Gene + virus + injury = disease? - new study and (my own) thoughts on vaccines

[Ms. Toad]

"One of the most detailed studies to date of how the interaction between genes and environment results in disease has demonstrated that an inflammatory bowel disease resembling human Crohn's needs a specific mutation, virus, and injury to develop in mice."

. . .

"Enter the murine norovirus -- a family of small, RNA viruses discovered by Virgin in 2003. The viruses are practically found in almost all mouse facilities except the new one, which was designed expressly to keep them out. . . . Stappenbeck and his team compared gene expression in mutant versus normal mice that are either infected or uninfected with the norovirus."

"They found that, when exposed to CR6 norovirus, the same set of genes that are down-regulated in normal mice are up-regulated in the mutant mice. As a result, in mutants, the Paneth cells are unable to secrete antimicrobial proteins -- leaving the microbe population in the gut unchecked. . . . "So really there were three environmental factors that were working together with the mutation: the viral infection, the composition of the microbiota (presumably induced by the viral infection), and a very specific inflammatory hit on the ," Blumberg said."

"It's a well-documented scientific example of how very particular environmental events and genes interact to result in disease," said Richard Blumberg, chief of gastroenterology at Brigham and Women's Hospital at Harvard Medical School, who was not involved in the study."

Read more: Gene + virus + injury = disease? - The Scientist - Magazine of the Life Sciences http://www.the-scientist.com/blog/display/57509/#ixzz0rnSxqASl

Now my own thoughts. There have been studies showing a correlation between simultaneous exposure to mumps and measles and the manifestation of IBD (crohns or ulcerative colitis). Our children are deliberately exposed simultaneously to mumps and measles as part of the MMR vaccine in the standard set of childhood vaccines. Partly because my daughter's IBD manifested itself shortly after receiving the MMR vaccine I have long encouraged parents to request that those vaccines be administered separately (in time - not just separate injections on the same day) as a precaution, suggesting that a genetic predisposition + a trigger (possibly the simultaneous exposure to the two viruses) might precipitate manifestation of the disease. Why not take the relatively simple precaution of separating the exposure.

That suggestion invariably gets characterized here on DU as "woo-woo-anti-science"

The article doesn't address the human variation of chrons, or the exposure to mumps and measles simultaneously. It does establish that a similar disease in mice (something close to human crohns) has been triggered by a mechanism similar to what I have suggested - a combination of a genetic predisposition, environmental injury, and exposure to a specific virus. The study will be published in a peer reviewed, and an apparently well respected, journal.

So much for "woo-woo-anti-science."

[tabatha]

1. I think there is still a lot to learn.

And those who dismiss it out of hand are displaying ignorance.

[MineralMan]

2. Do you have links to the human studies?

I'd be interested in reading them.

[MineralMan]

3. I tried to find a link to the studies you mentioned.

The only references I found were on alternative medicine sites. None of those sites provided any links to the studies, so I've found no way to confirm that such studies exist. Just generic claims that they do.

If you can find an actual study, I will go and find it and see what it says.

[Ms. Toad]

8. Here is the link to the article the OP announced

http://www.cell.com/fulltext/S0092-8674(10)00545-3 (you may need to cut and paste - the link splits between the 8674 and (10)

As to one of the studies I read years ago - I provided a link below. I believe there were more than one, but I didn't keep the references and didn't quickly find others tonight. You can be assured that what I read was in a peer reviewed medical journal, not an alternative medical site. I don't put much stock in wikis, blogs, run-of-the-mill alternative medical sites, etc.

Although the article I am currently able to retrieve is in a respected journal and one of the authors is still respected (Pounder), it does appear that at least one of the authors (Wakefield) is a flake. The point, though, was not whether the original studies proved the mechanism. The authors pointed to a correlation, and many reputable researchers since since then have suggested a viral (or other pathological) trigger in combination with a genetic predisposition may cause IBD (and other autoimmune diseases). (See, e.g. MS - http://www.ncbi.nlm.nih.gov/pubmed/10871246 , diabetes - http://www.ncbi.nlm.nih.gov/pubmed/1703973 , IBD (crohns & UC) - http://www.ncbi.nlm.nih.gov/pubmed/16378007 )) One common viral exposure is vaccines.

