Pythagoras: The fava of pharmacogenomics

Pythagoras' crippling fear of fava beans ultimately cost him his life, but also founded a now-booming field of medical research.

 
  Fava beans, shelled and lightly cooked.   Richard W.M. Jones/Wikimedia Commons  (public domain)

Fava beans, shelled and lightly cooked. Richard W.M. Jones/Wikimedia Commons (public domain)

 

Gene Dosage is a monthly column by Janan Arslan that finds out what genome science is uncovering about each individual's unique response to drugs and pharmaceuticals. Janan is a graduate student and pharmacogenomics researcher with a keen interest in personalised medicine.

We’ve all taken medications at some point in our lives. Perhaps you’ve used antibiotics, or plain ole analgesics like Panadol. Sometimes you respond perfectly to a medication, getting the benefits you need with no added ill effects. Other times, however, you may experience nasty side effects. That painkiller comes with a horrid side order of nausea, vomiting, and a speedy trip to the bathroom. 

There are some medications that don’t have any effect, and you wonder why your doctor prescribed that drug in the first place. Your varied response to different medications boils down to one primary factor: your DNA.

This variability in how we respond to drugs is explained through the science of pharmacogenomics, which uses genetics to understand drug response. Before we talk about pharmacogenomics as a science, its applicability, and its effect on our communities as a whole, I'd like to start this column with a history lesson. Don’t look the other way or go clicking elsewhere! It’s more interesting than you think.

Our story begins with the unsung hero of pharmacogenomics; the one who is often mentioned in passing, but never really given enough credit. Well, not enough in my opinion. Yes, that amazing mathematician, Pythagoras.

  A sculpted likeness of Pythagoras.   Unknown/Wikimedia Commons  (public domain)

A sculpted likeness of Pythagoras. Unknown/Wikimedia Commons (public domain)

Most of you probably know him by the Pythagorean theorem. You remember: you spent countless hours in maths class, trying to find the missing length of a right triangle using a² + b² = c². Well, that is just the tip of the iceberg of Pythagoras' achievements. 

Let us begin. Please excuse my dramatic flair as I tell this story in my own special way. Note that there are several versions of the tale, and many historians are not even sure it happened at all.

Picture it. In the year 495 BC, Pythagoras was fleeing from his enemies. Who he was running from, we really don’t know. Perhaps it was the enemies who had set fire to his meeting place in Croton, or perhaps it was a battle in Sicily where Syracusans had defeated the army of Acragas. In any case, Pythagoras ran and ran, until suddenly he came to a screeching halt. Finding himself at the edge of a fava bean (aka broad bean) field, he did not know what to do. One thing was for sure: he was definitely not going to cross that field. No matter what. The delay allowed Pythagoras' enemies to catch up with him. He was captured and later killed.

You're probably thinking "Okay, great. What does this have to do with anything?" Well, dear reader, Pythagoras had a very good reason to resist crossing that fava bean field. Around 510 BC, Pythagoras noticed a connection between fava bean ingestion and haemolytic anaemia: a blood disorder that causes weakness and fatigue. This connection worried him so much that he forbade his followers from ever eating the Vicia faba. He declared the sacredness of the bean, admonishing those who dared to consider eating it. It appears to have truly frightened him. This fear was the reason Pythagoras refused to cross the field on that fateful day.

Pythagoras’ unfortunate end was not in vain. Fast-forwarding to 1956, Carson et al. discovered that there was indeed a link between fava bean ingestion and haemolytic anaemia. Their publication defined this condition as favism: a hereditary abnormality of the red cell enzyme. Pretty amazing, huh? Imagine your work being recognised 2,500 years after your death. You most likely won’t care at that point, but it’s still amazing. With this discovery, Pythagoras unwittingly founded a new area of medicine.

This discovery began a sort of snowball effect. Steadily, more researchers recognised the connection between genetic variability and drug metabolism. In 1957, Motulsky further theorised the role of drug-gene interactions in drug efficacy. The term “pharmacogenetics” was coined around 1957‒1959 by Friedrich Vogel, and in 1961, Evans and Clarke published the first pharmacogenetics titled paper, suitably called “Pharmacogenetics”.

  Pythagoras’ greatest nightmare.   Brian Robert Marshall/Geograph  (CC BY-SA 2.0)

Pythagoras’ greatest nightmare. Brian Robert Marshall/Geograph (CC BY-SA 2.0)

Unlike its modern day counterpart pharmacogenomics, which describes the interaction of multiple genes and drug response, pharmacogenetics examined how one or two genes interact with a drug. Twin studies in the 1960s further inferred the role of genetic heritability in drug metabolism. These studies found discrepancies in drug response amongst fraternal (non-identical) twins, and remarkable similarities in identical twins. After this initial flurry of interest, pharmacogenetics publications plateaued until the early 2000s. 

As sequencing technologies improved and our processes evolved, so did the field. In the 1990s, the term pharmacogenomics was introduced. Perhaps it was the effect of the new millennium. Perhaps it was the completion of the HapMap project. Either way, people were once again looking to pharmacogenomics to explain discrepancies in drug response. 

Around 2013, scientific curiosity got the better of me. I wondered how many publications were available in the field. To my delight, I discovered 15,529 PubMed papers related to pharmacogenomics and pharmacogenetics since Evans’ publication in 1961. So evidently scientific interest is now moving at full speed. Today, there are 80 public and private companies that are either completely invested in the field or have a minor industrial interest. Not surprisingly, most of these organisations are found in the USA. Some organisations focus solely on research, while others have deviated into the clinical world, offering pharmacogenomics testing to doctors. But alas, that is a story for another time. 

Now, we’ve all caught up to speed. I’d like to give a big shout-out to Pythagoras: without you, I wouldn’t even be writing this column. 

Through regular posts about pharmacogenomics, I hope to educate the public about the many applications of pharmacogenomics, and also learn a few new things myself along the way. It's a vast world out there. And assuming I don't go near any fava bean fields, I have a projected lifespan of 45 years remaining to discover and absorb as much as I can.