Strategy to disarm the virus: New hope for a universal dengue vaccine

A new strategy that cripples the ability of the dengue virus to escape the host immune system has been discovered by A STAR's Singapore Immunology Network (SIgN). This breakthrough strategy opens a door of hope to what may become the world's first universal dengue vaccine candidate that can give full protection from all four serotypes of the dreadful virus.

Early studies have shown that a sufficiently weakened virus that is still strong enough to generate protective immune response offers the best hope for an effective vaccine. However, over the years of vaccine development, scientists have learnt that the path to finding a virus of appropriate strength is fraught with challenges. This hurdle is compounded by the complexity of the dengue virus. Even though there are only four different serotypes, the fairly high rates of mutation means the virus evolve constantly, and this contributes to the great diversity of the dengue viruses circulating globally.

In some cases, the immune response developed following infection by one of the four dengue viruses appears to increase the risk of severe dengue when the same individual is infected with any of the remaining three viruses.

With nearly half the world's population at risk of dengue infection and an estimated 400 million people getting infected each year[2], the need for a safe and long-lasting vaccine has never been greater.

The new strategy uncovered in this study overcomes the prevailing challenges of vaccine development by tackling the virus’ ability to ‘hide’ from the host immune system. Dengue virus requires the enzyme called Mtase (also known as 2'-O-methyltransferase) to chemically modify its genetic material to escape detection. In this study, the researchers discovered that by introducing a genetic mutation to deactivate the MTase enzyme of the virus, initial cells infected by the weakened MTase mutant virus is immediately recognised as foreign. As a result, the desired outcome of a strong protective immune response is triggered yet at the same time the mutant virus hardly has a chance to spread in the host.

Animal models immunised with the weakened MTase mutant virus were fully protected from a challenge with the normal dengue virus. The researchers went on to demonstrate that the MTase mutant dengue virus cannot infect Aedes mosquitoes. This means that the mutated virus is unable to replicate in the mosquito, and will not be able to spread through mosquitoes into our natural environment. Taken together, the results confirmed that Mtase mutant dengue virus is potentially a safe vaccine approach for developing a universal dengue vaccine that protects from all four serotypes.

The team leader, Dr Katja Fink from SIgN said, “There is still no clinically approved vaccine or specific treatment available for dengue, so we are very encouraged by the positive results with this novel vaccine strategy.

Our next step will be to work on a vaccine formulation that will confer full protection from all four serotypes with a single injection. If this proves to be safe in humans, it can be a major breakthrough for the dengue vaccine field.”

Associate Prof Leo Yee Sin, who heads the Singapore STOP Dengue Translational and Clinical Research (TCR) Program said, “We are into the seventh decade of dengue vaccine development, this indeed is an exciting breakthrough that brings us a step closer to an effective vaccine.”

Associate Professor Laurent Rénia said, “Dengue is a major public health problem in many of the tropical countries. We are very delighted that our collaborative efforts with colleagues in Singapore and China have made a promising step towards a cost-effective and safe dengue vaccine to combat the growing threat of dengue worldwide.”

The Singapore Immunology Network (SIgN), officially inaugurated on January 15, 2008, is a research consortium under the Agency for Science, Technology and Research (A*STAR)'s Biomedical Research Council.

The mandate of SIgN is to advance human immunology research and participate in international efforts to combat major health problems. Since its launch, SIgN has grown rapidly and currently includes 250 scientists from 26 different countries around the world working under 28 renowned principal investigators.

Through this, SIgN aims at building a strong platform in basic human immunology research for better translation of research findings into clinical applications.

SIgN also sets out to establish productive links with local and international institutions, and encourage the exchange of ideas and expertise between academic, industrial and clinical partners and thus contribute to a vibrant research environment in Singapore.

MNT

A well-connected core brain network helps humans to adapt

One thing that sets humans apart from other animals is our ability to intelligently and rapidly adapt to a wide variety of new challenges - using skills learned in much different contexts to inform and guide the handling of any new task at hand.

Now, research from Washington University in St. Louis offers new and compelling evidence that a well-connected core brain network based in the lateral prefrontal cortex and the posterior parietal cortex - parts of the brain most changed evolutionarily since our common ancestor with chimpanzees - contains “flexible hubs” that coordinate the brain's responses to novel cognitive challenges.

Acting as a central switching station for cognitive processing, this fronto-parietal brain network funnels incoming task instructions to those brain regions most adept at handling the cognitive task at hand, coordinating the transfer of information among processing brain regions to facilitate the rapid learning of new skills, the study finds.

“Flexible hubs are brain regions that coordinate activity throughout the brain to implement tasks - like a large Internet traffic router,” suggests Michael Cole, lead author of the study.

