Research Focus 2010:

The Southwest Association for Education in Biomedical Research members and other researchers are continually furthering research. This section will be to highlight ongoing research.

Painkiller from Sea Snail Venom

A new painkiller is 100 times more potent than other painkillers, tests on rats have revealed. The pill contains a group of chemicals called conotoxin peptides that are found in sea snail venom. The venom is used to immobilize the snail’s prey but in mammals has been shown to have pain-relieving effects. To date, the only conotoxin-derived medicine, ziconotide, was ineffective if administered orally as enzymes in the saliva and gut were able to break it down. Therefore it could only be administered by a pump surgically inserted into the abdominal wall – meaning treatment was invasive and expensive. This prompted researchers to develop a synthetic conotoxin, a circular peptide that could not be degraded as easily and could be given orally. The team tested its effect on rats in paw pressure tests. Conotoxin was judged to be 100 times more potent than gabapentin (another pain killer). Scientists believe the new pill is a more viable option and hope it will also relieve neuropathic pain – a problem stemming from nerve signals. - Angewandte Chemie, DOI: 10.1002/anie.201000620, 19 Jun 10

A novel study has uncovered a link between stomach bacteria and the development of rheumatoid arthritis in mice. A team of scientists raised a group of mice in a germ-free environment. These mice had a lower number of arthritis causing antibodies. After three weeks the mice were transferred to a non-germ-free facility, and put on a diet which included parts of bacteria commonly found in the intestines. Within four days they developed severe rheumatoid arthritis. Scientists suggest that this may have been due to the mice having a genetic susceptibility to rheumatoid arthritis, which is triggered by the presence of gut bacteria. When the bacterium was present, more T-helper white blood cells were released causing the immune system to react as if they were threatening cells. Rheumatoid arthritis ensued, inflaming the joints. The team stresses that this study cannot be applied to humans until more is known. In particular it wishes to study the mechanism by which the bacteria promote the T-helper cells and the role of bacteria in causing other autoimmune diseases such as type-1 diabetes. - Immunity, DOI: 10.1016/j.immuni.2010.06.001,17 Jun 10

Scientists are a step closer to producing artificial livers after successfully producing a rat liver graft from stem cells. Currently severe liver damage can only be treated by transplantation. Yet the number of livers needed far exceeds the number available. So a team of researchers developed a technique to create liver grafts with the hope of providing an alternative way to meet demand. They used the ‘decellularization’ technique, where an organ is stripped of cells (which can be reintroduced) leaving just a basic ‘scaffold’. After this, stem cells were introduced to the scaffold four times, each round containing approximately 12.5 million cells. This reseeding of cells rebuilt the organ. The graft functioned after transplantation into rats, but more research is needed before lab grown livers are suitable for human use. One of the main problems was that after transplantation the grafts only functioned for a few hours. Scientists believe this could be overcome by introducing a wider range of cells normally found in the liver, other than just the hepatocytes used in this research. Even so, this study is a major step forward. It has shown there is a viable technique for bioengineering the liver, which could make use of livers that would previously have been unsuitable for transplant. - Nature Medicine, DOI: 10.1038/nm.2170, 13 Jun 10

Rewriting the genetic code of the flu virus has helped to produce a stronger immune response, studies on mice have shown. The new vaccine contains exactly the same proteins as the flu virus it targets but the sequence code has been changed. A team of researchers found that by altering certain DNA sequences the virus replicated more slowly, allowing for a more efficient immune response. Scientists exploited this replication weakness after noticing that some of the three letter DNA sequences, known as codons, are favored for replication over others by the virus. Usually the sequences chosen by the virus are the ones that translate the code into proteins most efficiently. By changing the codons, the team made the virus replicate slowly. Mice that were given the vaccine remained healthy. After four weeks they were infected with a potentially fatal strain of flu which had little or no effect; three days later, the virus was undetectable in four fifths of mice. The researchers hope their vaccine will be especially useful when dealing with seasonal or pandemic flu strains. - Nature Biotechnology, DOI: 10.1038/nbt.1636, 13 Jun 10

Immune system molecules made from plastic have functioned successfully in the first tests involving mice. Infections are fought using antibodies in response to antigens which are foreign or unrecognizable molecules in the body. Some antigens are more difficult to attack but now researchers propose plastic antibodies as a solution. The team studied the immune response to the antigen melittin (found in bee venom) in mice. They were able to develop the specific antibody using the process of molecular printing, often likened to leaving a footprint in wet concrete. This involved mixing melittin with monomers, molecules which can bind to other molecules to form long chains, and leaving the plastic parts to harden. The melittin poison was then leached out leaving a mould with tiny toxin shaped spaces, available to attach to the toxin in an immune response. Mice were injected with the antigen, and some were then given a dose of the plastic melittin antibody. The mice that received the nano-sized antibodies had a significantly higher survival rate than those that did not. Researchers believe these results show plastic antibodies can be created and used to aid a variety of immune responses. - Journal of the American Chemical Society, DOI: 10.1021/ja102148f, 11 Jun 10

