Epigenetics. You keep using that word. I do not think it means what you think it means.

Epigenetics. You keep using that word. I do not think it means what you think it means.

I realize I overuse that little joke, but I can't help but think that virtually every time I see advocates of so-called "complementary and alternative medicine" (CAM) or, as it's known more commonly now, "integrative medicine" discussing epigenetics. All you have to do to view mass quantities of misinterpretation of the science of epigenetics is to type the word into the "search" box of a website like Mercola.com or NaturalNews.com, and you'll be treated to large numbers of articles touting the latest discoveries in epigenetics and using them as "evidence" of "mind over matter" and that you can "reprogram your genes." It all sounds very "science-y" and impressive, but is it true?

Would that it were that easy!

You might recall that last year I discussed a particularly silly article by Joe Mercola entitled How your thoughts can cause or cure cancer, in which Mercola proclaims that "your mind can create or cure disease." If you've been following the hot fashions and trends in quackery, you'll know that quacks are very good at leaping on the latest bandwagons of science and twisting them to their own ends. The worst part of this whole process is that sometimes there's a grain of truth at the heart of what they say, but it's so completely dressed up in exaggerations and pseudoscience that it's really, really hard for anyone without a solid grounding in the relevant science to recognize it. Such is the case with how purveyors of "alternative health" like Joe Mercola and Mike Adams have latched on to the concept of epigenetics.

Before we can analyze how epigenetics is being used by real scientists and abused by quacks, however, it's necessary to explain briefly what epigenetics is. To put it succinctly (I know, a difficult and rare thing for me), epigenetics is the study of heritable traits that do not depend upon the primary sequence of DNA. I happen to agree (for once) with P.Z. Myers when he laments that this definition is unsatisfactory in that it is rather vague, which is perhaps why quacks have such an easy time abusing concepts in epigenetics. As P.Z. puts it, the term "epigenetics" basically "includes everything. Gene regulation, physiological adaptation, disease responses…they all fall into the catch-all of epigenetics." Processes that are considered to be epigenetic encompass DNA methylation (in which the cell silences specific genes by attaching methyl groups to bases that make up the DNA sequence) and wrapping the primary DNA sequence around protein complexes into nucleosomes, which are made up of proteins called histones. Indeed, in eukaroytes, the whole histone-DNA complex is known as chromatin, and the "tightness" of the wrapping of the DNA into chromatin is an important mechanism by which the cell controls gene expressions, and this "tightness" can be controlled by a process known as histone acetylation, in which acetyl groups are tacked onto histones (or removed from them). Acetylation removes a positive charge on the histones, thereby decreasing its ability to interact with negatively charged phosphate groups elsewhere on the histones. The end result is that the "tightness" of the condensed (more tightly packed) histone-DNA complex relaxes into a state associated with greater levels of gene transcription. (I realize that this model has been challenged, but for purposes of this discussion it's adequate.) This process is reversed by a class of enzymes known as histone deacetylases (HDACs). In my own field of cancer HDAC inhibitors are a hot area of research as "targeted" therapies, although I must admit that I have a hard time figuring out how a drug that can affect the expressions of hundreds of genes by deacetylating their histones can be considered to be tightly "targeted." But that's just me.

I've only just touched upon a couple of the mechanisms of epigenetics, as discussing them all could easily push the length of this post beyond the epic lengths of even a typical post of mine; so I'll spare you for the moment. Suffice to say that epigenetic modifications can be viewed as mechanisms that can ensure accurate transmission of chromatin states and gene expression profiles over generations. We now recognize many epigenetic processes and mechanisms that can regulate the expression of genes, and their number seems to grow every year. It's become a hideously complex field.

