How to Win a Lasker? Take a Close Look at Bathers and Bulls

foreword

How to win a Lasker? Take a close look at Bathers and Bulls

Joseph L Goldstein

Some of our most influential scientists have “Cerebral chills” and “intellectual kicks” and 1913, he abruptly abandoned his signa- spent their spare time moonlighting as amateur In the last few years of his life, Hardy wrote a ture decorative style and invented a new type philosophers. Famous figures like the physi- short essay on how to become a great mathema- of modern art—one that at the time was radical ologist Claude Bernard, the biochemist Hans tician. Published in 1940 with the provocative in both its imagery and its technique. Krebs, the immunologist Peter Medawar, the title “A Mathematician’s Apology,” it received a With his new method of construction, physicist Richard Feynman and the molecular rave review in The Spectator by the British nov- Matisse would begin a painting with a realistic biologist James Watson have offered all sorts elist Graham Greene, who began by saying that scene that he eventually reduced to a nearly of guidance on how to become more creative Hardy had nothing to apologize for. “I know abstract image by reworking the surface of the and make groundbreaking discoveries. There of no writing—except perhaps Henry James’s canvas like a sculptor rather than a painter. is no shortage of advice to the young scientist. introductory essays—which conveys so clearly After applying multiple layers of paint to the The challenge is to distinguish the good advice and with such an absence of fuss the excitement canvas, he would scrape, scratch and incise from the not-so-good advice. of the creative artist,” Greene wrote. the surface and then reapply more thick paint, Aristotle said the one thing that distin- In the essay, Hardy likened mathematics to repeating the process over and over again guishes humans from all other animals is that art, arguing that the best mathematicians were until the perfect forms and sculptural depth “man is a list-making creature.” Not one to dis- those who approached their work like artists emerged. The stimulus for this profound appoint Aristotle, I present here my list of the rather than practitioners: “the mathematician’s change in Matisse’s thinking was the realiza- best advice in science, culled from the wisdom patterns, like the painter’s … must be beauti- tion that he was losing his top-dog position of the experts. f u l .” Hardy’s idea of mathematical beauty was a in the Parisian avant-garde scene to Picasso, • Ask the right question (Claude Bernard, piece of science that gave him a “cerebral chill” who was then inventing Cubism. As Samuel 1813–1878). and an “intellectual kick”—one that combined Johnson famously said, “there is nothing like • Select the right mentor, one who can teach the qualities of significance, generality and the prospect of a hanging to concentrate the you how to be ruthless in criticizing your own unexpectedness. These are the same qualities m i n d .” work (Hans Krebs, 1900–1981). that produce chills and kicks in members of The supreme example of Matisse’s new • Be passionate and obsessive about solving a the Lasker jury. approach to painting is the monumental problem (Peter Medawar, 1915–1987). If we follow the logic of Hardy, this purest Bathers by the River1. When Matisse started • Be audacious and take risks, or as Richard of all pure mathematicians, then the best way Bathers in 1909, it was intended as one of three Feynman (1918–1988) would say, “have your to learn how to become a great scientist is to large decorative panels commissioned for the tea with lemon and cream.” study how great artists—artists like Matisse and drawing room of a wealthy Moscow collector. • Avoid boring people (James Watson, Picasso—create their magic. And this brings The design for the original version of Bathers 1928–). me to two magical works, Matisse’s Bathers by was an idyllic landscape scene rendered in pas- Not a bad list, but also not a foolproof for- a River and Picasso’s The Bull. Bathers and Bull tel colors depicting five nude women, two of mula for a scientific breakthrough that will owe their power to two essential ingredients: whom were luxuriating in a waterfall (Fig. 1a). win you a Lasker Award or a Nobel Prize. In radical thinking and fearless experimentation. The Moscow patron bought two of the panels my view, the single most useful piece of advice but turned down Bathers—too much nudity for on how to achieve scientific greatness comes Matisse’s Bathers his grand staircase. The timing of this rejec- from