Mitochondrial replacement techniques are intended to avoid the transmission of mitochondrial diseases from mother to child. MRT represent a potentially powerful new biomedical technology with ethical, policy, economic and social implications. Among other ethical questions raised are concerns about the possible effects on the identity of children born from MRT, their families, and the providers or donors of mitochondria. It has been suggested that MRT can influence identity directly, through altering the genetic makeup and physical characteristics of the (...) child, or indirectly through changing the child's experience of disease, and by generating novel intrafamilial relationships that shape the sense of self. In this article I consider the plausibility and ethical implications of these proposed identity effects, but I focus instead on a third way in which identity may be affected, through the mediating influence of the wider social world on MRT effects on identity. By taking a narrative approach, and examining the nature and availability of identity narratives, I conclude that while neither direct genetic nor indirect experiential effects can be excluded, social responses to MRT are more likely to have a significant and potentially damaging influence on the generation of MRT children's narratives of identity. This conclusion carries some implications for the collective moral responsibility we hold to ensure that MRT, if implemented, are practised in ethically justifiable ways. (shrink)

This article argues that two forms of mitochondrial replacement therapy, maternal spindle transfer and pro-nuclear transfer, are not therapies at all because they do not treat children who are coming into existence. Rather, these technologies merely create healthy children where none was inevitable. Even if creating healthy lives has some value, it is not to be confused with the medical value of a cure or therapy. The article addresses a recent Bioethics article, ‘Mitochondrial Replacement: Ethics and Identity,’ by (...) Wrigley, Wilkinson, and Appleby, who argue that PNT is morally favorable to MST due to the Non-Identity Problem. Wrigley et al. claim that PNT, since it occurs post-conception, preserves the identity of the resulting child, whereas MST, since it occurs pre-conception, is an identity-altering technique. As such, a child born with mitochondrial disease could complain that her parents failed to use PNT, but not MST. The present article argues that the authors are mistaken: both MST and PNT are identity-affecting techniques. But this is of little matter, for we should be cautious in drawing any moral conclusions from the application of the Non-Identity Problem to cases. The article then argues that the authors are mistaken in inferring that PNT is a type of embryonic cure or therapy for children with mitochondrial disease. The article cautions against the mistaken life-saving rhetoric that is common in bioethics discussions of MRTs. (shrink)

Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin‐converting enzyme (ACE) is the central component of endocrine and local tissue renin–angiotensin systems (RAS), which also regulate diverse aspects of whole‐body metabolism and mitochondrial function (partly through altering mitochondrial UCP expression). We show that ACE expression also appears to be regulated by mitochondrial UCPs. In genetic analysis of two unrelated populations (healthy young UK men and Scandinavian diabetic patients) serum ACE (sACE) activity was significantly higher (...) amongst UCP3‐55C (rather than T) and UCP2 I (rather than D) allele carriers. RNA interference against UCP2 in human umbilical vein endothelial cells reduced UCP2 mRNA sixfold (P < 0·01) whilst increasing ACE expression within a physiological range (<1·8‐fold at 48 h; P < 0·01). Our findings suggest novel hypotheses. Firstly, cellular feedback regulation may occur between UCPs and ACE. Secondly, cellular UCP regulation of sACE suggests a novel means of crosstalk between (and mutual regulation of) cellular and endocrine metabolism. This might partly explain the reduced risk of developing diabetes and metabolic syndrome with RAS antagonists and offer insight into the origins of cardiovascular disease in which UCPs and ACE both play a role. (shrink)

In eukaryotes, folate metabolism is compartmentalized between the cytoplasm and organelles. The folate pathways of mitochondria are adapted to serve the metabolism of the organism. In yeast, mitochondria support cytoplasmic purine synthesis through the generation of formate. This pathway is important but not essential for survival, consistent with the flexibility of yeast metabolism. In plants, the mitochondrial pathways support photorespiration by generating serine from glycine. This pathway is essential under photosynthetic conditions and the enzyme expression varies with photosynthetic activity. (...) In mammals, the expression of the mitochondrial enzymes varies in tissues and during development. In embryos, mitochondria supply formate and glycine for purine synthesis, a process essential for survival; in adult tissues, flux through mitochondria can favor serine production. The differences in the folate pathways of mitochondria depending on species, tissues and developmental stages, profoundly alter the nature of their metabolic contribution. BioEssays 28: 595–605, 2006. © 2006 Wiley Periodicals, Inc. (shrink)

