Controlling systems and controlling legacies: Barbara McClintock's 1961 conversation with two bacterial geneticists.

Barbara McClintock (1902-1992), the renowned American maize geneticist, received the 1983 Nobel Prize "for her discovery of mobile genetic elements," becoming the seventh woman scientist to receive a Nobel Prize. However, Nathaniel Comfort points out that McClintock viewed her primary contribution as the elucidation of control systems, rather than the discovery of mobile elements. McClintock's interest in control systems dates back to the 1940s, and this paper investigates her 1961 conversation with François Jacob and Jacques Monod, where she sought to shape the interpretation of her work by drawing parallels between maize control systems and a bacterial system they had recently discovered. Despite McClintock's efforts, Jacob and Monod rejected her parallels and suggested that her contribution was limited to mobile elements. Through an examination of their published papers, I argue that Jacob and Monod's rejection stemmed from their failure to fully comprehend maize control systems. Disciplinary discrepancy helps explain Jacob and Monod's lack of comprehension: they were molecular geneticists working on bacteria, while McClintock was a classical geneticist studying maize. I further argue that gender played a role, as McClintock experienced the Matilda effect-the under-recognition of her contribution, reinforced by the reactions of two male geneticists, and ironically, by the award of the Nobel Prize. Control systems, stemming from McClintock's reverence for organisms, embodied what Evelyn Fox Keller defines as "gender-neutral science." This divergent view of science provides insight into why Jacob and Monod failed to grasp McClintock's work in 1961.

Dogs and their genes: what ever will they think of next?

The Edward Novitski Prize recognizes creativity and intellectual ingenuity in the solution of problems in genetics research. The prize honors scientific experimental work-either a single experimental accomplishment or a body of work. Ostrander is recognized for work developing the domestic dog as an experimental system for solving fundamental biological problems and identifying genetic sequences of relevance to human health and disease. Including work on disease and behavioral health, Ostrander has shown a dedication to creative methods for understanding canine genetics and the value of translating research organisms to human genetics.

"Oh, how beautiful life is and how terrible death is!" (Th. Dobzhansky and religion).

In the article, mainly based on the reference to the entries in the diary of Th. Dobzhansky, a geneticist and one of the founders of the "synthetic theory of evolution", examines how Dobzhansky tried to combine science, primarily evolutionary theory, and religion. It is argued that although Dobxzhansky was a believer during whole his life, he became a peculiar believer who revised for himself and for others the former, primarily religious answers to the "ultimate questions" of existence, and posed these questions in a new, evolutionary way. Even more, he tried to substantiate and justify religion and his belief in God through the evolutionary theory, to demonstrate that science and religion are not incompatible, and to offer his believe in the usefulness of science and religion to each other. This Dobzhansky's attempt was perceived and evaluated ambiguously by both scientists and religious figures. In addition, Dobzhansky owing to his search for these answers, made a number of world outlook and general cultural conclusions for himself and presented these conclusions in articles and books written not only for colleagues in the scientific community, but also for other people.

William Lawrence Tower's Beetles: Experimental Evolution and the Manipulation of Inheritance.

William Lawrence Tower's work on the evolution of the Colorado Potato Beetle (Leptinotarsa decemlineata), documenting the environmental induction of mutation and speciation, made him a leading figure in experimental genetics during the first decade of the 20th century. His research program served as a model for other experimental evolution studies seeking to demonstrate the environmental modification of inheritance. Tower enjoyed the support of influential figures in the field, despite well-known problems that plagued Tower's earlier academic career. The validity of his genetic work, and other findings reported by Tower, were later challenged. The Tower affair illustrates how questionable and possibly fraudulent scientific practices can be tolerated to explore certain experimental directions and theoretical frameworks, particularly at the frontier of expanding disciplines. When needed, those explorations can be forestalled or extinguished by exploiting conspicuous vulnerabilities of rogue practitioners. In Tower's case, both unrefuted allegations of scientific misconduct and personal problems dissolved his institutional support, leading to a swift ouster from academic science. Tower's downfall discredited soft inheritance and neo-Lamarckian conceptions in the field of experimental genetics, facilitating the discipline's embrace of a hard inheritance model that featured a hereditary material resistant to environmental modification.

Muller and mutations: mouse study of George Snell (a postdoc of Muller) fails to confirm Muller's fruit fly findings, and Muller fails to cite Snell's findings.

