My Brain Diary, Part 14

My Brain Diary, Part 14

And maybe, I hope, the last. Unless something miraculous happens and there are significant improvements or something terrible happens and I need more surgery. Neither case is very likely. Things are pretty well stabilized and my MRIs continue to look good.

It’s still very frustrating that my brain doesn’t work the way it did before. People see me and talk to me and say how amazing it is, they would never know I had a problem. I respond politely because their intentions are good and they can’t possibly know how much more difficult certain things are. I guess it’s a good thing that I have ADHD, because it’s taught me how to accept that I can’t change and figure out ways to compensate instead. That doesn’t mean I have to like it!

The anomia comes and goes. I’ll have days when I’ll forget most of the names of people whose faces come into my head, not be able to tell anyone what a thing I want or am looking for is called, or even identify something I’m holding in my hand verbally. But since it happens so often, I don’t get as agitated when people try to help me by suggesting words (that are often wrong) while dredging through my memory for a connection that’ll bring the word to the surface.

I’ve learned little tricks to work around my still slightly impaired sense of direction. Most of them involve planning ahead. That’s not my forte, but I try. When I don’t, I turn on navigation on my phone. I need to look at a larger picture to get a sense of relative position of everything, so even when I’ve already been somewhere I might pull out a map and spread it out so I can position the place mentally among multiple spots I’m already familiar with.

Since the last Brain Diary, I’ve been to school for Cosmetology and am waiting for my license to arrive any day (week, month. . .) I know, it doesn’t sound sciency at all. You’d be surprised, but that’s beside the point. Learning new things and performing services with my hands was not only great occupational therapy, but also gave me insight as to some particular effects I need to work around that I might not have noticed otherwise. For example, at the beginning, I would need to hold a picture of a hairstyle up to the mirror next to my mannequin head so they were both facing the same way, because I couldn’t mentally flip images. I still have to do some extra thinking sometimes, especially if I’m looking at something that’s asymmetrical, and sometimes I need to have my hands on a head at the same time as I’m looking at a picture. I also need to go very slowly right now to create symmetry, because as I go from one side to another my visual perception and body angle change unless I pay very close attention to altering my posture and directional gaze.

I simply can’t “do the same thing on the other side.” Braiding taught me this in a singularly humiliating way. I needed to find something that stayed the same no matter which hand was working because no matter how hard I tried, I couldn’t mirror what my right hand was doing with my left. If you watch me as I do it, you’ll see that I don’t hold my hands or the hair the same in both hands. The harder I try, the worse I do, and the more frustrated I get. I need to look at it almost as if it were two separate things I was doing. I described it to my fellow students as if I was trying to make a braid on two different heads, one hand for each. (Plus, I need to learn this for each different braid, and there are lots of them.) It was the first thing we learned, and the last thing I figured out. I’m still a ways from mastering it, and if I make up a stunning new design, it’ll be completely by accident!

This distorted sense of spatial relations is even worse on myself. Yeah, everyone says they have trouble doing their hair or makeup in the mirror, but I remember what that was like. It was like what I deal with now when working on someone else. Just like with the map, I need to establish points of reference that are outside myself that I can associate with one another. If the main point of reference is ON ME, that just can’t happen. I have become less inefficient at doing my own hair, but it’s still kind of comical how many different directions my comb and brush will go on different areas of my head and how many things I hit with the blow dryer that are not anywhere near my hair. My style is different every day because I can’t do it the same no matter what. I let people think it’s all creativity, but the most creative thing is figuring out how to get it to look like I did it that way on purpose. More often than not, I had an idea, tried to do it, then pulled out super strong holding products for damage control.

The other things I tried to do on myself were very useful for pinpointing specific deficits. I got it into my head that fake eyelashes would be better than mascara, and spent countless hours trying to put them on, went through three tubes of adhesive, and threw out 8 pairs of lashes and three packs of individuals before I gave it up. Towards the end, I realized that not only does my right eye not close independently without squinching it up tight, but it has weird “blind spots” where I can see colors and shapes but not “understand” what they are. I would finagle my way around getting a lash strip on my partially-open right eye, but when it came to the left, these “blind spots” made it impossible to put one on. I’d try with the left eye open enough so I could see through it, but each time my hands or wrists covered one eye or the other, my “sense of direction” would change. I’d have the strip placed perfectly, say, on the outer corner, but once I moved towards the center and one eye or the other was even partially blocked, I’d start pulling the strip in the wrong direction and sticking it to the middle of my eyelid, the tips of my lashes, or even pulling it off. It was during one of these frustrating sessions that I stopped and just covered and uncovered my eyes one at a time and realized that the world moved in different ways from one eye to the next and made more sense in the left than the right.

