Induced Pluripotent Stem Cells: The End of the Ethical Debate

Today, two truly momentous papers were published in Science and Cell, respectively. These papers were so important that even Yahoo! News recognized their importance, and news services prefer stories about giant bugs.

These “induced pluripotent stem cells” (or iPS, as opposed to embryonic stem cells, or ES) produced by these two labs are important for a variety of reasons.

First, these cells completely end the whole debate about whether or not obtaining stem cells from the destruction of a human embryo is ethical. That’s it. It’s over. Don’t want to hear any more about it.

Assuming these cells are indeed truly pluripotent, and there is every indication they are, and if none of the caveats below are a problem, then this is it. In the papers above, researchers used several different types of human cells, ones from an adult woman’s face (a 36-year-old Caucasian woman, in Takahashi, et al,) and foreskin fibroblasts (Yu, et al,), which are cells harvested during the circumcision of newborn boys.

(You didn’t think we just threw those cells away, did you? They’re essentially fetal cells, a veritable cell culture gold mine. They’re used for many kinds of research, especially growing viruses in culture. Plus, if you grow enough of them and sew them into a wallet, and then rub the wallet, it turns into a suitcase. Sorry, old joke.)

Second, there was an additional ethical problem with ES cells, though it was considered secondary to the destruction of human life issue. To obtain human ova to perform nuclear transfer and thus produce ES cells, a woman had to undergo hormone therapy and surgery. Granted, the procedures are pretty much the same as in IVF, but ovulation-inducing fertility drugs have been linked with later ovarian cancer.

Another concern is that human ova would be come very valuable as a cure for everything from spinal cord injuries to Parkinson’s to Alzheimer’s to genetic diseases, etc. Should you pay women for this valuable resource and to chance getting ovarian cancer at a later time?

Again, these debates are now ended. These iPS cells don’t need eggs.

Third, using cells from an adult woman’s face to produce iPS cells is truly a breakthrough. This provides the proof-of-concept that an adult’s cells can be reprogrammed to pluripotency. If only fetal cells or newborn cells were possible to reprogram, this technique would be useful to correct birth defects or inborn genetic diseases but could not help diseases like Parkinson’s or cure spinal cord injuries.

Fourth, this lentivirus technique is easy. Really easy. Many, many labs use the lentivirus vectors and selection techniques described in these papers to produce stably transfected cell lines. I’ve done it. When this technique is refined and, hopefully, declared safe, labs all over the country could begin using this protocol for patients.

Nuclear transfer (the “Dolly” technique) that uses ES cells, on the other hand, is much more difficult.

There are, as always, some caveats. This technique will probably produce stem cells suitable for many kinds of research. It’s going to be a huge boon to labs.

It may not safely work for people. The four genes used are transcription factors, and their upregulation (which means when more is produced) is associated with cancer cells. Cells produced using this technique may cause cancer instead of cures. Takahashi, et al, used Oct3/4, Sox2, Klf4, and c-Myc. (As a virologist, seeing Myc in there gives me the proverbial willies, even if it is the c-Myc gene and not v-Myc.) Yu, et al, used Oct4, Sox2, Nanog, and Lin28, though Lin28 may not be necessary.

“Lentiviruses” are retroviruses. The retroviruses used to insert the four genes into the cells may damage the cells’ DNA when they integrate into the chromosomes and thus cause cancer.

Yet, the possibility of a cure may outweigh the possibility of future cancer. Women choose the increased risk of future cancer to have children by ovulation induction, and they do it often.

Think of it this way: if you had a profoundly dehabilitating disease, such as Parkinson’s, or early-onset Alzheimer’s, or a spinal cord injury, you might be given the choice between a cure (or a profound reduction in symptoms,) but the risk might be a 10% chance of cancer in the next decade.

Wouldn’t you want the choice?

TK Kenyon, author of RABID: A Novel and CALLOUS: A Novel (Apr 2008)

RABID is “[A] philosophical battle between science and religion ... with four very subtle and intriguing central characters. This is a novel quite unlike most standard commercial fare, a genre-bending story--part thriller, part literary slapdown with dialogue as the weapon of choice.” –Booklist Starred Review

Read “Why Dante Became A Priest: Communion Is A Kiss,” the prequel to RABID! You can even read it on your Amazon Kindle!

Preventing Alzheimer's Disease:

Pickle Your Brain With Booze

And other good ideas

That’s right. The best and latest research shows that the best way to avoid, slow, or delay Alzheimer’s disease and preserve your brain is to pickle it with booze, cigarettes, caffeine, ibuprofen, and the occasional fish.

