Fighting darkness under the sun (7)
Published in General & Internal Medicine
1940, New York, U.S., the look of the fish
The first clue of how melanocytes went to dark side was told also by a pet animal. Instead of mice that exhibited abundant variation in coat color and patterns, it was a fish. Like the cases of Gregor Mendel and Abbie Lathrop, it required a born-to-be naturalist to find the clue.
Myron Gordon was born in Russia on November 13, 1899, and came to the United States as a child. His first professional relationship with animals was not in a research laboratory but in the open air. In 1920, at twenty years old, he took a position as a keeper at the New York Zoological Park (currently the Bronx Zoo). From 1921 to 1923 he worked as a Game Keeper, first at the State of Maryland Game Farm at Gwynnbrook, and then at the State of New York Game Farm at Middle Island. A game farm is purposed to raise wild, undomesticated animals; its keepers in the early twentieth century managed breeding populations of wild birds and mammals, observed their behavior and health across seasons, and developed the practical intuition about animal welfare and reproductive biology that no laboratory education could provide. Gordon learned the knowledge, in those years, of animals by noticing the unusual patterns either in appearance or behaviors.
In the summer of 1924, still without a college degree, he took a position as a field Collector for the College of Agriculture at Cornell University, working at McLean Bogs in New York. It was in this role that he enrolled as an undergraduate student at the New York State College of Agriculture, earning his B.S. in 1925 at the age of 36. He stayed at Cornell for graduate work, earning his M.S. in 1926 and his Ph.D. in 1929. During this period, a great enthusiasm for genetics was aroused by several professors who studied plant breeding at Cornell. They inspired Gordon to work on genetics. Instead of the paradigm established by Gregor Mendel in plant breeding, Gordon wanted to study the genetics of animals, and he remembered the tropical fish that he had kept as a teenager. One kind of them, platyfish, were a popular, peaceful freshwater fish native to Central America. They come in a dazzling array of colors and spots that were easy to identified. Moreover, the visible pigment patterns were inheritable and would be ideal markers to study genetics, like the characteristics of pea plant in Mendel's study. He began with just six domesticated platyfish, Xiphophorus. He mapped the spots and stripes on their flanks, named the cells responsible for them, and worked out the genetic logic by which the patterns were transmitted. In 1926, he coined the terms micromelanophore and macromelanophore to describe the two principal classes of pigment cells in these fish. The following year he added swordtails, and then something happened that he had not been looking for.
When certain platyfish were crossed with swordtails, some of their hybrid offspring attracted Gordon's attention: dark, rapidly growing melanomas arising specifically from the macromelanophores. He demonstrated through systematic crossing experiments , involving a platyfish species X. maculatus crossed with four others, that melanoma and pigment cell abnormalities were not restricted to a single cross but were a general phenomenon across the genus, each time traceable to contribution of a specific macromelanophore genetic factor from X. maculatus. In 1931, Gordon published these results, concluding that a specific hereditary element was responsible for tumor formation from macromelanophore.
He was not the only one who observe the pigmented tumor in the fish. At almost exactly the same moment, Curt Kosswig and Georg Häussler in Germany independently identified the pigmented tumors in the same hybrid fish. Neither man knew of the others. Their contributions were complementary but not identical: Kosswig pointed out that the melanoma was hereditary and associated with melanophore patterns from the platyfish, while Gordon clearly identified the macromelanophore gene of X. maculatus as being responsible for the tumor. This was the very first evidence that melanoma arose from a well characterized cell type, predisposed by a specific genetic locus.
Meanwhile, a question still nagged at him: was the melanoma an artifact of domestication, a consequence of crossing strains that had been reared in captivity for generations? Or did wild Xiphophorus populations, living in Mexican rivers, carry the same predispositions? A gamekeeper does not answer questions about wild animals by staying indoors. The only way to know was to go and look. He went.
