Leonardo's Foot

by Carol Ann Rinzler

  For centuries, most conditions causing joint pain were called rheumatism, from the Latin and Greek word rheum meaning flowing. In Old English rheum meant a thin watery discharge from your eye or nose, and, in the words of the Oxford English Dictionary, rheumatism was a medical condition assumed to be caused by “a ‘defluxion’ [sudden disappearance] of rheum,” perhaps because arthritic joints were perceived to turn dry and crackly when they lost their natural lubrication. Eventually, with more precise diagnosis and definition, the single illness, rheumatism, became the arthritides, a category of autoimmune miseries running from A (ankylosing spondylitis) through V (viral arthritis). All are conditions in which the body attacks itself, inflaming and destroying connective tissue, the fibrous material that connects and supports organs, bones, and joints.3

  Nobody called gout “gout” until the middle of the thirteenth century when Ralph Bocking (1197–1258), a.k.a. Randolphus of Bocking, a Dominican monk and chaplain to Richard de Wyche (1197–1253), Bishop of Chichester, proposed the name.4 Bocking’s choice of the word gout, from the Latin word gutta meaning a drop, reflected a view of disease adopted from Hippocrates’ theory of the four humours, the basis of the Pneumatic School, an ancient Greek and Roman school of medicine. The idea was that good health depended on vital air (pneuma) and a balance among the four humours—yellow bile, black bile, phlegm, and blood—drops of elements in the body whose relationship determined both personality and physical health. Each humor was linked to a season of the year, an element of the environment, a degree of temperature and moisture, and a psychological condition:

  Yellow bile= summer, fire, hot and dry, characterized by a hot temper.

  Black bile= autumn, earth, cold and dry, characterized by melancholy.

  Phlegm= winter, water, cold and moist, characterized by a calmness.

  Blood= spring, air, hot and moist, characterized by passion and optimism.

  The idea was scientifically wrong, but like most of Hippocrates’ theories, a giant step forward nonetheless. With “germs” a concept still centuries in the future, Hippocrates challenged the prevailing view of illness by proposing that a person’s health depended on conditions—humours—in the body rather than on divine intervention. As for Randolphus’ suggestion that an ache in the big toe was due to drops of something slipping from the blood into the joint, although primitive, the premise was a step in the right direction.

  Leading first to the dinner table.

  Podiatric protein problems

  Protein molecules are built of chains of amino acids. It was long assumed that the fewest number of amino acids required to build a protein molecule was forty to fifty, but in 2004, scientists at the National Institute of Advanced Industrial Science and Technology (AIST) in Japan were able to synthesize one containing only ten “amino acid residues,” amino acid molecules that have joined another amino acid and lost one water molecule in the process.

  Chemistry is a science of continuing wonder. The Japanese researchers made a very small protein. By comparison, Titin, a stretchable protein that acts like an elastic spring in cardiac and skeletal muscles, has 34,350 amino acids, 539,022 atoms, a chemical formula that reads C169,723 H270,464 N45 688, O52 243S912, and a chemical name 189,819 letters long, making it the longest word in the English language. It is not easy to find the complete name. The first sites I came across that promised full disclosure showed this:

  Methionylthreonylthreonylglutaminylala …

  ylglutaminylprolylleucylglutaminylsery …

  serylthreonylalanylthreonylphenylalan …

  ylglycylphenylalanylprolylvalylprolyl …

  anylarginylaspartylglycylglutaminylva …

  Assuming that the dots (…) meant, “Pick up next line here,” I spent about two hours doing just that. When I was done, I ran the stats and found I had filled fifteen pages, but had fewer than half the required number of letters. I finally discovered what purports to be the correct name, this time with 189,819 individual letters that filled 73 pages on my computer, which is why I am not reproducing it in its entirety here. Is what I found the correct sequence? I cannot say with absolute certainty. For all I know, the site that printed it missed or misplaced a letter here or there. But if it isn’t the real thing, it’s sure a good imitation. And it certainly beats antidisestablishmentarianism, the leading contender for world’s longest word when I was in grammar school and we gauged our intelligence by our ability to spell it.

