Dr. Coffin's Testimony to the CFSAC (Oct 09)

Cort

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Dr. Coffin is an acclaimed retrovirologist and the co-author of the leading text in the field. His testimony was arguably the most important of the CFSAC session on XMRV. Thanks (again) to Garcia for transcribing it.

http://aboutmecfs.org/Rsrch/XMRVCoffin.aspx

Reading this testimony brought up alot of interesting issues.

Activated vs non-activated Immune cells - Does it matter"

Coffin

It was in a really quite impressive fraction of cells that are isolated from blood, where after they’re activated. It’s unclear to me at this point, if you don’t activate the cells, what the fraction of actual infected cells is in blood. Which clearly, because the activation itself may cause the virus, may allow the virus to spread though the blood cells that you’re looking at. It almost certainly does I would say. The virus that you isolate is infectious for a number of human cell lines. It’s particularly infectious for the prostate cancer cell lines as was mentioned and also for b-cell and t-cell derived lines and for fresh activated PBMCs (Peripheral Blood Mononuclear cells) which are basically a mixture of b-cells and t-cells.
ME - After the WPI 'activated' the immune cells in their samples and tested them for XMRV they found that a surprisingly large fraction of them were infected. My understanding is that immune cells generally troll the body looking for pathogens; after they find one they undergo a metabolically expensive transition into killing machines. Most of the time most of our immune cells are not activated. Since the WPI only looked at activated immune cells Dr. Coffin is wondering here how many immune cells under normal conditions have XMRV infection. Dr. Klimas has stated that a large percentage of immune cells in chronic fatigue syndrome patients usually are activated however.
 

Cort

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Genetically Nearly Identical Viruses From Person to Person

COFFIN

One of the most very striking things is the very close relationship (in the viruses genetic makeup from person-to-person), and Dr Peterson showed you this and I’ve also got that on the slide in a minute, of how close these viruses are to one another. And the most distant pair actually, both of which were from prostate cancer, differs by only 0.3%. Now a patient whose been infected with HIV for one or two weeks has a greater diversity in his virus population than does virus isolated in different years, different parts of the country, different diseases of this virus.
It’s really remarkable how close that is and that’s a very important implication. It’s not that this virus has a lower mutation rate than HIV. These viruses probably have all about the same mutation rate. But its suggestive in fact that there are very few cycles of replication that separate the viruses that’s in one person from the virus that’s in another.
ME: Everytime any organism replicates very small changes are introduced in its genetic code. The the fact that this virus is so uniform from person to person suggests that it's not replicating very often. Could it also suggest that the virus came from a single source; ie - that a single contaminant somehow got into the CFS samples but not into the control samples? That was my first thought when I heard that it was genetically uniform. I'm sure it was theirs as well - so I assume they've checked it out and decided no - there's not really any concern about this.

http://aboutmecfs.org/Rsrch/XMRVCoffin.aspx
 

starryeyes

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They all seem very certain that there was no contamination. At one point, someone has said there wasn't any possibility of it, I think it was Dr. Peterson who said that in the talk he gave at the CFSAC. Also, a microbiologist who found XMRV on his/her own posted in a blog that the WPI did it right and some of what this person has to say is disparaging towards CFS and XMRV being related to it but they did seem to say that the test was tightly controlled and clean or something like that.

I don't know if this is truly related or not but I keep thinking about how geneticists say that there is tons of genetic diversity among chimpanzees but very little genetic diversity between humans. Yet chimps all look a whole lot more alike than all humans do. To me this shows how counter-intuitive mysterious genetics is.
 
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Well, DeRisi was one of those who evidently expressed worries about contamination, though I dont know why. Hes one of the most brilliant biologists there is; hes in the 99th percentile of governement-funded researchers, and there is a whole lot of difference between him and the median biomedical scientist. Presumably he wouldnt dream of commenting casually without thinking the thing over deeply. Thats the "code", and the more elite adhere to it more closely. But its not like he can never be wrong; especially about a subjective matter; he did not say the paper was wrong, just that he felt cautious and not totally satisfied.

