The abstract of the article gives for a professional a readable summary.
Mendelian laws provide the universal founding paradigm for the mechanism of genetic inheritance through which characters are segregated and assorted. In recent years, however, parallel with the rapid growth of epigenetic studies, cases of inheritance deviating from Mendelian patterns have emerged. Growing studies underscore phenotypic variations and increased risk of pathologies that are transgenerationally inherited in a non-Mendelian fashion in the absence of any classically identifiable mutation or predisposing genetic lesion in the genome of individuals who develop the disease. Non-Mendelian inheritance is most often transmitted through the germline in consequence of primary events occurring in somatic cells, implying soma-to-germline transmission of information. While studies of sperm cells suggest that epigenetic variations can potentially underlie phenotypic alterations across generations, no instance of transmission of DNA- or RNA-mediated information from somatic to germ cells has been reported as yet.
To address these issues, we have now generated a mouse model xenografted with human melanoma cells stably expressing EGFP-encoding plasmid. We find that EGFP RNA is released from the xenografted human cells into the bloodstream and eventually in spermatozoa of the mice. Tumor-released EGFP RNA is associated with an extracellular fraction processed for exosome purification and expressing exosomal markers, in all steps of the process, from the xenografted cancer cells to the spermatozoa of the recipient animals, strongly suggesting that exosomes are the carriers of a flow of information from somatic cells to gametes. Together, these results indicate that somatic RNA is transferred to sperm cells, which can therefore act as the final recipients of somatic cell-derived information.
Some background is needed to understand this rather technical summary.
- Darwinism has dominated biology since Darwin. The rules of classical Mendelian inheritance conform with the Darwinian view and can be reduced to genetic level. Various traits are inherited genetically by sexual reproduction and genome would change during lifetime only through mutations. Genome changes exremely slowly by random changes for offspring from which selection pressures choose the survivors.
Lamarckian view in turn assumed that the external circumstances experienced by organism leave a trace, which can be inherited but it could not be formulated in terms of modern molecular biology whereas the Darwinian dogma could be formulated in terms of Weissman's genetic barrier. Information flows from germ cells to soma but never in opposite direction. If it would do so, the soma interacting with environment could transfer information to germ cells and the experiences during lifetime could leave inheritable trace to germ cells.
An analogous dogma is that information is always transcribed from DNA to RNA to proteins but never in opposite direction. It is now known that this takes place in case of viruses and retroviruses: there are so called jumping genes which can also make copies of themselves. 5 per cent of human genome conists of endogenous retroviruses capable of doing the same. The huge genome of maize is due to this kind of proces.
- The development epigenetics has started to shatter the belief on Wessimann's genetic barrier. Gene expression is not fixed by genome alone and can be change even when genes are unaffected. Silencing of genes by DNA methylation and histone modification allow to modify gene expression. Silencing is essentially a locking of gene preventing its expression by transcription followed by translation.
It is now known that epigenetic changes in the gene expression can be inherited. The mechanisms are still poorly understood. What seems however clear the genome is more like a slowly changing hardware and gene expression or whatever is behind it is the software and programs can change very rapidly by just adding or deleting comment signs in the code. A deeper understanding of this software is needed.
- Epigenetic inheritance requires that genetic information is transferred from soma cells to germ cells. If only DNA or RNA are capable of representing genetic information, then DNA or RNA must be transferred from soma cells to germ cells. No instance of direct DNA or RNA mediated information from soma to germ cells had been observed before
the above mentioned experiments. One can of course challenge the assumption about DNA and RNA as the only representations of genetic information.
More technically: mouse model was xenografted with human melanoma cells stably expessing EGFP-coding plasmid (expressed in a manner possibly evoking emotions: human melanoma cancer tissue was implanted in mouse). EGFP-RNA is released from xenografted human cells to blood. One just looks whether it eventually ends up to the sperm cells of mice and tries to identify the transfer mechanism. Only transfer to sperm cells was studied. One might expect that the transfer of RNA can happen also to ovum. I guess that the sperm cells are easier to study.
What was observed?
- The transfer of RNA from soma cells to sperm cells was indeed found to occur. The transferred RNA can in turn induce epigenetic effects in germ cells known to be inherited by a mechanisms, which however remain poorly understood. Epigenetic mechanisms seem to be involved in the cases considered so that DNA is not changed, only its expression.
- The transfer mechanism was identified. The transferred RNA is contained by exosomes analogous to synaptic vesicles transferring neurotransmitters from presynaptic to postsynaptic cell. Transfer of RNA takes place via fusion of the membranes just like transfer of neurotransmitters. Maybe genetic engineering using exosomes or analogous structures to transfer the needed material to cells has been tried.
The precise mechanism of inheritance of epigenetic modifications is poorly understood. For instance, it is known that alleles (variants of game gene) can express themselves differently: this would be due to epigenetics. One allele can also induce other allele to express in the same manner. Somekind of "social pressure" like interaction seems to be involved.
TGD suggests the notion of magnetic body and cyclotron resonance as this interaction. The DNA of offspring get tuned to the DNA of mother during pregnancy and this gives to epigenetic inheritance. Various epigenetic mechanisms such as methylation and histone modification could affect cyclotron frequencies besides purely geometric modifications of DNA and locking at the level of gene could be accompanied kicking out of tune at the level of magnetic body. These aspects are discussed in earlier blog posting and the article Magnetic body, bio-harmonies, morphogenesis, and epigenetics.