  When you digest proteins, including the titins in beef, fish, poultry, lamb, and pork muscle foods, their large molecules break apart. One by-product of this process is purines, nitrogen compounds in protein foods. The name, chosen by German chemist Emil Hermann Fischer (1838–1914), awarded the Noble Prize in chemistry in 1902 for his synthesis of purines and sugars, comes from the Latin word purum meaning pure.

  To the chemist, a purine is a heterocyclic aromatic organic compound, consisting of a pyrimidine ring fused to an imidazole ring. To the layman, this translates as a compound comprising more than one kind of carbon-containing ring-shape molecule in a structure that includes one specific ring-shape crystalline molecule with nitrogen atoms stuck to another ring-shape molecule with nitrogen atoms. Some purines occur naturally in body cells; others enter your body with the proteins in your food. The purines in body cells are called endogenous purines; those made when you digest proteins are called exogenous purines.

  Caffeine, the stimulant that makes coffee stimulating, is an exogenous purine first isolated in 1819 also by a German chemist, Friedleib Ferdinand Runge (1795–1867). Runges’ other major achievement was the invention of paper chromatography, a process used to identify the chemicals in an unknown mixture by putting a drop of the mixture onto a piece of absorbent paper, adding a solvent, and then watching as the components in the mixture separate out at different speeds and migrate to different sites on the absorbent paper. Eventually, this produces a pattern called a chromatogram, which you can compare to a diagram of known chemicals and thus figure out what’s in your unknown mixture.

  After Runge scored his caffeine coup, other chemists working independently identified several stimulants in tea and chocolate and guarana without realizing that they had simply rediscovered caffeine. In 1840, the work of two chemists named Martins and Berthemot revealed that everything everyone had found was identical to the caffeine extracted from coffee beans. Alas, although Martins and Berthemot are mentioned in most histories of caffeine, their first names and where they worked seem to have been lost to history. Neither contemporary sources such as the first edition of the United States Dispensatory (1868) nor the mighty Google turn up anything other than the date, their last names and the “independent” nature of their research.

  As you can see from the drawings below, the chemical structures of caffeine, theophylline (from tea), and theobromine (from chocolate) are similar to the purines adenine and guanine, two endogenous purines found in DNA/RNA that play a role in the synthesis of DNA and the bonding of one cell to another.

  Like protein molecules, purine molecules break apart during digestion, a metabolic divorce that produces a waste product called uric acid. About 20 percent of the uric acid in our body comes from digesting proteins; the rest is made in our liver from adenine and guanine. Ordinarily, excess uric acid dissolves in our blood and is eliminated through our kidneys. But if our body makes much too much uric acid or doesn’t eliminate the compound efficiently, blood levels of uric acid rise (a condition known as hyperuricemia), and the excess uric acid crystallizes into sharp needles of monosodium urate, particles that clump together as chalky white tophi. The first person to see the uric acid crystals in tophi was the Dutch microscopy pioneer and naturalist, Anton von Leeuwenhoek (1632–1723) in 1679. In 1776, pharmacological chemist Carl Wilhelm Scheele (1742–1786) isolated uric acid in urine and mineralogist Tobern Bergman (1735–1784) found uric acid crystals in bladder stones. They did not have to look far to find their material: Both Scheele and Bergman were Swedes working in the
country that was home to the high-purine herring, to the sauna famed for its ability to soothe arthritic pain, and to Carolus Linnaeus (1741–1783), the professor of Natural History at Uppsala University whose own gout did not keep him from creating the genus/species system for naming and classifying living creatures.

  Before anyone knew about proteins or purines or uric acid, it was obvious that a diet rich in certain foods such as meat (particularly organ meats) and seafood (particularly anchovies and herring) were linked to a higher risk of gout. In 1905, Meals Medicinal, a collection of “Curative Foods from the Cook, in Place of Drugs from the Chemist,” by W.T. Fernie, M.D., of London, advised the reader that “unlike beer, or any other malt liquor, [cider] acts as an antidote to gout,” “natural” wine provides a “natural immunity,” fortified wines “set gout going viciously in the system,” apple juice “neutralizes acid products of digestion or gout,” blackberries and mulberries are “particularly wholesome,” and cabbage, a sort of panacea, cures “constipation and dysentery, headache, and lumbago; retention, and incontinence of urine, pains in the liver, and affections of the heart; colic, toothache, gout and deafness.”