the British scientist Godfrey H. Hardy In the first 20 years of his career, Henri Matisse tion coincided with the beginning of Matisse’s (1877–1947), who dominated the field of was best known for his vibrant paintings of new sculptural approach to painting. In a mathematics in the early 1900s. To the pure exotically dressed young women, lush interi- frenzy of experimentation over the next eight mathematician, Hardy’s major achievement ors and pastoral landscapes. By the beginning years, from 1909 to 1917, Matisse repeatedly was in analytic number theory. To the biomedi- of the twentieth century, he had become the reworked Bathers, revising the composition cal scientist, Hardy is best known for formulat- undisputed master of rich bright colors, as seen more than 20 times, as documented with the ing the Hardy-Weinberg Law, a basic principle in famous works such as The Red Room, The latest technologies of X-radiography, infrared of population genetics that is used to calculate Dance and The Woman with a Hat. Then, in reflectography and stereoscopic microscopy. gene frequencies. an astonishing five-year period between 1909 Conservatory experts at the Art Institute of

nature medicine volume 16 | number 10 | october 2010 iii foreword

Chicago have distinguished 17 different states a of color in the finished painting that were left over from earlier versions. Most amazing of all, the finished version contains traces of green and blue from the very earliest 1909 version. The finished Bathers by a River (Fig. 1b), which hangs today at the Art Institute, looks very different from the 1909 original (Fig. 1a). One of the five bathers has been removed, and the remaining four have been transformed from fleshy and languid women to abstract and totem-like figures, which are segmented in the four vertical bands of dark green, black, gray and light blue that define the spatial contours of the painting. The blue-and-white waterfall of the original has been transformed into the vertical black band, onto which a white snake crawls. Before Bathers was acquired by the Art Institute in 1953, it hung during the 1930s and 1940s in the lobby of an art gallery on East b 57th Street in New York. The eminent art critic Clement Greenberg claimed that he was so mes- merized by Bathers and saw it so often that he could copy it by heart. Bathers also influenced many budding young artists, such as Jackson Pollock, Willem de Kooning, Mark Rothko and Barnett Newman. Perhaps more than any other single painting, Bathers was the bridge that connected the representational art of Cézanne with the full-blown abstract expressionism of Jackson Pollock and his contemporaries.

Picasso’s Bull Like Matisse, Pablo Picasso was a radical thinker and a fearless experimenter. But there was one profound difference between Matisse and Picasso: Picasso produced his work with prodigious speed. He could take Figure 1 Matisse’s Bathers: from start to finish, eight years. (a) Henri Matisse, Composition No. II, the bull by the horns like no other artist. 1909. Watercolor on paper, 21.9 × 29.5 cm. State Pushkin Museum of Fine Arts, Moscow. This Not surprisingly, bulls—the iconic emblem watercolor was the starting design for what eventually became Bathers by a River. (b) Henri Matisse, of macho Spain—became one of Picasso’s Bathers by a River, 1917. Oil on canvas, 260 × 392 cm. Art Institute of Chicago. favorite subjects, second only to his wives and mistresses. To celebrate the end of World War II and exclaim, “look, we ought to give this bit to the Basic Award: conjoined mice, conjoined the liberation of Paris, Picasso engaged in a butcher. The housewife could say, ‘I want that discoveries nonstop orgy of lithographic printmaking, in piece or this one.’” In the last version, plate This year’s Basic Medical Research Award is which he used the bull to illustrate how the art- number 11, the bull was reduced to its essen- given to Douglas L. Coleman (The Jackson ist turns reality into abstraction2. Over a 45-day tial elements: the body was an outline of only a Laboratory) and Jeffrey M. Friedman (The period and with a single plate of stone, Picasso few strokes, the head the size of an ant and the Rockefeller University) for their discovery of produced a suite of 11 prints, each depicting the genitalia the size of a pea (Fig. 2d). Picasso’s 45 leptin, a hormone that regulates appetite and bull in a different body form. In the print from days of goring the bull captured the essence of body weight—a breakthrough that opened the the third lithographic plate, the bull emerged as the beast in as