Science Roundup


Single-Cell Mass Cytometry of Differential Immune and Drug Responses Across a Human Hematopoietic Continuum

Flow cytometry is an essential tool for dissecting the functional complexity of hematopoiesis. We used single-cell “mass cytometry” to examine healthy human bone marrow, measuring 34 parameters simultaneously in single cells (binding of 31 antibodies, viability, DNA content, and relative cell size). The signaling behavior of cell subsets spanning a defined hematopoietic hierarchy was monitored with 18 simultaneous markers of functional signaling states perturbed by a set of ex vivo stimuli and inhibitors. The data set allowed for an algorithmically driven assembly of related cell types defined by surface antigen expression, providing a superimposable map of cell signaling responses in combination with drug inhibition. Visualized in this manner, the analysis revealed previously unappreciated instances of both precise signaling responses that were bounded within conventionally defined cell subsets and more continuous phosphorylation responses that crossed cell population boundaries in unexpected manners yet tracked closely with cellular phenotype. Collectively, such single-cell analyses provide system-wide views of immune signaling in healthy human hematopoiesis, against which drug action and disease can be compared for mechanistic studies and pharmacologic intervention. See the related perspective here.


Red in Tooth and Claw Among the Literati

Some literary scholars have begun incorporating neuroscience, cognitive science, anthropology, and—most prominently and controversially—evolutionary psychology into their work. Their work explores how evolution might have shaped aspects of literature, the potential adaptive benefits of storytelling for our Pleistocene ancestors, and the mystery of why humans spend so much time immersed in it. Evolution provides a framework for understanding human behavior; evolutionary psychology explores the origins of mental phenomena and can bridge evolutionary biology and the humanities. Some recent evopsychology also emphasizes the plasticity of the human mind, which helps explain how universal human behaviors (such as storytelling) can exist but can nevertheless be expressed in different ways in different cultures. Many scientists encourage this work, although applying evolutionary thought to the human mind has never been popular in the humanities. But since 2007, the number of books and articles incorporating Darwinian and other scientific thought into literary studies has more than doubled. These scholars are convinced not only that evolutionary thought can improve literary research but also that literature can teach scientists a thing or two about human evolution.


Scaffold Proteins: Hubs for Controlling the Flow of Cellular Information

The spatial and temporal organization of molecules within a cell is critical for coordinating the many distinct activities carried out by the cell. In an increasing number of biological signaling processes, scaffold proteins have been found to play a central role in physically assembling the relevant molecular components. Although most scaffolds use a simple tethering mechanism to increase the efficiency of interaction between individual partner molecules, these proteins can also exert complex allosteric control over their partners and are themselves the target of regulation. Scaffold proteins offer a simple, flexible strategy for regulating selectivity in pathways, shaping output behaviors, and achieving new responses from preexisting signaling components. As a result, scaffold proteins have been exploited by evolution, pathogens, and cellular engineers to reshape cellular behavior.


The Emerging Race to Cure HIV Infections

Four years after Timothy Ray Brown received bone-marrow transplants to fight leukemia, the most sophisticated labs in the world cannot find any trace in his body of the HIV that had infected him for 12 years. Brown is the only living human, a growing consensus contends, to be cured. Brown's treatment clearly does not offer a road map for many others. After all, the expensive, complex, and risky transplant only made sense because Brown was dying from leukemia. Nor is it clear exactly which components of the extensive transplant regimen cleared the virus from his body. But Brown's case has moved the much-ridiculed idea of curing HIV onto the most scientifically solid ground it has yet occupied, say leading AIDS researchers. Brown's case showed for the first time that it is possible to rid the body of the virus—even from the minuscule reservoirs where the virus can hide out for years, evading both the immune system and antiretroviral drugs (ARVs). His astonishing turnaround also raised hopes that other, more practical drugs and immune system modulators might find and destroy every last bit of virus—or at least reduce it to such low levels that people no longer need ARVs.


Improved Learning in a Large-Enrollment Physics Class

We compared the amounts of learning achieved using two different instructional approaches under controlled conditions. We measured the learning of a specific set of topics and objectives when taught by 3 hours of traditional lecture given by an experienced highly rated instructor and 3 hours of instruction given by a trained but inexperienced instructor using instruction based on research in cognitive psychology and physics education. The comparison was made between two large sections (N = 267 and N = 271) of an introductory undergraduate physics course. We found increased student attendance, higher engagement, and more than twice the learning in the section taught using research-based instruction.

