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REPORT: Multi-Input RNAi-Based Logic Circuit for Identification of Specific Cancer Cells
Engineered biological systems that integrate multi-input sensing, sophisticated information processing, and precisely regulated actuation in living cells could be useful in a variety of applications. For example, anticancer therapies could be engineered to detect and respond to complex cellular conditions in individual cells with high specificity. Here, we show a scalable transcriptional/posttranscriptional synthetic regulatory circuit—a cell—type "classifier"—that senses expression levels of a customizable set of endogenous microRNAs and triggers a cellular response only if the expression levels match a predetermined profile of interest. We demonstrate that a HeLa cancer cell classifier selectively identifies HeLa cells and triggers apoptosis without affecting non-HeLa cell types. This approach also provides a general platform for programmed responses to other complex cell states.
Supporting online material
EDITORIAL: A Grand Challenge in Biology
Richard Feynman, a brilliant Nobel Prize–winning physicist, is often quoted for his statement that "What I cannot create, I do not understand." The remarkable advances in our knowledge of the chemistry of life achieved in the past few decades, published in Science
and many other journals, could lead nonexperts to assume that biologists are coming close to a real understanding of cells. On the contrary, as scientists learn more and more, we have increasingly come to recognize how huge the challenge is that confronts us. In this special issue, we review the progress made in the decade-old field called synthetic biology, which, as Feynman would advocate, creates biological networks in order to help us understand, and in some cases redesign, living systems. Along with its promise for the biotechnology industry, synthetic biology has the potential to become a powerful new tool for the long-term fundamental research needed to more effectively create breakthroughs in improving human health and welfare and the environment.
PERSPECTIVE: Demystifying DNA Demethylation
Variability and adaptability are necessary for overcoming the challenges of multicellular life. To address this need, nature has evolved a substantial enzymatic toolbox for altering cytosine within the genome. Methylation of the nucleotide cytosine (C) at the 5-position of the base has profound impacts on gene expression and cellular identity. The reverse of this process, DNA demethylation, is equally important for cleaning the genomic slate during embryogenesis or achieving rapid reactivation of previously silenced genes. Although the mechanism of DNA methylation has been rigorously established, active DNA demethylation in mammals has remained enigmatic, as disparate observations have failed to coalesce into a consistent model. Cytosine deamination, oxidation, and base excision repair enzymes have been proposed in a dizzying variety of combinations (1). Against this backdrop, two reports in this issue, by Ito et al
. (2) on page 1300 of the 2 September 2011 issue of Science
and He et al
. on page 1303 of the 2 September 2011 issue of Science
(3), help bring new clarity to the mechanistic model for DNA demethylation.
REPORT: The Endocast of MH1, Australopithecus sediba
The virtual endocast of MH1 (Australopithecus sediba
), obtained from high-quality synchrotron scanning, reveals generally australopith-like convolutional patterns on the frontal lobes but also some foreshadowing of features of the human frontal lobes, such as posterior repositioning of the olfactory bulbs. Principal component analysis of orbitofrontal dimensions on australopith endocasts (MH1, Sts 5, and Sts 60) indicates that among these, MH1 orbitofrontal shape and organization align most closely with human endocasts. These results are consistent with gradual neural reorganization of the orbitofrontal region in the transition from Australopithecus
, but given the small volume of the MH1 endocast, they are not consistent with gradual brain enlargement before the transition. Supporting online material
REPORT: Australopithecus sediba at 1.977 Ma and Implications for the Origins of the Genus Homo
Newly exposed cave sediments at the Malapa site include a flowstone layer capping the sedimentary unit containing the Australopithecus sediba
fossils. Uranium-lead dating of the flowstone, combined with paleomagnetic and stratigraphic analysis of the flowstone and underlying sediments, provides a tightly constrained date of 1.977 ± 0.002 million years ago (Ma) for these fossils. This refined dating suggests that Au. sediba
from Malapa predates the earliest uncontested evidence for Homo
Supporting online material
NEWS FOCUS: Which Way to the Island?
Theories of nuclear structure predict that certain key numbers of protons and neutrons in a nucleus, known as magic numbers, make it more stable and hence longer-lived than would normally be the case. Superheavy-element researchers call this area of the chart of nuclides, around the confluence of proton and neutron magic numbers, the island of stability. The half-lives of some of the heaviest elements made so far do show signs of increased stability, suggesting that those nuclei are on the shores of the island. Moving farther inland is an enticing prospect because the atoms we may find there could be exotic creatures indeed. But for the time being, the summit of the island's peak is out of reach because physicists haven't devised a way of making nuclei with enough neutrons.