minimal an image as possible—a field of obesity research to molecular explora- a beefy, plump, well-nourished beast (Fig. 2a). vivid example of radical thinking and fearless tion. Picasso then reworked the plate to create eight experimentation. The story begins 60 years ago, when an new versions of his original bull, with the bull Like Matisse and Picasso, this year’s Lasker obese mouse arose at random at The Jackson getting leaner (Fig. 2b) and leaner (Fig. 2c) in awardees are imaginative thinkers and fearless Laboratory. The mouse ate continuously and each successive version. He was deconstructing experimentalists, and their scientific accom- weighed three times as much as wild-type the bull by carving away slices of its beef from plishments fulfill G.H. Hardy’s three axioms for mice. Breeding studies showed that the obe- the stone lithographic plate. After slicing the scientific greatness: significance, generality and sity resulted from homozygosity for a muta- stone, Picasso would look at his assistants and unexpectedness. tion in a single gene, named ob. Ten years

iv volume 16 | number 10 | october 2010 nature medicine foreword later, in the early 1960s, Coleman identified in Escherichia coli, which, when administered a another massively obese mouse that sponta- to ob/ob mice, triggered dramatic weight loss neously appeared in the Jackson colony. The owing to a drop in food intake. Administration obesity in this new mouse also resulted from of leptin directly into the third ventricle of the homozygosity in a single gene, named db. db/ brain was 50-fold more effective in reducing db mice resembled ob/ob mice phenotypically food intake than an equivalent dose admin- in body weight, but diabetes was more severe istered intraperitoneally, pointing to the in the former than in the latter. brain as the site of action of the receptors Soon after the discovery of ob/ob and db/ for leptin. Shortly after the discovery of lep- db mice, Coleman began a series of ingenious tin, the putative gene for the leptin receptor and technically demanding experiments in was identified by Louis Tartaglia (Millenium which he conjoined the circulatory systems Pharmaceuticals), and one of its six encoded b of two mice, one of each type, in a technique isoforms (resulting from alternative splic- called parabiosis. When the ob/ob and db/db ing) was shown by Friedman and Tartaglia mice were sewn together, the ob/ob partner to be defective in the db/db mouse, putting stopped eating, lost weight and died of star- the final nail in the coffin for skepticism over vation, whereas the db/db partner remained Coleman’s parabiosis experiments. obese. Coleman concluded that ob/ob mice fail The discovery of leptin and its receptor has to produce a functional hormone that inhibits led to an explosion in knowledge of how fat appetite and eating, whereas db/db mice over- cells signal the brain to control energy balance. produce the hormone but lack the receptor Friedman showed that leptin acts directly in to respond to it. His conclusion that the db/ the hypothalamus to trigger a cascade of sig- c db mouse overproduces a satiety hormone to nals that regulate food intake. This key find- which it cannot respond was verified in further ing has prompted scientists to use leptin as the parabiotic unions of db/db mice with normal entry point for mapping neuronal circuits that mice, which resulted in starvation and death of mediate the complex feedback system regu- the normal partner. lating eating and energy expenditure. These In the early 1970s, when Coleman first circuits, which can be either inhibited or stimu- advanced the concept that the ob gene encodes lated by the leptin–leptin receptor system, are a circulating satiety hormone and the db gene responsible for the production of a variety of encodes its receptor, the idea was far too appetite-modulating neuropeptides and neu- radical to be taken seriously by mainstream rotransmitters such as neuropeptide Y, agouti- d endocrinologists. Its validation at a molecular related peptide and melanocyte-concentrating level did not come until 20 years later, when hormone. Friedman began his independent scientific The importance of leptin for humans has career with the bold goal of identifying the been shown by the clinical genetic stud- ob gene by positional cloning. This was an ies of Stephen O’Rahilly and Sadaf Farooqi especially arduous task because the ob trait is (Cambridge Institute of Medical Research), recessive, so heterozygous mice do not show who identified massively obese children with a phenotype. In a tour de