Category: Microbiology

Researchers have successfully created new nerve cells in the brains and spinal cords of living mammals without the need for stem cell transplants to replenish lost cells.

The new study, which was conducted at the University of Texas (UT) Southwestern Medical Center, offers hope to those suffering from traumatic brain injury or spinal cord damage and could be used to treat Alzheimer's disease.

However, the scientists involved have stressed that it is too soon to know whether the neurons created in these initial studies resulted in any functional improvements. 

Injuries to the spinal cord can lead to an irreversible loss of neurons. Along with scarring, they can ultimately lead to impaired motor and sensory functions. As adult spinal cords only have a limited ability to produce new neurons, biomedical scientists have sought to replace them using stem cells – but they have encountered difficulties with this approach.

Scientists in UT Southwestern's Department of Molecular Biology have successfully turned scar-forming astrocytes in the spinal cords of adult mice into neurons. Their findings are published in Nature Communications and follow previous findings published in Nature Cell Biology.

A transcription factor – a biological substance that regulates the expression of genes – was introduced into areas of the brain or spinal cord where that factor is not highly expressed in adult mice. A factor known as SOX2 switched fully differentiated, adult astrocytes to an earlier neuronal precursor, or neuroblast, stage of development.

The mice were then given a drug called valproic acid (VPA) that encouraged the survival of the neuroblasts and their maturation (differentiation) into neurons.

According to the study's senior author, Chun-Li Zhang, neurogenesis (neuron creation) occurred in the spinal cords of both adult and aged (over one-year old) mice of both sexes, although the response was much weaker in the aged mice.

SOX2-induced mature neurons created from reprogramming of astrocytes persisted for 210 days after the start of the experiment in the spinal cord study – the longest time the researchers examined.

A new technique has been developed to treat conditions such as Hepatitis B (HBV) without damaging cells infected by the virus.

Viruses such as HBV are able to survive by depositing their genes in their hosts' cell nuclei, where DNA is not normally degraded, which protects them from antiviral drugs. New research at the Helmholtz Zentrum, Munich and the Technische Universitat, Munich may pave the way to treating these viruses.

According to the World Health Organisation, more than 240 million people around the world are currently suffering from a chronic HBV infection, despite the availability of preventive vaccination. Sufferers of the disease are at risk of developing liver cirrhosis or even cancer as a result of the condition.

Antiviral medicines are available but they cannot completely eliminate the disease – as soon as treatment is discontinued, the virus is reactivated due to the presence of virus DNA (cccDNA: covalently closed circular DNA) "hidden" in the cell nucleus.

The cccDNA stored in the nuclei of infected liver cells (hepatocytes) serves as a template for the virus's own proteins and new viral genomes. The international team of scientists headed by Prof Ulrike Protzer and Prof Mathias Heikenwalder has found a way to selectively attack and eliminate the viral DNA without damaging the host liver cells in the process. 

"The degradation of viral DNA in the cell nucleus that we describe represents an important mechanism in the defence against the virus," Protzer reports. "Moreover, for the first time, the results offer the possibility to develop a treatment that can heal hepatitis B."

According to the scientists, in addition to interferons (the immune system's defence agents), activation of the lymphotoxin-beta receptor in the host cell promotes certain proteins and supports their function so that they chemically modulate and degrade viral cccDNA.

As a result of this process, the virus is prevented from reactivating and the disease cannot break out again following the cessation of treatment. The proteins do not affect the genetic information of the host cells and the team believe their research could lead to new treatments becoming available.

Regenerative medicine offers hope to sufferers of chronic conditions such as heart failure. Previous attempts to transform skin cells into heart muscle have only been partially successful, however, as the transformation is often incomplete.

Scientists at the Gladstone Institutes in California have come up with a new method of reprogramming skin cells in a way which renders them almost indistinguishable from heart muscle cells. Their findings are based on animal models and are described in the latest issue of Cell Reports. 

While heart disease remains the world's biggest killer, the chances of surviving a heart attack have been greatly improved due to recent medical advances. However, many people are now living with heart failure – a condition in which the heart does not beat at full capacity due to damage sustained during a cardiac arrest.

Previous research into regenerating heart muscle has required the insertion of several genetic factors to spur the reprogramming process. However, scientists have recognised problems with scaling this gene-based method into successful therapies.

Gladstone senior investigator Sheng Ding and colleagues used skin cells extracted from adult mice to screen for chemical compounds, known as 'small molecules', that could replace the genetic factors.

