Can’t count sheep? You could have aphantasia

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If counting sheep is an abstract concept, or you are unable to visualise the faces of loved ones, you could have aphantasia — a newly defined condition to describe people who are born without a “mind’s eye.”

Some people report a significant impact on their lives from being unable to visualise memories of their partners, or departed relatives. Others say that descriptive writing is meaningless to them, and careers such as architecture or design are closed to them, as they would not be able to visualise an end product.

Cognitive neurologist Professor Adam Zeman, at the University of Exeter Medical School, has revisited the concept of people who cannot visualise, which was first identified by Sir Francis Galton in 1880 A 20th century survey suggested that this may be true of 2.5% of the population — yet until now, this phenomenon has remained largely unexplored.

Visualisation is the result of activity in a network of of regions widely distributed across the brain, working together to enable us to generate images on the basis of our memory of how things look. These regions include areas in the frontal and parietal lobes, which ‘organise’ the process of visualisation, together with areas in the temporal and occipital lobes, which represent the items we wish to call to the mind’s eye, and give visualisation its ‘visual’ feel. An inability to visualise could result from an alteration of function at several points in this network. This problem has been described previously following major brain damage and in the context of mood disorder. Now, Professor Zeman and his team are conducting further studies to find out more about why some people are born with poor or diminished visual imagery ability.

The recent research came about by serendipity. The American science journalist, Carl Zimmer, wrote an article in Discover magazine about a previous paper by Professor Zeman reporting a man who lost his mind’s eye in his sixties following a cardiac procedure. Professor Zeman was then contacted by 21 individuals who recognised their own experience in the Discover article, but had never been able to imagine. Professor Zeman and colleagues describe these patients’ experience in a paper just published in the journal Cortex.

One of the responders, Tom Ebeyer, 25, from Ontario, Canada, keenly felt a sense of loss when he realised at the age of 21 that his girlfriend could visually “see” things in her mind’s eye in a way that he could not.

Tom said: “It had a serious emotional impact. I began to feel isolated — unable to do something so central to the average human experience. The ability to recall memories and experiences, the smell of flowers or the sound of a loved one’s voice; before I discovered that recalling these things was humanly possible, I wasn’t even aware of what I was missing out on. The realisation did help me to understand why I am a slow at reading text, and why I perform poorly on memorisation tests, despite my best efforts.”

For Tom, all types of sense are affected. He cannot conjure up any sound, texture, taste, smell, emotion, or any other type of imagery.

He said the condition had severely affected his relationships, as he is unable to visualise his partner if they are not together, or to recall shared experiences. He said: “After the passing of my mother, I was extremely distraught in that I could not reminisce on the memories we had together. I can remember factually the things we did together, but never an image. After seven years, I hardly remember her.”

“To have the condition researched and defined brings me great pleasure. Not only do I now have an official title to refer to the condition while discussing it with my peers, but the knowledge that professionals are recognising its reality gives me hope that further understanding is still to come.”

Niel Kenmuir, 39, from Lancaster in the UK, first realised he could not visualise images at primary school. “I can remember not understanding what ‘counting sheep’ entailed when I couldn’t sleep. I assumed they meant it in a figurative sense. When I tried it myself, I found myself turning my head to watch invisible sheep fly by. I’ve spent years looking online for information about my condition, and finding nothing. I’m very happy that it is now being researched and defined.”

Niel works in a bookshop and is an avid reader, but avoids books with vivid landscape descriptions as they bring nothing to mind for him. “I just find myself going through the motion of reading the words without any image coming to mind,” he said. “I usually have to go back and read a passage about a visual description several times — it’s almost meaningless.”

Niel studied philosophy, which is rich in visual imagery, but this aspect was lost on him. The way he explains it, though, he does understand the mechanics behind it. He said: “The mind’s eye is a canvas, and the neurones work together to project onto it. The neurones are all working fine, but I don’t have the canvas.”

Asked if it had impacted on his life, he said: “I have never been ambitious, and wondered if an inability to ‘imagine myself in a place ten years from now’ as a concrete image has affected this. I also find it difficult to jump from abstract thought to concrete examples, although I think a positive consequence is that I am perhaps better at thinking abstractly than many other people.”

Professor Zeman said: “This intriguing variation in human experience has received little attention. Our participants mostly have some first-hand knowledge of imagery through their dreams: our study revealed an interesting dissociation between voluntary imagery, which is absent or much reduced in these individuals, and involuntary imagery, for example in dreams, which is usually preserved.”

Professor Zeman is pursuing the study of aphantasia through an interdisciplinary project funded by the Arts and Humanities Research Council (AHRC), The Eye’s Mind — a study of the neural basis of visual imagination and its role in culture. The AHRC project involves, among others, the artist Susan Aldworth, art historian John Onians and philosopher, Fiona Macpherson.

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The above post is reprinted from materials provided by University of Exeter.

Epigenomic changes are key to innate immunological memory

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A research team led by Keisuke Yoshida and Shunsuke Ishii of the RIKEN Molecular Genetics Laboratory has revealed that epigenomic changes induced by pathogen infections, mediated by a transcription factor called ATF7, are the underlying mechanism of the memory of innate immunity.

It was long believed that acquired immunity — a type of immunity mediated by T- and B-cells — had memory, meaning that it could learn from new pathogens, making subsequent reactions more effective, whereas innate immunity — which is mediated by macrophages and other types of cells that react to certain molecules typically associated with pathogens — did not. However, it gradually became clear that things were not so simple. Plants and insects, which only have innate immunity, also seem to have immunological memory. Further, it has been reported that herpes virus infection increases the resistance against bacteria in vertebrates. These phenomena suggest that innate immunity also has memory, but researchers have been reluctant to accept the hypothesis given the lack of a mechanism Now, in research published in Nature Immunology, a research team led by Keisuke Yoshida and Shunsuke Ishii of the RIKEN Molecular Genetics Laboratory has revealed that epigenomic changes induced by pathogen infections, mediated by a transcription factor called ATF7, are the underlying mechanism of the memory of innate immunity.

The research began from the discovery that in ATF7 knockout mice, macrophages appear similar to wild-type macrophages that have been activated by exposure to molecules that occur commonly in infections. The group had previously reported that ATF7-related transcription factors mediated epigenomic changes induced by heat shock or psychological stress, and that these changes were maintained for long periods after the exposure to the stress. Therefore, they speculated that infections by pathogens could induce epigenome changes in macrophages via ATF7.

The group discovered that ATF7 binds to a group of innate immune genes and by doing so silences their expression, making the cell less responsive to infections. However, upon administration of lipopolysaccharidel (LPS), a molecule found in the outer membrane of Gram-negative bacteria, into mice, ATF7 was phosphorylated, weakening its activity so that immune-related genes were no longer silenced. Shunsuke Ishii, who led the group, says, “We were intrigued to find that even three weeks after the administration, the genes still showed increased activation. In mice, this status was shown to lead to increased resistance to Staphylococcus aureus, a Gram-positive bacteria.”

According to Ishii, this finding could increase our understanding of what is known as the “hygiene hypothesis” — the concept that pathogen infection and unhygienic environment during infancy reduces the risk of allergy later in life. This hypothesis has been put forward to explain why the incidence of allergies and asthma is increasing around the world despite better hygienic conditions. “Though many researchers believe the hypothesis,” says Ishii, “there is great uncertainty about how pathogen infection is memorized until adulthood. Since our research demonstrates that the pathogen-induced epigenomic changes mediated by ATF7 are maintained for a long period, this provides a plausible explanation of how the changes are induced. It also means that the genes that are affected can be used for the diagnosis of allergy.”

Another possible application of these findings is for the choice of adjuvants in vaccines. Adjuvants — the name used for substances that activate innate immunity — are a necessary ingredient of efficient vaccines. The effect of adjuvant has generally been thought to end within a few days, but the present research showed that its effect can be maintained for longer periods. Says Ishii, “These results could affect the selection method of adjuvants, and we hope that they will contribute to the development of more efficient vaccines.”

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The above post is reprinted from materials provided by RIKEN.

DNA-guided 3-D printing of human tissue is unveiled

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A UCSF-led team has developed a technique to build tiny models of human tissues, called organoids, more precisely than ever before using a process that turns human cells into a biological equivalent of LEGO bricks. These mini-tissues in a dish can be used to study how particular structural features of tissue affect normal growth or go awry in cancer. They could be used for therapeutic drug screening and to help teach researchers how to grow whole human organs.

A new technique — called DNA Programmed Assembly of Cells — allows researchers to create arrays of thousands of custom-designed organoids, such as models of human mammary glands containing several hundred cells each, which can be built in a matter of hours. Photo Credit: UCSF

The new technique — called DNA Programmed Assembly of Cells (DPAC) and reported in the journal Nature Methods on August 31, 2015 — allows researchers to create arrays of thousands of custom-designed organoids, such as models of human mammary glands containing several hundred cells each, which can be built in a matter of hours.

There are few limits to the tissues this technology can mimic, said Zev Gartner, PhD, the paper’s senior author and an associate professor of pharmaceutical chemistry at UCSF. “We can take any cell type we want and program just where it goes. We can precisely control who’s talking to whom and who’s touching whom at the earliest stages. The cells then follow these initially programmed spatial cues to interact, move around, and develop into tissues over time.”

“One potential application,” Gartner said, “would be that within the next couple of years, we could be taking samples of different components of a cancer patient’s mammary gland and building a model of their tissue to use as a personalized drug screening platform. Another is to use the rules of tissue growth we learn with these models to one day grow complete organs.”

Our bodies are made of more than 10 trillion cells of hundreds of different kinds, each of which plays its unique role in keeping us alive and healthy. The way these cells organize themselves structurally in different organ systems helps them coordinate their amazingly diverse behaviors and functions, keeping the whole biological machine running smoothly. But in diseases such as breast cancer, the breakdown of this order has been associated with the rapid growth and spread of tumors.

