More Than Just Science I: The Challenges of Epigenetics to our Traditional Ethics

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by Shea Robison (@EpigeneticsGuy)

Part I: The Declaration of Independence

I hope that after reading the title of this post you are quite skeptical and asking yourself ‘What could epigenetics possibly have to do with the Declaration of Independence?’ By the end of this series of posts, though, you will see that the answer to this question is ‘Much more than you might think,’ though probably not how you might think.

To be clear at the outset, I am not about to propose that epigenetic events in the lives of the Founding Fathers were somehow a cause for the Declaration of Independence or anything of that sort. As discussed here and here, there are already far too many facile and misconstrued interpretations of both genetics and epigenetics, and I do not want to contribute further to the confusion about what is epigenetics.

Instead, this connection stems from the concept of personhood reflected by the language of the Declaration of Independence as a seminal statement of modern personhood, and the challenges of epigenetics to this concept of what is a person. The particular conception of personhood expressed in the Declaration of Independence, especially as it pertains to legal and political and ethical issues, is still the basis of our contemporary concept of what it means to be a person. Although well over two hundred years old, this concept of personhood to us today still feels—as stated in the Declaration itself—self-evidently true. However, as discussed here, this is not the only possible way that persons can be conceptualized and situated within their environments, nor is this particular concept of self the outcome of random processes, but rather is the product of very specific historical and cultural processes.

Given the importance of the Declaration of Independence as a seminal moment in the subsequent formation of the political and legal institutions of the United States, it represents a unique platform upon which to demonstrate the significant implications for contemporary public policies from these fundamental ethical challenges from epigenetics.  Also, the unique historical placement of the Declaration of Independence serves to indicate just how fundamental are these challenges from epigenetics.

As discussed in more depth in other posts, the mechanisms of epigenetics present a number of fundamental challenges to this historically contingent conception of personhood, particularly as challenges to the ethics derived from this definition of personhood (discussed in regards to autism and mother blaming here).  For most people the current debates over epigenetics are merely a function of differences in scientific interpretation, in particular between conventional genetics and the emerging science of epigenetics, and are therefore resolvable through scientific means; I believe that these differences in scientific interpretation actually reflect much deeper ethical commitments masquerading as scientific positions—as evidenced, for example, by the ideological uses of and reactions to epigenetics before and during the Cold War discussed here and here.  To the extent that these differences are reflective of underlying ethical commitments, these ‘scientific’ debates will not be resolvable through science at least until these underlying value judgments are acknowledged and made explicit.

Epigenetics and the self-evident truth that “all men are created equal”

These challenges of epigenetics to conventional ethics and politics are best illustrated in regards to the famous opening of the Declaration of Independence attributed to Thomas Jefferson:

We hold these truths to be self-evident, that all men are created equal, that they are endowed by their Creator with certain unalienable Rights, that among these are Life, Liberty and the pursuit of Happiness.

The most relevant clause for the purposes of this post is “that all men are created equal.” Usually this phrase is invoked to justify the extension of rights to an ever-expanding circle of claimants (i.e., if all men—now generally interpreted to mean humans—are created equal, then all those now designated as humans are therefore deserving of these unalienable rights). Instead of this usual emphasis on the definition of ‘men,’ the relevant concepts in regards to the challenges of epigenetics to our conventional ethics involve what it means to be created equal, and how this pertains to the subsequent rights to Liberty.

Thomas Jefferson did not compose these words out of thin air; rather they are a reflection of the intellectual currents of the time in which Jefferson wrote them. As discussed in previous posts, these intellectual currents themselves are the product of a long cultural history extending all the way back to the Ancient Greeks. By the time of the American Revolution, this history had produced the conception of persons born as tabula rasa (or ‘blank slates’), by which is meant that individuals are born with no prior capacities or preconceptions but rather start anew from birth, which is the root of their self-evident equality.

This idea of newborns as blank slates has its roots in Aristotle’s theories of biology and psychology as filtered through St. Thomas Aquinas’ medieval Christian theology of the soul discussed in part here, but credit for the modern incarnation of this concept is usually given to the empiricism of John Locke (1632-1704). For Locke, persons are born as “white paper, void of all characters, without any ideas,” so that all our knowledge comes only from experience. Combined with the Thomist distinction between “substances” (which exist necessarily and essentially) versus “accidents” (which accrue to substances) in regards to soul and the body,[1] this notion of a blank slate was extended to also include our physical composition so that human persons are also born free of physical influences from the environment. This mental and physical independence from preexisting circumstances is an integral aspect of the distinctly Modern view of the autonomous rational individual born with the basic identity of the human species but still free to define the content of their character.

Notably, Locke was also a significant influence on the political philosophy of the Founding Fathers.  The pivotal phrase “life, liberty and the pursuit of happiness” in the Declaration of Independence is actually a paraphrase from Locke, as are many other parts of the Declaration of Independence and other founding documents, so much so that Locke’s political philosophy is often honored as the “foundation of liberal democracy.”[2]  Importantly, Locke’s political philosophy was interwoven with his epistemology as described above, and vice versa, such that invoking one of these aspects of Locke’s thought necessarily invokes the others.  Founding Fathers like Thomas Jefferson were well aware of this relationship and embraced both the political philosophy of Locke and the biological and psychological theories of personhood upon which this political philosophy was premised.

The political implications of this proposition of humans born as blank slates were literally revolutionary: If knowledge is gained only through experience, then—regardless of the circumstances into which a person is born—no one is born with special intellectual endowments.  All people are essentially born equal, and inequality only arises as a result of preexisting social and economic conditions to which the newly born had not consented. Given this lack of consent among essentially equal persons, existing social arrangements need not be taken as given but can rather be disputed and reasoned out and agreed upon through mutual consent by the parties involved.  As the neuroscientist Steven Pinker writes in his book-length treatment of the history of the Blank Slate, this notion “undermined a hereditary royalty and aristocracy, whose members could claim no innate wisdom or merit if their minds had started out as blank as everyone else’s,”[3] which helps explain why Lockean epistemology and political philosophy were so highly regarded by the American revolutionaries.