RESEARCH ARTICLE: Kepler-16: A Transiting Circumbinary Planet
We report the detection of a planet whose orbit surrounds a pair of low-mass stars. Data from the Kepler spacecraft reveal transits of the planet across both stars, in addition to the mutual eclipses of the stars, giving precise constraints on the absolute dimensions of all three bodies. The planet is comparable to Saturn in mass and size and is on a nearly circular 229-day orbit around its two parent stars. The eclipsing stars are 20 and 69% as massive as the Sun and have an eccentric 41-day orbit. The motions of all three bodies are confined to within 0.5° of a single plane, suggesting that the planet formed within a circumbinary disk.
Supporting online material
REPORT: A Diverse Assemblage of Late Cretaceous Dinosaur and Bird Feathers from Canadian Amber
The fossil record of early feathers has relied on carbonized compressions that lack fine structural detail. Specimens in amber are preserved in greater detail, but they are rare. Late Cretaceous coal-rich strata from western Canada provide the richest and most diverse Mesozoic feather assemblage yet reported from amber. The fossils include primitive structures closely matching the protofeathers of nonavian dinosaurs, offering new insights into their structure and function. Additional derived morphologies confirm that plumage specialized for flight and underwater diving had evolved in Late Cretaceous birds. Because amber preserves feather structure and pigmentation in unmatched detail, these fossils provide novel insights regarding feather evolution.
Supporting online material
PERSPECTIVE: Converging on an HIV Vaccine
Three decades after the discovery of AIDS we still do not have a vaccine against the causative agent, the human immunodeficiency virus (HIV). Multidrug therapy can extend life and health for those with HIV, but only holds the virus at bay, making treatment a lifetime proposition. Access to treatment or other promising infection prevention measures such as topical microbicides (1) are an economic and social challenge (2). A vaccine would be a simple and direct strategy for prevention. On pages 1593 and 1633 of the 16 September 2011 issue of Science
, Wu et al
. (3) and Scheid et al
. (4) detail the trajectory of an immune response to natural HIV infection that may provide a path to a vaccine.
NEWS & ANALYSIS: Aboriginal Genome Shows Two-Wave Settlement of Asia
Almost a century ago, British anthropologist Alfred Cort Haddon traveled the world seeking samples of human hair, among other curios, for his ethnographic studies of native people. The samples, which lay in a museum drawer for 90 years, included hair from a young Australian Aboriginal man. Now in a paper published online from the 23 September 2011 issue of Science
, geneticists report that they have extracted enough DNA from that hair to sequence the first complete genome of an Aboriginal. The genome offers the first good look at the origins of Aboriginals, showing that they are one of the oldest continuous populations outside of Africa, the authors say.
REPORT: Inbreeding Promotes Female Promiscuity
The widespread phenomenon of polyandry (mating by females with multiple males) is an evolutionary puzzle, because females can sustain costs from promiscuity, whereas full fertility can be provided by a single male. Using the red flour beetle, Tribolium castaneum
, we identify major fitness benefits of polyandry to females under inbreeding, when the risks of fertilization by incompatible male haplotypes are especially high. Fifteen generations after inbred populations had passed through genetic bottlenecks, we recorded increased levels of female promiscuity compared with noninbred controls, most likely due to selection from prospective fitness gains through polyandry. These data illustrate how this common mating pattern can evolve if population genetic bottlenecks increase the risks of fitness depression due to fertilization by sperm carrying genetically incompatible haplotypes.
Supporting online material
EDUCATION FORUM: The Pseudoscience of Single-Sex Schooling
In attempting to improve schools, it is critical to remember that not all reforms lead to meaningful gains for students. We argue that one change in particular—sex-segregated education—is deeply misguided, and often justified by weak, cherry-picked, or misconstrued scientific claims rather than by valid scientific evidence. There is no well-designed research showing that single-sex (SS) education improves students' academic performance, but there is evidence that sex segregation increases gender stereotyping and legitimizes institutional sexism.
In Science Signaling
Inositol Pyrophosphates as Mammalian Cell Signals
Abstract: Inositol pyrophosphates are highly energetic inositol polyphosphate molecules present in organisms from slime molds and yeast to mammals. Distinct classes of enzymes generate different forms of inositol pyrophosphates. The biosynthesis of these substances principally involves phosphorylation of inositol hexakisphosphate (IP6) to generate the pyrophosphate IP7. Initial insights into functions of these substances derived primarily from yeast, which contain a single isoform of IP6 kinase (γIP6K), as well as from the slime mold Dictyostelium. Mammalian functions for inositol pyrophosphates have been investigated by using cell lines to establish roles in various processes, including insulin secretion and apoptosis. More recently, mice with targeted deletion of IP6K isoforms as well as the related inositol polyphosphate multikinase(IPMK) have substantially enhanced our understanding of inositol polyphosphate physiology. Phenotypic alterations in mice lacking inositol hexakisphosphate kinase 1 (IP6K1) reveal signaling roles for these molecules in insulin homeostasis, obesity, and immunological functions. Inositol pyrophosphates regulate these processes at least in part by inhibiting activation of the serine-threonine kinase Akt. Similar studies of IP6K2 establish this enzyme as a cell death inducer acting by stimulating the proapoptotic protein p53. IPMK is responsible for generating the inositol phosphate IP5 but also has phosphatidylinositol 3-kinase activity—that participates in activation of Akt. Here, we discuss recent advances in understanding the physiological functions of the inositol pyrophosphates based in substantial part on studies in mice with deletion of IP6K isoforms. These findings highlight the interplay of IPMK and IP6K in regulating growth factor and nutrient-mediated cell signaling.
