Signal transducer and activator of transcription 3 (STAT3) is a ubiquitous and pleiotropic transcription factor that plays essential roles in normal development, immunity, response to tissue damage and cancer. We have developed a Venus‐STAT3 bimolecular fluorescence complementation assay that allows the visualization and study of STAT3 dimerization and protein‐protein interactions in living cells. Inactivating mutations on residues susceptible to post‐translational modifications (PTMs)  changed significantly the intracellular distribution of unstimulated STAT3 dimers when the dimers were formed by STAT3 molecules that carried different mutations (ie they were “asymmetric”). Some of these asymmetric dimers changed the proliferation rate of HeLa cells. Our results indicate that asymmetric PTMs on STAT3 dimers could constitute a new level of regulation of STAT3 signaling. We put forward these observations as a working hypothesis, since confirming the existence of asymmetric STAT3 homodimers in nature is extremely difficult, and our own experimental setup has technical limitations that we discuss. However, if our hypothesis is confirmed, its conceptual implications go far beyond STAT3, and could advance our understanding and control of signaling pathways. ATPadenosine triphosphateBiFCbimolecular fluorescence complementationBRETbioluminescence resonance energy transferDICdifferential interference contrastDelCTdeletion of the C‐terminusEGFPenhanced green fluorescent proteinFRETfluorescence resonance energy transferLIFleukemia inhibitory factorPCRpolymerase chain reactionPTMspost‐translational modificationsSDSsodium dodecyl sulfateSTAT3signal transducer and activator of transcription‐3V1Venus 1 (amino acids 1‐158)V2Venus 2 (amino acids 159‐238)1The signal transducer and activator of transcription 3 (STAT3) is a conserved transcription factor that plays key roles in development, immunity, response to injury and cancer.Three ingenious systems have been developed so far to visualize and study STAT3 dimerization in living cells, based on fluorescence resonance energy transfer (FRET),Here, we developed a suit of Venus‐STAT3 BiFC constructs that are not only an important addition to the existing STAT3 toolset, but were also successfully employed to generate an interesting hypothesis on the control of the STAT3 pathway by PTMs. Literature on STAT3 generally assumes that STAT3 homodimers are formed by two identically modified molecules. However, this is highly unlikely in a complex intracellular context, as PTMs do not occur in all the pool of STAT3 molecules at the same time or with the same efficiency. We aimed at determining the relative contribution of residues K49, K140, K685, Y705 and S727 to the dimerization and intracellular distribution of STAT3 homodimers.22.1We developed a suit of plasmids to study STAT3 dimerization in living cells, based on BiFC systems using Venus fragments as a reporter Figure A, as we Incubation with leukemia inhibitory factor LIF, 100 ng/mL) induced STAT3 phosphorylation and translocation to the nucleus in HEK293 and HeLa cells Figure B,C, but 00 ng/mL Naturally occurring STAT3 mutations cause hyper‐immunoglobulin E syndrome or inflammatory hepatocellular adenoma.Taken altogether, our results indicate that the behavior of the Venus‐STAT3 BiFC system is consistent with previous reports for tagged STAT3, and indicates that it could be useful for the analysis of environmental or genetic modifiers of STAT3 dimerization, protein‐protein interactions and intracellular traffic.2.2Next, we tried to elucidate the role that particular residues susceptible to PTMs could play on the dimerization and intracellular localization of STAT3 homodimers without adding exogenous cytokines. The residues chosen were K49, K140, K685, Y705 and S727, susceptible to acetylation, methylation or phosphorylation. The original idea was to establish a baseline for future experiments in the presence of cytokines, which enhance the frequency of these particular PTMs in STAT3. However, low levels of these PTMs in the absence of cytokines have been also described in the literature,2.3Like us, and to the best of our knowledge, the existing scientific literature on STAT3 implicitly assumes that STAT3 homodimers are formed by two identical molecules in all aspects, including PTMs. For example, it is still relatively easy to find articles and reviews where STAT3 is described to homodimerize only upon phosphorylation of both molecules at Y705,We then pooled and analyzed all results according to the number and type of PTM mutations present in each BiFC pair. Combinations carrying any one (asymmetric) or two K‐R substitutions (symmetric or asymmetric) significantly increased mitochondrial translocation, while decreasing the percentage of cells with STAT3 dimers predominantly in the cytoplasm Figure B. AsymmeSignal transducer and activator of transcription 3 contributes to cancer cell survival, proliferation and malignant transformation even in conditions where it is not stimulated by cytokines,3We have developed and validated a new BiFC assay for the visualization and study of STAT3 interactions in living cells. Our system responds as expected to pharmacological activation or inhibition of STAT3, disease‐associated genetic mutations, and potential protein interactors. The Venus‐STAT3 BiFC system is complementary to previously reported FRET,Our results indicate that asymmetric PTMs could constitute a new level of regulation of unstimulated STAT3 behavior and function. We must emphasize that this observation was very surprising and is put forward cautiously as a working hypothesis, rather than a conclusive result. To the best of our knowledge, there is no direct empirical evidence in the literature showing that asymmetrically modified STAT3 dimers actually happen in nature, and such demonstration would be currently extremely difficult from a technical point of view, even in vitro. Previous studies most often rely on systems that do not differentiate between monomers and dimers,Beyond the technical difficulties to confirm the existence of asymmetric STAT3 homodimers in nature, our experimental design has several limitations that may have determined our observations. First, we have tested our system in cells that express endogenous STAT3, which could somewhat interfere with the system. One argument against this possibility is that we observe changes in asymmetric combinations but not in symmetric combinations. We initially assumed endogenous STAT3 would interfere homogeneously in all possible combinations. If this is incorrect and endogenous STAT3 is interfering, especially with certain combinations, we would expect some degree of similarity between symmetric and asymmetric combinations having at least one mutation in common. However, symmetric combinations are similar between them and in most cases different to their asymmetric counterparts. It should also be noted that, while endogenous and exogenous STAT3 could carry different PTMs (besides the BiFC tags), a possible differential interference of