I discussed the most shocking finding, that smoking is negatively correlated with getting Alzheimer’s Disease, in a previous essay. Basically, there’s some good research out there, both on the epidemiological and the molecular scale, that shows that people who smoke are less likely to get AD, that nicotine binds to one of the proteins implicated in AD and reduces its aggregation, and that nicotine exposure increases the number of nicotinic acid receptors in a smoker’s brain. Read the previous article on AD and Smoking to understand what all that means.

But now, the rest of the prissy lifestyle choices will also destroy your brain. If you’re a teetotaling, caffeine-abstaining, chocolate-avoiding, pharmaceutical-abjuring vegan, then you can kiss your brain good-bye.

If you want to keep your brain happy and healthy, first, have a drink. Both wine in particular and alcohol consumption in general decrease risk of AD. One caveat: all of these studies focused on light to moderate drinking, on the order of one to three drinks per day, especially of red wine, and with the lower number of drinks for women. Any source of alcohol seems to help, though red wine is a good source of reversterol and tannic acid, which were helpful at a molecular level in other studies.

Next, eat Indian food or a Mediterranean diet, which has lots of fish, rice or pasta, red wine, and olive oil.

The spice turmeric contains the compounds curcumin and other curcuminoids that amyloid fibrils.

Eating the Mediterranean Diet reduced chances for AD, even when the researchers controlled for cohort, age, sex, ethnicity, education, apolipoprotein E genotype, caloric intake, smoking, medical comorbidity index, and body mass index.

Get married, or at least live with someone.

Stay in school. Go to college and grad school. Increasing educational levels have long been found to delay or prevent AD. If you’re past the college age, being mentally active in a variety of ways helps reduce your chances for AD. Specifically, novelty-seeking behaviors (trying new foods, new activities or hobbies like learning chess or knitting, listening to new types of music, or reading books on new subjects) and social activities that involve the exchange of ideas (talking about politics, but not merely social activities like playing a game you already know, like canasta,) reduce your chances.

Ah, yes, here it is. Eat chocolate! The darker, the better. It has huge amounts of anti-oxidants and other psychoactive peptides. Some people have noted that, if it wasn’t so prevalently and commonly used, if chocolate had been discovered recently, the government would probably regulate it as a controlled substance. Raise a cup of cocoa to lack of government intervention!

An Advil (or other NSAID, like Aleve, or generic ibuprofen) a day keeps the neurologist away. NSAIDs like ibuprofen and naproxen (Advil and Aleve) bind to amyloid plaques in the brain and may help clear them. However, be careful about gastrointestinal problems when you take NSAIDs. They’re rough on your tummy.

Take a walk or get other exercise. Both regular physical activity specifically and not being overweight in general have been found to reduce your risk of AD.

Eat a fish every week. At least one fish a week decreases your chances of getting AD by 60%. That’s HUGE.

Drink filtered water. Even one-tenth (10%) of the EPA allowable limits of copper in drinking water affected the formation of plaques in the brains of rabbits, dogs, and a mouse with Alzheimer’s-associated genes.

Don’t eat so much. In a study of mice with human mutant Alzheimer’s-associated genes, merely reducing their food intake (calorie intake, actually, not the volume of food) greatly increased their survival and reduced the pathology in their brains. This may be somewhat associated with the positive correlation between being overweight and being more prone to AD (see above.)

Some things that make no difference: No statistically significant association was found for family history of dementia, sex, history of depression, estrogen replacement therapy, head trauma, antiperspirant or antacid use, high blood pressure, heart disease, or stroke.

To summarize, the general consensus is that some booze, especially red wine, some coffee, a fish a week, some exercise, a dab of chocolate, and doing new stuff will reduce your chances of getting Alzheimer’s Disease.

If you found this article helpful, please Digg it.

TK Kenyon

How to Prevent Alzheimer's Disease:

Light up a cigarette.

No, seriously. Light up a cigarette.

Alzheimer’s Disease (AD) is Hell. It’s pretty close to my own personal definition of a literal Hell.

I’ll do just about anything to avoid AD. Chances are, because my three living grandparents are all over 88 years old, I’m going to live a while, assuming I avoid stepping in front of busses. Recent evidence suggests that damage due to the APOE4 allele only kicks in after the age of 80. Before that, it’s just laziness (or due to other neurodegeneration.)

So I’ve been incorporating all those prim little lifestyle changes that are supposed to guarantee a long, healthy, happy life. I’ve cut down on coffee and chocolate. I’ve never smoked and rarely have a drink. I try to minimize the number and amount of painkillers and other drugs that I take. I’m a vegetarian and eat lots of pretty colors of food every day and take my multivitamin.

If I don’t live forever, it will certainly seem that way.

