Multiple sclerosis and the curmudgeon trait

On the surface the story in Wired made perfect sense: Twin Study Deepens Multiple Sclerosis Mystery. It is about a new study from the National Center for Genome Resources that compared the genetic endowments of three sets of identical twins, one each of which contracted multiple sclerosis (MS), the other didn't. This was a full bore effort that wound up costing $1.5 million over a year and a half to sequence 2.8 billion base pairs in each twin, determine if they come from the mother or father and then -- and this is the amazing part -- determine the entire epigenome of the CD4 cell, one of the white cells in the immune system that plays a central part in MS. MS is thought to be an autoimmune disease where the patient aberrantly makes antibodies to his or her own nerve tissues. The epigenome consists in additional modifications to the genome that are acquired throughout life that don't involve the underlying sequence. They often involve attaching other small molecular groups, like the methyl group, onto the basic sequence without altering it. Twins have identical genomes but their epigenomes might diverge as they age and they encounter different environmental influences. So looking for the answer in the epigenome made a lot of sense. But the answer wasn't there. There was no difference in either the genomes (expected) or the epigenomes, or, for that matter, in the transcriptomes, the repertoire of what genes are actually expressed. Each twin looked the same but only one had MS.

As I say, that this surprise made sense on one level. It was a reasonable place to look. But I found another aspect of the story quite striking:

It’s still possible that some as-yet-unknown genetic factor, undetectable by even the most advanced tools, may explain the discordance in the study. However, [lead author and geneticist Stephen] Kingsmore thinks the culprit is probably an unknown environmental influence. “There must be a nongenetic factor, probably environmental,” that combines with known genetic and environmental risks, he said. (Brandon Keim, Wired)

What struck me about this was the tacit assumption that the cause of most chronic diseases would be found in our genes. This seems to be the idea that most people explains why some people smoke for a lifetime but don't get lung cancer while others don't smoke and at or smoked a half pack a day 20 years before do. Or why some people eat a steady diet of high fat junk food and live to be 100 and others eat right, exercise and take Lipitor but drop dead on the way to work. What else could the explanation be?

Genes could be part of the explanation and probably are. But if two comparable people each flip a coin and one of them gets heads and the other gets tails we don't say one of them has the "heads gene" and the other the "tails gene." Or if two reviewer read my grant proposal and one scores it high and the other low, I'm not likely to say one has the high scoring gene and the other the low scoring gene (I might be tempted to say the first is smart and the second an idiot, but not congenitally so).

No one says genes aren't important and the subject of "gene-environment interaction" has been a hot topic for years in the environmental health community. But in my fairly close-up observation, there has been a lot more attention given to the gene side than the environment side. "Gene-environment interaction" research frequently means the search for genetic susceptibility factors. If you are more susceptible to smoking-associated cancer from cigarette smoke, the best solution is not to smoke. In fact the best solution is for everyone not to smoke. Then it doesn't matter what your genes make you susceptible to. The same is true of other environmental contaminants. The problem with the idea that some people who drink contaminated water are more susceptible to getting sick from it shifts attention from where the public health focus should be: making sure the water isn't contaminated.

So I guess it's a big surprise to a lot of people they couldn't find any molecular evidence of a genetic component in this twin study and now they are grudgingly admitting that maybe there's an environmental factor. I'm a bit surprised, too. Maybe I've got the "surprise gene." I know I have the curmudgeon trait.

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People living with multiple sclerosis had many questions Wednesday about what Canada is doing to test the safety and effectiveness of an unproven surgical treatment and when it might be available in this country.

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The approach to MS that has excited so many patients was developed by Dr. Paolo Zamboni, an Italian vascular surgeon, who believes multiple sclerosis is a vascular condition, marked by blockages of veins in the neck. He claims many symptoms can be reversed with a simple but experimental surgical treatment to unblock the veins.

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From what I heard from Dr Zamboni is the success of his operation is around 45%.

Whatever it is he seems to have found something.


Revere, for a long time the default assumption (by those pushing genetic research) has been that âgenes cause everythingâ and that simply by looking at the genes, the scales will fall from our eyes and we will understand.

