IStock Photo 204169 © Greg Nicholas

The numbers we can see are interesting, but so are the ones we can’t, the dark matter of the odds of everyday life.

The story of our understanding of ulcers illustrates this wonderfully, and it is one I know well since I helped write a book which included the story of the discovery of cimetidine, or Tagamet® (Nayak and Ketteringham. Breakthroughs! Rawson Associate).

In the days before there was an effective treatment for ulcers, there appeared to be relatively few cases in the world. The Smith, Kline & French marketing director for gastrointestinal (GI) products described how he went about calculating sales potential for Tagamet. The total GI market was only $100 million a year, and most of this was over-the-counter antacids such as Maalox®. He bravely predicted $80 million in sales. “Are you saying we are going to get 80% market share?” came the inevitable challenge. Somehow a “peak year” target of $68 million was accepted, but many were skeptical. I mean, where would all these ulcers come from?

They came from somewhere, it turns out. The optimistic forecast of $68 million was breached in the first year and sales were so brisk the company worried it would have to ration a potentially life-saving drug, a morally hazardous task. The phenomenon of so many cases of ulcers appearing when they had not been diagnosed previously was called at the time, “the woodwork effect.” They came out of the woodwork, it seemed.

In retrospect we can understand why the actual prevalence of ulcers was so understated. Back in the 1960s there were only two treatments for ulcers: over-the-counter antacids like Maalox® and surgery. Why go to the doctor to be told to go buy an antacid at the pharmacy? Unless your problem was so severe that surgery was inevitable, why see your doctor at all?

Most cases of peptic ulcers went unreported, common facts of everyday life for many people, but uncounted by the medical system.

Just as today we know that the bacteria which can cause ulcers are found in half the digestive systems in the world but we do not know why only some cases “come out of the woodwork,” in the 1970s we didn’t have a clue that most cases were known only to the sufferer.

Two footnotes:

1. The discoverer of Tagamet® or the first H₂ antagonist, Dr. James Black, was also the discoverer of the beta blockers. What, one wonders, are the odds of a scientist discovering two entire classes of pharmaceuticals in a lifetime? What does this say about the possibility of serial discovery which on the face of it is miraculous?
2. The discovery of Tagamet® was a heralded example of what was called “rational drug discovery.” Rather than simply finding novel compounds and testing them to see what they can do, the Black team worked to engineer the compound they wanted. The number of possible variants of the starting compound for this search was 30 billion compounds! Incredibly, the SK&F team only developed about 700 compounds to test, and in the end the critical compound was found among the first 6 compounds Dr. Black designed.