An extra copy of chromosome 21 may boost protection against cancer, research on mice suggests. A study of mice with extra copies of chromosome 21 showed rates of tumor formation significantly lower than in control mice with the normal two copies. The extra chromosome included four genes involved in stopping angiogenesis – the formation of new blood vessels. The four genes were able to do this by blocking the growth factor VEGF, so the formation of blood vessels supplying tumors is not triggered. As consequence cancer cells are starved of nutrients and eventually die. An extra copy of chromosome 21 causes Down Syndrome. The team hope the mice will reveal more about boosting protection against tumor growth and provide alternative targets for treatment. Finding the additional genes which lower the risk of developing cancer may lead to gene therapy. - Nature, DOI: 10.1038/nature09106, 11 Jun 10

Research on mice has revealed the process which limits the accumulation of excessive scar tissue. Excessive tissue produced during the healing of chronic injuries can be damaging. For example, after a heart attack, scar tissue can build up in the heart and impair its ability to function properly. By studying scar tissue in mice, scientists found that fibroblast cells at wound sites stopped proliferating, entering the cell phase known as 'senescence'. To find how the fibroblasts were being controlled, the team studied mice developed specifically to lack the gene coding for the protein CCN1. These mice produced fibroblasts which were not arrested in their cycle and proliferated to form excessive amounts of scar tissue. Only after the researchers placed CCN1 on the skin wound did the fibroblasts enter senescence and limit scar tissue accumulation. Previously, cell senescence was though to occur only at tumor sites, to stop cancerous cells from reproducing. Now that cell proliferation at wound sites is known to be controlled by CCN1, scientists will be able to understand a wider range of conditions related to scarring. - Nature Cell Biology, DOI: 10.1038/ncb2070, 11 Jun 10

The mechanism which causes severe tremors in people with Parkinson's disease could be controlled through the spine, research on monkeys suggests. Scientist know that mild tremors can affect healthy individuals on a daily basis, for example when we are hungry. Yet for the sufferers of the severe form, arising from conditions such as Parkinson's and Multiple Sclerosis, there is a great difference. Some patients are unable to walk unaided or complete routine daily tasks. A team of scientists wanted to find the mechanism responsible for this difference in tremor experience, with the hope of reducing the severity of tremors in these patients. The researchers first studied body circuitry in healthy individuals. They calculated that constant brain waves from the area of the brain which controls movement means that everyone experiences mild tremors but in healthy people they are almost unnoticeable. The team then reasoned that there must be a mechanism that cancels out the tremors in healthy people but malfunctions in those who suffer from severe tremors. To locate this mechanism, the team taught macaque monkeys to move their index fingers back and forth, to intensify the tremors usually felt in healthy monkeys and humans. Using sensors, the researchers recorded the activity of the brain and spinal cord nerve cells through which the brain signals travel. Both types of nerve cells showed activity but the spinal cord acted differently to the brain, cancelling out the brains ‘movement signals' and therefore reducing the tremors. From this, scientists hypothesize that severe tremors may be linked to spinal malfunctions. Whereas previous research has focused on the brain, this study offers an alternate path to treat tremors through the spine. - Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.0906722106, 1 Jun 10

The mechanism by which lithium works to reduce inflammation in the brain has been discovered in a study on rats. Inflammation in the brain may lead to conditions such as bipolar disorder or Alzheimer's disease. Lithium has been used to successfully treat excessive brain inflammation in the manic phase of bipolar disorder, although exactly how the chemical achieved this was poorly understood. Researchers tackled this puzzle by studying the brains of rats that were stressed a result of brain inflammation, and comparing them to a control group of healthy rats. After they were treated with lithium for six weeks, the stressed rats showed lower levels of arachidonic acid in the brain, which is known to cause inflammation. They scientists also observed increased levels of an anti inflammatory compound, usually found in aspirin, made from an omega-3 fatty acid. Discovering lithium's double effect in reducing inflammation and increasing anti inflammatory compounds now makes it an ideal drug to treat excessive inflammation. With this better understanding of the treatment, scientists speculate that lithium could have more uses in medicine. - Journal of Lipid Research, DOI: 10.1194/jlr.M002469, 24 May 10

Growing hair cells from stem cells could offer personalized treatments for deafness in the future, scientists studying mice suggest. Humans have approximately 15,000 hair cells in each ear. When sound waves vibrate and reach the ear, the hair cells bend in response. This converts the waves into electrical signals which travel to the brain. It is the inability of the hair cells to regenerate which leads to 60-90% of cases of permanent hearing loss. Scientists examined these hair cells in mice. They studied two types of cells-embryonic stem (ES) and induced pluripotent stem (IPS) cells which were reprogrammed from skin tissue. The latter were then directed to form the ear hair cells using a special growth factor. Hair cells from both ES and IPS cells responded to sound currents, bending like the naturally occurring ones in the mouse ear. The newly generated cells could be used to study how damage occurs and the drugs which could be used to reverse it. There may even be a possibility of transplanting the hair cells into the ear to restore hearing. But first the team must study the feasibility of creating human hair cells. They make clear that creating human hair cells would be more complex and would take at least a couple of years of basic research. Although it may be a decade before any therapy is available, the potential to reverse hearing loss is real. - Cell, DOI: 10.1016/j.cell.2010.03.035, 18 May 10

