The 'Other' Stem Cells

Adult stem cells won't end the need for embryonic cells, says MU's Elmer Price. But they could produce powerful new therapies.

by Charles E. Reineke

Standing before an audience made up, in part, of babies born via in vitro fertilization, last summer George W. Bush used his first-ever presidential veto to reject bipartisan Congressional legislation aimed at restarting federal funding for embryonic stem cell research. "These boys and girls are not spare parts," the president said, with a nod toward the assembled infants. "They remind us of what is lost when embryos are destroyed in the name of research.''

Whether harvesting surplus blastocysts produced during fertility treatments -- a primary source for embryonic stem cells -- constitutes "destroying" embryos in the name of research is a matter of impassioned debate, one that has become a flash point in America's increasingly bitter culture wars.

Embryonic stem cells have the ability to generate any of the approximately 220 cell types that make up a fully formed human being. This remarkable pluripotency, scientists say, is reason enough to advocate additional federal support for embryonic stem cell research. Still, most would welcome an alternative to today's politically fraught status quo, one allowing them to investigate stem cells' potential for improving human health without engaging quite so many human emotions.

One way forward, pioneered by researchers at Advanced Cell Technology in Worcester, Mass., involves obtaining stem cells without destroying the blastocyst from which they are harvested. The method shows promise, but has thus far been only partially successful in generating stable cell lines. In addition, after publishing their work in the August 23 edition of Science, ACT revealed in a correction that their test method had, in fact, resulted in the destruction of the 16 surplus in vitro fertilization embryos used in the study -- an admission that immediately raised the ire of stem cell opponents.

Another promising, less controversial method involves developing stem cell lines obtained from mature tissues. Not only would such cell lines help researchers avoid origins-of-life issues, but some molecular biologists believe adult cells might actually be better suited to the type of medical applications envisioned by stem cell boosters.

One of these scientists, Elmer Price, an associate professor of biomedical sciences at MU's Dalton Cardiovascular Research Center, has recently brought life scientists closer to just such an understanding. Earlier this year, Price, working with samples of blood drawn from swine, isolated a line of adult stem cells -- defined as cells from mature mammals that share some of the same changeable qualities as the embryonic variety -- that he then directed to form the biological precursors to bone, blood vessel and nerve cells.

"Embryonic stem cells are able to give rise to the remarkable diversity of cell types that constitute a whole organism such as a human," Price reports. "However, this pluripotency can also be a curse, because ES cells can be misled by biochemical signals when they are transplanted into an adult during cell-transplantation experiments. This often leads to the generation of unwanted cell types and, on occasion, to tumor formation. Because of this, ES cell transplantation can raise serious safety issues. In this study, we developed adult stem cells from the blood of a mature animal that we were able to direct into specific cell types, such as neurons and blood vessel cells, but they were not as pluripotent as ES cells. We have not observed any evidence of tumor formation."

Price and other researchers have long known that adult stem cells play an important role in the body's ability to repair tissue damaged by disease or injury, and that they thus have great potential for patient care. But developing useful therapies has lagged, chiefly due to a host of unanswered questions related to the hows and whys of differentiation, the process by which stem cells eventually come to form the specialized cells that serve as the basis of the body's complex physical structures.

Adult stem cells are found in a variety of human organs and tissues, where they reside in what biologists refer to as a quiescent, or non-dividing state until ordered into action by the body. But they are notoriously tough to identify. One reason is that in any given organ or tissue sample there are precious few stem cells, perhaps as few as one in 100,000 cells. Another is that those that are present are virtually indistinguishable from other cells.

Scientists have overcome identification difficulties by ingeniously employing what they call "surface cell markers," chemical formulations containing molecules that adhere, or bind, to the "receptor" proteins found on the surface of every cell in the body. Because each cell type has its own combination of receptors, researchers have been able to develop a variety of these molecular markers to distinguish adult stem cells from their more numerous brethren.

For his current study, published in the August edition of the journal Stem Cells and Development, Price took the process a step further, identifying stem cells from special swine developed by his colleague and co-author Randy Prather, distinguished professor of reproductive biotechnology in MU's animal sciences department. Prather's genetically modified pigs are unique in that they have been engineered to contain a fluorescent gene that glows brightly when stem cells are exposed to a black light -- a circumstance that allows scientists to track the stem cells as they begin to form the precursors of tissues and organs.

The primary aim of Price's investigation involves inducing adult stem cells to differentiate in predictable ways by exposing them to chemical signals controlled by the researchers. Determining exactly which signals regulate stem cell proliferation and differentiation has long been a problem for researchers, especially those working with embryonic cells.

During the in vivo development of an embryo, Price explains, "the uterus provides all the biochemical signals required for the really complicated process by which a ball of cells turns into a human: into our skin, bones, eyes, ears, digestive tract, et cetera. But if you take one of these embryonic stem cells, these very, very powerful cells and implant it in a [lab rodent's] brain, sometimes it just goes crazy and you get tumors that have bone, hair, connective tissue ...it's almost as if the cell is telling you, 'I have no idea what to become.'"

Price says working with adult cells has helped to simplify things. "We've shown that if you can isolate adult stem cells, you can make them generate the appropriate type of cell with much more ease and specificity. One day, we may be able to isolate similar adult stem cells from a patient, manipulate the cells in a petri dish, and then reintroduce them back into that same patient as a therapy."

Price cautions that there is much work to be done before that day arrives. The next step, he says, is to determine whether his methods can produce a sufficient number of adult stem cells to pursue therapies, and whether such cells can be isolated from human patients.

"Most scientists who work on these are trying to pre-differentiate them in a dish before they're transplanted," he says. "The goal is to get the stem cell to commit to, say, a neuron that won't turn into unwanted cell types or a tumor."

So far, he adds, there's been much progress. Price and his team at Dalton have been able to locate and grow human adult stem cells for more than a year, creating large numbers of nerve and blood vessel cell precursors. Among other cells Price has identified is one that he recently described as a "very rare type" of stem cell from the blood. From just one or two of these original cells Price was able to develop a line containing some 100 million cells.

"They looked completely different from any other adult stem-cell line ever described in the literature," Price told the Kansas City Star in a front-page story describing his work.

"We think that these blood-derived adult stem cells are normally used by the body for regeneration and we have been able to isolate these cells, grow them in a lab, and direct them toward a specific cell type for eventual therapeutic use," Price says.

"I'm not going to tell you that these cells are going to eliminate the need for a walker for those with spinal cord injuries, or that they will end the need for medications to control Parkinson's. But I will tell you this: I am certain they will one day go a long way toward reducing human pain and suffering."