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Pattern Recognition and Gestalt Psychology: The Day Nüsslein‐Volhard Shouted “Toll!”

2010; Wiley; Volume: 24; Issue: 7 Linguagem: Inglês

10.1096/fj.10-0701ufm

1530-6860

Gerald Weissmann,

Circadian rhythm and melatonin

Christiane Nüsslein-Volhard (1942-), Nobel Prize in Physiology or Medicine, 1995. Image courtesy Corbis. Max Wertheimer (1880–1943), founder of Gestalt Psychology. Image courtesy American Psychological Association via the National Library of Medicine. Probably I just shouted: “Toll!” in a conversation with Eric Wieschaus, when he and I scored the fixed embryos together on a discussion microscope, when we shared a lab in Heidelberg. It was during the mutant screen in which we discovered the segmentation mutants in late 1979. This work was published in 1980 in Nature, and is the essential basis for our Nobel award. Christiane Nüsslein-Volhard, Personal communication to The FASEB Journal, May 14, 2010 Interviewer: Hat es in Ihrem Leben den Heureka-Moment gegeben? (Have you ever had a Eureka! moment in your life?) Nüsslein-Volhard: Immer wieder mal. Das ist ganz toll! (Again and again. That's what's so crazy!) Christiane Nüsslein-Volhard, 2009 (1) The fundamental of the Gestalt “formula” might be expressed in this way: There are wholes, the behavior of which is not determined by that of their individual elements, but where the parts are themselves determined by the innate nature of the whole. Max Wertheimer, Address to the Kant Society, 1924 (2) [Mountcastle, Hubel and Wiesel] confirmed the inferences of the Gestalt psychologists by showing us that … the brain does not simply take the raw data it receives through the senses and reproduces it faithfully. Instead each sensory system first analyzes and deconstructs, then restructures the raw incoming information according to its own connections and rules … shades of Immanuel Kant! Eric Kandel, In Search of Memory, 2006 (3) Lately, much of human pathobiology has been chalked up to Toll-like receptors (TLRs), molecules that tell our innate immune system that there is a stranger at the door. Within the past year, The FASEB Journal has published papers on the role of TLRs in stem-cell activation, dengue fever, bacterial sepsis, microRNA processing, release of leukotrienes, and—no kidding—obesity (http://www.fasebj.org). Other recent reports have implicated TLRs in human ailments that range from gingivitis to Lyme disease; from lupus to titanium hips, and from atherosclerosis to respiratory ailments brought on by the World Trade Center disaster (4–7). Toll-like receptors have now been identified up and down the great chain of being: plants, bacteria, sponges, worms, flies and us (8, 9). In humans, TLRs and other “Pattern Recognition Receptors” warn us against generic bacteria, viruses, protozoa, or even splinters in our fingers. But they don't tell us whether we've met an individual microbe before: they just assist the work of antibodies and cells of acquired immunity (4, 10). As an abbreviation, TLR is fast becoming as famous as RNA or DNA: PubMed lists over 17,000 papers devoted to TLRs. But where did “Toll” come from? It's been properly credited to Christiane Nüsslein-Volhard, and first appeared in print as “the Toll gene product” in two of her 1985 articles in Cell (11, 12). However, no first-hand account had been rendered of how, why, or when this peculiar name was chosen. The word Toll appears neither in her Nobel Prize-winning paper from Heidelberg with Eric Wieschaus (13), nor her eloquent Nobel lecture (14). To complete the record, The FASEB Journal wrote to Dr. Nüsslein-Volhard; in reply, she owned that “the original discovery has nothing to do with its present fame (Personal communication to The FASEB Journal, May 14, 2010).” She is too modest: a gene and gene product that tells an organism which way is up or down has everything to do with Toll's present fame. It's the Gestalt that counts. On the day that Christiane Nüsslein-Volhard shouted “Toll” she and Eric Wieschaus were working out the genetic control of morphogenesis in the fruit-fly, Drosophila melanogaster. Insects are segmented, and by studying the patterns of segmentation in many mutants of fly eggs, the Heidelberg scientists were able to identify 15 gene loci that control its final form, its Gestalt. These genes act at three levels of spatial