foreword

The card players of , Cézanne and Mark Twain: tips for getting lucky in high-stakes research

Joseph L Goldstein

To the scientist, the thrill of discovery is like card-playing experts, but from artists such as (Fig. 1b). In dazzling colors, La Tour depicts the the thrill of a royal flush to the poker player. Caravaggio and Cézanne and from writers such dangers of wine, women and gambling. Here we Scientists who receive Lasker Awards and Nobel as Mark Twain. see a trio of conniving cheats, highlighted by Prizes share many things in common with poker carefully orchestrated gazes and gestures. Is the superstars, both of whom take risks and gamble Caravaggio’s Cardsharps gaze of the woman with the plunging neckline for high stakes. Scientists pit their wits against In the late 1300s, when card playing first became intended for the maidservant to give her more Nature’s puzzles, betting that their efforts will a popular form of entertainment in Italy and wine, or is she signaling the cheat to play the ferret out those rare nuggets of truth embedded France, card cheats and crooked gamblers domi- ace of clubs? in a vast mountain of artifacts. Poker players pit nated the game, minimizing the skill factor of their wits against mathematical probabilities, the player. This state of affairs is wonderfully Cézanne’s Card Players wrestling with the fact that a deck of 52 cards captured in The Cardsharps, a 1594 painting Caravaggio’s celebrated compositional portrayal can be shuffled into 52! sequences, which is 52 × by the Italian artist Michelangelo Merisi da of trickery, greed and lust proved so seductive 51 × 50 × 49 and so on down to 1. This comes to Caravaggio (Fig. 1a). Art historians consider and powerful that artists continued to copy it 8.1 × 1067 possible card permutations—a num- The Cardsharps the most influential gambling- for 300 years. Then, in the 1890s, Paul Cézanne ber 53 orders of magnitude greater than the 1014 themed painting in the history of art. The reinvented the card-playing theme in a revo- synaptic connections in the human brain and 45 composition is simple and elegant. An innocent- lutionary way. Over a 5-year period, Cézanne orders of magnitude greater than the 1023 stars looking young man has been lured into a card executed five paintings of male peasants playing in the universe. game by a sinister, middle-aged man. Stealing a cards. Known collectively as The Card Players, Given the mathematical odds of being dealt peek at his victim’s cards, the older man signals the paintings in the series (three of which are a good card hand and the tightness with which with his fingers to an accomplice, who holds the shown in Fig. 2) vary in size and scale, but all are Nature guards her secrets, a key question is 5 of hearts tucked in his belt behind his back. formally based on a similar composition: two to whether success, in poker or in science, depends The object of the conspiracy—a stack of coins— five stone-faced, drably dressed, stocky men— predominantly on luck or on skill. Luck is diffi- sits at the edge of the table. all wearing unadorned hats—are depicted play- cult to define. Perhaps the best definition comes Caravaggio’s genius is the creation of a dra- ing cards and smoking clay pipes while gathered from the great film producer Samuel Goldwyn: matic scene of concealment in which all three around a plain table. The men look down at their “The harder I work, the luckier I get.” The skill characters are hiding something. The tension cards rather than at each other; they are totally element in poker depends on acquiring expertise and drama are heightened by details such as the and intensely absorbed in the ritual of their in statistics and probability and on mastering the split glove that allows the older man to easily feel game—a kind of “collective solitaire,” in the complexities of betting and bluffing—knowing the marked cards, the black hat of the innocent words of art critic Meyer Schapiro (Schapiro, when to bet, fold or raise at any decision point boy that hides the peering right eye of the older M., Paul Cezanne; Harry N. Abrams, Inc., New and knowing how many chips to put on the man, and the older man’s left hand that seems to York, 1952). The tense atmosphere of concentra- table. The skill element in science also depends come out of nowhere to rest close to the younger tion and solemnity is accentuated by shades of on being bold and knowing when to take risks— cardsharp’s dagger. The whole scene keeps the brown and blurs of blue. not to mention learning the art of asking the viewer on tenterhooks: any slight movement The contrast between the card players of right questions and pursuing experimentation might reveal the trickery. The young boy may Caravaggio and those of Cézanne is striking. passionately and fearlessly. be skillful at his game, but