Makeup is a bit more symmetrical now, but that also took some training. Initially, I had to use pencils or chopsticks or other long, straight guides to make marks on my face, and even then I would end up with one side higher or lower than the other, farther out, closer together, darker or lighter. I still have to step back frequently because up close the right and left sides are perceptually disconnected. I won’t lie, there have been a lot of tears. When you’ve been doing something for 30 years with almost no thought at all and suddenly it requires slow going and meticulous attention to seemingly superfluous details, it makes you feel impaired. Even if it’s just something as silly as having to give up eyeliner because you can’t draw a single smooth line on your face anymore.

The good thing about this is that with the improved awareness of what’s doing what, I am getting better at accepting and compensating for my new set of neurological differences. They’re not going to change, or they would have by now. So here I am.

Oh, noes, GMOs!

Oh, noes, GMOs!

GMO-corn

Everyone calling vociferously for labeling GMOs on the internet seems to go silent when they are asked specific questions about why, and how much labeling they’re actually asking for. Turns out, they usually don’t know how genetic modification is done, how many different kinds of modifications there are, how much actual potential harm there is or isn’t, or, quite frankly, how digestion works. (If it worked the way some alarmists believe it does, I’m afraid we might have to turn to cannibalism!)

Labeling something “Contains GMOs” is not only uninformative and misleading, but will add an average of $500 to each American’s food bill if it were to be instituted. Also, in order for a label to be useful and valid, it would need to be much more detailed. So I would like to break it down a little more realistically.

BT TOXINS!!

Bacillus thuringiensis is applied liberally on organic crops to control pests. Catalogs that sell Bt to home gardeners describe it as “Bacillus thuringiensis (Bt) is a natural occurring, soil-borne bacteria that has been used since the 1950s for natural insect control.” (Planet Natural) and “Bt is a naturally occurring bacteria with many powerful insect-specific strains. Like other biologicals, Bts biodegrade in sunlight and may require reapplication. Bt for Caterpillars & Worms: Safe for the user and the environment, Bacillus thuringiensis v. kurstaki is a pest control mainstay for organic vegetable growers.” (Grow Organic) You would not find any food in the supermarket that would be labeled “Genetically modified with Bt,” because those crops are not used to feed people, but for animal feed and other industrial uses. You would, however, find lots of foods labeled “Sprayed with Bt,” at least if labeling were honest.

So why is it that Bt is safe and organic when sprayed in large quantities (where it drifts and affects insects that are not feeding on the crops, including some beneficial species) but suddenly becomes “Bt toxin” when it is engineered into the crop and affects only the pests that feed on the crops? The EPA has done thorough testing on Bt (http://www.epa.gov/pesticides/biopesticides/pips/regofbtcrops.htm) and assured that GM crops with the gene that produces the Bt protein are not in foods meant for human consumption, even though humans do not have the body chemistry that allows Bt to be absorbed.

Big Organic wants to have its cake and eat it, too. In order to continue using Bt itself for pest control, but demonize it as a toxin when it’s made by the plant itself, the very sites that make these statements do some unscientific speculation as to how this is so and present it as factual. Were they to admit that Bacillus thuringiensis is Bacillus thuringiensis and is harmful only to specific species (not human) that are directly exposed to it, they would not be able to continue their hypocritical campaign to use and sell it while simultaneously representing it as a life-threatening dangerous substance.

ROUNDUP READY!!

You would see “Roundup Ready,” but that would be pretty uninformative, also, because many crops that are not “Roundup Ready” are treated with Roundup, because it is an effective dessicant. For example, a wheat farmer would use it to kill and dry his entire field so that all the wheat would be usable, and would not need careful (and expensive) sorting to ensure that a few green grains wouldn’t rot an entire silo of harvested wheat. So, GMO or not, a label saying “glyphosate exposed” would be much more useful. That, however, would be a decision one should make based on environmental concerns rather than personal ones, because glyphosate is toxic to humans in such large doses that you would need to drink about three gallons of it straight to get sick.

