The Need for Iodine Supplementation
By Wojciech Rychlik, Ph.D.
Feeling tired, having low energy or depression, gaining weight, memory problems, having dry skin, dry mouth or immune system issues? There is good chance your body needs iodine supplementation. Why iodine? Because this essential to human health element has been singled out as dangerous for several obscure reasons, it's been gradually eliminated from our diet, and even worse, replaced by its antagonist, bromine. This trend, that even acquired its term – iodophobia (1), is the cause of a widely spread hypothyroidism in most developed countries.
1. Symptoms of iodine deficiency
2. Treatments for hypothyroidism
3. History of iodine usage and iodophobia
4. Forms of iodine
5. Iodine uses
6. Inorganic iodine availability
1. Symptoms of iodine deficiency
Iodine deficiency is associated with (2, 3, 4):
-fibrocystic breast disease leading to breast cancer, stomach cancer,
- goiter (enlarged thyroid)
-mental issues from reduced alertness, lowered IQ, autism to cretinism, lack of iodine for the fetus leads to cretinism, and in milder cases to autism and ADHD
-slow metabolism, leading to tiredness, sluggishness, fatigue, apathy, depression and insomnia,
-inability to produce saliva, dry skin and lack of sweating,
-lack of optimal detoxification, especially of bromides, fluorides and heavy metals
-sensitivity to temperature changes, cold hands and feet,
-muscle pain, fibrosis, fibromyalgia,
-erectile dysfunction, infertility and miscarriages, low sex drive,
-high blood pressure, increased incidence of heart attacks and strokes
The Food and Agriculture Organization of the United Nations has published probable safe upper limits for dietary intake of iodine (5). They range from 150 micrograms (mcg) per kilogram (kg)per day in newborn infants to 30ug/kg/day in adults. That is 2 milligrams (2,000 micrograms) daily for a 146-pound adult. The safe upper limit is higher during pregnancy and lactation (40 mcg/kg/day).
2. Treatments for hypothyroidism
The simplest method to deal with hypothyroidism is proper supplementation with iodine, called orthoiodosupplementation (5). If the thyroid is damaged, than supplementation with thyroid hormones, thyroxine (T4) and triiodothyronine (T3, the main biologically active hormone) is unavoidable. Supplementation with inorganic iodine is much safer, as our bodies "know" how much T4 and T3 need to make. Supplementation with the hormones has to be done with close supervision of a medical professional. There are also drugs that change physiology of iodine metabolism, but this subject is beyond the scope of this article. Pharmaceutical companies put big pressure on doctors to stay away from ridiculously cheap orthoiodosupplementation, so you won't likely get a prescription for Lugol's solution from a mainstream practitioner.
One caveat to supplementation with iodine is the autoimmune illness called Hashimoto's disease, or chronic lymphocytic thyroiditis, which is one of the potential causes of hypothyroidism. Unfortunately, when hypothyroidism is diagnosed, the possibility that Hashimoto's disease underlies this condition has not always been properly tested. Therefore, Hashimoto's disease has often been mis-diagnosed. Doctors usually treat this condition with hormone replacement therapy, and some believe that excessive iodine intake may trigger it in susceptible people. Always ask your doctor if iodine supplements are right for you.
3. History of iodine usage and iodophobia
This subject has been covered in detail by Dr. Guy E. Abraham (6, 7, 8). In short, the iodine element has been discovered in 1811 by B. Courtois. In 1850-53 A. Chatin noted that goiter and cretinism are rare in places rich in iodine and frequent where iodine is in short supply, and goiter can be prevented by iodine supplementation. In 1895 E. Baumann proposed that iodine is the active element in the thyroid gland.