we’ll never know— Unlike Caravaggio’s masterpiece, Cézanne’s Philosophers of science have paid little atten- he’s the victim of bad luck. seminal series depicts no cheating, no money tion to the relative roles of luck versus skill. But The Cardsharps inspired many artists to take on the table, no melodrama, no skullduggery, in card-playing circles, the luck-versus-skill up the gambling theme. One famous imitation is no extravagant clothes. Cézanne is telling us that question has been debated for hundreds of The Cheat with the Ace of Clubs, an early-1630s card play is no laughing matter. The key to skill- years. Some of the best insights come not from painting by the French artist ful play and winning is focus, focus, focus. Luck

nature medicine volume 17 | number 10 | october 2011 iii foreword is not necessary when there are no distractions that Mark Twain’s literary experiment settled the a or trickery of the sort portrayed in Caravaggio. question of luck versus skill. Fortunately, the first As to which is more important, luck or skill, convincing scientific experiment on the subject Caravaggio leans toward luck and Cézanne was recently carried out by the University of favors skill. Chicago economist Steven Levitt. Levitt is the author of the best-selling book Freakonomics, Mark Twain’s Science vs. Luck which describes how the tools of economic To settle the argument, there is no one better research can be used to understand the workings than America’s greatest humorist and arguably of everyday events and problems. Several repre- most creative fiction writer—Mark Twain. Twain sentative examples Levitt tackles in his book are: was an unabashed lover of poker and was sad- “Which is more dangerous, a gun or a swim- dened by how few people in the US knew any- ming pool?”; “Why do drug dealers still live with b thing about the game, lamenting (in Johnson, their moms?”; and “What do school teachers M., A Bibliography of the Works of Mark Twain; and sumo wrestlers have in common?”. Harper & Brothers, New York, 1935), “I have Levitt’s study, called ‘Pokernomics,’ analyzed known clergyman, good men, kind-hearted, the performance of 32,000 players who took part liberal, sincere, and all that, who did not know in the 2010 World Series of Poker in Las Vegas. the meaning of a ‘flush’. It is enough to make Levitt divided the players into two groups—a one ashamed of one’s species.” In an 1870 essay highly skilled group and an ordinary group. entitled “Science vs. Luck,” Twain wrote about The highly skilled group consisted of the 720 a fascinating court case in Kentucky in which players—2.3% of the total—who had won the Figure 1 Two gambling-themed paintings. a dozen schoolboys were arrested for playing most money in 2009 tournaments. The ordinary (a) Caravaggio. The Cardsharps, c. 1594. Oil on poker for money. Back then, many states had group comprised the rest of the 32,000—97.7% canvas, 94.2 × 120.9 cm. Kimbell Art Museum, strict laws prohibiting “games of chance,” and of the total. In the 2010 World Series, the skilled Fort Worth, Texas, USA. (b) Georges de La Tour. even at enlightened institutions of higher learn- poker players made an average return on invest- The Cheat with the Ace of Clubs, c. 1630–1634. ing such as Harvard University, errant students ment of 30%, whereas the ordinary players had Oil on canvas, 97.8 × 156.2 cm. Kimbell Art incurred the heaviest fines not for drinking or an average loss of 15%. This large gap in return is Museum, Fort Worth, Texas, USA. fighting, but for playing cards. strong evidence that poker, as it is played today, The lawyer hired to defend the 12 poker- is a game of skill and not luck. for good fortune. He or she is discovery-prone playing boys in Twain’s essay came up with an in the sense of Louis Pasteur’s famous dictum: ingenious defense: poker was not a game of The luck factor in high stakes research “Chance favors the prepared mind.” chance but of skill, thus his clients could not Do scientists who win Laskers and Nobels pro- The driving force that moves a scientific field be punished until it was proven otherwise. duce award-winning research because they in a new direction is the unexpected result—the To make a short story even shorter, the pros- are luckier than other scientists? Is luck more surprise finding. The highest achievements in ecution’s witnesses (who were all deacons of important than skill in high-stakes research? science come from skilled and prepared-of- the Church) testified that poker was all luck, Quantifying the luck-versus-skill factor in mind individuals who can recognize the surprise whereas the defense’s witnesses testified in research is not as straightforward as in the case result, act on it and follow it wherever it leads. favor of skill. The judge was unable to render of Levitt’s Pokernomics study. But I