endogenous STAT3 does not necessarily invalidate our hypothesis. In normal conditions, the pool of STAT3 molecules will be heterogeneous, and the possible differential interference of endogenous STAT3 could actually correspond to the effect that other molecules would have on specific STAT3 homodimers. Nevertheless, the experiments should certainly be repeated in a STAT3 knockout context to remove possible confounders.Second, we overexpressed the constructs transiently, probably contributing to the high variability we observe between experiments. Higher‐than‐normal levels of STAT3 could produce interactions that would not occur in normal conditions. It was suggested to us that stable transfection on STAT3‐negative cells could both improve variability and produce levels of STAT3 similar to the endogenous levels in a parental cell line. This is not necessarily correct, since expression of proteins highly depend on their promoter, and similar attempts in the literature produced cell lines expressing higher levels than parental cell lines.Third, BiFC assays have their own technical limitations. BiFC assays frequently show some spontaneous reconstitution of the fluorophore that adds background and reduces the signal‐to‐noise ratio.In summary, our results must be considered as a working hypothesis, but they point at an exciting possibility: the behavior and function of protein homodimers could be controlled by PTMs in only one of the molecules. If asymmetric STAT3 dimers actually happen and play a relevant biological role, this would open a series of interesting questions: do they regulate specific sets of genes? Do they enable gradation of STAT3 transcriptional or mitochondrial activities? And if they do not happen, how do cells manage to achieve perfectly symmetrical STAT3 dimers with such high efficiency? Given the essential roles of STAT3 in development, immunity, tissue stress and cancer, addressing these questions could have important implications for the diagnosis, treatment and understanding of a wide spectrum of human pathologies.44.1HeLa human cervix adenocarcinoma cells and HEK293 human embryonic kidney cells were acquired from ATCC , LIF from R&D systems, and Stattic from Selleckchem.4.22 . Cell culture dishes were purchased from Techno Plastic Cultures (AG) unless otherwise indicated. For all experiments, cells were seeded at a density of 10 000 cells/cm2 regardless dish size. For flow cytometry assays, cells were grown on 6‐well plates (35 mm diameter). For cell viability and adenosine triphosphate (ATP) assays, cells were grown on 96‐well and 24‐well dishes, respectively. For microscopy, cells were seeded on glass‐bottom 35 mm dishes  and fixed with 4% paraformaldehyde in phosphate buffered saline (PBS) right before imaging. For protein extraction (PAGE and filter trap assays) cells were seeded on 60 or 100 mm dishes.HeLa and HEK293 cells were maintained in Dulbecco's minimal essential medium  supplemented with 10% fetal bovine serum (FBS) and 1% of a penicillin/streptomycin commercial antibiotic mixture , under controlled conditions of temperature and CO4.3http://jorgensen.biology.utah.edu/wayned/ape/) and synthesized by Invitrogen. Briefly, the cDNA sequence of STAT3‐alpha was fused to the sequence of two complementary, non‐fluorescent fragments of the Venus protein  . Deletion mutants lacking the C‐terminus (DelCT) of STAT3 were produced by PCR‐mediated subcloning using full‐length Venus‐STAT3 BiFC constructs as templates. The original lysine (K) residues on positions 49, 140 and 685 were replaced by arginine (R) residues, the tyrosine (Y) residue on position 705 by phenylalanine (F) and the serine (S) residue on position 727 by alanine (A) , trypsinized  and collected into BD Falcon Round‐Bottom Tubes (BD Biosciences). Cells were then resuspended in PBS at room temperature and analyzed by means of a Calibur flow cytometer (Beckton Dickinson). Ten thousand cells were analyzed per experimental group. The FlowJo software (Tree Star Inc) was used for data analysis and representation.4.5http://rsbweb.nih.gov/ij/).Images of transfected HeLa or HEK293 cells were acquired using an Applied Precision DeltavisionCORE system, mounted on an Olympus inverted microscope, equiped with a Cascade II 2014 EM‐CCD camera, using a 63× 1.4NA Oil immersion objetive, DAPI + DsRed + enhanced green fluorescent protein (EGFP) fluorescence filtersets and differential interference contrast (DIC) optics. Pictures were analyzed by means of the ImageJ free online software . Lysates were sonicated for 10 seconds at 5 mA using a Soniprep 150 sonicator (Albra) and centrifuged at 10 000× g for 10 minutes at 4°C, and supernatants were collected for analyses. Protein concentration was quantified by means of the Bradford assay. Equal amounts of protein (30‐50 μg) from each extract were prepared for analysis by western blotting under denaturing conditions. Loading buffer ; 40% glycerol; 6.3% β‐mercaptoethanol; 0.4% bromophenol blue) was added to the samples, which were then boiled for 5 minutes at 95°C and resolved on 12% SDS‐polyacrylamide gel electrophoresis with SDS‐containing running. Proteins were then transferred to nitrocellulose membranes, and transfer efficiency and equal sample loading was confirmed by Ponceau S staining. Membranes were blocked with 5% non‐fat dry milk in Tris‐HCl buffer saline‐Tween (TBS‐T)  for 1 hour at room temperature before addition of primary antibodies. Primary antibodies against the following proteins were used at the specified concentrations: STAT3 , phospho‐STAT3 (Tyr705) ; and GAPDH . Membranes were then washed 3 times in TBS‐T and incubated with a secondary mouse IgG Horseradish Peroxidase‐linked antibody . Signals were developed by enhanced chemiluminescence reagents (Millipore) and imaged with a Chemidoc device (Biorad).4.72. Then, medium was discarded and 100 μL of 100% dimethyl sulfoxide were added. Cells were lysed and MTT precipitates solubilized for 15 minutes at room temperature, and absorbance was measured in an automatic microplate reader  at 570 nm.Twenty‐four hours after transfection, 10 μL of 3‐ 2,5‐diphenyl‐2H‐tetrazolium bromide (MTT) solution in PBS (2 mg/mL) was added to each well, and incubated for 2 hours at 37°C and 5% CO4.8P < .05.Sigmaplot software  were used to perform the statistical analysis and graphical representation of data. Results are shown as the average ± SEM of at least 3 independent experiments, as indicated in figure legends. Statistical analysis was carried out by means of a one‐way ANOVA followed by a Bonferroni test adjusted for multiple comparisons. Results were in all cases considered significant only when The authors declare no conflicts of interest.RV is responsible for cloning, mutagenesis and flow cytometry studies, cell viability assays and part of microscopy analyses, and BC is responsible for most microscopy studies. CSA and AMR are responsible for the first optimization experiments with the BiFC system and LIF experiments, a small part of which are shown in Figure  Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file.