In 1931, Hermann J. Muller's postdoctoral student, George D. Snell (Nobel Prize recipient--1980) initiated research to replicate with mice Muller's X-ray-induced mutational findings with fruit flies. Snell failed to induce the two types of mutations of interest, based on fly data (sex-linked lethals/recessive visible mutations) even though the study was well designed, used large doses of X-rays, and was published in Genetics. These findings were never cited by Muller, and the Snell paper (Snell, Genetics 20:545-567, 1935) did not cite the 1927 Muller paper (Muller, Science 66:84, 1927). This situation raises questions concerning how Snell wrote the paper (e.g., ignoring the significance of not providing support for Muller's findings in a mammal). The question may be raised whether professional pressures were placed upon Snell to downplay the significance of his findings, which could have negatively impacted the career of Muller and the LNT theory. While Muller would receive worldwide attention, and receive the Nobel Prize in 1946 "for the discovery that mutations can be induced by X-rays," Snell's negative mutation data were almost entirely ignored by his contemporary and subsequent radiation genetics/mutation researchers. This raises questions concerning how the apparent lack of interest in Snell's negative findings helped Muller professionally, including his success in using his fruit fly data to influence hereditary and cancer risk assessment and to obtain the Nobel Prize.

Evelyn M. Witkin (1921-2023).

Pioneer of cell mutagenesis and DNA repair research.

Aplicaciones clínicas de la herramienta CRISPR-Cas / Clinical Applications of the CRISPR-Cas Tool

Resumen El desarrollo de tecnologías para la edición del genoma ha abierto la posibilidad de apuntar directamente y modificar secuencias genómicas en casi todo tipo de células eucariotas. La edición del genoma ha ampliado nuestra capacidad para dilucidar la contribución de la genética a las enfermedades al promover la creación de modelos celulares y animales más precisos de procesos patológicos y ha comenzado a mostrar su potencial en una variedad de campos, que van desde la investigación básica hasta la biotecnología aplicada y biomédica. Entre estas tecnologías, el uso de las repeticiones palindrómicas cortas agrupadas regularmente espaciadas ha acelerado, en gran medida, el progreso de la edición de genes desde el concepto hasta la práctica clínica, generando, además, interés debido, no solo a su precisión y eficiencia, sino también a la rapidez y a los costos necesarios para su implementación en comparación con otras tecnologías de edición genómica. En esta revisión se presenta información recabada de publicaciones indexadas en la base de datos PubMed que se encontraron mediante el uso de palabras claves asociadas con la tecnología y que se filtraron para retener solo aquellas con evidencias de avances clínicamente relevantes y que permiten demostrar algunas de las aplicaciones que tiene esta tecnología en la investigación, pronóstico y tratamiento de enfermedades genéticas, cardiovasculares, virales, entre otras; esto con el objetivo de dar a conocer la situación actual de los avances en aplicaciones clínicas de la herramienta CRISPR-Cas y fomentar aún más la investigación en esta tecnología, la cual, tal como se evidencia a lo largo de esta revisión, posee una gran versatilidad y un amplio rango de aplicaciones, lo que ofrece una enorme oportunidad en el campo de la medicina genómica, pero que, a su vez, requiere un mayor fomento en su investigación para mejorar la tecnología y acercarla aún más a consolidar aplicaciones clínicas de uso seguro, confiable y consistente.

Abstract The development of genome editing technologies has opened up the possibility of directly targeting and modifying genomic sequences in almost all types of eukaryotic cells. Genome editing has expanded our ability to elucidate the contribution of genetics to disease by promoting the creation of more precise cellular and animal models of disease processes and has begun to show its potential in a variety of fields, ranging from basic research to applied and biomedical biotechnology. Among these technologies, the use of clustered regularly spaced short palindromic repeats have greatly accelerated the progress of gene editing from concept to clinical practice, further generating interest due not only to its precision and efficiency, but also to the speed and costs required for its implementation compared to other genomic editing methods. This review presents information collected from indexed publications in the PubMed database that were found by using keywords associated with the technology and filtered to retain only those with evidence of clinically relevant advances that demonstrate some of the applications that this technology has in research, prognosis, and treatment of genetic, cardiovascular, and viral diseases, among others; this with the aim of show the current situation of advances in clinical applications of the CRISPR-Cas tool and further encourage research in this technology, which, as evidenced throughout this review, has a great versatility and a wide range of applications, which offers an enormous opportunity in the field of genomic medicine but which, in turn, requires greater support in its research to improve the technology and bring it even closer to consolidating clinical applications of safe, reliable and consistent use.

