Almost every human disease has both a genetic and an environmental component. Even a classical inherited condition such as hemophilia can be influenced by external factors—in fact, most of the pathogenic effects of the mutation can be avoided by judicious injections of clotting factor, leading to a nearly normal life expectancy. For infectious diseases, often considered as essentially environmental, there are well-documented inherited differences in susceptibility, one of the most striking being the resistance to HIV infection of homozygous carriers (...) of the delta-32 mutation in the CCR5 gene (Dragic et al. 1996). Nevertheless, a number of conditions are “mostly genetic,” others “mostly environmental,” while many .. (shrink)

Clustered regularly interspaced short palindromic repeats genome editing has already reinvented the direction of genetic and stem cell research. For more complex diseases it allows scientists to simultaneously create multiple genetic changes to a single cell. Technologies for correcting multiple mutations in an in vivo system are already in development. On the surface, the advent and use of gene editing technologies is a powerful tool to reduce human suffering by eradicating complex disease that has a genetic etiology. Gene drives (...) are CRISPR mediated alterations to genes that allow them to be passed on to subsequent populations at rates that approach one hundred per cent transmission. Therefore, from an anticipatory biomedical ethics perspective, it is possible to conceive gene drive being used with CRISPR to permanently ameliorate aberrant genes from wild-type populations containing mutations. However, there are also a number of possible side effects that could develop as the result of combining gene editing and gene drive technologies in an effort to eradicate complex diseases. In this paper, we critically analyse the hypothesis that the combination of CRISPR and gene drive will have a deleterious effect on human populations from an ethical perspective by developing an anticipatory ethical analysis of the implications for the use of CRISPR together with gene drive in humans. (shrink)

In the contemporary biomedical literature, every disease is considered genetic. This extension of the concept of genetic disease is usually interpreted either in a trivial or genocentrist sense, but it is never taken seriously as the expression of a genetic theory of disease. However, a group of French researchers defend the idea of a genetic theory of infectious diseases. By identifying four common genetic mechanisms (Mendelian predisposition to multiple infections, Mendelian predisposition to one infection, and major gene (...) and polygenic predispositions), they attempt to unify infectious diseases from a genetic point of view. In this article, I analyze this explicit example of a genetic theory, which relies on mechanisms and is applied only to a specific category of diseases, what we call “a regional genetic theory.” I have three aims: to prove that a genetic theory of disease can be devoid of genocentrism, to consider the possibility of a genetic theory applied to every disease, and to introduce two hypotheses about the form that such a genetic theory could take by distinguishing between a genetic theory of diseases and a genetic theory of Disease. Finally, I suggest that network medicine could be an interesting framework for a genetic theory of Disease. (shrink)

The study of mental illness by the methods of molecular genetics is still in its infancy, but the use of genetic markers in psychiatry may potentially lead to a Virchowian revolution in the conception of mental illness. Genetic markers may define novel clusters of patients having diverse clinical presentations but sharing a common genetic and mechanistic basis. Such clusters may differ radically from the conventional classification schemes of psychiatric illness. However, the reduction of even relatively simple Mendelian phenomena to (...) molecular genetics has been shown to be a surprisingly complex and problematic enterprise. Mental illnesses exist at many levels of including social, environmental, and developmental interactions. Reductionistic shifts in the classification of such a disease entity will have to address the interlevel dynamics that take place within the structure of theories of mental illness. The question of how molecular analysis of psychiatric disease will impact on the structure of existing theories and classification systems is the central topic of this paper. (shrink)

A significant portion of newborns cared for in the neonatal intensive care unit or other ICUs, such as the cardiac ICU, have a medical condition with a genetic component, including congenital malformations, the leading cause of death in the NICU. In many cases, however, it is not clear which condition the child has or what can be done to help him or her. Genomic sequencing of sick newborns has the potential to bypass the prolonged journey to a diagnosis, improving the (...) medical care of individual infants. Sequencing also has the potential to benefit others beyond the child whose genome is sequenced and his or her immediate family. Sequence data from sick newborns will expand medicine's understanding of genetic diseases, leading to improvements in clinicians’ ability to counsel family and to provide even more targeted care. Not only will more frequent use of sequencing lead to discovery of new genes; it will also provide unique insights into the full spectrum of known Mendelian genetic diseases, so‐called phenotypic expansion, when a gene previously recognized as associated with a phenotype is found to be associated with an expanded set of clinical features. Genetic and environmental changes that modify the expression of a genetic disease may also be elucidated. (shrink)

Prior to the genomic sequencing era, the bible for those working in clinical genetics was McKusick’s Mendelian Inheritance in Man, which appeared in multiple editions between the 1960s and the late 1990s. This catalogue was organized according to general patterns of inheritance and focused on phenotypes. Beginning in the mid-1980s, it was replaced by Online Mendelian Inheritance in Man, a continuously updated catalogue documenting molecular relationships between genetic variation and phenotypic expression. This paper explores this resource’s evolution with (...) attention to how disease is distinguished from clinically irrelevant variation and how phenotypic similarities are captured in cases where there is no obvious genotypic association. It is argued that hybrid compromises are encoded into OMIM®; in addition to serving its key original purpose of being a diagnostic catalogue, it also began to record detectable variations in the genome even if they were not known to be associated with phenotypically visible disorders or even phenotypic variations. Although the impacts of geneticization have been well recognized, particularly in popular media, this example allows exploration of some of the historic, epistemic, and methodological causes that underlie tendencies toward disease geneticization in contemporary medicine, while highlighting that such gene-focused strategies may in fact be warranted in some contexts. (shrink)