Lowering the production of specific immune cells could prevent asthma attacks, research on mice shows. Asthma attacks occur when the body overreacts to an infection, causing an excessive inflammation of the airways. Previous studies have focused on reducing the number of immune cells in the blood, in order to suppress the highly sensitive response which results in inflammation. Although this method can help, it is an ineffective solution as patients still need ongoing treatment. Now scientists have identified a new target for treatment which could actually prevent attacks from taking place. The targets are asthma-B cells: specific immune cells involved in the initiation of an asthmatic response. B cells are immune cells that secrete IgE molecules into the blood. Other types of IgE molecules are attached to the surface of the B cells and both types contribute to asthma attacks. A research team developed a mouse model which showed symptoms of asthma. The mice were treated with molecules called monoclonal antibodies - which are designed to target IgE attached to the surface of B cells. The results showed that treated mice had 90% fewer IgE molecules in the blood compared with an untreated control group. The treatment also caused an overall reduction in IgE producing B cells. This resulted in a protective effect against asthma, as the immune response did not overreact to infection. Although the effects of this treatment are longer lasting than previous methods, researchers still need to address the issue of immunological memory. The production of cells may be lowered, but the body's ability to ‘remember' how to produce the cells remains - an issue that scientists intend to tackle with future research. Currently 5.4 million people in the UK receive treatment for asthma which kills on average three people every day. - Journal of Clinical Investigation, DOI: 10.1172/JCI40141, 13 May 10

The cause of cystic fibrosis (CF) is becoming clearer after scientists used pigs as models instead of mice. For years scientists have been grappling with the question of whether infection or inflammation comes first in lungs of CF sufferers. Tracking the disease progression in newborn pigs revealed that those bred to display symptoms of CF tended to have more bacteria infecting their lungs than healthy pigs. Results also showed that within the first six months CF pigs were less able to cope with infections than healthy ones. Usually the lungs of human CF patients become infected, inflamed and produce large amounts of mucus in the air passages. As it is now evident that pigs are affected in a similar way, the next stage is to explore infection further to see if there may be any potential for human treatments. Using pig models scientists can test treatments at earlier stages of CF than they could in humans, and can conduct research into preventative therapies. Scientists involved in the work feel that this new model brings them a step closer to finding more answers for a condition which affects five babies born every week in the UK. - Science Translational Medicine, DOI: 10.1126/scitranslmed.3000928, 6 May 10

A chemical in broccoli can kill breast cancer cells and halt tumor growth, according to new research on mice. Sulforaphane is a naturally occurring chemical found in broccoli. Previous studies have shown it to have positive effects in the reduction of cancer cells. Now a team of scientists have found it works by killing cancer stem cells, resulting in a decrease in growth of new tumors. To obtain these results, scientists tested different concentrations of sulforaphane on breast cancer cells in mice. The results were promising, showing a significant reduction in the number of cancer stem cells. Consequently they decided to test the chemical on human breast cancer cell cultures. Results showed a 65-80% decrease in the number of cancer cells with almost a 75% reduction in tumor growth. Researchers stress that the concentrations used in tests would not amount to the equivalent that could be obtained from eating broccoli florets. They are developing ways to extract and preserve sulforaphane in the concentrations needed for medicinal use. - Clinical Cancer Research, DOI: 10.1158/1078-0432.CCR-09-2937, 1 May 10

Bone death, a side effect of steroid medication, could be prevented according to new studies using rabbits. Patients receiving the steroid depomedrol, which is used to treat conditions such as ulcerative colitis, asthma and kidney disease, can suffer a reduction in bone density. Eventually this can cause severe osteoporosis where bones become brittle or osteonecrosis-the loss of blood supply to the bone cells, resulting in their death. Scientists studied the hip bones of two groups of rabbits, both given doses of depomedrol. One group was also given a direct injection of hormone ACTH (adrenocorticotropic hormone). The group that received ACTH produced a larger amount of growth proteins and had significantly lower bone cell death than the control group. Researchers found that the proteins stimulated the production of new blood vessels. Consequently the bone cells received a greater amount of blood and were able to survive. The next challenge for scientists is to establish whether this hormone will have the same effect in other bones. Currently, hip replacement is the only treatment for osteonecrosis in the hip. Researchers hope that the discovery of the therapeutic potential of this hormone will lead to a more viable treatment option. - Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.0912176107, 30 Apr 10

