Celgene: The Pharmaceutical Phoenix

An early photograph of the Celgene staff. Courtesy of Sol Barer

By Sol Barer

I’d like to tell a story; a story with all the elements of a good yarn—bravery, adversity, humanity, disease, arrogance, altruism, greed, naïveté, and ultimate redemption. The story spans 50 of the most turbulent and productive years of medicine, includes tragedy of almost unbearable proportions, encompasses disbelief and cynicism, and ends happily (as all good stories do) with optimism and the validation of suffering. It’s also one hell of a business and science story.

At the end of the 1970s I was employed by Celanese Research Corporation, a multibillion-dollar global company that produced chemicals, fibers, and plastics. I was responsible for accelerating and diversifying our research platform, and since I gravitated toward the more esoteric and breakthrough-oriented research programs, I was charged with building an exploratory research function. Although I was directing research in solid-state physics, electrochemistry, and photochemistry, I became aware of the startling advances being made in the biological sciences. As a chemist, it was difficult for me in those days to acknowledge anything outside of chemistry and physics as true science, but the astonishing potential of the new field nevertheless beckoned me. Soon I found myself immersed in biotechnology.

But I’m getting ahead of myself. Flash back to 1953 when researchers at the Ciba corporation discovered a chemical that acted as a nonaddictive barbiturate. A German firm, Chemie Grünenthal, launched the drug under the trade name Contergan on 1 October 1957, but we remember it by its generic name: thalidomide. The drug was soon available over the counter in 46 countries and was promoted as “completely safe.” Thalidomide’s antinausea response made it an effective drug for morning sickness, and tens of thousands of pregnant women took it. Yet when the first inklings of the imminent global pharmaceutical disaster came in 1959, reporters focused on the drug’s neuropathological effects rather than on its teratogenicity. In 1961, however, a sensational outbreak of phocomelia (a congenital disorder in which babies are born with flipper-like hands and feet) erased any lingering doubts about thalidomide’s risks.

The drug was quickly withdrawn in every country in which it had been sold. In the United States the new drug application, which had been under significant scrutiny by the Food and Drug Administration, was withdrawn by its sponsor, Richardson-Merrell, in 1962. The fact that the drug had not been approved in the United States saved many children and indeed validated the FDA’s existence. The thalidomide incident gave the federal agency the force of both law and ethics in regulating drugs. In many ways the strength of the modern FDA can be traced back to this event.

Thalidomide became the most reviled drug in history. Its name was synonymous with suffering.

In 1965—long after the drug was withdrawn from the open market—Jacob Sheskin, working at Hadassah Hospital at Hebrew University in Jerusalem, provided it to a patient suffering from ENL (erythema nodosum leprosum), a painful dermatologic and rheumatologic condition associated with the mycobacteria that cause leprosy. Sheskin had prescribed the drug to help the patient sleep, but this patient, along with six others, responded dramatically. Within days most of the symptoms associated with the disease disappeared. Within weeks both skin lesions and rheumatologic symptoms had resolved, and the patients returned to normal. From that point on thalidomide became the standard of care for the treatment of ENL around the world, albeit with highly controlled distribution requirements—including, in some cases, sterilization prior to receiving the drug. Nevertheless, it was by no means clear why a drug having sedative and antinausea properties would have such a profound effect in a mycobacterium-mediated disease.

Unsurprisingly the industry wasn’t investing a lot of money in thalidomide research.

The mystery of Thalidomide’s action was finally unraveled in the early 1990s by Gilla Kaplan, a mycobacterial immunologist who worked at Rockefeller University in New York. As a South African–Israeli who came to the United States via a postdoctoral appointment in Norway, she was yet another eclectic entrant into the thalidomide story. Kaplan discovered that thalidomide’s mode of action in ENL was related to its ability to modulate TNF-α, an important cytokine produced by macrophages and T-cells. TNF-α turns out to be a prime villain in a number of diseases, including rheumatoid arthritis and Crohn’s disease. Her discovery marks a turning point in the story— the culmination of the drug’s progression from infamous toxin to cellular regulator—and sets the stage for the next chapter.

Now let’s return to Celanese. By this time the little group I had formed to explore biotechnology had spun off into a separate public company, Celgene. Although Celgene’s original mission to exploit biotechnology for the production of chemicals held promise, we set our sights on the big prize: pharmaceuticals. I was in charge of the new company’s R&D and also held a general manager role. Our senior scientist, David Stirling, and I were constantly on the lookout for a way into pharmaceuticals—ideally through some sort of government contract since the company was at that point barely able to keep the lights on, never mind conduct research. Stirling was on a trip to Rockefeller University when he discovered Kaplan and the improbable story of thalidomide and its potential uses in tuberculosis, ENL, and AIDS. No one with any pharmaceutical background had bought it, but we did.