This paper challenges the common assumption that some phenotypic traits are quantitative while others are qualitative. The distinction between these two kinds of traits is widely influential in biological and biomedical research as well as in scientific education and communication. This is probably due to both historical and epistemological reasons. However, the quantitative/qualitative distinction involves a variety of simplifications on the genetic causes of phenotypic variability and on the development of complex traits. Here, I examine three cases from the life (...) sciences that show inconsistencies in the distinction: Mendelian traits, Mendelian diseases, and polygenic mental disorders. I show that these traits can be framed both quantitatively and qualitatively depending, for instance, on the methods through which they are investigated and on specific epistemic purposes. This suggests that the received view of quantitative and qualitative traits has a limited heuristic power—limited to some local contexts or to the specific methodologies adopted. Throughout the paper, I provide directions for framing phenotypes beyond the quantitative/qualitative distinction. I conclude by pointing at the necessity of developing a principled characterisation of what phenotypic traits, in general, are. (shrink)

Over the past decade, research has revealed biomolecular condensates' relevance in diverse cellular functions. Through a phase separation process, they concentrate macromolecules in subcompartments shaping the cellular organization and physiology. In the nucleus, biomolecular condensates assemble relevant biomolecules that orchestrate gene expression. We here hypothesize that chromatin condensates can also modulate the nongenetic functions of the genome, including the nuclear mechanical properties. The importance of chromatin condensates is supported by the genetic evidence indicating that mutations in their members are causative (...) of a group of rare Mendelian diseases named chromatinopathies (CPs). Despite a broad spectrum of clinical features and the perturbations of the epigenetic machinery characterizing the CPs, recent findings highlighted negligible changes in gene expression. These data argue in favor of possible noncanonical functions of chromatin condensates in regulating the genome's spatial organization and, consequently, the nuclear mechanics. In this review, we discuss how condensates may impact nuclear mechanical properties, thus affecting the cellular response to mechanical cues and, eventually, cell fate and identity.Chromatin condensates organize macromolecules in the nucleus orchestrating the transcription regulation and mutations in their members are responsible for rare diseases named chromatinopathies. We argue that chromatin condensates, in concert with the nuclear lamina, may also govern the nuclear mechanical properties affecting the cellular response to external cues. (shrink)

Pleiotropy, in which one mutation causes multiple phenotypes, has traditionally been seen as a deviation from the conventional observation in which one gene affects one phenotype. Epistasis, or gene–gene interaction, has also been treated as an exception to the Mendelian one gene–one phenotype paradigm. This simplified perspective belies the pervasive complexity of biology and hinders progress toward a deeper understanding of biological systems. We assert that epistasis and pleiotropy are not isolated occurrences, but ubiquitous and inherent properties of biomolecular (...) networks. These phenomena should not be treated as exceptions, but rather as fundamental components of genetic analyses. A systems level understanding of epistasis and pleiotropy is, therefore, critical to furthering our understanding of human genetics and its contribution to common human disease. Finally, graph theory offers an intuitive and powerful set of tools with which to study the network bases of these important genetic phenomena. (shrink)

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)‐based “active genetic” elements developed in 2015 bypassed the fundamental rules of traditional genetics. Inherited in a super‐Mendelian fashion, such selfish genetic entities offered a variety of potential applications including: gene‐drives to disseminate gene cassettes carrying desired traits throughout insect populations to control disease vectors or pest species, allelic drives biasing inheritance of preferred allelic variants, neutralizing genetic elements to delete and replace or to halt the spread of gene‐drives, split‐drives with the core (...) constituent Cas9 endonuclease and guide RNA (gRNA) components inserted at separate genomic locations to accelerate assembly of complex arrays of genetic traits or to gain genetic entry into novel organisms (vertebrates, plants, bacteria), and interhomolog based copying systems in somatic cells to develop tools for treating inherited or infectious diseases. Here, we summarize the substantial advances that have been made on all of these fronts and look forward to the next phase of this rapidly expanding and impactful field. (shrink)

Between Theory and Interpretation of the Hereditary Transmission Process of Mental Disease. The Introduction of Mendelism in German and North American Psychiatry, 1911–19301911 saw the beginning of decisive developments in psychiatric genetic research. During that year, two expert papers dealing with the application of the Mendelian Theory were published in Germany and in the United States. Only a decade after the “rediscovery” of the Mendelian Laws simultaneous efforts were being made to better understand the hereditary transmission process of (...) mental diseases by means of the Mendelian Theory. The results of these efforts were disparate. While in the United States, the Mendelian theory was used to support the polymorphous theory of the hereditary transmission process of mental diseases, by which a common hereditary origin of mental diseases was assumed, the introduction of Mendelism in psychiatry in Germany focused on corroborating Emil Kraepelin’s concept of a disease entity. The Mendelian Theory especially helps to underpin the idea of a specific genetic origin of the clinical diseases described by Kraepelin. As German and North American psychiatric genetics were inspired by diverse disease and genetic concepts, so too was their use of the Mendelian Theory very divergent. Research linked to the use of the Mendelian Theory was both dissimilar and hotly contested. This was due to the fact that it was difficult, if not impossible to identify Mendelian patterns by studying the hereditary transmission process. As a result, the approach of studying the genetic basis of mental diseases was further developed in Germany. (shrink)

Between Theory and Interpretation of the Hereditary Transmission Process of Mental Disease. The Introduction of Mendelism in German and North American Psychiatry, 1911–19301911 saw the beginning of decisive developments in psychiatric genetic research. During that year, two expert papers dealing with the application of the Mendelian Theory were published in Germany and in the United States. Only a decade after the “rediscovery” of the Mendelian Laws simultaneous efforts were being made to better understand the hereditary transmission process of (...) mental diseases by means of the Mendelian Theory. The results of these efforts were disparate. While in the United States, the Mendelian theory was used to support the polymorphous theory of the hereditary transmission process of mental diseases, by which a common hereditary origin of mental diseases was assumed, the introduction of Mendelism in psychiatry in Germany focused on corroborating Emil Kraepelin’s concept of a disease entity. The Mendelian Theory especially helps to underpin the idea of a specific genetic origin of the clinical diseases described by Kraepelin. As German and North American psychiatric genetics were inspired by diverse disease and genetic concepts, so too was their use of the Mendelian Theory very divergent. Research linked to the use of the Mendelian Theory was both dissimilar and hotly contested. This was due to the fact that it was difficult, if not impossible to identify Mendelian patterns by studying the hereditary transmission process. As a result, the approach of studying the genetic basis of mental diseases was further developed in Germany. (shrink)

