Paul Zamecnik's work also led the way to a new class of drugs.
The cause was cancer, his daughter Karen Zamecnik Pierson said.
Dr. Zamecnik also discovered a method for blocking individual genes that pointed the way to a new class of drugs.
In the 1950s, Dr. Zamecnik (pronounced zam-ESS-nik) devised a system for modeling protein synthesis in a test tube, so he could more easily track the steps involved in translating the genetic information encoded in DNA into a chain of amino acids, the building blocks of a protein.
In 1956, Dr. Zamecnik and his colleagues Dr. Mahlon Hoagland (who died on Sept. 18) and Dr. Mary Stephenson discovered a critical element of the protein synthesis pathway: the molecule that shuttles amino acids to the cell’s protein factory, called the ribosome. There they are linked to create a chain that folds to form a protein. This newfound molecule they called transfer RNA, or tRNA. The discovery was a milestone in molecular biology.
Dr. Zamecnik’s work “advanced the study of protein synthesis,” taking it from a purely metabolic process “into proper biochemistry for the first time,” said Thoru Pederson, the Vitold Arnett professor of cell biology at the University of Massachusetts Medical School, who was a colleague and a friend. Dr. Pederson described him as “a transformative figure” during the very early years of molecular biology research.
In 1978, Dr. Zamecnik published the first work showing that a short, synthetic series of nucleotides, the chemical components of DNA and RNA, could be used to inactivate a specific gene. The concept, which he called antisense technology, is based on the double-stranded structure of a DNA molecule. One strand, called the sense strand, carries the genetic instructions; it is intertwined with the complementary antisense strand to form the double helix. A cell reads the genetic information encoded on the sense strand and creates a corresponding messenger RNA (mRNA) molecule, which delivers the genetic message to the ribosome.
In antisense technology, a short series of nucleotides recognizes a specific sequence on an mRNA strand, preventing it from being translated into a protein and blocking expression of a gene.
Although Dr. Zamecnik’s antisense concept was first met with skepticism, it has given rise to a new class of therapeutic compounds called antisense drugs, which are under active development in the biotechnology industry. One antisense drug is already on the market, and about a dozen more are in clinical trials.
Dr. Zamecnik’s antisense work “will change how medicines are developed,” said Sudhir Agrawal, president and chief executive of Idera Pharmaceuticals, who worked with Dr. Zamecnik over the years on developing the technology.
Paul Charles Zamecnik was born in Cleveland in 1912. He enrolled at Dartmouth at the age of 16. Five years later, in 1934, he had completed both his undergraduate degree and the two-year program at Dartmouth Medical School. He completed his medical degree at Harvard Medical School, graduating in 1936.
After he was put on a waiting list for a surgical internship, he did an internship in oncology at Huntington Memorial Hospital, work that first led to his interest in scientific research. He did a subsequent internship in medicine at University Hospitals in Cleveland. When an obese patient abruptly died there and the autopsy showed an abundance of fat tissue and too little muscle and protein, he began to seek answers to the question of how proteins are made.
To expand his knowledge of biochemistry, and protein chemistry in particular, he took additional classes and pursued a fellowship at the Carlsberg Laboratories in Copenhagen. After he returned to the United States, he worked for two years at the Rockefeller Institute for Medical Research in New York City. He then became an instructor at Harvard Medical School and established his laboratory at Massachusetts General Hospital. In 1956, he became the Collis P. Huntington Professor of Oncologic Medicine at Harvard Medical School.
Reaching the mandatory retirement age in 1979, he left Harvard and continued his research at the Worcester Foundation for Biomedical Research, in Massachusetts, where his former colleague, Dr. Hoagland, was the director. When the foundation merged with the University of Massachusetts Medical School in 1997, Dr. Zamecnik moved his laboratory once again, to Massachusetts General, becoming a senior scientist. He continued to work in his laboratory until several weeks before his death.
Dr. Zamecnik’s wife of 69 years, the former Mary Connor, who worked in his laboratory, died in 2005. In addition to his daughter Karen, of Cambridge, who also worked alongside him, survivors include his son, John, of Argentina and Washington; another daughter, Elizabeth Coakley, of Sedgwick, Me.; seven grandchildren; and two great-grandchildren.
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