Neither the pathogenesis nor the aetiology of Down's syndrome (DS) are clearly understood. Numerous studies have examined whether clinical features of DS are a consequence of specific chromosome 21 segments being triplicated. There is no evidence, however, that individual loci are responsible, or that the oxidative damage in DS could be solely explained by a gene dosage effect. Using astrocytes and neuronal cultures from DS fetuses, a recent paper shows that altered metabolism of the amyloid precursor protein and oxidative stress (...) result from mitochondrial dysfunction.1 These findings are consistent with considerable data implicating the role of the mitochondrial genome in DS pathogenesis and aetiology. BioEssays 24:681–684, 2002. © 2002 Wiley Periodicals, Inc. (shrink)

Recent preclinical studies have shown the feasibility of specific variants of nuclear transfer to prevent mitochondrial DNA disorders. Nuclear transfer could be a valuable reproductive option for carriers of mitochondrial mutations. A clinical application of nuclear transfer, however, would entail germ-line modification, more specifically a germ-line modification of the mitochondrial genome. One of the most prominent objections against germ-line modification is the fear that it would become possible to alter ‘essential characteristics’ of a future person, thereby possibly (...) violating the child's right to an open future. As only the nuclear DNA would contain the ingredients for individual characteristics, modification of the mtDNA is often considered less controversial than modification of the nuclear DNA. This paper discusses the tenability of this dichotomy. After having clarified the concept of germ-line modification, it argues that modification of the mtDNA is not substantively different from modification of the nuclear DNA in terms of its effects on the identity of the future person. Subsequently the paper assesses how this conclusion affects the moral evaluation of nuclear transfer to prevent mtDNA disorders. It concludes that the moral acceptability of germ-line modification does not depend on whether it alters the identity of the future child—all germ-line modifications do—but on whether it safeguards the child's right to an open future. If nuclear transfer to prevent mtDNA disorders becomes safe and effective, then dismissing it because it involves germ-line modification is unjustified. (shrink)

The tricarboxylic acid (TCA) or Krebs cycle, which takes place in prokaryotic cells and in the mitochondria of eukaryotic cells, is central to life on Earth and participates in key events such as energy production and anabolic processes. Despite its relevance, it is not perceived as tightly regulated compared to other key metabolisms such as glycolysis/gluconeogenesis. A better understanding of the functioning of the TCA cycle is crucial due to mitochondrial function impairment in several diseases, especially those that occur (...) with neurodegeneration. This article revisits what is known about the regulation of the Krebs cycle and hypothesizes the need for large‐scale, rapid regulation of TCA cycle enzyme activity. Evidence of mitochondrial enzyme activity regulation by activation/deactivation of protein kinases and phosphatases exists in the literature. Apart from indirect regulation via G protein‐coupled receptors (GPCRs) at the cell surface, signaling upon activation of GPCRs in mitochondrial membranes may lead to a direct regulation of the enzymes of the Krebs cycle. Hormonal‐like regulation by posttranscriptional events mediated by activable kinases and phosphatases deserve proper assessment using isolated mitochondria. Also see the video abstract here: https://youtu.be/aBpDSWiMQyI. (shrink)

Technical, ethical, and social questions of germ-line gene interventions have been widely discussed in the literature. The majority of these discussions focus on planned interventions executed on the nuclear DNA (nDNA). However, human cells also contain another set of genes that is the mitochondrial DNA (mtDNA). As the characteristics of the mtDNA grossly differ from those of nDNA, so do the social, ethical, psychological, and safety considerations of possible interventions on this part of the genetic substance.