When the honeybee genome was sequenced, Nature asked the lead author, the scientist who put together the consortium of the couple hundred researchers that did it, âwhat was the biggest surprise about the bee's genomeâ? His said the most surprising thing was that they âdid not come up with breakthroughs in understanding social behavior of the beeâ.

All genes tell you is what protein sequences are made. It doesn't tell you the function of the protein. It doesn't tell you what the protein does in cells, what the cells do when multiple proteins interact, or what multiple cells do when they interact, or what multiple organisms do when they interact. I think it is breath taking naiveté and hubris to think that by looking at the genome you could understand emergent social properties of organisms.

I think this is a very common mindset among gene researchers. I think that most of them still think that way. I think a large part of that is due to funding pressures. Who gets the funding, the person who says we need to know the gene sequence because that is important to know, or the person who says we need to know the gene sequence because then we will understand the social behavior of bees?

The key words âcomplex genetic disordersâ has almost 20,000 hits on PubMed. I don't think there is such a thing as a âcomplex genetic disorderâ. If there were such things they should be very rare, not very common. In terms of the frequency of gene caused disorders, I would expect single gene disorders to be the most common, followed by two gene, followed by three gene, and so on. This is what is observed; until you get to what are called âcomplex genetic disordersâ which are very common and involve many genes, with no single gene accounting for more than a few percent of the âproblemâ.

Why are there lots of single gene diseases, far fewer two gene disorders, fewer still three gene disorders and then a gigantic gulf until there are lots and lots of complex genetic disorders of many genes? The reason is because there really are not any so-called complex genetic disorders. They are not genetic at all.

Aren't there more incidences of MS in cooler climates? Seems like I read somewhere there are more cases in the Upper Midwest compared to the South. That would certainly be an environmental factor.

Very nice article.

By Faried Banimahd (not verified) on 30 Apr 2010 #permalink

The locality factor can fit a genetic model, of the "susceptbility plus environment" sort: the environmental factor might have to do with vitamin D, for example. (We know it's not 100% genetic, or the identical twin correlations would be a lot closer to 100%.)

Years ago, I saw a suggestion that locality was a proxy for ancestry, i.e., that the people who had the genes for susceptibility settled far from the equator. I think that one's been refuted, though.

I noted the drift of Scandinavian/Germanic/UK ancestry in the Canadian/US and Euro distributions of cases. When we were primarily agrarian, populations migrated to similar climes so that their agriculture and husbandry knowledge would remain useful. The southwest clusters might be due to retirement colonies.

Not sure that vitamin D would account for the 'west lake' clusters in the Great Lakes region, unless there is greater cloud cover west lake.

Is the spirochet theory discounted?

Thank you, great post!

The basic issue that I see is research bias - as complex as they are, genetic phenomena are still probably a lot easier to measure than environmental factors, hence more likely to produce publishable data, attract more funding etc etc.

In other words, if you don't look, you can't find. Whether it's because you don't know what to look for or how to measure it or whatever, the end result is we still don't know the answers.

Great post. As someone with MS I've done a fair amount of research plumbing to try and figure out why I, of all the generations of my family, should be so blessed, and it strikes me we may be looking at more than one disease, grouped under the same symptomatology. As researchers tease out genetics and environmental things and the whole CCSVI thing (which neglects to explain the geographic distribution and so remains puzzling to me), as well as infectious causes, I'm sure we'll find that there are at least three kinds of MS that lead to the very different clinical outcomes.
Still, my kids will be relieved to hear about the genetic non-link..
Re: the curmudgeon like - my observation after years of nursing is that the curmudgeons live longer and more vibrant lives than those who smile all the time. So curmudge on!

By Dorothyanne Brown (not verified) on 30 Apr 2010 #permalink

And if it's not genes, it's some personal habit or choice, like smoking or diet. Or personally controllable environmental factors. It seems like no one wants to talk about the industrial pollution that raises everyone's risks, even as only some are affected.

MS has been described loosely as "epidemic" in Slovenia, i.e., the medical community has seen a huge increase in cases over the past 20 years. I have the Primary Progressive(PPMS) variety and have spent a lot of time reading about the disease/condition. One study that impressed me came out of the Netherlands some years ago. Researchers decided to examine the effect of stress on the development of MS. The study was done over many years and involved thousands of people. Stress was defined as "losing a child under the age of 18". The study found that those who were stressed had a 50% greater chance of developing MS. (Unfortunately, I cannot offer you a connection to this article. A cursory search just now on Google did not turn it up.) This could help explain the "explosion" of cases in this small country.

