Ralph F. Hirschmann

Ralph F. Hirschmann was the leader of a team at Merck Research Laboratories that developed some of Merck’s most important and profitable drugs. (University of Pennsylvania)

Ralph F. Hirschmann, the leader of one of two teams that first broke through the seemingly unbreachable wall between chemistry and biology by synthesizing an enzyme -- a key component of life -- in the laboratory, died June 20 at his home in Lansdale, Pa., from complications of kidney disease. He was 87.

He also was the leader of a medicinal chemistry team at Merck Research Laboratories that developed some of Merck's most important and profitable drugs, including the cholesterol-lowering Mevacor, Vasotec for reducing blood pressure, and Proscar for shrinking enlarged prostates and preventing prostate cancer.


FOR THE RECORD:
Hirschmann obituary: The obituary of chemist Ralph F. Hirschmann in Friday's Section A said he was survived by his wife, a son and six grandchildren. He is also survived by a daughter, Carla Hummel. —



"His creative contributions to chemistry and chemical biology inspired a whole generation of scientists to pursue the discovery of new medicines," said chemist Paul S. Anderson, a former president of the American Chemical Society and a close friend.

Enzymes are proteins, composed of long strings of building blocks called amino acids, that carry out chemical reactions within cells. Without them, life is impossible. It was once thought that such complicated molecules could be produced only by living organisms.

The problem with trying to assemble amino acids into larger molecules is that each amino acid has more than one reactive site. In order to combine them in the same fashion they are connected in proteins, it is necessary to block all of the other sites except the one where a reaction is desired.

One of the key contributions of Hirschmann and his Merck colleague Robert G. Denkewalter and, independently, R. Bruce Merrifield and Bernd Gutte at Rockefeller University in New York, was to develop reagents that would block these sites specifically but that could later be removed for the attachment of another amino acid to the growing chain.

Over a period of 18 months, Hirschmann and Denkewalter slowly assembled the 124 amino acids that constitute the enzyme ribonuclease, joining pairs of them together, then combining those pairs into fragments that they eventually assembled into a fully functional molecule. Merrifield and Gutte synthesized the same molecule by adding one amino acid at a time to a growing chain.

On Jan. 16, 1969, the two groups jointly announced their success at a news conference at Rockefeller, producing front-page headlines around the country. Today, a similar synthesis can be achieved in a few hours using automated instruments that incorporate variants of the reagents originally developed by the two teams.

During the 1970s, Hirschmann led a research team at Merck that also developed Primaxin, an intravenous antibiotic that is used for many serious infections; Lisinopril, which is used to combat high blood pressure; and the antibiotic ivermectin, which is being used in sub-Saharan Africa to eliminate trachoma, the cause of river blindness. He is the inventor or co-inventor on nearly 150 patents.

When he reached the mandatory retirement age of 65 at Merck in 1987, he joined the University of Pennsylvania, where he pioneered the field of peptidomimetics, in which small molecules are designed to mimic the action of enzymes and other proteins. Failing health and the need for kidney dialysis forced his retirement from the university in 2006.

Ralph Franz Hirschmann was born in Furth, Germany, on May 6, 1922, the son of a Jewish banker. In 1936, after Hitler had come to power, the family moved to the United States, settling in Kansas City, Mo. He graduated from Oberlin College in 1943, then served three years in the U.S. Army in the Pacific Theater. After the war, he completed his doctorate in organic chemistry at the University of Wisconsin and joined the Merck laboratories in Rahway, N.J.

In 2000, President Clinton awarded him the National Medal of Science, and he received numerous other chemistry awards as well. Merrifield was awarded the Nobel Prize in Chemistry in 1984 for his efforts, and many researchers expressed dismay that Hirschmann wasn't honored too.

He is survived by his wife of 58 years, the former Lucy Aliminosa; a son, Ralph; and six grandchildren.

thomas.maugh@latimes.com