A group of substances similar to those that give chilies their kick are part of the body's pain mechanism, research on mice has shown. Scientists have found that the body releases a chemical called OLAM (oxidized linoleic acid metabolite) when injured. Surprisingly, OLAM resembles capsaicin: the naturally occurring ingredient in chilies which is known to cause their ‘burning sensation'. Capsaicin binds with a special type of receptor to activate the pain mechanism. Researchers wanted to find out how these receptors were activated when the body is injured. To find out, they took skin cells and neurons from mice and grew some of them with their pain receptors and some without. They then exposed the cells to water with temperatures of 43 degrees Celsius, which is the threshold after which a human would begin to feel discomfort. The cells with the receptors developed and released OLAM, which bound to the receptors and initiated the pain sequence. The results point to a previously unrecognized series of chemicals involved in triggering the pain sensation. Drugs could be developed which either inhibit or stop the creation of OLAM, leading to potential new treatments for the millions of people affected by chronic pain caused by disease or injury. - The Journal of Clinical Investigation, DOI: 10.1172/JCI41678, 28 Apr 10

In the past, research on epilepsy has focused on nerve cells, or neurons. But new research points to a type of brain cell called astrocyte cells as the potential trigger for over-activity in the brain which can lead to seizures. When an epileptic seizure occurs, tests reveal excessive signaling between neurons - cells involved in transmitting electrical messages in the body. Neurons are regulated by a family of cells known as glia to which astrocytes belong. To find out how these cells were contributing to seizures, scientists studied the star shaped astrocytes in the brains of mice. They found that when the cells swell (which occurs in some brain diseases), the enzyme glutamine synthetase is no longer regulated. Without the regulation of this enzyme, the astrocytes cannot inhibit the activity of neurons, leading to excessive signaling. Approximately one in 20 people will have an epileptic seizure at some time in their life. Not all seizures are convulsions; some people may go ‘blank' for a few seconds or not know where they are for periods of time. Sudden death from epilepsy is rare, affecting around 0.5% of those diagnosed. Researchers suggest that their findings on the inability to regulate neurons may relate to other conditions such as Parkinson's disease and various psychiatric disorders - Nature Neuroscience, DOI: 10.1038/nn.2535, 28 Apr 10

A medicine currently used to treat fungal infections successfully slows tumor growth in mice, according to new research. Itraconazole is normally used to treat aspergillus, a fungus which causes lung diseases in humans. Now tests on mice have shown that low doses of itraconazole are also effective in fighting cancer. A team of scientists studied two groups of mice, one of which was given the medication. They found itraconazole was most efficient when administered orally. It affects a signaling pathway known as ‘hedgehog', which helps cells and organs to develop properly, and had fewer side effects compared to other antifungal treatments tested in the study. Although it did not eradicate the tumors altogether, it did prolong the life expectancy of the mice. Mice that did not receive the treatment grew large tumors during the same study period. Cancer cells can develop if the hedgehog signaling pathway is abnormally switched on. Researchers found that many currently available medicines can affect this pathway so they screened 2,400 to find the best one. They saw that itraconazole stops the activation of the protein SMO which is usually activated by the hedgehog pathway. By preventing the activation and accumulation of SMO proteins, the drug stops tumors from developing and the pathway from proceeding further. The results suggest that cancer patients could benefit from taking low doses similar to those needed for fungal infections. As it is already on the market, human clinical trials for the use of the medicine in the treatment of tumors can progress at a faster pace than for new medicines. If successful, itraconazole could become a cheap way to boost the effectiveness of other cancer therapies. - Cancer Cell, DOI: 10.1016/j.ccr.2010.02.027, 14 Apr 10

Influenza protection can be transferred across species, say scientists who have identified a key gene in ducks. The gene, known as RIG-I, allows the immune system to contain the virus. This allows the duck to live unaffected by the flu. Yet flu can spread to chickens having fatal effects and evolve into lethal human strains such as H5N1. Scientists analyzed the genome of chickens and could not find the RIG-I gene. They then transferred RIG-I from the ducks into the chickens and found that their immune system was able to fight the flu more effectively. Normally once a chicken is infected it may die within 18 hours. Yet with the RIG-I gene, the immune system was able to cut viral replication by up to 50% in chickens. Inserting the gene could help mitigate the problem of virulent flu strains which are transferred from chickens to humans. Developing complete resistance in chickens would also protect poultry farms worldwide. - PNAS, DOI: 10.1073/pnas.1001755107, 5 Apr 10

A plastic capsule implanted under the skin could help regulate metabolic processes, a study on mice has revealed. Gout is a condition in which the body cannot regulate the amount of uric acid present. A build up of uric acid can result in the painful formation of salt crystals in the kidneys and joints. Researchers designed a small capsule, 0.2mm in diameter, containing cells genetically engineered to lower excess uric acid. The cells detect when the acid reaches harmful levels and secrete the enzyme urate oxydase to break down the excess. The mice in the study showed significant improvement once the capsule was implanted, metabolizing uric acid at a normal rate. In effect the capsule acted as an extra ‘organ', regulating the imbalance. Gout affects approximately one in a hundred people in the UK. Risk of developing the condition may increase as a result of drinking alcohol or eating foods high in purines, a type of acid found in red meat and seafood. Scientists believe the implant is an effective way for the body to regulate the metabolism without taking prescribed medication over long periods of time. In the future it could be used to treat other metabolic imbalances such as diabetes. Human trials of the synthetic organ could begin in two years. - Nature Biotechnology, DOI: 10.1038/nbt.1617, 1 Apr 10