In 1930, supported by the National Research Council and the Museum of Zoology at the University of Michigan, Gordon led his first expedition to Mexico, heading for the Rio Papaloapan in Oaxaca following the trail of the ichthyologist Seth Meek, who had collected 68 Xiphophorus specimens near El Hule in 1902. The expedition — Gordon, a malacologist from Cornell, and a Mexican physician — collected over 100 species of fish, ten of them new to science. In March 1932 he went again, accompanied by two sons of Cornell faculty. In 1939, he went to Chiapas, then one of the least-developed and most difficult regions of Mexico , accompanied by his wife Evelyn, who had arrived separately by boat at Veracruz. There, Gordon caught his first wild X. maculatus. The telegram he sent back to Cornell, announcing his success, had the feel of a dispatch from the field rather than a laboratory report. He collected the progenitors of the HX strain at the Rio Lancetilla in Honduras in 1951. During his many expeditions he discovered and named several new species; in 1963, Robert Rush Miller and W.L. Minckley honored him by naming Xiphophorus gordoni in his memory.
Like C.C. Little, Gordon was thinking to make the fish of his collection enduring for future research. In 1938 he moved his fish stocks to the New York Aquarium — an institution whose care of living animals he understood instinctively — and in 1939 established the Xiphophorus Genetic Stock Center, conceived explicitly to provide a reliable supply of genetically identical fish to cancer researchers who could not maintain their own colonies. About that time, working in Dr. George M. Smith's laboratory at the International Cancer Research Foundation at Yale University School of Medicine, Gordon and Smith demonstrated that melanoma and pigment cell abnormalities were not restricted to specific fish hybrids, but a general phenomenon across Xiphophorus species. Moreover, the pigmented tumor cells in hybrid fishes histologically resemble the cells of mammalian "melanosarcoma" (malignant melanoma) — they are also infiltrative and destructive to adjacent tissue. The fish melanoma had established its credentials.
In 1941, Gordon became a Research Associate in Genetics at the New York Zoological Society — the institution that had given him the first job as a zoo keeper two decades earlier — and took charge of the fish genetics laboratory in the American Museum of Natural History. It was a remarkable institutional arc: from cage keeper to faculty associate at the city's premier natural history museum, driven not by conventional academic ambition but by the steady pull of curiosity about animals and their pigment cells. At the AMNH he developed advanced systems to study genetic and molecular events in melanoma formation. In 1948, Gordon published his landmark study that identified five macromelanophore pigment patterns, Sd (spotted dorsal), Sp (spot-sided), Sr (stripe-sided), N (black-sided), and Sb (black-bottomed), which he believed that there are only five genetic alleles at the this locus. These results created a foundation of genetic studies for future melanoma researchers, who will continuously reveal more complex genetic networks in melanoma occurrence. At the same year, most consequentially for the field, Gordon organized the International Pigment Cell Conferences (IPCC), beginning in 1948. For the first time, there was a sustained institutional space in which pigment cell biologists, melanoma researchers, clinical oncologists, and developmental biologists met together for multidisciplinary conversation. Up to these days, IPCC is still held annually.
Gordon died suddenly on March 12, 1959. The line that best captures his intellectual legacy was not in any obituary; it was the title of the review he published in the last year of his life, in the edited volume Pigment Cell Biology that bears his name as editor: The Melanoma Cell as an Incompletely Differentiated Pigment Cell. Without any of the molecular vocabulary that would eventually prove it, Gordon had articulated the central thesis that the entire subsequent century of melanoma research would validate, that a melanoma cell is a pigment cell that has failed to complete its developmental journey. It was an insight born from watching animals — in zoo enclosures, on game farms, in rivers in Oaxaca and Honduras and Chiapas, and in the tanks of the New York Aquarium — across an entire working life spent asking what kind of cell a colored spot really is.
1958, Montreal, Canada. The farm keeper passed the torch to the survivor.