By the time Bauman identified large concentrations of iodine in the thyroid gland in 1895, pharmaceutical and apothecary preparations containing iodine, excluding thyroid extracts, were widely used as a panacea for most human ills. To quote Kelley: (9) "In the first flush of enthusiasm for the newcomer, physicians and surgeons tested it and tried it for every conceivable pathological condition. The variety of diseases for which iodine was prescribed in the early years is astonishing - paralysis, chorea, scrofula, lacrimal fistula, deafness, distortions of the spine, hip-joint disease, syphilis, acute inflammation, gout, gangrene, dropsy, carbuncles, whitlow, chilblains, burns, scalds, lupus, croup, catarrh, asthma, ulcers, and bronchitis - to mention only a few. Indeed, tincture of iodine, iodoform, or one of the iodides, was applied to almost every case that resisted the ordinary routine of practice; and between 1820 and 1840 there appeared a remarkable series of essays and monographs testifying to the extraordinary benefits to be achieved by this new and potent remedy. "Unfortunately, these monographs disappeared from US medical libraries. Since mid 1800's iodine became extremely popular for treatments of a wide range of illnesses. Treatments of some diseases called for ingestion of gram amounts per day, however, most treatments were from 5 to 50 mg daily. The recommended daily amount of iodine by Dr. G. Abraham is 0.1-0.3 ml Lugol containing 12.5-37.5 mg elemental iodine. This is exactly the amount of iodine needed for whole body sufficiency, based on a recently reported iodine/iodide-loading test (10). Thyroid gland sufficiency for iodide is achieved with a daily intake of 6 mg.
The first iodophobic authority emerged in early 1900's, Prof. T. Kochler who reported that he suffered from hyperthyroidism following ingestion of iodide (just a single individual case, not a statistical research study!) Despite this the number of applications grew. In an International Index published in 1956, and devoted exclusively to iodine pharmaceuticals, no less than 1,700 approved iodine-containing products were listed. In 1948 Wolff and Chaikoff published that serum inorganic iodide levels at a concentration of 1 µM blocks the synthesis of thyroid hormones, resulting in hypothyroidism and goiter in rats, but this conclusion was erroneous as they even did not measure thyroid hormones in the rats studied, and of course, hypothyroidism and goiter were not observed in those rats. There were many organic forms of iodinated drugs that were quite poisonous. Unfortunately, medical establishment did not make a distinction between organic and inorganic forms of iodine and iodophobia became more popular. I do not exclude Big Pharma role towards iodophobia popularization, because the more sick iodine-deficient people the better is the business. Iodine was added to bread so that one slice contained 150 mcg of iodine (current recommended daily allowance). In 1980, due to iodophobia, bromine replaced iodine in bread, and since bromide is an antagonist to iodine (it is goitrogenic), it deepened iodine deficiency in USA. Moreover, a big push to remove salt from our diet (the only grocery item still supplemented with iodine) exacerbated the problem. The only nation that resisted iodophobia is Japan, statistically the healthiest and longest living nation on the planet. Their average daily consumption of iodine is around 5 mg, with various reports ranging from 1 to 18 mg. In a study of reported daily iodine intake versus total number of clinical symptoms, an intake of approximately 1 mg per day correlated with the lowest number of reported symptoms, that is, the highest level of health (11). Recent popularization of bromides in our food supplies likely increased this amount.
According to Dr. G.E. Abraham (The Wolff-Chaikoff Effect: Crying Wolf? ), "proper amounts of iodine in the food supply should be considered one of a nation's greatest assets. Removing iodine from the food supply is a form major mistake. Supplying daily intake of iodine for whole body sufficiency (100-400 times the RDA) gives protection against goitrogens and radioactive iodine/iodide fallout; improves immune functions, resulting in an adequate defense system against infection; decreases singlet oxygen formation which is the major cause of oxidative damage to DNA and macromolecules, resulting in an anticarcinogenic effect in every organ in the human body; results in a detoxifying effect by increasing urinary excretion of the toxic metals lead, mercury, cadmium, and aluminum, as well as the goitrogens fluoride and bromide; normalizes hormone receptor functions resulting in improved response to thyroid hormones both endogenous and exogenous; and results in better control of blood sugar in diabetic patients; stabilizes cardiac rhythm, obviating the need for the toxic sustained release form of iodine, amiodarone; and normalizes blood pressure without medication in hypertensive patients. Iodine deficiency is the major cause of cognitive impairment, worldwide. Therefore, iodine sufficiency would result in optimal cognitive function, something of great importance to every nation."
The iodine-cancer connection.
The body requires iodine to metabolize both omega-3 and omega-6 fatty acids. A substance called delta-iodolactone, a derivative of arachidonic acid, which is produced in the thyroid gland and breast tissue, prostate, colon, and the nervous system, is a regulator of a process called cellular apoptosis ("cell death"). Ascorbic acid is required to stimulate intracellular hydrogen peroxide synthesis that, in turn, provides the energy to make iodine free radicals necessary for this reaction. When the level of delta-iodolactone is high enough, the process of apoptosis can then kill cancer cells (18).