When this concept of persons born as blank slates is combined with the very specific legal definition of persons as individuals distinct from the things and other persons around them—as expounded in Blackstone’s Commentaries on the Laws of England (1765)[4]what emerges is the prototypical independent and autonomous self of modernity.  The Commentaries have exerted a remarkable influence over the trajectory of modern Western thought coincidental with the spread of the British Empire[5]; in the United States the Commentaries have been credited with shaping “all our formative documents – the Declaration of Independence, the Constitution, the Federalist Papers and the seminal decisions of the Supreme Court,” ranking “second only to the Bible as a literary and intellectual influence on the history of American institutions.”[6]  As discussed here, Blackstone’s Commentaries represented the distillation of centuries of moral philosophy and legal reasoning specifically demarcating the bounds of personhood and locating ethical responsibility within this autonomous individual person-as-actor.

As mentioned before, the concept of equal, independent and autonomous persons indicated in the Declaration of Independence is still the basis of our contemporary ethics and jurisprudence and politics (e.g., the mantra ‘one man, one vote’ as the desiderata of political self-expression in contemporary liberal democracies).  As discussed in these other posts, because of a long common intellectual history, these philosophical assumptions about the independence and autonomy of persons also mirror many of the scientific assumptions about the independence and autonomy of genes—in particular Watson and Crick’s central ‘dogma’ of molecular biology, that information only flows out of and not back into DNA,[7] and the Weismann Doctrine, that variation cannot be inherited.[8]  As epigenetics challenges these scientific assumptions of genetics, it likewise challenges these deeply entrenched philosophical assumptions about what it means to be a person, which has significant implications for contemporary ethics and politics.  This is how epigenetics relates to the Declaration of Independence in a number of very fundamental ways.

The next post in this series will address the ethical and political challenges introduced by the research in epigenetics in the context of the concept of modern personhood as epitomized in the Declaration of Independence.  These ethical and political implications also help to explain the longstanding antipathy towards epigenetics (discussed here and here) which has only recently begun to give way as epigenetics is becoming more and more accepted as a valid and viable field of research (as demonstrated here and here).  However, if the scientific debates are ever to be resolved, then the ethical components of these challenges from epigenetics must also be recognized and addressed; otherwise the scientific debates will interminably circle around and around as unrecognized proxies for the underlying ethical positions.

I am curious to hear what you think so far. Leave your comments or questions below and I will respond.

Also, if you find these thoughts I’ve shared interesting and worthwhile, Like this post, Reblog it, or Tweet about it using the buttons below.

[1] For example, in the Summa Theologica when Aquinas writes that “We must assert that the intellectual principle which we call the human soul is incorruptible. For a thing may be corrupted in two ways—‘per se,’ and accidentally. Now it is impossible for any substance to be generated or corrupted accidentally, that is, by the generation or corruption of something else.”

[2] Steven Pinker (2002). The Blank Slate: The Modern Denial of Human Nature. New York: Penguin Books.

[3] Pinker (2002).

[4] William Blackstone (1765/2002). Commentaries on the Laws of England. Chicago: University of Chicago Press.

[5] J. Austin (1880). Lectures on Jurisprudence or the Philosophy of Positive Law. London: John Murray, Albemarle Street: 362-366.

[6] William D.Bader (1995). “Some Thoughts on Blackstone, Precedent and Originalism”. Vermont Law Review 19(5).

[7] Francis Crick (August 1970). “Central dogma of molecular biology.” Nature 227(5258): 561–3

[8] E.J. Steele (2000). “The Evidence for Lamarck.” Quadrant 364(3): 47 – ­56.

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When it Comes to Epigenetics, How Much Fun is Too Much? Comment and Reply

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by Shea Robison (@EpigeneticsGuy)

This post began as a simple reply to a comment from Alison M to this post about epigenetics and drug discovery, but suddenly bloomed into a full-fledged post of its own. Below is Alison M’s original comment in italics for purely aesthetic purposes, followed by my reply (and I think Alison is actually responding to more than one post here, including this one about epigenetics as a possible bridge between the sciences):

TBH, I don’t think that combining the fields [genomics and epigenetics], at least at this point, would be beneficial to either. Both are still in discovery, and the known mechanisms of action of genetics and epigenetics are different enough that they might not ever be appropriately combined. Epigenetics needs to be better presented, especially to the public, so that it doesn’t fall prey so much to magical thinkers – not only for the sake of understanding, but also so that its legitimacy can be embraced by other scientific fields.

In this, some researchers do themselves no favors. Even Dr. Jirtle has some articles on his site that present ideas that look more like speculation than hypotheses. These are good for getting attention, but what I see among laypeople as a result is the wrong kind of attention. Bruce-Lipton-level wrong kind of attention.

Thanks to Alison M for taking the time to post her comments.

First, I definitely appreciate her point about both fields still being in discovery mode, and how the known mechanisms of both genetics and epigenetics are possibly different enough to defy unification even in the future when they have both ‘matured’ so to speak. However, one of the questions I still have about this integration of epigenetics and genetics is ‘But why not?’ (How is that for an emotional/unscientific reply? Having said that, I think I have more than merely emotional responses to support this question)

In this post and this post I discuss the first divergence of epigenetics and genetics in the 1920s, which had both scientific and less-than-scientific components to it, and in this post and this post I discuss some of the political (i.e., non-scientific) reasons for the subsequent…stigmatization (for lack of a better word) of epigenetics until fairly recently. My question through all of these posts is what if these circumstances were different during these  pivotal times?

Just as biological evolution can take many different trajectories depending upon initial conditions and random events (e.g., killer asteroids, etc.), so can the evolution of science. Given the influence of these non-scientific influences just mentioned, it is easy to imagine alternative circumstances in which epigenetics and genetics evolved together at this relatively early stage of both their developments such that today there are no disciplinary boundaries between what we call genetics and epigenetics as Dr. Jirtle proposes. Forgive my philosophyspeak for a moment, but there are no “ontologically objective”[1] reasons that genetics and epigenetics are mutually distinct fields; in fact, there would seem to be more reasons for them being unified than being distinct fields. However, given the path dependent nature of both biological and scientific evolution as discussed here, because these fields diverged when and how they did, epigenetics now represents some pretty fundamental challenges to genetics in both methods and conclusions (e.g., transgenerational inheritance). Again, though, there is no objective reason this should be—all we know is that this is the case now.

