155
Evolutionary roots of iodine and thyroid hormones in cell–cell
signaling
Susan J. Crockford1
Department of Anthropology, PO Box 3050 STN CSC, University of Victoria, British Columbia, Canada V8W 3P5
Synopsis In vertebrates, thyroid hormones (THs, thyroxine, and triiodothyronine) are critical cell signaling molecules.
THs regulate and coordinate physiology within and between cells, tissues, and whole organisms, in addition to controlling
embryonic growth and development, via dose-dependent regulatory effects on essential genes. While invertebrates and
plants do not have thyroid glands, many utilize THs for development, while others store iodine as TH derivatives or
TH precursor molecules (iodotyrosines)—or produce similar hormones that act in analogous ways. Such common
developmental roles for iodotyrosines across kingdoms suggest that a common endocrine signaling mechanism may
account for coordinated evolutionary change in all multi-cellular organisms. Here, I expand my earlier hypothesis for
the role of THs in vertebrate evolution by proposing a critical evolutionary role for iodine, the essential ingredient in all
iodotyrosines and THs. Iodine is known to be crucial for life in many unicellular organisms (including evolutionarily
ancient cyanobacteria), in part, because it acts as a powerful antioxidant. I propose that during the last 3–4 billion years,
the ease with which various iodine species become volatile, react with simple organic compounds, and catalyze biochemical reactions explains why iodine became an essential constituent of life and the Earth’s atmosphere—and a potential
marker for the origins of life. From an initial role as membrane antioxidant and biochemical catalyst, spontaneous
coupling of iodine with tyrosine appears to have created a versatile, highly reactive and mobile molecule, which over time
became integrated into the machinery of energy production, gene function, and DNA replication in mitochondria.
Iodotyrosines later coupled together to form THs, the ubiquitous cell-signaling molecules used by all vertebrates.
Thus, due to their evolutionary history, THs, and their derivative and precursors molecules not only became essential
for communicating within and between cells, tissues and organs, and for coordinating development and whole-body
physiology in vertebrates, but they can also be shared between organisms from different kingdoms.
Introduction
In vertebrates, thyroid hormones (THs, a collective
term for thyroxine, T4, and/or triiodothyronine, T3)
are critical molecules for cell–cell signaling. THs
regulate and coordinate physiology within and
between cells and tissues on an organismal level, in
addition to controlling embryonic growth and development via dose-dependent regulatory effects on
essential genes [e.g., Gancedo et al. 1997; Hulbert
2000; Clément et al. 2002; Jones et al. 2005;
Liu and Brent 2005; Psarra et al. 2006; Walpita
et al. 2007; Ebbesson et al. 2008; additional
references in Crockford (2002, 2008), and specific
effects and actions of TH are described in more
detail in Crockford (2004, 2006)]. A number of
dose-dependent non-genomic TH actions (including
metabolic, ionic, and neurotransmitter-like effects)
that occur within minutes have also been
documented (e.g. Peter et al. 2000; Wrutniak et al.
2001; Davis and Davis 2002; Hiroi et al. 2006; Sarkar
et al. 2006; Lei et al. 2007). Last, it has now been
demonstrated that at least in rats, nerves connecting
the thyroid gland and suprachiasmatic nucleus of the
hypothalamus stimulate rapid release of TH
(Kalsbeek et al. 2000, 2006; Kleiverik et al. 2005),
which, when needed, allows the brain to bypass
classic pituitary-hormone-cascade control over TH
production (e.g. Hadley 2000).
Thus, through direct and permissive effects on
basic biochemical cell functions, regulatory genes,
and other hormones, THs are known to influence
virtually all biological systems from the point
of conception onward, including differentiation of
embryonic and adult brain stem cells; regulation of
early embryonic cell migration, differentiation, and
maturation; regulation of embryonic and postnatal
From the symposium ‘‘Cell–Cell Signaling Drives the Evolution of Complex Traits’’ presented at the annual meeting of the Society for
Integrative and Comparative Biology, January 3–7, 2009, at Boston, Massachusetts.
1
E-mail: [email protected]
Integrative and Comparative Biology, volume 49, number 2, pp. 155–166
doi:10.1093/icb/icp053
Advanced Access publication June 23, 2009
ß The Author 2009. Published by Oxford University Press on behalf of the Society for Integrative and Comparative Biology. All rights reserved.
For permissions please email: [email protected].