On September 27, 2016 people across the world looked down at their buzzing phones to see the AP Alert: “Baby born with DNA from 3 people, first from new technique.” It was an announcement met with confusion by many, but one that polarized the scientific community almost instantly. Some celebrated the birth as an advancement that could help women with a family history of mitochondrial diseases prevent the transmission of the disease to future generations; others held it unethical, citing (...) medical tourism and consequences for the future of the therapy. The child in question was actually born a few months earlier on April 6, 2016, but the research was published a few months later in the October edition of Fertility and Sterility. The mother carries DNA that could have given the baby Leigh Syndrome, a severe neurological disorder characterized by psychomotor regression that typically results in death between ages two and three.[1] Also known as subacute necrotizing encephalomyelopathy, Leigh Syndrome is caused by genetic mutations in mitochondrial DNA, which causes defective oxidative phosphorylation. Because people with this condition cannot re-form ATP, “demyleniation, gliosis, necrosis, spongiosis, or capillary proliferation”[2] can occur, thereby producing bilateral lesions across the central nervous system. The 36-year-old mother previously had four miscarriages and successfully birthed two children, both of whom survived less than six years due to the syndrome. For religious reasons, the mother opted for Spindle Nuclear Transfer instead of Pronuclear Transfer,[3] which many religious organizations oppose because it entails the destruction of fertilized eggs.[4] In Pronuclear Transfer, both the parent and donor egg are fertilized. The parent’s nuclear material is then removed from the egg containing mutated mitochondria and inserted into the fertilized donor egg—from which the original nuclear material has been removed and destroyed. Spindle Nuclear Transfer, on the other hand, removes the mother’s nuclear material from the egg with unhealthy mitochondria, then implants it into a donor’s egg. The newly created egg is then fertilized with the father’s sperm. This Spindle Nuclear Transfer was performed in Mexico by a team of doctors led by Dr. John Zhang, the founder of the New Hope Fertility Center in New York City. In their report, the doctors outline that five oocytes were successfully reconstituted, four of which developed into blastocysts. Only one was euploid: containing 46 XY chromosomes. Researchers then biopsied that blastocyst and found that the transmission rate of maternal mtDNA was, “5.10 ± 1.11% and the heteroplasmy level for 8993T>G was 5.73%.”[5] This indicates that at the blastocyst stage, around five percent of the mitochondria are from the original maternal egg with the mutation for Leigh Syndrome. After birth, they biopsied different tissues and found that they had an average of less than 1.60 ± 0.92% of transmitted mtDNA from the original maternal egg. The baby is reportedly doing well and the team of doctors concluded that “[h]uman oocytes reconstituted by SNT are capable of producing a healthy live birth. SNT may provide a novel treatment option in minimizing pathogenic mtDNA transmission from mothers to their babies."[6] Even when considered theoretically, Spindle Nuclear Transfer is controversial. Many doctors believe that the risks at this stage of research are too great. Dr. Trevor Stammers, a bioethicist at St. Mary’s University in London, points out: “We do not yet have a clear picture of the interaction between nuclear DNA and mitochondria.”[7] Others hold that faulty mitochondrial DNA can still be transferred during the procedure. Still more argue this technology could create problems because of germline modification.[8] Dr. Paul Knoepfler, a cell biologist at the UC Davis School of Medicine, explains: “Since this is uncharted territory and the children born from this technology would have heritable genetic changes, there are also significant unknown risks to future generations.”[9] However, proponents counter these arguments. They say the benefits outweigh the risks, as “mitochondrial replacement techniques [like Spindle Nuclear Transfer] would eliminate maternal transmission of mitochondrial disease… allowing a woman with a family history of mitochondrial diseases to ensure her children would not be affected.”[10] Additionally, experts say that no symptoms will occur if less than 20% of the transferred mitochondrial DNA is faulty.[11] And while opponents see potential germline modification as a problem, advocates answer that this could stop a family history of mitochondrial disease, which they deem a more serious concern. In this case specifically, however, there are more issues at hand. While the team of doctors did eliminate the possibility of germline modification by selecting a male embryo, there are other ethical concerns. Some argue that this case could be described as “medical tourism.” While New Hope Medical Clinic does maintain a branch in Mexico, Dr. Zhang stated that Mexico has “no rules.”[12] It is a country with underdeveloped regulations, making it difficult to confirm that doctors adhere to widely-held medical and ethical standards. Furthermore, while it is highly unlikely that the child will develop Leigh’s Syndrome, Dr. Dietrich Egli of the New York Stem Cell Foundation says the 5% mitochondrial transfer rate indicates that the technique “was not carried out well.”[13] He points to studies of embryos where the rate of mtDNA transfer was almost ten times lower. Spindle Nuclear Transfer is currently legal in the UK,[14] and many are hoping to see it legalized in the US, although Congress currently prohibits the FDA from considering applications that would entail trials in people.[15] While Dr. Zhang’s work is arguably revolutionary, many wonder if the manner in which this study was performed—in Mexico and with a high mitochondrial transfer rate—will impact the technology’s future in the US. Last week, Dr. Zhang presented the report to scientists gathered in Salt Lake City, saying that while science isn’t a race, it is “in a sense, a race for the family to find a cure, to find hope.”