think one There is no better example of the benefits of a a decision, and in his paralyzed state, he called can come up with a reasonable assessment, prepared mind than the story of the invention of upon the boys’ lawyer to suggest a solution. The depending on one’s definition of luck—that is, the microwave oven. In 1946, Percy Spencer, an lawyer quickly replied: “Impanel a Jury of six of whether one is referring to blind luck or insight- electrical engineer and physicist at the Raytheon each, Luck vs. Science. Give them candles and a ful luck. Blind luck is when a person en route to Company in Waltham, Massachusetts, visited a couple of decks of cards. Send them into the jury the Lasker Luncheon gets on the elevator at the lab where magnetrons, the power tubes of radar room, and just abide by the results.” Six deacons Pierre Hotel, finds a lottery ticket on the floor sets, were being tested. Suddenly, he felt a choco- were sworn in as the ‘Chance’ jurymen, and six of the elevator and wins $10 million. Insightful late peanut candy bar begin to melt inside his experienced poker players were sworn in as the luck is when the same person, en route to the shirt pocket. According to Raytheon history, ‘Science’ jurymen. Pierre, stops at the corner kiosk, buys a lottery Spencer immediately sent a messenger boy After 1 day of deliberation, the foreman of ticket and wins $10 million. to fetch a package of popcorn kernels. When the jury—one of the deacons—read the verdict: Blind luck is basically irrelevant to scientific Spencer held the kernels near the magnetron, “We, the Jury in the case of the Commonwealth discovery, but insightful luck is not. The person popcorn exploded all over the room. Nine years of Kentucky vs. John Wheeler et al. have carefully who purchases a lottery ticket has positioned later, in 1957, the first home microwave ovens considered the points of the case and do hereby himself or herself to win a prize. Whether or were sold by Raytheon, and in 1999, Spencer unanimously decide that the game is eminently not he or she wins is a matter of mathematical was inducted into the National Inventors Hall of a game of Science and not of Chance. In support probability. The same can be said for insight- Fame. Spencer was not the first person to notice of our verdict, we call attention to the fact that ful scientists who purchase their skills by doing that microwaves generate heat, but he was the the Chance men are all busted; and the Science experiments, making observations, reading the first to think of using their heat to cook food. men have got the money.” The judge declared literature and keeping the right company—by Spencer was a man with restless curiosity and the Chance theory a pernicious doctrine, and which I mean going to the right meetings and an intense passion to explore every wonder in then he ruled that poker playing was no longer a associating with people smarter than they are. the world. He clearly had skill and the itch to dis- punishable offense in the state of Kentucky. Such a scientist has deliberately positioned and cover. But did he have luck? Spencer created his I am sure that most of you are not convinced prepared him- or herself to be a strong candidate own luck by eating candy bars. What if he had

iv volume 17 | number 10 | october 2011 nature medicine foreword

a b c

Figure 2 Paul Cézanne. The Card Players. Three of the five paintings in this series are shown: (a) c. 1890–1892. Oil on canvas, 65.4 × 81.9 cm. The Metropolitan Museum of Art, New York. (b) c. 1892–1896. Oil on canvas, 47 × 56 cm. Musée d’Orsay, Paris. (c) c. 1892–1896. Oil on canvas, 60 × 73 cm. The Courtauld Gallery, London. been overweight and on a strict Atkins-like diet? aggregation and denaturation. How, then, is ortholog of Hsp60, referred to as GroEL, and its Then he would have had bad luck—as would proper folding achieved in the intact cell? co-chaperone GroES. Raytheon’s stockholders, not to mention couch A key insight came with the discovery of The basic function of the GroEL-GroES com- potatoes all over the world! protein-folding pathways and machines by this plex is as a protein machine that encapsulates All of the lucky scientists I know have a com- year’s Lasker awardees—Franz-Ulrich Hartl a single molecule of newly synthesized, non- mon phenotype: they are excessively inquisitive, (Max Planck Institute of Biochemistry) and native protein in a cage-like structure, seques- passionate and persistent, and they have the Arthur L. Horwich (Yale University School of tering it from the rest of the cell, thus allowing uncanny instinct for being in the right place at Medicine). Their now-classic work began in folding to occur unimpaired by aggregation. The the right time. And like Percy Spencer, they have 1989 with the publication of two papers—one GroEL component of the GroEL-GroES