force of molecular loss-of-function mutations in the leptin gene. biology, Friedman used virtually every tech- These human ob/ob equivalents have insatiable nique of modern genetics, including recom- appetites from birth: in one affected child, a Figure 2 Picasso’s Bull: from start to finish, binational analysis of distant mouse strains weight of 42 kg was recorded at three years of 45 days. This montage shows four of the 11 together with microdissections of sorted age. Leptin therapy reduced this child’s food progressive states of composition of Picasso’s chromosomes (done in collaboration with consumption and led to rapid weight loss. The Bull, created between 5 December 1945 and Rudolph Leibel), construction of yeast arti- O’Rahilly and Farooqi have also identified 17 January 1946. Lithographs on stone, 33.2 × ficial chromosomes bearing the ob gene, and mutations in the leptin receptor gene that pro- 43.2 cm. Printer: Mourlot, Paris. (a) State III. exon trapping in yeast to obtain probes that duce massive obesity in children—the human (b) State VI. (c) State VIII. (d) State XI. Museum of Modern Art, New York. allowed cloning of the definitive DNA. After equivalents of the db/db mouse. a seven-year search, the ob gene was identified Mutations in leptin and the leptin receptor in 1994 and found to encode a hormone-like are very rare in humans, and the vast major- to delineating the molecular basis for leptin polypeptide that Friedman named leptin (from ity of people with obesity have leptin levels resistance. the Greek leptos, meaning “thin”). that are actually higher than those of lean Obesity is now recognized as one of the Leptin is produced exclusively in white adi- individuals. This sounds counterintuitive if world’s major public health problems—possibly pose tissue, which was an unexpected finding the function of leptin is to suppress appetite. topping the list. Globally, there are more over- because fat cells were believed to function as But it turns out that as people become obese, weight people than undernourished people. a storage tissue for triglycerides and were not their expanding mass of adipose tissue pro- Obesity not only predisposes to type 2 diabetes, known to synthesize and secrete hormones. duces and secretes more and more leptin, the metabolic syndrome and atherosclerosis; it The availability of the ob gene sequence which in turn leads to leptin resistance at the is becoming apparent that it is also a substantial allowed Friedman and his colleagues to man- level of the receptors in the hypothalamus. risk factor for many types of cancers, including ufacture a recombinant version of the protein A major area of current research is devoted cancers of the colon, uterus and breast. Before

nature medicine volume 16 | number 10 | october 2010 v foreword the Coleman-Freidman discoveries, virtually nothing was known about the endocrinological and molecular aspects of the system that controls body weight. Their groundbreaking work has changed the public perception of obesity from a psychological condition marked by per- sonal failings and lack of willpower to a complex behavioral condition that can be influenced by one’s genetic makeup. The story of leptin is one of conjoined mice (ob/ob and db/db) and conjoined discoveries (physiological and molecular). The beauty and power of the conjoined state is marvelously illustrated in a sculpture entitled Conjoined by the contemporary American artist Roxy Paine (Fig. 3). Conjoined is a large (40 feet tall by 45 feet wide) hand-wrought stainless steel sculpture of two trees whose branches are united in mid-air. Each branch of one tree joins imper- ceptibly with a branch from the other tree in such a way that it is unclear where one tree Figure 3 Roxy Paine, Conjoined, 2007. Hand-wrought stainless steel, 40 × 45 ft. This sculpture of begins and the other ends. two conjoined trees was exhibited at Madison Square Park in New York in 2007. It was fabricated from 7,000 metal pipes and rod elements of 30 different diameters, assembled by cutting, bending, Clinical Award: a Napoleonic victory welding, grinding and polishing. The artist is represented by the James Cohan Gallery in New York. against blindness This year’s Lasker~DeBakey Clinical Medical Research Award is given to Napoleone Ferrara for more than 80% of cases of severe visual loss tumors produce factors that stimulate blood- (Genentech USA) for his discovery that vascu- and legal blindness, defined as a visual acuity of vessel proliferation, and several years later Issac lar endothelial growth factor (VEGF) is a major 