The study which the article I posted announced a scientifically rigorous demonstration that a crohns-like disease can indeed be caused by genes + virus + injury. As is far too common on DU, no one has even bothered to discuss (or perhaps even read) the substance of the article posted. Robin Warren and Barry Marshall would probably have been similarly dismissed if they had posted on a the equivalent of DU 35 years ago that ulcers had a bacterial cause - a theory that later won them a Nobel Prize.

Perhaps it is time to stop yelling "woo-woo" at people who suggest that exposure to viruses (or other pathogens) via vaccinations may play a role in the development of autoimmune disorders, and take a closer look at the underlying theory. We can't control most viral exposure, but we can control exposure via vaccines. Autoimmune disorders are incredibly costly to treat - my daughter's bills are currently $60,000 a year, and will rise to around half a million in the year(s) she needs transplant(s) - I know one 23 year old who has had 3 transplants so far. It doesn't take very many illnesses like my daughter's, or the 23 year old son of a friend, to create a significant payback if something as simple as adjusting deliberate exposure to viruses could prevent some of them. (Adjusting = looking at which ones are critical, unmandating those that are not critical, spreading out the vaccination schedule, de-aggregating the combo vaccines, doing genetic testing for genes found in GWAS to be linked to certain autoimmune disorders and minimizing deliberate exposure to pathogens in those people, etc.)

[trotsky]

15. Exposure to pathogens that HAVE NOTHING TO DO WITH VACCINES

can bring about autoimmune disorders. My aunt had a severe tooth infection as a teenager... and got RA as a result. Other bacteria in the mouth bear a chemical resemblance to heart tissue. An infection by these bacteria can cause the immune system to attack the heart.

So what still requires the "woo-woo" label is this total lack of understanding about what exactly vaccination is, what's in a vaccine, and how it works.

[Ms. Toad]

17. I never said vaccinations were the only exposure mechanism.

In fact, I believe my OP even stated that flat out. Vaccinations, however, are exposure paths that we have control over. To the extent that exposure to viruses via vaccination may be contributing to autoimmune disorders, avoiding exposure (or structuring the exposure in a way that minimizes the possibility it will act as a trigger) could save countless health dollars in the long run.

Regarding "this total lack of understanding" - nothing I have ever said even remotely suggests a lack of understanding about what exactly a vaccination is, what's in it, or how it works - yet when I suggest that we ought to consider controlling the viral exposures we have the ability to control, the vast majority of responses do nothing more than name call. That is inappropriate, particularly in light of the solid confirmation we are beginning to get, at an increasingly rapid rate, that viral exposure (as well as exposure to other pathogens) in combination with other factors can cause the manifestation of a variety of autoimmune disorders).

Does that risk rise to the level that genetic testing ought to be done early in life for the most common autoimmune disorders, before vaccination? Don't know - partly because the minute the word vaccination is used without the proper reverence people stop thinking and start either screaming "woo-woo" or blaming every ailment in the world in vaccinations (neither attitude is helpful). If the autoimmune disorder is common enough, if a particular virus is identified, if genetic testing can identify those most likely to be at risk, if the cost of the screening is low enough - perhaps. It's a pretty high cost solution - but if it can prevent the creation of even a handful of illnesses like my daughter has, which will likely cost around $3 million (in today's dollars) in direct treatment costs plus a lot of ancillary costs over her lifetime - even a relatively high cost screening test might be worth it.

Would it make sense to separate the combo-vaccines? Again, we don't know, at least across the board, for similar reasons. The study I linked to found a correlation between near simultaneous exposure to mumps and measles and subsequent development of crohns. Later studies I have seen have focused solely on a single exposure - to measles. More studies either verifying or refuting that original study would be a good idea - particularly now that it is clear that, even though one of the authors of the study failed to follow proper scientific protocols in a different study, the idea that viral exposure may contribute the development of IBD appears to be growing legs. In the mean time, separation of combo-vaccines is a pretty low cost option that might be beneficial - and certainly ought to be available and considered, particularly where there is a history of IBD in the family.

