Stem Cells: 5 Year Progress Report

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In a class on ES-cell lab techniques at the WiCell Research Institute, this culture dish holds oodles of embryonic stem cells. WiCell was just named a National Stem Cell Center. Photo: Jeff Miller, University of Wisconsin-Madison

Stem cell:
A cell that can change into other types.

Embryonic stem (ES) cell:
Cell from embryo, can become any cell type.

Adult stem cell: Stem cell from mature animal, often from bone marrow.

Differentiation: Process of becoming more specialized.

The best way to learn about adult stem cells is to study cell differentiation from embryonic stem cells.

Dolly's dilemma
Amid the skepticism about adult stem cells, one biologist's studies could not be dismissed. Catherine Verfaillie, of the University of Minnesota, has been working with what she calls multi-potent adult progenitor cells (MAPC), derived from bone marrow. Using a virus to insert marker DNA into the MAPCs, she has shown that they can differentiate into most cells in the mouse body.

A gloved hand holds a small lab dish.Although Verfaillie is not ready to call them stem cells, in a June, 2002 article in Nature, showed that MAPCs can differentiate into all three overarching cell lines from a mammalian embryo.

When she injected a few MAPCs into mouse embryos, the distinctive markers appeared throughout the body. "This occurs with one out of every three cells, and contribution is to all tissues of the mouse," said Verfaillie in a press release. "Some of the animals are 40 percent derived from the bone marrow stem cells, suggesting that the cells contribute functionally to a number of organs. Again this is similar to what one would expect of ES cells."

The cells can also be cultured without aging, a trick previously only found in ES cells.

The work impresses Malcolm Alison, a professor of experimental pathology at Imperial College London who also works with adult stem cells. "Her work, without a doubt, is the best example of multipotency" -- the ability to change into many cell types. "No one else has shown in-situ clonal expansion," ( the growth of one cell into a distinct lineage of differentiated cells at a remote location in the body).

And while such flexibility was not expected in adult stem cells, remember that Dolly was cloned from a regular adult cell, not even a stem cell. "Dolly does prove you can take an adult cell and reprogram it back to the pluripotent state," Thomson acknowledges. Still, he insists, "Most evidence of adult stem-cell plasticity turned out to be garbage, when they went back and controlled the experiments."

Alison, who reviewed the status of adult stem cells (see "Plastic Adult Stem Cells..." in the bibliography), is not convinced. He maintains, "Most of the data suggest that cell fusion isn't responsible, particularly in heart cells." Several clinical trials are trying to regrow heart muscle from a patient's own bone-marrow stem cells, he says. "It's being injected into heart muscle, and there are suggestions of objective improvements."

Got lemons? What would you like to drink?
That would not necessarily prove that cells were not fusion. But even if cell fusion proves to be responsible for some of the effects of adult stem cells, to a patient, Alison says, "that's not necessarily a bad thing. If healthy bone marrow reprograms the diseased liver cell, who cares?"

Just last month, Nature reported the appearance of fused cells, with double nuclei, in liver, brain and heart muscle, leading the authors to suggest the "possibility that cell fusion may contribute to the development or maintenance of these key cell types" (see "Fusion of Bone-Marrow Derived..." in the bibliography).

Gloved woman points to TV monitor showing cells.
Participants ogle a microscopic view of stem cells on a TV monitor at WiCell's stem cell boot camp, under the eagle eye of instructor Katie Vandenheuvel. Photo: Jeff Miller, University of Wisconsin-Madison

If adult stem cells seem almost as versatile as ES cells, and if they skirt the ethical qualms on working with cells derived from human embryos, and if they do not, unlike ES cells, form tumors when injected into the body, should we just skip ES cell research and concentrate on easily-available stuff from bones?

Alison says adult cells may offer an advantage, at least in the short term. "I rather like adult bone marrow. ... Embryonic cells appear to be more programmable, but in terms of clinical applications, you might envisage that adult cells might get in sooner."

That would seem to be the U.S. government line, if you follow the money. According to the National Institutes of Health press office, in fiscal year 2002, NIH spent $305 million on adult stem cell research, and $82 million on ES cell research.

But closing doors at this early stage would be a mistake, insist other stem cell researchers. Thomson, for example, says, "There is not a single credible stem-cell biologist that does not think there is great utility in studying adult and ES cells, including me."

Science does not advance by prematurely closing off research options, he insists. "Some developmental biologists study frogs, others study mice or flies. You'd never see them arguing about which one is better. There are certain questions where a certain system is better. There are things you can't do in one organism that you can do in other organisms."

Given the cross-fertilization between adult and ES researchers, he says, " The dichotomy between adult and ES cells is a creation of the press and politicians ...The argument is silly. Some questions will be better addressed with one, and some with the other."

Dolly the sheep's famous mug--in a picture frameWhat does Dolly the clone prove? That mature, specialized cells can return to a primitive state, without becoming diseased. Original photo: U.K. Department of Health

Diane Krause, of Yale University, has seen large-scale differentiation of adult stem cells (see "Multi-Organ ..." in the bibliography) . She wrote us to reinforce the idea that the two fields of research are intertwined: "Adult stem cells ... are not nearly as plastic as are embryonic stem cells, and will never be able to substitute for human embryonic stem cells. There is a huge amount that we have yet to learn about both adult stem cells and ES cells, and research on both must proceed. There are likely to be some clinical applications for which embryonic stem cells are most useful and others for which adult stem cells will be useful. Our data with adult stem cells should not in any way be misconstrued as suggesting that work on human ES cells is not needed. In contrast, the best way for us to learn more about adult stem cells is to study cell differentiation from embryonic stem cells, which are the true masters of cell plasticity."

Not a bad argument for reading our bibliography, eh?

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