Lindera obtusiloba has been found to have two sister genetic clades of chloroplast (cpDNA) and nuclear microsatellite (nSSR), both of which show discontinuous distribution in northern and southern East Asia. In this study, we used the Mantel test and multiple matrix regression with randomization (MMRR) to determine the relative contributions of IBD, IBE, and IBI with respect to L. obtusiloba populations. Independent Mantel tests and MMRR calculations were conducted for two genetic data sets (cpDNA and nSSR) and for different regions . We found a significant IBI pattern in nSSR divergence for all assessed regions, whereas no clear IBI pattern was detected with respect to cpDNA. In contrast, significant  divergent IBD patterns were detected for cpDNA in all regions, whereas although a significant IBE was apparent with respect to the overall range, the effect was not detected in the two subregions. The differences identified in nSSR and cpDNA population divergence may be related to differences in the heredity and ploidy of the markers. Compared with the southern region, the northern region showed less significant correlation patterns, which may be related to the shorter population history and restricted population range. The findings of this study serve to illustrate that comparing between markers or regions can contribute to gaining a better understanding the population histories of different genomes or within different regions of a species' range.Isolation by spatial distance (IBD), environment (IBE), and historical climatic instability (IBI) are three common processes assessed in phylogeographic and/or landscape genetic studies. However, the relative contributions of these three processes with respect to spatial genetic patterns have seldom been compared. Moreover, whether the relative contribution differs in different regions or when assessed using different genetic markers has rarely been reported.  We infer that different markers reflecting divergent processes may owe to the heredity and ploidy difference of genomes, while divergent extent of significant patterns in northern and southern regions may owe to different population history between regions. Our goal was to identify potential differences in the evolutionary processes occurring in the different regions and for different types of genetic markers.The findings of both field and common garden studies have indicated that the NEA and SEA populations of ion Dai, . In spite et al.  have pree et al.  found th22.1psbA–trnH, trnL–trnF, trnS–trnG, and rpl16) for 271 individuals. The individuals analyzed were derived from 28 populations  obtained from the WorldClim database , namely annual mean temperature, mean diurnal range, isothermality, temperature seasonality, maximum temperature of the warmest month, minimum temperature of the coldest month, mean temperature of the wettest quarter, annual precipitation, precipitation of the wettest month, precipitation of the driest month, and precipitation seasonality. Model validation was performed via 10 independent runs with 20% randomly selected data. High receiver operating characteristic (ROC) values (0.928 ± 0.025) have been reported for this type of modeling, which indicate its good accuracy. The established model was projected onto LGM (MIROC‐ESM) and LIG climatic models , and last interglacial  periods based on ecological niche modeling (ENM) in MAXENT , using the “create friction layer” function in the SDM toolbox . To disentangle the potentially complex interactions among geographical distance, environmental distance, and resistance distance and compare the relative contribution of IBD, IBE, and IBI on population differentiation, we used multiple matrix regression with randomization (MMRR) based on 10,000 permutations. All variables included in the aforementioned analyses were standardized using the “scale” function in the “vegan” package  and population genetic differentiation, we performed Mantel tests with 10,000 permutations for each genetic distance index of both marker types  accounted for 67.24% of the environmental variation. For PC1, environmental variables related to humidity  had the highest weights, whereas for PC2, temperature‐related variables  had the highest weights Appendix . NeitherENM results  and climatic instability resistance  based on the Mantel test  can explain more variance in STF or STR than geographical distance , whereas the Mantel test indicated that STR has a significantly positive relationship with environmental distance . This seemingly contradictory pattern may indicate a weak effect of IBE over the entire species range.nSSR analysis indicated that in both the NEA and SEA regions, t Figure . MMRR anSTF/STR  and STR  based on the MMRR analysis, whereas significant relationships were detected using the Mantel test. The contrasting patterns for geographical and environmental distances identified using the Mantel test and MMRR analysis may indicate the weak effects of these two factors on the nuclear genetic patterns in the SEA region.Both the Mantel test and MMRR analysis indicated a significantly positive relationship between climatic instability resistance and STR showed a relatively consistent IBI pattern. Although the Mantel test did not identify significant relationships for STR, with respect to geographical and environmental distances, it indicates a marginally significant positive relationship with climatic instability resistance  and a negative relationship with geographical distance  and climatic instability resistance , whereas MMRR analysis failed to identify any significant relationships for the three distance indices. Thus, on the basis of the present analyses, we were unable to identify any clear patterns in IBD or IBE in the NEA region.For the NEA region, the weak IBI pattern we identified may be attributable to the fact that only 3.3L. obtusiloba. Using the Mantel test, we found that genetic distance xyD, which indicates divergence since the last common ancestor between populations, was significantly correlated with the three factors . MMRR analysis revealed that xyD was only influenced by geographical distance  being identified for environmental distance . In this regard, we suspect that the results of MMRR analysis may be more accurate than those obtained the Mantel test, as MMRR simultaneously considers all factors. For STG, which only applies to the allele frequency between populations, both the Mantel test and MMRR analysis showed significantly positive correlation with environmental distance  but no clear IBE or IBI patterns , we were unable to detect any significant IBD, IBE, or IBI patterns with respect to genetic distance indices in the NEA region  nor heat (PC2), the habitat types in the NEA are unique when these two climatic factors are considered together. We suspect that habitat in the NEA region is a marginal type of that in the SEA region  O'Kane & Al‐Shehbaz  over either the entire species range or within the two distinct subregions (NEA and SEA) of this range. In contrast, we were unable to detect any significant IBI pattern with respect to the divergence of cpDNA. We envisage that changes in climatic change during the late Pleistocene have had a stronger influence on population divergence of the nuclear genome than that of the chloroplast genome, which can probably be attributed to differences in the inheritance mode and ploidy of these two genomes. Differences in the patterns of cpDNA divergence are assumed to be influenced by spatial distribution (IBD). In addition, local adaptation may have affected the divergence of the chloroplast between the northern and southern regions, whereas we detected no clear IBE pattern for nuclear divergence based on the set of nuclear loci analyzed in the present study.In this study, we compared the relative contributions of IBD, IBE, and IBI to the genetic divergence of L. obtusiloba in the NEA, we found this region to be characterized by a less significant pattern of genetic divergence than the SEA region. Collectively, the findings of this study serve to emphasize that even within a single species, analysis of different genetic markers or different regions can reveal differences in IBD, IBE, or IBI patterns or differing extent of significance. Such findings will contribute to gaining a more complete understanding of the population history of different genomes or patterns of divergence in different regions of a species' range.We also identified convergence in the correlation patterns of both the nuclear and chloroplast genomes in the NEA and SEA regions. However, due to the shorter population history and more restricted population range of Appendix S1Click here for additional data file.Appendix S2Click here for additional data file.Appendix S3Click here for additional data file.Appendix S4Click here for additional data file.Appendix S5‐S8Click here for additional data file.


