Paul C. Zamecnik, at 96; discoveries helped revolutionize biochemistry

"Why fat, I wondered. Why not protein, and how is protein synthesized anyway?" he wrote in a scientific paper.

This question put him on a path to a discovery that many of his colleagues said should have earned him a Nobel Prize, for helping to decipher genetic code in a way that revolutionized biochemistry and opened up areas of research.

"I think it's fair to say that he was a remarkable and admired figure in biomedical research, not only for his brilliant experimentation, but also his inspirational leadership," said Kurt Isselbacher, founding director of MGH Cancer Center and the Mallinckrodt distinguished professor of medicine at Harvard Medical School.

Always brimming with ideas on how to unravel the mystery of the stuff of life at the biochemical level, Dr. Zamecnik made at least two key discoveries during a sixdecade career, based mostly at Harvard Medical School and Massachusetts General Hospital.

His first discovery, with colleagues Mahlon Hoagland and Mary Stephenson, was the molecule needed for protein synthesis, tRNA, or transfer RNA (ribonucleic acid), which they found functions as a carrier of amino acids as protein is created.

His second major contribution was showing that antisense DNA, which is created to complement RNA, can halt, or deactivate, the expression of specific genes. This opened a new line of research into stopping protein synthesis in cancer and viral cells -- antisense therapeutics.

"He had such a vivid idea of how these things might work, and he wanted to tell you -- not because he wanted you to admire him -- but he wanted you to know," said Paul Russell, a professor of surgery at Harvard Medical School.

"It was his pleasure; he didn't consider it to be work," his daughter Karen Zamecnik Pierson of Cambridge said. "It was so exciting for him. He felt as if he was pushing the frontier of molecular biology."

Dr. Zamecnik, who held many patents in the field and received several noted awards, died Oct.

27 from cancer at his Beacon Hill home. He was 96.

He grew up in an Irish-Czech family, playing violin with his brother at homes for the elderly in and around his native Cleveland.

He initially thought music would be his métier.

His father was a branch manager for Union Trust Co. and his mother was a suffragette, who taught him to read at age 4.

In an oral history interview in 1995 for the Harvard Medical School archives, he explained that a teacher in Cleveland urged him to expand his horizons and leave the area for college.

He studied at Dartmouth College and enrolled in its medical school, a two-year program that started in his final undergraduate year. He earned his bachelor's degree in 1933 and transferred to Harvard Medical School, earning his degree in 1936.

Working in hospitals as a Harvard medical student in the 1930s could, at times, be frustrating.

"There was nothing you could do for patients," he told Dartmouth Medicine Magazine in 1993.

One of his first courses was obstetrics, and as part of the program, he spent two weeks delivering babies during house calls in the North End, Charlestown, East Boston, and Chelsea.

He lived at Norfolk House Center in Roxbury and spent a year getting medical histories from patients at Huntington Memorial Hospital, which later folded into Massachusetts General Hospital.

He spent a residency working for Dr. Joseph Aub, who was working at Huntington Memorial.

He was responsible for working with about a dozen cancer patients.

The case of an 18-year-old Fitchburg male who had Hodgkin's disease captivated him and helped him realize he was more interested in research than in working as a clinician. The patient was given three transfusions a week with blood collected from firefighters working with the teen's father, and within a month was feeling better.

"I thought, 'My God, there must be some immune response or other unknown factor that these people have given him that he was missing. Why shouldn't I study Hodgkin's disease?' " he said in the oral history.

He spent a year-and-a-half as a medical oncology resident and then moved home to do an internship at University Hospitals in Cleveland, to be closer to his mother, who had been diagnosed with cancer. She died shortly before the internship started, however.

"All of my colleagues in medicine and surgery were anxious to get out and make enough money to pay back their debts, allow their wives to have gold fillings, and then join a country club.

That was the prevailing route which I decided not to follow," he said in the oral history report.

