March 1, 2019, by Brigitte Nerlich

From epigenetic landscapes to epigenetic pancakes

As somebody interested in metaphor, art and science, I was just starting to read Susan Merrill Squier’s book Epigenetic Landscapes: Drawings as metaphor (2017) (I am grateful to Cath Ennis for sending me this book), when Aleksandra Stelmach alerted me to a blog post entitled “Epigenetic Pancakes”. It was therefore inevitable that I should write a blog post on how we got from science to pseudoscience, from Waddington, famous for his epigenetic landscapes, to woo, and epigenetic pancakes.

I started to write this post as a little joke, but soon began hurtling down an Alice in Wonderland rabbit hole, past a portmonteau and ending up bumping into Humpty Dumpty! I leave it to serious historians of science to explore that rabbit hole in more detail, map its contours and point out some dangers.

Three epigenetic landscapes

Squier’s book takes inspiration from three drawings of so-called ‘epigenetic landscapes’ to study Conrad Hal Waddington’s (1905-1975) life, which straddled art and science (fascinating stuff), and the ways in which these images inspired later explorations in architecture, medicine, and feminism for example. Waddington was “a British developmental biologistpaleontologistgeneticistembryologist and philosopher who laid the foundations for systems biologyepigenetics, and evolutionary developmental biology” (Wikipedia).

Epigenetics, as Squier points out, citing Alice in Wonderland, is a portmanteau word bringing together the two words epigenesis and genetics (p. 6). “The two meanings packed into this neologism fused the old Aristotelian expression for emergence, ‘epigenesis,’ with the rising field of genetics. Waddington formulated this new field in his Organisers and Genes (1940) […]. It was also in this work that Waddington presented the first version of his epigenetic landscape, a visual metaphor for the role played by stable pathways […] in the process of [embryological] development.” (Squier, p. 6)

This first epigenetic landscape was “a work of landscape art, commissioned by Waddington from his friend John Piper” (Squier, p. 11). It represented a paradoxical river flowing from and towards mountains and through it the central epigenetic concept of canalisation. In 1942, Waddington defined epigenetics as “the branch of biology which studies the causal interactions between genes and their products, which bring the phenotype into being” (Waddington, 1942).

In 1957 Waddington used the most iconic representation of the epigenetic landscape (the ‘ball on the hill’) in his book The strategy of the genes “to represent the process of cellular decision-making during development. At various points in this dynamic visual metaphor, the cell (represented by a ball) can take specific permitted trajectories, leading to different outcomes or cell fates.” (Goldberg et al., 2007)

The third image, also published in the 1957 book, represents the “underside of the landscape, wherein its surface topography is held in place by an apparatus of guy-wires and pulleys. Waddington meant for the guy-wires to represent the actions of genes, selected over the course of evolution to establish robust species-specific patterns of tissue differentiation. Such a landscape, with contours reinforced by strict genetic controls, would ensure that embryonic development proceeds in a robust and stereotyped fashion.” (Rajagopal and Stanger, 2016)

The second landscape become a ‘meme’, while the other two were largely forgotten. Waddington’s approach to epigenetics was side-lined by various developments in molecular biology and as early as “the 1950’s the term had become, in Lederberg’s view ‘a semantic morass’ (Lederberg, 2001)” (Tronick and Hunter, 2016). It still is a mess and a muddle. Some, like David Haig (2004), are a bit more charitable and show that epigenetics “had at least two semi-independent origins during the 20th century” and thus at least two independent meanings.

If you want to know more about how Waddington’s epigenetic landscapes were used over time, you should read not only Squier’s book, but also a 2013 article she quotes by Jan Baedke. He writes: “Until the late 1960s dozens of ‘landscape approaches’ emerged that applied the visual metaphor of the EL [epigenetic landscape] […] to highly diverse phenomena – in stem cell and evolutionary biology, but also in disciplines outside of biology such as topology, developmental psychology, science, technology, and society (STS) studies and cultural anthropology.” (p. 756)

Waddington and Chinese whispers

Once epigenetics emerged as part of molecular biology, rather than embryology and developmental genetics, Waddington’s metaphorical landscapes began to be transformed, almost through a process of Chinese whispers. John Greally has dissected one example of this, but there are many more. He looked at a 2017 article entitled “Genome-Wide Epigenetic Studies in Chicken: A Review” and then starts a twitter ‘thread’ by saying: “Let me show you how words get put into the mouth of Conrad Hal Waddington. A cautionary epigenetics tale”.