[MineralMan]

4. Continuing my online search, the only thing I could find were

references to Wakefield's discredited study. No wonder nobody's linking to these "studies" that show a link. It's Wakefield again. Never mind.

[SidDithers]

5. Thanks for doing the digging...

I'm not surprised it's come back to that fraud Wakefield.

Sid

[MineralMan]

6. Yes, and it's somehow been distorted, even then.

Wakefield's link was supposed to between the combined vaccine and what he decided was a new disease, "autistic bowel disease." There was no new disease, and, according to the evidence, he falsified some of the minimal data he used to suggest a link.

The problem is that the alternative health sites don't even name the source of their "European studies," and then don't even get their facts right. It's borderline criminal, I think, since most are using this content on their websites to sell one thing or another. I think it's time for the FDA to begin investigating these sales-oriented alternative medicine sites.

Here's a link to a blog that quotes an article, laying this whole Wakefield link all out:

http://blog.taragana.com/health/2010/04/15/experts-say-autism-bowel-disease-posited-by-flawed-study-that-caused-heath-scare-may-not-exist-21783/

[Ms. Toad]

7. Thanks for not even bothering to look at the article posted.

Which has NOTHING to do with Wakefield but is instead newly verified disease mechanism, that will be published tomorrow in Cell (a respected, peer reviewed journal), which confirmed that a crohns-like disease can be created in mice by exposure the genetically modified (to create the crohns-like illness) mice to an injuring mechanism and a virus.

If that mechanism can create disease in mice which are specifically to study how crohns develops and how to treat it), it isn't a "woo-woo" to suggest the same mechanism might create IBD (or other genetically linked diseases) when genetically predisposed individuals are exposed to viruses (by vaccination, or otherwise).

One of the studies showing the correlation between near simultaneous exposure is this one: Paramyxovirus
infections in childhood and subsequent inflammatory bowel disease. GASTROENTEROLOGY 1999;116: 796-803

There are any number of studies noting a correlation between viral exposure and the development of IBD in genetically predisposed individuals - and the article published tomorrow definitively establishes it as one way the manifestation of a crohns-like illness can be created in mice which are genetically predisposed to a similar illness.

[spooked911]

9. WHY is THIS in the dungeon ??

Jesus this ridiculous

[Ms. Toad]

10. Thanks for noticing - I have asked that question myself

of both the moderators and the administrators, and am awaiting an answer. (I posted it in GD, but it also could legitimately have been posted in LBN, since it is news that broke within the past 24 hours). I'm guessing it is here because I dared to utter the word vaccine without the proper reverence.

I'm pretty torqued about it, since this is mainstream research in a field that is changing so quickly that even people in the field have a hard time keeping up. Proving the mechanism by which an autoimmune disorder starts up is pretty exciting (and in this case, they not only established how it started, but discovered they could effectively treat it with an antibiotic, even though it had a viral cause).

The latter point is particularly exciting, since my daughter has spent the last year in a trial to see if treating one of her autoimmune diseases with an antibiotic will cause it to go into remission. Of course, since this is obviously a radical conspiracy theory, or rantings of a lunatic (why else would the thread have gotten dragged here) that must mean that Massachusetts General Hospital (where my daughter was in the trial study) has really declined from its glory days...

[Name removed]

11. Deleted message

Message removed by moderator. Click here to review the message board rules.

[Ms. Toad]

13. No - the disease she is in the trial for

is Primary Sclerosing Cholangitis, and the trial was open label. It is too rare a disease to have very many placebo controlled trials. The concept of treating an autoimmune disorder with antibiotics is not terribly intuitive, so the kids study about a decade ago was mostly ignored, and was scoffed at by prominent researchers as recently as 14 months ago (kinda like this thread being transferred to the conspiracy dungeon yesterday), but the treatment possibility is now being picked up by Mass General (my daughter's trial - which started perhaps 5 years ago) and the Mayo Clinic (which started recruiting for its trial this spring).

