FOREWORD

Juxtapositions in Trafalgar Square: tip-offs to creativity in art and science

Joseph L Goldstein

One of the delights and highlights of a trip to 175-year-old Trafalgar Square. A commission in the Order of the British Empire (MBE) for is a visit to Trafalgar Square, the city’s was authorized to hold a competition every one her services to the arts. premier public space. For the past 175 years, or two years, in which about 100 artists from Quinn’s sculpture, entitled Alison Lapper Trafalgar Square has been ’s favorite site around the world are invited to make a pro- Pregnant, is carved out of a single block of for political rallies and national celebrations. It posal. The winning artist is selected on the basis Carrara marble, and stands 3.6 meters high and is also the home of the , one of two criteria: (i) does he or she view Trafalgar weighs 13 tons (Fig. 2c). The sculpture is arrest- of the premier art museums in the world. In Square through fresh eyes that encapsulate the ing and beautiful, yet at the same time strange the past few years, Trafalgar Square has taken collision of Trafalgar’s two centuries of military and contentious—much like Velazquez’s dwarfs on a new venture: it has become the site of a heritage with the cutting edge of contemporary and Picasso’s eroticized biomorphic figures. living laboratory of discovery where as many art, and (ii) will the artist’s proposed sculpture The Alison Lapper piece stands in striking con- as 40,000 tourists each day can experience provoke the imagination of the 40,000 tourists trast to all the other monuments in Trafalgar firsthand what creativity and innovation are all who visit Trafalgar Square each day? Square, which commemorate dead, male mili- about. Before telling you about this exciting new In the past eight years, six sculptures have tary heroes and events of the past. The sculpture development, let me briefly review the history adorned the fourth plinth in a rolling program. celebrates events of the future and advances a and architectural layout of Trafalgar Square. I will tell you about my two favorites and the new structural model for female heroism and The square’s name commemorates the Battle artists who produced them: and humanity. During the two years that Alison of Trafalgar in 1805, a spectacular British naval Katarina Fritsch. Their work exemplifies the Lapper and Lord Nelson rubbed shoulders in victory over France during the Napoleonic type of exceptional creativity that wins Lasker Trafalgar Square, Quinn’s sculpture—not sur- Wars. At the center of the square stands a Awards and Nobel Prizes. prisingly—elicited diverse reactions, yet during 46-meter column on top of which sits a 5.5- its time on display it was the most popular tour- meter statue of Lord Horatio Nelson, England’s Marc Quinn’s juxtaposition: female nudity ist attraction and most widely discussed event greatest naval hero, who was killed during the and male heroism in London—a wonderful affirmation of Mark . Behind Nelson’s Column Marc Quinn, one of the original so-called Young Quinn’s creativity and innovation. sits the National Gallery, and surrounding British Artists of the late 1980s, who is still the column are four large pedestals, which the brimming with bright ideas while approach- Katharina Fritsch’s juxtaposition: British British call the Four Plinths of Trafalgar. Each ing age 50, conceived his sculpture from an heroes and French mascots plinth is located at one of the four corners of insight originating from two unconnected On 20 July of this year, a giant blue bird landed the square. The first plinth carries a sculpture of ideas: (i) people who go to museums gravitate on the fourth plinth and will remain there King George IV on horseback. The second and to fragmented nude statuary, such as the arm- until January 2015 (Fig. 3). This 4.7-meter-tall third plinths are taken up by sculptures of mili- less Venus de Milo, who is admired as a great rooster, provocatively entitled Hahn/Cock, is tary men whom no one has ever heard of. The icon of feminine beauty; and (ii) people who go made of fiberglass coated with polyester resin fourth plinth is the most fascinating (Fig. 1). to Trafalgar Square view Lord Nelson, who lost in a deep royal blue. It was designed by one of It consists of an imposing slab of stone that one arm in battle, not as a disabled person but Germany’s leading artists, Katharina Fritsch, was erected in 1841 and intended to display an as a great icon of military heroism (Fig. 2a,b). who is famous for creating oversized sculp- equestrian sculpture of King William IV. But Juxtaposing these two disparate insights, Quinn tures in a single intense color, such as yellow the cost was so exorbitant that the statue was produced a sculpture of a nude, heavily preg- Madonnas, green elephants, pink apples and never completed, and the fourth plinth has nant woman who was born without arms and men in purple suits. remained bare, distorting the symmetry of the with shortened legs caused by a condition called The creative spark that fired Fritsch’s imagi- square. phocomelia. The model for this sculpture is a nation may have stemmed from two uncon- Then, in 1999, a remarkable thing happened. critically acclaimed British artist, named Alison nected ideas: (i) the rooster is an iconic symbol The came up with a bold Lapper, who does not use artificial limbs; she of male preening and posturing, and its pres- way to solve the asymmetry problem: install paints with her mouth. Her paintings have been ence in Trafalgar Square would be appropriate on top of the fourth plinth a large contempo- exhibited widely in the UK and throughout the company for the likes of Lord Nelson, George IV rary sculpture that would infuse new life into world. In 2003, she was awarded a Membership and the two Victorian generals; and (ii) the