Unfortunately, the recommended daily allowance (RDA) for iodine - about 150 mcg per day - will not allow delta-iodolactone to be formed in the thyroid gland. The thyroid requires higher iodine concentrations to efficiently produce it. Researchers have found that 100 times the RDA amount of iodine is optimal to produce delta-iodolactone. That equates to taking about 15 mg of iodine per day (18, 19). These findings are important because they imply that there are some biochemical reactions that require much larger amounts of iodine than the current RDA. The mechanism by which delta-iodolactone induces cell death may be important pathway for curing some types of cancer.
4. Forms of Iodine
Inorganic iodine exists in 6 oxidative states, from -1 to +7. The most reduced form (with most electrons) is iodide (I-); an example is potassium iodide. Diatomic form of elemental iodine has no electrical charge. No electrical charge has also unstable and highly reactive monoatomic Iodine (free radical, labeled as I with a dot, ). It can be produced by exposing I2 to ultraviolet light (note that electric and magnetic field won't do it, as incorrectly suggested by Nascent Iodine manufacturers). More oxidized forms of iodine are: hypoiodite (I+1), iodite (I+3), iodate (I+5), and periodate (I+7). Our organism may convert (reduce) these forms to biochemically available iodide, but at the cost of wasting internal antioxidants. All forms of positively charged iodine are relatively poisonous, with established lethal doses (LD50) in the range of 35 (for hypoiodite, such as IO-) to 2100 (for iodates, such as [IO3]-) mg/kg. Elemental iodine (I2) and iodides (I-) are non-poisonous. However, a bad "antiseptic" non-culinary taste of iodine (I2) suggests to our senses that this is not so good choice for consumption.
Despite that adverse taste, almost all the research on iodine supplementation was done using Lugol's Solution (12). Original solution is called 5% Lugol's Iodine, but in reality it consists of 12.5% iodide/iodine or (I-/[I3]-) ions. Two drops of Lugol's Solution (0.1 ml) contain 12.5 mg iodine/iodide mix. Iodine tablets, Iodoral (there are other trade names as well, see Chapter 6), a solid form of Lugol's solution, was created to mask the taste and make the doses more precise for dietary supplementation.
I have some reservations to why Lugol's solution should be the main supplementation source. The problem with elemental (I2) iodine is that it is not naturally occurring in nature in solid form. Iodine crystals quickly end up in a gas state by a process of sublimation. In the air there is negligible amount of iodine, from 0.2 to10 ng per cubic meter of mostly I2 (and much less I-, OI-, or organic CHI3, CH2I2, etc.) Our bodies also may not 'know' how to handle I2 present in Lugol's, and possibly larger amounts of elemental iodine are only dissolved in lipoproteins and stored in cell membranes, mainly in the adipose tissue, without any active role in the metabolism. It simply gets stuck due to lack of efficient excretion mechanism. On average, it takes 3 months of Lugol's 50 mg/day diet to saturate the body. I'd be very interested how iodine loading test would work using plain potassium iodide instead. My guess is that much less iodide would be required and the body would achieve the saturation level in a shorter time. Another question is whether reaching the saturation level should be the goal - probably not. Iodine skin patch test is worthless in my opinion because mostly other factors than iodine deficiency is responsible for brown color fading. Measuring TSH and T4 may be a useful marker for iodine status, but some other iodinated compounds other than T4 and T3 are synthesized by our bodies, and there is no test for that.
I need to mention a few words about Edgar Cayce's atomidine. This great visionary made several readings about the best form of iodine supplement (14). Some people claim that this was iodine trichloride, but it can't be true as this compound is toxic by ingestion and damaging to mucous membranes. It decomposes to ICl and poisonous gas Cl2 at 77 degrees C and also in water at room temperature (15). Most likely Cayce's atomidine was simply a 1% iodine solution in 95% ethanol. Elemental Iodine is in diatomic form (I2), despite mentioned post-treatments (16), as mentioned above. I am surprised that there are educated people, even medical doctors who claim that "elemental monoatomic iodine" preparations (Atomidine, Nascent Iodine etc.) are the best forms of iodine supplements. May be it has something to do with efficient marketing? Elemental Iodine solubilizes in glycerin. This etanol to glycerol replacement makes these supplements more consumption-friendly indead, so they are sold by some vendors as superior products to Cayce's ethanol-formulated one. Personally, I think glycerol-based I2 products are inferior forms of iodine supplements to iodides, but they are excellent antseptics.
