2008: Exuberant Unpredictability: Sine Qua Non for Priceless And

foreword

Exuberant unpredictability: sine qua non for priceless and prizeworthy biomedical research

Joseph L Goldstein

Lasker Awards have been given for the past 63 with funds from the Wellcome Trust and is The Prize Paintings of Martin Kippenberger years and Nobel Prizes for the past 107 years. now on display in the Science Museum in One of the best insights into the sociology of But both of these prizes are relative newcom- London. prizes comes from the German painter and ers to the prize-giving scene. The mother of To award the first prize in history to some- sculptor Martin Kippenberger. Kippenberger, all prizes—scientific and nonscientific—is the one with the stature of a Charles Babbage sets who was born in 1953 and died prematurely Gold Medal of the Royal Astronomical Society a high standard for all prize-giving institu- from alcoholic cirrhosis in 1997, is regarded of London. This prize was first given in 1824, tions, sending the clear message that the as one of the most creative artists of his gen- and it has been given continuously for the ultimate prestige and influence of a prize is eration, often referred to as the German ver- past 184 years. Einstein won it in 1926 and, determined by how well the accomplishments sion of Andy Warhol. One of Kippenberger’s in more recent times, three heroes of modern of its recipients advance our understanding of most provocative works that exemplifies his astronomy have received it: Hubble, Hoyle and the natural world and stand the test of time. signature style of ‘exuberant unpredictabil- Hawking. This is especially worth noting as prize giving ity’ is a metal sculpture entitled Street Lamp has experienced a major growth over the past for Drunks in which the lamp post is bent and Charles Babbage, the first prize recipient 40 years. According to the standard reference curved, woozing back and forth without any The first recipient of the Royal Astronomical book on the subject published by the Gale human figure leaning on it (Fig. 1). Society’s Gold Medal was Charles Babbage, a Research Company, a total of 2,228 prizes In 1987 and 1994, Kippenberger produced brilliant and eccentric professor of mathemat- were given in 1969 in all fields of human two series of paintings that exploit the double ics at the University of Cambridge. Babbage endeavor. In 2007 the number had increased meaning of the German word ‘preis’, which received his medal in 1824 at age 33, the same to 23,000, covering everything from archery can be translated as ‘prize’ or ‘price’ depend- age at which James Watson received his Nobel to zymology (prizes in zymology are given ing on the context. In each painting, a varia- Prize. Babbage’s prize recognized several of his for the best homebrewed beer). Of the 23,000 tion of the word ‘preis’ appears emblazoned in accomplishments: producing the first accurate prizes given today, about 1,000 celebrate the fat, dark letters across a colorful abstract grid logarithmic tables, which modernized naviga- biomedical sciences. of checks or plaids, resembling a tablecloth or tion by allowing precise surveys of coasts; con- Awarding prizes in science and medicine drapes (Fig. 2). ceiving the first actuarial tables, which led to not only has become a growth industry but In his 1987 series of Preis Bilder (Prize life-insurance companies; and conceptualizing also is a competitive business. Inasmuch as Paintings, Fig. 2a–d), Kippenberger titled the modern postage system. Not bad, even for discoveries are often made by several individ- the works to suggest awards and hierarchy: a 33-year-old polymathic mathematician! uals in different institutions, figuring out who 1. Preis, 2. Preis, 3. Preis (First Prize, Second Unlike many scientists who achieve suc- did what and when they did it can become a Prize, Third Prize), and so on. Most art critics cess at an early age, Babbage refused to rest frustrating and paralyzing exercise in ambigu- called these works the Prize Paintings, but a on his laurels. Over the next 50 years, he ity. So it is not surprising that final decisions few caught the irony and called them the Price invented the speedometer, pioneered the art of selection committees can sometimes elicit Paintings, raising the question as to how one of lock picking, and relentlessly designed angry responses from the spurned scientists distinguishes a high-priced painting from a mathematical machines for making complex and snide comments from the academic com- low-priced one. Is 1. Preis really more valu- calculations and breaking codes. In 1888, he munity. Even in those rare situations in which able in a financial sense than 5. Preis or 17. designed the first programmable computer, there is no ambiguity in pinning down who Preis? consisting of a memory unit, a processing made the key discovery, selection committees In the 1994 series of Preis Bilder (Fig. unit and punch cards for giving instructions. are still faced with the judgmental challenge 2e–­ h), Kippenberger turned the tables in his Babbage’s now-famous ‘difference machine’, of deciding whether discovery A is more exuberantly unpredictable way and came up the forerunner of the modern computer, was important than discovery B or C. So, every with titles that are more suggestive of price constructed in 1991 from his original plans prize has its price. than prize: 1/2 Preis (is it half-price or half