156
somatic growth; regulation of embryonic and postnatal development of the brain and eyes; generation
of energy in mitochondria through regulation of
ATPase; regulation of mitochondrial DNA replication; regulation of cellular sodium/potassium and
calcium ion pumps; regulation of brain function
and neurogenesis; regulation of hair growth; regulation of production of adrenal hormones necessary
for stress response; regulation of pigment production
in the hair and skin; regulation of development and
function of the gonads; regulation of metabolism and
adaptation to daily and seasonal changes; regulation
of metamorphosis in amphibians and certain families
of fish; regulation of osmoregulatory changes in
anadromous and catadromous fish; regulation of
adaptive coloration; and regulation of mammalian
hibernation.
While invertebrates do not have thyroid glands,
many use ingested THs for initiating and/or
sustaining critical developmental stages, while many
organisms (including plants, insects, zooplankton,
and algae) are known to store iodine as TH
precursor molecules: mono-iodotyrosine (MIT),
di-iodotyrosine (DIT), iodocarbons, or iodoproteins
(Eales 1997; Johnson 1997; Heyland and Moroz
2005). While insects do not appear to use MIT or
DIT for TH-like developmental regulation, they
do produce similar hormones that act in TH-like
fashion (Nijhout 1999; Wheeler and Nijhout 2003;
Flatt et al. 2006), as do many plants (Eales 1997;
Farnsworth 2004). Gut-inhabiting bacteria use host
THs as a source of iodine (DiStefano et al. 1993).
Such common roles for THs, iodotyrosines, and
analogous molecules across kingdoms suggest that a
common endocrine signaling mechanism may
account for coordinated evolutionary change in
all multi-cellular organisms, as I have previously
proposed (Crockford 2004, 2006, 2008), via timedependent and dose-dependent effects on the fates
of cells, proliferation of cell lineages, and development of critical brain architecture.
Here, I expand my premise that THs or their precursor molecules are critical drivers of evolution
in multicellular organisms by suggesting that this
mechanism began with an essential role for iodine
in the first early cells. Iodine is the key constituent
of THs and iodotyrosines and is crucial to life for
virtually all extant organisms, including evolutionarily-ancient cyanobacteria. In part, iodine is critical,
because its antioxidant properties protect cell
proteins, nucleotides, and fatty acids from the chemically disruptive effects of oxygen (e.g. Salacinski
et al. 1981; Venturi and Venturi 1999; Hulbert
2000; Miller 2006; Küpper et al. 2008). Although
S. J. Crockford
essential in vertebrates, more generally iodine is
considered to be a non-essential trace element/
micronutrient (Kobayashi and Ponnamperuma
1985), a characterization that belies what is now
known about its utilization in unicellular organisms
and the critical role it plays in the Earth’s
atmosphere (Fuge and Johnson 1986; Councell
et al. 1997; Eales 1997; Gilmour et al. 1999; Wong
et al. 2002; Amachi et al. 2003, 2005a, 2005b; Baker
2005).
I propose that during the evolution of early cells,
the ease with which environmental iodine reacts with
water and simple biological compounds—its active
redox chemistry—explains why this relatively rare
inorganic element, over evolutionary time, became
a cornerstone of cell–cell signaling and a critical
component of our atmosphere. While some details
regarding iodine cycling from rock and soil, to water
and biota, and then to the atmosphere and back
remain obscure, it is clear that iodine in one form
or another is more essential to all life forms than has
been appreciated previously. In fact, it is entirely
possible that iodine may be the key to explaining
the origin of life on Earth, as suggested by
Gilmour et al. (1999).
Although precise details of the biochemical
machinery involving iodine and THs are not yet
fully understood, what I will try to do here is
incorporate what I have been able to tease from
the literature into a coherent and plausible scenario
to answer the question alluded to more than 10 years
ago by Johnson (1997): what are the evolutionary
roots of iodine dependency?
Unique properties of iodine
The molecular mass of iodine (126.90 U) is the
highest by far of all elements used in biological
systems. This unique character is also reflected in
its atomic number: the proton count per atom for
iodine (I 53) is significantly higher than any other
common or essential trace element used by living
organisms, including zinc (Zn 30) and iron
(Fe 26). The high mass and proton count relative
to other elements provides a partial explanation
for the fact that iodine is biochemically unique.
Iodine atoms, like other halogens (fluorine, chlorine,
bromine, and astatine), are highly reactive, because
they lack a full outer shell of electrons. All halogens
thus have a strong tendency to gain an electron and
regularly occur as diatomic molecules (e.g. I2). While
chlorine and bromine are relatively more abundant in
modern marine waters, iodine is the more biological
reactive (e.g. Küpper et al. 2008; Truesdale 2008).