NATURE MEDICINE VOLUME 19 | NUMBER 10 | OCTOBER 2013 1 FOREWORD

talking point among Londoners and tourists was first authoritatively examined by the for the next 15 months, waving his tail feath- Hungarian-British writer Arthur Koestler ers at the National Gallery and aiming his beak in his classic 1964 book, entitled The Act straight at Nelson’s back. of Creation: A Study in the Conscious and Unconscious Processes in Humor, Scientific François Jacob’s juxtaposition: enzyme Discovery, and Art. According to Koestler, the induction and lysogeny creative activities of scientists and artists are Like breakthroughs in art exemplified by the closely related to those of comedians. The hall- likes of Quinn and Fritsch, breakthroughs in mark of a good comedian is one who thinks biomedical research also arise by perceiving the unthinkable—not by thinking outside the and connecting disparate ideas. One of the box but by mentally uniting several boxes of most famous examples involves the work of unconnected thoughts to create a totally novel the brilliant French geneticist François Jacob, thought, which becomes the punchline of a who discovered in the early 1960s how genes good joke. James O’Jenkins, Institute of Contemporary Art are turned on and off. Jacob’s insight came in a Koestler chose to illustrate his point by ana- Figure 1 The fourth plinth of Trafalgar Square. This flash while watching a movie in a Paris cinema. lyzing a joke popularized by Sigmund Freud in imposing slab of stone, erected in 1841, remained bare until recently. Beginning in 1999, the City of When he closed his eyes to shut out a boring his essay on wit and paraphrased below: London began a rotating program in which different scene, he suddenly realized that two types of contemporary sculptures are selected to adorn the research going on at the Pasteur Institute that The marquis finds his wife in bed with a bare fourth plinth; each sculpture is exhibited for a were thought to be miles apart mechanisti- bishop. He doesn’t say a word, but goes to period of 1.5 to 2 years. cally were in fact two aspects of the same phe- the window and blesses the people walking nomenon. Jacques Monod’s work on induced under it. When his wife asks him what he rooster is also the national symbol of France, synthesis of enzymes and André Lwoff’s work thinks he is doing, he replies, “He is per- serving as a mascot for sporting events such as on phage lambda and lysogeny could both be forming my function; I will perform his.” soccer and rugby. Juxtaposing these two dispa- explained by a single theory involving repres- rate insights, Fritsch came up with a sculptural sors that inhibit gene activity. This joke juxtaposes two normally dissimi- installation that teems with humor and irony: François Jacob died earlier this year at age lar contexts, marital honor and the division of a French rooster, created by a German artist, 92. The key to his creativity, as pointed out in labor. This unexpected union produces an intel- invades England’s most sacred military ground multiple obituaries, was his masterful ability to lectual innovation—a eureka moment, which is that celebrates her greatest naval victory over see juxtapositions and analogies where others the essence of any creative action, whether it be the French. Napoleon would not be amused! saw only separate phenomena. a good joke, a scientific discovery like Jacob’s Marc Quinn’s Alison Lapper may have rubbed repressor theory, or a memorable piece of art shoulders with Lord Nelson, but Katharina Arthur Koestler’s theory of creativity like Quinn’s Alison Lapper or Fritsch’s Cock. Fritsch’s Cock will surely ruffle the admiral’s The concept that new ideas arise by the genera- In the past 50 years, thousands of books and feathers. Fritsch’s blue bird is destined to be the tion and juxtaposition of random combinations articles have been written on the subject of inno-