“Cells aren’t lonely little automatons,” Gartner said. “They communicate through networks to make group decisions. As in any complex organization, you really need to get the group’s structure right to be successful, as many failed corporations have discovered. In the context of human tissues, when organization fails, it sets the stage for cancer.”

But studying how the cells of complex tissues like the mammary gland self-organize, make decisions as groups, and break down in disease has been a challenge to researchers. The living organism is often too complex to identify the specific causes of a particular cellular behavior. On the other hand, cells in a dish lack the critical element of realistic 3-D structure.

“This technique lets us produce simple components of tissue in a dish that we can easily study and manipulate,” said Michael Todhunter, PhD, who led the new study with Noel Jee, PhD, when both were graduate students in the Gartner research group. “It lets us ask questions about complex human tissues without needing to do experiments on humans.”

To specify the 3-D structure of their organoids, Gartner’s team makes use of a familiar molecule: DNA. The researchers incubate cells with tiny snippets of single-stranded DNA engineered to slip into the cells’ outer membranes, covering each cell like the hairs on a tennis ball. These DNA strands act both as a sort of molecular Velcro and as a bar code that specifies where each cell belongs within the organoid. When two cells incubated with complementary DNA strands come in contact, they stick fast. If the DNA sequences don’t match, the cells float on by. Cells can be incubated with several sets of DNA bar codes to specify multiple allowable partners.

To turn these cellular LEGOs into arrays of organoids that can be used for research, Gartner’s team lays down the cells in layers, with multiple sets of cells designed to stick to particular partners. Not only does this let them build up complex tissue components like the mammary gland, but also to experiment with specifically adding in a single cell with a known cancer mutation to different parts of the organoid to observe its effects.

To demonstrate the precision of the technique and its ability to generalize to many different human tissue types, the research team created several proof-of-principle organoid arrays mimicking human tissues such as branching vasculature and mammary glands.

In one experiment, the researchers created arrays of mammary epithelial cells and asked how adding one or more cells expressing low levels of the cancer gene RasG12V affected the cells around them. They found that normal cells grow faster when in an organoid with cells expressing RasG12V at low levels, but required more than one mutant cell to kick-start this abnormal growth. They also found that placing cells with low RasG12V expression at the end of a tube of normal cells allowed the mutant cells to branch and grow, drawing normal cells behind them like a bud at the tip of a growing tree branch.

Gartner’s group plans to use the technique to investigate what cellular or structural changes in mammary glands can lead to the breakdown of tissue architecture associated with tumors that metastasize, invading other parts of the body and threatening the life of the patient. They also hope to use what they learn from simple models of different tissue types to ultimately build functional human tissues like lung and kidney and neural circuits using larger-scale techniques.

“Building functional models of the complex cellular networks such as those found in the brain is probably one of the highest challenges you could aspire to,” Todhunter said. “DPAC now makes a lofty goal like that seem achievable.”

Funders of the work include the Department of Defense Breast Cancer Research Program, the National Institutes of Health, the Sidney Kimmel Foundation, and the UCSF Program in Breakthrough Biomedical Research.

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The above post is reprinted from materials provided by University of California, San Francisco (UCSF).

Inducing metabolic catastrophe in cancer cells

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A study published in The Journal of Cell Biology describes a way to force cancer cells to destroy a key metabolic enzyme they need to survive.

Eliminating HK2 (shown here), which is a key enzyme for glucose metabolism, may be a way to prevent cancer cells from surviving, according to a new study in JCB. Photo Credit: Xia et al., 2015

Cancer cells survive the stressful environment inside a tumor in part through autophagy, the controlled digestion and recycling of damaged components. However, blocking the process doesn’t kill cancer cells, so researchers have been looking for a way to make cells vulnerable to autophagy shutdown.

Researchers at Harvard Medical School in Boston used an ovarian cancer cell line that is resistant to the autophagy inhibitor spautin-1 or an upgraded version of this molecule. After screening more than 8,200 compounds, they found that quizartinib was the most effective at enhancing the cells’ vulnerability to either of the autophagy blockers. Quizartinib inhibits FLT3, an enzyme that is important for the normal development of hematopoietic stem cells and a validated target for acute myeloid leukemia (AML). The drug is currently in clinical trial for treatment of AML, but its value beyond has not been well explored.

The team found that quizartinib and the improved version of spautin-1 killed tumor cells from a variety of cell lines while leaving noncancerous cells unscathed. Treating cancer cells with quizartinib alone inhibited an important metabolic pathway, glycolysis, and activated macroautophagy, the best known type of autophagy in which the cell digests a large portion of its contents. In contrast, cells that received both compounds couldn’t initiate macroautophagy, but they switched on chaperone-mediated autophagy, a selective form of the process that eliminates individual molecules.

One of its targets was the enzyme Hexokinase2 (HK2), which is crucial for glucose metabolism and is often overexpressed in cancer cells. By eliminating HK2, quizartinib and the autophagy inhibitor may prevent cancer cells from metabolizing absorbed glucose and mobilizing stored nutrients, thereby triggering cancer cell death. The study provides evidence that combining an FLT3 inhibitor with an autophagy blocker could be a new way to treat cancer.

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The above post is reprinted from materials provided by The Rockefeller University.

Why Pregnancy Really Lasts 9 Months

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New research by a University of Rhode Island professor suggests that the length of human pregnancy is limited primarily by a mother’s metabolism, not the size of the birth canal. The research, published in the Proceedings of the National Academy of Sciences the week of August 27, challenges the long-held notion of an evolutionary trade-off between childbirth and a pelvis adapted for walking upright.

Photo Credit: makelessnoise / flickr

Two traits that set humans apart from other primates — big brains and the ability to walk upright — could be at odds when it comes to childbirth. Big brains and the big heads that encase them are hard to push through the human birth canal, but a wider pelvis might compromise bipedal walking. Scientists have long posited that nature’s solution to this problem, which is known as the “obstetric dilemma,” was to shorten the duration of gestation so that babies are born before their heads get too big. As a result, human babies are relatively helpless and seemingly underdeveloped in terms of motor and cognitive ability compared to other primates.

“All these fascinating phenomena in human evolution — bipedalism, difficult childbirth, wide female hips, big brains, relatively helpless babies — have traditionally been tied together with the obstetric dilemma,” said Holly Dunsworth, an anthropologist at the University of Rhode Island and lead author of the research. “It’s been taught in anthropology courses for decades, but when I looked for hard evidence that it’s actually true, I struck out.”

The first problem with the theory is that there is no evidence that hips wide enough to deliver a more developed baby would be a detriment to walking, Dunsworth said. Anna Warrener, a post-doctoral researcher at Harvard University and one of the paper’s co-authors, has studied how hip breadth affects locomotion with women on treadmills. She found that there is no correlation between wider hips and a diminished locomotor economy.

“That throws doubt on the assumption that the size of the birth canal is limited by bipedalism,” Dunsworth said. “Wide hips don’t mean you can’t walk efficiently.”

Then Dunsworth looked for evidence that human pregnancy is shortened compared to other primates and mammals. She found well-established research to the contrary. “Controlling for mother’s body size, human gestation is a bit longer than expected compared to other primates, not shorter,” she said. “And babies are a bit larger than expected, not smaller. Although babies behave like it, they’re not born early.”

For mammals in general, including humans, gestation length and offspring size are predicted by mother’s body size. Because body size is a good proxy for an animal’s metabolic rate and function, Dunsworth started to wonder if metabolism might offer a better explanation for the timing of human birth than the pelvis.

To investigate that possibility, she enlisted the help of Peter Ellison of Harvard University and Herman Pontzer of Hunter College in New York, two experts in human physiology and energetics. Building on Ellison’s prior work on human pregnancy and childbirth, the researchers developed a new hypothesis for the timing of human birth called the EGG (energetics, gestation, and growth).

“Under the EGG, babies are born when they’re born because mother cannot put any more energy into gestation and fetal growth,” Dunsworth explains. “Mom’s energy is the primary evolutionary constraint, not the hips.”

Using metabolic data on pregnant women, the researchers show that women give birth just as they are about to cross into a metabolic danger zone.

“There is a limit to the number of calories our bodies can burn each day,” says Pontzer. “During pregnancy, women approach that energetic ceiling and give birth right before they reach it. That suggests there is an energetic limit to human gestation length and fetal growth.”

Those metabolic constraints help explain why human babies are so helpless compared to our primate kin, like chimpanzees. A chimp baby begins crawling at one month, whereas human babies don’t crawl until around seven months. But for a human to give birth to a newborn at the same developmental level as chimp, it would take a 16-month gestation. That would place mothers well past their energetic limits. In fact, even one extra month of gestation would cross into the metabolic danger zone, the researchers found.

“It would be physiologically impossible, regardless of pelvic bone anatomy, to birth a more developed baby,” Dunsworth said. “Our helplessness at birth is just a sign of how much more brain growth we have to achieve once we start living outside our mother.”

The energetics, gestation and growth hypothesis would downplay an implication of the obstetric dilemma that Dunsworth finds odd.

“We’ve been doing anthropology with this warped view of the male pelvis as the ideal form, while the female pelvis is seen as less than ideal because of childbirth,” she said. “The female births the babies. So if there’s an ideal, it’s female and it’s no more compromised than anything else out there. Selection maintains its adequacy for locomotion and for childbirth.

“If it didn’t, we’d have gone extinct,” Dunsworth said.

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‘Brainbow’ reveals surprising data about visual connections in brain

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Neuroscientists know that some connections in the brain are pruned through neural development. Function gives rise to structure, according to the textbooks. But scientists at the Virginia Tech Carilion Research Institute have discovered that the textbooks might be wrong.