nature medicine volume 14 | number 10 | october 2008 iii foreword of a prize?), Trostpreis (comfortable price or consolation prize?), Preisgünstig (budget price or cheap prize with a small honorarium?) and Preislos (priceless or prize-less?). Preislos (Fig. 2h) is a scathing commen- tary on the ridiculously high prices of the art market, where the price of a painting often has no relation to its artistic value. This priceless/prize-less metaphor applies aptly to the biomedical sciences. We are all familiar with examples of priceless research that has gone prize-less in the Nobel sense— for example, Avery’s discovery that DNA is the stuff of genes, and Boyer and Cohen’s development of gene cloning. And those who serve on prize selection committees are familiar with the occasional discussion where a priceless comment from a jury member can create a prize-less situation for a nominee.

Priceless and prizeworthy research The exuberant unpredictability of Kippenberger’s Prize Paintings is evident in the accomplishments of this year’s Lasker prize winners, whose unexpected discoveries have opened new fields of basic and clinical research. Their achievements are therefore both priceless and prizeworthy—even though (with apologies to Kippenberger) there is no single German word for such double praise.

Basic Award: exuberant unpredictability at its best This year’s Lasker Basic Award recognizes the discoveries that revealed an unanticipated world of tiny RNAs that regulate gene func- tion in plants and animals. The existence of tiny RNAs has changed the way in which sci- Figure 1 Laterne an Betrunkene (Street Lamp for Drunks). This 1988 sculpture by Martin Kippenberger shows a light post bent and curved, woozing back and forth like an inebriated person. This sculpture entists think about gene regulation and has exemplifies exuberant unpredictability, a characteristic of creative art and science. Steel, 280 × 40 × thrown a monkey wrench into the strict inter- 40 cm. © Estate Martin Kippenberger. Galerie Gisela Capitain, Cologne, Germany. pretation of the central dogma of molecular biology—information in a cell flows from DNA to RNA to proteins, which then carry cific protein-coding gene by base-pairing to earlier. This tiny RNA was broadly conserved out all of the cell’s structural, metabolic and a complementary sequence in the 3′ untrans- across a wide variety of animal species, regulatory activities. With the discovery of lated region of its mRNA. including humans—a finding that triggered tiny RNAs, we now know that RNAs not only For 6 years, this was the only example of an intense surge of interest in this class of tiny encode proteins but can also act on target a tiny RNA acting in this manner, and the RNAs, now called microRNAs. mRNAs to prevent them from being trans- Ambrose–Ruvkun discovery, although rec- The discovery of tiny RNAs as the univer- lated into proteins. ognized as a sophisticated piece of genetic sal mediator molecule for RNA-directed gene The scientists who are being honored for sleuthing, was generally considered a curi- silencing by Ambros, Ruvkun and Baulcombe the discovery of tiny RNAs are Victor Ambros osity of worm biology. But in 1999, David provided the conceptual framework for (University of Massachusetts), Gary Ruvkun Baulcombe, a botanist (then at the Sainsbury understanding the biochemical basis of (Massachusetts General Hospital) and David Laboratory in Norwich, UK) working on the RNA interference (RNAi), a phenomenon Baulcombe (University of Cambridge). problem of gene silencing as a mechanism described by Andrew Fire and Craig Mello In 1993, while carrying out genetic that plants use to fight viruses, identified the in 1998. A unifying view soon emerged: long analysis of a developmental pathway in second example of tiny, noncoding RNAs. double-stranded RNAs (either produced in Caenorhabditis elegans, Ambros and Ruvkun A year after Baulcombe’s discovery, cells endogenously for physiological purposes discovered the first short, noncoding RNA Ruvkun discovered a second tiny regulatory or introduced exogenously as an experimen- and established that this tiny molecule of 22 RNA in worms that silenced a different gene tal tool) are processed by ribonucleases to nucleotides silences the expression of a spe- from the one he and Ambros had described generate the single-stranded tiny RNAs that