The fact that some statement was said by some dude thats really elite, or that fact that something gets published in Science magazine, can never prove something. Which might mean in practice, 99.7% confidence. But it does significantly affect the odds that the statement or paper is correct, compared to a situation where you dont know the origin of the statement or paper. It does mean something, though it means less if you are super-experienced in that subfield and can evaluate the paper yourself better than almost anyone else alive. I cant read this paper well enough that I would take virtually no account of Coffin or DeRisi's opinion.

The world does not only run on true and false; cutting edge science in particular runs mostly on degrees of belief, your percent confidence, 60%, 80%, 99.7%, that a certain statement is true.
 

oerganix

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XMRV in breast cancer and ? for retrovirologists

1 -It's interesting that his quote and the paper mentioned have received little or no mention elsewhere:

"In a recent paper this virus was reported as being present using an immunological assay in about nearly a quarter of randomly chosen breast-cancer biopsies
..."

2 -I am having trouble reconciling the following two statements; perhaps a retrovirologist can help me understand:

"Its not that this virus has a lower mutation rate than HIV. These viruses probably have all about the same mutation rate. But its suggestive in fact that there are very few cycles of replication that separate the viruses thats in one person from the virus thats in another."

and:

" And in some ways the implications of that are both good and bad news. The bad news is that it suggests the virus is not actively undergoing ongoing replication during the course of infection of a single individual and that would not be good news if one were trying to use antiviral therapy. "

I intuit that I don't understand the significance of the difference between "mutation rate" and "cycles of replication" as mentioned above. Is he saying XMRV is not mutating quickly because it is not replicating often?
 

garcia

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I intuit that I don't understand the significance of the difference between "mutation rate" and "cycles of replication" as mentioned above. Is he saying XMRV is not mutating quickly because it is not replicating often?
Yes exactly. The mutation rate (= how fast it mutates relative to replication) is pretty constant in these viruses. So how much mutation you observe will be proportional to how much replication has gone on.

And given that the observed degree of mutation of XMRV in patients is much lower than HIV, a reasonable inference is that XMRV must be replicating at a much slower rate than HIV.
 

fds66

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1 -It's interesting that his quote and the paper mentioned have received little or no mention elsewhere:

"In a recent paper this virus was reported as being present using an immunological assay in about nearly a quarter of randomly chosen breast-cancer biopsies
..."
I remember hearing him say breast cancer while watching the live presentation and after being puzzled for a while came to the conclusion he had simply made a mistake and meant prostate cancer. I have just read the transcript and it would make sense that he was indeed mistaken and that he was referring to the prostate cancer publication. I may of course be wrong.

The whole quote from the transcipt is

XMRV was first reported in prostate cancer samples, particularly ones with a mutation as was pointed out in RNASE-L in 2005. In a recent paper this virus was reported as being present using an immunological assay in about nearly a quarter of randomly chosen breast-cancer biopsies and in a much smaller fraction of non-malignant prostate biopsies.
It seems too much of a coincidence that the recent prostate cancer paper found

A 2009 study of more than 300 prostate tissue samples collected from American men found that XMRV was present in 27 percent of the tumor samples and six percent of the noncancerous prostate samples in men who had not been diagnosed with prostate cancer.
from http://www.cancer.gov/newscenter/pressreleases/XMRV_QandA
 
G

George

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Yeah and I've looked everywhere for Breast Cancer Biopsies and XMRV and haven't been able to find anything.

The 2005 date for the XMRV discovery is correct. The study was done in November 2005 but not published untill spring 2006.

Anybody find anything on the breastcancer comment???
 

garcia

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Good detective work FDS! When transcribing I felt something was wrong when he mentioned breast cancer then non-malignant prostate biopsies in the same sentence.

I'm pretty sure it was a mistake and he meant to say prostate cancer.
 
C

cold_taste_of_tears

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At least he got breast and prostate mixed up, rather than the usual 'prostrate' disease that graduates from Typo University are tragically born with.