Their results were published today in Cell Reports.

“Retinal neurons associated with vision generate connections in the brain, and as the brain develops it strengthens and maintains some of those connections more than others. The disused connections are eliminated,” said Michael Fox, an associate professor at the Virginia Tech Carilion Research Institute who led the study. “We found that this activity-dependent pruning might not be as simple as we’d like to believe.”

Fox and his team of researchers used two different techniques to examine how retinal ganglion cells — neurons that live in the retina and transmit visual information to the visual centers in the brain — develop in a mouse model.

“It’s widely accepted that synaptic connections from about 20 retinal ganglion cells converge onto cells in the lateral geniculate nucleus during development, but that number reduces to just one or two by the third week of a mouse’s life,” Fox said. “It was thought that the mature retinal ganglion cells develop several synaptic terminals that cluster around information exchange points.”

The theory of several terminals blossoming from the same retinal ganglion cell had not been proved, though, so Fox and his researchers decided to follow the terminals to their roots.

Using a technique dubbed “brainbow,” the scientists tagged the terminals with proteins that fluoresce different colors. The researchers thought one color, representing the single source of the many terminals, would dominate in the clusters. Instead, several different colors appeared together, intertwined but distinct.

“The samples showed a true ‘brainbow,'” said Aboozar Monavarfeshani, a graduate student in Fox’s laboratory who tagged the terminals. “I could see, right in front of me, something very different than the concept I learned from my textbooks.”

The results showed individual terminals from more than one retinal ganglion cell in a mature mouse brain.

The study is a direct contradiction to some other research indicating neural development weeds out most connections between retinal ganglion axons and target cells in the brain, and Fox and his team have more questions.

“Is this a discrepancy a technical issue with the different types of approaches applied in all of these disparate studies?” Fox asked. “Possibly, but perhaps it’s more likely that retinal ganglion cells are more complex than previously thought.”

Along with the brainbow technique, Fox’s team also imaged these synaptic connections with electron microscopy.

Sarah Hammer, currently a sophomore at Virginia Tech, traced individual retinal terminals through hundreds of serial images.

The data confirmed the results from “brainbow” analysis — retinal axons from numerous retinal ganglion cells remained present on adult brain cells.

“These results are not what we expected, and they will force us to reevaluate our understanding of the architecture and flow of visual information through neural pathways,” Fox said. “The dichotomy of these results also sheds important light on the benefits of combining approaches to understand complicated problems in science.”

Albert Pan, an assistant professor in the Medical College of Georgia at Georgia Regents University, who is an expert in neural circuitry development, said the results are unexpected.

“The research provides strong evidence for multiple innervation and calls for a reevaluation of the current understanding of information flow and neural circuit maturation in the visual system” said Pan, who was not involved in the study. “The paper probably generates more questions than it answers, which is a hallmark of an exciting research study.”

The research continues, as Fox’s team works to understand exactly how many retinal terminals converge and how they might convey information differently. Once the scientists understand the intricacies of the brain’s visual circuitry, they might be able to start developing therapeutics for when it goes wrong.

“The lesson in this particular study is that no single technique gives us all the right answers,” Fox said. “Science is never as simple as we like to make it seem.”

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The above post is reprinted from materials provided by Virginia Tech.

Researchers use DNA ‘clews’ to shuttle CRISPR-Cas9 gene-editing tool into cells

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Researchers from North Carolina State University and the University of North Carolina at Chapel Hill have for the first time created and used a nanoscale vehicle made of DNA to deliver a CRISPR-Cas9 gene-editing tool into cells in both cell culture and an animal model.

When the nanoclew comes into contact with a cell, the cell absorbs the nanoclew completely — swallowing it and wrapping it in a protective sheath called an endosome. But the nanoclews are coated with a positively charged polymer that breaks down the endosome, setting the nanoclew free inside the cell. The CRISPR-Cas9 complexes can then free themselves from the nanoclew to make their way to the nucleus. Photo Credit: North Carolina State University

The CRISPR-Cas system, which is found in bacteria and archaea, protects bacteria from invaders such as viruses. It does this by creating small strands of RNA called CRISPR RNAs, which match DNA sequences specific to a given invader. When those CRISPR RNAs find a match, they unleash Cas9 proteins that cut the DNA. In recent years, the CRISPR-Cas system has garnered a great deal of attention in the research community for its potential use as a gene editing tool – with the CRISPR RNA identifying the targeted portion of the relevant DNA, and the Cas protein cleaving it.

But for Cas9 to do its work, it must first find its way into the cell. This work focused on demonstrating the potential of a new vehicle for directly introducing the CRISPR-Cas9 complex – the entire gene-editing tool – into a cell.

“Traditionally, researchers deliver DNA into a targeted cell to make the CRISPR RNA and Cas9 inside the cell itself – but that limits control over its dosage,” says Chase Beisel, co-senior author of the paper and an assistant professor in the department of chemical and biomolecular engineering at NC State. “By directly delivering the Cas9 protein itself, instead of turning the cell into a Cas9 factory, we can ensure that the cell receives the active editing system and can reduce problems with unintended editing.”

“Our delivery mechanism resembles a ball of yarn, or clew, so we call it a nanoclew,” says Zhen Gu, co-senior author of the paper and an assistant professor in the joint biomedical engineering program at NC State and UNC-CH. “Because the nanoclew is made of a DNA-based material, it is highly biocompatible. It also self-assembles, which makes it easy to customize.”

The nanoclews are made of a single, tightly-wound strand of DNA. The DNA is engineered to partially complement the relevant CRISPR RNA it will carry, allowing the CRISPR-Cas9 complex – a CRISPR RNA bound to a Cas9 protein — to loosely attach itself to the nanoclew. “Multiple CRISPR-Cas complexes can be attached to a single nanoclew,” says Wujin Sun, lead author of the study and Ph.D. student in Gu’s lab.

When the nanoclew comes into contact with a cell, the cell absorbs the nanoclew completely – swallowing it and wrapping it in a protective sheath called an endosome. But the nanoclews are coated with a positively-charged polymer that breaks down the endosome, setting the nanoclew free inside the cell. The CRISPR-Cas9 complexes can then free themselves from the nanoclew to make their way to the nucleus. And once a CRISPR-Cas9 complex reaches the nucleus, gene editing begins.

To test the nanoclew CRISPR-Cas delivery system, the researchers treated cancer cell cultures and tumors in mice. The relevant cancer cells had been modified to express a fluorescent protein. In short, they glowed. The CRISPR RNAs on the nanoclews were designed to target the DNA in the cancer cell that was responsible for making the fluorescent proteins. If the glowing stopped, the nanoclews worked.

“And they did work. More than a third of cancer cells stopped expressing the fluorescent protein,” Beisel says.

“This study is a proof of concept, and additional work needs to be done – but it’s very promising,” Gu says.

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Discovery of new code makes reprogramming of cancer cells possible

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Cancer researchers dream of the day they can force tumor cells to morph back to the normal cells they once were. Now, researchers on Mayo Clinic’s Florida campus have discovered a way to potentially reprogram cancer cells back to normalcy.

Lead authors Panos Anastasiadis, Ph.D., and Antonis Kourtidis, Ph.D. Photo Credit: Image courtesy of Mayo Clinic

The finding, published in Nature Cell Biology, represents “an unexpected new biology that provides the code, the software for turning off cancer,” says the study’s senior investigator, Panos Anastasiadis, Ph.D., chair of the Department of Cancer Biology on Mayo Clinic’s Florida campus.

That code was unraveled by the discovery that adhesion proteins — the glue that keeps cells together — interact with the microprocessor, a key player in the production of molecules called microRNAs (miRNAs). The miRNAs orchestrate whole cellular programs by simultaneously regulating expression of a group of genes. The investigators found that when normal cells come in contact with each other, a specific subset of miRNAs suppresses genes that promote cell growth. However, when adhesion is disrupted in cancer cells, these miRNAs are misregulated and cells grow out of control. The investigators showed, in laboratory experiments, that restoring the normal miRNA levels in cancer cells can reverse that aberrant cell growth.

“The study brings together two so-far unrelated research fields — cell-to-cell adhesion and miRNA biology — to resolve a long-standing problem about the role of adhesion proteins in cell behavior that was baffling scientists,” says the study’s lead author Antonis Kourtidis, Ph.D., a research associate in Dr. Anastasiadis’ lab. “Most significantly, it uncovers a new strategy for cancer therapy,” he adds.

That problem arose from conflicting reports about E-cadherin and p120 catenin — adhesion proteins that are essential for normal epithelial tissues to form, and which have long been considered to be tumor suppressors. “However, we and other researchers had found that this hypothesis didn’t seem to be true, since both E-cadherin and p120 are still present in tumor cells and required for their progression,” Dr. Anastasiadis says. “That led us to be believe that these molecules have two faces — a good one, maintaining the normal behavior of the cells, and a bad one that drives tumorigenesis.”

Their theory turned out to be true, but what was regulating this behavior was still unknown. To answer this, the researchers studied a new protein called PLEKHA7, which associates with E-cadherin and p120 only at the top, or the “apical” part of normal polarized epithelial cells. The investigators discovered that PLEKHA7 maintains the normal state of the cells, via a set of miRNAs, by tethering the microprocessor to E-cadherin and p120. In this state, E-cadherin and p120 exert their good tumor suppressor sides.

However, “when this apical adhesion complex was disrupted after loss of PLEKHA7, this set of miRNAs was misregulated, and the E-cadherin and p120 switched sides to become oncogenic,” Dr. Anastasiadis says.