[16] Only time will tell if this study set back other families racing and hoping for a cure. References 1. "Leigh Syndrome." Genetics Home Reference, US National Library of Medicine, 25 Oct. 2016. Accessed 26 Oct. 2016. 2. McKusick, Victor A., and Ada Hamosh. "LEIGH SYNDROME; LS." Online Mendelian Inheritance in Man, Johns Hopkins University, 20 Jan. 2016. Accessed 30 Oct. 2016. 3. Zhang, J, H Liu, S Luo, A Chavez-Badiola, and Z Liu. "First live birth using human oocytes reconstituted by spindle nuclear transfer for mitochondrial DNA mutation causing Leigh syndrome." Fertility and Sterility, vol. 106, no. 3, 2016, pp. e375-76. Accessed 30 Oct. 2016. 4. Sample, Ian. "‘Three-parent’ babies explained: what are the concerns and are they justified?" The Guardian, 2 Feb. 2015. Accessed 30 Oct. 2016. 5. Zhang, et al. 6. Ibid. 7. Knapton, Sarah. "Three-parent babies: the arguments for and against." The Telegraph, 3 Feb. 2015. 8. Ibid. 9. Ibid. 10. "Mitochondrial Replacement Therapy FAQs." New York Stem Cell Foundation Research Institute, New York Stem Cell Foundation. Accessed 30 Oct. 2016. 11. Reardon, Sara. "‘Three-parent baby’ claim raises hopes — and ethical concerns." Nature, 28 Sept. 2016. Accessed 30 Oct. 2016. 12. Hamzelou, Jessica. "Exclusive: World’s first baby born with new “3 parent” technique." New Scientist, 27 Sept. 2016. Accessed 30 Oct. 2016. 13. Reardon, Sara. "‘Three-parent baby’ claim raises hopes — and ethical concerns." Nature, 28 Sept. 2016. Accessed 30 Oct. 2016. 14. "3-Person IVF: A Resource Page." Center for Genetics and Society, 24 Oct. 2016. Accessed 30 Oct. 2016. 15. Ritter, Malcolm. "Baby born with DNA from 3 people, first from new technique." Associated Press, 27 Sept. 2016. Accessed 30 Oct. 2016. 16. Chen, Daphne. "Controversy swirls around first three-parent baby." Deseret News, 19 Oct. 2016. Accessed 30 Oct. 2016. Works consulted Swetlitz, Ike. "FDA urged to approve ‘three-parent embryos,’ a new frontier in reproduction." STAT, 3 Feb. 2016. Accessed 30 Oct. 2016. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:What Is Psychiatry About?Dominic Murphy, PhD (bio)There are no such things as minds, but there are animate objects who behave differently from other types of natural entity. They move around under their own power, and some of their activity seems to be very different from that of other natural objects. Furthermore, some of our predictions about these objects are disproved in interesting ways; if we make a false prediction (...) we do not revise our best theory about how such things generally behave, but we instead conclude that there is something wrong with the object of the prediction. These intelligent unpredictable things need a special vocabulary, and mental talk has arisen to serve as that vocabulary. But since a mind is not a thing in nature we face the problem of saying what the sciences of the mind are actually about.There are, then, intelligent systems that can be judged pathological, and some of them are our conspecifics. It is fair to say that there is no agreement about how such judgments are made or should be made. The question of what a mental illness is part of this larger picture, and it raises several different issues.First, how should we think about our practices of judging deviance? It would be contrary to accepted practice to wear a swimsuit to a state funeral, but what sort of norms would it violate and what state of mind would we ascribe to somebody who did it? Second, what is the difference between a judgment of deviance and a judgment of pathology? We have many ways of distinguishing between types of deviance, and the lines between criminality, immorality and pathology, to take three examples, are not always easy to discern. Third, what makes an illness a mental illness? This is Gough's topic, and I will get to it in a moment, but it worth situating it within this broader framework which asks what we are doing when we make these judgments of norm-violation.Gough begins by quite correctly pointing out that if we look at the domain of psychiatry as currently understood, we would have a hard time seeing what it is supposed to be the science of. It is customary to see psychiatry as dealing with the mental but, as Gough notes, there are some mental processes that psychiatry does not deal with, and some processes that psychiatry deals with that are not mental. Gough's response to this problem is a very interesting one, which starts from the idea that the point of psychiatry is to help those who need it; how different do things look if we start from this position? Conley and Glackin (2021) argues that the practical and therapeutic aspirations of psychiatry should constrain our understanding of mental illness. Glackin argues that we should [End Page 41] see this 'norms-first' view, as I will call it, as part of a broader liberal-democratic conversation about the ways in which we should live togetherA view that starts with norms is typically opposed to the 'naturalist' position. A naturalist begins with positive facts as the basis for diagnostic concepts, on the grounds that our concepts of disease and health are supposed to answer to facts about the physical and mental constitution of human beings. Gough's view is neither a norms-first view or a naturalist's view. We could call it an institutionalist view, or, if we were being a bit less kind, an ostensive one—"these things here, that's mental illness."David Hull (1988) taught us that every science (indeed, every intellectual formation or tradition) needs to be understood in two ways. First, we have the theoretical commitments that are taken to define it. Second, there are the practices and institutions that separate its practitioners off from others. Contemporary evolutionary biology, for instance, is built on the twin foundations of the modern synthesis—Darwinian natural selection and Mendelian genetics. These two theoretical commitments have been transformed and adapted and supplemented in diverse ways so that their modern forms no longer resemble their originals very closely. Still, they continue as the central undertakings about the nature of the living world that modern... (shrink)

