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Paul Zamecnik, M.D., '34: Life's work

autopsy on an obese woman who had died for no apparent reason, Zamecnik wondered why her body had so much fat and so little muscle and protein. He asked other doctors if they knew how proteins were made, but no one had an answer. One colleague, however, mentioned that a scientist at the Rockefeller Institute was studying protein synthesis. Zamecnik traveled to New York City and asked to join the lab but was told he didn't have enough experience doing chemistry research.

Determined to get that experience, Zamecnik applied for and received two fellowships to spend a year working with a leader in the field of protein chemistry at Carlsberg Laboratories in Copenhagen, Denmark. When the chief of medicine in Cleveland found out, he told a friend of Zamecnik's, "That young man is pouring his medical education down the sink." Zamecnik clearly relishes the remark—he's referred to it on many occasions over the years—and laughs as he notes that it "didn't worry me at all."

His stay in Copenhagen was cut short by Germany's 1940 invasion of Denmark; he ended up spending only seven months there. Even so, when he returned to the U.S. he was offered the job he wanted at the Rockefeller Institute. Two years later, he was appointed an instructor at Harvard Medical School and set up his own lab at MGH.

In the early 1950s, while Watson and Crick were figuring out the double-helix structure of DNA, Zamecnik was hot on the trail of how proteins were made. His invention of the first cell-free system—a combination of cellular components and amino acids that could synthesize proteins in a test tube—later played a role in breaking the DNA code.

Then in 1956, with two MGH colleagues—Drs. Mary Stephenson and Mahlon Hoagland—Zamecnik found that a small amount of seemingly useless RNA facilitates protein synthesis by carrying amino acids to ribosomes, organelles outside the cell nucleus, where they are pieced together to form proteins. This discovery, of what's now known as transfer RNA, explained how the language

Grew up: Cleveland, Ohio
Education: Dartmouth College '33 (A.B.), Dartmouth Medical School '34 (B.M.S.), Harvard Medical School '36 (M.D.)
Training: Resident, Huntington Memorial Hospital, Boston, Mass.; intern, University Hospitals, Cleveland, Ohio; fellowship in protein synthesis at Carlsberg Laboratories, Copenhagen, Denmark
Marital status: Widowed since 2005, after 69 years of marriage to Mary Connor Zamecnik
Awards: At least six honorary degrees, including one from Dartmouth (1988); National Medal of Science (1991); Lasker Award for Special Achievement in Medical Science (1996); and many more
Little known fact: Played the violin as a boy

The chief of medicine in Cleveland said that Zamecnik was "pouring his medical education down the sink."

of DNA is converted into a sequence of amino acids.

There was at that time a growing sense of competition among labs and institutions as the molecular underpinnings of medicine were being elucidated. But the environment in Zamecnik's lab remained collegial, says Hoagland, who in the 1960s chaired DMS's biochemistry department. "Paul was a remarkable man," Hoagland says. "He was very generous in acknowledging the contributions of his peers."

In 1956, Zamecnik was appointed Harvard's Collis P. Huntington Professor of Oncologic Medicine, a title he held until reaching the school's mandatory retirement age in 1979. He then took a position with the Worcester Foundation for Biomedical Research in Shrewsbury, Mass., where he was reunited with Hoagland, the director of the foundation at the time. In 1997, Zamecnik left the foundation to become a senior scientist at MGH.

Zamecnik's current research makes use

of antisense technology, a technique he developed in the 1970s to stop the expression of specific genes. The method works by preventing messenger RNA (mRNA) from functioning properly. Normally, mRNA carries the genetic information encoded in DNA to the ribosome, where that information is translated into specific proteins. Both DNA and mRNA are composed of strands of molecules called nucleotides; DNA has two strands—a sense strand and an antisense strand—while mRNA has only a sense strand. In 1978, Zamecnik showed that it's possible to create a short chain of nucleotides—a synthetic antisense chain—that can bind to a complementary nucleotide sequence on the mRNA strand. The result is double-stranded mRNA, which is unable to translate genetic information into proteins. Zamecnik then used the antisense technique to stop the growth of a virus by blocking a gene essential to its replication.

Zamecnik "might be considered the father of antisense technology," says Dr. Marcus Horwitz, a tuberculosis (TB) expert at the University of California, Los Angeles. Horwitz has been collaborating with Zamecnik for 12 years to use antisense technology against Mycobacterium tuberculosis, the bacterium that causes TB.

The bacterium's nearly impregnable cell wall is an important factor in TB's virulence, so it is an obvious target for fighting the disease. In 2000, Zamecnik and Horwitz showed that it is possible to employ antisense technology to hinder the growth of the cell wall. By 2002, they had identified targets in the bacterium's genome thatmight be vulnerable to antisense therapy. They have continued to refine their approach and last year published an article reporting success in inhibiting the growth of M. tuberculosis.

Zamecnik says there's still progress to be made before the findings can be translated into effective treatments, but he thinks the goal is within reach. With so much work to do, he sees no reason to stop now. "As long as you can be competitive," he says, "you might as well do what you like."

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Amos Esty, senior writer for Dartmouth Medicine, joined the magazine's staff in May of this year. He was previously an assistant editor at American Scientist.

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