Finally, I wholeheartedly support the suggestion that epigenetics needs to be presented better than it currently is. The core of my dissertation—soon to be made Flesh, so stay tuned—is discussion and analysis of the different narratives of epigenetics that are emerging in major media outlets. I have posted elsewhere about the impact of epigenetics in the sciences and academia relative to the mass media for public consumption, as well as about some of the current misconstruals and misinterpretations of epigenetics amongst the general public, precisely because such misconstruals bring the wrong kind of attention and distract from what epigenetics actually is and does. In my professional career—and personally, because I am just fascinated by this stuff—I am concerned with the political implications of epigenetics both in terms of policies based on epigenetics as well as the internal and external dynamics of the science of epigenetics. This is why I also think more rigorous and sound presentation of epigenetics within the scientific community and to the general public is critically important—though by no means does the careful use of terms and definitions guarantee anything, as we can all think of instances of the misappropriation of genetics despite the best efforts of geneticists, from the insipid use of genetics, such as “DNA Love Connection?”[2] to the truly scary uses, such as the eugenics movements of the early 20th century.

To this end, @EpiExperts and @EpgntxEinstein recently recommended a very cogent commentary in the form of a review of an incredibly interesting-looking book[3] on this issue of the recent popularization of epigenetics (not to mention the blog post which kicked this whole thing off). While the author of the article proposes a definition of epigenetics that is perhaps too restrictive for my tastes, I still appreciate the effort to rein in the ‘Bruce-Liptonizing’ of epigenetics as Alison M wrote in her comment (and no offense intended to Bruce Lipton, whom I do not know and who I assume is a wonderful and well-intentioned and sincere person).

In the end, although I appreciate the almost intoxicating excitement that comes from witnessing the emergence of a field of research like epigenetics, at this point more caution in the description, interpretation and popularization of epigenetics is probably better than less…but hopefully not so much caution that it takes all the fun out of it.

[1] By which is meant phenomena which are ‘observer-independent’ (from Searle, John R. The construction of social reality. Simon and Schuster, 1995: 9-10)

[2] Special thanks to @AlexisCarere for bringing this gold mine of an example of genetics gone awry to my attention

[3] Weissmann G. (2012) Epigenetics in the Age of Twitter. Bellevue Literery, New York, NY.

A Busy Couple of Days on The Nexus of Epigenetics

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by Shea Robison (@EpigeneticsGuy)

11 AM-ish

Screenshot 2014-08-19 10.57.43

Three hours later…

Screenshot 2014-08-19 13.54.21

And three hours after that…

Screenshot 2014-08-19 17.00.06

And now towards the end of the day:

Screenshot 2014-08-19 22.55.56

It has been an unbelievable day on this blog. My intention for beginning the Nexus of Epigenetics was to just have my epigenetics-related work posted in an accessible way to help me during job searches and for conferences and such. I thought perhaps a few people might stumble across what I’ve written, but I did not ever anticipate a response like the past couple of days and today. The action of today has been gratifying, as clearly there is an audience out there for this kind of thing. Thank you to everyone who has taken an interest in my work and found something they have liked.

More to come, so stay tuned.

Shea

Autism, Ethics and Epigenetics

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by Shea Robison (@EpigeneticsGuy)

In a recent post I summarize the May 2014 article “Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder.” This article details the gathering and analysis of genetic data in order to determine whether ASD has genetic or epigenetic causes. One of the causes associated with ASD is advanced maternal age (AMA), although the reasons for this association between the increased risk of ASD and AMA are unknown. What is known is that the eggs of older women are more prone to chromosomal abnormalities, so these genetic mutations have been suggested as a likely reason for this association between AMA and ASD. However, as the authors write, “age is also associated with a loss of control of epigenetic regulatory patterns that govern gene expression,” which suggests epigenetic dysregulation as a second potential mechanism.

To test whether increased risks of ASD associated with AMA are genetic or epigenetic in origin, the authors tested specific cell types from 47 individuals with ASD compared with 48 typically developing (TD) controls born to mothers of that were 35 years or older at the time of birth. Using a variety of sophisticated methods, the authors find that while the genes previously associated with ASD are still implicated in ASD, the causes of ASD associated with AMA operate through epigenetic dysregulation rather than through mutations in DNA sequences as commonly thought.

Besides the isolation of epigenetic mechanisms—and not genetic mutations—as the likely cause for the increased risk of ASD, there are a number of other aspects of the impact of epigenetics suggested by this article.

First, to test these competing hypotheses the authors utilized both genome-wide and epigenome-wide analyses on the same data. In doing so they were able to disqualify the genetic explanation for ASD and provide evidence to support an epigenetic cause. In other posts I have written about the benefits of combining genomic and epigenomic analyses. Gene sequencing processes are the preferred methods for analyzing genetic material for diagnostic and predictive purposes, but for however much these processes reveal about gene sequence they reveal nothing about the three-dimensional structure of the gene.

As discussed in more depth in this post, the physical structure of the gene can serve important regulatory functions because genes can be distant from each other in sequence but genes which are sequentially distant can actually be close to each other in three-dimensional space, which then allows them to interact in ways which are not detectable using conventional sequencing. As shown in this video, this three-dimensional structure is determined and manipulable through epigenetic mechanisms; therefore, this structure and its regulatory effects cannot be revealed through analyses of genetic sequence alone, but must include considerations of structure as well.

One practical area in which the combination of genomics and epigenetics would yield substantial results is in drug discovery, which currently relies almost exclusively on gene sequencing. As discussed in this post, epigenetic data can also be used to identify biological pathways linking a disease phenotype to an approved drug therapy. The article cited above provides yet another example of the benefits which can come from combining both genomics—for gene sequence—and epigenetics—for gene structure.

Another interesting point revealed by this article on the epigenetic dysregulation in ASD is one I also talk about in a series of posts about the challenges epigenetics pose not just to contemporary genetics but to contemporary ethics as well. Our contemporary ethics are based upon a very culturally specific and historically contingent conception of the self as distinct from the environment and from other selves. What is not well-known, though, is that the scientific concept of the modern genome as isolated from its environment has its own roots in this same cultural and historical history.

