Toward a Universal Influenza Vaccine

Diverse antibodies induced in humans by vaccination with an avian influenza virus vaccine may offer broader, more durable protection against multiple strains of influenza than today's vaccines typically provide, according to a study led by Florian Krammer, PhD, Assistant Professor in the Department of Microbiology at the Icahn School of Medicine at Mount Sinai, and Patrick Wilson, PhD, Associate Professor in the Department of Medicine at the University of Chicago. The research, published in the journal Cell Host & Microbe, suggests new pathways toward the long-cherished goal of a "universal vaccine" that would be effective against all strains of influenza virus.

Influenza epidemics lead to as many as half a million deaths annually around the world, according to the World Health Organization. While generally effective, vaccines against seasonal influenza must be reformulated every year at great cost based on educated guesses as to which strains of influenza virus will dominate. This dilemma is caused by "antigenic drift"--a phenomenon in which gene mutations constantly alter sites on the virus that can be targeted by antibodies of a vaccinated individual. A true universal influenza vaccine would defeat antigenic drift, improve vaccine efficacy, and eliminate the constant need to reformulate vaccines and revaccinate populations at risk.

"The research in this study provides insights into how we can generate broadly protective immune responses against influenza viruses," Dr. Krammer said. "It shows us mechanisms of protection we didn't understand, or appreciate, or even know of before. I believe it will have huge implications for the development of a universal influenza virus vaccine."

A key objective of the study was to understand and assess the protective antibodies that are induced when individuals are vaccinated against pathogenic H7N9 avian influenza viruses, and to characterize the sites on the virus, called epitopes, to which antibodies bind. Mount Sinai scientists, in collaboration with a University of Chicago team led by Dr. Wilson, characterized the binding and functional properties of 12 monoclonal antibodies induced by an experimental vaccine based on live-attenuated avian influenza virus (H7N9).

One important result was the identification of unique epitopes on the head and stalk of the virus, which could be important antibody binding sites for future vaccines. But perhaps the most significant result was an enhanced understanding of the protective power of "non-neutralizing" antibodies, a class of monoclonal antibodies whose activity is not currently recognized or utilized in the development of commercial influenza vaccines.

Today's influenza vaccines are designed to induce so-called neutralizing antibodies that target the glycoprotein hemagglutinin (HA), which carries many epitopes on the surface of the virus. Assays used to test the effectiveness of seasonal influenza vaccines--a step required by regulatory bodies such as the U.S. Food and Drug Administration before the vaccines can be licensed -- only measure antibody activity targeting the highly variable head region of the virus. The new study indicates this approach to developing, testing, and deploying vaccines may not be optimal.

"We have showed that the assay used every year to prove influenza vaccines are effective can only detect one portion of the antibodies you get after vaccination with avian influenza virus," Dr. Krammer said. "There are a number of other neutralizing and non-neutralizing antibodies, some of which target previously unrecognized epitopes on the HA protein, and which provide protection against lethal infection in mouse models."

"Our results suggest that non-neutralizing antibodies, a class of antibodies typically not examined in assessments of vaccine efficacy, may contribute to protection," said Dr. Wilson of the University of Chicago.

"The antibodies we characterized in this study are very broad," Dr. Krammer said. "They bind not only to the H7 strain but to H3 and other strains. These results show us that we see only a small part of a bigger picture when we assess vaccine efficacy using today's most widely accepted assays." The new study suggests tantalizing opportunities for optimizing influenza vaccines and, importantly, also supports the hypothesis behind the universal influenza virus vaccine candidate that the team at Mount Sinai is currently developing.

"Assessing which non-neutralizing antibodies contribute to protection and how to measure their significant contribution in vaccinees remains a difficult challenge," said Mount Sinai's Dr. Krammer. Dr. Krammer expressed optimism that further research into the protective mechanism of broadly-reactive neutralizing and non-neutralizing antibodies could provide significant insights into human immunology that could ultimately lead to universal influenza virus vaccines that protect against all types of influenza viruses.