“We believe that loss of the apical PLEKHA7-microprocessor complex is an early and somewhat universal event in cancer,” he adds. “In the vast majority of human tumor samples we examined, this apical structure is absent, although E-cadherin and p120 are still present. This produces the equivalent of a speeding car that has a lot of gas (the bad p120) and no brakes (the PLEKHA7-microprocessor complex).

“By administering the affected miRNAs in cancer cells to restore their normal levels, we should be able to re-establish the brakes and restore normal cell function,” Dr. Anastasiadis says. “Initial experiments in some aggressive types of cancer are indeed very promising.”

The study was supported by the National Institutes of Health grants R01 CA100467, R01 NS069753, P50 CA116201, R01 GM086435, R01CA104505, R01CA136665; the Florida Department of Health, Bankhead-Coley grants 10BG11; the Breast Cancer Research Foundation; the Swiss Cancer League; and the Jay and Deanie Stein Career Development Award for Cancer Research at Mayo Clinic.

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Artificial leaf harnesses sunlight for efficient fuel production

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Generating and storing renewable energy, such as solar or wind power, is a key barrier to a clean-energy economy. When the Joint Center for Artificial Photosynthesis (JCAP) was established at Caltech and its partnering institutions in 2010, the U.S. Department of Energy (DOE) Energy Innovation Hub had one main goal: a cost-effective method of producing fuels using only sunlight, water, and carbon dioxide, mimicking the natural process of photosynthesis in plants and storing energy in the form of chemical fuels for use on demand.

A highly efficient photoelectrochemical (PEC) device uses the power of the sun to split water into hydrogen and oxygen. The stand-alone prototype includes two chambers separated by a semi-permeable membrane that allows collection of both gas products. Photo Credit: Lance Hayashida/Caltech

Over the past five years, researchers at JCAP have made major advances toward this goal, and they now report the development of the first complete, efficient, safe, integrated solar-driven system for splitting water to create hydrogen fuels.

“This result was a stretch project milestone for the entire five years of JCAP as a whole, and not only have we achieved this goal, we also achieved it on time and on budget,” says Caltech’s Nate Lewis, George L. Argyros Professor and professor of chemistry, and the JCAP scientific director.

The new solar fuel generation system, or artificial leaf, is described in the August 24 online issue of the journal Energy and Environmental Science. The work was done by researchers in the laboratories of Lewis and Harry Atwater, director of JCAP and Howard Hughes Professor of Applied Physics and Materials Science.

“This accomplishment drew on the knowledge, insights and capabilities of JCAP, which illustrates what can be achieved in a Hub-scale effort by an integrated team,” Atwater says. “The device reported here grew out of a multi-year, large-scale effort to define the design and materials components needed for an integrated solar fuels generator.”

The new system consists of three main components: two electrodes–one photoanode and one photocathode–and a membrane. The photoanode uses sunlight to oxidize water molecules, generating protons and electrons as well as oxygen gas. The photocathode recombines the protons and electrons to form hydrogen gas. A key part of the JCAP design is the plastic membrane, which keeps the oxygen and hydrogen gases separate. If the two gases are allowed to mix and are accidentally ignited, an explosion can occur; the membrane lets the hydrogen fuel be separately collected under pressure and safely pushed into a pipeline.

Semiconductors such as silicon or gallium arsenide absorb light efficiently and are therefore used in solar panels. However, these materials also oxidize (or rust) on the surface when exposed to water, so cannot be used to directly generate fuel. A major advance that allowed the integrated system to be developed was previous work in Lewis’s laboratory, which showed that adding a nanometers-thick layer of titanium dioxide (TiO2)–a material found in white paint and many toothpastes and sunscreens–onto the electrodes could prevent them from corroding while still allowing light and electrons to pass through. The new complete solar fuel generation system developed by Lewis and colleagues uses such a 62.5-nanometer-thick TiO2 layer to effectively prevent corrosion and improve the stability of a gallium arsenide-based photoelectrode.

Another key advance is the use of active, inexpensive catalysts for fuel production. The photoanode requires a catalyst to drive the essential water-splitting reaction. Rare and expensive metals such as platinum can serve as effective catalysts, but in its work the team discovered that it could create a much cheaper, active catalyst by adding a 2-nanometer-thick layer of nickel to the surface of the TiO2. This catalyst is among the most active known catalysts for splitting water molecules into oxygen, protons, and electrons and is a key to the high efficiency displayed by the device.

The photoanode was grown onto a photocathode, which also contains a highly active, inexpensive, nickel-molybdenum catalyst, to create a fully integrated single material that serves as a complete solar-driven water-splitting system.

A critical component that contributes to the efficiency and safety of the new system is the special plastic membrane that separates the gases and prevents the possibility of an explosion, while still allowing the ions to flow seamlessly to complete the electrical circuit in the cell. All of the components are stable under the same conditions and work together to produce a high-performance, fully integrated system. The demonstration system is approximately one square centimeter in area, converts 10 percent of the energy in sunlight into stored energy in the chemical fuel, and can operate for more than 40 hours continuously.

“This new system shatters all of the combined safety, performance, and stability records for artificial leaf technology by factors of 5 to 10 or more ,” Lewis says.

“Our work shows that it is indeed possible to produce fuels from sunlight safely and efficiently in an integrated system with inexpensive components,” Lewis adds, “Of course, we still have work to do to extend the lifetime of the system and to develop methods for cost-effectively manufacturing full systems, both of which are in progress.”

Because the work assembled various components that were developed by multiple teams within JCAP, coauthor Chengxiang Xiang, who is co-leader of the JCAP prototyping and scale-up project, says that the successful end result was a collaborative effort. “JCAP’s research and development in device design, simulation, and materials discovery and integration all funneled into the demonstration of this new device,” Xiang says.

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The above post is reprinted from materials provided by California Institute of Technology.

Modified bacteria become a multicellular circuit

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Rice University scientists have made a living circuit from multiple types of bacteria that prompts the bacteria to cooperate to change protein expression.

In a microscopic image created at Rice University, two strains of synthetically engineered bacteria cooperate to create multicellular phenomena. Rice scientists created the biological circuit by programming bacteria to alter gene expression in an entire population. Their fluorescence indicates the engineered capabilities have been activated. Photo Credit: Courtesy of the Bennett Lab

The subject of a new paper in Science, the project represents the first time the Rice researchers have created a biological equivalent to a computer circuit that involves multiple organisms to influence a population.

The researchers’ goal is to modify biological systems by controlling how bacteria influence each other. This could lead to bacteria that, for instance, beneficially alter the gut microbiome in humans.

Humans’ stomachs have a lot of different kinds of bacteria, said Rice synthetic biologist Matthew Bennett. “They naturally form a large consortium. One thought is that when we engineer bacteria to be placed into guts, they should also be part of a consortium. Working together allows them to effect more change than if they worked in isolation.”

In the proof-of-concept study, Bennett and his team created two strains of genetically engineered bacteria that regulate the production of proteins essential to intercellular signaling pathways, which allow cells to coordinate their efforts, generally in beneficial ways.

The ability to engineer DNA so cells produce specific proteins has already paid dividends, for example, by manipulating bacteria to produce useful biofuels and chemicals.

“The main push in synthetic biology has been to engineer single cells,” Bennett said. “But now we’re moving toward multicellular systems. We want cells to coordinate their behaviors in order to elicit a populational response, just the way our bodies do.”

Bennett and his colleagues achieved their goal by engineering common Escherichia coli bacteria. By creating and mixing two genetically distinct populations, they prompted the bacteria to form a consortium.

The bacteria worked together by doing opposite tasks: One was an activator that up-regulated the expression of targeted genes, and the other was a repressor that down-regulated genes. Together, they created oscillations — rhythmic peaks and valleys — of gene transcription in the bacterial population.

The two novel strains of bacteria sent out intercellular signaling molecules and created linked positive and negative feedback loops that affected gene production in the entire population. Both strains were engineered to make fluorescent reporter genes so their activities could be monitored. The bacteria were confined to microfluidic devices in the lab, where they could be monitored easily during each hourslong experiment.

When the bacteria were cultured in isolation, the protein oscillations did not appear, the researchers wrote.

Bennett said his lab’s work will help researchers understand how cells communicate, an important factor in fighting disease. “We have many different types of cells in our bodies, from skin cells to liver cells to pancreatic cells, and they all coordinate their behaviors to make us work properly,” he said. “To do this, they often send out small signaling molecules that are produced in one cell type and effect change in another cell type.

“We take that principle and engineer it into these very simple organisms to see if we can understand and build multicellular systems from the ground up.”

Ultimately, people might ingest the equivalent of biological computers that can be programmed through one’s diet, Bennett said. “One idea is to create a yogurt using engineered bacteria,” he said. “The patient eats it and the physician controls the bacteria through the patient’s diet. Certain combinations of molecules in your food can turn systems within the synthetic bacteria on and off, and then these systems can communicate with each other to effect change within your gut.”

Ye Chen, a graduate student in Bennett’s lab at Rice, and Jae Kyoung Kim, an assistant professor at KAIST and former postdoctoral fellow at Ohio State University, are lead authors of the paper. Co-authors are Rice graduate student Andrew Hirning and Krešimir Josi?, a professor of mathematics at the University of Houston. Bennett is an assistant professor of biochemistry and cell biology.

The National Institutes of Health, the Robert A. Welch Foundation, the Hamill Foundation, the National Science Foundation and the China Scholarship Council supported the research.

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Imaging techniques set new standard for super-resolution in live cells

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Scientists can now watch dynamic biological processes with unprecedented clarity in living cells using new imaging techniques developed by researchers at the Howard Hughes Medical Institute’s Janelia Research Campus. The new methods dramatically improve on the spatial resolution provided by structured illumination microscopy, one of the best imaging methods for seeing inside living cells.