iv volume 14 | number 10 | october 2008 nature medicine foreword silence mRNAs by promoting their degrada- (LDL) and CHD. Building on that knowl- small molecule inhibitor is a prime example tion or inhibiting their translation. edge, scientists have successfully developed a of exuberant unpredictability: in 1971, there The crucial role of tiny RNAs in gene remarkably effective class of drugs that lower was not a scintilla of experimental evidence to silencing is a striking example of a basic bio- LDL-cholesterol levels in blood, reducing the suggest that fungi would produce and secrete logical process that was totally unpredict- frequency of CHD: the statins. such an inhibitor. able before the studies of Ambros, Ruvkun This year’s Lasker~DeBakey Clinical After 2 years of negative results involving and Baulcombe. Hundreds of scientists are Award is given to the scientist who discov- a nonstop effort at screening 6,000 different now working on tiny RNAs, and thousands ered the first statin and showed its clinical fungal strains, Endo and Kuroda discovered of papers have been published on the subject efficacy—Akira Endo, now at the Biopharm a strain of Penicillium citrinum that produced in the past 15 years. The implications of this Research Laboratories in Tokyo. the desired inhibitory activity. They spent discovery for the basic biology of plants and As a child growing up on a farm in north- the next several years purifying the inhibi- animals, as well as for agriculture and human ern Japan, Endo became fascinated with tor, working out its structure and identifying health, are profound. For example, we now mushrooms and molds, and as a young boy, 3-hydroxy-3-methyl-glutaryl (HMG)-CoA know that the human genome encodes 500– he read several biographies of Alexander reductase as the target enzyme. In 1976, Endo 1,000 microRNAs that regulate as many as Fleming and the discovery of penicillin in and his colleagues published their first two one-third of all genes—including genes that a fungus. After obtaining his PhD in bio- papers reporting the discovery and charac- affect embryonic development, genes that chemistry in 1957, Endo joined the Sankyo terization of the first statin, known today as cause cancer, genes that regulate immunity Company in Tokyo as a research scientist. His mevastatin or compactin. In the test tube, and genes that govern stem-cell differentia- main project was to identify and characterize compactin inhibited HMG-CoA reductase tion. This list is just the tiny tip of a large ice- fungal enzymes used in processing fruit juices in the low nanomolar range, and it potently berg of tiny RNAs. and wines. After succeeding in this endeavor, inhibited the production of cholesterol in Endo was rewarded in the late 1960s with cultured cells. For historical interest, it should Clinical Award: drug discovery at its best the opportunity to work on a drug project be pointed out that Endo’s now-classic 1976 Atherosclerosis of the coronary arteries, which of his own choosing. So, in 1971, he and his papers were not published in what is now leads to heart attacks, is responsible for more colleague Masao Kuroda began a search for called a ‘high-profile’ journal; the first one than one-third of all deaths in the developed inhibitors of cholesterol synthesis, reasoning appeared in Journal of Antibiotics and the world. As many as 16 million Americans alive that a decrease in cholesterol production in second one in FEBS Letters. today have a history of coronary heart disease the body would lower cholesterol in the blood Over the next several years, Endo carried (CHD), and 1.2 million will have a new or and therefore decrease CHD. out animal studies showing that mevasta- recurrent heart attack this year. Over the past Endo’s approach was to search fungal cul- tin lowered plasma cholesterol in dogs and 100 years, four lines of evidence—experimen- tures for secreted natural products that, when monkeys. He then began to collaborate with tal, genetic, epidemiological and therapeu- added to a cell-free system, would inhibit Akira Yamamoto, a physician at the National tic—have established the causal link between synthesis of cholesterol from radiolabeled Cardiovascular Centre in Osaka. Yamamoto cholesterol-carrying low-density lipoproteins acetate. His choice of fungi as a source of a gave oral compactin to several patients with genetic forms of hypercholesterolemia, all abcd of whom had been poorly responsive to available cholesterol-lowering drugs. They observed a dramatic result: compactin was extremely effective in lowering plasma cho- lesterol. These pioneering studies were pub- lished in 1980. By early 1978, many pharmaceutical com- panies, although originally skeptical about the safety of inhibiting cholesterol synthesis in the body, learned of Endo’s results and jumped ef gh on the statin bandwagon, feverishly searching for new HMG-CoA reductase inhibitors. The race to the finish line was won by the Merck Sharp & Dohme Research Laboratories. Led by Alfred Alberts, Merck scientists identified in 1979 a molecule secreted by Aspergillus terreus that differed from compactin by one methyl group. (Endo had independently isolated the same molecule from a differ- ent organism.) Merck’s molecule, lovastatin (Mevacor), in 1987 became the first statin Figure 2 Preis Bilder (Prize Paintings). This montage shows eight of the paintings from Martin approved for human use. Today, more than six Kippenberger’s Preis Bilder series of abstract paintings, in which Kippenberger exploits the double meaning of the German word ‘preis’—‘prize’ or ‘price’. (a–d) Four of the 14 paintings from the 1987 statins (both natural products and synthetic series: 1. Preis, 2. Preis, 5. Preis and 17. Preis. Oil on canvas, 180 × 150 cm. (e–h) Four of the five versions) have been developed and commer- paintings from the 1994 series: 1/2 Preis, Trostpreis, Preisgünstig and Preislos. Oil on canvas, 120 × cialized, the most popular being atorvastatin 100 cm. © Estate Martin Kippenberger. Galerie Gisela Capitain, Cologne, Germany. (Lipitor) and simvastatin (Zocor).