Landmark study shows acute myeloid leukaemia is at least 11 different diseases

Scientists at the Wellcome Trust Sanger Institute and their international collaborators have shown that Acute Myeloid Leukemia (AML) is not a single disorder, but at least 11 different diseases, and that genetic changes explain differences in survival among young AML patients. Published in the New England Journal of Medicine, the ground-breaking study on the genetics of AML could improve clinical trials and the way patients are diagnosed and treated in the future.

In the largest study of its kind, researchers studied 1540 patients with AML that were enrolled in clinical trials. They analysed more than 100 genes known to cause leukemia, to identify common genetic themes behind the development of the disease.

The researchers found that the patients were divided into at least 11 major groups, each with different constellations of genetic changes and distinctive clinical features. Despite finding common themes however, the study also showed that most patients had a unique combination of genetic changes driving their leukemia. This genetic complexity helps explain why AML shows such variability in survival rates among patients.

Full knowledge of the genetic make-up of a patient's leukemia substantially improved the ability to predict whether that patient would be cured with current treatments. This information could be used to design new clinical trials to develop the best treatments for each AML subtype, with the ultimate aim of bringing more extensive genetic testing into routine clinical practice.

Dr Peter Campbell, co-leader of the study from the Wellcome Trust Sanger Institute, said: "This is our first detailed look at how the genetic complexity of a cancer impacts on its clinical outcomes. Two people may have what looks like the same leukemia down the microscope, but we find extensive differences between those leukemias at the genetic level. These genetic differences can explain so much of why one of those patients will be cured, while the other will not, despite receiving the exact same treatment.

"We have shown that AML is an umbrella term for a group of at least 11 different types of leukemia. We can now start to decode these genetics to shape clinical trials and develop diagnostics."

Acute myeloid leukemia (AML) is an aggressive blood cancer that affects people of all ages, often requiring months of intensive chemotherapy in hospital. It develops in cells in the bone marrow.

This study shows that by using a comprehensive approach, scientists will be able to understand the complex interplay between the genetic changes seen in a cancer and the clinical outcomes of that cancer. This requires full genetic analysis of samples from large numbers of patients matched with detailed information about the treatment and survival of those patients. Further research into leukemia, and indeed other cancers, will allow researchers to understand the patterns of how the disease develops and how patients are going to respond to treatment.

Prof. Hartmut Döhner, Medical Director of Hematology/Oncology at Ulm University and chair of the German-Austrian AML Study Group, said: "This landmark study has showcased the importance of international collaboration between academic institutions and clinical trials and the large scale of the study. These results represent a major step forward in translating the exciting findings from molecular genetics into better disease classification, diagnosis, and improved care of our patients with acute myeloid leukemia."

Dr Elli Papaemmanuil, joint first author from the Sanger Institute and the Memorial Sloan Kettering Cancer Centre in New York, said: "Leukemia is a global problem with poor outcomes for most patients. We combined detailed genetic analysis with patient health information to help understand the fundamental causes of AML. For the first time we untangled the genetic complexity seen in most AML cancer genomes into distinct evolutionary paths that lead to AML. By understanding these paths we can help develop more appropriate treatments for individual patients with AML. We are now extending such studies across other leukemias."

Key to Parkinson's Disease Neurodegeneration .

Researchers at the University of Pittsburgh School of Medicine have uncovered a major reason why the Parkinson's-related protein alpha-synuclein, a major constituent of the Lewy bodies that are the pathological hallmark of Parkinson's disease (PD), is toxic to neurons in the brain. The finding has the potential to lead to new therapies that could slow or stop progression of the devastating illness. The new research appears online inScience Translational Medicine.

PD is a degenerative neurological disease characterized by tremor, slowness, and gait and balance difficulties that affects about 1 million people in the United States. The symptoms are caused by the degeneration and loss of neurons in the brain, particularly those crucial for the initiation and coordination of movement.

