Conversations with Laureates
Few scientists make a contribution of the monumental importance of Paul Zamecnik. 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.
In the 1950s, the mechanism of protein biosynthesis was a "black box." Prevailing ideas were naïve and without experimental support. Some biochemists had advanced the idea that proteins were assembled by the action of proteolytic enzymes in a reverse reaction.
But it was Paul Zamecnik and his team who unlocked the mystery, defining the biochemistry of amino acid activation and assembling its proteins. This provided the first hard evidence for transfer RNA, the key piece in the puzzle of how genetic information in DNA is translated into the specific sequence of amino acids that gives each protein its distinct molecular identity. His work provided a totally new picture of protein synthesis—one that did not simply overthrow a previous idea, but filled a void.
The key was the development of cell-free systems capable of carrying out net peptide bond formation, using 14C-amino acids for the first time. His results and discovery of an entirely new chemical mechanism were received throughout the scientific community with enormous enthusiasm.
Dr. Zamecnik's next major discovery was the conceptualization and demonstration that antisense DNA, in which short chains of DNA, chemically synthesized to be complementary to selected RNA targets in the cell, are used to selectively inactivate the expression of specific genes. This groundbreaking work has spawned the development of a new field of research, a novel approach to investigating new drugs using antisense DNA to block or stop the replication of viruses. Clinical trials of antisense DNA drugs for AIDS, cancer and infectious disease are conducted now in laboratories around the world because of Paul Zamecnik's discoveries—some of which are in his own laboratory, where he continues to be a major player, publishing new work regularly.
Paul Zamecnik was a Cleveland kid. Now, 70-odd years later, he is hard-pressed to explain why he entered into the practice of medicine in the late 1930s. The factors may not even have been clear to him back then. But whatever his reasons, it was not because of the money, since that was a time when most doctors were still getting paid in chickens, fruits and vegetables. The country was at the tail end of the Great Depression, and people were still gasping for their economic breath.
As an intern and resident, he was often sleep-deprived from working from one morning until the next. And as a doctor, he knew he could look forward to a lifetime of the same...of being yanked from sleep by a jangling telephone, of putting bare, warm feet on a cold floor in a house where a banked coal or wood furnace barely cut the midnight chill.
Perhaps Paul couldn't put it into words, but his reasons for choosing this tough life were likely rooted somewhere in his Midwestern upbringing—when someone stirred his idealism, igniting his need to care for others.
The late Lewis Thomas, physician-scientist and poet-laureate of medicine and research, described the medicine of the 1930s when Paul was becoming a physician as "severely lacking in the knowledge to cure."
Thomas says of his physician father, "I took the greatest interest in his black bag. It smelled of Lysol and ether. All he had in the bag was a handful of things. Morphine was the most important, and the only indispensable drug in the whole pharmacopoeia. Digitalis was next in value, syringes and needles and a small case for instruments."
In his book, "Medicine the Youngest Science," Thomas talked about the doctor's frustration: "There were so many people needing help, and so little that he (the doctor) could do for any of them." The doctor's primary job at that time was telling the person what disease they had, and when possible, to relieve the patient's discomfort as much as possible with the painkillers of the era. "Curing" sometimes amounted to helping patients cope emotionally with the impact of the disease, and the laying on of the physician's hands to show caring.
Zamecnik became more and more aware of this reality of medicine: "I found myself more interested in basic science than in clinical medicine. There was a gap, more of a gap (between knowledge and therapy) than there is now, between clinical medicine and its underpinnings."
His decision to take "the research road" was sealed one day early in his career. "I was an intern at University Hospitals in Cleveland—a very fat lady came in. She came 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. And so I wondered, 'Okay, now what determines the regulation of how much (protein is needed)? How do you make protein, anyway?' I asked that question…and I asked the people in medicine at the University Hospitals who were studying protein synthesis, and they all shook their heads. There was one paragraph in their biochemistry textbooks, [but it] didn't explain anything."
"This event was largely responsible for my decision that research was a better way to spend one's life, beginning at that time, than trying to butt one's head against the wall in treatment of diseases which had no therapy at all," he continued. This decision would lead Paul on a long and productive research journey, and among other things, the discovery of messenger RNA.
You can join Paul as he relives those several decades, including his years in Europe as Poland fell to the Nazis, and the beginning of his search for the understanding of proteins...along the way picking up an Albert and Mary Lasker Award, and in 1991, the National Medal of Science. Paul is interviewed by Richard Cohen, former CBS News Senior Producer.
Mahlon Hoagland comments: "Paul was a remarkable person to me. He created a laboratory atmosphere that was very informal, very relaxed, very good fun, and very little pressure of competition in the laboratory. He also was strikingly generous...and urged his associates to be generous in their acknowledgment of the work of other people. I think his whole attitude contributed significantly to an openness and sharing which, in turn, contributed to the success of the laboratory."