Glioblastoma is one of the most treatment-refractory human malignancies, and despite techniques that have allowed scientists and clinicians to better understand the molecular underpinnings of resistance, little progress has been made in improving the survival of patients with glioblastoma. We posit that dysregulated Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling represents one major hub of tumorigenesis and resistance to medical therapies and that clinical study of its targeted inhibition is warranted, as well as highlighting the lessons learned from historical investigation going forward.Glioblastoma remains one of the deadliest and treatment-refractory human malignancies in large part due to its diffusely infiltrative nature, molecular heterogeneity, and capacity for immune escape. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway contributes substantively to a wide variety of protumorigenic functions, including proliferation, anti-apoptosis, angiogenesis, stem cell maintenance, and immune suppression. We review the current state of knowledge regarding the biological role of JAK/STAT signaling in glioblastoma, therapeutic strategies, and future directions for the field. Despite decades of intense study, the prognosis for patients with glioblastoma (GBM) remains near universally poor, with inevitable therapeutic resistance and subsequent recurrence despite multimodality therapies. As advances in other solid and liquid cancers continue to be made, there remains an urgent unmet need for GBM therapeutics. Treatment resistance arises from a wide variety of mechanisms, including the blood–brain barrier (BBB), inter- and intra-tumoral heterogeneity, and a profoundly immunosuppressive tumor microenvironment (TME). As the mechanisms underlying these barriers have been and continue to be elucidated, a number of crucial oncogenic signaling pathways have been discovered that contribute redundantly in promoting tumorigenesis, disease recurrence, and confounding therapeutic strategies. Increasing evidence demonstrates the importance of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling as a pivotal molecular hub active in critical microenvironmental cellular populations, such as glioma cells, reactive astrocytes, and stromal and immune cells, that drives not only aggressive growth, invasion, treatment resistance, and cancer cell stemness but also tumor-mediated immunosuppression. Herein, we review the present knowledge to date of JAK/STAT signaling in promoting these activities, the historical approaches taken to target this pathway, and the future directions.The STAT family of transcription factors is comprised of seven proteins—STAT1, STAT2, STAT3, STAT4, STAT-5a, STAT-5b, and STAT6—which reside in the cytoplasm and are activated by phosphorylation as a downstream consequence of a number of signaling pathways, including cytokines, growth factors, or non-receptor tyrosine kinases .,25.24,25PTPRD gene encoding the receptor protein tyrosine phosphatase delta—an inactivating dephosphorylator of STAT3—is commonly found in GBM as a consequence of CpG hypermethylation on chromosome 9p [SOCS1 and SOCS3 promoter hypermethylation–which inactivates these genes—occurs in 24% and 35% of GBM, respectively, and is associated with poor prognosis [A lack of negative STAT3 regulation also contributes to its constitutive activation in gliomas. Indeed, epigenetic silencing of the osome 9p . Additiorognosis . SOCS3 krognosis ,38,39. Rrognosis . Finallyrognosis ,42,43. Arognosis ,47,48,49rognosis . PTEN, consequent AKT activation led to downregulation of cytokine receptor leukemia inhibitory factor receptor-β and inhibition of STAT3 signaling, thereby leading to IL-8-induced proliferation and invasiveness [PTEN-deficient GBM (found in ~35% of GBM), STAT3 may be tumor suppressive rather than oncogenic [PTEN status and response to STAT3 inhibition has not been shown, it would be premature to exclude such a significant proportion of patients with GBM from a clinical trial of a STAT3 inhibitor. PTEN status will likely need to be considered in the correlative analysis of outcome in any clinical trial involving STAT3 inhibition in GBM. In summary, the net balance favors aberrant STAT3 pathway activation as primarily tumorigenic in GBM.Adding a layer of complexity to the role of STAT3 in gliomagenesis is that the role of STAT3 may be to a certain degree genetically determined. In one notable in vitro study, de la Iglesia et al. demonstrated that in GBMs harboring inactivating mutations of siveness . A compasiveness . In othencogenic . These fOCT4, SOC2, and NANOG [STAT3 activation underlies a host of tumorigenic cellular pathways, the foremost of which is in transcriptionally regulating glioma stem cells (GSCs)—a critically treatment-resistant population of cells that give rise to recurrent disease ,55. Indend NANOG ,57,58. And NANOG . Anothernd NANOG ,61. miR-nd NANOG . STAT3 and NANOG ,64. Finand NANOG ,66. ThesBcl-xL, Mcl-1, and survivin [The multi-faceted tumorigenic roles of STAT3 in human glioma cells has been well established by both molecular and pharmacologic inhibition. Targeted inhibition of STAT3 in GSCs not only triggers apoptosis but also leads to decreased proliferation, multipotency, and neurosphere formation ,68,69. Rsurvivin ,71,72. Wsurvivin . VEGF [Angiogenesis is another hallmark of cancer that has been directly linked to STAT3. In histopathologic examination, phosphorylated STAT3 preferentially localizes to tumor endothelial cells along with vascular endothelial growth factor receptor-2 (VEGFR-2), suggesting an autocrine feed-forward loop promoting the hallmark neovascularization seen in GBM . Indeed,VEGF . GBM alsVEGF ,78,79,80VEGF ,82.With the surging enthusiasm for immunotherapy for other solid malignancies, immune therapeutic targeting of STAT3 is a compelling strategy for modulating tumor-mediated immune suppression, especially for a cancer like GBM that has in general not been responsive to immune checkpoint inhibitor monotherapies ,84. IndeIn GBM, interactions between tumor cells, reactive astrocytes, and microglia lead to high levels of IL-10 and TGF-β, which promotes a positive feedback loop of STAT3 signaling ,94. STATPreferential activation of the STAT3 pathway by the permissive cytokine milieu has profound effects on the innate immune system components of the TME, which are largely mediated by tumor-associated macrophages/microglia (TAMs), myeloid-derived suppressor cells (MDSCs), and other cells . NaturalSTAT3 activation also inhibits maturation of dendritic cells and their ability to express key molecules necessary for effective antigen presentation  and T cell activation  ,111. SimVarious cytokines—but particularly IL-6—are associated with the infiltration of MDSCs in the TME, which are positively correlated with glioma grade and have been shown to exert immune suppressive effects against T and NK cells through expression of enzymes such as arginase that trigger T cell arrest and apoptosis ,116,117.Constitutive STAT3 activation also has significant effects on the adaptive immune system. STAT3 activation alters the immune cell composition of the microenvironment, promoting decreased infiltration of effector CD4+ and CD8+ T cells and an increased proportion of Tregs . ActivatIn a pivotal early study, Kortylewski et al. demonstrated that hematopoietic cell-specific inhibition of STAT3 in tumor-bearing mice led to significantly enhanced functional activity of T, NK, and dendritic cells, resulting in antitumor immunity and growth inhibition . HussainIn summary, STAT3 signaling constitutes a crucial hub through which the tumor microenvironment is shaped and driven toward immunosuppression. 