Stem-Cell Experiments Continue to Excite

Stem-Cell Experiments Continue to Excite—and Sometimes Confuse

by David W. Sharp

WHAT'S HOT IN MEDICINE
Rank	Paper	Citations This Period (Jul-Aug 03)	Rank Last Period (May-Jun 03)
1	J.E. Rossouw, et al. (Women’s Health Initiat. Invest.), "Risks and benefits of estrogen plus progestin in healthy postmenopausal women. Principal results from the Women’s Health Initiative randomized controlled trial," JAMA-J. Amer. Med. Assoc., 288(3): 321-3, 17 July 2002. [8 U.S. institutions] *573AK	142	1
2	R. Collins, et al. (Heart Protection Study Collaborative Group), "MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled trial," Lancet, 360(9326): 7-22, 6 July 2002. [Authors’ affilations: multiple U.K. institutions, based at Radcliffe Infirmary, Oxford] *569JR	72	2
3	E.J. Lewis, et al., "Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes," New Engl. J. Med., 345(12): 851-60, 20 September 2001. [9 institutions worldwide] *473JW	62	8
4	W.C. Knowler, et al. (Diabetes Prevention Prog. Res. Group), "Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin," New Engl. J. Med., 346(6): 393-403, 7 February 2002. [35 U.S. institutions] *518UN	61	6
5	Y.-H. Jiang, et al., "Pluripotency of mesenchymal stem cells derived from adult marrow," Nature, 418(6893): 41-9, 4 July 2002. [U. Minnesota Med. Sch., Minneapolis] *659JL	58	†
6	B.M. Brenner, et al., "Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy," New Engl. J. Med., 345(12): 861-9, 20 September 2001. [8 institutions worldwide] *473JW	57	3
7	H.-H. Parving, et al., "The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes," New Engl. J. Med., 345(12): 870-8, 20 September 2001. [5 European institutions] *473JW	46	†
8	C.D. Furberg, et al. (ALLHAT officers and coordinators), "Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)," JAMA-J. Amer. Med. Assoc., 288(23): 2981-97, 18 December 2002. [Corresponding authors: Case Western Reserve U., Cleveland, OH; U. Texas Houston Health Center] *626CG	46	9
9	M.P. Manns, et al., "Peginterferon alfa-2b plus ribavarin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial," Lancet, 358(9286): 958-65, 22 September 2001. [8 U.S. and German institutions] *474YR	41	10
10	N. Terada, et al., "Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion," Nature, 416(6880): 542-5, 4 April 2002. [U. Florida Coll. Med., Gainesville] *537JY	41	†
SOURCE: ISI's Hot Papers Database. the full legend.

n November, 2003, the European Union appeared to relax its former opposition to stem-cell research, but so long as embryo cells are perceived as the basis for human studies, the topic is likely to remain controversial in medicine. This is why investigations suggesting that other types of cell have the potential to go down different routes are so important; there is a societal and ethical dimension as well as the clinical and scientific one. When Science Watch covered the topic in the November/December issue (13[6]: 5, 2002), it was done in the clinical medicine column, and just over a year later, the subject’s medical flavor has been retained (see paper #5). The previous peg was a Nature Medicine paper by Dr. Eric Lagasse and colleagues (6[11]: 1229-34, 2000) recording the apparent ability of stem cells normally committed to the generation of blood cells to yield cells with hepatic function. One of the outstanding questions then was uncertainty about how that transformation might be taking place. It is this question that paper #5, along with #10 and an adjacent Nature report that also appeared three months earlier than #5 but which remains outside this session's Top Ten (see Q.-L. Ying, et al., Nature, 416[6880]: 545-8, 2002, at #15, with 179 total citations), may illuminate.

The ability of cells to differentiate into several more specialized entities by crossing the boundaries previously thought to restrict such progress is called transdifferentiation. But does transdifferentiation exist? That is the spanner thrown in the works by the April 4, 2002, Nature contributions (#10 and #15). These experiments, with bone marrow and progenitor central-nervous-system cells, respectively, involved co-culture with embryonic stem cells, which are truly pluripotent, and the results lead to the suggestion that the changed potential observed is due to cell fusion not transdifferentiation.

The paper by Jiang and colleagues (#5) entered the Top Ten about a year ago, then dropped out but is now back. The authors offer another candidate as a source for cells that might be harnessed to the management of disease—namely, the multipotent adult progenitor cell from rodent bone marrow—and this, rather than any contribution to the cell-fusion debate, possibly explains the high citation rate. However, of interest to the transdifferentiation versus cell-fusion argument is the fact that these workers did not use co-culture with embryo stem cells and the like. Although they did not set out to try and exclude cell fusion as the mechanism, Jiang et al. do argue against this possibility.

Dr. Lagasse and Dr. Markus Grompe, contacted by Science Watch in connection with the earlier column, have continued to collaborate on work on bone-marrow-derived hepatocytes. Genetic studies on repopulating liver cells led to the conclusion that "hepatocytes derived from bone marrow arise from cell fusion and not by differentiation of hematopoietic stem cells."

Science Watch asked Dr. Naohiro Terada, University of Florida College of Medicine, Gainesville, lead author of paper #10, where the debate stood as 2003 drew to a close. He reminded us that since the late 1990s we have known that bone-marrow-derived cells (BMDC) "can contribute to the regeneration of diverse adult tissues including brain, liver, and heart," and that these findings had been met with enthusiasm and were initially assumed to be due to transdifferentiation. Today the "unexpected cell fate switches of BMDCs into hepatocytes, Purkinje cells, and cardiac myocytes in vivo" are ascribed to spontaneous cell fusion. "At the end of 2003 we are realizing that adult stem cells may not be as flexible as once proposed."

The possibility of using pluripotent adult stem cells "as a way of realizing medical gain without ethical pain" (to use Stuart H. Orkin and Sean J. Morrison’s happy phrase in Nature, 418[6893]: 25-7, 2002) remains on the table but it looks as if the more biological argument has some way to run before clinical excitement becomes real.

Mr. David W. Sharp, M.A. (Cambridge), is a contributing editor to The Lancet, London, U.K.

Science Watch^®, January/February 2004, Vol. 15, No. 1
Citing URL: http://www.sciencewatch.com/jan-feb2004/sw_jan-feb2004_page5.htm