“Like an Internet router, flexible hubs shift which networks they communicate with based on instructions for the task at hand and can do so even for tasks never performed before,” he adds.

Decades of brain research has built a consensus understanding of the brain as an interconnected network of as many as 300 distinct regional brain structures, each with its own specialised cognitive functions.

Binding these processing areas together is a web of about a dozen major networks, each serving as the brain's means for implementing distinct task functions - i.e. auditory, visual, tactile, memory, attention and motor processes. It was already known that fronto-parietal brain regions form a network that is most active during novel or non-routine tasks, but it was unknown how this network's activity might help implement tasks.

This study proposes and provides strong evidence for a “flexible hub” theory of brain function in which the fronto-parietal network is composed of flexible hubs that help to organise and coordinate processing among the other specialised networks.

This study provides strong support for the flexible hub theory in two key areas.

First, the study yielded new evidence that when novel tasks are processed flexible hubs within the fronto-parietal network make multiple, rapidly shifting connections with specialised processing areas scattered throughout the brain.

Second, by closely analysing activity patterns as the flexible hubs connect with various brain regions during the processing of specific tasks, researchers determined that these connection patterns include telltale characteristics that can be decoded and used to identify which specific task is being implemented by the brain.

These unique patterns of connection - like the distinct strand patterns of a spider web - appear to be the brain's mechanism for the coding and transfer of specific processing skills, the study suggests.

By tracking where and when these unique connection patterns occur in the brain, researchers were able to document flexible hubs’ role in shifting previously learned and practised problem-solving skills and protocols to novel task performance. Known as compositional coding, the process allows skills learned in one context to be re-packaged and re-used in other applications, thus shortening the learning curve for novel tasks.

What's more, by tracking the testing performance of individual study participants, the team demonstrated that the transfer of these processing skills helped participants speed their mastery of novel tasks, essentially using previously practised processing tricks to get up to speed much more quickly for similar challenges in a novel setting. “The flexible hub theory suggests this is possible because flexible hubs build up a repertoire of task component connectivity patterns that are highly practiced and can be reused in novel combinations in situations requiring high adaptivity,” Cole explains.

“It's as if a conductor practised short sound sequences with each section of an orchestra separately, then on the day of the performance began gesturing to some sections to play back what they learned, creating a new song that has never been played or heard before.”

By improving our understanding of cognitive processes behind the brain's handling of novel situations, the flexible hub theory may one day help us improve the way we respond to the challenges of everyday life, such as when learning to use new technology, Cole suggests. “Additionally, there is evidence building that flexible hubs in the fronto-parietal network are compromised for individuals suffering from a variety of mental disorders, reducing the ability to effectively self-regulate and thereforeexacerbating symptoms,” he says.

Future research may provide the means to enhance flexible hubs in ways that would allow people to increase self-regulation and reduce symptoms in a variety of mental disorders, such as depression, schizophrenia and obsessive-compulsive disorder.

- MNT

Cancer cells change while moving throughout body

For the majority of cancer patients, it's not the primary tumour; that is deadly, but the spread or “metastasis” of cancer cells from the primary tumour to secondary locations throughout the body that is the problem. That's why a major focus of contemporary cancer research is how to stop or fight metastasis.

Previous lab studies suggest that metastasising cancer cells undergo a major molecular change when they leave the primary tumour - a process called epithelial-to-mesenchymal transition (EMT). As the cells travel from one site to another, they pick up new characteristics. More importantly, they develop a resistance to chemotherapy that is effective on the primary tumour. But confirmation of the EMT process has only taken place in test tubes or in animals.

In a study, in the Journal of Ovarian Research, Georgia Tech scientists have direct evidence that EMT takes place in humans, at least in ovarian cancer patients. The findings suggest that doctors should treat patients with a combination of drugs: those that kill cancer cells in primary tumours and drugs that target the unique characteristics of cancer cells spreading through the body.

The researchers looked at matching ovarian and abdominal cancerous tissues in seven patients. Pathologically, the cells looked exactly the same, implying that they simply fell off the primary tumour and spread to the secondary site with no changes. But on the molecular level, the cells were very different. Those in the metastatic site displayed genetic signatures consistent with EMT. The scientists didn't see the process take place, but they know it happened.

“It's like noticing that a piece of cake has gone missing from your kitchen and you turn to see your daughter with chocolate on her face,” said John McDonald, lead investigator on the project. “You didn't see her eat the cake, but the evidence is overwhelming. The gene expression patterns of the metastatic cancers displayed gene expression profiles that unambiguously identified them as having gone through EMT.”