50 of TMZ and increased TMZ-induced apoptosis while upregulating Bcl-2 expression and downregulating Bax expression. Finally, they showed that STAT3 inhibition leads to increased TMZ-induced G0-G1 arrest and decreased cyclin D1 expression compared to TMZ alone. It should be noted that these findings are somewhat contradicted by recent work from Heynckes et al. [STAT1 and STAT3, although this was not seen in the commercial LN229 GBM cell line. The generalizability of the authors’ primary conclusion that TMZ treatment leads to inhibition of JAK/STAT signaling in recurrent GBMs is uncertain. Notably, this study had methodological limitations, including small sample sizes (three cell lines and fifteen tissue samples) and—most critically—the absence of microenvironmental JAK/STAT expression analysis. Nevertheless, the authors’ findings suggest that the role of aberrant STAT3 signaling in underlying chemoresistance is nuanced and further point to the fact that the optimal role and timing of STAT3 inhibition in combination with conventional therapeutic strategies remains to be determined.At present, the standard-of-care for patients with GBM consists of maximum safe resection followed by the “Stupp regimen”: alkylating chemotherapy temozolomide (TMZ) combined with radiation, followed by adjuvant TMZ. TMZ mediates its cytotoxic effects via the formation of O6-methylguanine adducts on DNA, leading to replication-associated double-stranded DNA breaks and apoptosis ,129. A ns et al. , which fMRE11 and RAD51 [There is also evidence that STAT3 is involved in mediating resistance to radiotherapy, which induces cell death largely via single- and double-stranded DNA breaks and oxidative damage . Rath etnd RAD51 ,142. Finnd RAD51 ,144. In There is substantial literature that supports the role of STAT3 activation in mediating resistance to targeted therapy. The reliance on several dysregulated—and often redundant—signaling pathways, including EGFR, PIK3CA, PDGF, and NF-κB, has been well-characterized in glioblastoma, and cross-talk between these have likely contributed in large part to the historical failures of targeted therapy ,145,146.From the preceding discussion, it is clear that the compensatory mechanisms of resistance to conventional, targeted, and immunotherapeutic strategies against GBM will likely thwart therapies based on a single vulnerability . ConsequWith regard to its well-characterized immunomodulatory effects, combining STAT3 inhibition with other immuno-oncologic strategies also represents an exciting prospect. For example, one preclinical study has shown improved effector functions of adoptively transferred CD8+ T cells in combination with STAT3 inhibition in myeloid cells . AnotherThe aforementioned convergence of multiple oncogenic and immunosuppressive cellular pathways on the JAK/STAT signaling axis makes it an attractive molecular target. Indeed, Stechishin et al. found that targeted JAK2/STAT3 inhibition in orthotopic GBM xenografts regardless of molecular strategy led to increased cytotoxicity of GSCs regardless of MGMT promoter methylation status . To dateTargeting aberrant upstream IL-6/IL-6R signaling is one potential avenue of JAK/STAT blockade. Treatment with IL-6 pathway blockade via its receptor  or binding soluble IL-6 (siltuximab) has been shown to inhibit glioma growth in vitro and reduce the expression of coinhibitory molecules such as PD-L1 on infiltrative myeloid cells ,159. A nA number of repurposed pharmacologic agents have been found to have STAT3 inhibitory activity; however, off-target effects due to lack of specificity and questionable CNS penetrance have limited their utility. Atovaquone is an anti-malarial drug FDA-approved for pneumocystis pneumonia that was found to have STAT3 inhibitory effects; notably, it appears to be poorly bioavailable in the CNS ,162. ArsA staggering number of natural compounds have been found to have STAT3 inhibitory activity in vitro, but the clinical utility of these in their native forms for GBM is largely hindered by unfavorable pharmacokinetic properties including low potency, unacceptable toxicity, rapid metabolism, and/or poor BBB penetrance. Plant/fruit-derived resveratrol, for instance, is capable of inhibiting proliferation and invasion of glioma cells in a STAT3-dependent fashion in vitro and when administered intrathecally in vivo. Sadly, it is rapidly metabolized when given systemically ,172. To JAK inhibition, although historically employed in the treatment of myeloproliferative disorders, represents another avenue of STAT3 pathway targeting in malignant glioma. As summarized in 50 15–44 µM for STX-0119), poor bioavailability, and/or unclear BBB penetrance limit the utility of these agents at this time.Peptidomimetics such as PY*LKTK were among the earliest in vitro STAT3 inhibiting strategies, designed to bind the SH2 domain and thereby prevent dimerization and DNA binding . Concerncis-element and transfected it into human GBM cells U251 and A172, finding specific blockade of STAT3 activation with subsequent cell-cycle arrest and apoptosis mediated by decreases in mRNA levels of c-Myc, cyclin D1, and Bcl-xL [Oligonucleotides represent another strategy of direct STAT3 modulation. In a proof-of-concept experiment, Gu et al. designed a decoy oligodeoxynucleotide comprised of a STAT3-specific DNA d Bcl-xL . Kortyled Bcl-xL . MicroRNd Bcl-xL . As oligonucleotides are susceptible to degradation by circulating nucleases, subsequent groups have developed various modifications to optimize stability and drug delivery. Yaghi et al. encapsulated miR-124 duplexes within lipid nanoparticles and demonstrated efficient uptake by immune cells with subsequent reduction in activated STAT3 and increased survival in a murine model of glioma . Linder Overall, the major challenges for nanoparticle-based delivery of oligonucleotides include ensuring adequate tissue distribution in tumors with a high degree of vascular heterogeneity and minimizing nonspecific uptake by non-tumor or stromal cells. Further study is certainly warranted to optimize these approaches before clinical application.A tremendous number of molecules have been synthesized to inhibit STAT3, usually acting by binding the SH2 domain required for interacting with phosphorylated tyrosine residues on receptors and STAT dimerization. Of these, only a handful have advanced to clinical trials for GBM, for reasons that will be discussed. Stattic was one of the earliest SH2-binding STAT3 inhibitors, and was found to exert anti-proliferative and radiosensitizing effects on GSCs, although a lack of specificity and in vivo efficacy data has prevented it from moving forward ,234,235.Attempts to improve the pharmacokinetic parameters of small molecules such as AG490 led to the development of subsequent compounds such as WP1193  and one 50s upon treatment with STAT3 inhibitors such as Stattic or WP1066 relative to those with STAT3-low gene signatures. Of note, STAT3-low tumors  upregulated insulin-like growth factor binding protein 2 (IGFBP2) and insulin growth factor-1R (IGF-1R) in response to STAT3 inhibition, and the combination inhibition of IGF-1R and STAT3 in orthotopic xenografts led to re-sensitization to STAT3 inhibition. Interestingly, their functionally determined gene signature outperformed conventional immunohistochemically determined phospho-STAT3 expression in identifying STAT3 inhibition responders, although an important methodological limitation to note is that these were validated in severe combined immunodeficiency (SCID) mice who by definition lack an antitumoral immune response. In addition, it is also notable that the authors did not comment on whether PTEN mutation was associated with a “STAT3-low” phenotype, as might be expected based on work by de Iglesia et al. [In view of the tremendous intra- and inter-tumoral heterogeneity of GBM, identifying patients most likely to benefit from targeted STAT3 inhibition is a critically important challenge. There is yet to be a consensus, for instance, on whether expression of phospho-Tyr705 STAT3, phospho-Ser727 STAT3, or both represents maximally abnormal STAT3 pathway activation with its concomitantly poorest prognosis ,244. Inta et al. . Future As increasingly sophisticated genomic, transcriptomic, proteomic, and bioinformatic analyses continue to propel the field of oncology into the molecular era, glioblastoma continues to represent a glaringly unmet need. Rational therapeutic strategies need to account not only for anatomic barriers such as the BBB but also the tremendous intra- and intertumoral heterogeneity that characterize this disease. As the preclinical studies have shown, JAK/STAT signaling is tremendously complex, and, while on balance, constitutive activation tends to promote tumor proliferation, angiogenesis, and immune escape, the effects of targeting upstream or downstream effectors are not always predictable. Nevertheless, it is our position that, on balance, there is sufficient evidence of the importance of dysregulated JAK/STAT signaling as an important driver of gliomagenesis and treatment resistance that human study continues to be warranted for this deadly disease. Because it is unlikely that strategies based on one or two key molecular vulnerabilities will be generalizable to the entire patient population, continued efforts to define and validate biomarkers to help stratify patients appropriate for JAK/STAT combination therapy are crucial to advancing our understanding of the disease.