The ArgumentPressures to lower health-care costs remain an important stimulus to eugenic approaches. Prenatal diagnosis followed by abortion of affected fetuses has replaced sterilization as the major eugenic technique. Voluntary acceptance has replaced coercion, but subtle pressures undermine personal autonomy. The failure of the old eugenics to accurately predict who will have affected offspring virtually disappears when prenatal diagnosis is used to predict Mendelian disorders. However, when prenatal diagnosis is used to detect inherited susceptibilities to adult-onset, common, complex disorders, (...) considerable uncertainty is inherent in the prediction. Intolerance and the resurgence of genetic determinism are current pressures for a eugenic approach. The increasing use of carrier screening and of prenatal diagnosis could itself generate intolerance for those who refuse the procedures. Genetic determinism deflects society from social action that would reduce the burden of disease far more than even the maximum use of eugenics. (shrink)

From the standpoint of the theory of medicine, a formulation is given of three types of reasoning used by physicians. The first is deduction from probability models (as in prognosis or genetic counseling for Mendelian disorders). It is a branch of mathematics that leads to predictive statements about outcomes of individual events in terms of known formal assumptions and parameters. The second type is inference (as in interpreting clinical trials). In it the arguments from replications of the same process (...) (data) lead to conclusions about the parameters of a system, without calling into question either the probabilistic model or the criteria of evidence. The third is illation (as in the elucidation of symptoms in a patient). It is a process whereby, in the light of the total evidence and the conclusions from the other types of reasoning, one may modify, expand, simplify or demolish a conceptual framework proposed for deductions, and modify the nature of the evidence sought, the criteriology, the axioms, and the surmised complexity of the scientific theory. (The process of diagnosis as applied to a patient may in extreme cases lead to the discovery of an entirely new disease with its own, quite new, set of diagnostic criteria. This course cannot be accommodated inside either of the other two types of reasoning.) Illation has something of the character of Kuhn's scientific revolution in physics; but it differs in that it is the nature, not the degree or frequency of change that distinguishes it from Kuhn's normal science. (shrink)

Incomplete penetrance and variable expressivity are non‐Mendelian phenomena resulting in the lack of correlation between genotype and phenotype. Not withstanding the diversity in mechanisms, differential expression of homologous alleles within cells manifests as variations in penetrance and expressivity of mutations between individuals of the same genotype. These phenomena are seen most often in dominantly inherited diseases, implying that they are sensitive to concentration of the gene product. In this framework and the advances in understanding the role of microRNA (...) (miRNA) in fine‐tuning gene expression at translational level, we propose miRNA‐mediated regulation as a mechanism for incomplete penetrance and variable expressivity. The presence of miRNA binding sites at 3′ UTR, co‐expression of target gene–miRNA pairs for genes showing incomplete penetrance and variable expressivity derived from available data lend support to our hypothesis. Single nucleotide polymorphisms in the miRNA target site facilitate the implied differential targeting of the transcripts from homologous alleles. (shrink)

The ArgumentMany associations have recently been discovered between phenotypic variation and genetic loci, causing some to advocate what Robert Sinsheimer has called “a new eugenics” that would treat genetic “defects” in individuals prone to a disease. The first premise of this vision is that genetic association studies reveal the biological cause of the phenotypic variation. Once the responsible genes are known, the second premise is that we should focus upon changing “nature” rather than “nurture” by correcting the “defective” genes.The first (...) premise is flawed because associations between genetic markers and phenotypes can be spurious, as shown by an example. Moreover, it is shown that using non-causative but associated genetic markers one at a time (the normal practice) can lead to incorrect predictions of disease risk for many individuals. Going from association to causation is a non-trivial step scientifically that has rarely been done in much of the human genetic research.Even when a particular locus does contribute to the phenotypic variation of interest, the first premise remains flawed because phenotypes in general arise from complex interactions among genes and between genes and environments as shown for genes associations with coronary artery disease (CAD). The ability of current molecular genetic tools to “fix” defective genotypes is extremely limited, but even if the technological problems could be overcome, the studies on CAD reveal no obvious “defective” gene to fix because the genetic effects are so context dependent (upon both other genes and environmental factors). Contrary to the second premise of the new eugenics, the more we learn about how different genotypes show variable responses to environments, themoreimportant the environment becomes for individual treatment.The paradigm of a “defective gene” may work for classical Mendelian genetic diseases that are due to loss-of-function mutations. However, such mutations affect only a small portion of humanity. When the focus is changed to common disease and behavioral phenotypes, the “defective gene” paradigm is biologically meaningless and often harmful when applied to individuals. Thus, even when genes clearly do influence common phenotypic variation, the premises of the “new eugenics” are biologically indefensible. (shrink)

Causation has multiple distinct meanings in genetics. One reason for this is meaning slippage between two concepts of the gene: Mendelian and molecular. Another reason is that a variety of genetic methods address different kinds of causal relationships. Some genetic studies address causes of traits in individuals, which can only be assessed when single genes follow predictable inheritance patterns that reliably cause a trait. A second sense concerns the causes of trait differences within a population. Whereas some single genes (...) can be said to cause population-level differences, most often these claims concern the effects of many genes. Polygenic traits can be understood using heritability estimates, which estimate the relative influences of genetic and environmental differences to trait differences within a population. Attempts to understand the molecular mechanisms underlying polygenic traits have been developed, although causal inference based on these results remains controversial. Genetic variation has also recently been leveraged as a randomizing factor to identify environmental causes of trait differences. This technique—Mendelian randomization—offers some solutions to traditional epidemiological challenges, although it is limited to the study of environments with known genetic influences. (shrink)

According to a classical narrative, early geneticists, failing to see how Mendelism provides the missing pieces of Darwin’s theory, rejected gradual changes and advocated an implausible yet briefly popular view of evolution-by-mutation; after decades of delay (in which synthesis was prevented by personal conflicts, disciplinary rivalries, and anti-Darwinian animus), Darwinism emerged on a new Mendelian basis. Based on the works of four influential early geneticists – Bateson, de Vries, Morgan and Punnett –, and drawing on recent scholarship, we offer (...) an alternative that turns the classical view on its head. For early geneticists, embracing discrete inheritance and the mutation theory (for the origin of hereditary variation) did not entail rejection of selection, but rejection of Darwin’s non-Mendelian views of heredity and variation, his doctrine of natura non facit saltum, and his conception of “natural selection” as a creative force that shapes features out of masses of infinitesimal differences. We find no evidence of a delay in synthesizing mutation, rules of discrete inheritance, and selection in a Mendelian-Mutationist Synthesis. Instead, before 1918, early geneticists had conceptualized allelic selection, the Hardy–Weinberg equilibrium, the evolution of a quantitative trait under selection, the probability of fixation of a new mutation, and other key innovations. Contemporary evolutionary thinking seems closer to their more ecumenical view than to the restrictive mid-twentieth-century consensus known as the Modern Synthesis. (shrink)

Deutsche Krankheit: eine Diagnosestellung mit Rückblick und Ausblick auf Krankheitsverlauf.

