The term “epigenetics” denotes control over the expression of genes in ways that are “above” or “in addition to” genetics itself. At the molecular level, it involves the addition of chemical markers to the DNA itself or to the histone proteins around which DNA is wrapped. The markers inactivate specific genes. More conceptually, we need epigenetics to explain, for example, that of two genetically identical twins, one may suffer autism or schizophrenia while the other does not.

As Adrian Bird of the University of Edinburgh recently noted in New Scientist, most definitions of “epigenetics” mention heritable changes within a cell that do not result from changes in DNA sequence, although the term actually encompasses “a vast array of molecular mechanisms that affect the activity of genes” (New Scientist, 217[2898]: i-viii, 5 January 2013).

The matter of whether genes are “expressed” or “silenced” by epigenetic activity, of course, has untold implications in many aspects of human physiology and health, including embryonic development and, later, susceptibility to disease—notably, some forms of cancer. Although much of epigenetic research has focused on cancer, recent years have seen an expansion into other areas of investigation, not only in disease but in behavioral or psychiatric manifestations of epigenetic influence passing through generations.

In all, epigenetics represents another reminder of how the ever-increasing knowledge of the genome has only underscored the daunting complexity of the biochemical and environmental factors at play in gene regulation and expression, not to mention the challenge of translating that knowledge into therapeutic interventions.

ScienceWatch first examined epigenetics as a Special Topic in 2009, based on a selection of pertinent papers indexed by Thomson Reuters between 1998 and 2008.

For the present survey, ScienceWatch decided on a deeper and more retrospective approach: 20 years of papers, published between 1992 and 2011. And, beyond searching for permutations of the term “epigenet*,” this study employed a detailed list of relevant keywords in an effort to capture the range of processes and agents involved in epigenetics. Such terms included “DNA methyl*,” “H3 lysine*,” “posttranslational modif*,” among many others. (See the “Methodology” tab below.)

The resulting sample consisted of more than 100,000 papers. From this selection, ScienceWatch identified the prominent players in epigenetics research over the last two decades. The accompanying tables feature highly cited and prolific authors, institutions, nations, and journals, along with a selection of most-cited papers. (To view this material, please see the designated tabs above, marked “Authors,” “Institutions,” “Papers,” etc.)

One measure is telling in itself: the graph showing the annual number of epigenetics papers indexed by Thomson Reuters over the 20-year period, illustrating an eight-fold increase from just over 1,000 papers in 1992 to more than 8,500 in 2011.

Following on this steady rise, epigenetics as a research field will undoubtedly get a further boost from the 2012 Nobel Prize in Physiology or Medicine, awarded to John B. Gurdon and Shinya Yamanaka. Gurdon showed that an adult frog nucleus contains all the genetic information needed to develop into a mature frog. Yamanaka discovered that just four genes could reprogram an adult skin cell into a pluripotent stem cell, capable of differentiating into all the specialized cell lines of an adult mouse. Both were effectively reversing a lifetime of epigenetic modifications to the cell.

When ScienceWatch last looked at epigenetics in 2009, a major research focus was the role of epigenetics in cancer and the mechanisms of DNA methylation, which linked environmental carcinogens to tumor formation. A fresh look at papers published since then reveals that many of the same topics remain of interest, but with additional areas coming to the fore. One highly cited paper, for example, comes from a group of researchers at McGill University in Montreal, Canada, who show that the altered response to stress of abused children is the result of epigenetic modifications to a specific glucocorticoid receptor molecule. The changes show up in brain tissue from suicides who were victims of child abuse, but not in suicides who were not abused or controls. (P.O. McGowan, et al., “Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse,” Nature Neuroscience, 12(3): 342-8, 2009; currently cited 473 times in Web of Science.)

This research, linking epigenetic events to observable changes in behavior, is a prominent aspect of more recent research. The effects of malnutrition during pregnancy, for example, are seen not only in the children of malnourished mothers, but in their grandchildren, too, and possibly beyond. Highly cited in nutrition and epigenetics is a paper by Sir Peter Gluckman, University of Auckland in New Zealand, and colleagues, reviewing epigenesis and chronic non-communicable diseases. It is a mismatch of conditions between early and late environments that seems to be the problem. Children of malnourished mothers faced with limited food in later life seem to do okay. Those who have an abundance of food develop cardiovascular and metabolic diseases. Epigenetic control is thus adaptive. (P.D. Gluckman, et al., “Epigenetic mechanisms that underpin metabolic and cardiovascular diseases,” Nature Reviews Endocrinology, 5(7): 401-8, 2009.)

Autoimmune diseases, too, are being explored through an epigenetic lens. A review by Anura Hewagama and Bruce Richardson, of the University of Michigan, investigates the ways in which environmental factors interact with specific predisposing genetic elements to trigger diseases such as lupus, multiple sclerosis and rheumatoid arthritis (A. Hewagama, et al., “The genetics and epigenetics of autoimmune diseases,” Journal of Autoimmunity, 33[1]: 3–11, 2009; 92 citations.)

The modern blossoming of epigenetics—from molecular mechanisms to effects on the organism as a whole—is a splendid vindication of Conrad Waddington’s original (1942) definition of the subject as “the branch of biology which studies the causal interactions between genes and their products, which bring the phenotype into being” (C.H. Waddington, Endeavour, 1, 18–20, 1942.) Waddington’s “epigenetic landscape” imagines the organism as a ball poised at the top of a hill, free to roll down a series of valleys to the final phenotype below. The landscape as a whole represents the genome of the organism, and as the organism develops it traces a route through the valleys. Its route is conditioned by epigenetic changes, the ridges between the valleys representing successive constraints. Gurdon and Yamanaka showed how the ball can be pushed back up to the top of the valley, where all things permitted by the genome are once again possible. Modern epigenetic research is determining the underlying orogenic forces, which throw up the ridges that guide the organism’s development and, in some cases, finding ways to kick the ball out of one valley and into an adjacent one that may result in a longer or smoother journey through life.