Nobelists Beat Adversity To Advance Science

The recipients of the 1997 Nobel Prizes in science, who will receive their awards on December 10, have traveled the vigorous intellectual journey of science. They all toppled old theories while building new ones. Along the way, they gained collaborations and corroboration from colleagues. They also endured skepticism, which in some cases still persists, despite their noted accomplishments. OPTICAL MOLASSES: Stanford physicist Steven Chu developed a technique to slow atoms using lasers, mirrors, and magnets. The biomedical winner, Stanley B. Prusiner, a professor of neurology and biochemistry at the University of California, San Francisco, swam upstream against a tide of criticism when he introduced a new kind of infectious agent. One of the three chemistry winners, Paul D. Boyer, a professor, emeritus, of biochemistry at the University of California, Los Angeles, described a molecular machine that critics thought impossible, while corecipient John E. Walker, senior scientist at the Medical Research Council Laboratory of Molecular Biology at Cambridge University, earned recognition for proving the structure functioned as Boyer predicted. Jens C. Skou, a professor of biophysics at Aarhus University in Denmark, also will share the chemistry prize for explaining how an enzyme acts as a tiny biochemical pump. The three physics winners-William D. Phillips, an atomic physics fellow at the National Institute of Standards and Technology; Stanford University physicist Steven Chu; and Claude Cohen-Tannoudji, a physics professor at Ecole Normal Supérieure in Paris-devised ways to break the theoretical limits for cooling atoms. PRION PROPONENT: UC-San Francisco's Stanley Prusiner met much criticism when he introduced a new kind of infectious agent. It may be fitting that Prusiner is the sole recipient of the 1997 Nobel Prize in physiology or medicine, since he stood seemingly alone in the face of opposition during the early stages of his work with prions. Shortly after publishing his first paper (S.B. Prusiner, Science, 216:136-44, 1982, subsequently cited more than 680 times) proposing that the prion, a protein-based infectious agent without genetic material, caused scrapie, he endured a wave of criticism from the media and the scientific community. Work conducted by Prusiner and many others has resulted in enough evidence to convince the Nobel Prize committee and much of the scientific community that prions play a role in causing neurodegenerative diseases including kuru, Creutzfeldt-Jakob disease, and transmissible spongiform encephalopathies such as scrapie and mad cow disease. Most scientists now accept Prusiner's hypothesis that prions-tiny proteins found in nerve cells, white blood cells, and the brain surface-sometimes mysteriously fold. These misshapen proteins somehow trigger neighbor proteins to behave similarly. The resulting chain reaction of destruction degenerates the brain. Prusiner; William J. Hadlow, a research veterinarian in pathology with the National Institutes of Allergies and Infectious Diseases; and the late Carl M. Eklund and other collaborators first tried to characterize the physical properties. "Together, we looked for 10 years for a small nucleic acid that would be part of the prion particle and we never could find one," Prusiner says. He remains convinced that no virus aids the transmission of the rare diseases-a stance that still has critics (K.Y. Kreeger, The Scientist, June 10, 1996, page 13). In 1982, Ted O. Diener, a plant virologist with the United States Department of Agriculture, furthered the argument against a viral basis by showing that prions were the opposite of viroids, tiny pieces of RNA that caused exotic diseases in plants (T.O. Diener et al., Proceedings of the National Academy of Sciences, 79:5220-4, 1982). After he initially posed the prion hypothesis, Prusiner expected some criticism because other infectious agents-bacteria, viruses, fungi, and parasites-contain genetic material. However, he did not anticipate the tone or the intensity of some of the attacks. "At a few points this became very personal," Prusiner recalls. "I became the target instead of the prion." He reflects on the irony that he never would have sustained such attacks if he had found the virus he had searched for earlier. "I didn't enter into this looking for something radical," he says. But the idea became less radical as evidence increased. In 1984, Leroy Hood, a geneticist at the University of Washington in Seattle, independently sequenced the prion-encoding gene, which enabled its cloning by Prusiner and Charles Weissmann, a molecular biologist at the University of Zurich (B. Oesch et al., Cell, 40:735-46, 1985). In 1989, Prusiner and colleagues reported that patients with the brain diseases also possessed a mutant version of this gene (K.K. Hsiao et al., Nature, 338:342-5, 1989; K.K. Hsiao et al., Science, 250:1587-91, 1990). In 1993, knockout experiments confirmed the gene's link to prion diseases (H. Büeler et al., Cell, 73:1339-47, 