20/200 or worse. As many as 1.5 million peo- Michaelson proposed that a diffusible factor mediator of angiogenesis and for his leadership ple in the US are afflicted with the advanced, produced by the retina is responsible for the role in the development of an effective anti- vision-threatening form of wet AMD, and mil- neovascularization in diabetic retinopathy. VEGF therapy for the severe wet form of macu- lions more have early ophthalmologic signs of Then, in 1968, two groups directly showed lar degeneration, a leading cause of blindness the disorder. Among individuals over age 50, that cancer cells release a diffusible factor that in the elderly. AMD causes 55% of all visual impairment promotes blood-vessel proliferation. These Age-related macular degeneration (AMD) and 25% of blindness. About 10% of people seminal studies by Melvin Greenblatt and is a chronic eye disease occurring in people between 65 and 74 years of age have evidence Philippe Shubick in melanoma cells and by over 50 years of age that involves damage to of AMD, and the prevalence increases to 30% Robert Ehrmann and Mogens Knoth in chorio- the macula, the part of the retina responsible at age 75 to 85. As the elderly make up a higher carcinoma cells provided the experimental and for high-acuity central vision. Because the and higher proportion of the population, AMD conceptual framework for an influential paper macula contains the densest concentration of will become an increasingly important public published in 1971 by Judah Folkman, in which photoreceptors in the retina, any damage to health problem. The National Eye Institute of he proposed the innovative idea of developing this region profoundly affects a person’s abil- the US National Institutes of Health estimates angiogenesis inhibitors to treat human cancer. ity to see fine detail, read, watch television and that by 2020 the number of people with wet Folkman’s paper inspired scientists throughout recognize faces. AMD occurs in several differ- AMD in the US will rise to 3 million. the world to search for tumor angiogenesis fac- ent forms. In the dry form, abnormal deposits Until recently, there was no therapy for tors. Over the next 20 years, many candidate of lipid and protein accumulate in the macula patients with severe wet AMD to improve their molecules were proposed to have activity in without substantial abnormal growth of blood visual acuity. This dismal situation has been various in vitro angiogenesis assays, but none vessels. About 10–20% of cases of the dry form transformed over the last five years because of of them—including Folkman’s original tumor progress to the wet form, in which neovascu- the imaginative thinking and fearless experi- angiogenesis factor, transforming growth fac- larization of the choroid layer of the retina mentation of Napoleone Ferrara, who identi- tor, epidermal growth factor, tumor necrosis develops and is accompanied by increased vas- fied VEGF as the long-sought master regulator factor, fibroblast growth factor (FGF) and cular permeability and fragility. The wet form of angiogenesis and then went on to lead efforts angiogenin—passed the acid test of stimulat- leads eventually to subretinal hemorrhages, at Genentech to develop an effective VEGF- ing tumor angiogenesis in vivo. detachment of retinal layers, fibrotic scars and specific monoclonal antibody therapy for wet Ferrara’s entry into the angiogenesis field blindness. The precise molecular pathways AMD. was not a traditional one. After graduat- leading to angiogenesis of the macula in wet The story of angiogenesis research has a fas- ing from medical school at the University of AMD have yet to be delineated, but a common cinating history beginning in the late 1930s, Catania in Italy, he did residency training in pathogenetic feature is an enhanced expression when Gordon Ide showed that the rapid growth obstetrics and gynecology. In 1983, he moved of angiogenic cytokines such as VEGF. of tumor explants is dependent on a rich blood to the University of California–San Francisco Although wet AMD constitutes only 10–20% supply to provide nutrients and oxygen. In for a research fellowship in reproductive endo- of all forms of AMD, it is the form responsible 1945 Glen Algire advanced the hypothesis that crinology, where he worked in the laboratory of