a b c

Figure 2 Marc Quinn’s sculpture for the fourth plinth, and the juxtaposition that inspired it. (a) Alexandros of Antioch (Hellenistic Age), Venus de Milo. ~100 bc. Marble. Height, 2.0 meters. Louvre Museum, Paris. (b) , Horatio Nelson. 1843. Sandstone. Height, 5.5 meters. Trafalgar Square, London. Both arms of the Venus de Milo were lost following discovery of the fragmented sculpture in 1820 on the island of Milos. The right arm of Lord Nelson was lost in battle. (c) Marc Quinn, Alison Lapper Pregnant. 2005. Height, 3.6 meters. Exhibited on the fourth plinth at Trafalgar Square, London, 2005–2007 (a,c from R. Rogers, M. Quinn and M. Mack, Fourth Plinth, Steidl, 2008).

2 VOLUME 19 | NUMBER 10 | OCTOBER 2013 NATURE MEDICINE FOREWORD vation and creativity, virtually all of which deal the all-or-none (or quantal) release of neu- focused primarily on the assembly of the fusion directly or indirectly with Koestler’s original rotransmitters. machine and Südhof primarily on the calcium- ideas. Two well-known examples of his influ- The key role of calcium in triggering rapid triggered regulatory mechanism, both of them ence are echoed in Jacob Bronowski’s famous and quantal release was first described 50 years contributed synergistically to the neurotrans- quote “The creative mind is a mind that looks ago by Bernard Katz, for which he received the mitter secretion story. From their original work for unexpected likenesses” and in Steve Jobs’s Nobel Prize in Physiology or Medicine in 1970. and that of others, the following model (briefly dictum “Creativity is just connecting the dots.” The molecular machinery responsible for the summarized here) has emerged: Even though we have a general idea of how calcium-triggered release of neurotransmitters Synaptic vesicle fusion is mediated by a the juxtaposition of disparate ideas produces was a complete mystery that began to be solved molecular complex formed by three mem- creative art and creative science, how the brain in the late 1980s when Scheller and Südhof ini- brane proteins: one protein (VAMP/synapto- generates these juxtapositions at the biologi- tiated their now-classic studies. Both of them brevin) residing on the synaptic vesicle and two cal and psychological levels is a great mystery started their research on synaptic vesicles proteins (SNAP-25 and syntaxin) on the target waiting to be solved—the Grand Challenge of as newly appointed assistant professors— plasma membrane. VAMP/synaptobrevin is Creativity. Scheller at Stanford University and Südhof at referred to as a v-SNARE (v for vesicle), and The last word on any discussion on creativity the University of Texas Southwestern Medical SNAP-25 and syntaxin as t-SNARES (t for belongs to arguably the two most creative indi- Center in Dallas. target). These v- and t-SNAREs assemble to viduals of the past 100 years, Albert Einstein At the time Südhof and Scheller began, not form a ternary complex that directs the two and Pablo Picasso. Both were asked by journal- a single protein important for neurotransmit- membranes toward each other, creating mem- ists, “What is creativity?” Einstein’s response: ter release had been functionally characterized. brane curvature and tension and producing an “The secret to creativity is knowing how to hide Genetic screens by the laboratories of Sydney intermediate state of hemi-fusion. Munc18-1, your sources.” Picasso’s response: “I don’t know, Brenner and Randy Schekman had identified a soluble protein, also appears to be essential and if I did I wouldn’t tell you.” gene mutations that disrupted synaptic trans- for synaptic vesicle fusion by complementing mission in Caenorhabditis elegans or blocked SNARE complex assembly in fusion. Basic Award: discovering how processing of proteins in the secretory system Opening of the fusion pore and release neurotransmitters are released in yeast, but the nature of the corresponding of a bolus of neurotransmitters is triggered This year’s Lasker Basic Medical Research genes and the function of the encoded proteins by the influx of calcium. This action of cal- Award is given to two scientists for their dis- were not known. cium is mediated by its binding to synapto- coveries concerning the molecular machinery After several decades of intense and origi- tagmin, a synaptic vesicle membrane protein and regulatory mechanisms that underlie the nal research involving an impressive array of that functions as the main calcium sensor in rapid release of neurotransmitters. The two approaches (biochemical, biophysical, cell bio- the system. Calcium binding to the two C2 recipients are Richard H. Scheller (Genentech) logical, electrophysiological and targeted mouse domains of synaptotagmin induces the asso- and Thomas C. Südhof (Stanford University), genetics), Scheller, Südhof and their colleagues ciation of synaptotagmin with the phospho- who 25 years ago independently embarked on had molecularly identified and functionally lipids of the hemi-fused membranes, which in a bold initiative to delineate the molecular basis characterized the major proteins involved in turn opens the fusion pore to trigger release. of synaptic vesicle fusion and its regulation by neurotransmitter release, and they had also Synaptotagmin cooperates with a SNARE- calcium. worked out the fundamental mechanism of associated soluble protein called complexin. Neurons communicate with each other by its regulation by calcium. Although Scheller In the absence of calcium, complexin acts as releasing chemical neurotransmitters into synaptic clefts that separate presynaptic and postsynaptic cells. The synaptic release of neu- rotransmitters is the basis of all neural function— from sensory perception to movement, from reasoning to memory. Hitting a baseball trav- eling more than 90 miles an hour is one of the most complex tasks imaginable, requiring the player to receive sensory information (see the ball), interpret it (process its image in the visual cortex) and respond (decide whether to swing) in about 200 milliseconds—all of which result from the coordinated transfer of neurotrans- mitters across billions of synaptic clefts between presynaptic and postsynaptic neurons. Neurotransmitters are packaged in tiny syn- aptic vesicles, each containing ~5,000 trans- mitter molecules that are released from the The Telegraph presynaptic neuron when an electrical action potential arrives at its nerve terminal and opens voltage-gated calcium channels. Calcium floods into the terminals, where it triggers the fusion Andy Rain, of pre-docked synaptic vesicles with the plasma Figure 3 Katharina Fritsch, Hahn/Cock. 2013. Fiberglass coated with polyester resin. Height, 4.7 meters. membrane and opens the fusion pore, allowing Exhibited on the fourth plinth at Trafalgar Square, London, 2013–2015.