In October 2015 the UK enacted legislation to permit the clinical use of two cutting edge germline-altering, IVF-based embryonic techniques: pronuclear transfer and maternal spindle transfer. The aim is to use these techniques to prevent the maternal transmission of serious mitochondrial diseases. Major claims have been made about the quality of the debates that preceded this legislation and the significance of those debates for UK decision-making on other biotechnologies, as well as for other countries considering similar legislation. In this (...) article we conduct a systematic analysis of those UK debates and suggest that claims about their quality are over-stated. We identify, and analyse in detail, ten areas where greater clarity, depth and nuance would have produced sharper understandings of the contributions, limitations and wider social impacts of these mitochondrial interventions. We explore the implications of these additional considerations for the protection of all parties involved, should the techniques transfer to clinical applications; the legitimacy of focussing on short-term gains for individuals over public health considerations, and the maintenance and improvement of public trust in medical biotechnologies. We conclude that a more measured evaluation of the content and quality of the UK debates is important and timely: such a critique provides a clearer understanding of the possible, but specific, contributions of these interventions, both in the UK and elsewhere; also, these additional insights can now inform the emerging processes of implementation, regulation and practice of mitochondrial interventions. (shrink)

The ribosomal polypeptide tunnel exit is the site where a variety of factors interact with newly synthesized proteins to guide them through the early steps of their biogenesis. In mitochondrial ribosomes, this site has been considerably modified in the course of evolution. In contrast to all other translation systems, mitochondrial ribosomes are responsible for the synthesis of only a few hydrophobic membrane proteins that are essential subunits of the mitochondrial respiratory chain. Membrane insertion of these proteins occurs (...) co‐translationally and is connected to a sophisticated assembly process that not only includes the assembly of the different subunits but also the acquisition of redox co‐factors. Here, we describe how mitochondrial translation is organized in the context of respiratory chain assembly and speculate how alteration of the ribosomal tunnel exit might allow the establishment of a subset of specialized ribosomes that individually organize the early steps in the biogenesis of distinct mitochondrially‐encoded proteins. (shrink)

Inflammatory mediators have an established role in inducing insulin resistance and promoting hyperglycemia. In turn, hyperglycemia has been argued to drive immune cell dysfunction as a result of mitochondrial dysfunction. Here, the authors review the evidence challenging this view. First, it is pointed out that inflammatory mediators are known to induce altered mitochondrial function. In this regard, critical care patients suffer both an elevated inflammatory tone as well as hyperglycemia, rendering it difficult to distinguish between the effects of (...) inflammation and hyperglycemia. Second, emerging evidence indicates that a decrease in mitochondrial respiration and an increase in reactive oxygen species (ROS) production are not necessarily manifestations of pathology, but adaptations taking shape as the mitochondria is abdicating its adenosine triphosphate (ATP)‐producing function (which is taken over by glycolysis) and instead becomes “retooled” for an immunological role. Collectively, these observations challenge the commonly held belief that acute hyperglycemia induces mitochondrial damage leading to immune cell dysfunction. (shrink)

Previous studies have shown that zinc deficiency leads to apoptosis of neuronal precursor cells in vivo and in vitro. In addition to the role of p53 as a nuclear transcription factor in zinc deficient cultured human neuronal precursors (NT-2), we have now identified the translocation of phosphorylated p53 to the mitochondria and p53-dependent increases in the pro-apoptotic mitochondrial protein BAX leading to a loss of mitochondrial membrane potential as demonstrated by a 25% decrease in JC-1 red:green fluorescence ratio. (...) Disruption of mitochondrial membrane integrity was accompanied by efflux of the apoptosis inducing factor (AIF) from the mitochondria and translocation to the nucleus with a significant increase in reactive oxygen species (ROS) after 24 h of zinc deficiency. Measurement of caspase cleavage, mRNA, and treatment with caspase inhibitors revealed the involvement of caspases 2, 3, 6, and 7 in zinc deficiency-mediated apoptosis. Down-stream targets of caspase activation, including the nuclear structure protein lamin and polyADP ribose polymerase (PARP), which participates in DNA repair, were also cleaved. Transfection with a dominant-negative p53 construct and use of the p53 inhibitor, pifithrin- ␮, established that these alterations were largely dependent on p53. Together these data identify a cascade of events involving mitochondrial p53 as well as p53-dependent caspase-mediated mechanisms leading to apoptosis during zinc deficiency. (shrink)