This is a still image from a video showing the interaction of filamentous actin (mApple-F-tractin, purple) with myosin IIA bipolar head groups (EGFP, myosin IIA, green) at 20-second intervals for 100 time points, as seen with high-NA TIRF-SIM. Photo Credit: Betzig Lab, HHMI/Janelia Research Campus

The vibrant videos produced with the new technology show the movement and interactions of proteins as cells remodel their structural supports or reorganize their membranes to take up molecules from outside the cell. Janelia group leader Eric Betzig, postdoctoral fellow Dong Li and their colleagues have added the two new technologies — both variations on SIM — to the set of tools available for super-resolution imaging. Super-resolution optical microscopy produces images whose spatial resolution surpasses a theoretical limit imposed by the wavelength of light, offering extraordinary visual detail of structures inside cells. But until now, super-resolution methods have been impractical for use in imaging living cells.

“These methods set a new standard for how far you can push the speed and non-invasiveness of super-resolution imaging,” Betzig says of the techniques his team described in the August 28, 2015, issue of the journal Science. “This will bring super-resolution to live-cell imaging for real.”

In traditional SIM, the sample under the lens is observed while it is illuminated by a pattern of light (more like a bar code than the light from a lamp). Several different light patterns are applied, and the resulting moiré patterns are captured from several angles each time by a digital camera. Computer software then extracts the information in the moiré images and translates it into a three-dimensional, high-resolution reconstruction. The final reconstruction has twice the spatial resolution that can be obtained with traditional light microscopy.

Betzig was one of three scientists awarded the 2014 Nobel Prize in Chemistry for the development of super-resolved fluorescence microscopy. He says SIM has not received as much attention as other super-resolution methods largely because those other methods offer more dramatic gains in spatial resolution. But he notes that SIM has always offered two advantages over alternative super-resolution methods, including photoactivated localization microscopy (PALM), which he developed in 2006 with Janelia colleague Harald Hess.

Both PALM and stimulated emission depletion (STED) microscopy, the other super-resolution technique recognized with the 2014 Nobel Prize, illuminate samples with so much light that fluorescently labeled proteins fade and the sample is quickly damaged, making prolonged imaging impossible. SIM, however, is different. “I fell in love with SIM because of its speed and the fact that it took so much less light than the other methods,” Betzig says.

Betzig began working with SIM shortly after the death in 2011 of one of its pioneers, Mats Gustafsson, who was a group leader at Janelia. Betzig was already convinced that SIM had the potential to generate significant insights into the inner workings of cells, and he suspected that improving the technique’s spatial resolution would go a long way toward increasing its use by biologists.

Gustafsson and graduate student Hesper Rego had achieved higher-resolution SIM with a variation called saturated depletion non-linear SIM, but that method trades improvements in spatial resolution for harsher conditions and a loss of speed. Betzig saw a way around that trade-off.

Saturated depletion enhances the resolution of SIM images by taking advantage of fluorescent protein labels that can be switched on and off with light. To generate an image, all of the fluorescent labels in a protein are switched on, then a wave of light is used to deactivate most of them. After exposure to the deactivating light, only molecules at the darkest regions of the light wave continue to fluoresce. These provide higher frequency information and sharpen the resulting image. An image is captured and the cycle is repeated 25 times or more to generate data for the final image. The principle is very similar to the way super-resolution in achieved in STED or a related method called RESOLFT, Betzig says.

The method is not suited to live imaging, he says, because it takes too long to switch the photoactivatable molecules on and off. What’s more, the repeated light exposure damages cells and their fluorescent labels. “The problem with this approach is that you first turn on all the molecules, then you immediately turn off almost all the molecules. The molecules you’ve turned off don’t contribute anything to the image, but you’ve just fried them twice. You’re stressing the molecules, and it takes a lot of time, which you don’t have, because the cell is moving.”

The solution was simple, Betzig says: “Don’t turn on all of the molecules. There’s no need to do that.” Instead, the new method, called patterned photoactivation non-linear SIM, begins by switching on just a subset of fluorescent labels in a sample with a pattern of light. “The patterning of that gives you some high resolution information already,” he explains. A new pattern of light is used to deactivate molecules, and additional information is read out of their deactivation. The combined effect of those patterns leads to final images with 62-nanometer resolution–better than standard SIM and a three-fold improvement over the limits imposed by the wavelength of light.

“We can do it and we can do it fast,” he says. That’s important, he says, because for imaging dynamic processes, an increase in spatial resolution is meaningless without a corresponding increase in speed. “If something in the cell is moving at a micron a second and I have one micron resolution, I can take that image in a second. But if I have 1/10-micron resolution, I have to take the data in a tenth of a second, or else it will smear out,” he explains.

Patterned photoactivation non-linear SIM captures the 25 images that go into a final reconstruction in about one-third of a second. Because it does so efficiently, using low intensity light and gleaning information from every photon emitted from a sample’s fluorescent labels, labels are preserved so that the microscope can image longer, letting scientists watch more action unfold.

The team used patterned photoactivation non-linear SIM to produce videos showing structural proteins break down and reassemble themselves as cells move and change shape, as well as the dynamics of tiny pits on cell surfaces called caveolae.

Betzig’s team also reports in the Science paper that they can boost the spatial resolution of SIM to 84 nanometers by imaging with a commercially available microscope objective with an ultra-high numerical aperture. The aperture restricts light exposure to a very small fraction of a sample, limiting damage to cells and fluorescent molecules, and the method can be used to image multiple colors at the same time, so scientists can simultaneously track several different proteins.

Using the high numerical aperture approach, Betzig’s team was able to watch the movements and interactions of several structural proteins during the formation of focal adhesions, physical links between the interior and exterior of a cell. They also followed the growth and internalization of clathrin-coated pits, structures that facilitate the intake of molecules from outside of the cell. Their quantitative analysis answered several questions about the pits’ distribution and the relationship between pits’ size and lifespan that could not be addressed with previous imaging methods.

Finally, by combining the high numerical-aperture approach with patterned photoactivatable non-linear SIM, Betzig and his colleagues could follow two proteins at a time with higher resolution than the high numerical aperture approach offered on its own.

Betzig’s team is continuing to develop their SIM technologies, and say further improvements are likely. They are also eager to work with biologists to continue to explore potential applications and refine their techniques’ usability.

For now, scientists who want to experiment with the new SIM methods can arrange to do so through Janelia’s Advanced Imaging Center, which provides access to cutting-edge microscopy technology at no cost. Eventually, Betzig says, it should be fairly straightforward to make the SIM technologies accessible and affordable to other labs. “Most of the magic is in the software, not the hardware,” he says.

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The above post is reprinted from materials provided by HHMI/Janelia Research Campus.

A barcode for shredding junk RNA

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A growing, dividing cell uses most of its energy store to make its “protein factories,” the ribosomes. An important player in their “assembly” is the exosome, a molecular shredding machine that breaks down excess ribonucleic acid (RNA). Researchers working with Prof. Dr. Ed Hurt at the Heidelberg University Biochemistry Center (BZH) have discovered how the exosome identifies its target RNA. The team identified a specific detection signal, comparable to a postal code or bar code that targets the exosome to the remote RNA. The results of the research were published in the journal Cell.

Photo Credit: Copyright Universität Heidelberg

According to Prof. Hurt, the production of ribosomes is an extremely complex process that follows a strict blueprint with numerous quality-control checkpoints. The protein factories are made of numerous ribosomal proteins (r-proteins) and ribosomal ribonucleic acid (rRNA). More than 200 helper proteins, known as ribosome biogenesis factors, are needed in the eukaryotic cells to correctly assemble the r-proteins and the different rRNAs. Three of the total of four different rRNAs are manufactured from a large precursor RNA. They need to be “trimmed” at specific points during the manufacturing process, and the superfluous pieces are discarded. “Because these processes are irreversible, a special check is needed,” explains Ed Hurt.

A substantial portion of this excess ribosomal RNA is broken down by the exosome, a molecular machine consisting of multiple protein subunits. Together they form a structure similar to a barrel, through which the RNA is channelled. The subunit of the exosome that degrades the RNA into its individual components, or nucleotides, sits at the end of this channel. “This process has already been well-described, but we still didn’t understand how the exosome detected its target RNA and distinguished it from the numerous RNA molecules that needed to remain intact,” explains Ed Hurt.

Matthias Thoms and Dr. Emma Thomson of Prof. Hurt’s research team have now been able to identify two ribosome biogenesis factors located near the target RNA on the unfinished ribosome that guide the exosome to its target. Both protein factors act during ribosome assembly, but operate at a different time and position. Although the two proteins are structured differently, they do share one important characteristic. The Heidelberg researchers discovered both have a short signal sequence similar to a barcode or postal code. Through this detection signal, a helper protein of the exosome is recruited to point to the target RNA. The exosome is then able to start its task and shred the unneeded RNA.

Prof. Hurt’s team of scientists now want to identify other proteins with the described signal sequence to find out how the exosome is able to eliminate such a broad spectrum of different RNA. “The exosome is a universal protein complex that is essential in all cells for RNA homeostasis, that is, the equilibrium between RNA creation and degradation. We assume that the type of target RNA detection we discovered represents a general mechanism for exosome regulation,” explains Prof. Hurt. “Our findings could also lead to a better molecular understanding of illnesses in which defects were identified in the exosome or their helper proteins.” This would establish the mutations in exosome components that could cause autoimmune diseases or multiple myeloma in humans.

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Fetal cells influence maternal health during pregnancy

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Parents go to great lengths to ensure the health and well-being of their developing offspring. The favor, however, may not always be returned.