nature medicine volume 14 | number 10 | october 2008 v foreword

Statins have now been tested in 14 random- made library, no matter how large, would the classic Boyer–Cohen cloning experi- ized multicenter trials, involving an unprec- ever be expected to yield de novo an HMG- ments of 1973 was provided to them by edented number of individuals—a total of CoA reductase inhibitor with the potency Falkow. Second, by virtue of his credibility as 90,056—who were followed for an average of and selectivity of Endo’s first statin. The the paramount expert in bacterial pathoge- 5 years. The results in every study have been complex structure of mevastatin, contain- nicity, Falkow played a leading role in refut- astonishingly consistent: treatment with statins ing seven asymmetric carbon atoms, evolved ing the most egregious overstatements made lowered plasma LDL by 25–35% and reduced over billions of years of evolution to target at the Asilomar meeting of 1975 about the the frequency of heart attacks by 25–30%. All the catalytic site of HMG-CoA reductase by dangers and pathogenic potential of cloning 14 trials were carried out in individuals with mimicking its natural substrate (HMG-CoA). genes in Escherichia coli. The consensus that an average age of 50–60 whose coronary arter- To paraphrase the second law of Leslie Orgel, ultimately emerged, which largely reflected ies already harbored clinically silent athero- the great British chemist, evolution is smarter Falkow’s influence, recommended modest sclerotic lesions. The reduction in event rate than chemical biologists. restrictions on genetic engineering of the would almost certainly be even more miracu- type that are still in place today. lous if therapy were 10 or 15 years and if it were Special Achievement Award: microbe Once the restrictions on cloning were started at age 40 or even 30, when lesions are hunting and scientific statesmanship at lifted, Falkow himself became one of its fewer and smaller. their best first and most ardent practitioners, cloning A noteworthy aspect of the 14 statin trials The Lasker~Koshland Special Achievement the heat-stable enterotoxin gene of E. coli in is that no major harmful effects of lowering Award is given every other year to honor a sci- 1976. This was the first bacterial virulence cholesterol, such as an increase in cancer or entist whose lifetime contribution to medical gene to be cloned and characterized. He and non-cardiovascular mortality, were observed. science is universally admired and respected his students went on to clone and charac- The remarkable safety of statins derives from for its creativity, importance and impact. In terize most of the virulence genes of many their unique mechanism of action involving essence, the Special Achievement Award hon- important pathogens, including those of the body’s sophisticated mechanism for cho- ors someone who exemplifies scientific states- Bordetella pertussis, Neisseria gonorrhoeae, lesterol homeostasis. When a statin is ingested, manship at its best. Vibrio cholerae, Helicobacter pylori and oth- the intestinally absorbed drug is routed pri- This year’s Special Achievement Award ers. Several breakthrough experiments took marily to the liver, where it binds and inhibits goes to Stanley Falkow of Stanford University place in 1985­–1987, when Falkow and his HMG CoA reductase, lowering cholesterol pro- School of Medicine. Falkow is honored for team established invasion assays to study the duction. This decrease in hepatic cholesterol a 51-year career as one of the great microbe entry of bacteria into human epithelial cells. triggers a compensatory feedback loop that hunters of all time, joining the ranks of This seminal work opened up a new field increases the number of LDL receptors dis- Robert Koch, Louis Pasteur, Walter Reed and of cellular microbiology in