folding the skills they need to create their own luck. To genetic and the other biochemical. In the first chamber is a cylindrical complex (of ~800 kDa) repeat Samuel Goldwyn’s dictum: “The harder paper, Horwich, Hartl and their colleagues car- consisting of two rings, each with seven identical I work, the luckier I get.” But the last word, as ried out a genetic screen in yeast, searching for 57-kDa subunits. The two ring-like GroEL com- always, belongs to James Watson of DNA fame: mutations that altered the folding and/or assem- ponents (referred to as the cis and trans rings) “I was very, very lucky. But, you know, they give bly of nuclear-encoded proteins after they had are positioned one on top of the other like two prizes for people who are lucky.” been imported into the mitochondria. One such stacked donuts. The single GroES component mutation, which impaired the function of a of the structure is a dome-shaped ring (70 kDa) Basic Award: an awesome piece of work mitochondrial heat-shock protein called Hsp60, consisting of seven identical 10-kDa subunits. This year’s Lasker Basic Medical Research was identified. But at what step was Hsp60 act- At any one time, the GroES ring is bound to only Award is given for discoveries concerning the ing: did it promote protein folding or subunit one of the two GroEL rings, capping one end of cell’s protein-folding machinery, exemplified assembly? In the second, biochemical paper, the cylinder in a lid-like fashion and produc- by cage-like structures that convert newly syn- Hartl and Horwich distinguished between these ing an asymmetrical structure. The GroES lid thesized proteins into their biologically active two possibilities by studying, in isolated mito- cycles on and off GroEL in a manner regulated forms. The story begins 50 years ago, when in chondria, Hsp60-mediated import of a mono- by the ATPase activity of the GroEL cylinder. the early 1960s, the protein chemist Christian B. meric enzymatic protein that did not require The GroEL-GroES structure is referred to as the Anfinsen established the principle that the pri- subunit assembly. Folding of the enzyme and GroEL-GroES chaperonin machine. mary amino acid sequence of an unstructured acquisition of its functional activity occurred on As soon as a newly synthesized polypeptide polypeptide chain contains all the informa- the surface of Hsp60 in an ATP-mediated reac- chain emerges from the ribosome, it undergoes tion required for it to fold into its native state. tion and was followed by release of the mature successive interactions with several different Anfinsen’s insights, for which he received the protein. These two landmark papers established chaperones (DnaK (or Hsp70), DnAJ, GrpE) 1972 Nobel Prize in Chemistry, emerged from unequivocally the principle of protein-assisted that relay the polypeptide to the GroEL-GroES in vitro denaturation-renaturation experiments protein folding—a radical departure from the chaperonin machine for final folding. The of a small 124-amino-acid, single-domain pro- earlier view that protein folding in the cell is a incompletely folded protein now binds to a tein (bovine pancreatic RNase) that was studied spontaneous process. patch of hydrophobic amino acids that line the at very dilute concentrations that were orders of Over the next 15 years, Hartl and Horwich interior rim of the non-lidded, or trans, ring of magnitude lower than those in the cytoplasm of carried out a series of incisive studies spanning the GroEL cylinder. Capture of the unfolded intact cells. Not surprisingly, most complex pro- the gamut from biochemical reconstitution to polypeptide triggers the binding and hydrolysis teins have proven notoriously difficult to refold electron microscopy to X-ray crystallography to of ATP in the open trans ring, which leads to spontaneously when studied at the high protein NMR spectroscopy. With these experiments, they dissociation of the GroES lid from the cis ring. concentrations that prevail in the cell. During elucidated a pathway for protein-assisted protein The released GroES, together with ATP, rapidly the several minutes it takes for the ribosome folding and dissected its mechanism. Although rebinds to either GroEL ring, apparently with to translate a typical protein of 400–600 amino the two scientists carried out their mechanis- equal chance. However, only the binding of acids, the emerging polypeptide chain exposes tic studies independently, their results were GroES to the polypeptide-containing GroEL non-native features, such as hydrophobic and remarkably complementary. For experimental ring will lead to productive folding. At this charged patches, that are prone to disordered simplicity, both scientists turned to the bacterial point, closing the lid induces a major confor-