Parasites which cause sleeping sickness can be killed by altering the proteins that they are dependent on, studies on mice show. The disease is caused by the parasite T.Brucei which has many similarities with human host cells. Yet it evolved some unique characteristics which make for possible targets for a new treatment. Scientists found that the parasite relies on the fatty acids attached to proteins for its survival. So they developed a drug that inhibits the enzyme NMT which is involved in the addition of fatty acids to proteins. When NMT is inhibited, the parasite can no longer make use of the fatty acids attached to proteins, and eventually dies. Researchers saw this effect in mice that were given low doses of the treatment. The medicine is exciting because it can be taken orally, and has much milder side effects than current arsenic-based treatments. However it was only effective in mice before stage 2 of the virus when the parasite invades the host's nervous system. The drug may also be dangerous in higher doses needed for the human treatment of the disease. The team of scientists wish to continue targeting other enzymes crucial to the parasite's survival. This study in particular has been important in highlighting the need for effective medicines which have all the desired characteristics and no side effects. The team think the treatment will be ready for clinical trials in around 18 months time. Sleeping sickness, also known as Human African tripanosomiasis, is one of the neglected tropical diseases which affect some of the world's poorest populations. The fatal illness infects tens of thousands of Africans each year. One of the challenges the team of scientists therefore face is trying to engage big pharmaceutical companies to invest in future treatments for these devastating diseases. - Nature, DOI: 10.1038/464689a, 31 Mar 10

Switching off' certain enzymes helps reduce tumors in mice, research has shown. Tumor growth is stimulated by the proteins Ras and Rho. For these proteins to function they need two enzymes: FT and GGT. Now a team of scientists have found that turning off the enzymes are more effective than using drugs to reduce enzyme activity. They discovered this by studying mice with genes engineered to switch off the production of FT and GGT. When FT was turned off mice developed fewer tumors as the cancerous cells were unable to divide. Consequently there was an increased survival rate. Similar results followed when GGT was switched off instead. Lastly they turned off both enzymes together and saw a sharp decline in number of lung tumors and a higher overall survival rate. Previous studies have shown drugs which target FT and GGT to have mixed results and researchers believe switching off the genes which produce the enzymes would be more efficient. Results have revealed this treatment to have no toxic side effects on the lungs. The next step for scientists is to see if switching off the enzymes may have any effects on other tissues. - Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.0908396107, 31 Mar 10

Mice lacking the p21 gene can be healed scar free, a study has shown. Scientists believe gene p21, known to protect against cancer, plays a key role in the regeneration of damaged tissues. They have now shown that switching the gene off allows adult cells in mice to turn into stem cells which assist the healing process. Researchers studied mice without the p21 gene and found they were able to regenerate tissue which had been removed from the ear. Within a few weeks the ears had re-grown healthy tissue, fully healing the damage with no signs of scarring. It is thought that most mammals lost the ability to regenerate limbs and organs as a result of evolution. The newt and flatworm are among the few species left that can grow limbs or demonstrate a similar regenerative action after damage. The study on mice has proven that the ability to heal scar-free may still lie dormant in mammals, and scientists suggest that switching off p21 may reactivate the healing pathway. The problem with switching p21 off is that, when active, it protects against cancer by halting the division of cells with damaged DNA. Despite this anti-cancer role, researchers found mice reverted to a fallback pathway when p21 was not present. This means that it could be possible to exploit the regenerative potential of p21 without encouraging tumor growth as a result. - Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.1000830107, 15 Mar 10

A new vaccine successfully blocks tapeworm infection in pigs, helping to break the cycle of infection between pigs and humans. Tapeworm is a parasite that can grow up to 10 meters, and can live inside the human body for several years. However, the tapeworm eggs, which hatch in the intestine and travel to the brain, can cause the brain disease neurocysticercosis. This disease may make a person more prone to seizures and epilepsy. Scientists developed the pig vaccine based on the cycle of infection between humans and pigs. They saw that pigs became infected when they came into contact with human feces containing the parasite. Humans would then feed on undercooked pig meat resulting in a repeat infection. Developing countries with poor sanitation are particularly vulnerable to this cycle, as humans and pigs can often live in close contact. The team of researchers first treated 240 piglets with drugs that killed off any parasites from before the study. They introduced the vaccine into half of them, and after 14 months, none of the vaccinated pigs showed signs of infection whereas 20 of the control pigs harbored live parasites. This research will benefit both pigs and humans. With the pig vaccine, tapeworm infection is blocked in humans who rely on and live in close proximity to the pigs. It also has the added bonus of reducing the need for a vaccine in humans. - International Journal for Parasitology, 9 Mar 10

