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Meanwhile, back in 1975 again, Elizabeth Carswell, Lloyd Old and their colleagues at Sloan-Kettering Research Institute in New York reported the discovery of a molecule that caused tumors to melt away in mice. Dubbed tumor necrosis factor, or TNF, the molecule incited the usual riot among investors and the usual hype from companies. In short order, the TNF gene was cloned, the protein mass-produced and an ugly truth unearthed:At doses humans could tolerate, patients derived no benefit whatsoever. By 1990, TNF had joined monoclonal antibodies in the pile of spent bullets in the war on cancer.

And now we arrive at one of the most interesting tensions in biotechnology: the always-yawning gap between pharmacological aspiration and biological reality. Although no one appreciated it in the early days, TNF is one of the body’s baddest actors when it comes to inflammation. Only in the late 1980s (and only, it should be noted, out of pure academic interest) did researchers discover that rheumatoid arthritis arises from a cascade of inflammatory proteins that collect in the joints, among which perhaps the worst of the bunch is-you guessed it-TNF. Separate research established that Crohn’s disease was also caused by an excess of the factor.

From that biological insight, it was a logical next step to suggest that a monoclonal antibody that neutralized TNF might short-circuit the ravages of rheumatoid arthritis and Crohn’s disease.Though Centocor’s earlier attempts to turn anti-TNF monoclonals into a viable drug to treat sepsis had failed, the company’s experience positioned it perfectly to develop monoclonals against TNF to treat rheumatoid arthritis and Crohn’s disease.

Henry Adams, in his autobiography The Education of Henry Adams, makes the wise point that any path that arrives at the destination is the right one. But it’s hard to square that haphazard form of navigation and everything it implies-luck, happenstance, accident, misdirection and perseverance-with the linear and often unforgiving thinking that goes into business plans, revenue streams and burn rates. The TNF story is a reminder that, for every success like Remicade, there are an awful lot of little white crosses on the side of the road.

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