RESEARCH ARTICLE: Small Molecule–Mediated Activation of the Integrin CD11b/CD18 Reduces Inflammatory Disease
Abstract: The integrin CD11b/CD18 (also known as Mac-1), which is a heterodimer of the αM (CD11b) and β2 (CD18) subunits, is critical for leukocyte adhesion and migration and for immune functions. Blocking integrin-mediated leukocyte adhesion, although beneficial in experimental models, has had limited success in treating inflammatory diseases in humans. Here, we used an alternative strategy of inhibiting leukocyte recruitment by activating CD11b/CD18 with small-molecule agonists, which we term leukadherins. These compounds increased the extent of CD11b/CD18-dependent cell adhesion of transfected cells and of primary human and mouse neutrophils, which resulted in decreased chemotaxis and transendothelial migration. Leukadherins also decreased leukocyte recruitment and reduced arterial narrowing after injury in rats. Moreover, compared to a known integrin antagonist, leukadherins better preserved kidney function in a mouse model of experimental nephritis. Leukadherins inhibited leukocyte recruitment by increasing leukocyte adhesion to the inflamed endothelium, which was reversed with a blocking antibody. Thus, we propose that pharmacological activation of CD11b/CD18 offers an alternative therapeutic approach for inflammatory diseases.
PERSPECTIVE: Met Receptor: A Moving Target
Abstract: The activated hepatocyte growth factor (HGF) receptor (Met) undergoes rapid endocytosis and ubiquitin-dependent sorting to the lysosomal degradative pathway. New data suggest that this mode of down-regulation can be circumvented by mutant receptors bearing kinase-activating mutations that instead recycle to the plasma membrane. These mutant receptors can elicit enhanced signaling from endosomes, which is critical for cell motility and tumorigenesis. A proportion of HGF-activated wild-type receptors will also take the endosomal recycling route. This requires the recruitment of the adaptor protein GGA3, mediated through the interaction of GGA3 with the activated form of the small guanosine triphosphatase Arf6 and indirect binding to phosphorylated Met receptor through the adaptor protein Crk. This ability of receptors and effectors to be spatially controlled by the endosomal recycling pathway may play a prominent role in cellular functions such as motility.
RESEARCH ARTICLE: A Synthetic Biology Approach Reveals a CXCR4-G13-Rho Signaling Axis Driving Transendothelial Migration of Metastatic Breast Cancer Cells
Abstract: Tumor cells can co-opt the promigratory activity of chemokines and their cognate G protein–coupled receptors (GPCRs) to metastasize to regional lymph nodes or distant organs. Indeed, the migration toward SDF-1 (stromal cell–derived factor 1) of tumor cells bearing CXCR4 [chemokine (C-X-C motif) receptor 4] has been implicated in the lymphatic and organ-specific metastasis of various human malignancies. Here, we used chimeric G proteins and GPCRs activated solely by artificial ligands to selectively activate the signaling pathways downstream of specific G proteins and showed that CXCR4-mediated chemotaxis and transendothelial migration of metastatic basal-like breast cancer cells required activation of Gα13, a member of the Gα12/13 G protein family, and of the small guanosine triphosphatase Rho. Multiple complementary experimental strategies, including synthetic biology approaches, indicated that signaling-selective inhibition of the CXCR4-Gα13-Rho axis prevents the metastatic spread of basal-like breast cancer cells.