Did Neandertals Linger in Russia's Far North?

On page 841 of this week's issue of Science, a research team claims that some of the last Neandertals may have taken refuge in the dark Arctic north rather than the sunny south as archaeological evidence has indicated. At the 32,000-year-old site of Byzovaya in Russia's Polar Ural Mountains, which at 65 degrees latitude is as far north as Iceland, archaeologists found stone tools they argue are typical of those long associated with Neandertals in Europe. If Neandertals did make the tools, it would push Neandertals' range northward by 1000 kilometers, and the site would be one of the youngest claimed for Neandertals, especially since recent redating has moved many Neandertal sites earlier in time. It would also show that the cold-adapted Neandertals could survive the rigors of the Arctic.

New Work Reinforces Megaquake's Harsh Lessons in Geoscience

The moment the Tohoku-Oki earthquake struck off northern Japan on 11 March, many researchers knew their expectations had been shattered. The great offshore fault could not be counted on to behave at all predictably. And using onshore observations to gauge whether an offshore fault is building toward failure has grave limitations. Now three papers published online this week in Science help show why the inevitable release of seismic energy failed to play out as expected and why monitoring from afar fell short. The papers also point to a possible huge quake to the south, closer to Tokyo. Seismologists are concerned, but they are also now acutely aware of their limitations.

Fukushima Revives The Low-Dose Debate

The ongoing crisis at Japan's Fukushima Daiichi nuclear power plant has thrust several thousand of Fukushima's 2 million residents into the middle of a scientific debate about the health effects of long-term exposure to low levels of radiation. Some researchers believe even unavoidable background radiation can be a factor in causing cancer. Others argue that tiny doses of radiation are not harmful. Some scientists even claim that low doses, by stimulating DNA repair, make you healthier—an effect known as hormesis. Studies in Fukushima could help clarify the picture. But getting answers will not be easy. Radiation exposure levels for most people were elevated so minutely above background that it may be impossible to tease out carcinogenic effects from other risk factors, such as smoking or diet. That has experts wondering whether and how to carry out such studies. A population study could nevertheless pay off scientifically.

Evolving Large and Complex Brains

During the Mesozoic (~250 million to 65 million years ago), two distantly related groups of reptiles—the cynodont (or mammal-like) reptiles and the coelurosaurian theropod dinosaurs—gave rise to mammals and birds, respectively. Both mammals and birds evolved brains some 10 times as large, relative to a given body weight, as those of their ancestors (1). In both groups, these brains contributed to the evolution of the ability to control body temperature (endothermy) and complex social interactions, including parental care and a reliance on learning that even involves tool use (2, 3). The size of most parts of the brain increased in birds and mammals, but the cerebral hemispheres and cerebellum, both of which are involved in sensory and motor integration, underwent particularly spectacular development (see the figure). Although mammals and birds evolved from distantly related groups of reptiles, the higher integrative centers and circuitry of their cerebral hemispheres are very similar, and comparative neurobiologists continue to vigorously debate whether these centers evolved from the same ancestral neural centers (4, 5) or from different ones (6–8). Speculation about the evolutionary steps leading to large and complex mammalian and avian brains is equally contentious and unresolved, in part because of the rarity of fossil skulls and, until recently, the need to destroy such skulls in order to expose the endocasts (casts molded by the cranial cavity). Typically, endocasts are the only record of the brain's outward appearance in a transitional form, because brains themselves are rarely fossilized.

Dyscalculia: From Brain to Education

Recent research in cognitive and developmental neuroscience is providing a new approach to the understanding of dyscalculia that emphasizes a core deficit in understanding sets and their numerosities, which is fundamental to all aspects of elementary school mathematics. The neural bases of numerosity processing have been investigated in structural and functional neuroimaging studies of adults and children, and neural markers of its impairment in dyscalculia have been identified. New interventions to strengthen numerosity processing, including adaptive software, promise effective evidence-based education for dyscalculic learners.