My daughter's study is a small preliminary study with 12 participants. There are two more after her and the results will be published sometime this fall. The first (a pediatric study with 14 patients) had 100% positive results for everyone prior to the late stage of the disease. My informal impression is that the results in the first adult study (my daughter's) were more mixed. (They intend to categorize participants as responders or non-responders, and as of the end of her year long participation she is on the borderline between the two categories; pathology reports will determine which camp she falls into.)

My daughter has UC (basically a sibling of Crohns), which is mostly under control as long as we keep poultry out of her diet (a trigger for her). No one knows why the antibiotic works to put PSC - the companion disease in remission, but one theory is that bad gut bacteria leaks up into the liver and starts an autoimmune reaction there. If that is the case, treating the gut bacteria might stop the upward leak and allow the reaction to stop. The role of the gut bacteria in UC is unclear - perhaps similar to the role the virus played in the Cell study.

I'm in the midst of a crash course in cellular biology so I can understand the most recent research on gene expression, nuclear receptors, proteins, ligands, etc. (My background is in the physical sciences - so it is whole new world, but a lot of what I am learning fits nicely to explain what I have observed and theorized about from a 10,000 foot level, including the role one or more viruses might play in causing IBD to manifest itself). The amount that is unknown (and the rate at which knowledge is being acquired) is pretty striking.

At any rate, what is going on with my daughter does fit nicely with the Cell article mechanism - in that case a gut disease created by a genetic predisposition, an injury, a pathogen (in that case a virus), and through a cascade of events ends up being treatable by an antibiotic. The vast majority of people with PSC also have IBD - and since now a gut bacteria is suspected as a factor - the possibilities are intriguing.

Thanks for the suggestion about LDN - I am aware of it. For now, it isn't something we're considering - but it may be down the road.

[hedgehog]

12. Just to throw some fat on the fire: Years ago I was researching

rheumatoid arthritis after my daughter developed juvenile rheumatoid arthritis. The theory then was that some infectious agent must be involved, because while pre-Columbian skeletons found in Peru showed evidence of the disease, the first mention in Europe came about 1650(?) and indicated a sudden outbreak of many cases. No one has ever found an agent. This would fit the model of a wide spread virus that does not cause disease except in individuals with the right genetics.

Making the connection is going to be very difficult since the autoimmune affected population is so small and the possible triggers so many. For example, one of my daughters is convinced that her lupus was triggered bu a nasty bug bite; horse fly, deer fly? Can anyone prove the connection? No way.

[Ms. Toad]

14. Where they are working now - with a lot of auto-immune illnesses

is GWAS (genome-wide association studies) to determine spikes of genetic markers which correlate with particular illnesses. Once they make the correlation, they can then start looking a the nuclear receptors which bind to those genomic regions to control genetic expression - and what ligands may be involved involved in that process.

Some of the fascinating stuff going on in the gut/liver has to do with DHA (one of the omega fatty acids), which acts as a ligand for a number of nuclear receptors found in liver and gut cells - many of the particular ligands are not yet identified, but some of the ones that are identified help explain why DHA aids in liver health and there is an intriguing (unproven) connection to the CLOCK gene. One of the frustrating problems of liver disease is sleep inversion - if DHA acts as a ligand to a nuclear receptor involved in expressing the CLOCK gene, it may provide a mechanism to help address the challenge of sleeping all day and lying awake all night.

(And, as I noted in an earlier post - I'm just delving into the cellular level research - so the above is perhaps a 1000 foot view, and I'm sure I'm missing some of the details.)

Anyway - the point of all that was to suggest that even though we don't know now, this is an area of real growth in knowledge, and we may well know more very soon.

[Ms. Toad]

16. FWIW -

Here's a recent article on Lupus - from a quick scan (1) it's pretty dense with out a background in cellular biology - and (2) it's looking at it from a disease management perspective.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2787273/pdf/ar2762.pdf

But it does talk about GWAS - which is one way to start narrowing down the field, particularly in rare diseases so they can start narrowing down the likely triggers.

[Jim__]

18. Thanks for posting this. Good information - n/t

[Rosa Luxemburg]

19. there's much more to do in this field

I'm not sure who came up with the suggestion that they should be given simultaneously?