ignorance, part six

In 2009 there was a study using pyrosequencing to compare the viral communities in sputum from the lungs of people with cystic fibrosis (CF) to viral communities in sputum of healthy individuals. Pyrosequencing (and 454 sequencing) is one of several competing methods generally referred to as deep sequencing. Details of the distinctions between them would take us far afield.

The important aspect of deep sequencing is that it is a massively parallel means of constructing DNA sequences for entire communities of organisms by piecing together information from a huge number of fragments. You do not have to guess what you are looking for the way you do with ordinary PCR probes.

The surprise from this work for me lay not in the discoveries concerning CF, but in the viral communities (viromes) of healthy individuals. They found an average of 243 species of virus, some 90% previously unknown in any context. This was with methodology that was not suitable for detecting RNA viruses, which predominate in respiratory infections.

They were not specifically looking for retroviruses either, (retroviruses are RNA viruses which must use reverse transcription to generate DNA they can insert). Sequences probably resulting from reverse transcription convinced them some unidentified retroviruses were present.

I want to reassure people that most viruses, even those in human beings, are not human pathogens. They are generally there to attack numerous bacteria, some of which may be pathogens. Viruses which attack bacteria are called bacteriophages, commonly abbreviated to phages. Dusting a powder with selected phage viruses on wounds has even been used (in the Soviet Union) as a means of protecting wounds from bacterial pathogens without damaging human cells around the wound, as antiseptics do.

For those interested in the history of science, this is a classic example of breakthrough research. Having the control group turn into the experiment is a pattern you will find over and over in breakthroughs. The main problem comes from researchers who may not recognize or want a shift in the direction of research. (The reaction Crookes or Thompson allegedly showed to the fogged photographic plates is a classic missed opportunity, in that case for the discovery of X-rays.)

What the above research revealed is that we have not even known the existence of most viruses we might find in the lungs of healthy people. All research on lung diseases prior to 2009 must be reevaluated with this in mind.

My special interest in this paper came from preliminary results showing the XMRV virus preferentially replicates on mucous membranes, of which the lungs have a large area. This suggested there might be evidence of retroviruses in the data from that research. The researchers, (who were certainly not thinking about CFS or XMRV,) said they thought retroviruses were present. For them this was a hopeful sign that vectors for inserting genes to correct the defects causing an appalling and fatal genetic disease were possible.

A secondary finding in the CF patients, who have seriously compromised lungs, was infection by a variety of viruses in the herpes family. For those who haven't been keeping track, I'll remind you that Epstein-Barr virus (EBV), Cytomegalovirus (CMV), roseola virus (HHV-6, HHV-7) and chickenpox or shingles virus (varicella zoster virus, VZV, HHV-3) are all suspects in ME/CFS, and all are herpes viruses, in addition to those specifically called herpes, HSV (HHV-1) and HHV-2. The idea that XMRV, or another human gamma retrovirus, has a special relationship with viruses in the herpes family is not at all far-fetched.

With the discovery that a great deal of what was known concerning viruses on mucous membranes, and their effect on associated bacterial communities, was just plain wrong, my confidence in my own ability to find clues experts had missed improved. I had noted earlier that many cases of contamination of cell lines by viruses resembling X-MLV had involved tissue xenografts from human tumors closely associated with mucosa. The idea that undetected latent provirus was emerging from human cells after they began dividing in an environment without a competent immune system was already one hypothesis I was using before I saw research specifically about XMRV and mucous membranes.

To reiterate for any who might be misled, I am not an expert. I also lack the biases and blinders of experts who have singularly failed to address our problems in a constructive way. What I am doing is simply playing with ideas, as an alternative to staring at the ceiling, and constantly contemplating my own mortality.

One mental activity has been building chains of possible inferences. The vast majority will be wrong, but the clues that turn up are tantalizing suggestions that this approach is productive. At the very least I am learning.

Here's a sequence which just happens to be on my mind now, as a sample. There is a suggested correlation between XMRV infection, ME/CFS and B-cell lymphomas. Research on B-cell lymphomas in mice showed an insertion site where the provirus might disrupt a gene labeled BMI1. This gene in turn affects another gene called P53, a tumor suppressor gene. This gene has been called a gatekeeper for cell growth and division.

