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The Marshall Protocol Study Site > PROF. MARSHALL'S PERSPECTIVE > Prof. Marshall's Perspective > "Genome-wide studies have been flawed from the outset"


"Genome-wide studies have been flawed from the outset"
 Moderated by: Prof Trevor Marshall
 

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Prof Trevor Marshall
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 Posted: Sat Jul 18th, 2009 12:54

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Take a look at this article from McGill University: "Study reveals major genetic differences between blood and tissue cells"

http://www.mcgill.ca/newsroom/news/item/?item_id=107673.
 
So it seems others are beginning to notice the metagenome, and realize that a whole field of Science, that which looks at genes as the cause of,  or cure for, disease "may have been flawed from the outset."

Sweet....
:)
 

kenc
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 Posted: Sat Jul 18th, 2009 15:19

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So by looking at mutations in the human genome that were assumed to be the same throughout the body, scientists have been missing the bigger picture, the metagenome. The metagenome could be used identify the microorganisms that cause the mutations in the local genome. The cause of disease is to found in the metagenome not in the genome. Is that correct?

How do these organisms cause the mutations in the local genome? Horizontal gene transfer? Why are these mutations not repaired? Is it because of the downregulation of innate immunity brought about by these organisms?



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Prof Trevor Marshall
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 Posted: Sat Jul 18th, 2009 15:28

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Ken,
It is even more complex than 'mutations'. If the computers assembling the genome info from the tissue were only told to look for fragments of human DNA they may have confused similar bacterial gene fragments to slightly different human ones. We will never know until these researchers, or the folk at West China Hospital, actually design their experiment with the metagenome in mind :)
 
 

kenc
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 Posted: Sat Jul 18th, 2009 16:04

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OK.

So, it looks like medical researchers are making two incorrect/questionable assumptions:

1) The human genome is the same throughout the body.
2) The cells of the body contain only the human genome.

From someone like myself with no medical training, these assumptions seem crazy. My background is in engineering and computer science. I don't even know the right words for describing a lot of this science but I'm learning a lot by participating in the this study. There must be some history behind these assumptions above that make them appear reasonable to someone in the field of medical science.

Ken



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Frans
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 Posted: Sat Jul 18th, 2009 16:39

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Ken,

You could look at the following animation about how DNA transcription works in the cells.

- http://www.youtube.com/watch?v=4PKjF7OumYo

At about minute 3, the narrator talks about factors that are getting together to start DNA transcription.

These factors are the transcription factors.

The VDR is one of those transcription factors.

It functions as an initiator of DNA transcription. PXR and RXR are other examples of those transcription factors. Some act together.

At 4.56 min, you see the RNA leaving the nucleus to be taken up by a ribosome.

Consider that bacteria are also replicating their DNA and chugging out proteins in the very same cell.

There will be lots and lots of interference between all those proteins, ribosomes, etc. as well as competition for all the resources available in those cells.

Hope this helps you to get a picture of the complexity. It helped me a lot to understand how interconnected everything is on a cellular level.

Best, Frans



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 Posted: Sun Jul 19th, 2009 07:12

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After viewing this video link, I am deeply inspired.

I cannot find words,

Sherry



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jcwat101
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 Posted: Sun Jul 19th, 2009 15:07

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This is the abstract that is referred to by the article Trevor posted the link to:

http://www.ncbi.nlm.nih.gov/pubmed/19514060

Here is more on the topic:  http://bacteriality.com/2008/04/06/genetransfer/

Here is an interesting quote from the discussion section of the article:
 
In a study of prostate cancer, laser capture microdissection
(LCM) was used to dissect prostate tumors into cancerous and
noncancerous tissue. Initial results [Alvarado et al., 2005]
supported the traditional hypothesis of somatic mutations as the
causal agents for carcinogenesis, because genetic alterations in the
androgen receptor gene (AR) were found in cancerous tissues, but
not in blood. However, in a follow-up study, AR alterations were
detected in completely disease-free prostate tissues, remarkably
even in prostate tissue from a 1-year-old child [Sircar et al., 2007].
Thus, unlike blood and other tissues, prostate tissue whether
diseased or nondiseased and of varying age and maturity,
contained variants of the AR gene. The results that we are
reporting in AAA would appear to be similar to those reported in
prostate cancer. These results are interesting, because they
question the primacy of the somatic mutation theory as the basis
of a common pathogenetic pathway for many multifactorial
diseases including atherosclerosis
[De Flora and Izzotti, 2007].
 