nature medicine volume 17 | number 10 | october 2011 v foreword mational change in the polypeptide-containing Starting with abandoned automobile parts at Stanford University), John Ellis (University ring, producing a shift in the surface properties and other industrial material, Chamberlain of Warwick), George Lorimer (Du Pont de of GroEL from hydrophobic to hydrophilic. The constructs sculptures by folding, bending and Nemours & Co.) and Hugh Pelham (Medical result is that the unfolded polypeptide (still with twisting the metals to form works of art, often Research Council) each identified and charac- its hydrophobic patches exposed) is released on a monumental scale. Figure 3 shows one terized components of the core protein machin- from the now-hydrophilic walls of GroEL into of Chamberlain’s recent assemblages, titled ery (such as phage assembly factors, Rubisco the chaperonin cavity, where it is allowed to fold. AWESOMEMEATLOAF. Chamberlain’s cham- subunit-binding protein, proteins upregulated The enclosure time is ~10 s, reflecting the time ber-like structure, not withstanding its title, is by stress and so on) that ultimately proved required for hydrolysis of seven ATP molecules itself an awesome piece of work, striking in its crucial for protein folding in the cell. In addi- in the polypeptide-containing ring. This second structural resemblance to the awesome GroEL- tion, Gottfried Schatz (University of Basel) and ATP binding and hydrolysis event triggers the GroES chamber created by Nature and revealed Walter Neupert (University of Munich) pio- rapid dissociation of the GroES lid, allowing the to us by the awesome studies of Horwich and neered the methodology for studying import polypeptide chain, whether native or not, to exit Hartl. of nuclear-encoded proteins into mitochondria the GroEL chamber. The discoveries of Hartl and Horwich are as used by Horwich and Hartl in their 1989 genetic Any incompletely folded intermediates that universal and basic to biology as understanding and biochemical studies. But what distinguishes still possess hydrophobic surfaces will be rapidly the nature of genes and how they are expressed the contributions of Hartl and Horwich from all recaptured by the hydrophobic GroEL ring for and translated into proteins. If proteins do others in the field is their elucidation of a specific another folding attempt. As many as ten folding not fold properly, cells will not function prop- and universal pathway for protein folding that cycles of capture, ATP binding and hydrolysis, erly. Horwich’s and Hartl’s pioneering work involves a container-like structure within which and release may be required for a protein to has stimulated many scientists to character- protein folding occurs—a revolutionary concept attain its native conformation. ize folding pathways and folding machines in in cell biology. In this regard, special mention Titia de Lange, Lasker jury member and pro- multiple organisms from all three kingdoms of should be made of the contributions of the late fessor at The Rockefeller University, has come up life. Bacterial cells and endosymbiotic organ- Paul B. Sigler, an exceptionally talented biophys- with a gambling metaphor that vividly illustrates elles, such as mitochondria and chloroplasts, icist and crystallographer who collaborated with the GroEL-GroES reaction cycle. In roulette, the use detachable lid–based GroEL-GroES chap- Horwich for 10 years. Together, they obtained little ball (the unfolded polypeptide chain) falls eronins of the Hartl-Horwich type. Archaea the crystal structure of the GroEL-GroES chap- into the wheel (the GroEL chamber), and the and eukaryotic cells use a folding machine that eronin, which provided invaluable insights into croupier says, “No further bets” (the closure of resembles the GroEL chamber in its dual ring how folding machines work. GroES lid). The ball bounces around, but then structure and its ATP requirement but that dif- the ATP runs out and the wheel stops (the open- fers in the amino acid sequence of its subunits Clinical Award: an awesome addition to ing of GroES lid). The ball may or may not be in and in its use of a built-in protrusion structure, the Medicine Cabinet the winning slot. Like the polypeptide chain, the rather than a GroES-lid structure, for encapsu- This year’s Lasker~DeBakey Clinical Medical ball is lifted out and thrown back in for another lation. Research Award is given to Youyou Tu (China chance (a new folding cycle) when the wheel The medical implications of the Horwich- Academy of Chinese Medical Sciences) for the (GroEL) binds ATP and starts spinning again. Hartl work are just starting to be realized. Human discovery of artemisinin, a drug therapy for The elegant GroEL-GroES chamber-like misfolding diseases occur when mutant proteins malaria that has saved millions of lives across structure for folding and assembling