THERE’S FISH GENES IN MY TOMATOES!!

There would also have to be a label for trans-species modification. Scientists take a gene for a trait from one species (usually another species of something that we also eat, so we’re eating that gene already, just in some other food) and insert it into another. You would need to do some serious mental gymnastics to see how this would be harmful. You would also have to start giving up a lot of foods, organic or otherwise, because this is also used to protect crops against diseases that would wipe them out. Bananas and papayas and oranges would no longer exist, or might go extinct in the future, without the modifications that allow them to resist the fungi that kill them. You might also want to check out foods that contain other foods, and perhaps stop using recipes. Your Manhattan Clam Chowder has fish genes and tomato genes. . .

THERE’S FISH GENES IN MY FISH!!

The last label would be a cross-species modification. This is when a gene for a particular trait is taken from one species and transferred to a related species – like the gene from one type of salmon that triggers larger size to a smaller sized salmon. Again, if you were to avoid foods with this label, you would need to deny yourself foods that have been cross-bred and hybridized by man for thousands of years, which would be everything we eat. It’s the same process, but accelerated and without the negative characteristics of traditional manipulation by sexual selection.

Look at what we’ve done to purebred animals – hip dysplasia in German Shepherds, seizures in Boxers and Spaniels. . .When we tried to breed a rot-resistant potato by hybridization, we ended up with a potato that was kinda poisonous. Genetic modification is working on a rot-resistant potato that won’t make you sick.

GENES FROM THE SAME PLANT!!

Golden rice was created by moving a gene that produces Vitamin A from the leaves and stem of the plant to the grain. This is a technology that may be applied to other species later on. People destroying entire crops of golden rice because it’s GMO is an example of uninformed hysteria. So we’d need a label for this at some point.

If all you want is a nice, simple label that says “Contains GMOs” so you can make buying decisions without thinking, then stick with buying things that say “GMO-Free.” The GMO labeling being proposed by the Organic Foods Industry is not designed to inform or help people make healthy decisions, but to direct buyers to their own products. If you want labels that actually give you useful information, they’re going to be on almost every item in the store, and it’s going to cost all of us. And if you really want to know what’s in your GM food, check the EPA, the ISAAA’s GM Approval Database, and consumer information from the FDA.

If you want to see why the studies being cited as proof that GMOs are dangerous are not valid evidence, here are a few links. Academics Review looks at a large selection of studies and explains what they actually found and whether those findings are accurate. The Seralini rat tumor study was so deeply flawed that even a low-impact journal retracted it out of embarassment – lots of scientific explanation and criticism is collected at David Tribe’s blog. Skeptical Raptor breaks down the information in a recent meta-analysis of 1,783 studies, including at least 600 independently funded, which found no tangible dangers and many benefits of GM crops.

(Image source Also a good article!)

Where I Go For Science

Where I Go For Science

A friend of mine asked me for a few links to science sites so she could learn a little more, so I set to copying and pasting my bookmarks for her. Now I know why I lose so much time sitting at the computer. Most of these sites are life sciences, so sorry about the lack of Chemistry and Physics and such. Here’s the list. . .

Sites in my WordPress Reader, loosely arranged by subject:

Skepticism/Critical Thinking
Science or Not?
I fucking hate pseudoscience
Edzard Ernst
Why Evolution is True
Doubtful
Violent Metaphors

Brain Stuff
Neurobollocks
Left Brain Right Brain
Mind Hacks
Neurologica Blog
Wiring the Brain
Science Over a Cuppa
Gabriela Tavares
BPS Research Digest

Medicine
Science Based Medicine
Science-Based Pharmacy
Science-Based Life
Drug Monkey

Genetics/Epigenetics
Bits of DNA
Code for Life

Vaccination/Disease
Skeptical Raptor’s blog
Shot of Prevention
The Poxes Blog

Other. . .
Inspiring Science
Double X Science
Bishop Blog

Not on wordpress:

Not Exactly Rocket Science Not only a lot of interesting articles on Biology, but a weekly roundup of interesting links. (You can also visit The Loom and Only Human from here, plus some others, but these three are my favorites.)
In The Pipeline Chemistry, but a lot of it related to Pharmaceuticals.
Skeptical Medicine A critical look at both conventional medicine and pseudoscience.
Scitable Nature Publishing Group’s educational site.