His interest in protein synthesis led him to well-known biochemist Max Bergmann at the Rockefeller Institute. But Bergmann told him that he did not generally take medical students and suggested that he get some experience in research.

So Dr. Zamecnik took a fellowship in Denmark, arriving the day the Germans invaded Poland, Sept. 1, 1939. He and his new bride, Mary (Connor), had set off in a freighter from Montreal to Bristol, England, and then traveled by train across England to the ferry that would take them to Denmark.

"Our greatest fear was not that we'd be caught in the war, but that the boat would return to Montreal, depriving us of an exciting year in Europe," he wrote in an article penned for the Harvard Medical Alumni Bulletin, Summer 2000.

He went to work for Kaj Linderstrom- Lang, who headed the Carlsberg Laboratory, working to measure respiration of a single cell and using the Cartesian diver technique the laboratory had developed.

As the war progressed, it became clear that he would have to make his way back to the United States. When Germany took over Denmark, he had to surrender his US passport, and watched as German planes flew overhead and dropped leaflets telling the local population that Germany had taken over to protect them from the British. And so his "fairy tale year" ended, he wrote. He and his wife pestered German officials until they got their passports back, and they returned to the United States.

Bergmann "must have seen stardust from Carlsberg on my shoulders, because in our interview the next day he agreed to take me into his laboratory as soon as new space permitted," he wrote in a scientific paper. So Dr. Zamecnik went to work for the institute for a time.

For one summer, he was a camp doctor at Camp Androscoggin in Maine.

In 1941, Aub invited him to join his team researching toxic shock on the World War II fronts.

He was asked to join what would ultimately be the Manhattan Project, but turned it down to work with Aub in a laboratory studying blood loss and toxic shock.

In 1942, he became an associate professor of medicine at Harvard Medical School. His research led many companies to work exclusively on antisense biotechnology.

He was forced into mandatory retirement from Harvard at age 65 and went to the Worcester Foundation for Biomedical Research, where he worked on blocking HIV with an antisense oligonucleotide.

He left the company to cofound Hybridon Inc. in 1990. He worked six-day weeks, telling Dartmouth Medicine Magazine in 1993: "Why don't I retire?

Well, I'm better at this than I am at gardening or carpentry."

"The lab is where the action is," he often said.

Pierson said he was "very intuitive about illnesses, and seemed to put things together that you might not think of."

"He was very much a gentleman; he was never autocratic or difficult to work with," she added.

"He was soft-spoken, but he was an enormous storyteller," his daughter Elizabeth Z. Coakley of Sedgwick, Maine said. "It was never dry with him; it was always some magical thing he would be talking about."

When the Albert Lasker Award for Special Achievement in Medical Science was bestowed on Dr. Zamecnik in 1996, the committee wrote that it was "for brilliant and original science that revolutionized biochemistry and spawned new avenues of scientific inquiry.

"Few scientists make a contribution of the monumental importance of Paul Zamecnik," the committee added. "Fewer still make two. But in a 60-year career characterized by sheer scientific originality and brilliance, this molecular biologist first provided the tools for deciphering the genetic code and then later was the first to conceive of the successful use of antisense DNA for the highly selective inhibition of gene expression."

"He was middling tall, with a pleasant voice and a manner that was -- above all -- deliberate, reflective, careful of statement," wrote Horace Freeland Judson in his book, "The Eighth Day of Creation:

Makers of the Revolution in Biology."

Judson later added, "Zamecnik was an experimentalist rather than a theorist; his results came to be recognized as careful, unhurried and -- above all -- trustworthy."

Dr. Zamecnik's wife died in 2005. In addition to his daughters, Karen and Elizabeth, Dr. Zamecnik leaves a son, John P. of Washington, D.C., and Alta Gracia, Argentina; seven grandchildren; and two great-granddaughters.

A memorial service will be held in the spring. Burial will be in Mount Auburn Cemetery in Cambridge.