Joyce Waterhouse



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Ruth Goold
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 Posted: Tue Jul 21st, 2009 07:04

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While this study is interesting, I am not sure that it adds (or detracts) much to our considerations of the human/bacterial metagenome.  One important aspect of the study is that DNA sequences from the vascular tissue (whether healthy or diseased) were of cDNA origin whereas the DNA sequences from blood tissue were exons amplified and sequenced from genomic DNA.  The genomic DNA is the entire genome carried by an organism that is located in the cell nucleus and is passed to daughter cells when cells divide in a growing organism.  Genomic DNA carries large areas of noncoding DNA sequence that are never translated into proteins.  Even within DNA sequences that code for proteins (called genes), there are interspersed coding sequences that ultimately determine the protein structure (called exons) and noncoding sequences of DNA (called introns).  When a cell needs the protein encoded by a certain gene, the code is transferred (through the process called transcription) to a mRNA (messenger RNA sequence) but the introns are spliced out.  Thus, the mRNA sequence for a protein is generally shorter than the genomic DNA from which it was created.  An enzyme called reverse transcriptase can reverse the the transcription process and make a matching cDNA sequence from the mRNA, but only in cells in which the protein of interest is being made (vascular cells in this case).  The mRNA sequence travels out of the nucleus to the cell cytoplasm where the protein is made.

In this study, the authors examined cDNA from the vascular tissue because they wanted to look at the functional BAK1 protein being created in AAA patients; their hypothesis was that unusual forms of this protein might be causing the disease.  In blood tissue, however, where the BAK1 protein is presumably not needed and therefore mRNA for it does not get transcribed, they had to look at the genomic sequences for BAK1.  To avoid looking at the intervening noncoding introns, they sequenced each of four exons independently.  Thus, they showed that cDNA from vascular tissue (whether healthy or diseased) differs in exon sequence from genomic DNA of blood tissue.   To be absolutely certain that the sequence differences weren’t simply introduced in the process of transcription in the vascular tissue, they should have also sequenced genomic DNA from the vascular tissue.  They addressed this issue a bit in the Discussion section on 'RNA editing.'

Nevertheless, it is interesting that somatic (non-inherited) DNA ‘mutations’ in tissues in which a gene is expressed might arise independently of the disease process, or so early in the disease process that they are found in apparently healthy tissue as well.  I doubt that the variant sequences were mis-identified bacterial sequences, their sequence homology to the ‘normal’ human sequence was too high.  Whether they are truly mutations or are sequence variants introduced in transcription (or even post-transcriptionally), the question of why they arise and their involvement in the disease process remains.  Certainly, it is possible that they simply reflect errors made in cells that are being disrupted by something, but whether that something is an environmental factor such smoking (as suggested by the authors) or underlying intracellular infection is an open question.   

Ruth



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Prof Trevor Marshall
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 Posted: Tue Jul 21st, 2009 07:19

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Ruth,
Good points. I haven't looked at the actual equipment they were using to read the sequences, and my suspicion about errors being introduced by the foreign genomes is based on the low signal-to-noise ratio one gets when trying to read un-amplified sequences, and the potential for error introduced when genes with unexpected homology are present. I apologize for not have had time to read the paper in any detail yet. Thanks for helping out with that :)
 

kenc
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 Posted: Fri Jul 24th, 2009 09:06

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Frans,

This animation (http://www.youtube.com/watch?v=4PKjF7OumYo) you provided is excellent. It has really helped me to understand the paper, Autoimmune disease in the era of the metagenome and other information posted on this site, like that posted under this topic.

I think I need some basic training cellular biology and genetics to really appreciate the work done by Dr. Marshall and his research team and the more I understand and appreciate this work the easier it is for me to bear the challenges I'm faced with while on the trial.

Perhaps it would be useful to have a section on basic cellular biology and genetics in the Knowledge Base. It would contain just enough information to understand the significance of the science behind the MP. Hopefully one doesn't need to aquire a biology degree or two for this.

Ken

Thanks.

Ken

 



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