157
Evolutionary roots of iodine and thyroid hormones
Fig. 1 Iodine cycles from land (via erosion of rock, dissolved in water) to the ocean, where it is taken up by marine organisms
and released in various organic and inorganic forms, some of which are volatized into the atmosphere, where they react with ozone
(O3) and other atmospheric gases and seed the particulate matter of clouds. Movement of clouds over land re-deposits iodine
dissolved in rainwater (largely as iodate, IO3– and iodide, I–), where some is taken up by soil bacteria and other terrestrial organisms
and released back into the soil and into ground water (Jones and Truesdale 1984; Fuge and Johnson 1986; Truesdale and Jones 1996;
Baker et al. 2000; Amachi et al. 2003; Baker 2005 also http://www.uea.ac.uk/e780/airseaiod.htm).
Iodine exists in several common inorganic oxidation states, including iodide (I–), molecular iodine
(I2), and iodate (IO3), providing the potential for
active redox chemistry. Iodate is the most thermodynamically stable form. I2 is a powerful catalyst
(Grätzel 2001; More et al. 2005; Ahmed and van
Lier 2006; Wu et al. 2006) and like many metals
capable of catalyzing biochemical reactions, it functions as a Lewis acid (Žmitek et al. 2006; Hazra et al.
2008). When incorporated into complex molecules,
such as glycoproteins, iodine appears to confer some
of its reactivity on the entire molecule. Iodotyrosines,
for example, are known to be good catalysts
(Harshman 1979).
Iodine is considered a trace element geochemically. It is rare in igneous rock but relatively more
common in sedimentary rock such as sandstone and
limestone (Fuge and Johnson 1986). Iodine is both
water-soluble and volatile in several of its inorganic
forms: it dissolves out of rock during weathering and
cycles with water and water vapor throughout the
lithosphre, cryosphere, and atmosphere (Jones and
Truesdale 1984; Fuge and Johnson 1986; Truesdale
and Jones 1996; Gilmour et al. 1999; Baker et al.
2000; Baker 2005), as depicted in Fig. 1.
Environmental iodine and the origin
of life
The six chemical building blocks of early life are
usually considered to be hydrogen (H), carbon (C),
oxygen (O), nitrogen (N), phosphorus (P), and
sulphur (S), which combine in various ways to
make up the essential sugars, fatty acids, amino
acids, and nucleotides that form the basic constituents of metabolism (Smith and Morowitz 2004;
Falkowski et al. 2008; Melkikh and Selezneu 2008).
Many of these elements are also important to the
Earth’s atmosphere (e.g. Commoner 1965; Kasting
and Siefert 2002). Researchers have attempted to
explain how and why these basic elements came
together in the earliest life forms (e.g. Bada 2003;
Griffiths 2008; Jalasvuori and Bamford 2008), and
while there is disagreement over whether the ability
158
to replicate (via RNA) or generate energy (via metabolism) came first, or whether both arose at the same
time (before or after the advent of cell walls), such
disputes are immaterial to this discussion.
The first early cells (LUCA, Last Universal
Common Ancestor) almost certainly had a simple
metabolism compared to modern forms, with less
than a full complement of essential amino acids
and perhaps a few non-specific enzymes (remembering that enzymes are simply biochemical catalysts
that are molecularly larger and more specific
than inorganic catalysts). Aromatic amino acids
(phenylalanine, tyrosine, and tryptophan) appear to
have arisen some time after LUCA arose, as did more
complex and specific enzymes (Ahmad and Jensen
1988). While the actual incorporation of iodine
into essential biochemistry appears to have come
after the rise of LUCA (Barrington 1962), I suggest
its influence probably started with LUCA itself.
To understand why this may be so, I review below
the role of iodine in modern organisms and the
atmosphere.
How modern organisms use iodine
Although it is not always clear exactly what iodine is
used for biochemically, plants are known to take up
iodine from water and store it, often as MIT, DIT,
or THs (Jones and Truesdale 1984; Eales 1997).
Iodine is also coupled to various carbohydrates,
polyphenols, and proteins (Küpper et al. 2008;
Truesdale 2008). Decaying vegetation absorbs and
fixes even more iodine (about 10 times more), so
that soils rich in organic matter, such as peat,
are known to be particularly rich in stored iodine
(Fuge and Johnson 1986). The question arises: how
and why does iodine enter cells?
Many unicellular marine phytotplanktonic species
(e.g., cyanobacteria, dinoflagellates, green algae, and
diatoms), and photosynthetic marine and aerobic
soil bacteria, are known to reduce inorganic iodate
to iodide at or within their cell walls (Wong et al.