"It's really exciting that we have found a mechanism we can target to create new treatments for this devastating disease," said lead investigator J. Timothy Greenamyre, M.D., Ph.D., Love Family Professor of Neurology in Pitt's School of Medicine and director of the Pittsburgh Institute for Neurodegenerative Diseases (PIND).

PIND's goal is an integrated, interdisciplinary approach to the study of neurodegenerative diseases and their mechanisms, with the aim of transforming cutting-edge science into novel therapies and diagnostics that directly benefit individuals affected by neurodegenerative diseases.

"With four different PIND investigators working together, the new study highlights the power of this collaborative approach," Dr. Greenamyre added.

Current treatments for PD can reduce symptoms, but they do not slow the inevitable worsening of the disease. To slow or halt illness progression, scientists must first determine why and how the neurons are dying.

Degenerating neurons contain large clumps of a protein called alpha-synuclein. People whose cells make too much alpha-synuclein or make a mutated form of the protein are at high risk of developing PD because of the protein's toxicity, researchers found. Scientists also demonstrated that the accumulation of alpha-synuclein in PD is toxic because it disrupts the normal functioning of mitochondria--the tiny powerhouses responsible for generating a cell's energy.

In the new study, Dr. Greenamyre and his team--led by coauthors Roberto Di Maio, Ph.D., and Paul Barrett, Ph.D., both of PIND--used a well-established rodent model of PD to show exactly how alpha-synuclein disrupts mitochondrial function. They found that by attaching to a mitochondrial protein called TOM20, alpha-synuclein prevented the mitochondria from functioning optimally, which resulted in the production of less energy and more damaging cellular waste.

Ultimately, this interaction between alpha-synuclein and TOM20 leads to neurodegeneration, Dr. Greenamyre explained.

The researchers then confirmed their animal findings in brain tissue from people with PD.

"The effects of alpha-synuclein on mitochondria are like making a perfectly good coal-fueled power plant extremely inefficient, so it not only fails to make enough electricity, but also creates too much toxic pollution," said Dr. Greenamyre.

Using cell cultures, the research team also found two ways to prevent the toxicity caused by alpha-synuclein: gene therapy that forced the neurons to make more TOM20 protein protected them from the alpha-synuclein; and a protein that was able to prevent alpha-synuclein from sticking to TOM20 prevented alpha-synuclein's harmful effects on mitochondria.

While more research is needed to determine whether these approaches could help PD patients, Dr. Greenamyre is optimistic that one or both may ultimately make it into human clinical trials in an effort to slow or halt the otherwise inevitable progression of PD.

Ancient Earth's Scars Affect Today's Earthquakes

Super-computer modelling of Earth's crust and upper-mantle suggests that ancient geologic events may have left deep 'scars' that can come to life to play a role in earthquakes, mountain formation, and other ongoing processes on our planet.

This changes the widespread view that only interactions at the boundaries between continent-sized tectonic plates could be responsible for such events.

A team of researchers from the University of Toronto and the University of Aberdeen have created models indicating that former plate boundaries may stay hidden deep beneath the Earth's surface. These multi-million-year-old structures, situated at sites away from existing plate boundaries, may trigger changes in the structure and properties at the surface in the interior regions of continents.

"This is a potentially major revision to the fundamental idea of plate tectonics," says lead author Philip Heron, a postdoctoral fellow in Russell Pysklywec's research group in U of T's Department of Earth Sciences. Their paper, "Lasting mantle scars lead to perennial plate tectonics," appears in the June 10, 2016 edition of Nature Communications.

Heron and Pysklywec, together with University of Aberdeen geologist Randell Stephenson have even proposed a 'perennial plate tectonic map' of the Earth to help illustrate how ancient processes may have present-day implications.

"It's based on the familiar global tectonic map that is taught starting in elementary school," says Pysklywec, who is also chair of U of T's Department of Earth Sciences. "What our models redefine and show on the map are dormant, hidden, ancient plate boundaries that could also be enduring or "perennial" sites of past and active plate tectonic activity."