The first brand of cranks to abuse epigenetics were, not surprisingly, creationists. In epigenetics and the observation that there are traits that are heritable that do not directly depend on the primary DNA sequence they saw what they thought was a "fatal flaw" in Darwin's theory of evolution. (Never mind that Darwin didn't even know what DNA was and nothing in his theory says what the mediator through which traits are passed from one generation to the next is.) Some even thought epigenetics as "proof" of Lamarckian evolution; i.e., the theory that existed before Darwin that postulated that acquired traits could be passed on to offspring. The most common example used to illustrate the Lamarckian concept of evolution is the giraffe, in which successive generations of primordial giraffes stretching their necks to reach higher branches of trees to feed on each passed on to their offspring a tendency to a slightly longer neck, so that over time this acquired trait resulted in today's giraffe's with extremely long necks. In any case, to be fair, one can hardly blame creationists for leaping on this particular concept of epigenetics as support for a form of neo-Lamarckian evolution, as several respectable scientists also argued basically the same thing, encouraging credulous journalists to label epigenetics to be the "death knell of Darwin" using breathless headlines. I even saw just such an article last week, which has the advantage of both touting arguments used to link epigenetics to CAM and arguments used linking epigenetics to the "consternation of strict Darwinists." (More on that later.) It's an argument that Jerry Coyne has refuted well on more than one occasion. In brief:

Their arguments are unconvincing for a number of reasons. Epigenetic inheritance, like methylated bits of DNA, histone modifications, and the like, constitute temporary “inheritance” that may transcend one or two generations but don’t have the permanance to effect evolutionary change. (Methylated DNA, for instance, is demethylated and reset in every generation.) Further, much epigenetic change, like methylation of DNA, is really coded for in the DNA, so what we have is simply a normal alteration of the phenotype (in this case the “phenotype” is DNA) by garden variety nucleotide mutations in the DNA. There’s nothing new here—certainly no new paradigm. And when you map adaptive evolutionary change, and see where it resides in the genome, you invariably find that it rests on changes in DNA sequence, either structural-gene mutations or nucleotide changes in miRNAs or regulatory regions. I know of not a single good case where any evolutionary change was caused by non-DNA-based inheritance.

Indeed. Moreover, epigenetic changes are not very stably heritable, rarely persisting anywhere near enough generations to be a major force in evolution.

Of course, I only dwelled on evolution briefly because (1) the same sorts of arguments are being made for epigenetic modifications as a "mechanism" through which various CAM modalities "work" and (2) evolution interests me and we don't talk about it enough in medicine. To boil it down, CAM advocates look to epigenetics as basically magic, a way that you—yes, you!—can reprogram your very own DNA (and all without Toby Alexander and the need to mess with all those messy etheric strands of DNA) and thereby heal yourself of almost anything or even render yourself basically immune to nearly every disease that plagues modern humans. Consequently, you see articles on Mercola.com and similar outlets with titles like How Your Thoughts Can Cause or Cure Cancer (through epigenetic modifications of your genome, of course, which you can supposedly control consciously!), Your Diet Could be More Important Than Your Genes, Can the theory of epigenetics be linked to Naturopathic and Alternative Medicine?, Falling for This Myth Could Give You Cancer (the "myth" being, of course, the central dogma of molecular biology in which genes make RNA, which make proteins), Epigenetics reinforces theory that positive mind states heal, Epigenetics discoveries challenge outdated medical beliefs about DNA, inheritance and gene expression, and Why Your DNA Isn’t Your Destiny. You also see videos like this interview with Bruce Lipton, one of the foremost promoters of the idea that you can do almost anything to your epigenome (and thus your health) just by thinking happy thoughts:

Can you count the number of straw men in Lipton's description of biology? Particularly amusing is how Lipton tries to argue that the central dogma of biology was never scientifically proven, which is utter nonsense. Now, I've said before that I really never liked using the word "dogma" to describe a scientific concept like the central dogma of molecular biology. In fact, I've always hated it, because it does indeed imply that what is being described is a religious concept; so it's no surprise that Lipton blathers on about how, back when he apparently still "believed in the old thinking," he was actually "teaching religion."