As discussed in more depth in this post, an important historical moment in this common history is the development of the concept of the ‘soul’ via Thomas Aquinas. In his conception of the soul, which eventually becomes our modern concept of the self and the genome, Aquinas relies heavily upon Aristotle’s ontogeny of form and matter. An important aspect of this historical moment is the emphasis both Aristotle and Aquinas place on substance versus accidents in the formation of things—substances are the pure expression of the combination of form (the soul) and matter; accidents are those things which accrue to substances but which are not those substances, and which therefore are not carried on by the soul after the death of the body.

The corollary of this ontogeny in genetics involves the central ‘dogma’ of molecular biology as enunciated by Francis Crick and discussed in this post which details how information only emanates out of but not back into DNA. One of the fundamental challenges of epigenetics to conventional genetics involves the inheritance of environmental ‘accidents’ which is fundamentally not allowed by Crick’s principle. While conventional genetics allows that environmental influences may affect the expression of the genes, except in rare cases these accidents (i.e., mutations) do not become part of the genome and are supposedly discarded via processes such as genomic imprinting, thereby rendering a pristine copy of the form (or soul) of the species to individuals of the next generation. However, as discussed in the article on epigenetic dysregulation and ASD above, it appears that these environmental ‘accidents’ may actually constitute an integral part of the ‘soul’ which is passed on to subsequent generations. This is one of the fundamental challenges of epigenetics to both conventional genetics and contemporary ethics.

An article recently published in Nature magazine titled “Society: Don’t Blame the Mothers” also discusses these ethical challenges from epigenetics. In this article, the authors warn that “careless discussion of epigenetic research on how early life affects health across generations could harm women.” The issue the authors have with the findings from research in epigenetics is how much emphasis is placed on women during maternity which could stigmatize women “making scapegoats of mothers, and could even increase surveillance and regulation of pregnant women.”

The main worry expressed in this article is that mothers will be held to unreasonable standards of behavior because of their close biological connection to the infant via the uterine environment. However, as discussed in epigenetics research too numerous to list, not just the environmental conditions and the choices of mothers are implicated by epigenetics but also those of fathers; and not just of the immediate parents but of grandparents, great grandparent and so on.

All this presents a prime example of the significant complications introduced into conventional ethics by epigenetics. Given our contemporary perception of self as an autonomous center of action, combined with the belief that we are all born with a genetic slate wiped clean of past environmental influences, humans are assumed to be largely responsible for their own individual choices and behaviors; this is the root of the justification we feel for punishing individuals for their actions. If humans were not autonomous, and actually owed significant aspects of their current constitution to the choices and environmental circumstances of parents and grandparents, then how justified is punishment or even stigmatization of the current individual? If such important aspects of self can be traced back and linked directly to the choices and behaviors of parents and grandparents and possibly even great-grandparents, how far back is it justifiable to locate credit or blame for contemporary outcomes? Likewise, how much regulation and even punishment of contemporary choices or behaviors is justified if these links to the health and well-being of two or three subsequent generations down the line can be scientifically demonstrated?

In other words, to truly incorporate the implications of epigenetics requires not only a fundamental reconceptualizing of many aspects of contemporary genetics and biology, but also a fundamental reconceptualization of not only just our ethics but also our political and legal systems to reflect these changes in ethics. For example, the authors of the Nature article recommend that to truly incorporate the findings from epigenetics in a reasonable manner would require acknowledging the complexities involved in human development—that just as intrauterine exposures “can raise or lower disease risk…so too can a plethora of other intertwined genetic, lifestyle, socio-economic and environmental factors that are poorly understood”—as well as recognizing the role of society as a whole in these conditions, as many of the intrauterine stressors identified as having adverse intergenerational effects are also correlated with social gradients of class, race and gender, which “points to the need for societal changes rather than individual solutions.”

These are not minor changes; these are sweeping conceptual, societal and political changes, which is an indication of just how much epigenetics challenges the basic conventions and institutions of contemporary life. As I discuss in one series of posts on the history of epigenetics and another series of posts on its implications for our ethical structures, this magnitude of the challenges of epigenetics to these fundamental social institutions is one reason for the entrenched resistance to epigenetics, though few realize it as such. Most base their objections to epigenetics on scientific grounds, but these kinds of disputes are or at least should be resolvable through scientific methods; what is interesting—as pointed out in this brief history of epigenetics—is how much effort has been and still is devoted to keeping these challenges from epigenetics from ever reaching the arena of dispute on scientific grounds. There is no real scientific basis for these efforts to exclude legitimately scientific treatments of epigenetics, which again suggests that these objections to epigenetics may have their roots in issues even deeper than science.

Am I completely off-base? Or is there something to what I’ve written? Are most of the objections to epigenetics reasonable and science-based, or might there be something more? I am curious to hear what you think. Leave your comments below and I will respond.

Also, if you find these thoughts I’ve shared interesting and worthwhile, Like this post, Reblog it, or Tweet about it using the buttons below.

Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder

Me2

by Shea Robison (@EpigeneticsGuy)

Mosaic Epigenetic Dysregulation of Ectodermal Cells in Autism Spectrum Disorder

Authors: Esther R. Berko, Masako Suzuki, Faygel Beren, et al.

Journal: PLosGenetics

Publication Date: May 29, 2014

This week’s paper deals with trying to trace the biological causes of Autism Spectrum Disorder (ASD). The authors begin by noting that one of the causes associated with ASD is the age of the mother, although the reasons for this increased risk are unknown. What is known is that the eggs of older women are more prone to chromosomal abnormalities, and so this has been suggested as a likely reason for this association between parental age and ASD. However, as the authors write, “age is also associated with a loss of control of epigenetic regulatory patterns that govern gene expression,” which suggests epigenetic dysregulation as a second potential mechanism. Thus, for this paper the authors tested both possibilities.

This effort to distinguish between genetic or epigenetic causes of ASD is the first reason for the selection of this paper as the paper of the week; the second reason is the extensive descriptions the authors give about the methods they use to test between these two mechanisms. For anyone interested in epigenetics, this discussion of the cutting edge of the technical side of epigenetics research can only be helpful.