To demonstrate the dominating effects that anomalies below the Earth's crust can have on shallow geological features, the researchers used U of T's SciNet -- home to Canada's most powerful computer and one of the most powerful in the world- to make numerical models of the crust and upper-mantle into which they could introduce these scar-like anomalies.

The team essentially created an evolving "virtual Earth" to explore how such geodynamic models develop under different conditions.

"For these sorts of simulations, you need to go to a pretty high-resolution to understand what's going on beneath the surface," says Heron. "We modeled 1,500 kilometres across and 600 kilometres deep, but some parts of these structures could be just two or three kilometres wide. It is important to accurately resolve the smaller-scale stresses and strains."

Using these models, the team found that different parts of the mantle below the Earth's crust may control the folding, breaking, or flowing of the Earth's crust within plates -- in the form of mountain-building and seismic activity -- when under compression.

In this way, the mantle structures dominate over shallower structures in the crust that had previously been seen as the main cause of such deformation within plates.

"The mantle is like the thermal engine of the planet and the crust is an eggshell above," says Pysklywec. "We're looking at the enigmatic and largely unexplored realm in the Earth where these two regions meet."

"Most of the really big plate tectonic activity happens on the plate boundaries, like when India rammed into Asia to create the Himalayas or how the Atlantic opened to split North America from Europe," says Heron. "But there are lots of things we couldn't explain, like seismic activity and mountain-building away from plate boundaries in continent interiors."

The research team believes their simulations show that these mantle anomalies are generated through ancient plate tectonic processes, such as the closing of ancient oceans, and can remain hidden at sites away from normal plate boundaries until reactivation generates tectonic folding, breaking, or flowing in plate interiors.

"Future exploration of what lies in the mantle beneath the crust may lead to further such discoveries on how our planet works, generating a greater understanding of how the past may affect our geologic future," says Heron.

The research carries on the legacy of J. Tuzo Wilson, also a U of T scientist, and a legendary figure in geosciences who pioneered the idea of plate tectonics in the 1960's.

"Plate tectonics is really the cornerstone of all geoscience," says Pysklywec. "Ultimately, this information could even lead to ways to help better predict how and when earthquakes happen. It's a key building block."

Genetic Cause of Multiple Sclerosis Found

Although multiple sclerosis (MS) is known to run in certain families, attempts to find genes linked to the disease have been elusive. Now for the first time researchers are reporting a gene mutation that can be connected directly to the development of the disease. The results appear June 1 inNeuron.

"This finding is critical for our understanding of MS," says Carles Vilariño-Güell, an Assistant Professor in the Department of Medical Genetics at the University of British Columbia (UBC) in Vancouver and one of the study's senior authors. "Little is known about the biological processes that lead to the onset of the disease, and this discovery has massive amounts of potential for developing new treatments that tackle the underlying causes, not just the symptoms."

MS is a neurodegenerative disease in which the immune system attacks the myelin that protects nerve fibers, upsetting the flow of information between the brain and the body. It affects about 2 million people worldwide, and in its more severe, progressive form, no good treatments are available.

About 10% to 15% of MS cases appear to have a hereditary component, but until now researchers conducting genetic studies have found only weak associations between the risk of developing MS and particular gene variants. In contrast, people who carry the newly discovered mutation have a 70% chance of developing the disease, the team determined.

In the current study, the investigators reviewed materials from the Canadian Collaborative Project on Genetic Susceptibility to MS, a large database that contains genetic material from almost 2,000 families across Canada. They looked at a family that had multiple cases of the disease--five cases over two generations--and did exome sequencing to look for rare coding mutations that were present in all family members who had the disease. After identifying a gene of interest, they went back to the database and found the same mutation in another family with multiple cases of MS. Interestingly, all patients in these families with the mutation presented with the progressive form of MS.