Stem cells can help repair severely damaged bones quickly, studies on sheep and humans have revealed. Scientists use stem cells from the periosteum tissue, which lines the outside of all bones, to repair damaged bones. To repair major bone damage, scientists can now shape the stem cell layer into a ‘sleeve' which wraps around major bone breaks, where the stem cells develop into bone to mend the fracture. For those without enough periosteum tissue researchers have developed an artificial substitute using sheep. The substitute is made of the same tissue stem cells but mixed with collagen, a protein. However results showed that sheep treated with periosteum-only stem cells had a faster repair (2-3 weeks) than the collagen mixed sleeve (4 weeks or more). An additional problem is that the stem cells may only turn into bone cells if given the correct cue such as stress from movement. Without the stress cue, stem cells may turn into tendons or cartilage instead. The results seem tentatively positive in humans too. A patient received the stem cell treatment, experiencing new bone growth a month later. Severe injuries such as this normally could not be repaired without complex surgery. Traditionally, patients rely on bone grafts, where one piece of bone from a non weight bearing place such as the hip is taken and placed in the damaged area. This new technique would offer faster and more effective treatments. - Presented at a meeting of the Orthopedic Research Society in New Orleans, 9 Mar 10

A new gene variant that increases resistance to diseases such as tuberculosis (TB) and leprosy, has been identified from studies on zebrafish and humans. Both diseases are caused by rod shaped bacteria named mycobacterium. Human contact with the bacteria can result in a range of outcomes. Some people are resistant to the bacteria, but others will harbor it and in some cases infection can result in life threatening symptoms. These differences led a team of scientists to set out to discover why some people develop resistance when others do not. They studied the action of a mycobacterium (M. marinum) in zebrafish which had not yet acquired an adapted immunity to infection. Early research showed that some zebrafish were more susceptible to the bacterium than others due to the presence of the gene Lta4h. The human equivalent of this gene is LTA4H, so subsequent research focused on this gene in humans. Comparing healthy volunteers to those already infected with the disease showed LTA4H to be common in people who were resistant to TB and leprosy in high risk areas. Therefore the gene may be a contributing factor in the natural resistance to both diseases. - Cell, DOI: 10.1016/j.cell.2010.02.013, 5 Mar 10

A hormone found in the stomach reduces inflammation and could ease liver diseases such as cirrhosis, research on rats has revealed. Previous studies of the hormone ghrelin had shown it to protect against other diseases such as Parkinson’s. Now a team of scientists has demonstrated that it also has a positive influence on conditions of the liver. The researchers decided to focus on the effects of ghrelin on liver fibrosis where there is an abnormal accumulation of proteins, often leading to a chronic liver illness. Rats with liver fibrosis were divided into groups and one was treated with ghrelin, the other used as a control. The group treated with ghrelin saw a 25% reduction in the number of fibrogenic cells compared to the untreated rodents. Researchers then investigated the action of the hormone on rats with acute liver disease. Results showed a significant reduction in liver damage and less inflammation in the rats treated with the hormone. Scientists are optimistic about the results of this study, and wish to carry out further research to evaluate the safety of ghrelin in patients with chronic liver disease. - Hepatology, DOI: 10.1002/hep.23421, 1 Mar 10

Damaged nerves in the brain are the cause of the eye disease glaucoma, rather than damage to the eye itself as was previously thought. This recent finding was the outcome of research using mice. Glaucoma affects the eye and leads to blindness - most commonly in elderly people. Scientists previously believed that the condition was caused by pressure in the eye that damaged the retina and optic nerves. Now a study using mice has shown that the earliest signs of glaucoma can be detected in the brain. A team of scientists researching cases of the disease noticed severe deterioration between the mid brain and optic nerve. This part of the communication pathway is involved in handling sensory information. They followed the path of degeneration and noticed that the last structures to deteriorate were the ones nearest to the eye. The new finding could lead to improvements in the way glaucoma is treated. In terms of therapy, the team hope the condition will be viewed as other age related neuron disorders, with the possibility of early detection using MRI scans. They are now designing medicines to improve and restore the damaged pathway. - Glaucoma begins with brain nerve deterioration, DOI: 10.1073/pnas.0913141107, 1 Mar 10

Pig models are becoming increasingly important in medical research into the causes of diseases, and have now shed new light on the causes of diabetes. In healthy people, glucose concentrations in the blood increase soon after they eat a meal. As a consequence, beta-cells of the pancreas release insulin, which helps to lower blood glucose levels. Type 2 diabetes can develop when the body cannot produce enough insulin to meet its needs. In recent research, scientists have been investigating the hormone GIP (glucose-dependent insulin-releasing polypeptide) in pigs with type 2 diabetes. The hormone helps in the production and release of insulin. In the past, diabetic patients have been found to be unresponsive to GIP as well as insulin. Scientists studied the hormone in pigs with a defective GIP pathway. Results showed that systems which could not respond to GIP had fewer beta-cells, resulting in a lower release of insulin. These findings suggest that defective GIP pathways may be a cause of type 2 diabetes rather than a consequence of the disease. In the UK, type 2 diabetes is becoming increasingly common. The majority of cases are linked to obesity and are more likely to occur in older people. Recently, however an increasing number of children are being diagnosed with diabetes, some as young as 7 years old. - Diabetes, DOI: 10.2337/db09-0519, 26 Feb 10