A Commemorative Issue in Honor of 200th Anniversary of the Birth of Gregor Johann Mendel: The Genius of Genetics.

In celebration of the bicentennial of the birth of Gregor Johann Mendel, the genius of genetics, this Special Issue presents seven papers [...].

The Gregor Mendel Bicentennial Tribute-Enduring Mementos of the Founder of Genetics.

This Arts and Medicine feature summarizes events and scholarship honoring Abbot Gregor Mendel, founder of the science of modern genetics, on the occasion of the bicentennial of his birth.

"Batesonian Mendelism" and "Pearsonian biometry": shedding new light on the controversy between William Bateson and Karl Pearson.

This paper contributes to the ongoing reassessment of the controversy between William Bateson and Karl Pearson by characterising what we call "Batesonian Mendelism" and "Pearsonian biometry" as coherent and competing scientific outlooks. Contrary to the thesis that such a controversy stemmed from diverging theoretical commitments on the nature of heredity and evolution, we argue that Pearson's and Bateson's alternative views on those processes ultimately relied on different appraisals of the methodological value of the statistical apparatus developed by Francis Galton. Accordingly, we contend that Bateson's belief in the primacy of cross-breeding experiments over statistical analysis constituted a minimal methodological unifying condition ensuring the internal coherence of Batesonian Mendelism. Moreover, this same belief implied a view of the study of heredity and evolution as an experimental endeavour and a conception of heredity and evolution as fundamentally discontinuous processes. Similarly, we identify a minimal methodological unifying condition for Pearsonian biometry, which we characterise as the view that experimental methods had to be subordinate to statistical analysis, according to methodological standards set by biometrical research. This other methodological commitment entailed conceiving the study of heredity and evolution as subsumable under biometry and primed Pearson to regard discontinuous hereditary and evolutionary processes as exceptions to a statistical norm. Finally, we conclude that Batesonian Mendelism and Pearsonian biometry represented two potential versions of a single genetics-based evolutionary synthesis since the methodological principles and the phenomena that played a central role in the former were also acknowledged by the latter-albeit as fringe cases-and conversely.

Christine Guthrie (1945-2022).

RNA trailblazer who illuminated splicing mechanics.

The genotype-phenotype distinction: from Mendelian genetics to 21st century biology.

The Genotype-Phenotype (G-P) distinction was proposed in the context of Mendelian genetics, in the wake of late nineteenth century studies about heredity. In this paper, we provide a conceptual analysis that highlights that the G-P distinction was grounded on three pillars: observability, transmissibility, and causality. Originally, the genotype is the non-observable and transmissible cause of its observable and non-transmissible effect, the phenotype. We argue that the current developments of biology have called the validity of such pillars into question. First, molecular biology has unveiled the putative material substrate of the genotype (qua DNA), making it an observable object. Second, numerous findings on non-genetic heredity suggest that some phenotypic traits can be directly transmitted. Third, recent organicist approaches to biological phenomena have emphasized the reciprocal causality between parts of a biological system, which notably applies to the relation between genotypes and phenotypes. As a consequence, we submit that the G-P distinction has lost its general validity, although it can still apply to specific situations. This calls for forging new frameworks and concepts to better describe heredity and development.

Gregor Johann Mendel: From peasant to priest, pedagogue, and prelate.

Gregor Mendel was an Augustinian priest in the Monastery of St. Thomas in Brünn (Brno, Czech Republic) as well as a civilian employee who taught natural history and physics in the Brünn Modern School. The monastery's secular function was to provide teachers for the public schools across Moravia. It was a cultural, educational, and artistic center with an elite core of friar-teachers with a well-stocked library and other amenities including a gourmet kitchen. It was wealthy, with far-flung holdings yielding income from agricultural productions. Mendel had failed his tryout as a parish priest and did not complete his examination for teaching certification despite 2 y of study at the University of Vienna. In addition to his teaching and religious obligations, Mendel carried out daily meteorological and astronomical observations, cared for the monastery's fruit orchard and beehives, and tended plants in the greenhouse and small outdoor gardens. In the years 1856 to 1863, he carried out experiments on heredity of traits in garden peas regarded as revolutionary today but not widely recognized during his lifetime and until 16 y after his death. In 1868 he was elected abbot of the monastery, a significantly elevated position in the ecclesiastical and civil hierarchy. While he had hoped to be elected, and was honored to accept, he severely underestimated its administrative responsibilities and gradually had to abandon his scientific interests. The last decade of his life was marred by an ugly dispute with civil authorities over monastery taxation.