Aggregators:

Phys.org
Research Blogging
Science News (limited access for free, but still a lot of good science.)
Science Seeker (you can filter what you see by checking the subject boxes to the right.)

I’m always checking for new places, especially those that would be good for people who are not scientists, but want to understand. I’ll take suggestions for anything that’s not behind a paywall or too difficult for non-academics!

Wednesday Links

Wednesday Links

genebrain

Genetic research has a meaningful place in psychiatry, as a major study has just found out. Thomas Insel of the NIMH blogs about the impact of a study on schizophrenia and explains its importance. 108 gene regions, put together, show a significant increase in the risk for the condition, and with 37,000 affected participants and over a hundred thousand controls, this is pretty big. Thank goodness several hundred million dollars have just been donated to psychiatric research.

What is complex about complex disorders? A paper by Kevin Mitchell explains what’s involved in finding the genes that contribute to polygenic disorders like ” schizophrenia, autism, depression, asthma, epilepsy, diabetes, rheumatoid arthritis, hypertension, coronary artery disease, obesity, Crohn’s disease, Alzheimer’s and Parkinson’s disease, multiple sclerosis and probably hundreds of other conditions”. Perhaps some of these will be discovered now that more funding is available!

Is “reductionism” in behavioral genetics a boon or curse? asks if and when reductionism is a bad thing. In behavioral genetics, most scientists are looking for complex genetics behind complex traits, but they need to be careful of how their public statements can be read. The author points out, “There is a difference between methodological reductionism, a tool, and philosophical reductionism, a guiding principle.”

Evan Thompson on core theories of neurophenomenology and time-consciousness opens, “Evan Thompson, one of the authors of 1991′s The Embodied Mind: Cognitive Science and Human Experience, in 2010 authored a sweeping, dare I say even magisterial, account of how science and philosophy should understand consciousness, embodiment, evolution, and neuroscience.” The piece that follows is brief but covers a lot of ground – and makes me interested in reading the book.

An interesting neurological phenomenon is auditory pareidolia – She’s Hearing Voices talks about this symptom that’s common in certain mental disorders and how even ordinary people can be prompted to hear things that aren’t there. In schizophrenia and OCD and certain types of depression and personality disorders, this may be a magnification of what is normally an adaptive trait, IMO.

Shakespeare, Vermeer, and the “Secrets” of Genius takes the almost revolutionary position that practice does not necessarily make perfect – sometimes you have to be born with talent.

Most of Us Still Don’t Get It: Addiction Is a Learning Disorder questions the idea that we have genes or areas in our brain that predispose us to certain addictions. I read it and thought that perhaps all addiction could be characterized as a salience disorder, because it takes the position that it’s a maladaptive state of a survival trait. Just read.

Wednesday Links

Wednesday Links

Sorry this is short. Time just got away from me. Enjoy!

Why all medical professionals need to study evolution. I think everyone should, period.

Excellent piece on gender disparities in the study of Autism by Virginia Hughes. This applies to ADHD, too, and it would be nice to see something this well-written on that.

Dorothy Bishop points out the shortcomings in a neuroimaging and genetics study, and in doing so, tells you some things you should be able to find in a good one.

Continuing on the potential pitfalls of neuroimaging studies, here’s a longread that explains in detail what happens when images are taken and analyzed for study. It should give you some perspective next time you see an article claiming that scientists have found something amazing in the brain that explains a huge chunk of cognition or emotion.

There was a scientific dust-up last week in which a journal had to retract a good number of papers because of problems with peer review. Nature suggests a double-blind system. Unfortunately, this isn’t much different from what’s supposed to be happening now, and it’s flawed. Nature even makes note of the bias in the current system, so I’m wondering why they are recommending this.

Kids who are raised by same-sex parents actually do pretty well.

Biodiversity is key to our survival. Scientific American shows us maps where biodiversity exists at high levels – right in the same spots that are threatened by global warming.

I love my pets, too, but this is kind of gross:

Wednesday Links

Wednesday Links

Image courtesy of Science Blogs

A recent MIT study said that glyphosate caused nearly every disease known to man. Except it wasn’t an MIT study at all.