2002; Amachi et al. 2003, 2005a; Chance et al. 2007;
Truesdale 2008). While some iodine apparently gets
transferred into the cytoplasm during this process,
much appears to be released as iodide and various
organic iodinated compounds, including methyl
iodide, CH3I (Baker et al. 2000; Wong et al. 2002;
Baker 2005). Macroalgae (kelp) also release iodide
and while they are known for their ability to
accumulate large quantities of iodine (primarily as
iodotyrosines), the function of these stored reserves
in kelp has not been determined (Küpper et al. 1998,
2008).
S. J. Crockford
For some single-celled organisms, including most
anaerobic bacteria, fungi, viruses, and yeasts, I2 is
toxic to the cell membrane (McDonnell and Russell
1999). However, at least some choanoflagellates and
most a-proteobacteria (Amachi et al. 2005b) are
resistant to I2, as are all animals. Just because some
organisms are killed by I2 does not necessarily mean
they do not use iodine, only that they must get their
iodine in another form. For example, the Escherischia
coli bacteria that inhabit rat intestines (for which I2 is
lethal) are known to bind significant amounts of
host THs to their outer cell membranes and to
excrete iodine in the form of iodide (DiStefano
et al. 1993), suggesting that some THs are converted
to DIT or MIT within the cell membrane and
utilized or broken to generate other iodine species
within the cell.
Certain ferric iron and sulphate-reducing
anaerobic bacteria can also reduce iodate to iodide
(Councell et al. 1997; Truesdale 2008), as can some
facultative anaerobes (Farrenkopf et al. 1997),
suggesting that the earliest anaerobic cells might
have had this ability also. The fact that virtually all
species are able to convert iodate to iodide and that
iodide is known to enter cells in many of these
suggests that iodine has always entered cell cytoplasm
and participated in essential biochemistry. While
more research is clearly needed to unravel the precise
roles that iodine and iodinated molecules play
in cellular metabolism, if iodine has always been
essential to cells then iodotyrosines may have a
longer evolutionary history than previously thought.
Iodotyrosines are known to form spontaneously
(Nishinaga 1968; Cahnmann and Funakoshi 1970),
although more slowly and with a lower yield than
when catalyzed by enzymes, as occurs in vertebrate
thyroid glands (Hulbert 2000). Iodotyrosines are
highly reactive with other molecules (Harshman
1979), suggesting they may have been one of the
first and most crucial molecules effecting cell–cell
signaling in multicellular organisms.
Iodine in the atmosphere
The ability of microbes to convert thermodynamically stable inorganic iodate to highly reactive
iodide (with some retained, most released into the
environment) explains why most iodine in deep
marine waters takes the form of iodate, whereas
marine surface waters (where most microorganisms
reside) have relatively more iodide (Amachi 2005b;
Truesdale 2008; Küpper et al. 2008). Iodide atoms at
the sea surface enter the atmosphere as volatized I2
and iodocarbons, which react readily with
Evolutionary roots of iodine and thyroid hormones
atmospheric oxygen. Volatized I2 and iodine compounds not only break down ozone (Wang et al.
2006; Read et al. 2008) but provide nuclei for the
particulate matter of clouds, the seeds of rain (Baker
et al. 2000; Baker 2005). The incorporation of iodine
into rain recycles it back to land, where it becomes
available for uptake by terrestrial plants and soil bacteria (Jones and Truesdale 1984; Fuge and Johnson
1986; Truesdale and Jones 1996; Amachi et al. 2003),
as summarized in Fig. 1.
The intimate relationship between iodine used by
unicellular marine organisms and atmospheric
cycling almost certainly has a long evolutionary
history. I suggest that iodine must have played a
crucial role in the development and evolution of
our atmosphere primarily due to its reactive relationship with oxygen. Three to 4 billion years ago (Ga),
the Earth’s atmosphere was very low in oxygen
(Falkowski et al. 2008). Most evidence points to a
dramatic increase in atmospheric oxygen just about
the time that the abundance of photosynthetic
cyanobacteria rose dramatically, 2.3–2.7 Ga
(Commoner 1965; Kasting and Siefert 2002;
Canfield 2005). Since the by-product of photosynthesis is oxygen, it is presumed that the sudden increase
in atmospheric oxygen was due to biological activity.