Dramatic research has shown that during pregnancy, cells of the fetus often migrate through the placenta, taking up residence in many areas of the mother’s body, where their influence may benefit or undermine maternal health. Photo Credit: Jason Drees, Biodesign Institute

Dramatic research has shown that during pregnancy, cells of the fetus often migrate through the placenta, taking up residence in many areas of the mother’s body, where their influence may benefit or undermine maternal health.

The presence of fetal cells in maternal tissue is known as fetal microchimerism. The term alludes to the chimeras of ancient Greek myth–composite creatures built from different animal parts, like the goat-lion-serpent depicted in an Etruscan bronze sculpture.

According to Amy Boddy, a researcher at Arizona State University’s Department of Psychology and lead author of a new study, chimeras exist. Indeed, many humans bear chimerical traits in the form of foreign cells from parents, siblings or offspring, acquired during pregnancy.

“Fetal cells can act as stem cells and develop into epithelial cells, specialized heart cells, liver cells and so forth. This shows that they are very dynamic and play a huge role in the maternal body. They can even migrate to the brain and differentiate into neurons,” Boddy says “We are all chimeras.”

Fellow ASU researchers Angelo Fortunato, Melissa Wilson Sayres and Athena Aktipis joined Boddy for the new study. Fortunato is with the Biodesign’s Institute’s Human and Comparative Genomics Lab. Wilson Sayres and Aktipis–both with Biodesign’s Center for Evolution and Medicine– are also researchers with ASU’s School of Life Sciences and Department of Psychology, respectively.

Mother’s little helpers?

While fetal microchimerism is a common occurrence across placental mammals, (including humans), the effects of such cells on maternal health remain a topic of fierce debate in the biological community.

In research appearing in the advanced online edition of the journal Bioessays, Boddy and her colleagues review the available literature on fetal microchimerism and human health, applying an evolutionary framework to predict when fetal cells are inclined to act cooperatively to enhance maternal health and when their behavior is likely to be competitive, occasionally leading to adverse effects on the mother.

Fetal cells may do more than simply migrate to maternal tissues. The authors suggest they can act as a sort of placenta outside the womb, redirecting essential assets from the maternal body to the developing fetus. Cells derived from the fetus–which can persist in maternal tissues for decades after a child is born–have been associated with both protection and increased susceptibility to a range of afflictions, including cancer and autoimmune diseases like rheumatoid arthritis.

But, as co-author Wilson Sayres, cautions, “it’s not only a tug of war between maternal and fetal interests. There is also a mutual desire for the maternal system to survive and provide nutrients and for the fetal system to survive and pass on DNA.”

If some degree of fetal microchimerism exerts a beneficial effect on maternal and offspring survival, it will likely be selected for by evolution as an adaptive strategy.

A review of existing data on fetal microchimerism and health suggests that fetal cells enter a cooperative relationship in some maternal tissues, compete for resources in other tissues and may exist as neutral entities–hitchhikers simply along for the ride. It is likely that fetal cells play each of these roles at various times.

For example, fetal cells may contribute to inflammatory responses and autoimmunity in the mother, when they are recognized as foreign entities by the maternal immune system. This may account in part for higher rates of autoimmunity in women. (For example, women have three times higher rates of rheumatoid arthritis, compared with men.)

Fetal cells can also provide benefits to mothers, migrating to damaged tissue and repairing it. Their presence in wounds–including caesarian incisions–points to their active participation in healing. In other cases, fetal cells from the placenta are swept through the bloodstream into areas including the lung, where they may persist merely as bystanders.

Parental discretion advised

Applying a cooperation and conflict approach, the authors make testable predictions about the circumstances favoring fetal cell cooperation or competition and attendant positive or negative effects on maternal health.

“Cooperation theory and evolutionary analyses are powerful tools for helping us to unravel the complex effects of fetal cells on the maternal body. They can help us to predict when fetal cells are likely to contribute to maternal health and when they may be manipulating maternal tissues for the benefit of the offspring and potentially contributing to maternal disease in the process,” says Aktipis.

Evolutionary theory suggests that fetal cells will act cooperatively to enhance maternal health where the economic cost of doing so is low, for example, in tissue maintenance. Where the cost to fetal cells is high, including the division of limited resources between fetus and mother, competition is the more likely outcome, with escalating conflict leading to harmful effects for mother, developing fetus or both.

Fetal cells appear to play a complex role in the female breast and have been detected in over half of all women sampled. Given the co-evolution of maternal and fetal cells over the 160 million year course of placental mammalian evolution, it appears likely that fetal cells are active participants in breast development and lactation.

Milk production is a vital but energy-intensive activity for the mother, requiring subtle regulation. Poor lactation–a common affliction–may be linked with low fetal cell count in breast tissue. (The hypothesis suggests that a simple, non-invasive test for fetal cell abundance in breast milk could provide the first conclusive evidence of fetal cell influence on maternal health.)

With respect to breast cancer, existing data paints a complex picture. Fetal cells are generally found in lower abundance in women with breast cancer, compared with healthy women, suggesting they may play a protective role. On the other hand, some data indicates that fetal cells may be linked with a transient increase in the risk of breast cancer in the years immediately following pregnancy.

The thyroid gland performs a broad range of regulatory functions and during pregnancy, is involved in the efficient transfer of heat from the mother to the offspring. Again, fetal cells found in the thyroid are implicated and may be manipulating thyroid activity to enhance heat transfer to the fetus, potentially at the energetic expense of the mother.

Fetal cells occur more frequently in both the blood and thyroid tissue of women with thyroid diseases including Hashimoto’s thyroiditis, Graves’ disease and thyroid cancer, compared with healthy women. (Intriguingly, cancer of the thyroid is the only non-sex-specific form of cancer found more frequently in women than men.) The authors suggest that the maternal system, in attempting to wrest control from fetal cell influence, may induce hazardous levels of autoimmunity and inflammation.

Fetal attraction

The current overview represents a tentative step toward untangling the myriad influences of fetal microchimerism on human health. One of the more tantalizing possibilities raised in the new study is that fetal cells may be commandeering neural pathways overseeing emotion and behavior. They may, for example, hijack mechanisms triggering the release of oxytocin, a hormone long associated with the emotional bonding of mother and infant.

Indeed, fetal cells could be suspects in a broad range of physical and emotional manifestations in the mother, including pregnancy-related afflictions like morning sickness or postpartum depression. Even early onset menopause could be the result of fetal cell efforts to remove the mother from further child-bearing, in order to secure maximum resources for the fetus and eventually, the growing child.

Finally, the authors note, fetal microchimerism may be one piece of a subtle and dizzyingly complex puzzle. Cell traffic is actually bi-directional, with the fetus receiving cells from the mother. Fetal cells from maternal tissue may cross the placental barrier during subsequent pregnancies, potentially influencing the health of later offspring. To further complicate matters, cells from later fetuses can also cross the placenta to enter the microchimeric arena, perhaps introducing sibling rivalries for the mother’s limited resources.

Fetal cells may eventually provide a novel and powerful means of diagnosing existing conditions and predicting long-term maternal health. As the authors note, they could also be applied therapeutically in the future, potentially for the treatment of poor lactation, for wound healing, tumor reduction and perhaps even pregnancy-linked psychological disorders.

Identification of fetal cells in maternal gut, liver or brain tissues is only a first step.

To tease out the true function of these cells, researchers need to examine their gene expression and interaction with maternal tissues. Inspection of maternal cells in surrounding tissue will help determine if they are immune cells targeting fetal cell interlopers or normal epithelial cells, existing in harmony.

“If future research bears out the predictions of this framework, it could transform the way we approach, treat and prevent a variety of diseases that affect women, especially new mothers,” says Aktipis.

Improved methods of screening will help scientists listen in on the intricate dialogue between fetal and maternal cells, deepening our understanding of maternal health and disease.

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The above post is reprinted from materials provided by Biodesign Institute.

New synthetic tumor environments make cancer research more realistic

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Tumors are notoriously difficult to study in their natural habitat – body tissues – but a new synthetic tissue environment may give cancer researchers the next-best look at tumor growth and behavior.

Chemistry professor Jeffrey Moore, graduate student Joshua Grolman and materials science and engineering professor Kristopher Kilian, led a research team to create a new synthetic tissue environment for more realistic cell biology research. Photo credit:L. Brian Stauffer

University of Illinois researchers have developed a new technique to create a cell habitat of squishy fluids, called hydrogels, which can realistically and quickly recreate microenvironments found across biology.

To illustrate the potential of their technique, the Illinois team mixed breast cancer cells and cells called macrophages that signal cancer cells to spread and grow into a tumor. They were able to observe how differently cells act in the three-dimensional, gel-like environment, which is much more like body tissues than the current research standard: a flat, hard plastic plate.

Led by materials science and engineering professor Kristopher Kilian, chemistry professor Jeffrey Moore and graduate student Joshua Grolman, the team published its results in the journal Advanced Materials.

Kilian said his team’s synthetic microenvironment lies somewhere in the middle of two extremes in the field of modeling biology: the hard plastic plate, and expensive mouse avatars that are created by injecting human tumor cells into mice.

“This is really the first time that it’s been demonstrated that you can use a rapid methodology like this to spatially define cancer cells and macrophages,” Kilian said. “That’s important, because once you have that architecture, then you can ask fundamental biological questions.”

Kilian said these questions range from the basic – how macrophages signal to the breast cells – to the more long-term: Can therapeutics be used to disrupt that communication?

What sets the team’s model apart from mouse avatars and hard plastic plates is that it can replicate much more accurately the sizes and shapes of the microenvironment within the patient’s problem area. The materials that pharmaceutical companies use to test drugs’ effects on cells don’t allow for three-dimensional vascularization, a network of capillaries that carry drugs and other materials throughout the body. The team’s model does, creating networks that go from straight, to snakelike, to any shape.