Genetic mutations have long been proposed as the predominant cause for ASD, but the explanation of epigenetic mechanisms has recently gained credence as a cause for ASD. The authors cite three recent studies in particular which support epigenetic dysregulation as a potential mechanism in the incidence of ASD. A 2012 paper reported the discovery of distinctive chromatin features in the brains of subjects with ASD.[1] Authors of a paper published in 2013 tested blood leukocytes and found differences in DNA methylation between a monozygotic twin affected with ASD and their unaffected twin.[2] A second paper published in 2013 found differences in DNA methylation from subjects with ASD and subjects without ASD.[3]

Methods

To test whether ASD is the result of these genetic or epigenetic causes, the authors tested “homogeneous ectodermal cell types” from 47 individuals with ASD compared with 48 typically developing (TD) controls born to mothers of ≥35 years. Genome-wide tests were then performed on these cells to look for unusual chromosome numbers to test the hypothesis of genetic mutations; epigenome-wide analyses (EWASs) were used to test DNA methylation patterns in regards to the hypothesis of epigenetic dysregulation. This study, the authors note, “represents the largest epigenome-wide analysis to date testing a single cell type in ASD.”

The choice of this specific cell type served a couple of different purposes. First, the type of cell was selected because comes from the same developmental origin as brain cells. Second, the selection of this specific cell type minimizes the problem of “mixed cellularity” which has been already identified as a problem with EWASs.

The authors also addressed other such problems with EWASs, the biggest issue being “that the generally small changes in DNA methylation found may not be substantially in excess of the noise introduced by technical or biological effects influencing DNA methylation that have no relationship to the phenotype being tested.” To achieve what the authors call “the currently necessary level of stringency for EWAS studies,” the authors incorporated parallel SNP genotyping and “Surrogate Variable Analysis” (SVA) to account for these different possible sources of variability, as well as stringent pre-processing of the microarray data that was gathered and iterative use of this preprocessing data as means to focus in on only those regions of the DNA sequence that are being differentially methylated (i.e., to avoid ‘false positives’). Through these different efforts, the authors reduced the impact of these methodological issues due to “cell type and subpopulation heterogeneity, chromosomal aneuploidy, copy number variability, genetic polymorphism, age, sex and technical influences.” The authors go into considerable detail as to how these different approaches resolve these issues, so anyone interested should the relevant sections of the original paper.

Results

Using these rigorous and intensive methods to test the competing hypotheses of mutations in DNA versus epigenetic dysregulation as increasing the risk for ASD, the authors discover 15 differentially methylated regions (DMRs) at 14 genes which distinguished the ASD and TD samples. From subsequent analysis of these DMRs, the authors conclude that “DNA methylation patterns are dysregulated in ectodermal cells” in individuals with ASD, but did not find evidence of chromosomal abnormalities in those same DMRs. In their own words, the authors conclude that “of the two mechanisms we originally proposed for AMA causing ASD, covert aneuploidy occurring at detectable levels (≥20%) is not as likely to be involved as epigenetic dysregulation.”

Interestingly, though, the genes in these DMRs are those already associated with ASD, which means that instead of genetic mutations this analysis reveals “a perturbation by epigenomic dysregulation of the same networks compromised by DNA mutational mechanisms.” In other words, the genes previously associated with ASD are still implicated in ASD, but through epigenetic dysregulation rather than through mutations in DNA sequences. However, the exact pathways of this epigenetic dysregulation are still unclear. Given the results of their study, the authors suggest aging parental gametes, environmental influences during embryogenesis, or mutations of the chromatin regulatory genes implicated in ASD as the most likely possible environmental factors in this epigenetic dysregulation.

Commentary

Some additional points of interest about this study are worth mention:

First, mosaicism in this context usually refers to differences in chromosomal makeup between cell populations within the same individual (the “covert aneuploidy” just mentioned). As this was not found to be significant, the “mosaicism” in the title of this paper refers not to chromosomal differences between cell types but rather “the presence of a mosaic subpopulation of epigenetically-dysregulated, ectodermally-derived cells in subjects with ASD.”

Second, the authors note prior epigenetic studies of ASD had used mixed cell types, which may have limited the ability to detect the effects found by the authors and their use of homogeneous ectodermal cell types.

Third, the authors note that their study implicated the same gene in epigenetic dysregulation (OR2L13) as found in two previous studies associated with altered DNA methylation in individuals with ASD. This replication suggests this gene is “especially labile in ASD in terms of DNA methylation and expression.”

Fourth, the authors observe that while the epigenetic changes they observed from a cohort of subjects born to mothers with AMA may be the result of the aging of the mother’s egg, the sperm of the fathers—who are likely as old as the mothers—may also be experiencing epigenetic changes of their own which are contributing to the epigenetic dysregulation observed in their study; as this was not controlled for in their study, subsequent efforts should include such controls.

Finally, given the ages of the parents and the increased probability of mutational events, the authors allow that the observed epigenetic dysregulation may actually be a secondary effect of the mutations in the genes involved, and not actually the cause but rather a symptom of ASD. What is most interesting to me about this suggestion is the authors’ recommendation that “combined genetic and epigenetic analyses of the same subjects will be needed to test these possibilities.” I have written about the substantial benefits of this combination of epigenetics and genomics before in terms of the need to identify the impacts of both gene sequence and three-dimensional structure on gene expression in general, and as it pertains to expanding the scope of disease phenotypes which are amenable to drug discovery in particular, and this paper provides yet another concrete example of the need to combine both epigenetics and genomics.

[1] Shulha HP, Cheung I, Whittle C, Wang J, Virgil D, et al. (2012) Epigenetic signatures of autism: trimethylated H3K4 landscapes in prefrontal neurons. Arch Gen Psychiatry 69: 314-324.

[2] Wong CC, Meaburn EL, Ronald A, Price TS, Jeffries AR, et al. (2013) Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits. Mol Psychiatry.

[3] Ladd-Acosta C, Hansen KD, Briem E, Fallin MD, Kaufmann WE, et al. (2013) Common DNA methylation alterations in multiple brain regions in autism. Mol Psychiatry.