The EMT process is an essential component of embryonic development and allows for reduced cell adhesiveness and increased cell movement. According to Benedict Benigno, director of gynaecological oncology at Atlanta's Northside Hospital, “These results clearly indicate that metastasising ovarian cancer cells are very different from those comprising the primary tumour and will likely require new types of chemotherapy if we are going to improve the outcome of these patients.”

Ovarian cancer is the most malignant of all gynaecological cancers and responsible for more than 14,000 deaths annually in the United States alone. It often reveals no early symptoms and isn't typically diagnosed until after it spreads.

“Our team is hopeful that, because of the new findings, the substantial body of knowledge that has already been acquired on how to block EMT and reduce metastasis in experimental models may now begin to be applied to humans,” said Loukia Lili, co-author of the study.

- MNT

Seeking a clinical test for breast cancer

An international scientific collaborative led by the Harvard Stem Cell Institute's Kornelia Polyak, MD, PhD, has discovered why women who give birth in their early twenties are less likely to eventually develop breast cancer than women who don't, triggering a search for a way to confer this protective state on all women.

The researchers now are in the process of testing p27, a mammary gland progenitor marker, in the tissue of thousands of women collected over a 20-year period - women whose histories have been followed extremely closely - to see if it is an accurate breast cancer predictor in a large population of women. If the hypothesis is confirmed, likely within a few months, Polyak says the commercial development of a clinical test for breast cancer risk would follow.

In a paper in Cell Stem Cell, the researchers describe how a full-term pregnancy in a woman's early twenties reduces the relative number and proliferative capacity of mammary gland progenitors - cells that have the ability to divide into milk-producing cells – making them less likely to acquire mutations that lead to cancer.

By comparing numerous breast tissue samples, the scientists found that women at high risk for breast cancer, such as those who inherit a mutated BRCA1 or BRCA2 gene, have higher-than-average numbers of mammary gland progenitors. In general, women who carried a child to full term had the lowest populations of mammary gland progenitors, even when compared to cancer-free women who had never been pregnant. In addition, in woman who gave birth relatively early, but later still developed breast cancer, the number of mammary gland progenitors were again observed to be higher than average.

“The reason we are excited about this research is that we can use a progenitor cell census to determine who's at particularly high risk for breast cancer,” said Polyak, a Harvard Stem Cell Institute Principal Faculty member and Harvard Medical School professor at the Dana-Farber Cancer Institute. “We could use this strategy to decrease cancer risk because we know what regulates the proliferation of these cells and we could deplete them from the breast.”

Research shows that two trends are contributing to an increase in the number of breast cancer diagnoses - a rise in obesity and the ever-increasing number of women postponing child bearing. The scientists’ long-range goal is to develop a protective treatment that would mimic the protective effects of early child bearing. The research, which took five years to complete, began with conversations between Polyak and John Hopkins University School of Medicine Professor Saraswati Sukumar.

The two scientists formed collaborations with clinicians at cancer centres that see large numbers of high-risk women in order to obtain breast tissue samples. They also worked with genomics experts and bioinformaticians to analyse gene expression in different breast cell types. At times, Polyak and Sukumar had trouble convincing others to help with the study, which is unique in the breast cancer field for its focus on risk prediction and prevention.

“In general people who study cancer always want to focus on treating the cancer but in reality, preventing cancer can have the biggest impact on cancer-associated morbidity and mortality,” Polyak said. “I think the mentality has to change because breast cancer affects so many women, and even though many of them are not dying of breast cancer, there's a significant personal and societal burden.”

- MNT

Obese mothers' children ‘more likely to die young’

Children born to obese mothers are 35 percent more likely to die before they reach 55, a study has found.

They also have a 29 percent increased chance of being admitted to hospital for heart attacks, angina and stroke than those born to mothers of a normal weight. Experts analysed data for 37,709 babies delivered between 1950 and 1976 in Scotland. Their mother’s weight was recorded during her first antenatal appointment in pregnancy.

The results showed that offspring were 35 percent more likely to have suffered an early death by the age of 55 if their mother had been obese in pregnancy (body mass index of 30 or over). This held true even after other factors, including mother’s age, socio-economic status, sex of the child and current weight, were taken into account. Writing in the British Medical Journal , the experts concluded: “Maternal obesity is associated with an increased risk of premature death in adult offspring.” Among the 28,540 mothers, 21 percent (5,993) were overweight and four percent (1,141) were obese.The researchers, from the universities of Aberdeen and Edinburgh, said the results were a “major public health concern”, especially seeing as only four percent of mothers in the study were obese, “far smaller than current levels in the US and UK”.

- The Independent