Cloned embryos can’t fool a womb

See the following link for an interesting paper on the ability of the womb to discern between a cloned embryo and an embryo made by means of fertilization. See this link for the article.

Embryonic stem cells from cloned embryos are indistinguishable from those made from embryos made by fertilization.  They express the same genes (see  DJ Guo et al., Proteomics. 2009 Apr 22, and this article), show the same biological behaviors (see this link for this paper), show normal embryonic stem cell morphology, express key stem-cell markers, and can differentiate into multiple cell types in vitro and in vivo (JA Byrne, Nature 450 (2007): 497-502).

Since embryonic stem cells are made from the internal cells of the embryo (the inner cell mass), the inner cell mass cells from cloned embryos are rather normal (ML Condic, Cell Proliferation 41, suppl 1: 7-19).  However, the outer layer of cells (trophectoderm) that engage the endometrium and work with it to implant the embryo into the inner layer of the uterus do not differentiate normally in cloned embryos (DR Arnold et al. Reproduction 132, no. 2 (2006): 279­-90).  Trophoblast cells  in cloned embryos are normal at the early stages (S. Kishigami et al., FEBS Letters 580, no. 7 (2006): 1801-6), but they go on to make abnormal placentas (DR Arnold et al, Placenta 29 Suppl A (2007): S108-10).

Now this paper shows that the differentiating placenta of the cloned embryo does not interact normally with the surrogate mother’s uterus.  This is probably one of the main reasons why cloned embryos and fetuses tend to die prior to birth.  The endometrial cells of the mothers who were carried the cloned embryos showed substantial variation in the genes they expressed in comparison to endometria that carried in vitro fertilized embryos (S. Bauersachs et al., PNAS 106, no. 14 (2009): 5681-6).  Thus cloned embryos fail to properly communicate with the mother’s uterus.

Implantation is a very complex process.  It requires cross talk between the embryo and the uterus.  Without this cross talk, implantation does not occur successfully.  Without successful implantation, the embryo perishes.

Here again we find another reason to not clone humans.  We are subjecting them to a process that is less robust than fertilization.  The chances of the embryo surviving are far less than an embryo concieved in the usual manner (fertilization).  We should simply ban this process in humans overall.

This is so cool!

Induced Pluripotent Stem Cells are usually engineered with genes to become embryonic stem cells. However, some enterprising people have taken the proteins encoded by the four genes (c-Myc, Klf4, Oct4 and Sox2) that are typically used to reprogram cells. They placed a eleven-amino acid tag on the front of the protein that helped them pass through the cell membrane. Then they soaked mouse fibroblast cells in a solution that contained these proteins plus a chemical called valproic acid. This reprogrammed the cells so that they were “morphologically indistinguishable” from embryonic stem cells and expressed similar markers.

Thus they were able to make protein-induced pluripotent stem cells (piPSCs) with no genetic engineering.  No embryos were killed in this process.

Huntington Disease therapy fails

Huntington Disease in a fatal, inherited disease that causes degeneration of the central nervous system. It clinically manifests itself as severe movement and cognitive problems, and the patient gradually loses control of their body in a slow, painful slide to death that is difficult to watch.

A treatment for Huntington Disease that generated a far amount of hope in the 1990s was to transplant healthy neural tissue from fetuses. In particular, the striatum — the brain region most severely affected in Huntington disease was replaced by fetal neural tissue. Unfortunately, this tissue came from babies who were killed by selective abortion. Unfortunately, clinical follow-up of this approach has shown that technique does not work (Cicchetti, F. et al. Proc. Natl Acad. Sci. USA advance online publication doi:10.1073/pnas.0904239106 (2009).


University of South Florida neurosurgeon Thomas Freeman and his colleagues have conducted a post-mortem analysis of the brains of three people with Huntington’s disease who received fetal striatal-tissue transplants a decade before they died. The results were rather clear – instead of slowing or stopping the progression of the disease, the grafts degenerated even more severely than the patients’ own tissue.

Early results for this procedure generated some hope.  Animal experiment in rats (Kendall, A. L. et al. Nature Med. 4, 727-729 (1998) and non-human primates (Isacson, O. et al. Nature Med. 1, 1189-1194 (1995) showed that transplanted tissue could replace lost striatal neurons and improve behavioural symptoms.  Also, early clinical results tended to support the efficacy of this technique.  Patients who had received these striatial grafts showed modest improvements and autopsies showed that the grafts of fetal neural tissue had survived and integrated into the brain (see Hauser, R. A. et al. Neurology 58, 687-695 (2002), and Bachoud-Lévi, A.-C. et al. Lancet Neurol. 5, 303-309).

Unfortunately, this more recent examination shows that the animal models were deceptive.  The animals were treated with chemicals that destroyed the striatum but left the rest of the brain intact.  In the case of human patients, the entire brain is diseased, and dying neurons release extensive amounts of neurotransmitters that kill neurons by overdosing them on these neurotransmitters.  The transplanted tissue is killed by neurotransmitter overdose.

This has implications for stem cell treatments of Huntington Disease.  Transplanted stem cells or neural progenitor cells will be subjected to this same cocktail of death.  Therefore another strategy is needed.

Fortunately, some cells can surround transplanted cells and protect them from death by neurotransmitter overdose.  For example, co-transplantation of testicular Sertoli cells with neural grafts not only produce an area of localized immuno-suppression (due to local secretion of GDNF by the Sertoli cells) but they can push stem cells into dopaminergic neurons, which are killed in Parkinson Disease (see Halberstadt C, Emerich DF, Gores P. Expert Opin Biol Ther. 4, (2004): 813-25).  Therefore, some new thinking on this front might provide a new treatment scheme.