The team tested various combinations of small molecules before settling on a four-molecule 'cocktail' called SPCF that could aid the transformation of skin cells into heart cells. Although the resulting cells exhibited some behaviour characteristic of heart muscle cells, the transformation was incomplete.

An additional factor, Oct4, was therefore added to the cocktail, enabling the team to generate a completely reprogrammed, beating heart cell.

"Once we added Oct4 to the mix, we observed clusters of contracting cells after a period of just 20 days," explained Dr Ding. "Remarkably, additional analysis revealed that these cells showed the same patterns of gene activation and electric signaling patterns normally seen in the ventricles of the heart."

The researchers believe this may be a more desirable reprogramming method and are confident it represents progress towards their goal of an developing an entirely pharmaceutical-based method to regrow heart muscle.

New research conducted at the Warwick Medical School has solved an enduring mystery of biology by uncovering the key role of a protein in shutting down endocytosis during mitosis.

Their study outlines the role of actin, a protein, in shutting down clathrin-dependent endocytosis during mitosis.

Endocytosis is the process by which cells absorb molecules that are too large to pass through the plasma membrane, such as proteins. Normally, this takes place via clathrin-dependent endocytosis.

During this process, clathrin forms a pit on the inner surface of the membrane which allows the cell to engulf and bring in a small volume of fluid from outside the cell.

The question of how clathrin-dependent endocytosis shuts down during mitosis was first posed by American cell biologist Don Fawcett in 1965. He became aware of the phenomenon but scientists have hitherto been unable to find out the reason behind it.

Two competing theories emerged as possible explanations. One suggested the tension of the plasma membrane is too high for endocytosis to occur; the other that mitotic phosphorylation – the addition of a phosphate group to the cell proteins – switches off the proteins.

Recently, it was found that endocytosis can still occur in non-dividing cells with high membrane tensions because actin can be recruited to help clathrin overcome the high tension in the membrane.

The Warwick team found membrane tension in dividing cells is much higher than in non-dividing cells, raising the question of why actin does not help in this case. They found that actin is used to form a stiff cortex in cells during mitosis and thus cannot be used to facilitate endocytosis.

Endocytosis was re-started in mitotic cells when the researchers tricked them into making actin available during mitosis. According to the team, mitotic phosphorylation does not inhibit the process and their paper argues against the alternative theory.

Team leader Dr Steve Royle commented: "The implications for human health are truly fascinating; by knowing the role played by actin we can look to use it to restart endocytosis during cell division. That could mean that we're able to make dividing cells receptive to pharmaceuticals or other medical treatments in a way that we haven't before."

Researchers have identified a new type of regulatory blood cell that is able to combat hyperactive T-cells responsible for degenerative diseases such as multiple sclerosis (MS).

Diseases like MS occur when hyperactivity of the immune system results in a chronic state of inflammation. Scientists at BRIC, the University of Copenhagen, stimulated the regulatory blood cells and thereby reduced the level of brain inflammation and disease in a biological model. The results are published in the journal Nature Medicine.

The new blood cells belong to the group of white blood cells known as lymphocytes. A molecule called FoxA1, responsible for the cells' development and suppressive functions, is expressed by these cells.

When inserting FoxA1 into normal lymphocytes using gene therapy, the team found they were able to modify them to actively regulate inflammation and inhibit multiple sclerosis.

FoxA1-expressing lymphocytes were previously unknown. Headed by professor Shohreh Issazadeh-Navikas, the BRIC researchers examined the blood of patients with multiple sclerosis, before and after two years of treatment with the drug interferon-beta. They discovered that patients who benefit from the treatment increase the number of this new blood cell type, which fight disease.

"From a therapeutic viewpoint, our findings are really interesting and we hope that they can help find new treatment options for patients not benefiting from existing drugs, especially more chronic and progressive multiple sclerosis patients. In our model, we could activate lymphocytes by chemical stimulation and gene therapy, and we are curious whether this can be a new treatment strategy", said professor Issazadeh-Navikas.

The next phase of the team's research is to focus on developing such treatments. They have begun testing whether the FoxA1-expressing lymphocytes are able to prevent degradation of the nerve cell's myelin layer and brain degeneration in a model of progressive multiple sclerosis.

A number of other autoimmune diseases could potentially be treated by the team's research into preventing chronic inflammation, including type one diabetes, inflammatory bowel disease and rheumatoid arthritis.

During the past five years, the number of people suffering from MS has increased by ten per cent globally. It currently affects 100,000 people in the UK.