Of course, Lipton is a well-known crank, whose central idea seems to be a variant of The Secret, in which wanting something badly enough makes it so and that "modern science has bankrupted our souls." Basically, he questions the "Newtonian vision of the primacy of a physical, mechanical Universe"; that "genes control biology"; that evolution resulted from random genetic mutations; and that evolution is driven by the survival of the fittest. As is the case with epigenetics in evolution, there are some scientists who provide the basis for Lipton's claims in such a way that he can be off and running into the woo-sphere with claims that start out as being reasonable speculations based on the new science of epigenetics. No less a luminary than cancer biologist Robert Weinberg was, after all, quoted in an article entitled Epigenetics: How our experiences affect our offspring as saying that the evidence that epigenetics plays a major role in cancer has become "absolutely rock solid." And so it has. If it weren't, HDAC inhibitors wouldn't be viewed as such a promising new class of drugs to use to treat cancer. Some, however, take a good idea a bit too far and claim that cancer is an "epigenetic disease"; it's probably likely that it's a combination of epigenetic and genetic changes that lead to cancer and that the relative contribution of each depends on the cancer. Even so, cancers virtually all have what I like to call (using my favorite scientific term, of course) "messed up genomes" so complicated that it's no wonder we haven't cured cancer yet.

Is it any wonder that a couple of years ago, Der Spiegel did a ten page feature on epigenetics? The cover of the issue in which this feature was published touted it with a nude blonde (and oh-so-Nordic) female emerging from the water with a DNA double helix-like twist of water covering up her naughty bits, with the headline proclaiming, "The victory over the genes. Smarter, healthier, happier. How we can outwit our genome."

Then we have books like Happiness Genes: Unlock the Positive Potential Hidden in Your DNA by James D. Baird and Laurie Nadel, in which we are told, "Happiness is at your fingertips, or rather sitting in your DNA, right now! The new science of epigenetics reveals there are reserves of natural happiness within your DNA that can be controlled by you, by your emotions, beliefs and behavioral choices."

I'm not sure how epigenetics will make you happy, but I'm sure Baird and Nadel are more than happy to explain if you buy their book. Not surprisingly, naturopaths are jumping on the bandwagon, claiming that epigenetics is at the root of how naturopathy "works":

Generally speaking, if we want to express a gene and turn it into a protein, we would express certain DNA machinery (through histone proteins, promoters, regulators, etc) to make that happen, and vice versa to turn a gene off. So speaking from a naturopathic viewpoint, what we put into our bodies, the type of water that we drink, the way that we adapt to stress influences whether or not a certain gene is going to be turned on. For a more personal example, what I put into my body is going to influence my genetic code to promote or stop transcription and translation of the BRCA1 or BRCA2 genes, which could eventually result into cancer.

I would suggest that any woman with a BRCA mutation, as Ms. Plonski apparently has, who relies on diet to prevent the adverse effects of cancer-causing BRCA mutations is taking an enormous risk.

Whenever I see the hype over epigenetics (which, let's face it, is not just a quack phenomenon—it's just that the quacks take it beyond hype into magical thinking), one thing that always strikes me about it is that there is often a blending (or even confusing) of simple gene regulation compared to epigenetics. In other words, do the diet and lifestyle changes that, for example, Dean Ornish has implicated in inducing changes in gene expression profiles in prostate epithelium work through short-term gene regulatory mechanisms or through epigenetic mechanisms that persist long term? Certainly, he argues that things start happening short term; one of his favorite examples is a graph that suggests that a single high-fat meal transiently impairs endothelial function and decreases blood flow within hours. When you see typical arguments that "lifestyle" or "environment" can overcome genetics, the term "epigenetics" becomes such a broad, wastebasket term as to be meaningless. Basically, anything that changes gene expression is lumped into "epigenetics," whether those changes are in fact heritable or not. For example, in this brief blog post, we are told that food can cause or cure certain cancers. The reason:

Genes tell our bodies what to do and rebuild new cells so that we can continue to live a normal life. Our bodies have a system outside of our genes that was designed to keep our bodies running well. This system looks to turn off failing genes and activate genes needed to fight diseases. This management system is called epigenetics. We obviously need food, water, and nutrients to live. These things come from our food source. If we constantly eat bad foods we will knock the management system off-key just like putting bad fuel in our cars will eventually destroy the engine.