To defend correctness of Cayce's vision, in thyroid, I- ion and amino acid tyrosine react through a short intermediate step by forming monoatomic free radical (selenium and hydrogen peroxide are involved) to make monoiodotyrosine. Diiodotyrosine is formed analogical way, and finally, two of these molecules combine to final product of thyroxine, see diagram in ref. 17 and reactions listed below. All those steps are carried by enzyme thyroid peroxidase, attached to protein thyroglobulin. So, yes, monoatomic iodine exists in human bodies, and it directly reacts with tyrosine, but no, it wouldn't be healthy to consume iodine free radicals as their high reactivity would prevent safe transport through various membranes (a good analogy would be to transport a live armed bomb  versus disarmed component [I-]).
Since mid 1930's thyroid hormone thyroxine became available on the market. This was a blessing for people who had damaged their thyroid. Unfortunately, doctors started to prescribe this hormone to just about anybody with hypothyroidism, arrogantly thinking that they can control better thyroid hormone levels than our bodies can. Iodine is an iodine, no-matter-in-what-form mentality became a dangerous trend, understandably fueling iodophobia scare, especially that most medical bureaucrats do not recognize the difference between raw material (iodine) and its product (hormone). Yes, you may mess up your metabolism by taking unmonitored amounts of the hormone, but not so much by supplementing your food with moderate amounts inorganic iodine.
Pharmaceutical industry came up with lots of organic forms of iodine (organic, meaning that iodine is bound to a carbon atom containing molecule and NOT meaning it's grown in a pesticide-free environment), all relatively toxic and certainly not to be used without strict medical supervision. In summary, only inorganic forms of iodine, I- and I2, are safe for supplementation (20, 21)
Examples of iodine-involved reactions in our body:
I2 + H2O <-> OI-(aq) + 2H+(aq) + I-(aq)
I2+I- -> [I3]-
Thyroid peroxidase reaction:
Tyrosine + I- + H+ + H2O2 ->-> Monoiodotyrosine + 2H2O
Iodotyrosine + I- + H+ + H2O2 ->-> Diiodotyrosine + 2H2O
Monoiodotyrosine + Diiodotyrosine -> Triiodothyronine (T3) + Alanine
Diiodotyrosine+ Diiodotyrosine -> Thyroxine (T4) + Alanine
Deiodinase reaction: T4 -> T3 + I-
5. Iodine Uses
Iodine plays critical role in human metabolism. According to the opinion of many researchers the RDA (recommended daily allowance) value of 150 mcg for iodine is too low, especially when this element is commonly substituted with competing element bromine. Therefore, the main use of iodine is the dietary supplementation. There is a number of medical conditions where iodine is either essential or helpful, see Chapter 1. For the optimal results, iodine/iodide should be supplemented with selenium, magnesium, copper (there is usually enough of it in tap water as copper is widely used in plumbing), vit. B2 (riboflavin) and B3 (niacin). For heavy metal and halides (fluoride, bromide) detoxification combining chlorides (NaCl, KCl or NH4Cl are the main ones, about 6 g) with iodides speeds this process up several fold. Potassium iodide is my favorite choice, iodides are found in Kelp (22; they function there as antioxidants) and other sea algae. Ask your doctor before taking any iodine supplements, especially if you are on medications.
Elemental iodine (I2) is antibacterial and antifungal, so that iodine or iodine/iodide solutions are used topically to sterilize wounds, or internally to fight infections, such as vaginitis and sore throat, and also to sanitize drinking water. Because I2 is antibacterial, drinking it may cause friendly bacterial flora to suffer and result in diarrhea and stomach cramps (the same applies to Lugol's solution, but to a lesser extent as it contains iodides as well).
Ingestion of iodides prevents destructive radioactive iodine to incorporate into the body (mainly into the thyroid) in case of nuclear accidents. It also may help flushing already incorporated radioactive iodine from the thyroid, although too much iodine inhibits secretion of T4/T3 from the gland.
Lugol's solution is also used to detect starch and glycogen by forming a dark blue complex.