20 years ago Slovenia became independent and changed from a socialist society where most of Slovenians' basic needs, i.e., food, housing, jobs, etc, were guaranteed and was then thrust into a capitalist culture with its competition and associated stresses. Unemployment hit 13%. Heroin addiction shot up and, at one point, Slovenia had a higher rate per capita of suicide among young people than Japan, usually the world leader in that grisly statistic.

Given the stresses of society in 2010, it is unsurprising that the number of cases of MS is on the rise. One more environmental factor.

Slovenia: magnitude of effect of single variable at 50% is unusually high for an 'unrecognized' etiology. Low hanging fruit get plucked early. Very similar but not at all is a Dutch study of somewhere about 70 pts, whose symptoms doubled when stress, measured by about 20 different factors, was 'high.' I.e., stress increases symptoms but is unlikely to cause dx. Otherwise the whole lot of us would have MS.

Easy, a genetic predisposition only means you have a weakness for a disease. If you put no stress on the weakness the disease will not show up. It is like the old saying about the weakest link in a chain. You will never find the weak link in the chain if you never pull on it.

Naturopathic Doctors like myself believe that there are five avenues that allow disease into our lives. One, what you bring into your body via food, water, air. Two, what is not eliminated the toxins that buildup encouraging the disease to start. Three a lack of movement and exercise cause poor blood flow encouraging toxic buildup, poor nutrition and low oxygen to cells. Four, stressful people and situations in the work place and at home. Five, a poor spiritual foundation no belief in higher power. These are the stresses that can cause one twin to put more stress on their genetic chain and end up with MS.

If you just have a genetic weakness then make sure that you place no stress on those five areas. If you already have the disease such as MS then relieve the stress by undoing what you have done. That would be change what you put into your body by giving it the best quality. Use rigorous cleansing and detoxing to expel all the toxicity you can. Exercise to move the blood bringing nutrition and oxygen to all cells. Get rid of all stressful people and situations at work and home, you are fighting for your life. Find your spiritual center and place in this universe your higher power whatever that is for you.

Cate. Sorry, I wasn't clear enough. I did not intend to say that stress causes MS. Only that it seems to be an important factor in the development of the disease/condition. My guess is there are many "triggers", MS showed up two years after I fell about 3 meters and knocked myself unconscious. I've often wondered if that fall played any role in the development of my MS.

Stress most definitely pushes many emerging diseases/conditions over the tipping point from accomdation to acute symptomotoly. I firmly believe in the stress-dyathesis model, it is a major principle in my field. But stress is not driving the MS locality clusters, or at least I cannot make a case for it, so another factor is operating.

We, as a nation, are killing ourselves and our children and our companies and our environment and . . . with unneeded stress. It's as though people just can't get enough stress. So they ramp it up yet one notch more. But why, especially when it seems very likely that stress is causing the epidemic level of chronic disease that is undermining our country?

Cate says "We, as a nation, are killing ourselves and our children and our companies and our environment and . . . with unneeded stress" and asks why. At one level, of course, that "why" has at least one clear and expected answer. Since the silent beautiful Oregon countryside where I've chosen to live now confronts invasion by industrial-strength wind-turbines, and industry-supported research claims these do not cause stressful noise/infranoise whereas actual humans living near them claim it does (not to question that one can be near them in low winds for brief periods without stress), I began researching who these "green" manufacturers are: GE, Seimens(sp?), Vesta, and (in conjunction with a California company) UTC--one of the big napalm makers during the Vietnam War and now the parent company for Blackhawk military helicopters--and a recent nice pile of monies has gone, for research into carbon-tungsten (or some other carbon-based alloy) WT blades, Dow; I'm sure Revere and some others here will remember Dow's role in Vietnam. In short, I would suggest that--again, on a socioeconomic level--a major cause of the pile-on of stress is indeed globalized monopoly capitalism. Sounds hokey and old-fashioned, but hey.