Epigenetics By Any Other Name? What Epigenetics Should and Should Not Be

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by Shea Robison (@EpigeneticsGuy)

As discussed here and here, epigenetics is rapidly emerging as a prominent focus of study in the natural and life sciences, but has not quite yet made much of an impact on public awareness. (For those unfamiliar with epigenetics, the name comes from the Greek root epi-, meaning ‘above’ or ‘over,’ which when combined with genetics denotes the study of genetic processes ‘above’ the genome.) Epigenetics is gradually making inroads into public consciousness in a number of different ways, and this blog is my contribution to this effort. However, there is a problematic trend in the popularization of epigenetics that needs to be pointed out and corrected when possible: the overbroad definition epigenetics. The danger from this trend is that it damages the legitimacy of epigenetics, dilutes the potential impact of epigenetics, and obscures the true magnitude of the implications of epigenetics for mapping the genome for diagnostic and predictive purposes and drug discovery, as well as for policy.

I have observed this problem in a number of different places before, but what prompted me to write this post was a recent article on the health and fitness site BreakingMuscle.com titled “Getting Personal: Working Out the Way Your DNA Intended” in which the guest author refers to the use of epigenetics in the creation of personalized fitness programs. To many this might seem like a trivial case that doesn’t merit much attention, but it actually demonstrates a serious problem regarding the popularization of epigenetics. Research in epigenetics has produced a number of novel insights into how our genes work and how our genes interact with our environments, many of which have direct application to health and fitness, so I was intrigued to see how the author applied epigenetics in this domain. Instead, what I found was a good demonstration of this common misunderstanding about and misuse of epigenetics.

“Getting Personal” with Epigenetics

In this article, the author recounts his interactions with a new training client who was having difficulty reaching her fitness goals following conventional exercise regimes. Her knees were also swelling and in pain, and she was getting injured. “At this juncture,” the author writes, “she was both mentally and physically exhausted. And none of her considerable efforts were showing any sign of making a difference in her body.”

In his consultation, the author promises her that by understanding her epigenetics they will create an individualized fitness plan that is truly effective. He explains to her that “epigenetics [is] a way to understand the effect of her lifestyle and environment on the way her genes were expressed in her body,” and that “the key would be to develop a personalized program and training regimen that took into account her body structure and epigenetic demands.”

The author does this first by measuring her different body parts, which are a function of her “genetic makeup.” This information (called “anthropometry”) is then used to find the best exercise regimes for her individual body type and body mechanics. Next the author writes about the role of hormones in exercise and fitness, observing that because “your shape is a function of your hormones…if you change your hormonal levels, then the shape of your body may also change.” The author then writes how activation of muscles stimulates organs and supports hormonal balance which strengthens metabolic functions and improves performance and well-being, but that doing the wrong kinds of exercises for a body type can result in inflammation, injury and fatigue.

The rest of the article details how the author applies these anthropometrics and other personal information about his client to construct a personalized exercise and diet plan for her, and of the success of this approach. The author concludes with the observation that “for Alice, an individualized fitness plan based on gene expression and epigenetics made working out rewarding both internally and externally and revealed a path to optimal well-being,” and the recommendation that “for other coaches, I encourage you too to discover the power of these scientific insights to help your clients reach their goals. And for athletes, ask your coach about epigenetics or anthropometry or seek out a coach who specializes in this approach.”

What is Epigenetics, and Why Should You Care When it Comes to Health and Fitness?

I do not dispute the merit of personalization for designing effective exercise programs, and I concede to the authors considerable expertise in regards to training clients. However, I do take issue with the author’s use of ‘epigenetics’ to describe this approach to training and fitness, which I think fatally misconstrues epigenetics and obscures much of what is truly exciting about epigenetics.

Other than a basic definition, the author does not provide much explanation of his references to epigenetics in the body of the article. However, in the comments to his article the author does distinguish between a medical or scientific definition of epigenetics which refers to specific processes which act on the genes “from the outside,” versus a health industry context which defines epigenetics “in a general sense [as] our environment or lifestyle,” which includes anything with “the potential to effect the expression of our genes, and our ultimate health” from climate to stress levels to diet and exercise, and that he is utilizing the latter.

While in a very broad sense ‘epigenetics’ by definition includes anything which affects gene expression from outside the genome, this definition is much too ambiguous to draw any useful distinctions because basically everything that isn’t specifically from the genes is therefore epigenetic (e.g., under this definition, gravity is an epigenetic factor). The author states that he intentionally uses this amorphous definition as a means to illustrate “some basic concepts to consider regarding personalized training and epigenetics [to] those fairly new to the field.” While I appreciate the intention to inform and educate those who are not yet aware of epigenetics, nothing of value is gained by extending the scope of epigenetics to include practically everything that is not specifically genetic in origin. In the end this overly ambiguous definition of epigenetics does more harm than good, and actually dilutes and obscures the more profound implications of the science of epigenetics for health and fitness and longevity.

For these reasons limiting the definition of epigenetics to those biological processes which influence or regulate gene expression is the most appropriate and useful definition, even for those new to epigenetics (see this video from the University of Utah Genetic Science Learning Center for a good visual introduction about epigenetics defined in this way). This definition of epigenetics is at once specific enough to make meaningful exclusions but yet still comprehensive enough to include most of the environmental factors mentioned by the author in the original article, especially because the biological pathways of most of these factors have already been the focus of research in epigenetics. A significant caveat, though, is that limiting epigenetics to these biological processes may disqualify many of the facile uses often called ‘epigenetic;’ still, the gains in rigor from this limitation more than offset any such ‘losses’ in description.

For example, ‘epigenetics’ as used by the author of the article that prompted this post meant “the climate we trained in (outdoor v indoor airconditioned), time of training session (based on hormone production and fluctuations), fuel/food consumed pre-, during, and post- workout (according to desired biochemical outcomes), type/intensity/frequency of exercise (according to neuro-predictors of mood/stamina/engagement), solo versus group training (determined by personality type, time of cycle, etc), and many more which all effect the way our genes express;” however, how the recommendations for diet and exercise from these factors influenced genetic expression was never addressed. In the words of a commenter to this original article, instead of a true epigenetics-based treatment this method is just “personalized training based on individual phenotypic variation,” to which the author basically agreed.

