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From so simple a beginning endless forms most beautiful and most wonderful have been, and are being, evolved.
—Charles Darwin, 1859 (1)
Organized beings are reproduced, from generation to generation, with characters identical to the ones that they possessed during their first emergence.
—Louis Agassiz, 1869 (2)
If you want the correct explanation Why embryos grow into men The Alsatian begets an Alsatian The hen’s egg gives rise to a hen Why insects result from pupation Why insects grow out of a seed Then just murmur "canalization" [epigenetics] For that is the word that you need
—Barnet Woolf on C. H. Waddington’s 50th Birthday, 1955 (3)
It suddenly struck me what an important part fashion had played in the development of our science ... and it occurred to me that this would make a rather suitable subject for a female president at a Paris congress. So this is what I am going to talk about: fashion in cell biology.
—Dame Honor B. Fell: "Fashions in Science," 1960 (4)
EPIGENETIC FASHION
FOR SEVERAL SEASONS now, the runways of biological fashion have been awash in epigenetics. We define epigenetics as stable changes in cellular phenotype independent of changes in the Watson-Crick pairing of DNA bases. Since epigenetic changes can be passed to daughter cells in mitosis or meiosis, they can cross generations (5
, 6)
. Open any journal to see the latest epigenetic style. Over 5000 publications on epigenetics are listed on PubMed this year alone; the field has its own journal—Epigenetics, of course (http://www.landesbioscience.com/journals/epigenetics/); and—in keeping with current fashion—a "human epigenome project" has been launched. (http://www.epigenome.org). As Vogue might say, epigenetics is so NOW!
Experimentally, epigenetics explains imprinting and gene silencing in mammals, type-switching in yeast, and paramutation in plants. Clinically, it’s been held responsible for cancer, schizophrenia, alcoholism, and obesity. Epigenetics also explains the discordant course of disease in identical twins and is credited for cloning of Dolly the sheep (7)
. No wonder The Times of London headlined its primer on epigenetics: "How your behaviour can change your children’s DNA (8)
." Indeed, if acquired characteristics can be passed to our progeny, the unthinkable is abroad again: Emma Whitelaw noted that some of "[these new] findings raise the spectre of Lamarckism and epigenetics is now being touted as an explanation for some intergenerational effects in human populations (6)
".
But the new epigenetics is not only Lamarck vs. Darwin revisited. Our interest in the inheritance of methylated characteristics is probably just the latest swing of the fashion pendulum between nature and nurture in human affairs. Aristotle proposed that humans developed from the interplay of nature, or "preformation," and nurture, which he called "epigenesis (9)
." Once genetics became a science, and "evo" joined "devo," nature and nurture were revived in the guise of Mendelian vs. non-Mendelian heredity; Weismann’s immortal germ plasm vs. mortal protoplasm; and Mayr’s "soft" inheritance vs. the "hard" kind (10)
. More recently, Dawkins’ selfish gene (nature) has been countered by E. O. Wilson’s altruistic biology (nurture) (11
, 12)
. Right now the epigenetic style is in high fashion with us and, like all high fashions, attracts the attractive. Dame Honor anticipated this sentiment in her presidential address to the First International Congress of Cell Biology in Paris:
Sartorially speaking we are probably not an outstandingly fashionable group but where our research is concerned, we can be as fashion-conscious as the most elegant woman in this City. In science, as in the world of dress, fashions recur ... . (4)
Research over the last decades has indeed reversed the fashion of Watson-Crick determinism. Lamarck is back, one covalent link after another. First came DNA methylation of dinucleotides (CpG) in the helix itself, then other heritable modifications of histones and/or nucleosomes were identified: methylation, acetylation, phosphorylation, ubiquitylation, sumolyation, und so weiter. Genes for micro and small interfering RNA’s also undergo epigenetic change in the course of gene silencing. And now, histone codes have joined the "methylomes" of DNA on the catwalks of our journals (13
, 14)
.