1993). Prusiner notes that the trigger causing the prion to fold abnormally and the subsequent chain reaction of infection remain mysteries. "If we could understand the details of this structural transition, this will help us enormously," he maintains. "There must be another protein-Protein X-that acts as a chaperone in the unfolding and folding." The ultimate tests-isolating normal prions in a test tube and forcing them to collapse, or purifying prions, then injecting them into an animal to cause disease-have not been conducted yet because of the difficulty of purifying the insoluble molecules. However, Fred Cohen, a computational biologist at the University of California, San Francisco, has made a prion scrapie "mini" molecule that "seems to be soluble," Prusiner adds. Descriptions of the molecular motor that creates cellular energy and the biochemical pump that transports it across a cell's membrane earned three biologists the 1997 Nobel Prize in chemistry. MOLECULAR MACHINE: UCLA's Paul Boyer described a molecular machine that manufactures ATP. Both mechanisms increase understanding of adenosine triphosphate (ATP), the universal carrier of energy in all living organisms. ATP acts as an energy broker, taking in energy from the combustion of nutrients and releasing it for reactions that need it. Before Boyer began studying ATP in the 1950s (his most cited paper, "Spectrophotometric study of the reaction of protein sulfhydrl groups with organic mercurials," Journal of the American Chemical Society, 76[17]:4331-7, 1954, has been cited more than 2,000 times), biologists thought that the enzyme that makes ATP, called ATP synthase, required energy to build it. Instead, Boyer drew a theoretical picture that showed energy entered the equation later by binding adenosine diphosphate with another phosphate, then releasing it (P.D. Boyer, Biochimica et Biophysica Acta, 1140:215-50, 1993, cited more than 200 times). To make this complicated series of chemical reactions viable, Boyer proposed the binding change mechanism, which the Nobel nominating committee compared to a water-driven minting press that stamps out chemical currency as it spins. "It's a splendid little molecular machine," Boyer says. Built of proteins, the "machine" consists of a base, bound to the cell's mitochondrial membrane, and a spoke, with three subunits arranged around its hub. One subunit binds ADP, one binds ATP, and one remains empty. In order for the mechanism to work, however, the wheel must turn continuously, like a water wheel spun by a stream of protons. "The only way I could readily explain our data was to have this internal rotation relative to it," Boyer recalls. However, skeptics remained after Boyer first published his theories in 1971: "My colleagues were not nearly as convinced as I that that's the way it behaved." Although Walker never directly collaborated with Boyer, the British scientist's work eventually corroborated the American's. In the 1980s, Walker and his colleagues determined the amino acid sequences of the machine's genes (J.E. Walker et al., EMBO Journal, 1:945-51, 1982, cited more than 1,450 times). In the 1990s, Walker used X-ray crystallography to take a picture of the structure (J.P. Abrahams et al., Nature, 370:621-8, 1994, cited more than 350 times). The pictures showed that the wheel of the machine was built as Boyer predicted more than 20 years earlier. "When it came out, it was very convincing," Boyer recalls. "It was a scientific and emotional high." Then, this year a team from the Tokyo Institute of Technology filmed the rotation in action (H. Noji et al., Nature, 386:299-302, 1997). Most remaining skeptics were then won over. Boyer notes that some work remains, including determining the machine's base. "I haven't shown what makes the wheel turn initially," he notes. TINY PUMP: Aarhus University's Jens Skou explained how an enzyme acts as a tiny biochemical pump. While Boyer and Walker described the structure of the machine that makes ATP, Skou explained how an ATP-degrading enzyme shuttles ions through cell membranes (J.C. Skou, Biochimica et Biophysica Acta, 23:394-401, 1957, cited more than 1,500 times). Previous laureate Alan Hodgkins had shown that stimulating a nerve makes sodium ions pour into the nerve cell. After a series of experiments, Skou characterized the enzyme as having two subunits, with molecules that straddle the gate of the cell membrane, exposing surfaces on each side (J.C. Skou, M. Esmann, Journal of Bioenergetics and Biomembranes, 24:249-61, 1992). The enzyme works by maintaining different concentrations of ions on each side of the border, creating biochemical pressure akin to the physical pressure of a water pump. Since Skou's initial discovery, biochemists have discovered other ion pumps that have similar structures but different functions, including one that controls muscle contractions and another that produces hydrochloric acid in the stomach. Deploying magnets, lasers, and a healthy exchange of scientific ideas allowed three scientists to bring atoms to a halt and earn