Mice could be more useful in the study of hepatitis than previously thought, as research into the possibility of growing a human liver in a mouse has proven successful. In the past, hepatitis research has been limited to a small number of animal models. Now scientists have created a mouse with a human liver suitable for studies on conditions which affect the liver. To do this they first engineered the livers of mice to be dependent on drugs for survival. After some time, they ceased administering the drugs and injected human liver cells instead. Results showed that the liver cells went directly to the mouse liver, helping it survive. The mouse livers also began to act like the human liver by producing chemicals such as human albumin. Human liver cells began to replace the dying mouse liver cells. In some mice, up to 95% of liver cells merged into a hybrid of human and mouse cells. When infected with Hepatitis, mice were also successfully cured. Hepatitis is a condition where the liver becomes inflamed and if left untreated can lead to permanent scarring of the liver. Scientists hope that the new mouse model will be used to help future research into this condition as well us other diseases that affect the liver, such as malaria and cirrhosis. - Journal of Clinical Investigation, DOI: 10.1172/JCI40094, 24 Feb 10

Using a deactivated form of HIV as a vaccine may be the best new treatment for fighting the HIV virus, concluded scientists after studying primate responses to the treatment. Research has shown that monkeys are responsive to the primate form of the vaccine, with virus concentrations falling by at least 95%. The number of immune cells did not decrease either, suggesting that the immune system was supported enough to withstand infection. After the trial, monkeys were able to continue suppressing the virus and lead a healthy life. Now the scientists who have developed the vaccine would like to extend this research to humans. Once approved for trials in humans the vaccine will first be tested in people already infected with HIV, in order to minimize any potential risk of infection in those who aren’t HIV positive. However the team are confident the vaccine will not result in the re-activation of the 'dead' virus. To eliminate this danger, they will remove genes that the virus uses for replication, allowing it to infect only, but not reproduce. The success of the primate studies is a positive indication that the HIV vaccine has the potential to be safe and effective. - Conference of Retroviruses and Opportunistic Infections, 19 Feb 10

Slower brain development may be the reason some children reject all physical affection, research on mice has shown. Fragile X syndrome is a genetic condition which can affect a child's physical and mental health, often causing children to reject physical affection. It is caused by a change in a specific DNA sequence which codes for the protein FRMP, needed in the development of neurons. When the protein is lost, nerve cells are unable to develop properly. New research has been looking at the development of affected cells in mouse models. Researchers studied the interaction of brain cells with touch sensors on the whiskers of mice, during the first few weeks of life. This is an important period as the brain creates a ‘map of neurons' which is shaped and altered before becoming fixed later in life. Scientists found higher levels of the protein FRMP in control mice during the critical early period than in mice with the syndrome, suggesting it is needed in to help develop the sense of touch. Brains of Fragile X mice also showed signs of mapping activity after the normal time it ends at 21 days. This may be because the lack of the protein causes neurons take longer to mature and become fixed. Although both groups of mice had similar maps by the end of the development stage, the research illustrates that the presence of the protein, and timing, are both crucial factors. However researchers hope to study condition in humans to see if mistiming is an important contributing factor to Fragile X in children. - Neuron, DOI: 10.1016/j.neuron.2010.01.02, 11 Feb 10

Drugs such as Valium and Xanax could be redesigned after a study on mice has revealed the mechanism which makes them addictive. Valium belongs to the group of drugs named the Benzodiazepines (BDZs). It is used to treat anxiety, agitation and hallucinations among many other symptoms. Previous research shows that Valium works by stimulating the release of dopamine, the natural ‘reward' chemical in the brain. Now scientists have discovered it also acts on another brain pathway which they believe makes patients become addicted to the drug. Researchers studied the pathway in mice after injecting them with a dose of BDZ. In particular they investigated the proteins found on the surface of brain cells, electrical currents and the numbers of neuro-transmitting molecules involved. Results showed that BDZs activate a neurotransmitter, GABA, which helps to increase the release dopamine. The increase in dopamine reflects activity from use of other addictive drugs such as heroin which works via a similar pathway. Hence they have proposed a medicine such as Valium may be addictive because it works using the GABA pathway. Although scientists warn that Valium is not the same as illegal drugs like heroin, they do suggest that both stimulate similar dopamine mechanisms. Further research could prompt pharmaceutical companies to redesign BDZ drugs like Valium and Xanax to exclude the addictive side effect. - Nature, DOI: 10.1038/nature08758,10 Feb 10

Premenstrual disorder may be linked to a specific gene, research on mice has shown. In a unique study scientists have linked part of the genome to mood disorders related to the menstrual cycle. They looked at a protein called BDNF which works with estrogen, a hormone used to regulate the menstrual cycle. Both BDNF and estrogen work together to help make neurons adapt better in the part of the brain involved in memory and mood. However, a change in the gene which makes the protein can instead lead to the production of another protein called BDNF Met. Studies have revealed that the protein BDNF Met is found in approximately 20-30% of Caucasian women. The team studied mice that produced BDNF Met and found them to be more skittish compared to mice with the normal protein. For the tests both groups of mice had to complete two tasks. In the first they had to remember where an object was placed and in the second they had to tell the difference between two objects such as a small pill bottle and a nail varnish bottle of the same size. Mice with BDNF Met performed much worse in both tasks than mice with the normal protein. It is hoped that this research will bring a greater understanding of problems related to the menstrual cycle such as PMDD (Premenstrual dysphoric disorder). Common symptoms of this disorder include mood swings, fatigue and panic attacks. Scientists also believe that this study will prove useful for future researchers investigating the role of the cell and hormones outside of reproduction in areas such as anxiety. - Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.0915105107, 9 Feb 10