Since modern cyanobacteria and photosynthetic
marine bacteria release significant amounts of
iodine that subsequently enter the atmosphere, it is
reasonable to suggest that in evolutionary terms,
iodine became an important constituent of the atmosphere at the same time as oxygen. This simultaneous rise of atmospheric oxygen and iodine appears to
have been a turning point for the history of life on
Earth, because only after iodine and oxygen became
major constituents of the atmosphere did eukaryotes
and multicellular organisms arise. I suggest that
oxygen alone would not have done the trick.
Iodine, tyrosine, and the evolution of
photosynthesis
Iodine and oxygen became critical to multicellular
life and the evolution of vertebrates (e.g. Falkowski
et al. 2005) only after the amino acid tyrosine came
into the picture. As stated previously, tyrosine and
other aromatic amino acids apparently arose some
time after LUCA. Phosphorylated tyrosines, which
are critical cell-signaling molecules for all living
metazoans and their closest protist relatives (e.g.
choanoflagellates), require the actions of a tyrosine
kinase for their synthesis. The genes for these
enzymes are known to be evolutionarily ancient
(King 2004; Manning et al. 2008). Tyrosine in
159
vertebrates is an essential precursor to melanin, catecholamines (including neurohormones such as dopamine, epinephrine, and norepinephrine) and of
course, THs and all iodotyrosines. Tyrosine is also
required for the PSII component of water-based
oxygen photosynthesis (Gupta 2003; Nugent et al.
2004). Tyrosine has been described as uniquely
reactive (Harshman 1979), especially with iodine.
Tyrosine has thus been available and critical to
cellular function for a very long time, although
it was not present initially. So when and how did
tyrosine enter the picture? In all living organisms,
tyrosine is synthesized from other compounds via
an enzyme-mediated process (e.g. Smith and
Morowitz 2004) that LUCA did not possess
(Ahmad and Jensen 1988; Griffiths 2008). I suggest,
therefore, that early in its evolutionary history,
tyrosine was initially generated by the catalytic
actions of iodine in the cytoplasm of LUCA, as
outlined below.
Oxidation reactions with iodate at surface of
LUCA cells would have produced iodide, some of
which probably entered the cytoplasm (as I2)
through permeable cell walls (Deamer 2008;
Melkikh and Seleznev 2008). I2 in the cytoplasm,
acting as a catalyst, would have made new kinds of
compounds available to the cell. One of those
compounds may have been the amino-acid tyrosine.
I suggest that some descendants of LUCA might
have had the ability to generate tyrosine from an
available sugar, with I2 acting in its capacity as a
metal-like catalyst, before the specialized enzymes
now necessary for biosynthesis of this molecule had
evolved (Ahmad and Jensen 1988; Griffiths 2008).
Catalysis of this sort has previously been proposed
(utilizing a little-known metal, montmorillonite)
to explain the origins of RNA (Ferris 2006).
Once tyrosine was present, the metabolic steps to
photosynthesis could evolve and once tyrosine as a
component of photosynthesis had become necessary
for survival, non-specific enzymes could evolve into
specialized ones capable of synthesizing tyrosine
faster and more efficiently. This kind of selective
process has been used to explain the evolution of
other specialized essential enzymes (Gehring 2005;
Badger et al. 2006).
As tyrosine is especially reactive with iodine, some
iodotyrosines probably formed spontaneously in
these primitive cells. Iodotyrosines and iodoproteins
are rather reactive themselves because of their iodine
component; they bind to other molecules to make
more complex compounds and can insert themselves into lipid membranes (Harshman 1979).
160
Iodotyrosines also catalyze other reactions and
scavenge free radicals (Oziol et al. 2001).
Such reactivity would have made iodotyrosines
useful biochemically well before they were used
as cell–cell signaling molecules in multicellular
organisms.
Origin of multicellularity and a new role
for THs
The first multicellular organisms appear to have
needed two critical innovations: a way for cells to
come together and a way for them to communicate.
It has been suggested, for example, that multicellularity might have arisen as a consequence of
incomplete cell division, a development that would
have created connections between cells, such as seen
in some colonies of modern volvocine algae.
Multicellular organisms might also have arisen
subsequent to the production of extracellular matrices that bind cells together (Sachs 2008), as such
matrices create unique opportunities for cell–cell
communication (Brodsky 2006). The essential
biochemical machinery for effective cell–cell communication, it turns out, is found in mitochondria.
It is now widely accepted that photosynthetic
a-proteobacteria became the mitochondria of
eukaryotic cells (Meyerowitz 2002; Gabaldón and
Huynen 2003; Gupta 2005). Some modern cyanobacteria that have both chloroplasts and mitochondria
are known to form self-colonies as well as symbiotic
colonies with fungi and yeast (Badger et al. 2006), a
life style similar perhaps to the first multicellular
organisms. Since it is clear that such organisms
probably possessed iodotyrosines (the precursors of
THs), it should come as no surprise that the primary
sites of action for THs, at least in vertebrates, are in
mitochondria.