6. Inorganic Iodine Availability
The most common form of iodine supplement is Lugol's solution (12). The original solution contains 5% of iodine and 10% iodide. It is readily available on Amazon and eBay, made by many companies. J.Crow's brand is perhaps the best known, but basically any brand is just about equal to this one because of extreme simplicity of the contents. A solid form of Lugol's solution, a pill, is called Iodoral, originally made by Optimox, but sold also as other brand names such as Advanced Iodine Complete, IodoRx, Triple Iodine Complex or IO Plus are the examples. Iosol is an iodine/ammonium iodide mix in glycerol, an inexpensive and more pleasant alternative to Lugol's for supplemental iodine source. As late as 1995, the 19th Edition of Remington's Science and Practice of Pharmacy, continued to recommend between 0.1-0.3 ml daily of Lugol 5% solution in the treatment of iodine deficiency and simple goiter.
Potassium iodide (KI) is available as tablets as well. Besides the salt generic name, it may be sold under various names, High Potency Iodine, Pure Encapsulations Potassium Iodide are the examples. Various products that have Kelp in their names are iodides as well. There is a variety of products in liquid form. Ionic Iodine and Liquid Iodine are diluted in water KI. Liqui-Dulse or Liquid Dulse, Liqui-Kelp Progena Meditrend are the examples of algae extracts containing iodides. Check the label how much you buy for the dollar as some of them are very diluted. Other seaweeds also contain appreciable amounts of iodides. There is some in sea fish, and milk or yogurt, potatoes and cranberries provided they lived in not iodine-depleted areas.
Elemental iodine. It is extremely difficult to find iodine solution in alcohol from a company that is not hyped on marketing and not promising supernatural monoatomic iodine. Detoxified Iodine Cayce Concepts Brand (Juanitas Mexican Food Emporium) is the actual Cayce's formula, being 1% iodine in ethanol. 2% iodine in isopropyl alcohol, intended for external use on animals is sold (half a liter for under $10; this is a good indicator how cheap this product should be) by Leedstone. These are the closest ones to Edgar Casey's atomidine that I could find on the Internet. Walgreens used to sell Iodine Tincture but not any more. I suspect it is hard to find this solution because it used to be sold for a very low price. Iodine crystals you may buy on eBay and make it by yourself very easily (using either alcohol or glycerol). So, the next closest one to Cayce's formula is iodine dissolved in glycerol. Magnascent Iodine, Nascent Iodine and Detoxadine are the examples. Contrary to the manufacturer's claims, it is diatomic. One or 2% iodine solution in glycerol, that's all it is. All the 'monoatomic' hype was created to inflate the price several fold. Besides, if the monoatomic claims were really true, who would really want to drink free radicals? They are not transported freely in our bodies because they are too reactive. Actually, elemental iodine preparations including iodine dissolved in glycerol are better products for external antiseptic use rather than a supplement, in my opinion.
Other forms of iodine supplements. Thyadine is a mixture of some algae and thyroid extract in glycerin, water and ethanol. It is likely not harmful because T3 and T4 are in very small amounts, and the whole iodine serving size is also small. Other complex formulae are Thyroid Support, Thyrax, Thyroid helper. Povidone-iodine (23) is a good antiseptic, but not a good supplement. Atomidine as iodine trichloride, a supposedly Edgar Cayce's remedy, should be avoided as a supplement because it is too toxic.
Overdosing any of the iodine supplements may lead to swollen salivary glands, metallic aftertaste and skin rash and itching (that are usually due to rapid process of detoxification from heavy metals fluorides and bromides), faster heartbeat or palpitations and diarrhea. The symptoms should disappear quickly, usually within one day, when supplementation is stopped. Iodine stabilizes thyroid hormone production, so it is an adaptogen, but in rare cases, such as acquiring allergy to iodine, it may actually misbalance it.
1. Established RDA allowance for iodine (150 mcg/day) is inadequately low, especially in populations supplemented with bromides and fluorides. It seems like in order to maintain optimum health adults need 2-5 mg of iodide daily. Actually, it is in line with the upper safe limit of dietary intake of iodine established by FAO (30 mcg/kg/day). In case of a dysfunctional thyroid or other illnesses, such as fibrocystic breast disease or cancer, 15-50 mg daily may be needed. Ask your doctor what are the alternatives to hormone therapy or taking iodine-containing organic drugs because the cheap "orthoiodosupplementation" is not his first choice.