In a common day at Germany, Fritz Anders happily got the notice that he was qualified for university admission. He dreamed to be an academic research for career since being a young boy. Unfortunately, that was 1938, when the World War II broke out in Europe. Rather than proceeding immediately to academic study, he was conscripted first as a Arbeitsmann (labor corps) and then as a soldier. Even worse, he was sent to the Eastern Front. In 1943, he was held as a prisoner of war in Russia. When he was released from the Russian prison camp in 1948, his scientific education was delayed by nearly a decade. He committed himself to academic study with extraordinary determination.
He found his first scientific position at the Geilweilerhof, a federal grapevine breeding station in the Palatinate wine country of southwestern Germany, studying the tumor-inducing principle in grape plants. On this job, Anders was acquiring the same foundational skill that made Gregor Mendel the first geneticist: the capacity to observe and analyze. He habilitated on the same plant tumor topic at the University of Saarbrücken, where he was appointed University Lecturer in General Genetics and Zoology. By the late 1950s, Anders had a solid reputation in plant tumor genetics. He asked if he could apply his knowledge to study tumors in animals.
The answer came in Montreal in 1958, at the Tenth International Congress of Genetics. He walked into the exhibition hall and stopped. At a booth attended by a compact, energetic American, a series of small tanks held living fish — some of them carrying dark, aggressive tumors spreading across their flanks and fins. That was Myron Gordon, from the American Museum of Natural History, demonstrating what he had spent thirty years building: a living genetic model of hereditary melanoma, produced reliably by crossing two species of Xiphophorus. Gordon explained the cross, the patterns, the tumors, which made Anders stay at that booth for a long time.
He returned to Germany and pivoted his laboratory entirely. Gordon died less than a year later, on March 12, 1959, never knowing what the man he had briefed in Montreal would do with the fish. But the pivot Anders made was in every meaningful sense a continuation of Gordon's work — the same question, pursued now with a new decade's molecular tools and a European geneticist's appetite for formal rigor.
At the Justus Liebig-University in Giessen, in 1964, Anders began formalizing what Gordon's crosses had implied. In the backcross of F1 hybrids to X. hellerii, he found exactly one quarter of offspring developing melanoma. To a trained geneticist, that number carried a precise message: the tumor was generated by two independently segregating loci — one that drove tumor formation, and one that suppressed it. He named the driver locus Tu, for tumor, and the suppressor R, for repressor — also called Diff, for differentiation. Tu was sex-linked, residing on the same sex chromosomes that carried Gordon's five pattern alleles — Sd, Sp, Sr, N, and Sb. Those five patterns, Anders realized, were not five separate genetic systems. They were five allelic variants of the same Tu locus, each specifying where on the body the melanoma would erupt. Gordon had described five phenomena, and Anders showed they were actually one. This was the first time that the concept of "tumor suppressor gene" was introduced.
The R/Diff locus was not linked to sex chromosome ("autosomal"). This was established not by molecular sequencing but by years of repeated backcrossing of X. maculatus with X. hellerii while retaining the sex carrying Tu locus. As each generation diluted the R locus, melanoma incidence climbed in exact proportion. It was a slow, methodical proof requiring hundreds of fish scored across multiple generations, but it demonstrated beyond doubt that R and Tu resided on different chromosomes and counteracted with each other. Together these two loci determined with Mendelian precision which fish lived and which died of cancer. In 1983, Morizot and Siciliano gave R/Diff its first biochemical chromosomal address, linking it to an esterase marker on what would be formalized as Xiphophorus Linkage Group V.
Anders's team then pushed further into molecular territory. Among the more than twenty Xiphophorus oncogenes they characterized, one stood apart: x-erbB, the fish homolog of the epidermal growth factor receptor gene. In hybrid melanomas, x-erbB had — through a duplication event unique to the platyfish lineage. In the absence of R/Diff, it would turn itself on to set the entire malignant cascade in motion. Anders recognized that x-erbB was not merely one oncogene among many, but the ignition switch. No single oncogene makes a tumor alone, he argued. But every network has a trigger, and in Xiphophorus melanoma, that trigger was x-erbB.