Mitochondria are the ‘‘power plants’’ of
eukaryotic cells; they generate energy via oxidative
phosphorylation of ATP, which forces cations
(Hþ or Naþ) across cell membranes. In vertebrates,
THs up-regulate the production of the ATPase
enzyme that drives this potassium-sodium pump
(Hadley 2000; Hulbert 2000). ATPases are found in
all life forms (Axelsen and Palmgren 1998), including
living Archaea, which suggests that the cellular
machinery required for ATP production is ancient
(Müller and Grüber 2003) and that enzymes specific
for ATP production arose very early in the evolution
of life itself.
Therefore, although this remains to be demonstrated, I suggest it is possible that iodinated
tyrosines, as evolutionary and biochemical precursors
S. J. Crockford
of THs, may up-regulate the production of ATPase
in non-vertebrate mitochondria. Plants and invertebrate cells also have potassium-sodium pumps driven
by ATPase, which suggests that stored MIT, DIT,
and/or THs may play a role in the regulation of
ATPase (Glynn 1993; Gimmler 2000). In vertebrates,
THs also up-regulate mtDNA replication (Wrutniak
et al. 2001), enabling cells to increase the absolute
number of mitochondria available to generate energy
when needed (Hulbert 2000). THs also up-regulate
the expression of many mitochondrial genes in
muscle cells at work (Clément et al. 2002).
As THs perform such significant communication
within vertebrate cells, it seems eminently plausible
that iodinated tyrosines, or other TH derivatives,
play similar roles in non-vertebrates and also that
such signaling roles are evolutionarily ancient.
Highly reactive iodinated tyrosines, because they
form spontaneously and move readily through permeable membranes, would have made exceptionally
good cell–cell signaling molecules.
TH and the origins of coordinated
development
In vertebrates, THs of maternal origin, either
deposited in egg yolk or supplied via the placenta
(Crockford 2006, 2008) regulate embryonic development of the adult thyroid gland. In vertebrates with
metamorphic stages, THs from egg yolk regulate
initiation of embryonic development of the thyroid
gland, which, on further growth, produces the THs
needed for subsequent transformation to the adult
form (Inui and Miwa 1985; Kluge et al. 2005).
Jawless cyclostomes (lampreys, hagfish), the most
primitive living vertebrates, have a thyroid gland as
adults but retain an endostyle (the evolutionary
precursor of the thyroid gland) during their larval
stage. Lamprey larvae (ammocoete) are freshwater
forms and the larval endostyle produces the THs
necessary for metamorphic transformation to the
adult marine form (Barrinton 1962; Kluge et al.
2005). Protochordates, such as amphioxus
(Branchiostoma sp.) and ascidians (sea-squirts), also
possess an endostyle (Barrington and Thorpe 1965;
Frederikkson et al. 1984) that synthesizes both
iodotyrosines and THs. While the endostyle of
adult amphioxus has been shown to integrate iodinated compounds into a specialized mucoprotein
used in feeding, it has recently been demonstrated
that metamorphosis is regulated by triiodothyroacetic acid, a TH derivative produced by the
endostyle of the larva (Paris et al. 2008). Note that
in lampreys, TH production in the primitive thyroid
Evolutionary roots of iodine and thyroid hormones
gland begins in larvae just before the yolk sac is used
up (Kluge et al. 2005), which appears to be a general
vertebrate pattern.
Thus, endogenously produced THs initiate
metamorphosis in vertebrates, while non-vertebrates,
such as echinoderms, that are known to use THs as
developmental signaling molecules, use exogenous
THs extracted from ingested algae to initiate
metamorphic transformation (Heyland and Moroz
2005; Flatt et al. 2006; Heyland et al. 2006). I contend, therefore, that iodinated tyrosines necessary for
the regulation of larval development must be present
in the maternally produced egg sacs of protochordates and primitive vertebrates, suggesting that the
ability to use TH derivates for regulation of larval
development must already have existed before even
the most primitive vertebrates arose.
TH, metamorphosis, and
osmoregulation: the origin of lungs
THs regulate metamorphosis in a number of vertebrate taxa in which the transformation involves not
only morphological change but osmoregulatory ones
necessitated by a profound shift in habitat. Thus,
lampreys transform from freshwater larvae into
marine adults, and amphibians (frogs, toads, and
salamanders) change from freshwater to terrestrial
forms.