A researcher discusses harassment by animal rights activists and explains why animal research is needed (and how he treats his animals) in Defending Animal Research

Food is not magic, and superfoods do not prevent disease.

Vaccines are safe, according to an analysis of 67 independent papers. We know this because it’s been covered in newspapers and magazines in print and online. Here’s the paper itself.

Along the vaccine lines, it didn’t take long for the conversation at USA Today to turn to Miracle Mineral Solution (aka Miracle Mineral Supplement or just MMS) being a cure for autism. Because, of course, vaccines cause autism. (How do vaccines cause autism?) In case you don’t know, this is a solution that misguided people give their autistic children orally or rectally (the same people who complain about the trauma of getting a needle are giving their autistic kids frequent, regular enemas. . .) because they think it’s going to “fix” them.

But this stuff is industrial strength bleach, which is used to treat water that won’t be used for drinking, and to strip textiles. The FDA warns people to throw it out if they have it. Advocates of alt-med and “natural solutions” even warn you away from it – Johnathan Campbell, who believes food is medicine, does not pull any punches explaining how and why it’s dangerous. Signs of the Times, a site that’s entirely woo-friendly, has nothing good to say about it, either. Health Wyze, otherwise supportive of alternative medicine, calls it a Fraud.

So it’s not only science-based sites that decry this stuff. The Guardian warns people away, Science-Based Medicine explains why it is dangerous woo, The Thinking Person’s Guide to Autism considers this stuff even more appalling than chelation and chemical castration., and Thinking is Dangerous explains the chemistry behind MMS. James Randi Foundation informs us that if this stuff isn’t scary enough for you, you can buy MMS2, which is essentially pool shock.

Liz Ditz provides a long list of links from science sites and bloggers telling about the dangers of MMS. PLoS has some additional links.

If all this doesn’t scare you, have this lovely video:

Wednesday Links

Wednesday Links

hysteria
GMOs

The environmental benefits of genetically modified crops is explored in Conservation Tillage, Herbicide Use, and Genetically Engineered Crops in the United States: The Case of Soybeans

A piece on the claim that GMOs are under-studied, With 2000+ global studies affirming safety, GM foods among most analyzed subjects in science pretty much demonstrates that no, they are not.

Neonicotinoid pesticides are sprayed on crops, and they are bad for good insects. But they’re good for selling plants. Engineered pest resistance doesn’t get sprayed and affects only pests that attack the specific crops. Just sayin’.

Organic foods may have been sprayed with pesticides, too – and isn’t necessarily any better for you. Being free of GMOs makes no difference.

Vaccines

A friend and I were blocked from commenting on an online discussion on the terrible, horrible things that are vaccines. This is a typical technique of anti-vaxxers. A detailed description of what it means to be anti-vaccine is on Science-Based Medicine It’s from 2010, but classics never get old.

Because of a new study analyzing the actual risks of vaccination (hint – nearly none, even less compared with disease outcomes) the pro-vaccine message is finally getting the press it deserves. USA Today, The Daily Beast, Think Progress (I know, not a big anti-vaxxer magnet) The New York Times and Time. Even The Economist reminds us that we should take our medical advice from science, not celebrities.

Medicine

Viruses may be responsible for several cancers. The Big Idea That Might Beat Cancer and Cut Health-Care Costs by 80 Percent explores a virus that may trigger certain kinds. Vaccination to prevent cancer might work better than treating it after the fact, ya think?

Quadruple amputee soldier learns to adapt to life with transplanted arms.

‘Molecular movies’ will enable extraordinary gains in bioimaging, health research

Video

This is stupid, which means it made me laugh a lot.

Wednesday Links

Wednesday Links

reality check

Debunking!

In the wake of pretty much every outbreak of every vaccine-preventable disease, comments on the news articles fill up with people who still think that vaccines cause autism. One article keeps getting referred to, “22 Studies that Prove Vaccines Cause Autism.” I’m not going to link, it doesn’t need any more hits, because it already shows up on the first page of many searches on vaccines. Instead, I’m going to direct you to Liz Ditz’s excellent rebuttal.

Foodbabe proves over and over that she’s all style and no substance. The Foodentists dissect her attack on Lean Cuisine and the Grocery Manufacturers Association with many facts about GMOs that she apparently doesn’t know – or chooses to ignore.