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Denis Gospodarowicz, a leading figure in the oped a humanized VEGF-specific monoclo- tist whose lifetime contribution to medical FGF field. In his research with Gospodarowicz nal antibody (bevacizumab; Avastin), which science is universally admired and respected on basic FGF and its role in angiogenesis, received approval from the US Food and Drug for its creativity, importance and impact (or Ferrara became aware that none of the puta- Administration (FDA) in 2004 as a first-line as G.H. Hardy might say, for its significance, tive angiogenic factors known at the time had therapy for metastatic colorectal cancer, in generality and unexpectedness). In essence, panned out in physiological studies, suggest- combination with chemotherapy. this award honors someone who exemplifies ing that the relevant molecules remained to be Soon after the discovery of VEGF, several scientific statesmanship at its best. This year’s discovered and that a radical new way of think- groups of ophthalmologists reported elevated awardee, David Weatherall (University of ing was needed. During his postdoctoral work, levels of VEGF in ocular fluid samples from Oxford), is not only a statesman of biomedi- Ferrara began experimenting with pituitary individuals with various eye diseases caused cal science but an international statesman follicular cells as a source of new angiogenic by neovascularization of the retina. These to boot. Weatherall is honored for a 50-year factors. These cells were later to play a key part observations led Genentech and collabora- career exemplified by his discoveries concern- in the discovery of VEGF. tors to carry out clinical trials of anti-VEGF ing genetic diseases of the blood (the thalas- As a card-carrying obstetrician and gynecol- therapy in subjects with wet AMD. For this semias and other hemoglobinopathies) and ogist with research experience in reproductive purpose, Genentech developed a Fab frag- for his leadership role in bringing improved endocrinology, Ferrara was hired in 1988 by ment of the humanized anti-VEFG (ranibi- clinical care to thousands of children in the Genentech to work on a project that aimed to zumab; Lucentis) that is injected intravitreally developing world who are afflicted with develop the polypeptide hormone relaxin as a on a monthly basis. Lucentis was approved severe anemia. treatment to promote cervical relaxation dur- by the FDA in June 2006 for treatment of wet The thalassemias are a group of inherited dis- ing labor. Unfortunately for Ferrara, relaxin AMD. The approval was based on clinical tri- orders in which production of one of the globin turned out to be more potent in rodents than als showing that, over a two-year follow-up chains in hemoglobin is reduced; hundreds of in primates, and the project was eventually period, Lucentis slowed the rate of progression different point mutations or deletions in either discontinued. But fortunately for Ferrara, in virtually all patients and that 33% of treated the α-globin gene or the β-globin gene can give Genentech gave him the freedom to pursue his patients (as compared to only 3.8% of controls) rise to the deficit. If the body fails to produce own ideas while struggling with relaxin, and actually had their vision improved by 15 letters the correct amount of either globin chain, a he followed up on his postdoctoral observation or more on an eye chart. Serious side effects of deficiency of hemoglobin results, causing ane- that pituitary follicular cells secrete factors with the monthly injections were minimal—uveitis mia. As a group, the α- and β-thalassemias are an angiogenic activity. and endophthalmitis occurring in less than 3% among the most common monogenic diseases In 1989 Ferrara reported the identification, of treated patients. in humans, occurring with the highest fre- purification and cDNA cloning of a potent Avastin and Lucentis are both recombinant quencies in Mediterranean countries, Africa, endothelial cell mitogen that he named VEGF. versions of humanized antibodies directed the Middle East, India, southern China and The protein was active at a concentration of against VEGF. The two antibodies differ in Southeast Asia. 1 ng ml–1 and showed high specificity for their size and affinity for VEGF. Avastin is a In 1956, Weatherall received his MD endothelial cells. Concurrent with Ferrara’s full-length antibody with two binding sites for degree from the University of Liverpool, and publication, scientists from Monsanto reported VEGF, whereas Lucentis is a Fab fragment with after two years of house-officer training he the purification and cDNA cloning of a secreted a single affinity-matured VEFG binding site, so joined the UK’s Royal Army Medical Corps factor from tumor cells that induced the per- its affinity for VEGF is several-fold higher than to