DISEASE X is the codename given by the World Health Organisation to a pathogen currently unknown to science that could cause havoc to humankind. Emerging infections are sending us multiple warnings that another Disease X is looming. We've had SARS in 2002, H5N1 bird flu in 2004, H1N1 'swine flu' in 2009, MERS in 2012, Ebola in 2014, Zika in 2015 and now COVID-19. These events are not freak events, but are happening continually, and at an increasing cadence. Written by (...) a long-standing ex-Reuters global health and science correspondent, DISEASE X will use privileged access to the body leading international efforts to control viruses, the Coalition for Epidemic Preparedness Innovations (CEPI), and its CEO, Dr Richard Hatchett. CEPI seed-funded three successful COVID vaccines, including Astra-Zeneca and Moderna. DISEASE X will explore the emergence of the novel coronavirus and the crisis it caused, analysing the responses of global health organisations and experts, including the WHO, national governments such as Britain, China and the USA, COVAX, the global vaccine allocation facility, pharmaceutical companies, and leading research scientists. Weaving in insights from the likes of Bill Gates, Sir Jeremy Farrar, Dr Anthony Fauci and Sir Patrick Vallance, the book will explain how the world's public health scientists are embarking on a 100 Days Mission to snuff out future threats before they become deadly pandemics. This is the inside story written for the public. (shrink)

SummaryIt is argued that Hugo de Vries's conversion to Mendelism did not agree with his previous theoretical framework. De Vries regarded the number of offspring expressing a certain character as a hereditary quality, intrinsic to the state of the pangene involved. His was a shortlived conversion since after the ‘rediscovery’ he failed to unify his older views with Mendelism. De Vries was never very much of a Mendelian. The usual stories of the Dutch ‘rediscovery’ need, therefore, a considerable reshaping.

‘Twelve Step' recovery programmes such as Alcoholics Anonymous teach that an alcoholic, or other addict, has a disease, and needs to accept that she is ‘powerless' over her addiction before recovery can begin. However, the disease model of addiction has been criticised on the grounds that some addicts recover without external intervention. This critique is questionable, not because such recovery does not occur, but because many genuine diseases are self-limiting. However, the disease model is better criticised on other grounds. (...) Central here is the idea of powerlessness. This article explores various supposed instances of powerlessness, including that induced by extreme fear, provocation and obsessive-compulsive disorder. It is argued that while addiction is a genuine phenomenon, it is strictly inaccurate to describe it as a lack of power. However, there is a deeper sense in which the autonomy of addicts is compromised, although this does not show that addiction is a disease. (shrink)

Philosophical debates about the concept of disease, particularly of mental disease, might benefit from reconsideration and a closer look at the established terminology and conceptual structure of contemporary medical pathology and clinical nosology. The concepts and principles of medicine differ, to a considerable extent, from the ideas and notions of philosophical theories of disease. In medical theory, the concepts of disease entity and pathologicity are, besides the concept of disease itself, of fundamental importance, and they are essentially connected to the (...) concepts cause of disease or etiological factor, natural course or natural history of disease, and pathological disposition. It is the concept of disease entity that is of key importance for understanding medical pathology and theory of disease. Its central role is shown by a short reconstruction of its main features and its intrinsic connection to the concept of pathologicity. The meaning of pathologicity is elucidated by explicating the underlying criteria. (shrink)

Summary In 1979, Robert C. Olby published an article titled ?Mendel no Mendelian??, in which he questioned commonly held views that Gregor Mendel (1822?1884) laid the foundations for modern genetics. According to Olby, and other historians of science who have since followed him, Mendel worked within the tradition of so-called hybridists, who were interested in the evolutionary role of hybrids rather than in laws of inheritance. We propose instead to view the hybridist tradition as an experimental programme characterized by (...) a dynamic development that inadvertently led to a focus on the inheritance of individual traits. Through a careful analysis of publications on hybridization by Carl Linnaeus (1707?1778), Joseph Gottlieb Koelreuter (1733?1806), Carl Friedrich Gärtner (1772?1850), and finally Mendel himself, we will show that this development consisted in repeated reclassifications of hybrids to accommodate anomalies, which in the end allowed Mendel to draw analogies between whole organisms, individual traits, and ?elements? contained in reproductive cells. Mendel's achievement was a product of normal science, and yet a revolutionary step forward. This also explains why, in 1900, when the report he gave on his experiments was ?rediscovered?, Mendel could be read as a ?Mendelian? (shrink)

Neglected diseases are severe conditions that mainly affect the world's poorest people. Those suffering from neglected diseases are mostly suffering from tropical infections that have failed to receive priority in pharmaceutical research and development programs, as well as in public health policies aimed at improving availability and access to preventive, diagnostic and curative medicine. The World Health Organization has issued a number of documents directing attention to the plight affecting one third of the world's population, assisted by active (...) support from private organizations, notably the Bill and Melissa Gates Foundation, but the overall situation remains dismal. In the wake of major socioeconomic processes including globalization, steadily growing economic disparity, healthcare inequality, the instability created by rogue states and terrorism, as well as massive migration, and epidemic outbreaks, the features of neglected diseases have been changing. Neglected populations affected by tropical diseases are suffering increasingly from non-infectious degenerative conditions and disabilities due to untreated chronic maladies. Pockets of poverty and neglect can also be detected in high-income countries, contributing to the emergence of new diseases and the reemergence of infections believed to be disappearing such as tuberculosis and the measles. Included in the issues of neglect are rare diseases, mostly of genetic origin, affecting a small number of patients that suffer from multiple life-shortening functional impairment and organ defects. Effective medicines are extremely expensive, allegedly because research and development of appropriate drugs is resources and time consuming, requiring exorbitant prices to recoup investment from a small number of consumers. Bioethics has been tardy in addressing the suffering and destitution of neglected and rare diseases. Convinced that permanently repeated denunciations blunt the sensitivity towards suffering, whereas statistics are bloodless and unable to elicit commitment, this book attempts to explore a different strategy. In an upstream approach, bioethics needs to engage in ethnographic fieldwork that confronts and shares the context in which people suffer, vividly presenting what epidemiological research has blunted into statistical data. Additionally, a downstream approach is suggested, requiring bioethics to vigorously and openly denounce unethical biomedical and pharmaceutical research, misdeeds in registration and marketing of drugs, and misalignment of policies with the unmet healthcare needs of the destitute. More than being critical observers, bioethicists ought to shed lurking conflicts of interests and seek active participation in planning research and public healthcare practices aimed at improving the lives of medically neglected populations. (shrink)

The target article by Charney on behavior genetics/genomics discusses how numerous molecular factors can inform heritability estimations and genetic association studies. These factors find application in the search for genes for behavioral phenotypes, including neuropsychiatric disorders. We elaborate upon how single causal factors can generate multiple phenotypes, and discuss how multiple causal factors may converge on common neurodevelopmental mechanisms.