Here’s the joke: My heart may be in pretty decent shape, but that Baptist nun approach to life is a recipe for Alzheimer’s Disease.

That’s right. The best and latest research shows that the best way to avoid, slow, or delay Alzheimer’s disease and preserve your brain is to pickle it with booze, cigarettes, caffeine, ibuprofen, and the occasional fish. Oh, and eating your vegetables doesn’t help at all.

First of all, the biggest shocker: smoking reduces your chances of getting AD. Ref1 Ref2

Seriously, it’s true. It’s not widely publicized because it’s terribly politically incorrect.

Smoking also reduces your chance of getting Parkinson’s Disease.

Actually, to maximize your chance of avoiding AD and living a long life: smoke for a while, then stop. (Easier said than done.)

Before we go any farther, I don’t think anyone is recommending that you take up smoking. That particular device, the cigarette, has thousands of other compounds that cause heart disease, cancer, halitosis, body odor, and wrinkles. Smoking also vastly increases your chances of getting a vascular form of dementia caused by many small strokes. So, it’s really not a good idea. I don’t smoke. Never have. Never will.

I have considered the nicotine patch or gum, however.

But there’s good evidence that smoking reduces your risk of AD. The studies are pretty good, and they’re not sponsored by the tobacco companies. They have controlled for other risk factors, including the “Hardy Survivor” effect, which basically means that if smoking doesn’t kill you, nothing will. Ref1 Another study controlled for weight of the subjects, which is important because smokers generally aren’t as chubby as non-smokers, and being overweight is associated with AD. Ref2.

One theory as to why smokers are less susceptible to AD involves nicotinic acid receptors. When you smoke, your brain makes more receptors for the nicotine. Ref1. However, people who have dementia with Lewy bodies (DLB) have fewer nicotinic acid receptors. Ref2 People with AD also have fewer nicotinic acid receptors in their brains. Ref3

But can nicotine or smoking reduce your chances of getting AD?

First, some basic neuroscience. One of the most supported theories for the cause of AD (and we aren’t sure what causes AD) is a protein called beta-amyloid, also called Ab, A-beta, or bAP. (Thus, the folks who espouse this theory are called bAP-tists.)

Beta-amyloid protein occurs naturally in your brain, though no one knows what it does. The normal form is soluble, which means that it dissolves in water. Forms of beta-amyloid that are less soluble and tend to form clumps (aggregate) are thought to be more pathogenic. The forms that may be associated with AD are called Ab40 and Ab42. Ab42 is thought to be worse for your brain (more pathogenic) than Ab40.

The more pathogenic forms Ab40 and Ab42 are found in higher amounts in non-smokers’ brains than in smokers, Ref1 especially in areas of the brain that are associated with age-related dementia. Ref2. In general, higher concentrations of Ab40 and Ab42 have been found to be associated with AD.

Now can smoking reduce your chances for AD? In a mouse model of AD (and mouse models are imperfect for a whole variety of reasons, but that’s another essay,) mice who produce a mutated human gene for amyloid (that is associated with getting AD in humans) make amyloid plaques in their little mousy brains. When you feed them nicotine, they make fewer gunky amyloid plaques in their little mousy brains.

How can that happen? Well, it’s been found in humans that the chemical that nicotine turns into in your body, (called Nornicotine,) bonds to amyloid and reduces it’s gunking into plaques.

Nicotine also breaks down fibrils of amyloid, which are thought to be what the plaques are made of.

Some recent studies, however, have found that smoking increases your chances of dementia. Ref1. Ref2. Yet, the molecular evidence suggests that Ab disposition is less in smokers and in nicotine-ingesting mice. Why is that?

Well, there’s a whole host of possible reasons.

(1) Alzheimer’s Disease, like all “lifestyle” diseases, is multi-causal. Slightly changing the way you pick your subjects will drastically change your results. Different model. Different study.

(2) Many of the studies found positive links between smoking and dementia, not smoking and AD. You can’t definitively diagnose AD unless you autopsy the brain. (This is contraindicated in people who are still using their brains.) Therefore, these studies may be finding vascular dementia, which is very common and associated with smoking.

(3) The last possibility is that the beta-amyloid hypothesis of Alzheimer’s Disease is wrong, or at least the Ab42-is-bad hypothesis is wrong. This means that all the studies are correct. Smoking, therefore, increases your risk of AD while decreasing your load of Ab42-associated plaques.

One hypothesis suggests that the plaques are formed to keep the Ab42 (or a precursor, like ADDLs) from floating around. The floating Ab42 kills brain cells. Therefore, tying up the Ab42 in plaques is actually a defense mechanism. Thus, smokers have fewer defensive plaques, more floating Ab42, and more AD.