NATURE MEDICINE VOLUME 19 | NUMBER 10 | OCTOBER 2013 3 FOREWORD a clamp to arrest the fusion reaction; when a fundamental biological problem, which in calcium is present, synaptotagmin releases the Popper sense has moved the problem the complexin block, thus ensuring tight and from ‘cloud’ to ‘clock’. rapid regulation of fusion-pore opening and Inspired by Popper’s essay, the contempo- release of neurotransmitters. After transmitter rary American artist Terry Winters, known release, the SNARE complex is disassembled for his lush abstract paintings influenced by by an ATPase called NSF, an action essential biological structures, recently created a series for multiple rounds of fusion and release. of prints and paintings entitled Clouds and In 2002, James Rothman and Randy Clocks. One of Winter’s paintings resembles a Schekman received the Lasker Basic Medical synaptic vesicle filled with neurotransmitters Research Award for their discoveries of the (Fig. 4). Even though Scheller’s and Südhof’s mechanism that orchestrates the budding and work has moved us into the ‘clocks’ of regu- fusion of membrane vesicles in non-neuronal lated neurotransmitter release, we remain Figure 4 Terry Winters, Clocks and Clouds/5. cells. One of the proteins that Rothman and in the ‘clouds’ in terms of understanding 2012. Oil on linen. 65.4 × 84.5 centimeters. Schekman found to be required in their in how alterations in synaptic vesicle proteins Courtesy of Matthew Marks Gallery, New York City. vitro fusion reactions in mammalian and influence diseases of the brain and abnor- yeast cell extracts was NSF (SEC18 in yeast). malities in behavior. Hopefully, this cloudy fibers. The nerve fibers in turn transmit the In the course of identifying new proteins that situation will clear up as the US National acoustic information along the eighth cranial interact with NSF, Rothman discovered in Institutes of Health’s newly inaugurated Brain nerve to the brain, where the original sound 1993 that bovine brain (a fortuitous choice of Research through Advancing Innovative is interpreted. The cochlea is organized tono- tissues, in retrospect) contained three mem- Neurotechnologies (BRAIN) Initiative teaches topically, such that hair cells located at dif- brane proteins that formed a complex that us more and more about how the brain works. ferent sites along the basilar membrane are bound tightly to his NSF affinity column. The stimulated by different sound frequencies in three proteins—which he named SNAREs— Clinical Award: creating a prosthetic a highly organized fashion that is projected turned out to be identical to three of the syn- sensory organ in an identical pattern through the auditory aptic vesicle proteins—VAMP/synaptobrevin, This year’s Lasker~DeBakey Clinical Medical nerve fibers to the brain. syntaxin and SNAP25—that Scheller, Südhof Research Award is given to Graeme M. Clark As recently as 35 years ago, there were and others had identified earlier. Rothman’s (University of Melbourne), Ingeborg J. no effective treatments for profound hear- affinity column experiment immediately Hochmair (Med-El, Innsbruck) and Blake ing loss resulting from severely damaged implicated these three proteins in synaptic S. Wilson (Duke University) for the devel- hair cells. Such treatments were considered vesicle fusion, a finding that rapidly cata- opment of the modern cochlear implant, a impossible because of the engineering chal- lyzed research in the fast-moving field of device that bestows hearing on individuals lenge of bypassing a defective cochlea so as neurotransmitter release. with profound deafness. More than 320,000 to stimulate the