Gene expression activity is heterogeneous in a population of isogenic cells. Identifying the molecular basis of this variability will improve our understanding of phenomena like tumor resistance to drugs, virus infection, or cell fate choice. The complexity of the molecular steps and machines involved in transcription and translation could introduce sources of randomness at many levels, but a common constraint to most of these processes is its energy dependence. In eukaryotic cells, most of this energy is provided by mitochondria. A (...) clonal population of cells may show a large variability in the number and functionality of mitochondria. Here, we discuss how differences in the mitochondrial content of each cell contribute to heterogeneity in gene products. Changes in the amount of mitochondria can also entail drastic alterations of a cell's gene expression program, which ultimately leads to phenotypic diversity. (shrink)

Flavin‐containing monooxygenases (FMOs), traditionally known for detoxifying xenobiotics, are now recognized for their involvement in endogenous metabolism. We recently discovered that an isoform of FMO, fmo‐2 in Caenorhabditis elegans, alters endogenous metabolism to impact longevity and stress tolerance. Increased expression of fmo‐2 in C. elegans modifies the flux through the key pathway known as One Carbon Metabolism (OCM). This modified flux results in a decrease in the ratio of S‐adenosyl‐methionine (SAM) to S‐adenosyl‐homocysteine (SAH), consequently diminishing methylation capacity. Here we discuss (...) how FMO‐2‐mediated formate production during tryptophan metabolism may serve as a trigger for changing the flux in OCM. We suggest formate bridges tryptophan and OCM, altering metabolic flux away from methylation during fmo‐2 overexpression. Additionally, we highlight how these metabolic results intersect with the mTOR and AMPK pathways, in addition to mitochondrial metabolism. In conclusion, the goal of this essay is to bring attention to the central role of FMO enzymes but lack of understanding of their mechanisms. We justify a call for a deeper understanding of FMO enzyme's role in metabolic rewiring through tryptophan/formate or other yet unidentified substrates. Additionally, we emphasize the identification of novel drugs and microbes to induce FMO activity and extend lifespan. (shrink)

Despite abundant evidence associating CD38 overexpression and CD4 T cell depletion in HIV infection, no causal relation has been investigated. To address this issue, a series of mechanisms are proposed, supported by evidence from different fields, by which CD38 overexpression can facilitate CD4 T cell depletion in HIV infection. According to this model, increased catalytic activity of CD38 may reduce CD4 T cells’ cytoplasmic nicotin‐amide adenine dinucleotide (NAD), leading to a chronic Warburg effect. This will reduce mitochondrial function. Simultaneously, (...) CD38's catalytic products ADPR and cADPR may be transported to the cytoplasm, where they can activate calcium channels and increase cytoplasmic Ca2+ concentrations, further altering mitochondrial integrity. These mechanisms will decrease the viability and regenerative capacity of CD4 T cells. These hypotheses can be tested experimentally, and might reveal novel therapeutic targets. (shrink)