Because I was looking for specific types of tumors which might be affected I was recently excited when others turned up a link from P53 to connective tissue growth factor (CTGF). Following this line of reasoning allowed me to connect with classes of neoplasms which had not seemed to fit earlier ideas, like rhabdomyosarcomas.

Mucosa have to constantly replace surface layers, and adjust to changing shapes of organs. CTGF is an important signaling molecule for their normal activity, not just in pathological situations. We don't really understand why sometimes the process crosses the boundary between health and pathology. We do know there are associations between some anomalies which may be signs of precancerous changes.

One such sign is the formation of polyps. These can appear in intestines, colon, nasal or pharyngeal mucosa. Anomalies in CTGF seem to be present when these are found.

Another possible correlation is between fibroids, endometriosis and several cancers of female reproductive organs. At this time we don't know if the common appearance of problems at similar times is due to some general factor, like aging, or to a specific cause like an infectious agent.

Following the trail in another direction takes us to neoplasms of the bladder and kidneys. Many separate research paths are beginning to converge, after decades of wandering apart.

Does the above mean we are all going to die of cancer? Not at all. If true, it just means there is some increased risk if the infection persists for a long time.

Why am I interested in such nasty possibilities? Because these consequences are unmistakable. Doctors can't always tell the sick from the healthy. When they do, they don't always get the diagnosis right. They are remarkably good at distinguishing the quick and the dead. This is a solid fact researchers can seize hold of and follow. It is also a guaranteed motivation for funding.

Back at the start of the controversy over CFS, the late Stephen Straus begin removing any patient from his cohort who developed a serious organic illness. To his mind, this meant the original diagnosis had been wrong. Bill Reeves and Simon Wesseley extended this to exclude anyone with any signs of organic illness from cohorts they put together.

The result was a social construct rather than an illness. It couldn't have anything suitable for laboratory study -- by definition. The resulting hypothesis was not falsifiable, putting it outside of science.

While we focus on the damage this did to us, as patients with ME/CFS, we tend to overlook the damage this did to those with diseases which start out in this category. It was impossible to diagnostically separate patients with lymphomas from ME/CFS patients prior to onset of serious lymphoma. This broad category extended to a great many other cancers in which initial complaints center around fatigue.

The same problem turned up with MS. Prior to the appearance of characteristic sclera, there was no way to distinguish atypical MS from ME/CFS. This can be extended to a number of rheumatic illnesses which don't reveal themselves for years. The result was that there was no way to investigate or interrupt pathology in these diseases before it was well established, and hard to treat. The doldrums of ME/CFS research have also left research on many other illnesses which start with such non-specific symptoms spinning its wheels.

This is why researchers shy away from the subject. Nobody wants to waste time seeking a cause for a disease that may not exist. Hard-headed biological researchers don't want to depend on psychological checklists and subjective scales for data. Once such a mess exists, it is only natural for most researchers to run, not walk, in the opposite direction. This need not involve planning and central direction.

Tracing a single course of pathology from initial infection to life-threatening disease would dramatically alter the picture. In a rational world, it would also make us, as people who can survive infection for long periods, mostly without developing those dire consequences, unusually interesting. Our bodies are mounting a defense, perhaps weak and imperfect, but still able to arrest a progression to terminal disease. By the time a patient with prostate or ovarian cancer winds up on the operating table, most clues to the origin of the problem have been obscured by messy sequelae.

I am not some prophet who can tell you the specific path by which coming history will unfold. What I can say is that all indications tell me we have all been extraordinarily ignorant for the last generation, and great changes lie close at hand.


Can't play out ideas with you anciendaze but much appreciated your thought about something of a special relationship - the Herpes family of viruses and XMRV or another gamma retrovirus. And the thought of tracing a course from initial infection to life threatening disease if this includes all the developing symptoms in the course of this illness - precisely what threw my own Docs off the case. They seem to have a static snapshot view and my old bod couldn't oblige (no concept of "progression" so to state the obvious initial cause would help us all).
you are so smart and eloquent. i envy, value and appreciate you and your posts.


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