auditory nerve fibers in a In addition to Rothman’s contribution, the people have received cochlear implants, either tonotopic way that would faithfully reflect work of Scheller and Südhof was advanced in one or in both ears. different sound frequencies. A key historical by contributions from many other scientists: Impairment in hearing affects as many event in cochlear implant research occurred Cesare Montecucco (University of Padua), as 600 million people worldwide, most of in 1961, when William F. House, a physician who first reported in 1993 that SNARE pro- whom can be helped with hearing aids that and otologist in Los Angeles, inserted a gold teins are the substrates for tetanus and bot- amplify sound. But about 10% of deaf people wire a short distance into the cochlea of two ulinum neurotoxins that selectively block with severe sensorineural hearing loss cannot of his deaf patients. Electrical stimulation of synaptic vesicle fusion via proteolytic cleav- hear at all, owing to genetic disorders, infec- this single electrode allowed the patients to age; Reinhard Jahn (Max Planck Institute tions (rubella and meningitis), certain drugs hear sounds, but they could not understand for Biophysical Chemistry, Göttingen) and (kanamycin, streptomycin and cisplatin) or speech. This initial surgically implanted Axel T. Brunger (Stanford University), who overexposure to loud sounds. In such deaf device was eventually rejected by the body. together provided structural evidence for the people, hearing aids are of no benefit because But after many years of refining the materials tight assembly of the SNARE fusion com- sound cannot be transmitted to their brain, of his implants, House produced a long-lasting plex; and Reinhard Jahn (Göttingen) and no matter how much it is amplified. This is version that was successfully implanted in Josep Rizo (University of Texas Southwestern because the sensory hair cells of the cochlea, 1969. With this improved device and sub- Medical Center, Dallas), whose long-time col- a snail-shaped structure in the inner ear, are sequent ones that he and others developed, laboration with Südhof led to the biophysical severely damaged. limited speech perception was achieved in a and genetic discovery that synaptotagmin is In people with normal hearing, sound trav- few patients. the long-sought calcium sensor. els through the external ear canal to the ear- Despite notable improvements in the House One of the great philosophers of science, drum, which transfers the vibrations in the single-channel device, most otologists as Karl Popper, wrote an essay in 1965 entitled air to three tiny bones in the middle ear. The recently as the late 1980s questioned the theo- “Of Clouds and Clocks,” in which he divided innermost of these bones relays the vibrations retical rationale of House’s approach. How is it scientific phenomena into two categories: to the cochlea’s basilar membrane, where the possible that stimulating the cochlea with only those with a known mechanism (‘clocks’) delicate sensory hair cells are arranged in a a single implanted electrode can substitute for and those with unpredictable behavior precise way. The ~20,000 hair cells in each the 20,000 sensory hair cells and 30,000 audi- (‘clouds’). The current understanding of syn- cochlea respond to the incoming vibrations tory nerve fibers normally required to produce aptic vesicle fusion and function at a detailed and convert them into an electrical signal acoustic information in the brain? Despite the biochemical level explains the mechanism of that travels along 30,000 auditory nerve controversial nature of his work, House (who