Effective therapies are now available that can stop the progression of HIV infection and significantly delay the onset of AIDS. The “highly active antiretroviral therapy” (HAART) is a combination of potent antiretroviral drugs such as viral protease inhibitors or nucleoside-analogue reverse-transcriptase inhibitors, that has a variety of serious side effects, including lipodystrophy, a pathology characterized by accumulation of visceral fat, breast adiposity, cervical fat-pads, hyperlipidemia, insulin resistance as well as fat wasting in face and limbs. There is still an open (...) debate that concerns the precise responsibility of HAART as well as metabolic pathways and mechanisms that are involved in the onset of lipodystrophy. The similarities with multiple symmetric lipomatosis (MSL), in which mitochondria impairment plays a crucial role, lead to the hypothesis that drug-induced damages to mitochondrial DNA are able to alter mitochondria functionality to an extent that is similar to what occurs in MSL. In addition, several evidences indicate that HAART is also linked to a deregulated production of tumour necrosis factor-α, which uses mitochondria as intracellular targets. In this paper, we review data concerning the role of mitochondria in the pathogenesis of lipodystrophy, and advance a unifying hypothesis involving either direct or indirect effects of the drugs employed during HAART. BioEssays 23:1070–1080, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Gliomas can display marked changes in the concentrations of energy metabolism molecules such as creatine (Cr), phosphocreatine (PCr) and lactate, as measured using magnetic resonance spectroscopy (MRS). Moreover, the BOLD (blood oxygen level dependent) contrast enhancement in functional magnetic resonance imaging (fMRI) can be reduced or missing within or near gliomas, while neural activity is not significantly reduced (so-called neurovascular decoupling), so that the location of functionally eloquent areas using fMRI can be erroneous. In this paper, we adapt a previously (...) developed model of the coupling between neural activation, energy metabolism and hemodynamics, by including the venous dilatation Balloon model of Buxton and Frank. We show that decreasing the cerebral blood flow (CBF) baseline value, or the CBF increase fraction, results in a decrease of the BOLD signal and an increase of the lactate peak during a sustained activation. Baseline lactate and PCr levels are not significantly affected by CBF baseline reduction, but are altered even by a moderate decrease of mitochondrial respiration. Decreasing the total Cr and PCr concentration reduces the BOLD signal after the initial overshoot. In conclusion, we suggest that the coupled use of BOLD fMRI and MRS could contribute to a better understanding of the neurovascular and metabolic decoupling in gliomas. (shrink)

Novel technological developments mean that gene editing – making deliberately targeted alterations in specific genes – is now a clinical reality. The inherited metabolic disorders, a group of clinically significant, monogenic disorders, provide a useful paradigm to explore some of the many ethical issues that arise from this technological capability. Fundamental questions about the significance of the genome, and of manipulating it by selection or editing, are reviewed, and a particular focus on the legislative process that has permitted the (...) development of mitochondrial donation techniques is considered. Ultimately, decisions about what we should do with gene editing must be determined by reference to other non-genomic texts that determine what it is to be human – rather than simply to undertake gene editing because it can be done. (shrink)

CB1 receptors are functionally present within brain mitochondria, although they are usually considered specifically targeted to plasma membrane. Acute activation of mtCB1 alters mitochondrial ATP generation, synaptic transmission, and memory performance. However, the detailed mechanism linking disrupted mitochondrial metabolism and synaptic transmission is still uncharacterized. CB1 receptors are among the most abundant G protein-coupled receptors in the brain and impact on several processes, including fear coping, anxiety, stress, learning, and memory. Mitochondria perform several key physiological processes for neuronal (...) homeostasis, including production of ATP and reactive oxygen species, calcium buffering, metabolism of neurotransmitters, and apoptosis. It is therefore possible that acute activation of mtCB1 impacts on these different mitochondrial functions to modulate synaptic transmission. In reviewing and integrating across the literature in this area, we describe the possible mechanisms involved in the regulation of brain physiology by mtCB1 receptors. Activation of mitochondrial CB1 but not of plasma membrane CB1 decreases brain mitochondrial activity, glutamatergic synaptic transmission, and memory performance. Several processes can be involved in this alteration of brain physiology, including mitochondrial ATP and ROS production, axonal mitochondrial transport, Ca2+ homeostasis, and/or metabolism of the neurotransmitter glutamate. (shrink)

