Evolutionary roots of iodine and thyroid hormones in cell–cell signaling
_http://icb.oxfordjournals.org/content/49/2/155.full
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 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 time-dependent 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 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).
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 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).
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 α-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. {A clue as to why lower doses of iodide feed microorganisms instead of killing them?} 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 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 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). 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 α-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 (H+ or Na+) 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 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 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 less-armored 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 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 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 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 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.
)... Could it be that some critters are being activated by the iodine (as the Cs said) and, besides the detox symptoms, this could be due to a mycoplasma infection that "wakes up" with the lower doses? In that case, what would be the best approach to not wake the infection and, at the same time, not overwhelm the body with a "nuke" dose?
