why we have prizes and monuments, I thought at the time. To carve something in stone for a kid to look up to.
THE STORY OF dsRNA-MEDIATED gene silencing wasn’t always carved in stone for a kid to admire. The work of Mello and Fire bears the hallmarks of a “seminal discovery,” a term usually applied in retrospect and of three aspects. First, the unexpected often comes from a field far removed from the scientist’s own field of expertise. Next, it stares one in the face, unexpectedly, like Mendel’s sweet peas or Darwin’s finches. Finally, it tips its hand when the seminal publication uses key words like “unexpected” or “surprise” in title or abstract. Here’s how siRNA (small interfering RNA) was announced in the 1998 paper that Fire, Mello, and others published in Nature: “To our surprise, we found that double-stranded RNA was substantially more effective at producing interference than was either strand individually.”
While the role of siRNA-mediated gene silencing is now written in stone, the path to its discovery was by no means straightforward: it began with petunias, led to worms, then finally on to yeast and beast. Andrew Fire recalled in his conversation with Adam Smith, “Well, we were led to it pretty much by our experimental noses. The people in the plant field had done tremendous work on gene silencing and so we, sort of, were following in their footsteps in trying to sort out what was responsible for this weird silencing phenomenon in the worm.”
Their experimental noses had a long trail to sniff. Deciphering what George Sen and Helen Blau called “the silence of the genes” began with decoding the color purple in petunias and has wound up producing compounds of promise in disease. In 1990, plant scientists Carolyn Napoli, Christine Lemieux, and Richard Jorgensen were studying the formation of anthocyanin, the pigment that makes petunias purple. Testing whether the enzyme chalcone synthase was the protein critical for the color purple, they overexpressed chalcone synthase (CHS) in petunias. In their paper they wrote, “Unexpectedly the introduced gene created a block in anthocyanin biosynthesis,” and 42% of the plants became white or had chimeric purple–white patterns. They had silenced the gene for CHS, and this silencing proved to be heritable: “progeny testing showed that the novel phenotype co-segregated with the introduced CHS gene.” Purple no longer, by heredity.
Sure enough, “unexpectedly” was the operative word in the petunia paper, and the work it described led directly to Fire and Mello’s “surprise” at finding double-stranded RNA interference in worms. Many viruses contain double-stranded RNA, which, when injected into a cell, binds to a complex series of proteins (one called Dicer) that degrade viral RNA, and so the cell survives the infection.
These days, when I pass by that monument on Columbus Avenue, I’m reminded of petunias, and all those messages sent by “phone lines, email connections, and delivery services between Baltimore and Worcester.” Going viral, indeed.
PLANNING FOR THE NOBEL MONUMENT in New York began with discussions in December 2001, when the Nobel Foundation celebrated its centenary in Stockholm. Most of the living Nobel laureates in Physiology or Medicine (including a good number of Americans: Joshua Lederberg, Barry Blumberg, Alfred Gilman, Joseph Goldstein, Michael Brown, Eric Kandel, among others) showed up to revisit their grandest moment. The occasion was celebrated by lectures, symposia, concerts and the grandest of all banquets in Stockholm’s splendid Town Hall. My wife and I were guests, and we were lucky enough to have been seated at the banquet table with the senior American laureate present, Tom Weller of Harvard (1915–2008). He told a story that described one way to make a great discovery: make a great error, and correct it.
Over wines of not inconsiderable vintage, Weller reminded his dinner companions that the first time American scientists had been feted in this hall, it was for a dazzling cure based on luck and error. In 1934, two Harvard clinicians, George R. Minot and William Murphy, joined George C. Whipple, a Rochester pathologist, on the podium in Stockholm. From the wrong animal model, they had found a cure for pernicious anemia.
George Richards Minot, a patrician Bostonian, had been a professor of medicine at Harvard since 1928. He also maintained an active private practice oriented to hematology. William Parry Murphy, on the other hand, was a Westerner of decidedly nonpatrician stock. After one year at the University of Oregon Medical School he won a scholarship to Harvard Medical School, graduated in 1922, and in the midst of his Boston residency Minot made Murphy an offer he could not refuse.
Minot, as the story goes in Medicine at Harvard, was accustomed to picking young physicians of Peter Bent Brigham Hospital as associates to run his office practice, which consisted in good part of patients with diseases of the blood—and with homes on Beacon Hill. As senior resident, Murphy was next in line for this plum job, but it was customary for the young men to earn their credentials by publishing one or more papers before they started. Murphy took to the journals and found a recent report by George Whipple and Frieda Robscheit-Robbins that dogs made anemic by repeated bleeding could be restored to health by being fed huge quantities of uncooked liver. If it worked in dogs, why not in humans?
The first patients to whom Murphy fed slightly cooked liver were patients with pernicious anemia. One of these patients was an old woman who had recently become cranky and obstreperous, but whom, after a mighty contest of wills, Murphy cajoled into taking her daily ration of half a pound of liver. Murphy described his everlasting “surprise” that not only did her red blood cells respond to a week or so of this cumbersome regimen, but also that she was relieved of her mental symptoms. She soon reverted to her former, agreeable self. Eventually, his lucky observation of her mental improvement persuaded Murphy that the active factor in liver must work not only in the marrow but also elsewhere in the body. Iron alone could not do the trick.
By May 1926, Minot and Murphy had treated each of forty-five patients with half a pound of liver a day. Soon Minot persuaded a young biochemist, E. J. Cohn, to make a liver extract, which would be rich in the anti–pernicious anemia factor. The extract briskly revved up red cell production by the marrow and cured the disease as readily as raw liver. Indeed, it remained the primary treatment for pernicious anemia until Alexander Todd isolated and named vitamin B12 in 1948. It was among the first miracle drugs to cure a hitherto fatal disease.
Ironically, Whipple’s dogs had not suffered from pernicious anemia—they had iron-deficiency anemia caused by repeated bleedings, and their response was due to the iron present in massive doses of liver. Whipple’s error and Minot’s luck led directly to the first Nobel Prize in Physiology or Medicine awarded for work in the United States.
There’s more to the Minot story, and it touches on Mello’s conversation with Adam Smith of the Nobel Foundation. Like Mello’s young daughter, Minot suffered from what we would now call type I diabetes: he was gravely ill when he made his great discovery. A strapping six-footer, Minot had developed a severe case of diabetes, and by 1922 his weight had dropped to 120 pounds. As luck would have it, Charles Best and Frederick Banting in Toronto, following the approach of John Macleod (Medicine and Physiology, 1923) had prepared the first useful batches of insulin. Minot was in the initial group of patients treated with the hormone by Eliott Joslin, the first American specialist in diabetes. One Nobel led to another: had insulin not been discovered, vitamin B12 might have been a distant dream. It’s what Robert Hooke predicted in 1665 when the Royal Society began its assault on “not precisely Knowing”: “By this means they find some reason to suspect that those [phenomena] confessed to be occult, are performed by the small machines of Nature.”
THE NAMES OF FIRE AND MELLO are now up there with those of Minot and Murphy, carved in stone on that pink granite slab behind a New York museum. More likely than not, some other kid from the neighborhood will point up at those names and start to wonder about what it takes to discover the new.