the 1997 Nobel Prize in physics. MAGNETIC TRAP: NIST Fellow William Phillips developed ways to slow atoms using lasers and magnets. "Each of us has built on the work of others," says NIST's Phillips, who embarked upon his quest to stop atoms for closer scrutiny in the late 1970s. He describes using lasers to stop atoms as akin to shooting a hail of ping-pong balls at an oncoming bowling ball. The atom-the metaphorical bowling ball-has a disproportionate amount of energy compared with the individual photon ping-pong balls that make up the laser beam. Complicating matters further, the atom will absorb the photons only if they are the right frequency-or color. "The trouble is, if we are successful and slow it down, the frequency shifts again." Phillips's early work involved finding ways to rectify this problem. First, he used a Zeeman slower, a coil with a varying magnetic field, along with an opposing laser. The varying magnetic field dealt with the changing energy needs of the oncoming atoms, but the trap proved weak, since atoms needed to be extremely cold to remain ensnared. Phillips and a group of physicists separately also developed a technique called chirping, which involves adjusting the frequency of the laser as the atoms' frequency changes. "As the atoms slow down, you change the frequency to compensate." In 1985, Chu-then at Bell Laboratories in Holmdel, N.J.-and his coworkers found that using a series of mirrors to split the laser into three pairs of beams could chill atoms to a near standstill. The beams' frequencies were adjusted as the atom's color changed. But that technique did not completely capture atoms either. Gravity pulled them out of what Chu called the "optical molasses" created at the lasers' intersection. So in 1987, Chu and his colleagues added two magnetic coils to create a weaker magnetic effect than the one Phillips had used earlier. The results yielded an effective trap that could hold atoms for study and experiments (E.L. Raab et al., Physical Review Letters, 59:2631-4, 1987, cited more than 300 times). "The trap that was developed in 1987 is the workhorse trap that everyone uses now," Chu says. After Chu's initial success with optical molasses, Phillips similarly trapped atoms. He also developed ways to measure their temperature with a laser and found that scientists could cool the atoms six times below the theoretical limit. "The temperature you can cool atoms down to by using optical molasses could be much lower than we thought," Chu notes, adding that Phillips's experiments helped refine the trapping technique. "That's certainly a nice interplay." Meanwhile, Cohen-Tannoudji and his colleagues at Ecole Normal Supérieure in Paris had developed theoretical models that explained why Phillips was able to break the cooling limit and revealed that physicists could slow atoms even further. Phillips collaborated with the Paris group, and they obtained even lower temperatures (C.N. Cohen-Tannoudji, W.D. Phillips, Physics Today, 43:33-40, 1990). One more boundary riddle remained. The atoms continued to move slightly because the laser forced them to absorb, then emit, photons. Cohen-Tannoudji and colleagues applied a method that converted the slowest-moving atoms to dark atoms no longer capable of absorbing photons. The result was helium atoms creeping about at two centimeters a second and a shared Nobel Prize. "To work in the environment of having these ideas going back and forth is amazing," comments Phillips, who adds that laser cooling has since become commonplace. Chu, too, notes that creating the cooling techniques yielded an explosion in new theories. Now, physicists are harnessing the technique for practical applications, like etching minute surfaces with atomic lithography, building an atomic clock potentially 100 times more accurate than existing ones, and creating Bose-Einstein Condensation (BEC), a condition in which a cloud of atoms falls into a single quantum state and essentially behave as a single atom. Some Nobel watchers predicted BEC would win the award this year, but instead the work making its demonstration possible was recognized. Two economics professors, Robert C. Merton of Harvard University and Myron S. Scholes of Stanford University, will receive the prize for economics. The two, in collaboration with the late Fischer Black, developed a pioneering formula for the valuation of stock options. Italian dramatist and actor Dario Fo, who the Nobel committee says "emulates the jesters of the Middle Ages in scourging authority and upholding the dignity of the downtrodden," will receive the 1997 Nobel Prize for literature. Jody Williams, the coordinator of the International Campaign to Ban Landmines, will be awarded the Nobel Peace Prize for 1997 for work in banning and clearing of anti-personnel mines.

Nobelists Beat Adversity To Advance Science

The recipients of the 1997 Nobel Prizes in science, who will receive their awards on December 10, have traveled the vigorous intellectual journey of science.

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