In Science Translational Medicine
RESEARCH ARTICLE: Noninvasive Electroanatomic Mapping of Human Ventricular Arrhythmias with Electrocardiographic Imaging
Abstract: The rapid heartbeat of ventricular tachycardia (VT) can lead to sudden cardiac death and is a major health issue worldwide. Efforts to identify patients at risk, determine mechanisms of VT, and effectively prevent and treat VT through a mechanism-based approach would all be facilitated by continuous, noninvasive imaging of the arrhythmia over the entire heart. Here, we present noninvasive real-time images of human ventricular arrhythmias using electrocardiographic imaging (ECGI). Our results reveal diverse activation patterns, mechanisms, and sites of initiation of human VT. The spatial resolution of ECGI is superior to that of the routinely used 12-lead electrocardiogram, which provides only global information, and ECGI has distinct advantages over the currently used method of mapping with invasive catheter-applied electrodes. The spatial resolution of this method and its ability to image electrical activation sequences over the entire ventricular surfaces in a single heartbeat allowed us to determine VT initiation sites and continuation pathways, as well as VT relationships to ventricular substrates, including anatomical scars and abnormal electrophysiological substrate. Thus, ECGI can map the VT activation sequence and identify the location and depth of VT origin in individual patients, allowing personalized treatment of patients with ventricular arrhythmias.
PERSPECTIVE: Hidden Immunotherapy Targets Challenge Dogma
Abstract: In 7 September 2011 issue of Science Translational Medicine, Guo et al. discuss the intriguing possibility that intracellular tumor antigen–specific monoclonal antibodies (mAbs) inhibit tumor growth and metastasis and prolong survival of tumor-bearing mice. Here, I discuss the implications of using intracellular targets in mAb-based immunotherapy as well as the possible underlying mechanisms of action.
RESEARCH ARTICLE: Gαs-Biased β2-Adrenergic Receptor Signaling from Restoring Synchronous Contraction in the Failing Heart
Abstract: Cardiac resynchronization therapy (CRT), in which both ventricles are paced to recoordinate contraction in hearts that are dyssynchronous from conduction delay, is the only heart failure (HF) therapy to date to clinically improve acute and chronic function while also lowering mortality. CRT acutely enhances chamber mechanical efficiency but chronically alters myocyte signaling, including improving β-adrenergic receptor reserve. We speculated that the latter would identify unique CRT effects that might themselves be effective for HF more generally. HF was induced in dogs by 6 weeks of atrial rapid pacing with (HFdys, left bundle ablated) or without (HFsyn) dyssynchrony. We used dyssynchronous followed by resynchronized tachypacing (each 3 weeks) for CRT. Both HFdys and HFsyn myocytes had similarly depressed rest and β-adrenergic receptor sarcomere and calcium responses, particularly the β2-adrenergic response, whereas cells subjected to CRT behaved similarly to those from healthy controls. CRT myocytes exhibited suppressed Gai signaling linked to increased regulator of G protein (heterotrimeric guanine nucleotide–binding protein) signaling (RGS2, RGS3), yielding Gas-biased β2-adrenergic responses. This included increased adenosine cyclic AMP responsiveness and activation of sarcoplasmic reticulum–localized protein kinase A. Human CRT responders also showed up-regulated myocardial RGS2 and RGS3. Inhibition of Gαi (with pertussis toxin, RGS3, or RGS2 transfection), stimulation with a Gαs-biased β2 agonist (fenoterol), or transient (2-week) exposure to dyssynchrony restored β-adrenergic receptor responses in HFsyn to the values obtained after CRT. These results identify a key pathway that is triggered by restoring contractile synchrony and that may represent a new therapeutic approach for a broad population of HF patients.
RESEARCH ARTICLE: A Plasmablast Biomarker for Nonresponse to Antibody Therapy to CD20 in Rheumatoid Arthritis
Abstract: An important goal for personalized health care is the identification of biomarkers that predict the likelihood of treatment responses. Here, we tested the hypothesis that quantitative mRNA assays for B lineage cells in blood could serve as baseline predictors of therapeutic response to B cell depletion therapy in subjects with rheumatoid arthritis (RA). In samples from the REFLEX trial of rituximab in inadequate responders to antibodies to tumor necrosis factor–α, a 25% subgroup of treated subjects with elevated baseline mRNA levels of IgJ, a marker for antibody-secreting plasmablasts, showed reduced clinical response rates. There were no significant efficacy differences in the placebo arm subjects stratified by this marker. Prospective testing of the IgJ biomarker in the DANCER and SERENE rituximab clinical trial cohorts and the SCRIPT ocrelizumab cohort confirmed the utility of this marker to predict nonresponse to anti-CD20 therapy. A combination mRNA biomarker, IgJhiFCRL5lo, showed improved test performance over IgJhi alone. This study demonstrates that baseline blood levels of molecular markers for late-stage B lineage plasmablasts identify a ~20% subgroup of active RA subjects who are unlikely to gain substantial clinical benefit from anti-CD20 B cell depletion therapy.
IMAGE CREDITS (In order of appearance): HENNING DALHOFF/BONNIER PUBLICATIONS/PHOTO RESEARCHERS, INC, GSI HELMHOLTZZENTRUM FÜR SCHWERIONENFORSCHUNG, A. ZSCHAU, CATHERINE YEULET/ISTOCKPHOTO.COM