Sperm, eggs and embryos are made up of more than genes, and there are indications that changes to non‐genetic structures in these elements of the germline can also be inherited. It is, therefore, a mistake to treat phrases like ‘germline inheritance’ and ‘genetic inheritance’ as simple synonyms, and bioethical discussion should expand its focus beyond alterations to the genome when considering the ethics of germline modification. Moreover, additional research on non‐genetic inheritance draws attention to a variety of means whereby (...) differences can be inherited in offspring generations that do not rely on differences in germline structures. Research on these diverse forms of inheritance challenges the notion that there is some special form of ethical concern that falls on germline interventions in general, and on interventions to the nuclear genome within the germline in particular. (shrink)

This book defends Frank Jackson’s knowledge argument against physicalism. According to physicalism, consciousness is a physical phenomenon. The knowledge argument stars Mary, who learns all objective, physical information through black-and-white media and yet acquires new information when she first sees colors for herself: information about what it is like to see in color. Based partly on that case, Jackson concludes that not all information is physical. The book argues that the knowledge argument succeeds in refuting all standard versions of physicalism: (...) versions on which consciousness is grounded by what objective science reveals. It also argues that given further, plausible assumptions, the knowledge argument leads to Russellian monism, on which there are intrinsic properties that both constitute consciousness and underlie properties physics describes, such as mass and charge. It explains how the knowledge argument establishes those two conclusions and defends the argument against numerous objections. (shrink)

Yoga has come to be an icon of Indian culture and civilization, and it is widely regarded as being timeless and unchanging. Based on extensive ethnographic research and an analysis of both ancient and modern texts, Yoga in Modern India challenges this popular view by examining the history of yoga, focusing on its emergence in modern India and its dramatically changing form and significance in the twentieth century. Joseph Alter argues that yoga's transformation into a popular activity idolized for its (...) health value is based on modern ideas about science and medicine. Alter centers his analysis on an interpretation of the seminal work of Swami Kuvalayananda, one of the chief architects of the Yoga Renaissance in the early twentieth century. From this point of orientation he explores current interpretations of yoga and considers how practitioners of yogic medicine and fitness combine the ideas of biology, physiology, and anatomy with those of metaphysics, transcendence, and magical power. The first serious ethnographic history of modern yoga in India, this fluently written book is must reading not only for students and scholars but also practitioners who seek a deeper understanding of how yoga developed over time into the exceedingly popular phenomenon it is today. (shrink)

Russellian monism offers a distinctive perspective on the relationship between the physical and the phenomenal. For example, on one version of the view, phenomenal properties are the categorical bases of fundamental physical properties, such as mass and charge, which are dispositional. Russellian monism has prominent supporters, such as Bertrand Russell, Grover Maxwell, Michael Lockwood, and David Chalmers. But its strengths and shortcomings are often misunderstood. In this paper we try to eliminate confusions about the view and defend it from criticisms. (...) We present its core and distinguish different versions of it. We then compare these versions with traditional theories, such as physicalism, dualism, and idealism. We also argue that the knowledge argument and the conceivability argument are consistent with Russellian monism and that existing arguments against the view, such as the argument from weirdness, are not decisive. We conclude that Russellian monism is an attractive view that deserves serious consideration. (shrink)

According to Russellian monism, consciousness is constituted at least partly by quiddities: intrinsic properties that categorically ground dispositional properties described by fundamental physics. If the theory is true, then consciousness and such dispositional properties are closely connected. But how closely? The contingency thesis says that the connection is contingent. For example, on this thesis the dispositional property associated with negative charge might have been categorically grounded by a quiddity that is distinct from the one that actually grounds it. Some argue (...) that Russellian monism entails the contingency thesis and that this makes its consciousness‐constituting quiddities epiphenomenal—a disastrous outcome for a theory that is motivated partly by its prospects for integrating consciousness into physical causation. We consider two versions of that argument, a generic version and an intriguing version developed by Robert J. Howell, which he bases on Jaegwon Kim's well‐known “exclusion argument.” We argue that neither succeeds. (shrink)

Consciousness in the Physical World collects historical selections, recent classics, and new pieces on Russellian monism, a unique alternative to the physicalist and dualist approaches to the problem of consciousness.