“Now, researchers can ask more sophisticated biological questions than they could,” Kilian said.

And they can do it quickly. The process the team came up with to produce the synthetic environments takes an estimated 15 minutes, discounting the time it takes to grow the cells and a few other steps, Grolman said.

Grolman described it as a tool that could not only help inform science, but also aid in drug screening.

“The microenvironment actually has a significant effect on how the cells respond to a drug,” Grolman said. “These companies might have the next big drug, but they might not know it.”

“The long-term vision would be: A patient goes in and finds out they’ve been diagnosed with some sort of solid tumor,” Kilian said. “You take a biopsy of those cells, you put it into this device, grow them and see how they respond to different treatments.”

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Nasal Spray Device for Mental Illness

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Researchers at the University of Oslo have tested a new device for delivering hormone treatments for mental illness through the nose. This method was found to deliver medicine to the brain with few side effects.

The illustration shows that oxytocin can reach the brain in two ways: either indirectly, through the blood, or directly, along nerve pathways. A: Particles from a nasal spray. B: Route. C: Mucous membrane. D: Sensory nerve cell. E: Blood vessel. F: Nerve pathway. G: Nerve. Photo Credit: Image courtesy of University of Oslo, Faculty of Medicine

About one out of every hundred Norwegians develop schizophrenia or autism in the course of their lifetime. Moreover, at any one time some 20,000 people are receiving treatment for these problems. Many psychiatric disorders such as autism, schizophrenia and bipolar disorder are characterised by poor social functioning.

Oxytocin is a hormone that influences social behaviour and has shown promise for the treatment of mental illness.

Researchers at UiO have now discovered that low doses of oxytocin may help patients with mental illness to better perceive social signals. As part of this project, they have collaborated with the company OptiNose, who have developed a new device designed to improve medicine delivery to the brain via the nose.

Regulates social behaviour

Oxytocin has historically been known to play a crucial role in child rearing as it facilitates pregnancy, birth, and the release of milk during nursing. Further, oxytocin helps regulate cardiac functions and fluid levels. More recent research has revealed the importance of oxytocin for social behaviour.

Oxytocin is a neuropeptide and was discovered in 1953. Peptides are a group of molecules that consist of a chain of amino acids. Amino acids are also known as the building blocks of proteins, which we find in all types of cells. Oxytocin is produced in the hypothalamus, which is the brain’s coordinating centre for the hormone system.

Medicine through the nose

Because of oxytocin’s role in social behaviour, researchers have explored the possibility of administering the hormone for the treatment of mental illness. As oxytocin is a relatively large molecule, it has trouble crossing the barrier between the brain and circulating blood. Thus, researchers have administered oxytocin to patients through the nose as this route offers a direct pathway to the brain that bypasses this barrier.

However, researchers have a poor understanding of how oxytocin reaches and affects the brain. The most effective dose for treatment has also received little research attention.

Professor Ole A. Andreassen and his research team have collaborated with OptiNose on a project that evaluated two different doses of oxytocin and on how they affect the way in which social signals are perceived.

Low doses work best

Sixteen healthy men received two different doses of oxytocin, along with placebo. Volunteers were also given an intravenous dose of oxytocin, for a comparison of the effects of oxytocin in circulating blood. The research showed that only those administered a low dose of oxytocin experienced an effect on how they perceived social signals.

Professor Ole A. Andreassen explains: “The results show that intranasal administration, i.e. introducing oxytocin through the nose, affects the function of the brain.

As no effect was observed after intravenous treatment, this indicates that intranasally administered oxytocin travels directly to the brain, as we have long believed. The fact that we have shown the efficacy of a low dose of oxytocin on social perception is even more important.

A dose that is lower, but that still influences behaviour, will entail a lower risk of affecting other regulatory systems in the body. Very high doses of oxytocin could, in fact, have the opposite effect on social behaviour.”

The scientists also discovered that individuals with larger nasal cavities had a stronger response to a low dose of oxytocin.

Breathing helps

OptiNose uses a new technology to distribute medicine to the brain, making use of the user’s breath to propel medicine deep into the nasal cavity.

The device administers oxytocin high up into the patient’s nasal cavity. When the medicine is targeted deep inside the nose, it enables brain delivery along nerve pathways from the uppermost part of the nasal cavity. Conventional nasal spray devices are not suited to consistently deliver medicine high up enough into the nose.

The device also expands the nasal cavity, facilitating nose-to-brain medicine delivery. As the user exhales into the device, this closes the soft palate and prevents the medicine from being lost down the throat.

Since less medicine is lost along the way, patients can take smaller doses and accordingly experience fewer side effects.

May yield new treatments

The next step in the research is to carry out the same tests on people with mental illness.

“We are now running tests in volunteers diagnosed with autism spectrum disorders,” says Dr Quintana.

“We hope that this research project is the first step in the development of a series of new medicines that may be of great help to more people with mental illness,” concludes Professor Andreassen.

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The above post is reprinted from materials provided by University of Oslo, Faculty of Medicine.

Generating potentially safer stem cells in the laboratory

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BIOENGINEER.ORG http://bioengineer.org/generating-potentially-safer-stem-cells-laboratory/

Damaged tissue, such as pancreas, heart, and neuronal tissue, which is regenerated to treat cardiovascular diseases, diabetes, or neurodegenerative diseases. This is one of the ambitious scenarios to which regenerative medicine aspires and that is being announced as one of the great promises of twenty-first century biomedicine for the treatment of a long list of diseases affecting people today. The focal point is the use of stem cells, which are capable of producing different types of cells or tissue.

DNA damage (red) in cells submitted to replicative stress, similar to those observed during cell reprogramming. Photo Credit: CNIO

2006 marked a turning point in this field, when the Japanese scientist, Shinya Yamanaka, managed to generate pluripotent stem cells in the lab for the first time. These are capable of becoming any type of cell, whether insulin-producing beta cells (pancreas) or cardiomyocytes (heart), and are known as iPS cells. This cell reprogramming technique eliminated one of the great ethical dilemmas of the time: until then, pluripotent stem cells could only be obtained from embryos which, in order to achieve this, had to be destroyed.

However, as Óscar Fernández-Capetillo, head of the Genomic Instability Group at the Spanish National Cancer Research Centre (CNIO), says: “the drawback of this new technology is that Yamanaka’s method damaged the stem cell genome, leading to certain safety concerns regarding these cells.” While the fact that the method damaged the DNA of iPS cells was known, the reasons were not.

According to an article published this week in Nature Communications, the team headed by Fernández-Capetillo states that the damage to the genome of iPS cells lies in a very specific kind of stress that the cells are subjected to during cell reprogramming: replication stress, which occurs when the cells increase the pace of division. In addition, and based on these findings, the authors of the paper have managed to develop strategies to reduce this type of stress, resulting in pluripotent stem cells with less damage to their genome.

The results represent a significant step forward regarding the possible use of iPS cells, because after almost a decade since they were developed, there is now a more efficient way of obtaining them, with less damage to the DNA, making them potentially safer.

The CNIO Telomeres and Telomerase groups, headed by María Blasco, and the Tumoral Suppression Group, headed by Manuel Serrano have also participated in this study, together with groups from the Pasteur Institute in Paris, Toronto University and the Pompeu Fabra University in Barcelona.

Stem Cells With More Stable Genomes

The nature of the damage to the DNA observed in iPS cells has been intensely discussed for some years, due to the fact that it is linked to the rearrangement of large fragments of chromosomes which could lead to potentially dangerous mutations if used clinically.

In a paper published in Nature in 2009, the team led by María Blasco, with the collaboration of Fernández-Capetillo’s group, described how the damage to the DNA had important consequences in cell reprogramming by limiting the process and making it less efficient.

Now the team headed by Fernández-Capetillo has not only identified the origin of the damage, replication stress, but has managed to reduce it significantly; potentially improving the safety of induced stem cells for use in biomedicine.

To reduce damage to stem cells and thus achieve more stable genomes, the scientists have used a dual approach: genetics, increasing the production of the Chk1 protein, which repairs DNA damage due to replication stress; and chemical, based on supplementing the medium in which the cells are fed with nucleoside, the source compounds of the bricks that build DNA.

“Based on previous research performed by the group, we knew that an additional input of nucleoside reduces replication stress, probably by facilitating the successful replication of DNA as it increases the rate of cell division during the reprogramming process,” explains Sergio Ruiz, whose signature appear in first place on the paper.

The simplicity of this nucleoside-based strategy means that it can be implemented easily by laboratories around the world working with iPS cells, and thus contribute significantly to the field of regenerative biology, one of the greatest aspirations of biomedicine this century.

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The above post is reprinted from materials provided by Centro Nacional de Investigaciones Oncologicas (CNIO).

HIV particles do not cause AIDS, our own immune cells do

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BIOENGINEER.ORG http://bioengineer.org/hiv-particles-cause-aids-immune-cells/

Researchers from the Gladstone Institutes have revealed that HIV does not cause AIDS by the virus’s direct effect on the host’s immune cells, but rather through the cells’ lethal influence on one another.

HIV can either be spread through free-floating virus that directly infect the host immune cells or an infected cell can pass the virus to an uninfected cell. The second method, cell to cell transmission, is 100 to 1000 times more efficient, and the new study shows that it is only this method that sets off a cellular chain reaction that ends in the newly infected cells committing suicide.

“The fundamental ‘killing units’ of CD4 T cells in lymphoid tissues are other infected cells, not the free virus,” says co-first author Gilad Doitsh, PhD, a staff research investigator at the Gladstone Institute of Virology and Immunology. “And cell-to-cell transmission of HIV is required for activation of the main HIV death pathway.”