In his latest years, Anders received many honors. In 1993, the German Cancer Society awarded Anders and his wife, Annerose Anders, who was his long-term collaborator (reminding us Meenhard and Dorothee Herlyn), jointly the Deutscher Krebspreis for the biological identification of oncogenes and suppressor genes in Xiphophorus. In 1997, the Japanese Foundation for Cancer Research awarded Anders the Prince Hitachi Prize for Comparative Oncology, recognizing his contribution in "The Genetics and Biology of Cancer as Studied in Fish Melanoma". He died on December 21, 1999. After his death, the European Society for Pigment Cell Research established the Fritz Anders Medal, awarded to scientists for outstanding contributions to pigment cell and melanoma research.
The arc was long. A Russian-born child in New York became a game keeper, crossed two tropical fish species, and found hereditary melanoma. A German boy who wanted to be a scientist was sent to war, returned from Russia to study grape tumors, walked into an exhibition hall in Montreal, and saw a man standing before a tank of diseased fish. The scientific torch was passed, as one generation's question became the next generation's answer.
1970s, Giessen, Germany. The student in the room where it happened.
There are moments in a scientific life that choose you before you choose them. For Manfred Schartl, that moment came in the corridors of Justus Liebig-University in Giessen, Germany, in the 1970s. He had enrolled to study chemistry and biology, but something was already waiting for him in those hallways: the fish tanks of Fritz Anders.
Anders had built his Xiphophorus colony there, and by the time Schartl arrived as a student, the fish were famous in the building — living proof that cancer could be predicted, produced at will, and studied with the rigor of classical genetics. The classical genetics had already identified two loci — Tu and R/Diff — but what proteins did they encode? What was the actual molecule that, when released from its suppressor, drove a pigment cell into malignancy? A student drawn to genetics, to molecules, and to the question of how normal cells go wrong could not walk past those tanks without stopping. Schartl stopped. He joined Anders's research group for his doctoral degree, and Anders introduced him to the Xiphophorus melanoma system.
After completing his doctorate, Schartl remained at Giessen for an initial postdoctoral period alongside Anders and his wife Annerose. But he wanted to learn the molecular tools he needed at the places where they were being perfected, and that led him to the laboratory of Robert Gallo at the National Cancer Institute, NIH. Gallo was then one of the most celebrated figures in retroviral oncogene research, a man whose laboratory sat at the productive center of molecular cancer biology in the 1980s. In Gallo's lab, Schartl sharpened his skills in oncogene cloning, receptor tyrosine kinase biochemistry, and the analysis of aberrant signaling in tumor cells. He returned to Germany carrying those tools with a clear objective: to find the actual gene at the Tu locus — the problem Anders had posed and that earlier researchers had intuited before either of them.
He and his team found the answer in 1989. The Tu locus encoded a novel receptor tyrosine kinase, a cell-surface protein that senses and transmits signals into the cell. They named it Xmrk — Xiphophorus melanoma receptor kinase. When they compared its sequence to the catalog of known human proteins, the match was striking. Xmrk was a mutant, locally duplicated copy of the fish orthologue of the epidermal growth factor receptor (EGFR) — one of the most consequential signaling proteins in cancer biology, already implicated in human glioblastoma, lung, and breast malignancy. The fish tumor and the human patient's melanoma were speaking, it turned out, the same molecular language. The publication appeared in Nature.
The discovery did not arrive without friction. Anders's group had independently identified an EGF-receptor-related sequence at the Tu locus the previous year. Both groups had converged on the same answer through different experimental routes — a scientific coincidence almost as uncanny as the simultaneous independent discovery of the melanoma itself by Gordon, Kosswig, and Häussler sixty years before. Teacher and former student, working in institutions barely forty kilometers apart, found themselves in the awkward position of rivals over a discovery both had legitimately earned. What settled the question was not priority but proof. Schartl's group demonstrated conclusively that Xmrk was not merely located near Tu but was Tu itself — the functional oncogene whose constitutive activation, in the absence of the R/Diff suppressor, drove the melanoma.