I guess these things happen occasionally when you have an IQ of 167. :cool:
 

joyscobby

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From what I remember he was doing this off the cuff at short notice so not suprised if there where some mistakes or inconsistancies. Not an easything to do even for people like Coffin. There was that mouse, mice, moose thing as well. He more than likely was refering to prostate cancer. I do not think it is wise to analyze what he said verbatum in light of this but take what he said in general terms. He reminded me of a philosophy proffessor I once had who was highly inteligent an expert in his subject but who could never remember where he parked his car. Despite this Coffin, in general he did a good job at getting across the most important relevant information, available to him at that time, in an understandable manner. It is a complex, specialist and technical subject after all.
 

garcia

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From what I remember he was doing this off the cuff at short notice so not suprised if there where some mistakes or inconsistancies. Not an easything to do even for people like Coffin. There was that mouse, mice, moose thing as well. He more than likely was refering to prostate cancer. I do not think it is wise to analyze what he said verbatum in light of this but take what he said in general terms. He reminded me of a philosophy proffessor I once had who was highly inteligent an expert in his subject but who could never remember where he parked his car. Despite this Coffin, in general he did a good job at getting across the most important relevant information, available to him at that time, in an understandable manner. It is a complex, specialist and technical subject after all.
I was going to say the same thing Joy. The guy was given less than 24 hours notice to prepare his talk, was in between his two places of work and had to shoot off back to work before noon. I think we can cut him some slack! Unlike almost everyone else who spoke, he was talking almost completely off-the-cuff, just from memory, which given the length & complexity of his talk was a pretty formidable thing to do. Transcribing Coffin was a nightmare because of the speed at which he thinks/speaks.

Dr Coffin is clearly a great intellect, and we are lucky to have someone of his calibre on our side.

It's amazing he only made one mistake (the MUS/Moose thing wasn't a mistake. MUS is a genus of mice).
 
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yes

Yes, and the absent minded professor thing is a fit. My grandfather and my mother are that way. I actually think they may have the XMRV virus. My grandfather was undiagnosed bi-polar, and he self-medicated. But he was highly intelligent. He was an attorney.

Also, my mother is that way.

I am a little. I used to say, "How can I keep up with where my keys are when I have world peace on my mind."

Tina
 

oerganix

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XMRV in breast cancer

I'm not so sure he simply mispoke. So, I emailed him and asked him. We shall see.

I did search for other references and found quite a few that link breast cancer with retroviruses, including one from mice called the HMTV (I think) (Human Mammary Tumor Virus) which comes from a mouse virus (MMTV) that causes breast cancer in mice.

2006 - mouse virus in breast cancer
http://www.webmd.com/breast-cancer/news/20061214/mouse-virus-link-breast-cancer

1999 - EBV implicated in breast cancer
http://www.cancer.org/docroot/NWS/c...Barr_Virus_May_Be_Linked_to_Breast_Cancer.asp

2001 - EBV in breast cancer
http://www.cancer.med.umich.edu/news/virus.htm

Dec 1, 2009 - "Inherited Mouse Cancer Virus"
http://www.autoimmune.com/HMTVGen.html

This last article has a very good explanation of how retroviruses work, in general, excellent for the layperson's understanding of it.

The connection between breast and prostate cancer may lie in how the retroviruses can mimic progesterone at receptor sites, as mentioned in another thread and in a blog by a retrovirologist, that I also posted elsewhere.
 
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The MMTV in man thing has been around for a while, before 2006. It doesnt seem to be agreed upon still. I'm not sure why. Early on there was a big feud between labs that could find it in human breast tumors by PCR, and other labs that could not.
 

Cort

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I was so impressed with Coffin; he really seemed like he was in his element - just rattling off fact after fact. He seemed like he was in complete control throughout which was encouraging.

Thanks to Garcia for putting together spoken testimony so well - its amazing how we speak in truncated sentences and even more so that we understand them so well - I guess when we're listening we just smooth it all out.

Thanks Organix for those links - gotta check them out.
 

oerganix

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molecular biologist blog on hormones, cancer and XMRV

http://cfidsresearch.blogspot.com/20...-xmrv-pt1.html

"....So, as a molecular biologist, it leaves me to theorize that if this virus can mimic progesterone, it can create a state that allows the immune system to ignore the virus, very much like it ignores a developing fetus - scary isn't it? It is also worth noting that mutations in XPR1 bear a strong association with miscarriage, and that such women often bear masculine-like features. Observations reveal that high rates of estrogen, or high rates of testosterone in the absence of progesterone tend to favor the growth of XMRV - progesterone inhibits the formation of DHT. It seems to indicate that succeptibility to ME/CFS is strongly hormone driven, and why ME/CFS and FM are strongly female prevalent."