Mendel and Darwin.

Evolution by natural selection is an explicitly genetic theory. Darwin recognized that a working theory of inheritance was central to his theory and spent much of his scientific life seeking one. The seeds of his attempt to fill this gap, his "provisional hypothesis" of pangenesis, appear in his notebooks when he was first formulating his evolutionary ideas. Darwin, in short, desperately needed Mendel. In this paper, we set Mendel's work in the context of experimental biology and animal/plant breeding of the period and review both the well-known story of possible contact between Mendel and Darwin and the actual contact between their ideas after their deaths. Mendel's contributions to evolutionary biology were fortuitous. Regardless, it is Mendel's work that completed Darwin's theory. The modern theory based on the marriage between Mendel's and Darwin's ideas as forged most comprehensively by R. A. Fisher is both Darwin's achievement and Mendel's.

The "New Synthesis".

When Mendel's work was rediscovered in 1900, and extended to establish classical genetics, it was initially seen in opposition to Darwin's theory of evolution by natural selection on continuous variation, as represented by the biometric research program that was the foundation of quantitative genetics. As Fisher, Haldane, and Wright established a century ago, Mendelian inheritance is exactly what is needed for natural selection to work efficiently. Yet, the synthesis remains unfinished. We do not understand why sexual reproduction and a fair meiosis predominate in eukaryotes, or how far these are responsible for their diversity and complexity. Moreover, although quantitative geneticists have long known that adaptive variation is highly polygenic, and that this is essential for efficient selection, this is only now becoming appreciated by molecular biologists-and we still do not have a good framework for understanding polygenic variation or diffuse function.

Mimush Sheep and the Spectre of Inbreeding: Historical Background for Festetics's Organic and Genetic Laws Four Decades Before Mendel's Experiments in Peas.

The upheavals of late eighteenth century Europe encouraged people to demand greater liberties, including the freedom to explore the natural world, individually or as part of investigative associations. The Moravian Agricultural and Natural Science Society, organized by Christian Carl André, was one such group of keen practitioners of theoretical and applied scientific disciplines. Headquartered in the "Moravian Manchester" Brünn (nowadays Brno), the centre of the textile industry, society members debated the improvement of sheep wool to fulfil the needs of the Habsburg armies fighting in the Napoleonic Wars. Wool, as the raw material of soldiers' clothing, could influence the war's outcome. During the early nineteenth century, wool united politics, economics, and science in Brno, where breeders and natural scientists investigated the possibilities of increasing wool production. They regularly discussed how "climate" or "seed" characteristics influenced wool quality and quantity. Breeders and academics put their knowledge into immediate practice to create sheep with better wool traits through consanguineous matching of animals and artificial selection. This apparent disregard for the incest taboo, however, was viewed as violating natural laws and cultural norms. The debate intensified between 1817 and 1820, when a Hungarian veteran soldier, sheep breeder, and self-taught natural scientist, Imre (Emmerich) Festetics, displayed his inbred Mimush sheep, which yielded wool extremely well suited for the fabrication of light but strong garments. Members of the Society questioned whether such "bastard sheep" would be prone to climatic degeneration, should be regarded as freaks of nature, or could be explained by natural laws. The exploration of inbreeding in sheep began to be distilled into hereditary principles that culminated in 1819 with Festetics's "laws of organic functions" and "genetic laws of nature," four decades before Gregor Johann Mendel's seminal work on heredity in peas.

Mendel the fraud? A social history of truth in genetics.

Two things about Gregor Mendel are common knowledge: first, that he was the "monk in the garden" whose experiments with peas in mid-nineteenth-century Moravia became the starting point for genetics; second, that, despite that exalted status, there is something fishy, maybe even fraudulent, about the data that Mendel reported. Although the notion that Mendel's numbers were, in statistical terms, too good to be true was well understood almost immediately after the famous "rediscovery" of his work in 1900, the problem became widely discussed and agonized over only from the 1960s, for reasons having as much to do with Cold War geopolitics as with traditional concerns about the objectivity of science. Appreciating the historical origins of the problem as we have inherited it can be a helpful step in shifting the discussion in more productive directions, scientific as well as historiographic.