organization. The first set of genes dictates the pattern of segmentation of the entire egg along the body axis: anterior/posterior and dorsal/ventral. The next group of genes governs development of every second segment, while the third group of genes fine-tunes the structure of each segment in the adult (14, 15). The Toll gene tells the developing larva which is front and which is back, and the Toll mutant gets it wrong. “The Toll mutant was so fascinating because we knew already the dorsalised phenotype, and I just had described ‘dorsal’ which displays this polarity loss along the dv axis in lack of function alleles. Toll was the first mutant with a ventralized phenotype, and initially we were tempted to call it” ventral. “But the first name got stuck” (Personal communication to The FASEB Journal, May 14, 2010). The mutant was all back and no front: Toll, indeed! But words shouted in the heat of discovery have more than their dictionary meaning. My émigré father used “toll” when he meant “crazy,” but also “curious” or “amazing;” he used it when he first treated a patient with cortisone. These days German-speakers also use toll instead of “cool” or “droll,” “outrageous” or “awesome.” So toll has all sorts of meanings, but none more profound than when first applied to the “ventralized phenotype:” the topsy-turvy fruit fly in Heidelberg. We had bets if it would fit into the dorsalisation series pathway, (which it did, according to the subsequent genetic analysis performed mainly by Kathryn Anderson and Gerd Jürgens as postdocs in my laboratory at the FML in Tübingen). The polarity loss of the original Toll allele is not complete, and Toll has recessive alleles (null alleles recovered as revertants) which show a completely dorsalised phenotype (11) (Personal communication to The FASEB Journal, May 14, 2010). After Kathryn Anderson had gone on to clone the Toll gene it looked quite a bit like the human interleukin 1-receptor, (IL-1R) (16, 17). Since IL-1 is an endogenous pyrogen—it causes fever in man and beast—the next question was how a signal for spatial orientation in flies could possibly explain features of innate immunity: that's what a good number of those 17,000 papers are all about (18). They suggest that the Heidelberg lab was on the right track at the very beginning. When you turn a creature topsy-turvy, you've changed its overall pattern—it's Gestalt. Wieschaus explained that “Christiane and I were both primarily interested in spatial patterns.” Sure enough, in his Nobel lecture “From Molecular Patterns To Morphogenesis: The Lessons From Drosophila,” the words pattern or patterns appear 43 times (15). But Nüsslein-Volhard beats him out in the pattern-count: in her Nobel lecture the word appears 57 times (14)! Their Nobel Prize might be said to recognize the importance of pattern recognition. As Nüsslein-Volhard wrote, TLRs are certainly more “famous” today in immunology than in developmental biology (Personal communication to The FASEB Journal, May 14, 2010). It turns out that the genes that determine the Gestalt of fruit flies also dictate innate immunity in mice and men. The intracellular signaling pathway is also ubiquitous, it begins with MyD88 and ends with David Baltimore's workhorse of immunity: NF-κB (18, 19). The major cells of innate immunity—monocytes, dendritic cells, and neutrophils—are chock full of TLRs. When TLRs recognize a discrete pattern on a microbe, virus, or foreign debris, they signal where contact has been made. As the phagocyte writhes in response to invaders, the cell remains properly oriented by its two paired centrioles—their built-in gyroscope. The centrioles, which are oriented at right angles to each other, have a unique microtubular architecture that permits its distant radiations to sense signals from any direction. The gyroscope keeps the cell on track as the gymnastics of digestion or secretion change its sense of front and back (20–22). By this means, TLRs dictate what Wirschaus called the “spatial pattern,” of the cell. All creatures develop according to eternal laws And the earliest image is hidden in the most complex form (14) Regardless of whether or not one believes that [visual] relationships depend upon past experience, the question remains … Do such relationships exhibit the operations of intrinsic laws or not, and if so, which laws? Such a question requires experimental