Regenerative medicine would use cells, grown outside the body in test tubes, as replacements for organs to treat everything from diabetes to heart failure. But amid the promise, suggests the study, there may be peril.
A Kyoto University team first created the cells in 2006, led by biologist
Shinya Yamanaka. Yamanaka has since been on many folk's short list for the Nobel Prize in Medicine, because the cells seemed to offer a way out of the legal, political and ethical thicket facing researchers trying to turn human embryonic stem cells into transplant tissues over the last decade.
Just like
human embryonic stem cells, induced stem cells seem "pluripotent" — able to turn into just about
any type of tissue, from blood to brain to bone, and more. Unlike embryonic stem cells, induced ones can be grown from skin cells, and don't require the destruction of donor human embryo for their initial creation.
Why does that matter? Because in 2001, President George W. Bush
limited federal funding of medical research on human embryonic stem cells to ones from already existing lines, citing moral objections about creating an incentive for the death of human embryos. The rest of the decade was consumed with a political fight over the cells that still continues in the courtroom, where a case contesting President Barack Obama's 2008 reversal of the Bush decision faces a federal judge and looks headed toward the Supreme Court. On the plus side, a Geron Corp., clinical trial of the cells
enrolled its second patient, for spinal cord injury, this week at Chicago's Northwestern Memorial Hospital.
Induced stem cells went around this fight. Yamanaka and his successors showed that "reprogramming" regular cells, basically ramping the activity of four genes, would be enough to "induce" cells into becoming embryonic stem cell lookalikes — induced stem cells. Reprogrammed from the patients' own skin cells, induced stem cells could in theory be grown into whatever new transplant tissues people might need as they grew older or got sick. Hello, new brain.
A
Science Translational Medicinejournal paper out this week shows some of the promise. Led by Hua Liu of the Johns Hopkins School of Medicine in Baltimore, a team showed that human induced stem cells grown into liver cells could thrive after transplantation into mice genetically engineered to have cirrhosis. Although 20,000 people are waiting for liver transplants nationwide, only about 7,000 of the operations take place every year, the study authors note, making finding an alternative source of liver transplant tissue a priority.
So, what's the catch? "Because they have been derived from the patient, it has been assumed these cells should be immune-tolerated once transplanted into patients," says Xu, the
Nature study author, in a briefing for reporters. Immune system rejection is the
bane of transplant patients. At best, transplant patients usually have to take immune-system suppressing drugs to continue tolerating the foreign tissue. At worst, patients see their own immune system attack the transplanted organ, a potentially-deadly event.
So, "we decided to investigate whether these (induced stem) cells indeed are immune tolerated by the patients," Xu said. The patients in this case were mice, for which the researchers grew both embryonic stem cells and two kinds of induced stem cells. One kind of induced stem cell was grown in a way that permanently altered the genes that "reprogrammed" them and the other had their reprogramming genes only briefly activated as they were created. The team then implanted the cells into the mice.
For decades, researchers have shown that embryonic stem cells implanted in their basic state into animals grow into "teratomas," messy tumors built of every kind of cell. Teratomas are one of the famously gross oddities of medicine, mixes of skin, bone and cartilage, that have appalled anatomists for decades. ("Sometimes they contain long black hair, sometimes a set of teeth. This has both hair and teeth," the fictional Dr.
Stephen Maturin tells a companion who has discovered a teratoma in place of a pistol in the physician's holster, in Patrick O'Brian's
novel Post Captain. "It belonged to a Mr. Elkins of the City, an eminent cheese-monger. I prize it much.") In the
Nature study, Xu and colleagues found that mouse embryonic stem cells grew into these teratomas, and so did the induced stem cells.
"What we found was the cells derived from the embryonic stem cells were completely immune-tolerated," Xu said, as expected. However the teratomas from the induced stem cells caused an immune response, the team found. Most worrisome, the immune response, he said, "is the same, actually, as the one involved in organ transplant rejection."
The team suspects that some of the induced cells give off foreign proteins as they grow, triggering an immune system attack. "We cannot conclude that all these cells are immunogenic (safe)," Xu concludes, for human transplant patients.
Stem cell biologists have argued for the last half-decade over subtle genetic differences between embryonic and induced stem cells, says
biologist Joseph Ecker of the Salk Institute for Biological Studies in La Jolla, Calif. The new study says that debate, "misses the point that even one misregulated gene might cause havoc —in this case — rejection," Ecker says. "So it's not about quantity of misregulated genes in (induced) vs. (embryonic) cells but really quality of the level of effects on genes that have been observed."
The promise of the liver cells seen in the Science Translational Medicine study makes the situation even more confusing, Ecker adds, by email. "I think the bottom line message here is that there is an enormous long term potential for (induced stem) cells for regenerative medicine and in the near term, for studies of diseases like Parkinson's (syndrome) using patient cells." However, he concludes, a lot more work needs to be done before anyone transplants them into people.
In other words, stem cell scientists still have
a lot of work ahead, as Abraham Flexner might have predicted. "The fear that the conquests of science may shortly leave research nothing to do vanishes," Flexner wrote, with each new generation of scientists.
