Dr. Paul Zamecnik dies at 96; scientist made two major discoveries

Most scientists are fortunate if they can make one major discovery in their lifetime. Dr. Paul Zamecnik made two, each of which should have won him a Nobel Prize.

Working with Dr. Mahlon Hoagland, he discovered transfer RNA, a crucial molecule in the synthesis of proteins in the cell. Later, he invented the idea of antisense therapy, in which strands of DNA or RNA are used to block the activity of genes -- a concept that is now being turned into a new class of drugs for cancer, HIV and a host of other diseases.

Zamecnik died of cancer Oct. 27 at his home in Boston. He was 96.

Although he was nominated repeatedly for the Nobel and rumors circulated each year that he would finally receive it, the prize never came. He did, however, win a 1996 Lasker Award, the prestigious American prize that is often a precursor of the Nobel, and the National Medal of Science in 1991.

Hoagland, who died Sept. 18, said the failure to give the Nobel to Zamecnik “was a major oversight. I don’t mind saying this of the Nobel committee. His contributions are just enormous compared to a great many people who did get the prize.”

Working at Massachusetts General Hospital in the early 1950s, Zamecnik developed a cell-free system from rat livers that could synthesize proteins. When he and Hoagland added radioactively labeled amino acids to the system, they discovered that radioactivity was soon found throughout the mixture.

But when they stopped the process quickly, they observed that it was concentrated in large structures called ribosomes, which were soon identified as the site of protein synthesis.

In 1956, they reported that amino acids to be added to the growing protein chain had to be activated so they could form a chemical bond with the chain. They found that this activation involved adding adenosine triphosphate, or ATP, to the amino acid, making it highly reactive.

Two years later, they reported the discovery of transfer RNA, commonly called tRNA, which binds to individual amino acids, marking them for identification by the ribosomal machinery so the correct amino acid is added at each stage of construction. In 1960, Nobel laureate Sydney Brenner showed that genetic information was ferried from nuclear DNA to the ribosome by a different molecule, called messenger RNA, completing our understanding of the process.

Once the structure of DNA was determined, Zamecnik had another key insight. The double helix of DNA is composed of two strands of DNA. One strand, called the sense strand, is the pattern for making proteins and other molecules needed by the cell. The second, or antisense strand, binds tightly to the sense strand to stabilize it and serves as a pattern for the production of new sense strands when cells replicate.

Zamecnik reasoned that this tight binding could be used to inactivate specific genes. Although he did his initial work with the Rous sarcoma virus, which has RNA in its genome, the principle is the same. He made small segments of RNA that were the antisense copies of crucial genes in the virus.

When the antisense molecule was introduced, it bound tightly to the corresponding site on the genome of the virus, preventing a key protein from being made and thus preventing replication of the virus.

Other researchers scoffed at Zamecnik’s theory, but, in 1978, he showed that the strands of DNA or RNA used for the technique could get inside cells and carry out their designed function.

Most antisense therapies now are targeted at messenger RNA. By blocking mRNA, it is possible to block the construction of crucial proteins. Only one antisense drug is now on the market -- fomivirsen, or Vitravene, which has been approved by the Food and Drug Administration for treatment of retinitis caused by cytomegalovirus -- but others are in the pipeline.

Paul Charles Zamecnik was born Nov. 22, 1912, in Cleveland. At 16, he enrolled at Dartmouth College “just to get a change of scenery from the Midwest.” He earned bachelor’s degrees in chemistry and zoology in 1933, then his medical degree at Harvard in 1936.

His interest in research was strengthened while an intern at University Hospitals in Cleveland. “A very fat lady came in,” he said. “She waddled in and she was out of breath, and they put her in bed and thought, well, we will go easy on her, but we will gradually reduce her in weight.

“She died a week later. And at the autopsy they didn’t find anything -- except everywhere they looked, she had too much fat and too little protein, really. And so I wondered, ‘OK now, what determines the regulation of how much? How do you make protein anyway?’ I asked that question. ‘How do you make protein?’ And I asked the people in medicine at the University Hospitals, ‘Who is studying protein synthesis?’ And they all shook their heads.”

To learn more about molecular biology, in 1939 he took a fellowship at Carlsberg Laboratories in Copenhagen, just as war was spreading in Europe. When the Nazis attacked Denmark, he returned to the United States, taking a post first at the Rockefeller Institute for Medical Research, then a teaching position at Harvard during the war.

When he reached the mandatory retirement age in 1979, he moved his research to the Worcester Foundation for Biomedical Research in Massachusetts, where his friend Hoagland had become ensconced. When that institution was absorbed by the University of Massachusetts, he reestablished his lab at Massachusetts General, where he worked until just before his death.

In 1990, he co-founded Hybridon Inc. in Cambridge, Mass., to work on the development of antisense drugs. It merged with Idera Pharmaceuticals in 2004.

Zamecnik’s wife of 69 years, the former Mary Connor, who worked beside him in the laboratory, died in 2005. He is survived by two daughters, Karen Zamecnik Pierson of Cambridge and Elizabeth Coakley of Sedgewick, Maine; a son, John, of Argentina and Washington; seven grandchildren; and two great-grandchildren.

thomas.maugh@latimes.com