proteins adopt non-native conformations that promote the globe, especially in the developing world. brings to mind the artistic creations of John aggregation and formation of pathological intra- For more than 500,000 years, mosquitoes have Chamberlain, a contemporary American sculptor cellular and extracellular deposits. The most been biting humans, producing malaria and famous for his mastery of the art of assemblage. common neurodegenerative diseases arise from eluding every remedy ever devised. Today, altered protein misfolding and accumulation of more than 250 million people are infected abnormal deposits in the brain—amyloid in every year, and about 1 million die from it, Alzheimer’s disease, Lewy bodies in Parkinson’s most of them children. disease, and polyglutamine-rich proteins in The name mal aria, meaning “bad air,” origi- Huntington’s and other CAG-triplet repeat dis- nated in ancient Rome, where it was believed that eases. Another pattern of protein-misfolding the fever of malaria was caused by unwholesome disease, as in cystic fibrosis and retinitis pig- vapors emanating from the ground. To avoid mentosa, is one in which the mutant proteins, the dreaded vapors, the ancient Romans built although functionally active, fail to reach their their grand villas high in the hills and prayed for final destination in the cell, owing to impaired relief to Febris, the goddess of fever. In the sec- transport out of the endoplasmic reticulum. The ond century ad, the Roman emperor Caracalla concept that disordered proteins can be chaper- concluded that praying to Febris was a no-win oned into their native state provides a therapeu- situation, and he challenged his physician, a tic approach to these diseases that is now being clever man named Serenus Sammonicus, to vigorously pursued by many scientists. develop a cure for malaria. Sammonicus’s inge- Prior to and contemporaneous with the work nious solution turned out to be the world’s first of Horwich and Hartl, many scientists work- antimalarial quick fix—wear an amulet around Figure 3 John Chamberlain. ing on a variety of different biological systems your neck inscribed with a powerful incanta- AWESOMEMEATLOAF. 2011. Painted and provided biochemical insights that were highly tion: “Abracadabra.” Sammonicus’s Abracadabra chrome-plated sheet. 106 × 118 3/4 × 82 in. influential to Hartl and Horwich in their early invention has stood the test of time, becoming Gagosian Gallery, New York. studies. In particular, Costa Georgopoulos (then the universal secret weapon that explains how

vi volume 17 | number 10 | october 2011 nature medicine foreword all magicians create their magic—by relying on with a molecular weight of 282. Shortly there- both luck and skill. after, in collaborative clinical trials, Guo-Qiao In the last 100 years, we have had four more Li (Guangzhou College of Traditional Chinese Abracadabra cures for malaria. The first, Medicine) and Keith Arnold (Roche Far East appearing in the early 1900s, involved spray- Research Foundation, Hong Kong) showed ing mosquito-infected puddles of water with the effectiveness of combined therapy using a thin layer of oil to smother the larvae. The artemisinin and the quinine-like drug meflo- second cure came in the 1930s with the drug quine. The publications of these trials in The quinine, soon followed in the 1940s by a third Lancet in 1982 and 1984 were highly influential cure, chloroquine. Then, in the 1950s, the fourth in bringing artemisinin to the attention of the Abracadabra cure, DDT, was hailed as the per- Western world. fect insecticide. Together, antimalarial drugs and In the late 1980s, scientists at the Academy DDT sent the global malaria toll plummeting of Military Medical Sciences in Beijing recog- from 350 million cases a year to 100 million. But nized the superior effectiveness of artemisinin this success didn’t last long: mosquitoes rapidly when it is combined with a quinine-like aryl developed resistance to drugs and chemicals. By alcohol called lumefantrine. These two drugs the time of the Vietnam War in the mid-1960s, differ in molecular target, and in mode and quinine- and chloroquine-resistant strains of duration of action. Once human hemoglo- malaria had become widespread. bin is taken up and degraded in the parasite’s They were so widespread that Ho Chi Min, the digestive vacuole, the released iron-containing leader of North Vietnam, entered into a secret heme cleaves artemisinin’s endoperoxide ring, Figure 4 Damien Hirst. Medicine Cabinet: military project with China to discover new generating reactive oxygen radicals that kill the Problems. 1989–2010. Glass, faced particle drugs for chloroquine-resistant malaria. Project parasite. Lumefantrine is believed to prevent board, ramin, wooden dowels, plastic, aluminum and pharmaceutical packaging. 