"The mutation we found, in a gene called NR1H3, is a missense mutation that causes loss of function of its gene product, LXRA protein," says neuroscientist Weihong Song, Canada Research Chair in Alzheimer's Disease at UBC and the study's other senior author. Together with other members of the same family, LXRA controls transcriptional regulation of genes involved in lipid homeostasis, inflammation, and innate immunity.

Mice with this gene knocked out are known to have neurological problems, including a decrease in myelin production. "There is clear evidence to support that this mutation has consequences in terms of biological function, and the defective LXRA protein leads to familial MS development," Song says.

"One thing that's important to note is that although this mutation is present in only about 1 in 1,000 people with MS, by doing association analysis we've also found common variants in the same gene that are risk factors for progressive MS," Vilariño-Güell adds. "So even if patients don't have the rare mutation, treatments that target this pathway would likely be able to help them."

The researchers say that the discovery of this mutation will enable them to develop cellular and animal models for MS that are physiologically relevant to human disease--tools that have not previously been available. "These models will provide a good way for us to study the mechanism underlying the disease, as well as to screen for drugs that target it," Song says.

The researchers note that there is already interest in targeting this pathway for drug development in other diseases, including atherosclerosis. "These are still early days and there is a lot to test, but if we are able to repurpose some of these experimental drugs, it could shorten the time it takes to develop targeted MS treatments," Vilariño-Güell says.

Genes linked to effects of mood and stress on longevity identified

The visible impacts of depression and stress that can be seen in a person's face -- and contribute to shorter lives -- can also be found in alterations in genetic activity, according to newly published research.

In a series of studies involving both C. elegans worms and human cohorts, researchers from the Indiana University School of Medicine and the Scripps Research Institute have identified a series of genes that may modulate the effects of good or bad mood and response to stress on lifespan. In particular, the research pointed to a gene known as ANK3 as playing a key role in affecting longevity. The research was published May 24, 2016 in the Nature Publishing Group journal Molecular Psychiatry, the top ranked journal in the field of psychiatry.

"We were looking for genes that might be at the interface between mood, stress and longevity," said Alexander B. Niculescu III, M.D., Ph.D., professor of psychiatry and medical neuroscience at the IU School of Medicine. "We have found a series of genes involved in mood disorders and stress disorders which also seem to be involved in longevity.

"Our subsequent analyses of these genes found that they change in expression with age, and that people subject to significant stress and/or mood disorders, such as people who completed suicide, had a shift in expression levels of these genes that would be associated with premature aging and reduced longevity" said Dr. Niculescu, who is also attending psychiatrist and research and development investigator at the Indianapolis Veterans Affairs Medical Center.

The research began with studies in C. elegans, a worm widely used in life sciences research. An earlier study by one of the study co-authors, Michael Petrascheck, Ph.D., of the Scripps Research Institute, found that exposing C. elegans to the antidepressant mianserin, which is used to treat mood and stress disorders, extended the animal's lifespan.

In the Molecular Psychiatry study, the researchers methodically conducted a series of analyses to discover, prioritize,

