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FOP Gene Identified as First Human Metamorphogene: A Skeleton Key to the Metamorphosis

"When I use a word," Humpty Dumpty said, in a rather
scornful tone, "it means just what I choose it to mean - neither
more nor less." The word metamorphogene entered the medical
lexicon in 2007 at a scientific meeting in New York City and later
in print in an article entitled: "Morphogen Receptor Genes and
Metamorphogenes: Skeleton Keys to the Metamorphosis" (by
Drs. Kaplan, Groppe, Pignolo and Shore) in The Annals of the
New York Academy of Sciences.

The term metamorphosis refers to any striking
developmental change of an animal's form or structure. While
the only defined biological examples of metamorphoses are those
in insects and amphibia, the medical concept of metamorphosis
implies a pathological process that transforms one normal tissue
or organ system into another, as in FOP.

Just as proto-oncogenes (normal cellular genes that
regulate cell division) become oncogenes (cancer causing genes)
when they are damaged in very specific ways, morphogen
receptor genes (normal cellular genes that regulate cell fate)
become metamorphogenes (genes causing metamorphosis, as in
FOP) when they are damaged in very specific ways.

Take Katagiri, Ph.D., of Saitama Medical University
in Japan visits Drs. Eileen Shore and Fred Kaplan
at the FOP Lab

Genetic changes occur when a proto-oncogene becomes an
oncogene and send cells hurdling down dangerous pathways
that result in malignancy. Similarly, genetic changes occur when
a morphogen receptor gene (such as ACVR1) becomes mutated.
The changed metamorphogene dramatically shifts and distorts
the differentiation repertoire by which connective tissue stem
cells and progenitor cells respond to injury and trauma, leading
to the transformation of one normal tissue into another normal
tissue through a pathological process of metamorphosis.

The study of metamorphosis in FOP provides profound insight
into the molecular mechanisms that ensure the stable identity
of tissues following their formation and that regulate the
repertoire of cellular responses to environmental signals.
These mechanisms, just now beginning to be understood as a
result of the FOP gene discovery, ordinarily lay deeply hidden in
the highly conserved signaling pathways that regulate cell fate.
It's as if a trap door in development, firmly sealed for over
500 million years of evolution, were suddenly unlocked by a
single misspelled letter in the genetic code and in so doing
revealed a previously unknown process of both terrifying mortal
danger (as in FOP), or dazzling therapeutic potential (as in the
construction of new skeletal elements).

Metamorphosis (as a result of the action of
metamorphogenes) thus joins the ranks of wound healing,
regeneration, tumor formation, and aging as one of the
key biological processes in which to study and therapeutically
manipulate tissue behavior following morphogenesis (tissue
and organ formation). As Thomas Maeder wrote in an article
in the Atlantic Monthly (February, 1998): "FOP and its problems
lie at the crossroads of several seemingly unrelated disciplines.
Answers to questions that FOP poses will also address grander
issues of how the body first creates its shape and then knows
where to stop, how tissues decide how to become what they are,
and why they don't turn into something else."