4 VOLUME 19 | NUMBER 10 | OCTOBER 2013 NATURE MEDICINE FOREWORD died last year at age 89) was clearly a pioneer thoughts astir, and keeps us in the intel- whose one-channel device paved the way for lectual company of man. the therapeutically effective multichannel devices developed during the past 20 years by Thanks to the accomplishments of Clark, this year’s Lasker~DeBakey winners. Hochmair and Wilson, as well as the contribu- Graeme Clark and Ingeborg Hochmair are tions of numerous other electrical engineers largely responsible for the key hardware devel- and otologists, most users of modern cochlear opments and Blake Wilson for the key soft- implants can now communicate with ease ware strategies that made possible the modern in everyday conversation and are no longer prosthetic cochlear device: the so-called deprived of “the intellectual company of man.” multichannel implant. A typical multichan- To cite one example, most implant users have nel implant consists of several components: no difficulty with cell phone conversations. a small microphone for picking up the sound The use of the cochlear implant device by a (worn behind the external ear), a highly min- previously deaf person is unquestionably a iaturized digital speech processor for con- life-changing event. verting the sound into electrical signals, an The American contemporary artist Robert external and internal transmission system Gober, known for his three-dimensional for relaying the signal to the implanted com- sculptures of everyday objects and isolated ponents, and a tiny array of 12–22 electrodes body parts, has created an isolated human that is surgically implanted into the cochlea ear cast in a gypsum polymer (Fig. 5). The for delivering the electrical signals to the audi- Figure 5 Robert Gober, Untitled. 2008. Cast ear hangs alone on the wall, listening and tory fibers of the cranial nerve. gypsum polymer. 36 × 27 × 15 centimeters. eavesdropping on the viewer, who wonders In the multichannel devices designed Courtesy of Matthew Marks Gallery, New York City. whether the person who was the model for independently by Hochmair and Clark, the this ear has normal hearing or whether he or implanted electrode array takes advantage to an electrode array with 12–22 electrodes she is totally deaf and can have his or her hear- of the tonotopic representation of stimu- in a manner that would reflect the tonotopic ing restored with a cochlear implant. lus frequency along the basilar membrane actions of the cochlea’s 20,000 hair cells and of the cochlea. Each individual electrode in the 30,000 auditory nerve fibers. Wilson’s Joseph L. Goldstein is Chair of the the prosthesis is designed to excite a single speech strategy, referred to as continuous Lasker Awards Jury. subset of auditory nerve fibers that are sen- interleaved sampling (CIS), filters speech e-mail: [email protected] sitive to similar sound frequencies, and the or other input sounds into bands of differ- combined set of 12–22 electrodes in the array ent frequencies. The output of each band is Lasker Award recipients receive an honorarium, stimulates 20–24 different subsets of auditory then channeled into a single electrode of the a citation highlighting their achievement and fibers, thus mimicking a complex sound com- implanted array, thus mimicking the general an inscribed statuette of the Winged Victory of posed of many different frequencies. In addi- frequency mapping of the normal cochlea. Samothrace, which is the Lasker Foundation’s tion to their innovative design developments, Helen Keller wrote, in a letter to J.K. Love, symbol of humankind’s victory over disability, Hochmair (together with her husband Erwin MD (which accompanied a paper by him in disease and death. S. Hochmair) and Clark directed or spun off Laryngoscope 20, 596–611, 1910): two of the three main companies that brought To read the formal remarks of speakers at the cochlear implants to the marketplace. I am just as deaf as I am blind. The prob- Lasker ceremony, as well as detailed information In pioneering the software aspects of the lems of deafness are deeper and more com- on this year’s awardees, please refer to the Lasker modern cochlear implant, Blake Wilson and plex... than those of blindness. Deafness is website at http://www.laskerfoundation.org/. his colleagues solved the tricky problem of a much worse misfortune. For it means the turning acoustic signals into multichannel loss of the most vital stimulus—the sound COMPETING FINANCIAL INTERESTS electrical stimuli; that is, delivering electricity of the voice that brings language, sets The author declares no competing financial interests.

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