What Schartl had proven, in molecular terms, was the mechanism behind everything that Gordon and Anders had described in genetic terms across six decades. In purebred platyfish, Xmrk existed as a proto-oncogene, kept silenced by its companion locus R/Diff. The evolutionary event that created the oncogene was a nonhomologous recombination — a gene duplication in which the Xmrk copy acquired a new promoter from an adjacent anonymous sequence, making it constitutively transcribed in cells where it had no business being active. When hybridization with a swordtail replaced the chromosome carrying R/Diff with one that lacked the suppressor, the constitutively expressed Xmrk sent a ceaseless growth signal into the macromelanophore. The pigment cell, receiving a perpetual instruction to divide, had no choice but to comply. That was the melanoma. Sixty-five years after Gordon had first watched the tumors appear in his hybrid fish, someone had finally found the molecule he had been describing all along. And most importantly, Schartl's identification of Xmrk as an EGFR orthologue established a principle that would prove to be the organizing logic of melanoma molecular biology for the next three decades: the signaling pathways that normally govern melanocyte survival and proliferation during development are the very pathways that melanoma corrupts. Melanoma oncogenes are developmental signaling components running without brakes.
When the Fritz Anders Medal was established by the European Society for Pigment Cell Research in memory of his mentor, Schartl was among the scientists who received it — awarded for outstanding contributions to pigment cell and melanoma research. He also received the Prince Hitachi Prize in 2007, the same prize that Anders received exactly a decade ago. The student who had trained in the room where Anders had built his Xiphophorus colony had come back to find the molecule that Anders had spent a career looking for, was now honored with his mentor's name. Gordon had passed the question to Anders in a Montreal exhibition hall. Anders had passed it to Schartl in the corridors of Giessen. The efforts of generational melanoma researchers live on.
2000s, Boston. The new fish in the field.
What Gordon, Anders, and Schartl had established over eighty years, that a genetically defined fish could serve as a rigorous, visually accessible window into the mechanisms of melanoma, became the founding premise of a new generation of melanoma researchers. The next instrument would be a different fish, which was the consequence of one researcher's frustration with a frog.
Leonard "Len" Zon had not planned to use fish in his research, nor to study cancer at all. Trained as a clinician and drawn initially toward a career as a family doctor, Zon found out during his fellowship years that he loved research. He therefore joined the laboratory of developmental biologist Douglas Melton to pursue the question of how hematopoiesis, the process by which a stem cell commits to becoming blood, was initiated in a vertebrate embryo. The model Melton's laboratory favored was Xenopus, the African clawed frog, whose large transparent eggs had made it a workhorse of developmental biology for decades. Zon spent several years studying how the frog embryo triggered blood cell production, but the work chafed against a persistent limitation: Xenopus offered almost no genetic tools. You could inject things into the eggs and watch the embryo develop, but you could not easily make stable mutants, run forward genetic screens, or build the kind of experimental infrastructure that systematic biology requires. At a meeting in 1992, where Zon presented his work on the frog, a colleague suggested zebrafish (Danio rerio).
Zebrafish had been championed since the late 1960s by George Streisinger at the University of Oregon as a vertebrate genetic model, and a handful of dedicated laboratories had begun building mutant libraries, but the animal was still a minority interest in developmental biology, far from the mainstream that worked in mice, flies, or worms. What Zon immediately recognized was the combination that Xenopus lacked: genuine genetic tractability, together with an embryo that was completely transparent, allowing a real-time view of every organ and cell type as they formed. You could watch a zebrafish embryo make blood, genetically modify the fish, screen thousands of offspring, and identify the genes responsible for specific developmental failures. In the 1990s, Zon built his laboratory around that logic, establishing a zebrafish hematopoiesis program that would become one of the most productive in the world, identifying mutants in blood development that illuminated the molecular basis of rare human anemias and blood disorders. The fish came first, and it came because a frog had run out of genetic runway.
Zon used zebrafish to study hematopoiesis for the next decade, until a young researcher from UK came to his lab, suggesting that zebrafish would be a perfect tool to study melanoma. Her name is Elizabeth Patton.
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