which the focus played on the liver-cell surface. The increased Paul Erhlich—four great scientists of the shifted from growing bacteria in broths in number of LDL receptors selectively grab onto late nineteenth and early twentieth centuries the incubator to exploring new aspects of more LDL (but not HDL), remove the LDL whose work in microbiology revolutionized microbial pathogenesis, such as identifying from the blood and deliver it to lysosomes, medicine. Falkow is a latter-day incarnation the bacterial gene products that perturb the where the LDL is digested, and its released cho- of these classic microbe hunters. transport processes and signal transduction lesterol becomes available to the liver cell for In the early 1960s, Falkow used the then mechanisms of host human cells. metabolic purposes. The net effect is that the new technique of cesium chloride gradient During his half-century career, Falkow amount of cholesterol in the liver is maintained centrifugation to physically isolate from bac- has mentored more than 100 students and at a normal level, while the amount of LDL in teria a distinct band of DNA that comprised postdoctoral fellows, many of whom are now blood is kept low. If all drugs worked in such the genetic material responsible for antibiotic distinguished leaders in the fields of micro- a perfect way, the drug industry would be in resistance. This work explained for the first biology and infectious disease. Seldom has a perpetual pharmaceutical heaven. time how bacteria resist antibiotics and laid single individual so completely dominated The statins are the drugs taken at present the conceptual framework for all subsequent a field for so long and with such an incom- by the largest number of patients through- studies on the molecular basis of plasmid parable battery of talents: creative scientist, out the world: an estimated 30 million peo- biology and antibiotic resistance. Drawing bridge to clinicians, stimulating teacher, wise ple worldwide take statins, including 30% of on this expertise, Falkow was the first, in the mentor and great citizen—all executed with all Medicare patients in the United States. late 1970s, to warn the international com- an irreverent sense of humor. The millions of people whose lives will be munity about the relationship between the Joseph L. Goldstein extended through statin therapy owe their use of antibiotics in farm animal feed and the Chair, Lasker Awards Jury good fortune to the immense contributions emergence and spread of antibiotic resistance Lasker Award recipients receive an honorarium, of Akira Endo. Without the exuberant unpre- among human clinical isolates. a citation highlighting their achievement and dictability of Endo’s hunt through 6,000 fun- In the early days of the recombinant an inscribed statuette of the Winged Victory of gal extracts 35 years ago, the statins might DNA era, Falkow played two key catalytic Samothrace, which is the Lasker Foundation’s never have been discovered. roles. First, he arranged the famous mid- symbol of humankind’s victory over disability, Despite the triumphant success of Endo’s night meeting at a delicatessen on Waikiki disease and death. approach to drug discovery, the major phar- Beach in Honolulu between Herbert Boyer maceutical companies have surprisingly and and Stanley Cohen, a meeting that hatched To read the formal remarks of speakers at the largely abandoned the screening of natural the Boyer–Cohen collaboration that led to Lasker ceremony, as well as detailed information products in favor of the screening of syn- their development of recombinant DNA on this year’s awardees, please refer to the Lasker thetic chemical libraries. No random man- technology. The RSF1010 plasmid used in website at http://www.laskerfoundation.org/.

vi volume 14 | number 10 | october 2008 nature medicine