Philosophers have proposed various kinds of relations between Mendelian genetics and molecular biology: reduction, replacement, explanatory extension. This paper argues that the two fields are best characterized as investigating different, serially integrated, hereditary mechanisms. The mechanisms operate at different times and contain different working entities. The working entities of the mechanisms of Mendelian heredity are chromosomes, whose movements serve to segregate alleles and independently assort genes in different linkage groups. The working entities of numerous mechanisms of molecular biology (...) are larger and smaller segments of DNA plus related molecules. Discovery of molecular DNA mechanisms filled black boxes that were noted, but unilluminated, by Mendelian genetics. (shrink)

This article critically interrogates contemporary forms of addiction medicine that are portrayed by policy-makers as providing a ‘rational’ or politically neutral approach to dealing with drug use and related social problems. In particular, it examines the historical origins of the biological facts that are today understood to provide a foundation for contemporary understandings of addiction as a ‘disease of the brain’. Drawing upon classic and contemporary work on ‘styles of thought’, it documents how, in the period between the mid-1960s and (...) the mid-1970s, such facts emerged in relation to new neurobiological styles of explaining and managing social problems associated with drug abuse, and an alliance between a relatively marginal group of researchers and American policy-makers who were launching the ‘War on Drugs’. Beyond illustrating the political and material conditions necessary for the rise of addiction neuroscience, the article highlights the productivity of neurobiological thought styles, by focusing on the new biological objects, treatments and hopes that have emerged within the field of addiction studies over the last several decades. (shrink)

Mendelian Inheritance in Man, a computerized catalogue of human genetic disorders authored and maintained by cardiologist and medical genetics pioneer Victor A. McKusick, played a major part in demarcating between a novel biomedical science and the eugenic projects of racial betterment which existed prior to its emergence. Nonetheless, it built upon prior efforts to systematize genetic knowledge tied to individuals and institutions invested in eugenics. By unpacking the process of digitizing a homespun cataloguing project and charting its development into (...) an online database, this article aims to illuminate how the institution-building efforts of one individual created an ‘information order’ for accessing genetic information that tacitly shaped the norms and priorities of the field toward the pursuit of specific genes associated with discernible genetic disorders. This was not by design, but rather arose through negotiation with the catalogue's users; it accommodated further changes as biomedical research displaced the Mendelian paradigm. While great effort was expended toward making sequence data available to investigators during the Human Genome Project, MIM was largely taken for granted as a ‘legacy system’, McKusick's own labour of love. Drawing on recent histories of biomedical data, the article suggests that the bibliographical work of curation and translation is a central feature of value production in the life sciences meriting attention in its own right. (shrink)

This paper examines what it is for a condition to be a disease. It falls into two sections. In the first I examine the best existing account of disease (as proposed by Christopher Boorse) and argue that it must be rejected. In the second I outline a more acceptable account of disease. According to this account, by disease we mean a condition that it is a bad thing to have, that is such that we consider the afflicted person to have (...) been unlucky, and that can potentially be medically treated. All three criteria must be fulfilled for a condition to be a disease. The criterion that for a condition to be a disease it must be a bad thing is required to distinguish the biologically different from the diseased. The claim that the sufferer must be unlucky is needed to distinguish diseases from conditions that are unpleasant but normal, for example teething. Finally, the claim that for a condition to be a disease it must be potentially medically treatable is needed to distinguish diseases from other types of misfortune, for example economic problems and legal problems. (shrink)

Conceptual analysis of health and disease is portrayed as consisting in the confrontation of a set of criteria—a “definition”—with a set of cases, called instances of either “health” or “ disease.” Apart from logical counter-arguments, there is no other way to refute an opponent’s definition than by providing counter-cases. As resorting to intensional stipulation is not forbidden, several contenders can therefore be deemed to have succeeded. This implies that conceptual analysis alone is not likely to decide between naturalism and normativism. (...) An alternative to this approach would be to examine whether the concept of disease can be naturalized. (shrink)

