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Embryonic Stem Cells and Cancer

Prof. Stewart Newman of New York Medical College contributed this important item.

In light of recent public proclamations about the "enormous promise" of therapies based on human embryo stem cells, people might be surprised to learn that mouse embryo stem cells have been worked on for 20 years.

There are many mouse models for human diseases, but there do not appear to be any scientific papers reporting cures, and fewer than a half dozen describing any amelioration, of any of these mouse conditions with mouse embryo stem (ES) cells. It should also be of interest that one of the major distinguishing characteristics of mouse ES cells when they were first identified was that they caused cancer when injected into mice. This fact, which is also likely to apply to human ES cells implanted in humans, has not figured in the public discussions of potential therapeutic uses of such cells.* Indeed, until human embryonic stem cells were identified and patented during the last three years there seems to have been no significant discussion in the scientific literature (as indexed in Medline) of using ES cells as therapeutic agents.

The abstract of the first report of mouse ES cells [1] is printed below.

"This report describes the establishment directly from normal preimplantation mouse embryos of a cell line that forms teratocarcinomas when injected into mice. The pluripotency of these embryonic stem cells was demonstrated conclusively by the observation that subclonal cultures, derived from isolated single cells, can differentiate into a wide variety of cell types. Such embryonic stem cells were isolated from inner cell masses of late blastocysts cultured in medium conditioned by an established teratocarcinoma stem cell line. This suggests that such conditioned medium might contain a growth factor that stimulates the proliferation or inhibits the differentiation of normal pluripotent embryonic cells, or both. This method of obtaining embryonic stem cells makes feasible the isolation of pluripotent cells lines from various types of noninbred embryo, including those carrying mutant genes. The availability of such cell lines should made possible new approaches to the study of early mammalian development."

*Editor's note: The danger of teratoma formation was mentioned in "The unnecessary evil of 'therapeutic human cloning', by Mae-Wan Ho and Joe Cummins, ISIS News 7/8, Feb. 2001. It is very good to have the original paper cited, which we did not do.

Adult Bone Marrow Cells Mend Heart without Transplant

Hearts damaged by lack of blood supply can be mended by the body's own bone marrow cells, researchers have now demonstrated. This gives the lie to the claim that embryonic stem cells research is necessary.

Sudden blockages of a major artery to the heart cuts off blood supply and lead to rapid death of the muscle cells and blood vessels in the heart. This condition, myocardial infarction, is a common form of heart disease.

Despite the demonstration that some of the heart muscle cells can multiply and new vessels formed, regeneration is restricted to the living part of the heart wall. The 'infarcted' or dead area is irreversible, and in time, scar tissue is formed. Attempts to replace the dead tissue by transplanting heart muscle cells or skeletal muscle cells have failed to mend the damaged part properly.

In previous experiments on mice, researchers in New York Medical College and the National Institute of Health injected bone marrow cells along the border of the damaged area of the heart, and found that the cells did differentiate into muscle and blood vessels. But this surgical intervention killed a high number of the mice and the grafting success was only 40%. This prompted them to consider a 'non-invasive' method, which involved stimulating the mice to overproduce bone marrow cells before and after myocardial infarction was induced [1].

For the purpose, the mice were given daily injections of two cytokines (small molecules that influence the activities of cells), stem cell factor (SCF) and granulocyte-colony-stimulating factor (G-CSF), which increased the number of circulating stem cells two to three hundred fold.

Mice given cytokines had a survival rate of 73% after the operation, compared with 20% in controls not given cytokines. There were clear signs of repair in the damaged area of the heart in the cytokine-injected group, both new heart muscle and blood vessels were formed, whereas only scar-tissue was found in controls. The hearts of the cytokine-injected group also performed significantly better than the controls.

The experimental results looked impressive enough even though the protocol of inducing myocardial infarction in such large numbers of animals is debatable. In addition, there is an unaccountably small number of experimental animals, only 15 compared to 52 in the group of controls. This may be because the researchers excluded mice that died within 48h of the operation, "to minimize the influence of the surgical trauma". But could it be that the mice died from stress of overproduction of bone marrow cells caused by the cytokines injected? There are certainly more ways to be invasive; and much more effort should be devoted to reducing unnecessary and stressful interventions, both physical and chemical.

It is most important to clarify the effects of the cytokines before these are recommended for clinical trials.

MWH

Vaccine Turns Harmless Virus into Lethal Pathogen

The debate over the efficacy and safety of mass vaccination has gone on for decades. One circumstantial evidence against mass vaccination is that previously relatively harmless viral diseases have become lethal conditions. Researchers have now provided molecular genetic evidence to show how a vaccine has turned a harmless virus into a lethal pathogen by recombining with the virus [1].

Bovine viral diarrhea virus (BVDV) is one of the most important pathogens of cattle, it can cause abortion, diarrhea, and hemorrage. Most frequently, however, the infected animal does not show any symptoms. Such nonpathological BDDV can be passed on to the offspring through the placenta. The offspring become immunologically tolerant to the original BVDV strain, but may come down with mucosal disease, which is fatal. In addition to the persistent, non-pathogenic BVDV, a pathogenic strain can always be isolated with mucosal disease.

Previous research by the same group has suggested that the pathogenic BVDV has evolved from the non-pathogenic strain by non-homologous RNA recombination, ie, recombination that does not depend on similarity of base sequences. Pathogenic strains are altered in their genomes, and frequently have gene sequences from the cells of cattle inserted, together with large duplications of viral sequences and genomic rearrangements and deletions. One important difference between pathgenic and nonpathogenic strains is the expression of a certain gene for a non-structural protein, NS3, which presumably plays a role in regulating the expression of other genes.

In the new publication, independent fragments of the pathogenic BVDV were isolated from cattle that died of mucosal disease, in addition to the nonpathogenic strain which represents the persistent infection. All the fragments of the pathogenic BVDV isolated have the same structure, indicating that they came from a single strain. They all carry the same sequence acquired from the cell, which encode part of a ribosomal protein S27a fused to a truncated gene for ubiquitin lacking the first 3 codons. Moreover, this insertion, as well as the viral sequence flanking either side of the insertion, are more than 99% identical to that previously identified in a BVDV vaccine.

Detailed analysis indicate that both nonhomologous and homologous recombination have occurred between the vaccine and the nonpathogenic virus to generate the pathogenic virus causing fatal mucosal disease.

1. Belcher P, Orlich M and Thiel H-J. RNA recombination between persisting pestivirus and a vaccine strain: generation of cytopathogenic virus and induction of lethal disease. Journal of Virology 2001, 75, 6256-64. MWH

I-SIS News 11 index

Article first published October 2001


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