The Prion Heretic

For 30 years, Laura Manuelidis of Yale School of Medicine has rejected the dominant theory that misfolded proteins called prions are the infectious agents behind a cluster of rare, transmissible, and fatal brain diseases called transmissible spongiform encephalopathies. When first proposed by Stanley Prusiner, the theory was widely dismissed as bizarre. Biology then held that infectious disease was caused by organisms built from DNA, RNA, or both, like viruses and bacteria—something containing a nucleic acid sequence that can replicate and spread through a cell. Proteins lack these sequences. But today, Prusiner's view dominates. Manuelidis regards the protein not as the cause of infection but as a pathological reaction to it and believes that mad cow disease and others like it are triggered by viruses—although no one has found them. She's not the only prion doubter, but her voice is by far the loudest. In part that's because as a tenured professor she's safe. Her unpopularity among top prion scientists leaves her unfazed.

Differences Between Tight and Loose Cultures: A 33-Nation Study

With data from 33 nations, we illustrate the differences between cultures that are tight (have many strong norms and a low tolerance of deviant behavior) versus loose (have weak social norms and a high tolerance of deviant behavior). Tightness-looseness is part of a complex, loosely integrated multilevel system that comprises distal ecological and historical threats (e.g., high population density, resource scarcity, a history of territorial conflict, and disease and environmental threats), broad versus narrow socialization in societal institutions (e.g., autocracy, media regulations), the strength of everyday recurring situations, and micro-level psychological affordances (e.g., prevention self-guides, high regulatory strength, need for structure). This research advances knowledge that can foster cross-cultural understanding in a world of increasing global interdependence and has implications for modeling cultural change.

In Science Signaling

a-Catenin Is a Tumor Suppressor That Controls Cell Accumulation by Regulating the Localization and Activity of the Transcriptional Coactivator Yap1

The Hippo pathway regulates contact inhibition of cell proliferation and, ultimately, organ size in diverse multicellular organisms. Inactivation of the Hippo pathway promotes nuclear localization of the transcriptional coactivator Yap1, a Hippo pathway effector, and can cause cancer. Here, we show that deletion of aE (a epithelial) catenin in the hair follicle stem cell compartment resulted in the development of skin squamous cell carcinoma in mice. Tumor formation was accelerated by simultaneous deletion of aE-catenin and the tumor suppressor–encoding gene p53. A small interfering RNA screen revealed a functional connection between aE-catenin and Yap1. By interacting with Yap1, aE-catenin promoted its cytoplasmic localization, and Yap1 showed constitutive nuclear localization in aE-catenin–null cells. We also found an inverse correlation between aE-catenin abundance and Yap1 activation in human squamous cell carcinoma tumors. These findings identify aE-catenin as a tumor suppressor that inhibits Yap1 activity and sequesters it in the cytoplasm.

In Science Translational Medicine

Genetic Testing Enters the Genomic Era

Regulatory T cells (Tregs) manipulated ex vivo have potential as cellular therapeutics in autoimmunity and transplantation. Although it is possible to expand naturally occurring Tregs, an attractive alternative possibility, particularly suited to solid organ and bone marrow transplantation, is the stimulation of total T cell populations with defined allogeneic antigen-presenting cells (APCs) under conditions that lead to the generation or expansion of donor-reactive, adaptive Tregs. Here we demonstrate that stimulation of mouse CD4+ T cells by immature allogeneic dendritic cells combined with pharmacological inhibition of phosphodiesterase 3 (PDE) resulted in a functional enrichment of Foxp3+ T cells. Without further manipulation or selection, the resultant population delayed skin allograft rejection mediated by polyclonal CD4+ effectors or donor-reactive CD8+ T cell receptor transgenic T cells and inhibited both effector cell proliferation and T cell priming for interferon-? production. Notably, PDE inhibition also enhanced the enrichment of human Foxp3+ CD4+ T cells driven by allogeneic APCs. These cells inhibited T cell proliferation in a standard in vitro mixed lymphocyte assay and, moreover, attenuated the development of vasculopathy mediated by autologous peripheral blood mononuclear cells in a functionally relevant humanized mouse transplant model. These data establish a method for the ex vivo generation of graft-reactive, functional mouse and human Tregs that uses a clinically approved agent, making pharmacological PDE inhibition a potential strategy for Treg-based therapies.

IMAGE CREDITS (In order of appearance): M.TWOMBLY/SCIENCE, BLOOMBERG/GETTY IMAGES, JOHN-INGE SVENDSEN; L. SLIMAK ET AL., SCIENCE (2), MICHAEL MARSLAND/ YALE UNIVERSITY OFFICE OF PUBLIC AFFAIRS