For Thomas Clegg, the Obama administration's decision in March to lift certain restrictions on government funding of stem cell research was beside the point. The 58-year-old congestive heart failure patient had received an experimental stem cell therapy before the new president even took office. In November, researchers at Methodist DeBakey Heart & Vascular Center in Houston removed some of Clegg's bone marrow and sent it off to a lab, where the best and hardiest of its stem cells were extracted and concentrated. Less than a month after Obama's historic election, those cells were injected directly into Clegg's heart, where the researchers hope they will spark healing and regeneration.
While the attention of the public and ethicists has been focused on embryonic stem cells, research into other kinds of stem cells—including the kind of adult bone-marrow stem cells Clegg received—has been advancing and, in some cases, exploding. "I have never been in a field that is moving at this pace," says Jonathan Chernoff, deputy scientific director at the Fox Chase Cancer Center in Philadelphia. Adult stem cells have been used in bone marrow transplants for 40 years, and trials like the one involving Clegg are expected to expand their use. Meanwhile, many scientists predict that induced pluripotent stem cells, or iPS cells, created by turning back the biological clock of normal adult cells, will one day supplant embryonic stem cells.
But scientists still call embryonic cells the "gold standard" for stem cells, which is why they've been the subject of privately- and state-funded research while federal funds were restricted. It's also why researchers are excited about Obama's move to allow the government to fund research using lines of embryo-derived cells, as long as the embryos are left over from fertility treatments, not created solely for research purposes.
A maturing field. The earliest therapeutic breakthroughs are likely to arise from adult stem cells, which exist in everybody in many subtypes—blood-producing stem cells in the bone marrow, for example, and stem cells in the brain that can become neurons and other brain cells. "In the short term—say, the next five years—most of the therapeutic applications from stem cells will be from adult stem cells," says Steven Stice, director of the Regenerative Bioscience Center at the University of Georgia. Their most likely uses: disorders of the blood and blood vessels, bone, and immune systems, he says.
A host of ongoing projects are testing adult stem cells. In one, researchers at the University of California-San Diego are studying whether stem cells derived from a patient's own fat cells might help treat multiple sclerosis. At UCLA, scientists are looking at using blood stem cells from melanoma patients to create immune cells that recognize and attack their disease. The cells may work in other ways than simply creating new cells to replace diseased ones. In the heart, for example, research suggests they increase blood vessel growth rather than create new heart muscle.
Or, they may lead to new drugs.
"The way stem cells [used as therapy] exert much of their power is to provide the chemical signal to turn on [existing but dormant] stem cells in the body," says Robert Hariri, chief executive officer of Celgene Cellular Therapeutics, which is studying possible treatments based on placental stem cells. So treatments could be derived from those cells, then used to turn on the body's existing stem cells.
But adult cells can be reprogrammed into only a limited number of other cell types, which is where they fall short of more versatile embryonic stem cells. The latter are pluripotent, which means they can become pretty much any type of human tissue. But that comes with problems. "They're the teenagers of stem cells; they have great potential, but we can't always get them to do what we want them to do," says Michael Reardon, chief of cardiac surgery at Methodist.
Guiding their differentiation—their journey to becoming a specialized cell or tissue—with a lab-made brew of growth factors and other chemicals is a big scientific challenge, and it's not the only one. "You want to be sure you can differentiate [the stem cell] into the therapeutic cells," says Judith Gasson, codirector of the Broad Stem Cell Research Center at UCLA. "Once it's differentiated, you have to get it to go to the right physical location in the patient—the nervous system, pancreas, whatever. That's not necessarily going to be trivial." The new cell also has to be integrated into a diseased or damaged tissue, says Martin Pera, director of the Institute for Stem Cell and Regenerative Medicine at the University of Southern California. And how to do that, he says, "is an enormous black box at the moment." Even if scientists can accomplish that, there's no guarantee of a lasting therapeutic effect.
So eyes are on Geron, a biotechnology company that this year won the Food and Drug Administration's approval to conduct the first-ever study of embryonic stem cells in humans. The small trial will probe the safety of the treatment in patients with spinal cord injuries; subsequent trials will be required to determine if it's effective. There are reasons for caution. For one, embryonic stem cells can form tumors. And because the cells are biologically foreign—like a transplanted organ—recipients will need to take powerful immunity-suppressing drugs, which have a host of side effects, to prevent rejection.
It's that latter problem that makes scientists particularly excited about iPS cells, which would have the clinical potential of embryonic cells but can be created from a patient's own cells. Reprogramming an adult cell into an embryolike, more malleable state sidesteps the issue of immune rejection, not to mention the moral debate. It's also simple in concept—adding just four genes to an adult cell can do the trick. But the virus needed to transport the genes into adult cells poses a cancer risk. In late April, scientists reported a breakthrough in mice: They induced pluripotency by inserting proteins, which don't require a virus to carry them, instead of genes, which do. In June, researchers said they'd accomplished the same thing with human cells.
Less than perfect. Some scientists, including Geron founder Michael West, who's now CEO of the stem cell technology company BioTime, are betting iPS cells will eventually supplant embryonic stem cells. "But right now," he says, "iPS cells are less than perfect, and they're enough less than perfect that I don't know any scientist who feels they would be safe in humans as of today." For that reason, this is no time to scrap research on embryonic cells, he says.
It will be years, if not decades, before iPS cells can be refined enough to use in patients. But even if treatments are years off, Chernoff says iPS cells have another, more immediate use: to study the progression of a disease. Researchers could take normal and malignant cells from a pancreatic cancer patient, for example, turn back the clock on both, and then reprogram the cells to form pancreatic tissue. They could then monitor the cancer-derived cells to see what, exactly, goes wrong.
Despite the obstacles, scientists are cautiously optimistic that iPS, embryonic cells, or both can lead to new therapies. Type 1 diabetes and certain disorders of red blood cells are good targets, says Gasson. Replacing retinal cells damaged by macular degeneration, regenerating the immune system, and creating new cartilage in arthritis patients are, in theory, also relatively straightforward applications, adds West. If stem cells can be made to work in those simpler cases, they may be able to tackle more complex conditions, like Alzheimer's or even limb regeneration, he says. And more technical leaps may be coming; research in mice suggests it might be possible to avoid turning an adult cell's clock back entirely and instead reprogram it directly into another type of adult cell.
As for Clegg, it's too soon to tell if his will be an early success story in a stem cell treatment revolution. So far, 13 other patients have enrolled in the same trial, and the company running it, Aastrom Biosciences, aims to recruit a total of 40. (Recruitment temporarily halted after one participant died and resumed only after the FDA and other experts determined the patient had died of causes unrelated to the stem cell treatment.) Meantime, doctors are monitoring Clegg. Within months after his surgery, his ejection fraction, a measurement of the percentage of blood pumped from the heart with each beat, had improved to almost 30 percent. While shy of what's normal, that's nearly three times what it was before his procedure.
"His heart function has improved, and he's going to the gym. Can I say it's all [a direct result of] the stem cells? No," says Brian Bruckner, Clegg's primary surgeon and principal investigator of the trial at Methodist. "It's potentially an isolated instance, or it may be the tip of the iceberg."
The same could be said for every apparent stem cell advance. With each, patients and the public are waiting, hopeful it's the latter.