Scientists have opened up a possible new avenue for leukaemia treatment after disarming a gene responsible for tumour progression.

Researchers at the Institute for Research in Immunology and Cancer (IRIC) of the Université de Montréal targeted the Brg1 gene – a key regulator of leukaemia stem cells that are the root cause of the disease, resistance to treatment and relapse. 

The team have spent the past four years studying the gene in collaboration with another research group at Stanford University in California; their results are reported in the scientific journal, Blood.

One of the major problems faced by researchers targeting cancer stem cells is that many genes essential to their proper functioning are also essential for normal stem cells. Therapies that target them can thus also end up harming healthy cells.

"Strikingly, we showed that the Brg1 gene is dispensable for the function of normal blood stem cells, making it a promising therapeutic target in leukaemia treatment," said Pierre Thibault, principal investigator at IRIC and co-author in this study.

While promising results have been obtained on animal models and human leukaemia cells, clinical trials remain some way off. The next stage in the research will be to demonstrate the clinical relevance of the study by developing a small-molecule inhibitor to block Brg1 function in leukaemia.

Experiments are currently underway to identify drugs that can disarm the Brg1 gene and prevent leukaemia stem cells from generating malignant cells.

Cancer cells are often responsible for relapse as they are more resistant to radiotherapy and chemotherapy than the 'bulk' of the tumor. Inhibiting the division of such cells is therefore the key to obtaining irreversible impairment of tumour growth and long-term remission in patients.

Leukaemia is a cancer of the white blood cells and bone marrow. It is the twelfth most common cancer in the UK, accounting for more than two per cent of all cancers. It is the most common cancer of childhood – around a third of all cancers diagnosed in children are leukaemias.

Scientists at the University of Berkeley have discovered new evidence which shows how chronic stress can generate long-term changes in the brain and may predispose people to mental problems such as anxiety and mood disorders later in life.

It is hoped the research could help to develop treatments to reduce the risk of developing mental illness following stressful events.

People with stress-related illnesses, such as post-traumatic stress disorder (PTSD), are known to have brain abnormalities, including differences in the relative amounts of grey and white matter. 

Grey matter consists of cells called neurons, which store and process information and support called glia. White matter is composed of axons, which create a network of fibres that interconnect neurons. A fatty, myelin sheath surrounds axons and speeds the flow of electrical signals between cells.

The researchers found that chronic stress leads to the creation of more myelin-producing cells, resulting in an excess of myelin and white matter, which disrupts the balance between timing and communication in the brain.

According to Daniela Kaufer, UC Berkeley associate professor of integrative biology, people with PTSD could develop a stronger connectivity between the hippocampus and the amygdala – the seat of the brain's fight or flight response – and lower than normal connectivity between the hippocampus and prefrontal cortex, which moderates our responses.

In a study conducted on rodents, the team focussed on neural stem cells located in the hippocampus. Stem cells were previously only thought to develop into neurons or a type of glial cell called an astrocyte – but the new research found they can also develop into another type of glial cell called an oligodendrocyte, which produces the myelin that covers nerve cells.

Oligodendrocytes could play a key role in long-term and possibly permanent changes in brain chemistry which could lead to later mental problems.

As chronic stress reduces the number of stem cells that develop into neurons, this could explain how the condition affects learning and memory.

Kaufer is now conducting research into how stress in infancy affects the Brain's white matter and whether stress in early life reduces resilience later in life.

Scientists have developed a new method of identifying blood vessel plaques using nanotechnology.

The researchers, led by a team at Case Western Reserve University, designed a multifunctional nanoparticle that enables magnetic resonance imaging (MRI) to identify the plaques caused by atherosclerosis.

Currently, the method of pinpointing such plaques involves an invasive procedure, with a doctor inserting a catheter inside a blood vessel in a patient's arm, groin or neck. This emits a dye that enables X-rays to show whether the vessel is narrowing.

However, the new study used a nanoparticle built from a rod-shaped virus commonly found on tobacco, which can locate and illuminate plaque in arteries more effectively and requires just a tiny fraction of the dye.

It raises the possibility that particles could be specifically designed to distinguish vulnerable plaques from stable ones, as they are able to home in on biomarkers. Untargeted dyes are unable to do this. 

"From a chemist's point of view, it's still challenging to make nanoparticles that are not spherical, but non-spherical materials are advantageous for medical applications," said Nicole Steinmetz, assistant professor of biomedical engineering at Case Western Reserve. "Nature is way ahead of us. We're harvesting nature's methods to turn them into something useful in medicine."