Biofictions: Race, Genetics and the Contemporary Novel; Clare Hanson’s Genetics and the Literary Imagination; and Lara Choksey’s Narrative in the Age of the Genome: Genetic Worlds.1 This special issue seeks to consolidate this growing body of critical work on cultural representations of genetics and to further diversify its range of interests and applications. Collectively, we explore the circulation of ideas about genes, the genome and genetic science in cultural texts across a range of forms—from poetry to genre fiction, rap music to TED talks, popular science to historical fiction and postcolonial literature—and from diverse cultural locations.This special issue has developed out of a research symposium on global genetic fictions, funded by Wellcome, which was held at the University of Leeds in April 2019. Involving historians, literary and cultural critics, it was a welcome opportunity to sample the wealth of humanities-based scholarship on genetic science, its cultural representations and its ethical implications. This is a field that is gathering momentum; the 2 years since that symposium, for instance, have seen the publication of three important literary critical books on genetics: Josie Gill’s fictions refers not only to the imaginative narratives found in literary texts, although many of the articles do draw on literature to make their arguments. Rather, following Gill’s conceptualisation of the ‘biofiction’ of race in genetic science, the ‘genetic fictions’ in this issue consist of the ideas about genetics  that are ‘constituted through the complex entanglement of scientific and fictive forms’, with ‘fiction’ encompassing both literary texts and a more general sense of ‘the conjured up, the imaginary and the fictional’, the narratives about genes that are ‘formed in the political, social and cultural spheres’.2 This is important because, as biocultural critique has firmly established, cultural discourse about genetics does not just reflect, explain, interpret and popularise emerging scientific knowledge; it fundamentally contributes to the production of that ‘knowledge’ itself. A slightly earlier phase of scholarship conducted by historians of science and literary critics, which emerged alongside and in the wake of the Human Genome Project’s sequencing of the human genome (1990-2003), has demonstrated how the language and metaphors used to describe genes and the genome  were integral to shaping the development of scientific disciplines and methods in genomic research. Linguistic, textual and informatic metaphors—’the “secret of life,” the code, the book, the alphabet, sentences, words, chapters, histories, the Rosetta stone, the Holy Grail, the recipe, the blueprint, the text, the map, the homunculus, software, and others’3—not only rendered complex biological processes comprehensible to lay audiences through journalism and popular science , but also structured the conceptual frameworks and thus the research directions and priorities of molecular biologists, ‘both enabl[ing] and constrain[ing] the[ir] thoughts and actions’4.Our focus on genetic 5 And as Everett Hamner puts it: ‘It is not that genetic fiction decides what scientists do in the lab on a day-to-day basis [...] rather [...] genetic fiction becomes a key background against which both scientists and the public imagine this work’s reper-cussions’.6 Some of the influential ‘genetic fictions’ considered and critiqued in this issue include, in Natalie Riley’s essay, the rise in the 1990s of a reductive brand of genetic determinism associated with neoDarwinist public figures such as Richard Dawkins; in Shital Pravinchandra’s article, the fiction of the purity and pending extinction of Indigenous DNA; and and how, as Lucy Burke demonstrates, life with disability is cast ‘as intrinsically diminshed and burdensome’ in bioethical discussion of genetic conditions such as Down’s syndrome.7 These are all pervasive and persistent narratives that shape public thought but also, crucially, contribute to scientific outcomes: the development of reproductive biotechnologies such as non-invasive prenatal testing is dependent on assumptions (fictions) about the quality of disabled lives, while priorities in population genetics are driven by the perceived need to capture ‘rare’ Indigenous genetic data before they are lost forever. As Hamner notes, the ‘mutated narratives’ that emerge in the translation of complex genomic science to its popular conceptualisations can ‘double back and colonize the research and applications that find private and public financing’.8 With this in mind, our essays pay particular attention to how the form of cultural texts operates to produce and to destabilise particular genetic fictions, from how, in Jerome de Groot’s article, intertextuality in contemporary poetry and the rhythm, rhyme and ‘spitting’ of rap lyrics creatively reform DNA test results to how, as Loredana Filip shows, the conventions of the TED talk as a genre of ‘self-improvement’ lend themselves to narratives of genetic enhancement or ‘self-fashioning’.More recently, Gill has shown how genetic fiction is ‘intimately and inextricably bound up in the formation of scientific fact, shaping and impacting upon the development, expression, transmission and ultimately the public understanding of the new science of race’, arguing persuasively that ‘fiction is part of truthmaking’.9 Both in material forms—cell samples moving between laboratories— and in the abstracted form of ‘data’ or information, the ‘exchange, circulation, and distribution of biological information and materials’ is one of the defining technologies of a globalised world.10 This produces distinct forms of economic valuation, or biocapital, meaning both that genomic science is inextricable from these forms of capitalist production and that life itself is continually ‘redefined through the contradictory processes of commodification’.11The entanglement and co-constitution between ‘fictional’ public discourses about genetics, scientific activity in the lab and research infrastructure point towards another central focus of this special issue. The human genome is, inevitably, a ‘global genome’ (to borrow Eugene Thacker’s term), since the infrastructure of the life sciences exists at a globalised level, bringing together state and corporate interests with international property law, global health priorities, and the transnational operations and markets of Big Pharma and the biotech industries.global in the conceptualisation of this special issue, then, we aim to register the inequitable global distribution of biocapital and biotechnology, the unevenness of policies regarding benefit sharing, and the racial and cultural politics of genetic science. As Choksey points out, one preoccupation of ‘[n]arrative in the age of the genome’ is tracing how 21st century genomics positions human beings variously ‘as producer-consumers of data in the Global North or as peripheral and precarious manufacturers of technologies for interpreting these data in the Global South’.12 As several articles in this issue discuss, marketing for direct-to-consumer genetic ancestry testing has targeted Black and Indigenous communities whose ancestry or kinship ties may have been severed by the violence of slavery and settler colonialism.13 And major population genetics projects, which rely on the ‘distinctive’ genetic ‘data’ of Indigenous communities to trace human evolution, genetic diversity and histories of migration, have been censured for adopting ideological rationales and extractive methods of data collection that amount to contemporary forms of ‘biocolonialism’.14In emphasising the 15 As the articles in this issue demonstrate, there are indeed other ways of knowing—other frameworks for genetic knowledge, other conceptualisations of the human genome, identity, heredity, kinship, health and human-environment rela-tionality. Paul Hamann-Rose’s essay, for example, examines Amitav Ghosh’s representation of Indian ‘counterscience’ in The Calcutta Chromosome (1995), a fictional epistemological framework that destabilises the positivism of ‘Western’ knowledge systems and produces new genetic biotechnologies, and Frances Hemsley considers the epigenetic imaginary that emerges in the context of environmental racism in apartheid South Africa. To give another example, Maori  novelist Patricia Grace describes genes as ‘the ancestors within us’ in Baby No-Eyes (1998), while Indigenous Science and Technology Studies scholar Kim TallBear (Sisseton-Wahpeton Oyate) writes that according to an ‘indigenous metaphysic’, ‘matter is lively’ or alive.16 To centralise Indigenous genetic epistemologies not only radically transforms