In contrast, this more rigorous definition of epigenetics allows for some truly epic health- and fitness-related discussions that extend far beyond the design of a personalized training regimen. One such epigenetic process for which evidence has been found is that the physical condition of parents at the time of conception—in particular whether they are obese or not obese—actually contributes significantly to the obesity of their children through specific biological pathways.[1] Further, additional research on both humans and animals also suggests these epigenetic effects can be passed on for up to four generations.[2] In other words, one of the real implications of epigenetics for health and fitness is that maintaining proper physical fitness may not only be important for one’s own well-being, but may also have significant health benefits (or costs) for one’s children, grandchildren and possibly great grandchildren; and this is only one example of the repercussions epigenetics.

Consider the political and philosophical implications of this evidence that the choices as to diet and exercise of an individual in one generation can extend two, three or even four generations down the line: Obesity is already recognized as a multi-billion dollar factor in rising health care costs in both developed and developing countries, and as such is becoming an increasing focus of government policy, but these policies are being discussed only in the non-epigenetic context of the effects of obesity on current individuals and society—how much more pressing does addressing obesity become if the health and well-being of future individuals and societies two or three generations distant are directly implicated? Likewise, how does this impact of present choices on future generations interact with the importance placed on individualism in political cultures like that of the United States? What is the appropriate balance between protecting the liberties of currently living individuals and safeguarding the conditions of future individuals and societies? These kinds of questions about the political implications of epigenetics are explored further in this post about epigenetics and autism and in this series of posts.

These are just some examples of the scope of the issues and the incredibly profound questions which are posed by this more rigorous definition of epigenetics, and is just one illustration of why definitions are important.

Can you think of any other examples in which a less rigorous definition of epigenetics is possibly distracting from the true magnitude of the implications of epigenetics? Or am I blowing this out of proportion?

I am curious to hear what you think. Leave your comments below and I will respond.

Also, if you find these thoughts I’ve shared interesting and worthwhile, Like this post, Reblog it, or Tweet about it using the buttons below.

[1] Martínez, J. A., Cordero, P., Campión, J., & Milagro, F. I. (2012). Interplay of early-life nutritional programming on obesity, inflammation and epigenetic outcomesProceedings of the Nutrition Society, 71(02), 276-283; Soubry, A., Schildkraut, J. M., Murtha, A., Wang, F., Huang, Z., Bernal, A., … & Hoyo, C. (2013). Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohortBMC medicine, 11(1), 29; Wu, Q., & Suzuki, M. (2006). Parental obesity and overweight affect the body‐fat accumulation in the offspring: the possible effect of a high‐fat diet through epigenetic inheritanceObesity reviews, 7(2), 201-208.

[2] Guerrero-Bosagna, C., & Skinner, M. K. (2012). Environmentally induced epigenetic transgenerational inheritance of phenotype and disease. Molecular and cellular endocrinology, 354(1), 3-8; Heijmans, B. T., Tobi, E. W., Stein, A. D., Putter, H., Blauw, G. J., Susser, E. S., … & Lumey, L. H. (2008). Persistent epigenetic differences associated with prenatal exposure to famine in humansProceedings of the National Academy of Sciences, 105(44), 17046-17049; Manikkam, M., Haque, M. M., Guerrero-Bosagna, C., Nilsson, E. E., & Skinner, M. K. (2014). Pesticide Methoxychlor Promotes the Epigenetic Transgenerational Inheritance of Adult-Onset Disease through the Female GermlinePloS one, 9(7), e102091; Manikkam, M., Tracey, R., Guerrero-Bosagna, C., & Skinner, M. K. (2013). Plastics derived endocrine disruptors (BPA, DEHP and DBP) induce epigenetic transgenerational inheritance of obesity, reproductive disease and sperm epimutationsPLoS One, 8(1), e55387; Tobi, E. W., Lumey, L. H., Talens, R. P., Kremer, D., Putter, H., Stein, A. D., … & Heijmans, B. T. (2009). DNA methylation differences after exposure to prenatal famine are common and timing-and sex-specificHuman molecular genetics, 18(21), 4046-4053.

Epigenetics and Environmental Ethics IV: Did Aristotle and Aquinas Discover DNA?

Me2

by Shea Robison (@EpigeneticsGuy)

Epigenetics and Environmental Ethics I

Epigenetics and Environmental Ethics II

Epigenetics and Environmental Ethics III

The next step in the chain of reasoning that produces both the modern self and the genome, and which also helps to explain both the scientific and non-scientific objections to epigenetics, is the elaboration of the soul in relation to the body, principally through the scholastic theology of Thomas Aquinas (AD 1225 to AD 1274).

In defining the fundamental nature of persons, Aquinas and other scholastic theologians of his time borrowed heavily from Aristotle for their definitions of basic terms such as substance, form and matter as they pertain to the soul and the body. ‘Matter’ in this Aristotelian sense should not be understood in the purely tangible sense that we understand today, but rather as “that which has the potentiality to be actualized into an existent entity,” while ‘form’ is to be understood as “the inherent principle which makes the existent entity what it is.”[1] In other words, matter is not of itself real because it cannot exist by itself without this form, and this form is only actualized through matter. ‘Substance’ is therefore neither form nor matter, but rather the combination of the two which results in a determinate individual able to exist independently.[2]

This Aristotelian typology was applied by Aquinas and the other scholastic theologians to explain the soul as the source of physical individuation which constitutes an individual person distinct from its surroundings and from other persons. In Aquinas’ own words—in language remarkably reminiscent of the description of genes in the Modern Synthesis—not only is the soul “the primary actuality of a physical bodily organism,”[3] the soul is also “a substance in the manner of a form that determines or characterizes a particular sort of body,”[4] to the extent that “it is impossible that a soul, one in species, should belong to animals of different species.”[5] In other words, “the type of essence (soul) instantiated defines what type of entity the particular entity is—it defines the natural kind to which the individual belongs,”[6] such that for Aquinas and the other scholastic theologians living substances were distinguished by their souls, which imbued them with their basic species-specific attributes.[7]

The conceptual similarities between this theological soul—which is the seat of our contemporary ethics—and scientific DNA—which is the focus of contemporary genetics—are, I hope, at least apparent at this point. These conceptual similarities between our ethics and our science, because they share the same ontological roots, are also are the locus of the challenges of epigenetics to both our contemporary ethics and genetics.

