[Cangen-L) Epigenetics

The Meaning of Epigenetics
By Joshua Lederberg


Epigenetics is the buzz word. The term was introduced by Conrad H. Waddington in
1942.1 To paraphrase an erudite epistolary exchange in Science, he is said to 
contrast
genetics with epigenetics, the study of the processes by which genotype gives 
rise to
phenotype. In 1942 we had barely any clue as to what those processes are, so
"epigenetic" had no connotation of the underlying chemical mechanism, whatever 
it was
that modulated cell differentiation.
In 1994, as cited in the same issue of Science, Robin Holliday voiced a commonly
apprehended drift in meaning, and redefined epigenetic as "Nuclear inheritance 
which
is not based on differences in DNA sequence." These two memes are freely 
circulating
and can cause muddle or mischief mainly when they recombine, namely when 
epigenetic-H
is automatically applied to epigenetic-W.

For example, epigenetic-H might be taken to imply that the developmental 
modulation of
cell phenotype is always nuclear but not sequence-related (what I will suggest 
be
called epinucleic). But there are many epigenetic-W (read developmental) 
processes
that do depend on sequence-related changes, such as cellular senescence 
following upon
telomere-shortening, or immunocyte diversification from promiscuous 
recombination and
mutagenesis. Cytoplasmic heredity is still contentious, but it has strong 
foundations
in studies of protozoa. If nuclear in epigenetic-H means chromosomal, then we 
have
innumerable exceptions in the role of mitochondria and other endocellular 
plasmids and
symbionts, which indubitably play roles in phenotypic development, sometimes 
even to
the point of its extinction, not to mention sex determination.

Conversely, genetic transmission through the germline may be subject to 
imprinting and
other epinucleic phenomena. So there are many traps for the unwary, especially 
the
presumption that epigenetic-W is never to be traced back to nucleic sequence 
changes,
the dogma of the invariance of somatic cells. That dogma greatly delayed the
formulation and acceptance of the clonal selection theory of immunity; and who 
knows
what else may be impeded by it?

In 1958, epigenetic was already a semantic morass. At a conference on somatic 
cell
variation,2 I attempted to "define a category of genetic information as being 
nucleic;
that is, depending on the sequence of nucleotides in a nucleic acid. By 
contrast,
epinucleic information is expressed in another form; that is, as an aspect of 
nucleic
acid configuration other than nucleotide sequence [e.g.,] polypeptide or 
polyamine
adjuncts to the polynucleotide. We also have extranucleic information in 
molecules or
reaction cycles not directly connected with nucleic acid. In accord with 
Ephrussi's
suggestion, we might propose that nucleic information has the pervasiveness and 
static
precision connoted by genetic, whereas the epinucleic information regulates the
manifestation of nucleic potentialities in the dynamic, temporally responsive
functioning of actual development." (I knew nothing of methylation in those 
days; it
would be prototypically epinucleic.)

This neology of nucleic, epinucleic, extranucleic, has attracted few followers, 
I
think largely because so few people had really thought through the 
distinctions. There
is much merit in Ben Johnson's caution about unbridled proliferation of terms: 
"A man
coins not a new word without some peril, and less fruit; for if it happen to be
received, the praise is but moderate; if refus'd, the scorn is assur'd." But is 
a
polysemy to be preferred, with thought-muddling as a further peril?

Joshua Lederberg is Raymond and Beverly Sackler Foundation Scholar at the 
Rockefeller
University and chairman of the Editorial Advisory Board of The Scientist.
References
1. C.H. Waddington, Endeavor, 1:18, 1942.

2. J. Lederberg, "Genetic approaches to somatic cell variation: summary 
comment,"
Journal of Cellular and Comparative Physiology, Suppl. 1, 52:383-402, 1958.

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