narratives of ancestry, heredity and the inheritance of traits, but also holds significant implications for how genetic ‘samples’ should be stored, cared for and used.17Just as the uses and applications of genetic science are tied up with histories (and continuing presents) of racism, colonialism and exploitation, the global apprehension of genomics also differs according to diverse epistemologies and scientific practices. When Lily Kay pointed out in 2000 that the genetic imaginary according to which DNA is understood as ‘code’ and genes as vehicles for ‘information’ is ‘historically specific and culturally contingent’, ‘a manifestation of the emergence of the information age’—a particular facet of globalisation—she speculated that ‘there were (and probably could be) other ways of knowing’.18 But withthe exception of recent studies such as Gill’s and Chok-sey’s monographs,most research on literary and cultural representations of genetics has so far focused ontexts from the Global North that centralise EuroAmerican scientific epistemologies, withan understandable emphasis on the science fiction genre.19 In ‘Global Genetic Fictions’, we havecollectively attempted to offer geographically diverse and culturally situated readingsof genes, the genome and genetic science, drawing on cultural texts from variedlocations, socioeconomic milieux and epistemological traditions. We are aware of AnneWhitehead and Angela Woods’ caution that globalising the medical humanities isnot just about ‘expanding the canon of humanities texts that might be used inthis context, to include postcolonial authors and/or works by indigenouswriters’—although I believe this is important in a field in which aparticular dominant scientific epistemology is often taken to be universal—butmust necessarily also ‘contest or complicate a binary of “the West and therest”, [and] think through in more complex terms the messy and unevenentanglement of subjects that globalisation inevitably entails’.20 In this special issue we hope tocontribute to doing both, and Choksey’s pertinent question in the Introduction toNarrative in the Age of the Genome applies just as well to theconcerns of many of the articles in this issue: ‘how does the messiness of whatgenomics does not account for — other histories, other forms of inheritance,other modes of being - interrupt and destabilize the seemingly implacable logic of causeand effect bound up in the idea of a molecular script?’21As Choksey argues emphatically in this issue, ‘Genomics is not a universalontology, but a regional manifestation of a particular worldview that has becomeglobalised and whose globalisation has been facilitated by violent processes ofextraction’.22In the articles to follow we see multiple examples of this messiness, which emerges in cultural texts that engage, incorporate and grapple with genetic discourse while also asserting the importance of what genomics does not account for, of alternative ways of seeing and knowing the world and being and thriving within it. The analysis in this issue therefore participates in the kind of politicised critical activity that Jenny Reardon has deemed characteristic of ‘the postgenomic condition’—the period since the sequencing of the human genome in which attention has turned from accumulating genetic knowledge to acts of interpretation and meaning-making. As Jay Clayton argues in his essay on ‘genome time’, tests as simple as a cheek swab can now render our past (our deep ancestry) and our future (susceptibility to disease) immediately knowable in the present moment, but the consequences of having this information at our fingertips, and the ethics of making such knowledge available to individuals and families , are still far from clear. Genetic fictions—both literary texts and pervasive cultural narratives—are important sites of encounter and entanglement, and the essays in this issue contribute to the ongoing project of postgenomic recalibration, contextualisation and reflection on what kinds of knowledge are necessary or desirable at a time when ‘people around the world are raising questions about how to know meaningful life on a data-rich but environmentally depleted, and interconnected-yet-fractured planet’.23The articles in this issue are wide-ranging but share a number of key concerns. The first of these is how biotechnologies such as gene editing and prenatal diagnosis might ‘enhance’ or eradicate aspects of human diversity. Loredana Filip examines how the TED talk—one of the most ubiquitous and accessible global forms for the dissemination and popularisation of scientific knowledge—contributes to shaping global discourse about genetics. In the context of debates about genetic enhancement prompted by CRISPR-Cas9 and gene editing technologies, Filip argues that the TED talk can be situated within a tradition of ‘self-help and selfimprovement’, characterised by optimism, inspirational storytelling, and motivating narratives of success. TED talks on the possibilities of genetic science generate the sense of wonder that we often associate with science fiction and perpetuate narratives of visionary scientific genius. But Filip finds that several influential talks bypass concerns about privacy and ethics and espouse ableist assumptions about the desirability of genetic enhancement. Ultimately, the culture of self-fashioning that forms the TED genre also shapes the portrayal of gene editing itself as an exciting new mode of self-improvement. As Filip demonstrates, ‘seemingly harmless rhetorical choices’ in popular cultural forms ‘may all contribute to the rise of human enhancement ideals’.24 Burke unpacks debates within health economics and reproductive bioethics about prenatal diagnosis and selective abortion in relation to genetic conditions including Down’s syndrome. All too frequently, she demonstrates, these discussions pivot on unevidenced and ableist assumptions about burdensome disabled children and suffering mothers. Burke then turns to Icelandic author Yrsa Sigurdardóttir’s crime novel Someone To Watch Over Me (2013). Set in the aftermath of the global financial crash of 2008 and concerned with questions of state power, truth and justice, this text offers an alternative view on human value. When the resolution of the crime narrative is achieved through the Foucauldian ‘subjugated knowledges’ of characters with learning disabilities, Burke argues that the novel profoundly challenges neo-utilitarian approaches to prenatal diagnosis. Framing her arguments with feminist disability studies perspectives, Burke exposes and problematises the economic logic surrounding reproductive technologies that ‘render some groups of people with genetic conditions existentially vulnerable’.25Exploring another angle on the eugenic potential of genetic knowledge, Lucy Burke makes a powerful argument about how ‘the history of genomic discourse is entangled with biopolitical and economic considerations that subject the value of some lives to the instrumentalist logic of the cost/benefit analysis’.26 These temporal formations are not simply theoretical models but impact directly on public policy and consumer behaviour, as demonstrated by the thriving markets for both direct-to-consumer genetic ancestry research and genetic health risk testing. Clayton considers genome time in relation to the different temporal implications of nanotechnology and climate science, and through a queer reading of a classic science fiction short story, Samuel R Delaney’s Time Considered as a Helix of SemiPrecious Stones (1969), he argues that genome time can be aligned with forms of queer temporality, constituted not necessarily by deterministic logic or foreclosed futures but by notions of potentiality and possibility.Other essays are concerned with the histories of genetic science and the temporalities of genetic knowledge. Jay Clayton elaborates on his previously articulated concept of ‘genome time’, the notion that genomics has produced a new, distinctive temporality, characterised by both simultaneity and linearity, presentness and the ongoingness of history, which promises ‘that all times will become discoverable in the present’.27 In poetry and lyrics about DNA, they also testify to the historical specificities of their own, postgenomic, moment, forging new ways of engaging with the self, the other, ancestry, kinship, race, ethnicity and the materiality of the human body in relation to their new genetic knowledge. Like Clayton, de Groot identifies opportunities for innovation, creativity and critique within these postgenomic imaginaries: the writers he considers ‘are not inflected by their genetics but rather make the possibilities work for them’.28Jerome de