Greally quotes the following definitions of epigenetics from the 2017 article: “Waddington defined an epigenetic trait in the 1950s as ‘a trait with a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence’. Nowadays, epigenetics is commonly defined as the molecular mechanisms involved in the regulation of gene expression that are reversible and heritable (by mitosis and potentially meiosis) without alteration of the DNA sequence.” The authors don’t reference Waddington, but only secondary sources!

However, as Greally stresses: “Repeat after me: Waddington’s #epigenetic landscape described how cell fates (epigenesis) could be affected by mutations (genetic). He fused the words epigenesis and genetics to create the word #epigenetic. He was not talking about heritability or memory at all.” And a later tweet in the thread says: Waddington’s #epigenetic landscape was a depiction of gene x *cell fate* (epigenesis), definitely not environment.”

Interestingly, environment and heritability have become the focus of interest in fields like ‘environmental epigenetics’, ‘Developmental Origins of Health and Disease’, and in STS. Some researchers are especially fascinated by transgenerational epigenetic inheritance. This is, as Kevin Mitchell explains, the rather misguided idea that “molecular memories of our ancestors’ experiences affect our own behaviour and physiology.” Transgenerational epigenetic inheritance has been demonstrated in some plants and animals, but never in humans. Despite this, there are many speculations about its potential impacts on policy and healthcare.

So, how were both heritability and environment gradually foregrounded in epigenetics? Here we have to look at research carried out by David L. Nanny and Robin Holliday.

As Greally points out: ”It was later that DL Nanney used the word #epigenetic (having been told by a Greek scholar that his preferred word paragenetic was not appropriate) to refer to cellular memory, the condition of persistent homeostasis after an exposure. We took the ball from Nanney and ran with it, even turning #epigenetics into transgenerational cellular memory, and eventually back-translated epi (above/upon) genetics (DNA sequence) to refer to all transcriptional regulation.” (For a more formal history of this transformation of ‘epigenetics’, see Lappalainen and Greally, 2017)

This back-translation of epigenetics almost gets us to the pancakes…but there is a bit more history to get through.

Holliday’s contribution to epigenetics is discussed in a paper (“What do you mean, ‘Epigenetic’?”) to which Greally links in the thread: “The addition of heritability to Waddington’s original definition by Holliday was a significant change. While Waddington’s definition does not preclude the inheritance of expression states [indeed Waddington (1942a) did briefly discuss heritability in his paper “The Epigenotype”], this aspect was not a fundamental part of his concept of epigenetics. Despite the more thorough discussion of heritable expression states by Nanney and others, this was the first definition to make heritability a necessary part of epigenetics.” Haig (2004) suspects that Hollidays 1987 article “The inheritance of epigenetic defects “was the critical paper that lit the fuse for the explosion in use of ‘epigenetic’ in the 1990s”.

Nowadays, epigenetics is everywhere, from molecular biology to STS, and with this appropriation of epigenetics come various interpretations and extrapolations. It has become the study of gene expression and gene regulation and its most popular metaphor is no longer the epigenetic landscape but the epigenetic switch. It is often defined in this way: “Epigenetics, as a simplified definition, is the study of biological mechanisms that will switch genes on and off.” Now we have almost come to the pancakes. One more step.

From epigenetic whispers to epigenetic wind

Over time, between the 1940s and now, epigenetics was linked ever more closely to the external environment and it also acquired an often transgenerational memory, so to speak. Many, especially social science commentators, saw this new type of inheritance and ‘memory’ as ‘deflating’ “the role of genes as causally privileged determinants of phenotypes” (Meloni and Testa, 2014: 434), as opening ways to overcoming old-fashioned reductionist, gene-centric and determinist genetics (Squier, 2017), and as freeing people from “the mainstream view of biology as an unchangeable form of secular destiny” (Meloni, 2014).

Using Squier’s book on Waddington’s landscapes as inspiration, Meloni speculates that “a hidden genetic potential can be reactivated by environmental exposures” (stressing however that this becomes increasingly difficult at ‘each bifurcation’ in the landscape) (Meloni, 2018).