In several groups of teleost fish, THs are critical
for osmoregulation during life-history shifts from
marine to freshwater or freshwater to marine, transitions that are accompanied by moderate to profound
metamorphic transformations. For example, flatfishes
transform from pelagic larvae living in brackish
estuaries to benthic saltwater forms (with a dramatic
change in morphology), three-spined sticklebacks
change from heavily armored marine forms to lessarmored freshwater forms, and juvenile salmon
change from spotted freshwater parr to unspotted
marine smolts (Barrinton 1962; Inui and Miwa
1985; Peter et al. 2000; Schreiber 2001; Klaren
et al. 2007).
Clearly, endogenously produced THs are required
for metamorphosis in all chordates, a process that
often involves an osmoregulatory transformation as
well as a morphological one. In this context, the fact
that the thyroid gland derives from foregut tissues is
relevant to the observation that the gut is a key
osmoregulatory organ in vertebrates (Specker 1988).
Thus, the salt-balancing and ion-balancing role of
THs in relation to shifts in life-history or evolutionary changes in marine versus freshwater habitats may
be more important than previously thought because
161
of the role that THs also play in embryonic
development.
The critical role that THs are known to play in
osmoregulation suggests that iodinated tyrosines and
THs stored in endostylar cells may have been
essential to the evolutionary transformations from
saltwater to freshwater and from water to land, similar to the developmental metamorphosis associated
with changes in habitat by some vertebrates, as discussed in the previous section. Since THs and their
precursors have a long evolutionary history
of regulating early development, I suggest that the
up-regulation of TH production in gut tissue, a
necessary response for adaptation to freshwater by
a marine organism, may have initiated enough
of a developmental shift to generate an involution
of gut tissue in the embryos of the first freshwater
colonizers, a pouch that went on to became the
primitive thyroid gland. Another involution in the
same tissue (the lung) may have been created as an
inevitable consequence of this developmental shift in
response to adaptation to freshwater, or it may have
come later, with the shift to land.
Support for this hypothesis is provided, in part,
by studies on the function of specific genes that
are critical for vertebrate development. For example,
thyroid transcription factor (TTF-1 or nkx2.1) is a
homeobox gene required for embryonic development
of the forebrain, lung, and thyroid gland. This gene
has a homologue in the amphioxus embryo that
regulates development of the cerebral vesicle and
the endostyle (Rohr and Concha 2000; Kluge et al.
2005). As THs are known to be required for the early
embryonic expression of the fibroblast growth factors
and bone morphogenic proteins required for differentiation of the thyroid gland and lung tissue
from foregut mesoderm (e.g. Sekine et al. 1999;
Ishizuya-Oka et al. 2001; Cardoso and Lü 2006), it
is quite likely that nkx2.1 is also regulated by THs.
The placement of iodine-storing, TH-manufacturing gut cells inside the organism, concentrated
within a discrete organ (the endostyle) may have
provided a distinct advantage to these primitive
vertebrates, because it permitted more efficient
osmoregulation in fresh water, ensuring the perpetuation of this change. Subsequent selection and
modification of the endostyle into a thyroid gland
would have further refined this design.
A move from saltwater to land could have
precipitated a similar, but not identical, shift in gut
development as a consequence of the osmoregulatory
response of TH-generating tissues to a complete lack
of salt (which, in terms of salt balance, would be
physiologically similar to a change from saltwater
162
to freshwater). This transformation involved two
involutions of embryonic gut tissue, one that
became the thyroid gland and the other, the lung.
Eventually, due to a slight offset in the control of
timing during development of the gut, features of
lung development could be selected somewhat
independently from features of the thyroid gland
(although they remain closely linked). It is nevertheless significant that while both the thyroid gland and
the lung derive from the same tissue, the thyroid
gland begins to form first (in humans, about 1 day
before lungs begin).
Summary and conclusions
Due to the unique chemical properties of iodine, it
probably became critical to life on Earth as soon as
LUCA arose, between 3 and 4 Ga (Fig. 2). Early cells
that used the conversion of idodate to iodide as
a protective measure against oxidative damage to
their cell membranes would have survived the longest. In these cells, some iodide almost certainly
migrated into the cytoplasm as a consequence of
oxidation reactions at the membrane interface with
the environment (a hypothesis that is testable experimentally using primitive cell types under a variety of
conditions that, to the best of our knowledge, could
have existed 3–4 Ga). Since iodide naturally combines to form I2, which is a powerful catalyst,
the presence of I2 within cytoplasm might initially
have catalyzed the reactions necessary for the generation of energy and for salt/ion balance, and later,
the non-enzymatic synthesis of tyrosine molecules
from simple available sugars (such hypotheses are
S. J. Crockford
also testable experimentally). Once tyrosine was
available for inclusion in cellular metabolism, the
biochemical machinery for photosynthesis could
evolve.
