Favism is an inherited deficiency of the enzyme G6PD, which produces the important antioxidant NADPH. The G6PD gene is located on the x-chromosome at Xq28.
The fact that falafel probably didn’t exist in 500 BC isn’t the only reason that Pythagoras didn’t eat them. This biochemist inside joke revolves more around what falafel is made of, rather than the food itself. Fava beans, the core ingredient in falafel, is what Pythagoras had a problem with. He famously advised his students “…Be far from the fava bean consumption…”
What’s wrong with fava beans?
Fava beans have a long history among humans. Since their cultivated appearance during the Neolithic Age in the Near East, they have been shrouded in superstition and have led to some delicious condiments. They have been revered, feared and chewed on for centuries. Throughout history, it was seen that some people who consumed fava beans became anemic. No one could understand why this happened. It was only in the past few decades that the fava bean mystery was finally cleared up.
This clarity didn’t happen overnight. It took the first half of the 20th century to understand RBC metabolism and the effects that various drugs may have on it. The Korean War provided the last pieces of essential information.
During that war, American soldiers were given primaquine, a drug to help fight malaria. That lifesaving drug turned out to have some unforeseen consequences. Many African-American soldiers given primaquine developed severe hemolytic anemia (when RBCs burst inside the body). After the war ended, scientists began their primaquine investigations. What they found was a genetic disorder resulting in the deficiency of a particular enzyme. It didn’t take long for scientists to connect these dots to fava bean consumption, which is why the disease came to be called Favism.
What is Favism?
Favism is an inherited disorder that causes a deficiency of an enzyme called Glucose-6-phosphate dehydrogenase, or G6PD for short. The gene for this enzyme is located on the X chromosome of the sex chromosome pair, meaning that a mutation in the G6DP gene in an XY combination leads to a deficiency of the enzyme. Females with XX combinations would require both copies of the X chromosomes to have a mutation in the gene. The gene is located at position 28 on the long arm of the X chromosome, and is denoted as Xq28.
There are 2 normal versions of the G6PD gene – GdA+ and GdB. There can be hundreds of different disease-causing mutations that can be categorized roughly depending on the origin – GdA- of African origin and GdMed of Mediterranean origin. Not all individuals with mutations in this gene will have a deficiency to the same extent. Some individuals only have mild hemolytic anaemia, which can be managed and treated, while in other individuals the response to certain drugs and foods can be life-threatening!
What is G6PD and why is it so important?
G6PD is an enzyme that catalyses the first reaction in the pentose phosphate pathway. This reaction produces a molecule called NADPH, which is short for Nicotinamide Adenine Dinucleotide Phosphate Hydrogen, by reducing (adding electrons) to NADP+. NADPH is an important electron-donating molecule, i.e., it can reduce other molecules. Cells use NADPH when they are building new biomolecules or as a protective measure against oxidative stress.
Oxidative stress occurs when a cell has a build-up of certain free radicals. These free radicals are highly reactive molecules or ions produced as byproducts during metabolic reactions. Free radicals like peroxide, hydroxide radical (OH–), superoxides, singlet oxygen (oxygen with an unpaired electron), and alpha-oxygen are called Reactive Oxygen Species or ROS. These ROS can react with biomolecules like proteins, lipids and nucleic acids (DNA and RNA), causing them to become defective. This can eventually lead to mutation or cell death.
Protecting the RBCs: NADPH and glutathione
In most cells, this isn’t a problem, even with a G6PD deficiency, as they have other ways of protecting themselves. In times of oxidative stress, however, cells produce a host of protective proteins that offset the damage caused by free radicals. However, RBCs do not have a nucleus or genetic material. They cannot generate any protective proteins and therefore rely solely on certain built-in protective mechanisms. NADPH produced by G6PD plays a central role in this protection.
NADPH interacts with another protein called glutathione to shield the cell from free radicals. Glutathione, just like NADP+, exists in two forms—a reduced form (GSH) and an oxidized form (GSSG). The first step of the antioxidant defense is NADPH reducing GSSG using glutathione reductase. This produces two reduced glutathione molecules. These reduced glutathione molecules go on to reduce free radicals, especially peroxides, which are the biggest threats to the RBCs. The glutathione returns once more to its oxidized state as GSSG waiting to be reduced by another NADPH molecule. An NADP+ molecule is generated in the first reaction, which goes on to G6PD to get reduced again, repeating the cycle over and over.
Without enough G6PD, the RBC will have a shortage of NADPH. Without NADPH, glutathione won’t be able to reduce free radicals, and the result will be Chaos! Anarchist free radicals will oxidize lipids that make up the cell membrane and the proteins that hold the membrane together. The RBC’s walls get weaker and weaker until it breaks apart, a condition called hemolytic anaemia. The RBCs that burst open will spill their toxic free radicals into their surroundings, where they can cause even more damage to the surrounding cells.
How do Fava beans cause this havoc?
The culprit molecules in the beans are vicine and convicine. These molecules, otherwise inert, get converted into a toxic free radical, divicine, by gut bacteria. The intestines absorb divicine, so it ends up in the blood, where it poses a risk in individuals with favism. Divicine produces more free radicals in RBCs, which pile up, finally causing hemolysis. If too many RBCs are lost, a person will experience a case of hemolytic anaemia! The anti-malarial drug used in Korean War behaves in a similar way, which explains the mysterious ailment that affected so many soldiers.
Did Pythagoras know about fava bean’s disease-causing capabilities? It’s contentious. His motives against the fava bean might be more superstition than knowledge of the disease itself. Philosophers like Aristotle, Aulus Gellius, a Roman author, Diogenes Laertius, and many more throughout the ages speculated about the reason for Pythagoras’ aversion to this bean. Reasons ranged from superstition, since the beans looked like the gates of Hades, or perhaps because they looked like genitals, testicles or eggs. Orphics believed that the beans harbored the souls of the dead, and said, “Eating fava beans and gnawing on the heads of one’s parent are one and the same thing”. Some like Diogenes Laertius believed in Pythagoras’ logic, proposing that because the beans caused gas and an upset stomach, they were to be avoided.
What Pythagoras actually believed is anyone’s guess, but it was these very beans that caused his ultimate death. Refusing to pass through a fava bean field, Pythagoras was caught by his enemies and killed in 495 BC. Tragic irony, indeed.