In a previous investigation, the scientists discovered that 95% of cell death from HIV is caused by immune cells committing suicide in self-defense after an unsuccessful infection. When the virus tries to invade a cell that is “at rest,” the infection is aborted. However, fragments of viral DNA remain and are detected by the resting host cell. This triggers a domino effect in the cell’s defense system, resulting in the activation of the enzyme caspase-1, which ultimately causes the induction of pyroptosis, a fiery form of cell suicide.

In the new study, published in Cell Reports, it was revealed that this death pathway is only activated through cell-to-cell transmission of HIV, not from infection by free-floating viral particles. Using lymphoid tissue infected with HIV, the scientists compared cell death rates between cell-to-cell and cell-free virus transfer. They discovered that while overall rates of infection remained the same, there was significantly more CD4 T cell death if HIV was spread by infection from other cells than by free-floating virus.

“Although free-floating viruses establish the initial infection, it is the subsequent cell-to-cell spread of HIV that causes massive CD4 T cell death,” says co-first author Nicole Galloway, PhD, a post-doctoral fellow at the Gladstone Institute of Virology and Immunology. “Cell-to-cell transmission of HIV is absolutely required for activation of the pathogenic HIV cell-death pathway.”

To confirm this finding, the researchers perturbed viral transfer through a number of means: genetically modifying the virus, applying chemical HIV inhibitors, blocking inter-cellular synapses, and increasing the physical distance between the cells so they could not come into contact with one another. Notably, disruption of cell-to-cell contact effectively stopped the death of CD4 T cells. What’s more, only during cell-to-cell transmission was caspase-1 activated within the target cells, thereby initiating pyroptosis, the pro-inflammatory cell-suicide response.

The scientists speculate that the difference in cell death rates between the two methods of infection is due to the increased efficiency of cell-to-cell transmission. Aborted viral DNA fragments are quickly removed during infection by cell-free HIV particles, so they are not detected by the cell’s defensive system. However, in cell-to-cell transmission, the viral DNA fragments overwhelm cell maintenance, building up until they surpass a threshold and are detected. This then triggers caspase-1 activation and pyroptosis.

“This study fundamentally changes our mindset about how HIV causes massive cell death, and puts the spotlight squarely on the infected cells in lymphoid tissues rather than the free virus,” says senior author Warner C. Greene, MD, PhD, director of the Gladstone Institute of Virology and Immunology. “By preventing cell-to-cell transmission, we may able to block the death pathway and stop the progression from HIV infection to AIDS.”

Other investigators on the study include Kathryn Monroe, Zhiyuan Yang, and Isa Muñoz-Arias from the Gladstone Institutes, and David Levy from New York University College of Dentistry. Funding was provided by the National Institutes of Health, National Institute of Allergy and Infectious Diseases, the UCSF/Robert John Sabo Trust Award, and the Giannini Foundation Postdoctoral Research Fellowship.

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The above post is reprinted from materials provided by Gladstone Institutes.

Life expectancy climbs worldwide but people spend more years living with illness

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Global life expectancy has risen by more than six years since 1990 as healthy life expectancy grows; ischemic heart disease, lower respiratory infections, and stroke cause the most health loss around the world.

People around the world are living longer, even in some of the poorest countries, but a complex mix of fatal and nonfatal ailments causes a tremendous amount of health loss, according to a new analysis of all major diseases and injuries in 188 countries.

Thanks to marked declines in death and illness caused by HIV/AIDS and malaria in the past decade and significant advances made in addressing communicable, maternal, neonatal, and nutritional disorders, health has improved significantly around the world. Global life expectancy at birth for both sexes rose by 6.2 years (from 65.3 in 1990 to 71.5 in 2013), while healthy life expectancy, or HALE, at birth rose by 5.4 years (from 56.9 in 1990 to 62.3 in 2013).

Healthy life expectancy takes into account not just mortality but also the impact of nonfatal conditions and summarizes years lived with disability and years lost due to premature mortality. The increase in healthy life expectancy has not been as dramatic as the growth of life expectancy, and as a result, people are living more years with illness and disability.

“Global, regional, and national disability-adjusted life years (DALYs) for 306 diseases and injuries and healthy life expectancy (HALE) for 188 countries, 1990-2013: quantifying the epidemiological transition” examines fatal and nonfatal health loss across countries. Published in The Lancet on August 27, the study was conducted by an international consortium of researchers working on the Global Burden of Disease study and led by the Institute for Health Metrics and Evaluation (IHME) at the University of Washington.

“The world has made great progress in health, but now the challenge is to invest in finding more effective ways of preventing or treating the major causes of illness and disability,” said Professor Theo Vos of IHME, the study’s lead author.

For most countries, changes in healthy life expectancy for males and females between 1990 and 2013 were significant and positive, but in dozens of countries including Botswana, Belize, and Syria healthy life expectancy in 2013 was not significantly higher than in 1990. In some of those countries, including South Africa, Paraguay, and Belarus, healthy life expectancy has actually dropped since 1990. People born in Lesotho and Swaziland in 2013 could expect to live at least 10 fewer years in good health than people born in those countries two decades earlier. People in countries such as Nicaragua and Cambodia have experienced dramatic increases in healthy life expectancy since 1990, 14.7 years and 13.9 years, respectively. The reverse was true for people in Botswana and Belize, which saw declines of 2 years and 1.3 years, respectively.

The differences between countries with the highest and lowest healthy life expectancies is stark. In 2013, Lesotho had the lowest, at 42 years, and Japan had the highest globally, at 73.4 years. Even regionally, there is significant variation. Cambodians and Laotians born in 2013 would have healthy life expectancies of only 57.5 years and 58.1 years, respectively, but people born in nearby Thailand and Vietnam could live nearly 67 years in good health.

As both life expectancy and healthy life expectancy increase, changes in rates of health loss become increasingly crucial. The study’s researchers use DALYs, or disability-adjusted life years, to compare the health of different populations and health conditions across time. One DALY equals one lost year of healthy life and is measured by the sum of years of life lost to early death and years lived with disability. The leading global causes of health loss, as measured by DALYs, in 2013 were ischemic heart disease, lower respiratory infections, stroke, low back and neck pain, and road injuries. These causes differed by gender: for males, road injuries were a top-five cause of health loss, but these were not in the top 10 for females, who lose substantially more health to depressive disorders than their male counterparts.

Ethiopia is one of several countries that have been rising to the challenge to ensure that people live lives that are both longer and healthier. In 1990, Ethiopians could expect to live 40.8 healthy years. But by 2013, the country saw an increase in healthy life expectancy of 13.5 years, more than double the global average, to 54.3 years.

“Ethiopia has made impressive gains in health over the past two decades, with significant decreases in rates of diarrheal disease, lower respiratory infection, and neonatal disorders,” said Dr. Tariku Jibat Beyene of Addis Ababa University. “But ailments such as heart disease, COPD, and stroke are causing an increasing amount of health loss. We must remain vigilant in addressing this new reality of Ethiopian health.”

The fastest-growing global cause of health loss between 1990 and 2013 was HIV/AIDS, which increased by 341.5%. But this dramatic rise masks progress in recent years; since 2005, health loss due to HIV/AIDS has diminished by 23.9% because of global focus on the disease. Ischemic heart disease, stroke, low back and neck pain, road injuries, and COPD have also caused an increasing amount of health loss since 1990.The impact of other ailments, such as diarrheal diseases, neonatal preterm birth complications, and lower respiratory infections, has significantly declined.

Across countries, patterns of health loss vary widely. The countries with the highest rates of DALYs are among the poorest in the world, and include several in sub-Saharan Africa: Lesotho, Swaziland, Central African Republic, Guinea-Bissau, and Zimbabwe. Countries with the lowest rates of health loss include Italy, Spain, Norway, Switzerland, and Israel.

Country-level variation also plays an important role in the changing disease burden, particularly for non-communicable diseases. For communicable, maternal, neonatal, and nutritional disorders, global DALY numbers and age-standardized rates declined between 1990 and 2013. While the number of DALYs for non-communicable diseases have increased during this period, age-standardized rates have declined.

The number of DALYs due to communicable, maternal, neonatal, and nutritional disorders has declined steadily, from 1.19 billion in 1990 to 769.3 million in 2013, while DALYs from non-communicable diseases have increased steadily, rising from 1.08 billion to 1.43 billion over the same period.

The study also examines the role that socio-demographic status — a combination of per capita income, population age, fertility rates, and years of schooling — plays in determining health loss. Researchers’ findings underscore that this accounts for more than half of the differences seen across countries and over time for certain leading causes of DALYs, including maternal and neonatal disorders. But the study notes that socio-demographic status is much less responsible for the variation seen for ailments including cardiovascular disease and diabetes.

“Factors including income and education have an important impact on health but don’t tell the full story,” said IHME Director Dr. Christopher Murray. “Looking at healthy life expectancy and health loss at the country level can help guide policies to ensure that people everywhere can have long and healthy lives no matter where they live.”

Countries with highest healthy life expectancy, both sexes, 2013

1 Japan

2 Singapore

3 Andorra

4 Iceland

5 Cyprus

6 Israel

7 France

8 Italy

9 South Korea

10 Canada

Countries with lowest healthy life expectancy, both sexes, 2013

1 Lesotho

2 Swaziland

3 Central African Republic

4 Guinea-Bissau

5 Zimbabwe

6 Mozambique

7 Afghanistan

8 Chad

9 South Sudan

10 Zambia

Leading causes of DALYs or health loss globally for both sexes, 2013

1 Ischemic heart disease

2 Lower respiratory infection

3 Stroke

4 Low back and neck pain

5 Road injuries

6 Diarrheal diseases

7 Chronic obstructive pulmonary disease

8 Neonatal preterm birth complications

9 HIV/AIDS

10 Malaria

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The above post is reprinted from materials provided by The Lancet.