What is the nature of consciousness? How is consciousness related to brain processes? This volume collects thirteen new papers on these topics: twelve by leading and respected philosophers and one by a leading color-vision scientist. All focus on consciousness in the "phenomenal" sense: on what it's like to have an experience. Consciousness has long been regarded as the biggest stumbling block for physicalism, the view that the mind is physical. The controversy has gained focus over the last few decades, and (...) phenomenal knowledge and phenomenal concepts--knowledge of consciousness and the associated concepts--have come to play increasingly prominent roles in this debate. Consider Frank Jackson's famous case of Mary, the super-scientist who learns all the physical information while confined in a black-and-white room. According to Jackson, if physicalism is true, then Mary's physical knowledge should allow her to deduce what it's like to see in color. Yet it seems intuitively clear that she learns something when she leaves the room. But then how can consciousness be physical? Arguably, whether this sort of reasoning is sound depends on how phenomenal concepts and phenomenal knowledge are construed. For example, some argue that the Mary case reveals something about phenomenal concepts but has no implications for the nature of consciousness itself. Are responses along these lines adequate? Or does the problem arise again at the level of phenomenal concepts? The papers in this volume engage with the latest developments in this debate. The authors' perspectives range widely. For example, Daniel Dennett argues that anti-physicalist arguments such as the knowledge argument are simply confused; David Papineau grants that such arguments at least reveal important features of phenomenal concepts; and David Chalmers defends the anti-physicalist arguments, arguing that the "phenomenal concept strategy" cannot succeed. (shrink)

: Phenomenal knowledge usually comes from experience. But it need not. For example, one could know what it’s like to see red without seeing red—indeed, without having any color experiences. Daniel Dennett (2007) and Pete Mandik (forthcoming) argue that this and related considerations undermine the knowledge argument against physicalism. If they are right, then this is not only a problem for anti‐physicalists. Their argument threatens to undermine any version of phenomenal realism— the view that there are phenomenal properties, or qualia, (...) that are not conceptually reducible to physical or functional properties. I will argue that this threat is illusory. Explaining why will clarify what is and is not at issue in discussions of the knowledge argument and phenomenal realism. This will strengthen the case for physically and functionally irreducible qualia. 2 Phenomenal knowledge usually comes from experience. For example, I know what it’s like to see red because I have done so. Does knowing what it’s like to have an experience with phenomenal character X require having an experience with X? No. A famous counterexample is Hume’s missing shade of blue, in which one can extrapolate from phenomenally similar experiences (A Treatise of Human Nature, Bk. I, Pt. I, Sec. I).1 One might think that a weaker version of the no‐phenomenal‐knowledge‐without‐experience thesis remains tenable, e.g., that knowing what it’s like to see in color requires having or having had color experiences. But this thesis also seems doubtful. Peter Unger (1966) devised plausible counterexamples over four decades ago, and since then others (e.g., Lewis 1988, Alter 1998, Stoljar 2005) have done the same. One could have phenomenal knowledge of color experiences without having such experiences. Indeed, one could have such knowledge without having experiences that are remotely like color experiences. What is the significance of this observation for contemporary debates about consciousness and physicalism? Daniel Dennett (2007) and Pete Mandik (forthcoming) suggest that it undermines the knowledge argument against physicalism.2 That is because they take the claim that someone who has never seen in color could not know what it’s like to see in color to be the basis of the knowledge argument’s main epistemic premise: the premise that (roughly put) 3 no amount of physical knowledge is sufficient for phenomenal knowledge of color experiences. If they are right, then this is not only a problem for anti‐ physicalists. Many physicalists (e.g., Loar 1990/97, Papineau 2002, 2007) accept the knowledge argument’s epistemic premise. Dennett’s and Mandik’s arguments threaten all versions of what David Chalmers (2003) calls phenomenal realism, the view that there are phenomenal properties, or qualia, that are not conceptually reducible to physical or functional properties.3 I will argue that this threat is illusory. Explaining why will clarify what is and is not at issue in discussions of the knowledge argument and phenomenal realism. The net result will be to strengthen the case for physically inexplicable qualia. (shrink)