  Modern research confirms the culpability of some, but not all high protein, high purine foods. As a general rule, those yielding 150–1,000 milligrams purine in a 100-gram (3/5 ounce) serving are considered high in purine. Moderate purine foods yield 50–150 milligrams per 100 grams; low purine foods, 0–50 milligrams per 100 grams. If you have gout and must watch your diet, your doctor or nutritionist is likely to hand you a food list that looks something like this:

  High purine foods: Game (quail, rabbit, venison), organ meats (brains, heart, kidney, liver, sweetbreads), fish (anchovies, herring, sardines), shellfish, beer and wine.

  Moderate purine foods: Poultry (other than game), red meat (beef, lamb), fish other than the high purine varieties, whole grain bread, cereal and pasta, legumes (beans, peas and peanuts).

  Low purine foods: Dairy products (butter, eggs, milk, yogurt), fruits, broccoli, cauliflower, mushrooms, spinach—most vegetables other than asparagus—nuts and spice.

  White, brown, or “raw,” sugars are also low purine foods, thus considered acceptable for people with gout. More complicated sweeteners turn out to be more complicated.

  In 2004, investigators at Massachusetts General Hospital (Boston) released the results of a 12-year-long study tracking the dietary habits of nearly 50,000 men who were gout-free at the start. Yes, the men who ate lots of meat (particularly organ meats) were more likely to develop gout, but gorging on high-protein vegetables such as beans and peas had no such effect, and eating lots of high-protein dairy foods actually lowered the risk. Four years after that, researchers discovered a new culprit hiding on the grocery shelf: The fructose-sweetened beverages targeted by anti-obesity experts and the Mayor of New York City who, in 2012, proposed banning soda servings larger than 16 ounces in public venues such as sports stadiums, thus making himself seriously unpopular with a wide swath of the populace. In 2008, nutrition scientists at the Arthritis Research Centre of Canada/University of British Columbia (Vancouver) announced that data from their own 12-year study of more than 46,000 male volunteers showed a higher-than normal incidence of gout among men drinking soft drinks sweetened with this particular sugar. Compared with men who drank less than one fructose-sweetened soda a month, the risk for men drinking 5-to-6 sweetened sodas per week went up 30 percent; it was 45 percent higher for men drinking a soda a day and a whopping 85 percent higher for those whose daily diet included two or more sweetened sodas.

  Diet soft drinks? No problem. Substituting fruit juices? Possible problem. “[F]ructose rich fruits and fruit juices,” the study authors warned, “may also increase the risk.” This is one case in which an apple a day won’t keep the doctor away because apples, applesauce, apple juice, pears, dates, and watermelon are all high fructose foods, and too much fructose may reduce your body’s ability to flush away the excess uric acid that turns into crystals that turn into gout.

  Blame it on your genes.

  As you know, the early Greeks suspected that it made good sense to pair animals with “good” characteristics to produce “good” offspring, and that in humans some abnormalities such as clubfoot ran in families. In 451 BCE, Hermodorus took Plato’s theories of eugenics for humans to the Decemvirs in Rome who wrote into law a father’s duty to dispose of infants with birth defects. Six hundred years after that, Aretaeus of Cappadocia (c. 130–200), a Greek physician practicing in Rome, identified and named diabetes with the Greek word for siphon, a reference to the diabetic’s frequent urination. Then he came up with a word to describe the source of human abnormalities, diathesis, Greek for tendency. Aretaeus didn’t say a diathesis caused a specific disability, disease, or medical condition; his very smart and very advanced idea was simply that having the tendency—what we may now call a genetic predisposition–made a person more susceptible to developing the problem.