complete the military service that was then meability of blood vessels. This vascular per- that of Avastin. Although Avastin is approved compulsory in Britain. Even though he had meability factor (VPF), which had originally for the treatment of colorectal and other can- no training in pediatrics, he was assigned to a been discovered in 1979 by Harold F. Dvorak cers, it has not yet been approved for wet AMD. children’s ward at the British Military Hospital (Beth Israel Deaconess Medical Center), turned Nonetheless, it has been used off label to treat in Singapore. One of his patients was a Gurkha out, surprisingly, to have the same amino acid wet AMD by many ophthalmologists, who child from Nepal who had a mysterious form sequence as VEGF, indicating that VEGF and believe that Avastin remains in the eye longer of anemia requiring multiple blood transfu- VPF were one and the same molecule. than Lucentis and thus may allow for less fre- sions. Although he had no training in either In subsequent work, Ferrara identified and quent injections. The National Eye Institute has hematology or medical genetics, he diagnosed cloned the first VEGF receptor (with L.T. recently started a multicenter clinical trial to homozygous β-thalassemia after discovering Williams), extensively characterized the physi- compare the relative safety and effectiveness of high HbA2 concentrations in the blood of ological role of VEGF in animal tumor models Avastin and Lucentis. the child’s heterozygous parents. HbA2 is a and observed that heterozygous VEFG mutant Blindness ranks with cancer as one of minor variant form of hemoglobin contain- mice die at midgestation from vascular insuf- the most feared diseases afflicting humans. ing α-chains and δ-chains, but no β-chains. ficiency. These pioneering studies, more than Napoleone Ferrara’s discovery of VEGF as a To make the diagnosis, Weatherall had to any other single body of work, contributed to master regulator of angiogenesis and his lead- find someone in Singapore who had experi- the currently accepted view that VEGF is the ership in the development of anti-VEGF ther- ence with the then-new technique of starch- sought-after master angiogenesis factor that apy for the severe wet form of AMD is saving gel electrophoresis, which revealed the HbA2 regulates vascular growth in response to tis- the eyesight of millions of people throughout variant—an early example of his remarkable sue hypoxia. the world. resourcefulness. In 1993, in a historic experiment, Ferrara Weatherall excitedly wrote up his clinical showed that inhibition of VEGF by specific Special Achievement Award: honoring discovery and published his first paper in the monoclonal antibodies markedly suppressed international statesmanship British Medical Journal in 1960. Much to his growth of a variety of mouse tumors in vivo. The Lasker~Koshland Special Achievement amazement, he was summarily reprimanded With his colleagues at Genentech, he devel- Award is given every year to honor a scien- by his military superiors for publishing infor-

nature medicine volume 16 | number 10 | october 2010 vii foreword mation about bad genes without official per- from deletions of the region of chromosome “The principal problem for those who edu- mission. Fortunately for biomedical science, 16 that harbors the α-globin genes. cate our doctors of the future is how, on the Weatherall was not intimidated by the British In 1989, Weatherall created the Oxford one hand, to encourage a life-long attitude War Office, and the rest is history: he went Institute of Molecular Medicine, the first of critical, scientific thinking to the manage- on to become the world’s foremost expert on such institution of its kind. This 400-per- ment of illness and, on the other, to recognise the thalassemias, mastering every aspect of son endeavor was renamed the Weatherall that moment when the scientific approach, the disease—its natural history, population Institute in 2000 to honor its founder. For the because of ignorance, has reached its limit genetics, molecular pathology, diagnosis and last 30 years, the Institute has maintained a and must be replaced by sympathetic empiri- treatment. research partnership with institutions in cism. Because of the dichotomy between the Stimulated by the Gurkha patient, countries throughout the developing world. self-confidence required at the bedside and Weatherall became a fearless experimentalist It invites physicians from its partner coun- the self-critical uncertainty essential in the in developing a method to accurately and rap- tries (including