Science Watch found it hard to decide if paper #5 should be allocated to medicine or biology. The work was supported by the U.S. National Institutes of Health and the American Liver Foundation; it attracted an accompanying commentary by a children’s cancer specialist; and it rode on the medical horse in Nature’s stable. However, the research is in mice—in particular, mice rendered deficient in the enzyme fumarylacetoacetate hydrolase (FAH), which constitute an animal model for a human inborn error of metabolism called tyrosinemia type I.

Inherited enzyme deficiencies generally are not easy to treat, and clinical management has included drugs, dietary control, enzyme replacement, organ transplantation, and gene therapy. In tyrosinemia, with its life-threatening liver damage, there has been some clinical success (and in the murine model too) with the compound 2- (2-nitro-4-trifluoromethylbenzyol)- 1,3-cyclohexanedione, but a novel approach is offered by the dawning realization that stem cells may demonstrate plasticity—in short, neural stem cells are not committed only to the nervous system, for example, while hematopoietic stem cells may give rise to liver and muscle cells as well as the expected blood cells of various types.

Five of the authors on paper #5 work at StemCells, Inc., Sunnyvale, California, where lead author Eric Lagasse is director of liver stem cell discovery. This company’s bold vision is "To alter the practice of medicine by stem cell technology." In the experiments reported here, on FAH-deficient mice given unfractionated bone-marrow cells from mice with FAH, there was microscopic and biochemical evidence of restoration of function, and only strictly identified hematopoietic stem cells (HSC) possessed this restorative potential.

Stem-cell biology is attracting a lot of attention, and the basic science would be interesting even if there were no possibility of clinical application—and if there is, it would not be limited to the management of tyrosinemia, a rare disease. However, Markus Grompe from Oregon Health Sciences University, Portland, Oregon, and coauthor on #5, is cautious. He tells Science Watch that recent findings from his laboratory (Am. J. Pathol., 161: 349-50, 2002), though they do not contradict the earlier work of paper #5, do indicate that "the degree of liver replacement by hematopoietic stem cells is minimal and certainly below the threshold for clinical impact without major improvements." Nor do we yet know exactly how these stem cells become hepatocytes. These data from Grompe’s group do not suggest that hematopoietic stem cells are a physiological source of hepatocytes when the liver is damaged.

Lagasse admits that two years on "we know only a little bit more" but he seems unfazed by recent findings, including a publication in September (Science, 297:2256-9, 2002), in which Irving L. Weissman’s team note that transdifferentiation of circulating HSC is "an extremely rare event, if it occurs at all." In their animal studies, single HSC reconstituted peripheral blood leukocytes but contributed hardly anything to non-hematopoietic tissues, including liver. Even so, these workers concede that HSC might be "recruited into atypical functions in the face of severe injury and/or selective pressure."

"We will present our side of the story later this year, " Lagasse tells Science Watch, so this fascinating line of work clearly has a good way to run. Which Science Watch columnist is better suited to cover future developments could depend on the direction the research takes from now on.