We may now ask the question: In what historical perspective should we place the work of Richard Goldschmidt? There is no doubt that in the period 1910–1950 Goldschmidt was an important and prolific figure in the history of biology in general, and of genetics in particular. His textbook on physiological genetics, published in 1938, was an amazing compendium of ideas put forward in the previous half-century about how genes influence physiology and development. His earlier studies on the genetic and geographic (...) distribution of the various species and races of Lymantria contributed soundly to an understanding of the inheritance and development of sex, as well as the genetics of speciation. He was a curious mixture of the experimentalist, empiricist, and theorizer, who could grasp both the large and the small at once and wrap them into the same integrated and coherent package.In insisting on trying to relate genetics to development, Goldschmidt was continually forced to speculate and to forsake experimental fact for generalized theory. In refusing to reconcile a physiological and developmental conception with a corpuscular theory of the gene, he forced himself to substitute for a large body of experimentally verified evidence, vague and general speculations which did not lead in any precise direction. L. C. Dunn summarizes succinctly the effect of Goldschmidt's thinking on the development of genetic theory: Although Goldschmidt's ideas had a considerable influence in directing attention to the developmental processes intervening between genes and characters, they did not lead to the establishment of a general theory of development in genetical terms. In fact, at the end of the period, as signalized by Goldschmidt's book of 1938 [Physiological Gentics] doubt remained whether there was a field with a defined problem which could be identified as developmental genetics.Yet the frequency with which Goldschmidt is cited by later writers suggests that there is a more positive side to his contribution than this. The early Mendelians had recognized the genic constitution of organisms and the Drosophila workers had uncovered in detail the chromosomal mechanism of heredity. These great discoveries were of classical character, solidly based on a multitude of well established facts. By themselves, however, they would not have been sufficient to place genetics in the central position within biology which it was to assume. Beyond the “static” analysis of gene transmission an insight was needed into the dynamic role of genes in cellular physiology, biochemistry, and development. Goldschmidt recognized this aspect and outlined in brilliant generalizations a physiological theory of genetics. Necessarily the prophetic nature of this achievement — romantic in the sense of Ostwald's classification of great scientists and their discoveries — transcended its factual basis. It was the audacity of the theoretician unimpeded by the still scanty data which gave a new focus to biological thought.Some have called Goldschmidt an “obstructionist” in the history of genetics—one whose efforts were largely directed toward useless and continual criticism — challenge for the sake of challenge. As this line of argument goes, time wasted answering Goldschmidt's poorly conceived criticisms could have been better used to pursue new lines of thought within the classical gene theory. Sometimes historians are upbraided for studying the work of such “obstructionists,” or even the work of those whose ideas have later proved to be inadequate. This argument misses the point of history and the lessons which it can teach. Perhaps Goldschmidt did take the time of a number of the classical geneticists who tried to answer his objections to the gene theory; and perhaps many of his own ideas about genes were, by today's view, “wrong.” These are always easier judgments to make by hindsight than at the moment. But that is not the point. Goldschmidt had a considerable influence on his contemporaries, and to dismiss him as an obstructionist because his opponents later proved to be more nearly right, distorts history and obscures significant questions which we might well be asking. It might be valuable to know why Goldschmidt felt compelled to be an iconoclast —and how that impulse, psychological in orgin, led him to overlook critical items of evidence which his opponents considered more carefully. It might also be valuable to try and understand how a contemporary of Goldschmidt or. Morgan really viewed the gene theory — what were its strong and weak point? Such questions are not readily answered by studying the work of only those men who were correct by later standards.Answers to some of the above questions can be gleaned from this study of Goldschmidt — though the first, and most psychologically oriented, question is largely untouched here.On the one hand, Goldschmidt forced classical geneticists to reexamine the foundation of their ideas about the nature, inviolability, and even physical dimensions of genes. He also kept alive the very real problems of gene physiology and its relations to development — a relationship that was given less attention by the Drosophila school in their pursuit of the transmission process. On a broader level he emphasized to the biological community a principle that was in danger of being lost in the enthusiasm surrounding the expansion of the Mendelian-chromosome theory. The point was that all theories in science are transient, logical constructs which should not be held as sacred. Time and again, as the history of science has shown, theories become rigid structures which retard new modes of thought. From Goldschmidt's perspective, the gene theory was in danger of performing just that function, for it was preventing workers from viewing the gene in a functional as well as a structural light.On the other hand, examining the work of critics (or even of outright “obstructionists”) gives the historian an opportunity to observe how the more established community of scholars at some point in time reacts to challenges of its cherished ideas. The fact that many workers in his own day (such as Beadle, Luria, Delbruck, Sturtevant, Bridges, and others), as well as most geneticists today, saw Goldschmidt as having been largely “obstructionist” is useful historical (and/or sociological) data. Clearly, as this paper has tried to show, Goldschmidt's ideas were not all obstructionist, and his viewpoint that genes must be considered functionally was one which was clearly valid, premature as it may have been from an experimental and technique point of view. Perhaps Goldschmidt's major fault was that he developed alternative theories which were not easily testable. Nonetheless, his challenge to a fundamental and established idea brought forth a reaction from many members of the genetic community which indicates how unwilling they were to reconsider the formalized theory on which their work was based. While many of Goldschmidt's criticisms — and particularly his way of making them — arose out of his own idiosyncrasies, they were also a product of his times. His view of the nature of theory-construction, and his rejection of old-style reductionism and mechanism, were part of a growing awareness within the world scientific community that explanations based on reducing complex phenomena to ultimate particles or units were clearly inadequate. The success of the Mendelian-chromosome theory had obscured that fact for many geneticists, but to Goldschmidt it was a point that could not be allowed to pass unnoticed. (shrink)

Rare genetic diseases collectively impact millions of individuals in the United States. These patients and their families share many challenges including delayed diagnosis, lack of knowledgeable providers, and limited economic incentives to develop new therapies for small patient groups. As such, rare disease patients and families often must rely on advocacy, including both self-advocacy to access clinical care and public advocacy to advance research. However, these demands raise serious concerns for equity, as both care and research for a given (...) disease can depend on the education, financial resources, and social capital available to the patients in a given community. In this article, we utilize three case examples to illustrate ethical challenges at the intersection of rare diseases, advocacy and justice, including how reliance on advocacy in rare disease may drive unintended consequences for equity. We conclude with a discussion of opportunities for diverse stakeholders to begin to address these challenges. (shrink)

In this paper I will argue that Aristotelian accounts of disease cannot provide us with an adequate descriptive account of our concept of disease. In other words, they fail to classify conditions as either diseases, or non-diseases, in a way that is consistent with commonplace intuitions. This being said, Aristotelian accounts of disease are not worthless. Aristotelian approaches cannot offer a decent descriptive account of our concept of disease, but they do offer resources for improving on the ways (...) in which we think about the harms that afflict human beings. While they cannot offer an account of ‘disease' they can offer an account of ‘harm'—and this it turns out, is ultimately of greater importance. (shrink)

The concept of disease remains hotly contested. In light of problems with existing accounts, some theorists argue that the disease concept ought to be eliminated. We answer this skeptical challenge by reframing the discussion in terms of the role that the disease concept plays in the complex network of health-care institutions in which it is deployed. We argue that while prevailing accounts do not suffer from the particular defects that critics have identified, they do suffer from other deficits, and this (...) leads us to propose a new account that satisfies the desiderata for a concept of disease in human medicine. (shrink)