A LANDSCAPE AT THE COCKTAIL HOUR
Not all the fashion critics are in love with the new style. Joshua Lederberg suggested that the terms "nucleic" and "non-nucleic" would better describe the chemical modifications of nature or nurture; he found epigenetics unnecessary for explanations of gene activation (15)
. Nor is Mark Ptashne convinced by all those acetylated histones:
As a glance at the literature will reveal, histone modification—acetylation, phosphorylation, methylation, and so on—are now often explicitly called "epigenetic modifications." This despite the fact that, so far as I am aware, no histone modification has been shown to be heritable (16)
In fact, the new epigenetics didn’t begin with studies of heritability or evolution, it addressed problems of development: devo anteceded evo. The notion was proposed by the Cambridge polymath, Conrad Hal Waddington (1905–1975), while working with Honor B. Fell at the Strangeways Research Laboratory on nuclear-cytoplasmic interactions. Waddington used Fell’s hanging drop cultures to identify "organizing" factors that could dictate the fate of limbs, eyes, or spinal column in the chick embryo. In a 1939 treatise, he formulated the nature/nurture problem in the then fashionable terms of nucleus and cytoplasm:
The interaction of these constituents [nuclear and cytoplasmic] in the egg gives rise to new types of tissue and organ which were not present originally, therefore development must be considered as "epigenetic (17)
."
Waddington argued that notions of genotype and phenotype were not adequate or appropriate to describe the difference between an eye and a nose in the course of individual development. But while he was quite innocent of the biochemistry behind the biology of evo/devo, he seems to have anticipated modern signal transduction pathways in a telling analogy:
The general picture that emerges from all this is that the embryonic cell is rather like a room where a cocktail party is going on with the radio set with press button tuning in the centre of it. The switching on of a particular battery of genes, controlling the synthesis, say, of nerve proteins, corresponds to pressing one particular button which brings in a programme precisely from one station. But you may succeed in getting this button pressed by jogging the elbow of somebody at the other side of the room, who stumbles against the next man, and so on down the line until somebody finally falls against the radio set, and this may be sufficient to click on whichever of the tuning buttons is most insecure (18)
Plus or minus our modern repertoire of acetylases, demethylases, the Ras’s, ING’s, and Runx’s, that seems like a pretty good description of epigenetics at a cocktail party. But his studies of embryology soon led him afield to ask why "The Alsatian begets an Alsatian / The hen’s egg gives rise to a hen (3)
." Waddington contended that classical Darwinian evolution ought to be amended by taking phenotype into account. He formulated a notion called "canalisation" to explain reciprocal interactions between environment and phenotype on the one hand (nurture) and genotype and phenotype on the other (the nature of nature) (18)
.
To illustrate his point, he drew another analogy, one a little tougher to handle than his cocktail party. He introduced the notion of an "epigenetic landscape" in which a heritable phenotype—a cell, say, or a nucleus—is propelled like a craft on a swift stream flowing between high ridges (the environment). Successive generations of the same phenotype will tend to seek the same path and the phenotype will become fixed, or "canalized" regardless of the variability of its environment or genotype (19)
. Alsatians will beget Alsatians, because Alsatian ridges select for survival of those fittest for the Alsace (3)
. Waddington’s epigenetic landscape proposed a dynamic model of evolution that should pass muster for all seasons of fashion. It’s also an extension of the Darwinian origin of species that’s worth teaching in these days of "intelligent design."