Thailand, India, Myanmar research laboratory, it may always be dif- idly measure the synthesis of different globin (Burma), Sri Lanka, Indonesia, Vietnam ficult to achieve this balance. Can one person chains in the blood of people with thalas- and Kenya) to go to Oxford, where they are ever combine the two qualities? Possibly not, semia. In 1965 he and his colleagues John trained in the clinical and laboratory study but this is the goal to which medicine must B. Clegg and Michael A. Naughton achieved of thalassemias. The training provides the a s p i r e .” this goal by incubating intact reticulocytes molecular tools to identify local mutations, with radioactive amino acids, separating allowing the visiting physicians to establish David Weatherall is one person who, for the individual radiolabeled globin chains by prenatal diagnostic programs in their home 50 years, has successfully combined the two carboxymethyl-cellulose chromatography and countries. More than 300,000 children are essential qualities of the physician-scientist— quantifying them by scintillation counting. born each year with a severe monogenic self-confidence at the bedside and self-critical With their new method, Weatherall and his hemoglobin disorder that can be detected uncertainty at the bench—another example of colleagues provided the first clear-cut dem- prenatally. The program’s participants are the beauty and power of the conjoined state. onstration that the thalassemias result from also instructed in the latest therapies for an imbalance in the production of either prevention and treatment of iron overload, Joseph L. Goldstein is chair α- or β-globin chains. Yuet Wai Kan, recipi- a potentially fatal condition that occurs in of the Lasker Awards jury. ent of the 1991 Lasker Clinical Award for his patients with thalassemia who receive mul- e-mail: [email protected] discovery of DNA polymorphisms and their tiple blood transfusions. use in diagnosis of human diseases, said he Not only is Weatherall an institution Lasker Award recipients are given an honorar- was attracted to the hemoglobin field by the builder, he is also a tireless educator. He ium, a citation highlighting their achievement “sheer elegance” of the Weatherall technique has reached a global audience through pro- and an inscribed statuette of the Winged Victory for measuring globin chain synthesis3. To this lific writing—authoring or coauthoring of Samothrace, the Lasker Foundation’s symbol day, Weatherall’s classic experiments, done 45 more than 600 primary research articles, 85 of humankind’s victory over disability, disease years ago, remain some of the earliest and best review articles and 14 books. His book The and death. examples of what is now referred to as trans- Thalassemia Syndromes, now in its fourth edi- lational medicine. tion, is the bible of the hemoglobin field. Also To read the formal remarks of speakers at the The Weatherall scientific oeuvre includes of note is The Oxford Textbook of Medicine, Lasker ceremony, as well as detailed information many other original contributions, such as the which Weatherall began in 1984 as the first on this year’s awardees, please visit the Lasker discovery and molecular characterization of international medical textbook with a special website at http://www.laskerfoundation.org/. new hemoglobin variants (for instance, those emphasis on tropical diseases. Currently in producing methemoglobinemia and poly- its fifth edition, the text is 4,500 pages long, COMPETING FINANCIAL INTERESTS The author declares no competing financial interests. cythemia), the development of a sheep model and Weatherall, wisely, is no longer the lead for studies of the switch from fetal to adult editor. Finally, there is Weatherall’s marvelous 1. D’Alessandro, S. & Elderfield, J. Matisse: Radical Invention 1913-1917 (Yale University Press, New hemoglobin synthesis, the pioneering use of 1994 book on the history of medical research Haven, Connecticut, USA, 2010). recombinant DNA techniques for prenatal from Galen to the present, entitled Science 2. Lavin, I. Picasso’s bull(s): art history in reverse. Art in diagnoses of the hundreds of different muta- and the Quiet Art, in which he espouses his America 81, 76–93, 121, 123 (1993). 3. Kan, Y.W. 2003 William Allan Award Address: intro- tions causing the thalassemias, and the discov- philosophy on the education of physicians in ductory speech for Sir David Weatherall. Am. J. Hum. ery of a form of mental retardation resulting the molecular era: Genet. 74, 382–384 (2004).

viii volume 16 | number 10 | october 2010 nature medicine