• In C. elegans, 231 genes were identified whose activities were altered after administration of mianserin and for which there were 347 similar genes in humans.
• The 347 human genes were cross-referenced with a genome analysis of data from 3,577 older adults to identify those genes that might be associated with depressive symptoms in humans, resulting in 134 genes that overlapped.
• The 134 genes were prioritized for involvement in mood disorders and stress disorders, using the Niculescu lab's Convergent Functional Genomics approach and comprehensive databases of human and animal model genetic and gene expression studies in psychiatric disorders. The top scoring gene from the list was ANK3, which in recent years has become well known as playing a role in psychiatric disorders.
• Returning to the C. elegans model, the researchers tested the effects of mianserin and of oxidative stress on worms with mutated -- and therefore inactive -- versions of the ANK3 gene, compared to non-mutated wild-type worms. ANK3 expression increases with age in worms. Mianserin maintains lower, youthful levels of ANK3 expression, but does require some ANK3 to be present for its effects on longevity. Thus, there seems to be a "Goldilocks" effect.
• Next, using more than 700 blood samples from patients diagnosed with psychiatric disorders, as well as studying samples from the Marion County (Indianapolis, Ind.) Coroner's office of people who had committed suicide, the investigators found significantly higher levels of expression of ANK3 in older (middle aged) patients than in younger patients, and a shift towards higher ANK3 levels in those who had committed suicide. Higher levels of ANK3 have also been reported independently by others in individuals with Hutchinson-Gilford progeria syndrome, a form of accelerated aging.
• Adding genes that had scored nearly as high as ANK3 in the Convergent Functional Genomics analysis to create a panel of biomarkers showed similar but somewhat stronger results, particularly among those who had committed suicide.
• Mitochondrial dysfunction was the top biological pathway where the top candidate genes for mood and stress-modulated longevity mapped. Over the last decade, accumulating evidence has suggested a causative link between mitochondrial dysfunction and aging.
• A few of the genes identified in this study are changed in opposite direction in longevity compared to previous reports in Alzheimer's disease, raising the possibility that the treatment of mood and stress disorders earlier in life might have an impact on later life Alzheimer's disease.
• A large number of top genes identified in this study were changed in opposite direction in longevity compared to patterns of expression in suicide revealed by previous studies from the Niculescu group, suggesting the possibility of an evolutionary organismal "life switch," actively controlled by mood and stress.
• Bioinformatics drug repurposing analyses revealed a series of compounds that may act on these genes and promote longevity, such as the relatively innocuous omega-3 fatty acid DHA (docosahexaenoic acid), piracetam, quercetin, vitamin D and resveratrol, along with a series of existing drugs, such as estrogen-like compounds, antidiabetics and rapamycin.

The authors said that "these studies uncover ANK3 and other genes in our dataset as biological links between mood, stress and lifespan, that may be biomarkers for biological age as well as targets for personalized preventive or therapeutic interventions."

Protein to Modify Brain Function, Memory

Scientists at USC have developed a new tool to modify brain activity and memory in targeted ways, without the help of any drugs or chemicals.

The GFE3 protein may help researchers map the brain's connections and better understand how inhibitory synapses modulate brain function, said lead author Don B. Arnold, a professor of biological sciences at USC Dornsife College of Letters, Arts and Sciences.

It also may enable them to control neural activity and lead to advancements in research for diseases or conditions ranging from schizophrenia to cocaine addiction, Arnold said.

The new tool is a protein that carries a death sentence for synaptic proteins in specific cells. The protein can be encoded in animal genomes to effectively switch off their inhibitory synapses -- connections between neurons -- increasing their electrical activity.

"GFE3 harnesses a little known and remarkable property of proteins within the brain," Arnold said.

The protein takes advantage of an intrinsic process -- the brain's cycle of degrading and replacing proteins. Most brain proteins last only a couple of days before they are actively degraded and replaced by new proteins. GFE3 targets proteins that hold inhibitory synapses together to this degradation system and as a result, the synapses fall apart.

"Rather than a cell deciding when a protein needs to be degraded, we sort of hijack the process," Arnold said.

For the study published in the journal Nature Methods on June 6, the team of scientists studied the protein's effect in both mice and zebrafish. The researchers found that GFE3 protein triggered the neurons on the two sides of the spine to work in opposition, generating uncoordinated movements.

Previously, drugs could be used to inhibit inhibitory synapses in the brain, for instance benzodiazapines, which treat anxiety, insomnia or seizures. But the drugs inhibit all the cells in a particular area, not just the neurons that are the intended target.

"Unfortunately, cells that have very different, even opposite functions tend to be right next to each other in the brain," Arnold said. "Thus, pharmacological experiments are especially difficult to interpret. By encoding GFE3 within the genome, we can target and modulate the inhibitory synapses of specific cells without affecting other cells that have different functions."