Yes, and no. Again, epigenetics, strictly defined, is about heritable changes in gene expression. What is being described here is any change in gene expression that can be induced by outside influences. They are not the same. Again, epigenetic changes are long term changes that are potentially heritable, and, as I pointed out above, most epigenetic changes are not passed on to offspring, certainly not to the point that they have a detectable effect on evolution. The rest is gene regulation, which is often transient but, depending on the process, can continue long term for as long as the stimulus causing the change in regulation is present. As is frequently pointed out, the quickest way to get an organ to start to return to normal is to stop doing the bad things to it that were causing it dysfunction in the first place. As P.Z. Myers put it:

In part, the root of the problem here is that we’re falling into an artificial dichotomy, that there is the gene as an enumerable, distinct character that can be plucked out and mapped as a fixed sequence of bits in a computer database, and there are all these messy cellular processes that affect what the gene does in the cell, and we try too hard to categorize these as separate. It’s a lot like the nature-nurture controversy, where the real problem is that biology doesn’t fall into these simple conceptual pigeonholes and we strain too hard to distinguish the indistinguishable. Grok the whole, people! You are the product of genes and cellular and environmental interactions.

Moreover, the straw man frequently (and gleefully) torn down by CAM advocates that doctors believe that genes are "destiny" notwithstanding, in reality, as far as I've been able to ascertain, doctors have been trying to subvert people's "genetic destiny" for a long time, perhaps even longer than we have known that there is even such a thing as genes. For example, women with BRCA mutations that produce an alarmingly high lifetime risk of developing breast and/or ovarian cancer are often advised to take Tamoxifen to lower that risk, to undergo frequent screening to try to catch such cancers early, or even to undergo bilateral mastectomies and oophorectomies to remove as much of the tissue at risk of developing cancer as possible. People with a strong family history of heart disease are regularly advised to exercise and switch to a diet that lowers their risk of progression of atherosclerosis. People with type II diabetes similarly are advised to exercise and lose weight, which can in many cases decrease the level of glucose intolerance from which they suffer, sometimes to the point where they no longer fit the diagnostic criteria for type II diabetes. None of this is new or radical. What is new is the realization of the possibility that some of the mechanisms behind these changes involve epigenetic changes. And this is all fine.

Understanding epigenetics is likely to help us to understand certain long-term chronic diseases, but it is not, as you will hear from CAM advocates, some sort of magical panacea that will overcome our genetic predispositions. Nor will it be likely to allow us to "pass the health benefits of your healthy lifestyle...to your children through epigenomes' reprogramming your DNA," as is frequently claimed, as much as one might want to do that. Moreover, the science of epigenetics is in its infancy. There are still some serious methodological problems to overcome when doing epidemiological research of the effects of epigenetic changes, as this presentation by Dr. Jonathan Mill explains, an explanation that he echoed in a commentary entitled The seven plagues of epigenetic epidemiology. The worst of the "plagues" include that we do not know what to look for or where; the technology is very imperfect; sample sizes are way too small; whatever we do it won't be enough to fully account for epigenetic differences between tissues and cells; and we might be trying to find small effect sizes using sub-optimal methods. Note the small effect sizes. Proponents of epigenetics as the heart of all "efficacy" of CAM tend to exaggerate the potential benefits. Again, remember how they claim that epigenetics can completely overcome genetics. There's really no good evidence that I'm aware of that it can.

In the end, what is most concerning about the hype of epigenetics is how it feeds into what I've referred to (ironically, of course) as the "central dogma" of CAM: Namely The Secret. I fear that epigenetics is being grafted onto such mysticism such that not only can "positive thoughts" heal, but that they induce permanent (or at least long-lasting) changes in our genome through epigenetics. Besides the obvious danger that thinking does not usually make it so, which is a dangerous delusion for patients, the embrace of epigenetics as giving us "total control" over our health also produces the flip side of The Secret, which is that if one is ill it is his fault for not doing the right things or thinking happy enough faults.