Groot is interested in the contemporaneity and historicity of genomic artefacts—both material DNA samples and the creative texts that represent and explore the postgenomic condition. He analyses the postgenomic imaginaries on display in the 21st century art of Marc Quinn, poetry of Zaffar Kunial, Michael Symmons Roberts and Hannah Sullivan, and the rap lyrics of Kendrick Lamar and Residente. This diverse group of creative practitioners variously reflects on past modes of knowing the human— ‘the resonance of the then in the now’— through intertextual ‘updates’, formal innovations, translations and adaptations of their literary and musical inheritances.Babel Tower (1996), Zadie Smith’s White Teeth (2000) and Jenny Diski’s Monkey’s Uncle (1994)—mobilise the formal features of historical fiction, including anachronism, repetition and asynchronicity, as ‘a means of critiquing and destabilising the explanatory promise of human genomics’.29 Respectively engaging with linguistic nativism (the idea that a capacity for language is hard-wired in the human brain), the continuing presence of scientific racism within contemporary bioengineering, and reductive genomic explanations for depression, these texts share a sense of genomic scepticism. Riley demonstrates how, by drawing attention to the importance of context, translation and interpretation in making meaning out of ‘data’, these 1990s texts ‘highlight how the logics and cultural capital of genetics has always been, and must continue to be, disrupted, refused, and undermined’.30Natalie Riley’s article is also centrally concerned with the relationship between genetic science and history, focusing on the 1990s—the decade of the Human Genome Project—and the neo-Darwinian accounts of human heredity and behaviour popularised by public intellectuals such as Richard Dawkins and Steven Pinker. Riley argues that in contrast with the genetic determinism of these narratives, three British novels—A.S. Byatt’s The Calcutta Chromosome (1995) and Zadie Smith’s White Teeth (2000). Since genetic science (and ancestry testing in particular) has produced new ways to trace migration patterns around the globe, the concept of genetic kinship has special relevance to the articulation of postcolonial and diasporic narratives of home, family, relatedness and belonging in a globalised world. In White Teeth, which navigates between London, Bangladesh and Jamaica, genetic discourse is deployed by characters to ‘fortify a cultural and national continuity across the gulf of globalisation and diaspora’—not always successfully—while in The Calcutta Chromosome, Indian counterscience produces new genetic biotechnologies that allow the personalities of individuals from different ethnic and national backgrounds to be fused within a single ‘geneticised diasporic body’.31 Hamann-Rose argues that discourses of genetic kinship offer to postcolonial writers a new facet to the production of cultural identity in diaspora, and in turn postcolonial literatures demonstrate how kinship cannot ultimately be reducible to biological relations.Many of the articles in this issue engage with postgenomic questions regarding ancestry, race and inheritance, questions that have also long been central to the concerns of postcolonial literature. Paul Hamann-Rose explores narratives of genetic kinship that emerge in Amitav Ghosh’s 32 Metis author Cherie Dimaline’s young adult novel The Marrow Thieves (2017) is set in a near future in which the Earth has been ravaged by climate change and all non-Indigenous humans have mysteriously lost the ability to dream. In this context, indigeneity has acquired a particular form of desirable biovalue since the ‘greater good’ of the human race now depends on the forcible extraction of Indigenous bone marrow. Pravinchandra shows how Dimaline employs genetic framings of identity and relationality alongside ‘more than biological’ Indigenous articulations of self-recognition, kinship and heredity in order to expose the limitations of genetic discourse. Importantly, she argues, the novel’s affirmation of queer kinship confirms ‘the complexities of Indigenous kin-making’ and reorients ‘tradition’ to ensure community survivance while resisting the heteroreproductive logic of biological heredity.33Kinship is also central to Shital Pravin-chandra’s analysis of Indigenous counter-genetic fictions. She explores an emerging trope in fiction and film, in which Indigenous bodies are immune to ‘an array of maladies plaguing all other humans’, and argues that ‘the idea of the biomed-ically distinctive Indigenous Person as a preyed-upon asset’ responds directly to the extractive logic of population genetics projects.34 We are much more interdependent with our environments  than previous science ever realised. But the implications of epigenetic research for social, environmental and racial justice movements are complex and messy, with the potential both to challenge and to entrench difference and stigmatisation. Frances Hemsley examines the potential for epigenetics to ‘allow us to better conceptualise the biopsycho-socially constitutive nature of racist environments’ while acknowledging the risk that it simultaneously holds the potential to ‘pathologis[e] particular social or ethnic groups as biologically damaged’.35 The racist environments in question in Hemsley’s article are the racially segregated slum areas of Cape Town in apartheid South Africa, spaces of poverty that both materialise and perpetuate the ideology of apartheid. Hemsley analyses Bessie Head’s The Cardinals, a novella written in the early 1960s in Cape Town’s District Six. While this text predates scientific research into epigenetics, Head generates an ‘epigenetic imaginary’ that interrogates the intersections of race, heredity and environment, complicating these entanglements through creative modes of self-invention and an incest narrative that emphasises the complexity of development. Hemsley concludes with appropriate caution that epigenetics ‘may still prove conceptually useful to postcolonial politics, environmental justice and antiracism’, but to do so it must operate in tandem with a critique of ‘material inequality’.36The rapidly diversifying field of epigenetics, ‘the study of mechanisms that regulate gene expression in response to environmental signals’, has profoundly complicated ‘the gene-centrism and genetic reductionism of the genomic age’ and as such constitutes ‘an archetypal postgenomic science’.37 She then discusses Jay Bernard’s ‘Chemical’ (2019), a poetic testimony to, and elegy for, the death of residents (many of whom were not British citizens) in the 2017 Grenfell Tower fire in West London. Reading ‘Chemical’ alongside the state’s problematic enquiry into soil contamination around Grenfell, Choksey demonstrates how Grenfell’s surviving residents have been subjected to state-endorsed environmental racialisation. The ghostly presences in Bernard’s poem, in contrast, work against such fixing and ‘stay [...] with the dead’ in ways that suggest ‘the messiness of entanglements between the living and the dead, as well as their endurance’, and that emphasise ‘influence, reparation and responsibility’.38Lara Choksey examines what it is possible to know about environmental ‘influence’ in the context of epigenetic research. While epigenetics may trouble models of genetic determinism that seek to produce categories of ‘race’, and while it may hold reparative potential in contexts of health inequalities, Choksey evidences the ways in which epigenetic studies may also ‘participate in processes of environmental racialisation’: ‘The logic moves from the racialisation of defect to the racialisation of defective influence’, and environments become racialised ‘through imaginaries of bad influence’.The articles collected in this special issue testify to the vibrancy and vision of creative genetic imaginaries. Genetic fictions show how epistemological, political and bioeth-ical debates play out in the context of real and imagined lives and relations, and allow different ways of knowing to exist alongside one another. With this special issue we hope to contribute to the growing momentum in a rich area of the critical medical humanities, in particular by emphasising the diversity of epistemological frameworks for apprehending the applications and implications of genetic science. The relationship between genetic fictions and emerging bioscientific knowledge may be one of commentary, reflection, influence, critique, affirmation, inspiration, amplification and/or distortion, but there is no doubt that cultural texts and their critical analysis have much to offer in the unfolding context of postgenomic meaning-making.