2. The best and safest form of iodine supplementation for a healthy adult is iodide. Iodides are naturally produced in larger quantities by various seaweeds. No significant natural supplement source of elemental iodine exist.
Disclaimer. Please consult your doctor about iodine supplementation, as in your particular case it may be contraindicated. Medical doctor is the only authority who may legally give you advice on your health.
Article from Massage Magazine about iodine.
1. The History of Iodine in Medicine Part III: Thyroid Fixation and Medical Iodophobia; Guy E. Abraham, M.D. http://optimox.com/pics/Iodine/IOD-16/PUB_16.htm
2. Best Kept Secret, John Dommisse, MD (2009) http://www.westonaprice.org/modern-diseases/best-kept-secret/#sthash.vdrKPaJw.dpuf
4. Iodine deficiency in Egyptian autistic children and their mothers: relation to disease severity. Hamza RT1, Hewedi DH, Sallam MT. (2013) Arch Med Res. 44(7):555-61. http://www.ncbi.nlm.nih.gov/pubmed/24120386
5. The Concept of Orthoiodosupplementation and Its Clinical Implications, Guy E. Abraham, MD; https://www.optimox.com/pics/Iodine/IOD-06/IOD_06.htm
6. The History of Iodine in Medicine Part I: From Discovery to Essentiality, Guy E. Abraham, M.D. http://optimox.com/pics/Iodine/IOD-14/PUB_14.htm
7. The historical background of the Iodine Project, Guy E. Abraham, M.D. http://www.optimox.com/pics/Iodine/IOD-08/IOD_08.htm
8. The History of Iodine in Medicine Part II: The Search for and the Discovery of Thyroid Hormones. Guy E. Abraham, M.D. http://optimox.com/pics/Iodine/IOD-15/PUB_15.htm
9. Kelly FC. "Iodine in medicine and pharmacy since its discovery – 1811-1961." Proc R Soc Med, 1961; 54:831-836. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1869599/
10. Abraham G.E. "The safe and effective implementation of orthoiodosupplementation in medical practice." The Original Internist, 2004; 11(1):17-36. http://www.hakalalabs.com/Research/Abraham_OI_Mar04.pdf
11. The Great Iodine Debate, S. Fallon Morell (2009); The WestonA. Price Foundation, http://www.westonaprice.org/modern-diseases/the-great-iodine-debate/
12. Bacteriological Analytical Manual, R40 Lugol's Iodine Solution (2001), http://www.fda.gov/Food/FoodScienceResearch/LaboratoryMethods/ucm062245.htm
13. A Product with Many Purposes, Elaine Hruska, True Health Newsletter, http://www.cayce.com/Atomic_Iodine_True_Health.html
14. Review of Atomidine, International Wellness Directory, http://www.mnwelldir.org/docs/reviews/atomidine.htm
15. Material safety data sheet, http://www.mnwelldir.org/docs/history/Iodine_Trichloride.pdf
16. Making atomidine: http://www.johncfish.com/silver/nascentIodine/index.html
18. The Cancer-Iodine Connection, D. Brownstein, M.D. (2015) http://www.newsmax.com/Health/Dr-Brownstein/iodine-cancer-cell-death-fish-oil/2015/06/10/id/649877/
19. 6-Iodolactone, key mediator of antitumoral properties of iodine, M. Nava-Villalba, C. Aceves, (2014) Prostaglandins & Other Lipid Mediators 112, 27-33. https://www.researchgate.net/publication/263856609_6-Iodolactone_key_mediator_of_antitumoral_properties_of_iodine
20. The historical background of the Iodine Project, G. E. Abraham, M.D., http://www.optimox.com/pics/Iodine/IOD-08/IOD_08.htm
21. A Rebuttal of Dr. Gaby's Editorial on Iodine, G. E. Abraham, MD and D. Brownstein, MD (2005) Townsend Letter, The Examiner of Alternative Medicine, http://www.townsendletter.com/Oct2005/gabyrebuttal1005.htm
22. Iodide accumulation provides kelp with an inorganic antioxidant impacting atmospheric chemistry; Küpper, F.C. et al. (2008) Proc. Natl. Acad. Sci. USA 105, 6954-6958. http://www.pnas.org/content/105/19/6954.full