In recent years, epigenetics has expanded to embrace the study of environmental, psychological, and even nutritional exposures. There is now a whole new field of ‘environmental epigenetics’ and another, rather niche one, of ‘nutritional epigenetics’. This new addition to the ever-expanding epigenetic family has been surveyed by one of the most prominent social scientists dealing with epigenetics, Hannah Landacker, in an article entitled “Food as exposure: Nutritional epigenetics and the new metabolism”.

Landecker reproduces an image of Waddington’s epigenetic landscape that has been slightly modified by the nutritional epigeneticist Roger Waterland. We see a human-faced cloud blowing at the ball at the top of the slope and the legend underneath the figure explains that this represents “nutrition as the wind that additionally influences cells during development, adding a contemporary variation to the classic [Waddington] diagram”.

Overall, epigenetics seemed to open doors to flexibility and plasticity. As Landecker points out: “the great hope of epigenetics is the essential plasticity of the body: if the body is open to environment, then it is open to environmental intervention”. Even advertisers of alternative health products and heath advice got in on the game and proclaimed “Genoplasticity: Maximise your Being”!

And this is where the pancakes come in!

From epigenetic landscapes to epigenetic woo

Nutritional epigenetics is (probably) a respected scientific subfield of epigenetics. However, nutritional advice, especially by alternative healthcare providers, has also been infiltrated by epigenetics and not in a good way.

For example (and there are many more), in 2014 a book appeared with the title Epigenetics: The Death of the Genetic Theory of Disease Transmission. Here we read: “This nexus between nutrition and so-called genetic disease has been observed in both humans and primates, and it is the central theme of Epigenetics… Epigenetics is of vital importance to anyone who wants real knowledge about how the human body functions, and it provides a path for better health. Epigenetics dispels the dogma and misinformation propagated by medical institutions and doctors resistant to change. Epigenetics is the beginning of a new era of well-being on this planet.”

Just as some natural and many social scientists use epigenetics to challenge old genetic and genomic dogmas, so alternative health providers use epigenetics to challenge conventional medicine.

And so we finally come to the pancakes. The blog post entitled “Epigenetic pancakes” appeared on a blog maintained by a nutritionist and states: “This week on the blog we’re diving into a really awesomely inspiring topic: Epigenetics. What on earth does this have to do with pancakes? Well- the pancakes you choose to eat might just have an affect on how your genes choose to express themselves.”

Using a well-known metaphor she goes on to say: “What few of us realize is that we can change, or alter the genetic cards we’ve been dealt. We may have a certain set of cards in our hand, but we have the ability to re-regulate the DNA sequence to alter its expression. That is what epigenetic is about. Epigenetics is the ability to alter the expression of our genes by epi or outer influencing factors.” Epi is the magic word!

She has three lessons for us:

“1. The type of pancakes you eat could very well determine whether you get that hereditary disease as well as the health of your unborn children.
2. You can totally blame your parents for the gene card you’ve been dealt and the work you have to do to work against it, but you absolutely CAN NOT EVER shrug your shoulders as you eat your Big Mac and say “kidney stones, cancer, diabetes, arthritis, glaucoma, and heart attacks run in my family- it’s inevitable so I might as well enjoy this cow cocktail of a burger”.
3. We have absolutely every reason to do all we can to redefine our own genetic expression to help ensure the genetic switches responsible for diseases of degeneration and decay don’t get turned on and hopefully, don’t get passed on.”

This is the dream of gaining control over our genes through epigenetics – through life-style choices, nutrition, meditation, and so on. But, as many scientists and bloggers have pointed out: “All such claims are nonsense. All such claims are nonsense. All such claims are nonsense.”

From portmanteau to Humpty Dumpty

When epigenetic landscapes gradually turn into epigenetic pancakes, we are not only dealing with metaphorical transformation and creativity, but with Kafkaesque metamorphosis. How did we get there? I think this is partly due to not distinguishing metaphor from reality. Waddington’s metaphorical landscapes were supposed to make us think in new ways about biology, especially embryo development and genetics. They did that in spades. However, their creative potential became distorted over time, leading to a situation where epigenetics is not only what Alice in Wonderland called a portmanteau word, but also what she might have called a Humpty Dumpty word.

As Edith Heard, a renowned specialist working in the field of epigenetics, said recently, epigenetics has become “une discipline en plein boom depuis le début des années 2000 et qui fait couler beaucoup d’encre de par les espoirs, mais aussi les fantasmes, qu’elle suscite”.

Beware of paddlers of epigenetic fantasies!



Posted in epigenetics