For example, if you substitute ‘DNA’ for ‘soul’ in Aquinas’ own words you get “[DNA] is the primary actuality of a physical bodily organism” and that “[DNA] is a substance…that determines or characterizes a particular sort of body,” and that “it is impossible that [DNA] one in species, should belong to animals of different species.” By way of comparison, the definition of DNA given on Nature magazine’s Scitable website is as a substance which “a human, a rose, and a bacterium have in common…along with every other organism on Earth,” but also which “ultimately determines each organism’s unique characteristics.”[8] Likewise, the entry for DNA on simple.wikipedia describes how “DNA stores information that tells the cells how to create that living thing,” and how “parts of this information that tell how to make one small part or characteristic of the living thing – red hair, or blue eyes, or a tendency to be tall – are known as genes.”[9] The only basic aspect of DNA that is not mentioned by Aristotle and Aquinas is how it is inherited; this will be addressed in subsequent posts.

That the roots of this form/matter ontogeny which at once both produced the modern self and the modern genome extend all the way back to Aristotle, prompted Max Delbrück, one of the founders of molecular biology and a Nobel laureate himself, to suggest the appropriateness of a posthumous Nobel prize for Aristotle “for the discovery of the principle of DNA.”[10] Others have also remarked upon the deep conceptual similarities between this Aristotelian and Thomist concept of the soul and DNA. Thomas Jackson, in an article published in The Guardian newspaper, observes how well our contemporary concept of genes reflect these ancient and Medieval ideas:

“Most of all, though, Aquinas would have been entranced by the idea of genes. If ever there were an Aristotle-friendly idea this is it. Genes illustrate both of Aristotle’s two fundamental principles. One is that immaterial forms do not exist in some nebulous heaven, as Plato thought, but are embedded in material things themselves. This is exactly what we find in genes.”

Jackson also observes how our modern concept of genes reflect “Aristotle’s other big idea,” which is “act and potency”:

“Everything is potentially the something else that it is already ordained to be. Bronze becomes statues, not primroses, live humans become dead ones, not alarm clocks. The whole essence of genes is that they are potentially the actual things that they already in some essential sense are. Genes are potentially phenotypes and phenotypes are activated genes.”

Jackson does not pursue the implications of this congruence between this theological concept of the soul and the scientific conception of genes, but the molecular biologist and bioethicist Alex Mauron does in an article in Science titled “Is the Genome the Secular Equivalent of the Soul?” In this article Mauron writes:

“With the complete human genome sequence now at hand the notion that our genome is synonymous with our humanness is gaining strength. This view is a kind of “genomic metaphysics”: the genome is viewed as the core of our nature, determining both our individuality and our species identity. According to this view, the genome is seen as the true essence of human nature, with external influences considered as accidental events…Part of the prima facie plausibility of our genome as the definition of our humanness comes from the blending of ideas of nature, stability, immutability, and genes – if a trait is in the genes, there is nothing that can be done about it.”[11]

With these last observations of Mauron, we are getting closer to explaining—at least in part—the roots of the antagonism against epigenetics often observed from geneticists, as well as the implications of epigenetics for environmental ethics. There are a couple of other important coincidences between this theology of souls and the science of genes which are relevant to the challenges presented by epigenetics which will be discussed in more depth in the next post in this series.

One coincidence mentioned by Mauron is the emphasis both Aristotle and Aquinas place on substance versus accidents in the formation of things, and its corollary in genetics of Crick’s central ‘dogma’ of molecular biology which details how information emanates out of but not back into DNA. The other coincidence is the idea of souls as essences which precede and endure after the dissolution of the individual body, which has its genetic corollary in the transmission of the genome through inheritance.

For now it is enough to say that one of the fundamental challenges of epigenetics to conventional genetics involves the inheritance of environmental ‘accidents.’ While conventional genetics allows that environmental influences may affect the expression of the genome, these accidents are supposedly discarded via processes such as genomic imprinting, rendering a pristine copy of the form or soul of the species to the next generation. Research in epigenetics, though, demonstrates that in certain contexts these accidental influences are not erased and are actually passed on to subsequent generations—in Thomist/Aristotelian terms, the pure form of the soul becomes accidental, which cannot be within the ontological framework erected to support this notion of the soul; in genetic terms, traits acquired during the life of an organism are inherited, which within the ontological framework erected around modern genetics also cannot be. In both cases, substantial changes are required to incorporate this new evidence from epigenetics.

Is there substance to these historical connections I am drawing between the development of this ‘self’ as the seat or our ethics and the genome and genetics? Or is this just historical happenstance? What further support is needed to validate this connection? What do you think?

I am curious to hear what you think so far. Leave your comments below and I will respond.

Also, if you find these thoughts I’ve shared interesting and worthwhile, Like this post, Reblog it, or Tweet about it using the buttons below.

[1] J.P. Moreland and Stan Wallace, “Aquinas versus Locke and Descartes on the Human Person and End-of-Life Ethics,” International Philosophical Quarterly (Vol. Xxxv, No. 3 Issue No. 139 Sep. 1995).

[2] Aristotle. Metaphysics: 1029a28

[3] Thomas Aquinas, Commentary on Aristotle’s De Anima, trans. K. Foster et al (London: Kegan Paul, 1951), II.1. 233.

[4] Ibid. II.1. 221

[5] Thomas Aquinas. The Summa Theologica of St. Thomas Aquinas, trans. Fathers of the English Dominican Province (New York: Benziger Bros. 1981), I.76.2.

[6] J.P. Moreland and Stan Wallace, “Aquinas versus Locke and Descartes on the Human Person and End-of-Life Ethics,” International Philosophical Quarterly (Vol. Xxxv, No. 3 Issue No. 139 Sep. 1995).

[7] Mauron, A. “Is the Genome the Secular Equivalent of the Soul?” Science 291.5505 (2001): 831-832.

[8] http://www.nature.com/scitable/topicpage/DNA-Is-a-Structure-that-Encodes-Information-6493050

[9] http://simple.wikipedia.org/wiki/Genetics#DNA

[10] Delbruck, M. “Aristotle-totle-totle.” Of Microbes and Life. Ed. J. Monod and E. Borek. New York: Columbia University Press, 1971. 50-55

[11] Mauron, A. “Is the Genome the Secular Equivalent of the Soul?” Science 291.5505 (2001): 831-832.