Once unicellular photosynthetic organisms were
prospering, tyrosine was a well-established amino
acid. Iodinated tyrosines probably became important
about this time, in part, because they were good
catalysts, reacted readily with others to form new
complex molecules, and moved easily through
permeable membranes. It is probable that iodinated
tyrosines became regulators of ATPase production in
early mitochondria and if so, their role as gene
regulators may predate the first eukaryotes (this
hypothesis can be tested experimentally by investigating whether iodinated tyrosines or their derivatives
are able to up-regulate the production of ATPase in
non-vertebrate mitochondria). Due to the fact that
iodinated tyrosines could move easily between cells,
they were likely utilized as cell–cell signaling
molecules in multicellular organisms, especially for
the coordinated operation of mitochondrial metabolism (including regulation of essential genes) as well
as for replication of mtDNA. Eventually, MIT, DIT,
and THs became ubiquitous signaling molecules used
in communicating within and between cells, tissues,
and organs, and for coordinating whole-body physiology and embryonic development; they could even
be shared between organisms from different
kingdoms.
Therefore, for very early life forms, iodine would
have served as a critical antioxidant and catalyst for
the synthesis of new biomolecules and thus, may
Fig. 2 Approximate dates and sequence of events for the roles of iodine, iodotyrosines (T1/T2) and thyroid hormone (TH, T3/T4)
in evolution (Barrington 1962; Valentine et al. 1999; Meyerowitz 2002; Blair and Blair Hedges 2005; Canfield 2005; Falkowski et al.
2005; Deamer 2008; Paris et al. 2008; Sachs 2008).
163
Evolutionary roots of iodine and thyroid hormones
have been essential for the development of life itself.
Either by itself, or coupled to tyrosine, iodine
became key to the maintenance of salt balance and
the generation of energy in early cells. Therefore, it
appears that iodinated tyrosines and their derivatives,
which are so important to vertebrate development
and physiology, have a very ancient history.
Clearly, the coupling of iodine with tyrosine was a
critical step in the evolution of complex cell–cell
signaling and thus crucial to evolution itself.
These profound effects were not limited to living
organisms, however; because of the way that biochemical processes mobilize and transform inorganic
forms of iodine into organic forms that cycle with
water and water vapor throughout the lithosphere,
cryosphere, and atmosphere, the utilization of
iodine by early cells actually transformed the
Earth’s environment. The innovation of photosynthetic metabolism billions of years ago changed,
forever, the composition of the Earth’s atmosphere
by dramatically increasing levels of oxygen and
iodine. This atmospheric enrichment with oxygen
and iodine set the stage for the rise of metazoans
and subsequent evolution of vertebrates. If not for
the conversion of thermodynamically stable iodate to
iodide at the surface of the ocean by marine organisms, volatile forms of iodine would not have been
available for addition to the atmosphere; if not for
the active conversion of iodine species by marine
organisms and the subsequent participation of these
molecules in cloud formation, dissolved iodine
would not have cycled back to continents. Without
this atmospheric cycling of iodine from the ocean to
terrestrial habitats, there would not have been
enough bioavailable iodine present to support life
on land, even with abundant oxygen in the
atmosphere.
A significant role for iodine in biological and
atmospheric evolution has not previously been suggested, which is why many of the statements made
here must be tentative. Clearly, more research is
needed on the basic chemical nature of iodine.
However, it is apparent even now that iodine cycling
is a significant and perhaps unique phenomenon that
links inorganic chemistry to biology and geological
processes to organic evolution. Life as we know it
probably would not have evolved without iodine.
Acknowledgments
I am indebted to John Torday (LA Biomedical
Research Institute, Harbor-UCLA) for invaluable
intellectual support in the development of the concepts described in this article. I am also most grateful
to Alex Baker (Environmental Sciences, University of
East Anglia, UK) and Naseem Ahmed (Department
of Chemistry, Institute of Technology, Roorkee,
India) for helpful responses to technical questions,
and to Dwight Cordero, MD (Brigham and
Women’s
Hospital/Harvard
Medical
School,
Department of Obstetrics and Gynecology, Boston)
for discussion and feedback. However, the ideas
expressed in this work are my own and any errors
my sole responsibility.
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