Former Merck CEO discusses drug discovery

Roy Vagelos, the former CEO and chairman of Merck, discussed three strategies that pharmaceutical companies use to discover new drugs in the 12th Annual Ross Lecture Series hosted by the Dartmouth chemistry department on Oct. 16.

Vagelos, who had a distinguished career at Merck first as a scientist and then as a corporate leader, detailed the massive changes in strategies for drug research and development from the early 1970s to the present day.

Three revolutionary drug discoveries formed the basis for his lecture and illustrated the differences between observation-based research of the past to the targeted proteonomic and genomic approaches of the modern era.

The first scientific breakthrough that Vagelos described was Merck’s discovery of Lovastatin in the 1970s, which reduces cholesterol by inhibiting the main limiting enzyme of the cholesterol synthesis process: HMG-CoA reductase.

Rather than being able to rely on protein synthesis or genetic knowledge, Vagelos emphasized that the first strategy of earlier pharmaceutical research was to observe natural processes such as the fungi fermentation that gave rise to Lovastatin.

The second strategy in Vagelos’ lecture was chemical manipulation. He demonstrated this process with the discovery of a drug that could reverse benign prostate growth. The natural world was once again utilized for inspiration, as the subject of this research was a group of pseudo-hermaphrodites from the Dominican Republic.

Benign prostate growth, male-pattern baldness and prostate cancer are caused in part by the androgen Dihydrotestosterone (DHT), which is produced from testosterone by 5-alpha reductase. Researchers at Merck found that the pseudo-hermaphrodite group’s unique sexual qualities were a result of a 95 percent deficiency of 5-alpha reductase in the prostate, which led to a 70 percent reduction of DHT. These hormonal abnormalities prevented prostate growth.

Vagelos described the work of Gary Rasmus, a researcher at Merck, in order to illustrate the chemical synthesis strategy of pharmaceutical companies. Rasmus created a steroid molecule with nitrogen on the A-ring, which could act as a competitive inhibitor to 5-alpha reductase. The synthesizing of new chemicals offered enormous benefits and flexibility over the original method of simply harvesting naturally occurring chemicals.

The third and final story involved the TRAP method (Target-Related Affinity Profiling). TRAP uses knowledge of the sequenced human genome to fuse cell receptor regions to antibodies in order to create disease blockers.

The reason for these customized antibodies is that many ailments such as bone diseases, arthritis, cancer and metabolic disorders are caused by over-production of cellular messengers. These messenger proteins are reliant upon receptor sites in order to convey their messages.

Vagelos described how the company Regeneron has implanted human immune systems that code for the custom receptor-site antibodies into mice.

Thus, disease-specific antibodies can be created at the accelerated rate of a mouse’s immune system and then released into a human to attach to and neutralize disease-causing cellular messengers.

“So that is the next generation, that’s another way of getting to new drugs,” Vagelos said.

Thus, through observation of nature, chemical synthesis, and now genetic manipulation, Vagelos has shaped the last thirty years of pharmaceutical advances.

Listen to a DUJS Podcast of Roy Vagelos’ lecture:

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