inquiry and cannot be answered by the mere expression “past experience” (26). In Frankfurt, he bought a “zoetrope,” a child's toy based on a moving picture machine invented by Eadweard Muybridge two decades earlier. A strip of pictures is placed inside the machine, it's rotated, and when viewed though slits on the side, the stationary images come alive as a single, moving picture. Wertheimer took the device to his hotel room where he made his own picture strips, not of real objects but of simple abstract lines. By adjusting their geometry, he worked out the minimal variation required to produce the illusion of motion. The effect is now known as “apparent movement” (27) and is the reason that millions of people today can gawk at animated avatars. We see pictures, not pixels. Wertheimer stayed on in Frankfurt and landed a position at the new Psychological Institute. There he was able to make use of a fast-shutter projector, the formidable “tachistoscope.” This machine permits the investigator to flash images on and off a screen at precise intervals. Using as experimental subjects two younger colleagues, Wolfgang Köhler and Kurt Koffka, Wertheimer concluded that the apparent movement flashed on the screen is not dictated by individual elements but by the overall kinetics of their appearance: the Gestalt. We see the whole picture, rather than the sum of its parts, but only when the timing is right. By 1912 he'd published “Experimental Studies of the Perception of Movement,” the seminal work of Gestalt psychology (28). In 1914, Wertheimer, Koffka, and Köhler were separated by the Guns of August. Köhler was stationed in the Canary Islands during World War I, and did experimental work on the local apes. He confirmed the Gestalt notion that perception of the field is innate rather than acquired (29). After the war, Gestalt entered its golden age. Wertheimer had accepted a faculty appointment at the University of Berlin, and Köhler was appointed Director of its Psychological Institute. The graduate program they established, which favored experimental over theoretical work, drew wide attention and a flock of bright graduate students; their new journal, called Psychologische Forschung (Psychological Research), became the house organ. In the fifteen years between the Armistice and Hitler, the institute and the Gestalt psychologists started a movement, some even called it a counter-rebellion against behaviorism. It crossed the Atlantic, and its apostles included Rudolf Arnheim, Kurt Lewin, Wolfgang Metzger, Hans Wallach, and Kurt Gottschaldt (30). Pattern recognition diagram from the “dot essay” illustrating “the tendency of like parts to band together (26).” Image courtesy Springer. As the nationalist (read Nazi) movement spread to pose an ever more serious threat to the Weimar Republic, the Gestalt psychologists paid ever more frequent visits to the United States. Coast to coast, they challenged the ruling behaviorist school and made the occasional convert. Koffka left Europe for the United States in 1924 where he taught at Smith. And when the brownshirts came to power in 1933, Lewin was able to get to Iowa and Cornell. Wertheimer came to the New School in New York, where Alvin Johnson had established his graduate faculty as a “University in Exile.” Köhler remained in Berlin until 1935, was harassed for associating with “the Jew Wertheimer,” and arrived in the United States in 1935 to a scholar's welcome at Swarthmore (30). But the temporal and spiritual home of the Gestalt movement was the New School first and last. With frequent lectures by Lewin, Arnheim, and the founding triumvirate, the graduate faculty attracted students and American faculty members of the first rank (31). The tradition has continued to the present. Not too long ago, a distinguished professor came from Sarah Lawrence to teach experimental psychology at the New School: Gertrude Baltimore, David's mother. Wertheimer would have been delighted: pattern recognition and NF-κB in one family. It probably comes from connecting the dots. With heartfelt thanks to Prof. Dr. Christiane Nüsslein-Volhard (Max-Planck-Institut für Entwicklungsbiologie, Tübingen, Germany) for her historic contributions—and her historic note to The FASEB Journal. Thanks also to Ann Weissmann, (M.A., New School) who first connected the dots of pattern recognition in psychology and immunology.