54 × 40 × 9 in. 523, so named for the date of its announcement, the detoxification of heme, thus prolonging the White Cube Gallery, London. began on 23 May 1967, just after the beginning action of artemisinin. The combination drug of the Chinese Cultural Revolution. Chairman containing an artemisinin derivative (short act- Mao Zedong empowered multiple teams of ing) and lumefantrine (long acting) is called worldwide. WHO now lists artemisinin in its scientists at the China Academy of Traditional Coartem. When tested in several Asian coun- catalog of ‘Essential Medicines’. Artemisinin Medicine to explore every Chinese herb known tries in the late 1980s, Coartem had virtually also deserves its place as an awesome addi- to exist. The scientist selected to lead one of the no toxicity and was highly effective, with cure tion to the Medicine Cabinet series by Damien teams was a phytochemist named Youyou Tu. rates of over 96%, even in areas of multi-drug- Hirst, the contemporary British artist famous After 5 years of screening 380 herbal extracts in resistant disease. for his iconic body of work that includes form- a mouse model of malaria, Tu’s team discovered In 1990, Chinese officials met with repre- aldehyde-pickled sharks, butterfly assemblages antimalarial activity in the leaves of a sage bush sentatives of Novartis Pharmaceutical Corp., and diamond-encrusted skulls. Hirst’s Medicine called Artemisia annua L. (or sweet wormwood), and the two parties agreed to develop, manu- Cabinets, one of which is shown in Figure 4, is a a medicinal herb that in China had been used facture and patent Coartem through a joint series of 14 cabinets displaying rows of packaged for over 2,000 years to treat all types of fevers. venture—the first such collaboration of its kind drugs—each carefully placed and meticulously The standard medicinal extraction procedure— and involving the first internationally patented selected—behind a glass cover. The sculptures boiling herbs at high temperatures—yielded no drug in Chinese history. In 2001, Novartis and convey the impression that society places drugs anti-malarial activity. The key to Tu’s discovery the World Health Organization (WHO) signed on a pedestal with the hope that they will cure was the use of a radically different method: an agreement to distribute Coartem at cost to our ills, even in the face of hopelessness. Today, extraction with ether at low temperatures. the public sector of malaria-endemic countries. we are hopeful that artemisinin will not disap- Convinced of its safety after toxicity studies in This unprecedented agreement is now backed by point. mice and in normal human volunteers, Tu’s team many other organizations, including UNICEF, administered the extract to patients infected Doctors without Borders and the US President’s Joseph L. Goldstein is Chair with Plasmodium vivax and Plasmodium falci- Malaria Initiative, as well as the Holy Trinity of of the Lasker Awards jury. parum and compared the results with those for a Gates, Bono and Clinton. email: [email protected] control group treated with chloroquine. Because Over the last 10 years, Novartis has sup- these clinical studies were done secretly during plied, without profit, more than 340 million Lasker Award recipients receive an honorarium, the Cultural Revolution, there are no contempo- treatments of Coartem, including a dispersible a citation highlighting their achievement and raneous publications documenting the observa- form designed for infants. The price per treat- an inscribed statuette of the Winged Victory of tions. But according to retrospective interviews ment pack for the developing world is 76 cents Samothrace, which is the Lasker Foundation’s with Tu and other team members, the very first for adults and 36 cents for children. More than symbol of humankind’s victory over disability, clinical results were impressive: the Artemisia 1 million lives have been saved. Coartem has disease and death. extract reduced fever and decreased the number been approved for use in 80 countries and of malaria parasites in blood much faster than received US approval in 2009. To read the formal remarks of speakers at the chloroquine. Will Coartem end up as another Abracadabra Lasker ceremony, as well as detailed information By 1977, Tu and her team had purified cure for malaria? Only time will tell, but for on this year’s awardees, please refer to the Lasker the active component of the extract, named the moment, the discovery of artemisinin by website at http://www.laskerfoundation.org/. it artemisinin, and determined its chemical Youyou Tu and her team has revolutionized the COMPETING FINANCIAL INTERESTS structure—a sesquiterpene lactone peroxide treatment of malaria, saving millions of lives The author declares no competing financial interests.

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