THE LANDSCAPE OF INTELLIGENT DESIGN
This fall, surrounded awhile by the red and gold foliage of the Adirondacks, I was reminded of Waddington’s epigenetic landscape: the ridges were high, the streams free-flowing and we stayed in a green valley. We had crossed the very lakes and streams over which a century and a half ago Darwin’s arch-enemy had passed (20)
. Harvard’s Jean Louis Rodolphe Agassiz (1802–1873) was the preeminent natural philosopher of his day, his stay at what came to be called the "Philosopher’s Camp" at Follensby Pond has become legendary.The scenery, as described by his companion Ralph Waldo Emerson, evokes Waddington’s landscape:
... a small tortuous pass Winding through grassy shallows in and out, Two creeping miles of rushes, pads, and sponge ... Northward the length of Follansbee we rowed, Under low mountains, whose unbroken ridge Ponderous with beechen forest sloped the shore. A pause and council: then, where near the head On the east a bay makes inward to the land Between two rocky arms, we climb the bank ... (21)
Agassiz, Emerson, and their colleagues—ten gentlemen and scholars from Boston—had been corralled by the artist-diplomat William J. Stillman to engage in a long canoe trip to camp among the streams, lakes, and forests of the then-virgin Adirondacks. Emerson was pleased by his scientific companion:
We flee away from cities, but we bring The best of cities with us, these learned classifiers, Men knowing what they seek, armed eyes of experts. We praise the guide, we praise the forest life; But will we sacrifice our dear-bought lore Of books and arts and trained experiment, Or count the Sioux a match for Agassiz (21)
The expedition included not only Agassiz and Emerson, who was the country’s leading moral philosopher, but also by Dr. Jeffries Wyman, the eminent Harvard anatomist; the jurist Ebenezer Hoar; James Russell Lowell of The Atlantic Monthly; Dr. Oliver Wendell Holmes’ brother John, and other Brahmin elders. They "swept with oars the Saranac," endured "Hard fare, hard bed and comic misery—the midge, the blue-fly and mosquito," they ate what they shot, fished, and plucked by roaring fires—all with the aid of local guides and woodmen. "Ten famous intellectuals, playing Indian" a fan of the area quipped. (22)
Indeed, there could have been more of them. Stillman had asked Henry Wadsworth Longfellow to join the group.
"Is it true that Emerson is going to take a gun?" Longfellow asked. "Yes" [Stillman] replied" "Then I shall not go," said Longfellow, "somebody will be shot (23)
Under canvas in the Philosophers’ Camp, each Boston nabob did what he did best. Lowell shot at an osprey and climbed a pine. Emerson sniffed pine, wrote verse, and fired two shots from his rifle. He missed both the bear at which he took aim and his hunting partners. (Pace, Mr. Cheney.) Agassiz was the one most completely in his element. With Wyman as assistant, he "dissected the slain deer, weighed the trout’s brain," captured "lizard, salamander, shrew crab, mice, snail, dragon-fly, minnow and moth." Agassiz regaled his colleagues with stories of his student days with Baron Cuvier in Paris, his theories of glaciers and the ice age, and the mating habits of European fish. He preached opposition to the "classifications" of Linnaeus and Haeckel, and pleased his companions by insisting that Lamarck and Darwin were wrong. Species did not arise from others, they were all created in infinite variety by—you guessed it:
In the infinite variety of their structure, I see the direct action of an intelligence, made manifest in the most diverse ways, rather than the development of successive generations by means impossible to define (2)
It is difficult these days to understand why bluff Agassiz, whose legacy to modern science is dubious, was so highly treasured by the lettered folk of his time. Lowell, Holmes, Wyman, and Emerson—indeed all the lights of Boston—were in awe of this Swiss polymath. But if we measure his works against those of the grand system-builders of Europe—Linnaeus, Buffon, Lamarck, Cuvier, Lyall, Darwin—or look into the accounts of his shady business ventures, it becomes easier to understand why he left Switzerland for fame and fortune in the New World.
Having left his first wife to die of tuberculosis in Europe, Agassiz insinuated himself into the Brahmin aristocracy. Indeed, his second wife, Elizabeth Cabot Cary Agassiz, was to become the first president of Radcliffe, and her paternal grandfather was Col. Thomas H. Perkins, the benefactor who established the Perkins Institution for Dr. Samuel Gridley Howe, husband of Julia Ward Howe of "The Battle Hymn of the Republic." In an 1863 letter to Howe, appointed by Lincoln to head the American Freedmen’s Inquiry Commission, Agassiz expressed his views of fixed racial types:
Conceive for a moment the difference it would make in future ages for the prospect of republican institutions and our civilization generally, if instead of the manly population descended from cognate nations, the United States should hereafter be inhabited by the effeminate progeny of mixed races, half Indian, half Negro, sprinkled with white blood. In whatever proportion the amalgamation may take place, I shudder at the consequences (24)
He also found time to explain to Dr. Howe that the coloreds were genetically inferior, that mulattos were sure to prove sterile, and that amalgamation of the races was biologically unsound.
