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Wonder — is not precisely Knowing And not precisely Knowing not—
Emily Dickinson (1)
NOBEL ON COLUMBUS AVENUE
Last month, the King of Sweden honored five Americans who had won all the 2006 Nobel prizes in the natural sciences. Andrew Z. Fire of Stanford University and Craig C. Mello of the University of Massachusetts shared the Prize in Physiology or Medicine, Roger D. Kornberg of Stanford University took the solo award in Chemistry, while the prize in Physics went to John C. Mather of NASA and George F. Smoot of the University of California, Berkeley.
Later this year, their names, together with that of Edmund S. Phelps of Columbia University, the 2006 Economics laureate, will be carved into a pink granite monument at the corner of Columbus Avenue and 81st Street. The monument, dedicated to Alfred Nobel and to American Nobel laureates past and present, stands behind the American Museum of Natural History in a park named after Theodore Roosevelt, the first American laureate (Peace Prize, 1906). The names of 290 other American Nobel Prize winners have been inscribed on the sides of the monument, with ample space for more to come.
The monument in New York came to mind as I read Craig Mello’s response to Adam Smith of the Nobel Foundation, who called Mello right after THAT phone call from Stockholm in October:
AS: Well, first of all, many, many congratulations on being awarded the prize. CM: Thank you so much. AS: Where were you when you heard the news? CM: I was checking my daughter’s blood sugar. She has type 1 diabetes, so I was actually up, one of the few, I guess, in the North Americas who was awake. AS: Yes, I imagine so. CM: We check her frequently and I just happened to be up, checking her blood sugar. And she had a good sugar actually, 95, which is normal. AS: That’s good news, yes. CM: I was on my way back to bed and the phone rang. AS: So two good pieces of news at once! I imagine you were thinking of other things but what was your first thought on being told? CM: Well, you know, gee, that’s a really hard question! You know first it’s disbelief, and I don’t think it sinks in quickly. I felt I was sort of too young to get it this soon and thought, if it happened, it would be a few years from now. So I wasn’t ready at all (2).
Ready or not, 46 year-old Mello will join other striplings carved in granite, among them Joshua Lederberg and James Watson (aged 33 and 34, respectively, when they received their telephone calls).
The Nobel monument is a recent addition to the New York scene. The slab was unveiled on a damp October day in 2003 by Mayor Michael Bloomberg, with appropriate remarks by Swedish and Norwegian dignitaries, choral music, and a stirring address by Eric Kandel (Physiology or Medicine, 2000) who paid tribute to the city’s public school system of which he was a product. The audience was filled with many Nobelists, their guests, consular and civic officials, and platoons of students from high schools in the neighborhood.
As the flock of VIPs dispersed, a teen-aged couple made their way to the monument. Arm draped about his girlfriend’s shoulder, a gangly youth pointed up at the open space under all those names: "I’m gonna to be the first black guy up there in science!" That’s why we have prizes and monuments, I thought at the time, to carve something in stone for a kid to look up to.
Reflecting on the 2006 Nobels in life science, it occurs to me that science gets written in stone as a result of thinking inside the box, thinking outside the box, or simply running into pure luck. Luck, especially, since (to quote Lewis Thomas), "Chance favors the prepared grind (4)
."
THINKING INSIDE THE BOX
Much of what we learn in science comes from looking in depth at what we partially understand already, something at the "not precisely Knowing" level of Dickinson. But if we have a new notion of where, or how, to dig even deeper, if we end up precisely Knowing something important, the results are often astonishing. I’d call this "thinking inside the box" and the work of Roger Kornberg illustrates this sort of discovery. Joining the tools of structural biology and molecular genetics, Roger Kornberg isolated Mediator, a precisely defined complex of 20 proteins that serves as the interface between gene-specific regulatory proteins and the transcription apparatus. It’s the central link in the enhancer
activatorMediatorpolII
promoter pathway of sixty proteins that has been conserved from Neurospora to primate and Kornberg’s pictures show precisely how that apparatus serves to spew out mRNA (5)
. We already knew a good number of the moving parts, but it took Kornberg to show us how they work in concert from yeast to beast. In his Nobel interview he explained:
RK: ... The remarkable thing about the machinery is the extent to which it truly functions in the way you and I imagine or think of a machine ... AS: Do you know what speed it works at? RK: It copies approximately ten DNA, or RNA (as they are called), letters per second. AS: And it must achieve an extraordinary fidelity in its copying because the room for error is very small. RK: It achieves very great fidelity, but beyond that it has inherent mechanisms for proof- reading and correcting errors that may be made in the process. AS: Perfect machine (6)
Mechanical analogies seem to run in the family. Arthur Kornberg, Roger’s father, received the Nobel Prize in Physiology or Medicine in 1959 (they are one of six Nobel father/son pairs and the only Americans). Kornberg père had discovered the enzyme that made DNA, sharing the platform in Stockholm with my mentor, Severo Ochoa, who had accomplished the synthesis of RNA. Arthur Kornberg recalled the first reaction in which DNA was put together from its constituents:
While this represented only a few micromoles of reaction, it was something. Through this tiny crack we tried to drive a wedge, and the hammer was enzyme purification (7)
Father and son suspected that if one took the genetic machinery apart and put it together properly, one could figure out precisely how it worked. 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 (8)
THINKING OUTSIDE THE BOX
The opposite of the "digging-ever-deeper" approach to science is to encounter something new and puzzling, and to figure it out. The hallmarks of discoveries like these are easy to spot - in retrospect. First-off, the unexpected often comes from a field far removed from the scientist’s field of expertise. Secondly, it stares him in the face, like Mendel’s sweet-peas or Darwin’s finches. Finally, it tips its hand when the seminal publication sports words like "unexpected" or "surprise" in title or abstract. Here’s how RNAi was announced in the 1998 Fire, Mello paper in Nature:
To our surprise, we found that double-stranded RNA was substantially more effective at producing interference than was either strand individually (9)
While the role of double strand RNA-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 remembered in his Nobel interview that:
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 (10)
Their experimental noses had a long trail to sniff. The history of the "Silence of the Genes," as Sen and Blau recorded in these pages (11)
is complex, indeed.
In 1990, plant scientists at a biotechnology company (Carolyn Napoli, Christine Lemieux, and Richard Jorgensen) were studying enzymes that formed anthocyanin, the pigment that makes petunias purple. Testing whether chalcone synthase (CHS), was the rate-limiting enzyme in anthocyanin biosynthesis, they overexpressed chalcone synthase in petunias: "Unexpectedly the introduced gene created a block in anthocyanin biosynthesis" (12)
and 42% of the plants became white or had chimeric purple-white patterns (see picture on previous page). They had silenced the gene for CHS and this proved to be heritable: "progeny testing showed that the novel phenotype co-segregated with the introduced CHS gene (12)
."
Sure enough: "unexpectedly" was the operative word in the petunia abstract, the work it described led directly to Fire and Mello’s "surprise" in worms, and to that pink granite monument on Columbus Avenue.
A LUCKY ERROR
Planning for the Nobel monument in New York began with discussions in December of 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, and 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 the splendid Town Hall of Stockholm. Guests lucky enough to have been seated at the banquet table with the senior American laureate present, Tom Weller of Harvard University, heard a story that described the third way to make a great discovery: make a great error, and recognize your luck.
Over wines of not inconsiderable vintage, Weller reminded his dinner companions of 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. Based on the wrong animal model, they had found a cure for pernicious anemia (13)
.
George Richards Minot, "a Yankee of the Yankees," had been a Professor of Medicine at Harvard since 1928. He also maintained an active private practice oriented to hematology (14)
. William Parry Murphy, on the other hand, was a Westerner of decidedly non-patrician 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, so the story goes, was accustomed to picking young physicians of the 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 (15)
that dogs made anemic by repeated bleeding could be restored to health by feeding them 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 obstreperous, fretful, cantankerous old woman, whom Murphy cajoled into taking her daily ration of half a pound of liver only after a mighty contest of wills. Murphy described his everlasting "surprise," not only did her red blood cells respond to a week or so of this cumbersome regimen, but she was also relieved of her mental symptoms and soon reverted to her agreeable self. Eventually, his lucky observation of her mental improvement persuaded him that the 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 of 1926, Minot and Murphy had treated each of 45 patients with half a pound of liver a day (16)
. Soon Minot persuaded a young biochemist, E. J. Cohn, to make a liver extract 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 isolated and named vitamin B12 in 1948. It was among the first "miracle drugs" to cure a hitherto fatal disease (17)
.
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 for work accomplished in the USA.
But there’s more to the Minot story, and it touches on that telephone call Mello received from Stockholm. Like Mello’s young daughter, Minot suffered from what we would now call Type 1 diabetes: he was also gravely ill when he made his great discovery. A strapping six-footer, Minot had developed a severe case of diabetes, by 1922 his weight had dropped to 120. As luck would have it, Charles Best and Frederick Banting in Toronto, following the digging-ever-deeper approach of John Macleod (Medicine and Physiology, 1923), had prepared the first useful batches of insulin. Minot became one of the first patients treated with the hormone by Eliot Joslin. One Nobel led to another: had insulin not been discovered, vitamin B12 might have been a distant dream (17)
.
Soon the names of Fire, Mello, and Kornberg will join those of Minot and Murphy carved in stone on that pink granite slab in back of 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.
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