  In The Book of Animals, African Arab scholar Al-Jahiz (Abu Uthman Amr ibn Bahr al-Kinani al-Fuqaimi al-Basri, c. 776–869) described natural selection centuries before Darwin. Latin translations of his work were in the libraries of Linnaeus and of Jean-Baptiste Lamarck (1774–1829), the latter most famous for wrongly proposing that an acquired characteristic could be passed along to succeeding generations. In Al-Tasrif (The Method of Medicine), another medical and surgical encyclopedia, the Arab physician, surgeon, and chemist Abu al-Qasim Khalaf ibn al-Abbas Al-Zahrawi, a.k.a. Albucasis (936–1013) seems to have been the first to describe the hereditary nature of hemophilia.

  But then, amazing as it seems, the study of genetics receded into the scientific background until 1865, when a Moravian monk named Gregor Mendel (1822–1884) delivered two lectures on his observations of the plants in his monastery garden to the Natural History Society of Brunn (now known as Brno, in the Czech Republic) and then published them in the Verhandlungen des naturforschenden Vereins, the Proceedings of the Natural History Society in Brünn. Mendel was ignored as Raymond Dart had been when he wrote about the Taung Child, and like Dart, he was eventually rediscovered and rewarded, at least intellectually. In May 1900 British zoologist William Bateson (1861–1926), having come across Mendel’s original article, arrived at a meeting of the Royal Horticultural Society in London to cite Mendel in a lecture on “problems of heredity as a subject for horticultural investigation.” A mere 59 years later, Jerome Lejeune identified Trisomy 21 as the cause of Down syndrome, the first conclusive link between a chromosomal aberration and a medical condition. Forty-one years after that, on July 1, 2000, the Human Genome Project released the first draft of the human genome; in 2003, the map of the 20,000–25,000 genes that characterize the human race was completed. In 2012, ENCODE (Encyclopedia of DNA Elements), a multi-institution federal follow-up to the Human Genome Project, discovered that bits of DNA once regarded as “junk” actually contain several million “switches” that play an important role in the behavior of body cells, tissues, and organs.

  That brings us to a less earth-shaking, but important moment in 2009, one year after the fructose/soda study, when a team of scientists from the MRC Human Genetics Unit at Western General Hospital, Edinburgh, and other centers in Britain, Croatia, and Germany, zeroed in on a genetic link between fructose and a higher risk of gout. One in four people born with clubfoot has a relative with the same problem; so does one in every four people with gout. The gene linked to clubfoot is called Pitx1. According to the MRC-led team, the genetic culprit for gout appears to be SLC2A9 (solute carrier family 2, facilitated glucose transporter member 9). This gene ferries sugars, including fructose, and uric acid about the body; a variant (mutation) seems to inhibit the body’s ability to wash uric acid out of the bloodstream, send it to the kidneys, and then out into the world.

  Of course, gene or no gene, not every pain in the toe means you have to give up your soda pop because not every pain in the toe is true gout.

  Pseudogout, known colloquially as f
alse gout and formally as calcium pyrophosphate deposition disease (CPPD), is a form of arthritis that commonly hits at the knees, ankles, elbows, and wrists. Like true gout, it is triggered by the collection of sharp crystals in the joints, but in this case the crystals are calcium pyrophosphate not monosodium urate. The calcium crystals are most likely to occur in older adults, often after severe dehydration leads to chondrocalcinosis, the formation of calcium deposits in cartilage.

  Modern food safety rules have eliminated another risk factor that can make a toe ache: lead. The silvery gray metal was among the first four to be discovered, either along with or after the Big Three: gold (c. 6000 BCE), copper (c. 4200 BCE), and silver (c. 4000 BCE). Unlike gold, copper, and silver, lead is not found alone in nature; it is locked into the sulfur and lead ores galena (lead sulfide) and anglesite (lead sulfate), as well as the carbon and lead ore cerussite (lead carbonate). This was not a problem; lead melts at the relatively low temperature of 327°C / 620°F, so it is easy to extract.5 What the Romans got when they extracted lead was a soft, easily molded, and non-corrosive material perfect for the pipes that carried water throughout Rome and its provinces, thus bequeathing to us the word plumbing from the Latin word for lead, plumbum, meaning soft metal; the chemical symbol for lead is Pb.