Science Editor

Therapeutic stem cell science played a double-header yesterday: Nature published a brace of articles on the subject, one dated June 20, 2002, the other June 23, 2002 - but both released online June 20, 2002.

Both senior authors, Catherine Verfaillie and Ron McKay, faced the media Thursday morning to present their Nature papers at a teleconference at the University of Minnesota in Minneapolis, where Verfaillie directs the Stem Cell Institute. Her article bears the title: "Pluripotency of mesenchymal stem cells derived from bone marrow."

Neuroscientist McKay heads the laboratory of molecular biology at the National Institute of Neurological Diseases and Stroke in Bethesda, Md. His paper's title: "Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease."

McKay told the assembled journalists - and those tuned in electronically - that "embryonic stem cell research is going on all over the world. To use human ESCs clinically in the nervous system," he noted, "the problem is how to get at the cells there. This involves specific intermediate stages, with stops along the way, as if you were driving from New York to Los Angeles.

"Parkinson's disease [PD] is caused by the loss of midbrain neurons that synthesize the dopamine neurotransmitter," he explained. "There is a serious deficit in which those cells die. We know," he pointed out, "that fetal tissues grafted into the brains of PD patients provide benefit. The major difficulty in this highly experimental work is to find the extremely rare embryonic cells that reside in a specific part of the brain.

"We are interested in growing those cells in our lab," he continued, "to overcome that major difficulty. We got them out of developing brain tissue as they divided into dopaminergic neurons, and saw that they worked in PD animal models. If they didn't," he added, "there'd be no need for this press conference."

McKay recalled that he and his colleagues turned to ESCs two years ago. Previously, they used neural progenitor cells. "Only one kind of neuron, supplying dopamine, works in the disease, as we report in today's Nature. Afficionados in PD therapy were not convinced."

For starters, the NINDS authors created a strain of rats dosed with a specific brain toxin that turned them into mimics of parkinsonian brain and behavior. "Then," McKay recounted, "we injected several tens of thousands of ESCs into one half of each rat brain, so each could serve as control of the other. Large numbers of the right cells went right to the right neurons, which recognized the cells we wanted.

"PD is a disorder of movement," McKay recalled. "The untreated brain half showed a clear lack of effect. Those rats rotated in circles, the equivalent of parkinsonian disorder. When we switched brain halves for a second round of ESC therapy, they reversed direction of rotational movement. This was no cure, of course," McKay observed, "just evidence that the ESC cell-replacement treatment worked. That conveys an important implication in medical practice."

Now en route to some day perhaps trying the cell therapy approach in human PD patients, the NINDS group is fixing its sights on larger-than-rat subhuman primate PD models. Responding to a listener's question, McKay confirmed that "we are not contemplating human embryonic stem cell trials."

Embryonc Stem Cells From Bone Marrow

Verfaillie, who chaired the session, cited "first-time evidence that adult bone marrow-derived cells can differentiate in vitro and in vivo into cells of all three embryonic germ layers - endoderm, ectoderm and mesoderm - similar to embryonic stem cells." Her group terms them "multipotent adult progenitor cells [MAPCs]."

She reported that cells grown from adult rat and mouse bone marrow could be cultured without aging and with active telomerase. Her lab showed that single MAPC cells can contribute to most, if not all, tissues of mice, after they had been injected into the embryo's blastocyst - the modified stage of mammalian embryos. "The result," she recounted, "included brain, retina, lung, myocardium, skeletal muscle, intestine, kidney, spleen, bone marrow, blood and skin. Some of the animals," she went on, "are 40 percent derived from the bone marrow stem cells, suggesting that these contribute functionally to a number of organs, similar to what one would expect of ES cells.

"In contrast to ES cells," Verfaillie went on, "when we injected the bone marrow stem cells into recipient animals, they responded to local organ cues, and differentiated into blood cells as well as epithelium of liver, gut and lung. Adult stem cells," she told the press conference, "may hold therapeutic promise, but a large number of studies is still required to fully characterize the potential of MAPC. Side-by-side comparison of adult and embryonic stem cells," she added, "must be done to determine which are most useful in treating a particular disease. Adult stem cells, cultured under the specific conditions, may be suitable for in vivo treatment of inherited or degenerative disorders."

Gold Standard ESCs Are Ethically Tarnished

Human ESCs are considered the ultimate therapeutic stem cell because of their dual ability to proliferate and to differentiate into all of the body's cells and tissues. But they are ethically contentious because 5-day-old embryos must be destroyed to derive them. Adult stem cells have shown promise as an ethically preferable alternative, but scientists have not been able to show that they are as versatile as ES cells until now, the two authors reported.

Verfaillie's team cultured rat and human adult bone marrow mesenchymal stem cells. From these cultures they isolated rare multipotent stem cells that can proliferate indefinitely in culture. Injected into mouse embryos, the rat cells differentiated into most, if not all, of the cells in the mouse body. They also showed that these cells engrafted and differentiated in response to cues, when injected intravenously into adult rodents.

Natalie DeWitt, a senior biological sciences editor at Nature who attended the Minnesota press conference, observed, "While the two papers will no doubt rekindle the debate on the relative merits of embryonic vs. adult stem cells, together they emphasize the outstanding potential of stem cells and the need for continued research in all areas of stem cell biology."