On the topic of GMOs, Gilles-Eric Séralini’s paper linking glyphosate to tumors in rats, which was retracted last year because of methodological and statistical flaws, has been re-published in a journal with apparently less exacting standards. I’m thinking along the lines of “repeat a lie often enough and it becomes the truth.”

SFARI tells us that autism is not the only neurodevelopmental disorder that’s on the rise. The numbers may actually be a good thing, because it means that more people are getting needed treatment.

You know that study that said watching porn shrinks your brain? Well, maybe not so much. Christian Jarrett at Wired talks about the study’s many shortcomings.

Business Insider has an interesting piece on the Myers-Briggs personality test. By the way, I’m ENFP.

Sometimes things are partly true, or true but misrepresented. In those cases, we don’t need debunking, we need. . .

Critical Thinking

I got a little gut-punch here, because I hate neuroscience hype, but I also did a few little happy dances reading about optogenetics. I pick on optogenetics, but… and Moving on from optogenetic frustrations are actually not too far from the mark, though. I think it is possible to get excited about a new method without looking at it as a be-all and end-all breakthrough. . .as long as you look at the research and stay away from the media version.

Another thing that gets oversold is brain imaging. Again, cool, but not as magical as it’s portrayed sometimes. Lots of times. Virginia Hughes talks realistically about the limits and potential of neuroimaging.

A longread (28 pages) on critical thinking. I have to admit, it’s still open in another tab as I write this. Written from a legal viewpoint, as in how something would stand up in court when exposed to scrutiny, but relevant in a general sense as well.

I often take issue with people who are strict “nurturists” because they are so unspecific about what “environment” is and what it does. Genetics and epigenetics are mechanisms that are, while still being incompletely understood, more logical and straightforward than the more nebulous claims of environmental influence. Many of the people I’ve run across take a Lamarckian viewpoint, or even imagine evolution as a personal change (more akin to Pokemon evolution than anything we see in biology!) So I read Developmental Plasticity and the “Hard-Wired” Problem all the way through, and was pleasantly surprised to see a thoughtful and detailed approach to the “Nature vs. Nurture” question. I don’t know how convinced I am, but it’s more than I’ve been by anyone else presenting this argument.

Genetics/Epigenetics

If you wish to make a gene from scratch explains that, well, it’s not really as easy as that.

Cath Ennis explains how epigenetics works in two parts.

Video – Pallas Cat kittens

Somehow not as freaky when they’re kittens, and funny to see domestic cat behavior in response to the intrusion of the camera.

Wednesday Links

Wednesday Links

I’m going to try to start up with this again, because I’ve lost track of some of the neat things I’ve found. This is going to be a slightly different format, just because the easier I make it, the more likely it is that I’ll be able to keep up with it. It’s also short, because I threw it together in just a couple of days.

Brain stuff:

NIH scientists take totally tubular journey through brain cells I haven’t gotten far enough in DD#2’s Neuroscience textbook to read about microtubules, but now I think I have to. Cool stuff.

DARPA is a US government run defense program that is working on a lot of cool technology, and some of that is on the brain. There’s a lot of potential for electronic stimulation to treat mental illness in a way that is more targeted than medications. New venture aims to heal disrupted brain circuitry to treat mental illnesses looks at some of what they hope to be able to do.

MIT is doing some fascinating research at the molecular level into mental illness. Shining Light on Madness is a somewhat long article, but well worth reading to the end if you want to know what’s being tested, why, and how it’s going to be examined. h/t to Antonei B. Csoka for linking it on Twitter.

In the meantime, The Brain Initiative is finding fascinating information about how the brain works.

Pseudoscience

Lynn Stuart Parramore has an excellent article, Excuse me, is that snake oil gluten free? that explores some of the magical thinking behind the free pass we give Big Placebo, and why we need a little more skepticism.

Deepak Chopra has issued a “challenge” to, essentially, disprove every single claim he’s ever made in a single paper. Steve Novella explains it brilliantly. Easily movable goalposts included.

Video:

Learning From Research – The Discussion

Learning From Research – The Discussion

It’s been a while, and I’ve had a lot of stuff going on both in my life and in my mind, but I’m determined to finish this thing. Previous posts:

Part 1
Part 2

This is the section in which everything that was talked about before is kind of recapped and explained and, well, justified. I approached this in a much simpler format, because that’s really all it needs. My comments are bolded.