Agassiz was convinced that the purpose of God is fixed and could be read in the facts of nature. "Study Nature, Not Books" reads the motto of Agassiz, now preserved in the library of the Marine Biological Laboratory at Woods Hole. "Study Books, You’ll Learn More" cracked Eugene Bell, the late and wise embryologist. Haeckel would have helped the Harvard professor.
THOUGHT’S NEW-FOUND PATH
In camp at Follensby, evolutionary thought was interrupted by electric news. Visitors arriving by canoe reported that the first trans-Atlantic submarine cable between Newfoundland and Ireland had been successfully connected. The philosophers exulted over the news:
Of the wire-cable laid beneath the sea, And landed on our coast, and pulsating With ductile fire. Loud, exulting cries From boat to boat, and to the echoes round, Greet the glad miracle. Thought’s new-found path Shall supplement henceforth all trodden ways, Match God’s equator with a zone of art, And lift man’s public action to a height Worthy the enormous cloud of witnesses (21)
Emerson was energized by the possibility of communication between the continents. He imagined that it might someday be feasible to use electrical impulses to mimic—or to substitute for—the machinery of human mentation. Electricity for Emerson was:
A spasm throbbing through the pedestals Of Alp and Andes, isle and continent, Urging astonished Chaos with a thrill To be a brain, or serve the brain of man (21)
But even the Adirondacks, that Arcadia of lake and that epigenetic landscape of gorge and canalization, contained the serpent of preformation. Emerson had learned from Agassiz that if races were created all at once by the direct action of intelligent design (l’action immédiate d’une intelligence se manifestant), why Nature must be destiny, and Self-Reliance its gospel. How appropriate, then that "a manly population descended from cognate nations" had found thought’s new-found path. How happy we should be that:
It is not Iroquois or cannibals, But ever the free race with the front sublime, And these instructed by their wisest too, Who do the feat, and lift humanity (21)
These days we’ve relegated preformation to the history books. We’re busy working out the latest fashions in signal transduction on the Web and thought’s new-found paths makes their wireless way to every nook of the Adirondacks. There is a new problem, however: the signal to noise ratio is getting harder to overcome. Dame Honornad had already issued that warning in Paris in 1960:
Our scientific world is becoming like a crowded cocktail party, in which everyone shouts a little louder in the hope of making himself heard, until at last the volume of speech is such that almost nothing can be distinguished (4)
One hopes that cacophony in science may itself be a transient fashion, which, like the biological fancies of the Philosophers’ Camp, will also pass with time. Alas, as one heard during the recent election campaign, the serpent of biological racism remains abroad in the land, well tended by Darwin-deniers. On the other hand, those heirs of Agassiz are so very not NOW.
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FOOTNOTES
The opinions expressed in editorials, essays, letters to the editor, and other articles comprising the Up Front section are those of the authors and do not necessarily reflect the opinions of FASEB or its constituent societies. The FASEB Journal welcomes all points of view and many voices. We look forward to hearing these in the form of op-ed pieces and/or letters from its readers addressed to journals{at}faseb.org.
REFERENCES
This article has been cited by other articles:
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  C. Bui, M. Ouzzine, I. Talhaoui, S. Sharp, K. Prydz, M. W. H. Coughtrie, and S. Fournel-Gigleux Epigenetics: methylation-associated repression of heparan sulfate 3-O-sulfotransferase gene expression contributes to the invasive phenotype of H-EMC-SS chondrosarcoma cells FASEB J, February 1, 2010; 24(2): 436 - 450. [Abstract] [Full Text] [PDF]
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