In collaboration with Xin Yu, a professor of biomedical engineering, who specialises in developing MRI techniques to investigate cardiovascular diseases, Steinmetz created a device that transports and concentrates imaging agents on plaques.

Elongated nanoparticles have a higher chance of being pushed out of the central blood flow and targeting the vessel wall; they also adhere better to plaques.

The surface of the virus was modified to carry near-infrared dyes used for optical scanning and gadolinium ions (which are linked with organic molecules, to reduce toxicity of the metal). This method increases the relaxivity – contrast with healthy tissue – by more than four orders of magnitude.

As the contrast agent is delivered directly to the plaques, the scientists were able to use 400 times less of it. 

Steinmetz and Yu now want to take the research further in order to distinguish stable plaques from ones vulnerable to rupture, which require treatment. Plaques that rupture can set off the train of events which leads to a heart attack or stroke.

Researchers have discovered that a molecule which can spur the growth of muscle tissue can have the opposite effect in the endothelial cells of patients with diabetes.

The study, which was conducted at the Beth Israel Deaconess Medical Center (BIDMC), demonstrates that caution is needed when developing treatments based on a molecule known as PGC-1 alpha, as it can have different effects in different situations.

Diabetes patients are at increased risk of developing microvascular complications, which occur when the body's small blood vessels become diseased. If wounds fail to heal properly, sufferers are at risk of developing ulcers and chronic infections and, in the most serious cases, may need to undergo limb amputations.

According to the researchers, high levels of blood glucose – which occur in diabetes sufferers – stimulate production of PGC-1 alpha in the endothelial cells which line the blood vessels. This prevents the cells from functioning properly and inhibits blood vessel growth.

More than a decade's worth of studies by the laboratory has revealed the PGC-1 alpha molecule has a number of different functions. When body parts are affected by poor circulation, the molecule senses low levels of oxygen and nutrients in muscle cells and promotes angiogenesis – the growth of new blood vessels. 

A series of studies was conducted on cell cultures and mouse models, which found diabetes induces PGC-1 alpha in endothelial cells. This strongly inhibits endothelial migration and angiogenesis, leading to vascular dysfunction.

"These findings were definitely surprising, because the effects of PGC-1 alpha in endothelial cells are the opposite of its effects in muscle cells," explained senior author Zoltan Arany, an investigator at BIDMC's CardioVascular Institute and associate professor of medicine at Harvard Medical School. "In muscle cells, it's pro-metabolic and will call forth more blood vessels which come to the rescue when an injury or artery blockage leaves normal tissue starved for blood."

He said the findings show that a molecule can have dramatically different effects in different situations, so a medication which has positive effects in one cell type could have negative effects in another. Caution is therefore required when developing drugs based upon PGC-1 alpha.

Scientists have discovered a mechanism which enables the body to combat cancerous immune B cells before they develop into cancers. The new research could help to develop early intervention techniques for people at risk of developing the disorder.

Research conducted at the Walter and Eliza Hall Institute found the immune system is responsible for eliminating potentially cancerous B cells before they develop into B cell lymphomas. Their findings are published in the latest edition of the journal Nature Medicine.

According to the research team, the results of the study account for the relative rarity with which B-cell lymphomas occur in the general population, considering the high frequency of these mutations in the general population. It could lead to the development of an early warning system which identifies patients at risk of developing these cancers. 

Dr Axel Kallies, associate professor David Tarlinton, Dr Stephen Nutt and colleagues carried out the research. Dr Kallies said a paradox had existed relating to the rarity of the incidence of such cancers given the high frequency of mutations. "Our finding that immune surveillance by T cells enables early detection and elimination of these cancerous and pre-cancerous cells provides an answer to this puzzle, and proves that immune surveillance is essential to preventing the development of this blood cancer," he commented.

Some 2,800 people a year develop B cell lymphoma in Australia, where it is the most common form of blood cancer. Patients with a weakened immune system are at a particularly high risk of developing the disease.

The discovery was made when the research team was investigating how B cells change during the development of lymphoma. T cells were disabled in order to depress the immune system and under these conditions lymphoma developed in a matter of weeks rather than years.

Associate professor Tarlinton said the research would enable the development of a diagnostic system that identifies people in the early stages of the disease. Therapies already exist which can be used to remove these malfunctioning B cells in at-risk patients and once a test is developed it would not be long before it could be put to clinical use.