DISCUSSION

It was first demonstrated here that the fidelity of replicating methylation patterns of CGIs in the promoter regions is significantly higher than that of CGIs outside the promoter regions. (CGIs in promoter regions replicate themselves more accurately than the ones outside of promoter regions.) It was also demonstrated here that methylated genomic regions show much higher fidelity than unmethylated genomic regions. (If the genes are methylated, they tend to stay methylated, if they’re unmethylated, they can become methylated.) These showed that maintenance methylation of hemimethylated CpG sites into fully methylated CpG sites at DNA replication was highly reliable, while unmethylated CpG sites tended to be methylated by de novo methylation. (Methylation sticks.) It is well-known that exogenous DNA is exposed to a de novo methylation pressure (Doerfler et al. 2001; Bird 2002), and a similar methylation pressure seems to be working on the endogenous DNA. (Unmethylated sites are vulnerable to methylation from outside sources.) To maintain the unmethylated status of CGIs, protection mechanisms from the de novo methylation pressure seem to be necessary. (Unmethylated CGIs need something that protects them from methlyation or they’re vulnerable to it.) Since the MPERs were significantly lower in CGIs in the promoter regions than in CGIs outside the promoter regions, the presence of a protection mechanism(s) specific to the promoter regions, in addition to a mechanism(s) common to all CGIs, was indicated. (Promoter region CGIs probably have stronger protection against methylation of unmethylated regions, because they resist methylation better than non-promoter-region CGIs do.) Although the details of the mechanisms are still unknown, binding of transcriptional factors, such as Sp1, has been indicated as a promoter-specific mechanism (Han et al. 2001). (Hint, hint – this is something someone might want to look into, guys, ‘cuz our grant has been spent! Heh.)

The differential fidelities in replicating methylation patterns of CGIs in the promoter regions and those outside indicated that aberrant methylation of CGIs would occur at different rates depending upon their locations. This will be important when tumors are analyzed for the CGI methylator phenotype (CIMP), which are considered to be caused by molecular defects that allow accumulation of aberrant CGI methylations (Toyota et al. 1999). The differential fidelities shown here suggest that there are two types of CIMP, one due to a defect(s) in the protection mechanisms common to all CGIs and the other due to a defect(s) in the protection mechanisms specific to CGIs in the promoter regions. Actually, a correlation between the CIMP and the diffuse-type histology was clearly observed in gastric cancers when CGIs in the promoter regions were used for CIMP analysis (Kaneda et al. 2002b), while it was unclear when CGIs outside the promoter regions were used. (This will help us do more research that will help with cancer prediction/prevention/treatment, in case you don’t think that these findings have a worthwhile purpose of their own. When in doubt, reference cancer. For people with maybe a little less vision or curiosity. Just sayin’.)

In order for an impaired fidelity in maintaining a methylation pattern to exert any biological effect, methylation statuses of multiple CpG sites in a CGI must be altered. (One change at a single location isn’t going to make a big difference.) A significant increase of MPERs would be necessary for this, and quantitative analysis of MPERs in cells with suspected increase of MPERs is necessary. (We don’t know how many besides “more than one,” so another study would be required.) DMR of the H19 gene had a polymorphism at nt. 391 (nt. 8217; GenBank accession no.AF125183), and this served to distinguish the two alleles clearly. (This location was where we could best see what happened.) The G-allele was methylated in all of the six cultures, and the T-allele was unmethylated. The methylation patterns of the T-alleles were similar in HMEC11 and HMEC15, but were essentially variable among the six cultures. This indicated that, although the original cells in HMEC11 and HMEC15 might have had a common ancestral cell, methylation patterns in a tissue alter significantly during a human life span. (Methylation may change because of time, not necessarily because something came in and methylated stuff. No pointing at a specific environmental influence like a chemical or somesuch. Just demonstrating that it happened, and where and why it would be more or less likely to happen.)

Future clarification of what protection mechanisms are involved and how they are impaired in various diseases will contribute to understanding of aging (Ahuja et al. 1998; Issa et al. 2001) and various pathological conditions. (This is a single step in a huge process, but it puts us on a track to learning more than what we know now.)