Taking a special ‘bone pill' could be the key to healing brittle bones, research on mice has shown. Osteoporosis is a condition where bones become thin and weakened. Living with the condition means that bones are more likely to fracture or break, which can be very painful. It can affect all age groups but most likely older women. This is because bone density naturally decreases from the age of 40 years and onwards and women tend to have smaller bones than men. Previous research has shown that the chemical serotonin, produced in the stomach, can inhibit the growth of early stage bone cells. Now scientists have developed a pill which stops the action of serotonin from the stomach without blocking brain derived serotonin which is vital for bone growth. A team of scientists studied the action of the serotonin inhibitor, at various dosages, in female mice. Results showed that mice treated with the drug inhibitor, regardless of the dosage, had an increase in bone density. In mice that had already suffered severe bone density loss, the drug reversed the effects completely, restoring the normal bone mass level for a healthy adult mouse. Although the study is promising for future treatments in humans, there is still a lot more research needed. For example, there are differences between bone metabolism in mice and humans which need to be investigated. Serotonin is also an important gut chemical, which if inhibited in humans may have adverse effects. Scientists believe that this study is proof of the concept that a ‘bone pill' may be viable one day for human treatments. - Nature Medicine, DOI: 10.1038/nm.2098, 8 Feb 10

Old mice have had their bone marrow rejuvenated after receiving blood supplies from younger mice, a new study has revealed. During the ageing process fewer cells are fully repaired or replaced. This can lead to muscle damage, bone deterioration and irregular production of blood cells. In particular the bone marrow ‘niche stem cells' can be affected and cannot fulfill their role in nourishing and creating new blood cells. Now scientists have been able to revitalize the niche cells using the blood of younger mice. Whilst older mice were able to produce more blood stem cells than younger mice, many were flawed and did not repair as effectively as those from younger mice. Researchers realized that older mice produced more myeloid cells which increase the risk of inflammation and cancer. In addition, older mice have a reduction in the number of lymphoid blood cells which aid tissue repair. In this latest study, the research team looked at two groups of mice. Half were 21 months old and the other half aged only two months. Older mice were joined to younger mice using a process called parabiosis. This involved joining the mice for up to 5 weeks so blood could be exchanged. Results suggested that certain unidentified components of the younger blood caused the reversing effects in the older animals. These components may block a hormone called IGF-1, which accelerates ageing in niche cells. Previously it has been shown that an injection of antibodies works in the same way by neutralizing the hormone. However blocking IGF-1 is not entirely helpful. The hormone is needed for muscle and bone growth and antibodies may leak, blocking it in unexpected areas. Scientists are looking for ways to refine this experiment by specifically targeting the bone marrow. Although the ageing of mice cells were reversed, scientists stress that a ‘one-off' exposure to blood would not suffice and that a constant exchange would be needed. - Nature, DOI: 10.1038/nature08749, 1 Feb 10

Skin cells have been transformed directly into functioning brain cells for the first time in a new study using mice. Previously scientists believed that adult cells first needed to revert back to stem cells in order to take on a new function. Now researchers have been able to directly change skin cells into nerve cells, bypassing the time-consuming stem cell stage. The nerve cells could potentially be used in therapeutic treatments for Alzheimer's and Parkinson's disease. As well as providing possible treatments for disease, the findings will provide an alternative to using induced pluripotent stem (iPS) cells. IPS cells are mature cells that have been turned back into their stem cell state so they can then develop into other types of cell. However iPS cells are volatile and may promote cancer, which is why this new research - which skips the iPS stage - could provide better treatments. The researchers behind this new finding initially studied 19 genes involved in the process of transformation and neuronal development. A modified virus, called lentivirus, was used to infect mouse skin cells and introduce the genes. Results showed that only three genes were truly necessary in the transformation from skin cell to brain cell and if this trio of genes were switched on, approximately 20% of skin cells turned into brain cells within one week. These neurons were able to create connections and send signals, which is crucial if the research is eventually to be used as therapy for Parkinson's or Alzheimer's disease. What surprised the scientists was the flexibility and efficiency of these cells in their ability to change function. That’s because if cells are so versatile, it raises the question of why they do not naturally switch function during their lifespan. One solution could be that once certain genes are switched on, they automatically remain in the same mode unless there is artificial involvement. This breakthrough is likely to revolutionize research into treatments that rely on the use of stem cells. - Nature, DOI: 10.1038/nature08797, 28 Jan 10

Running a few days a week can stimulate the brain to grow new cells, research on mice has revealed. A team of scientists studied the effects of exercise on two groups of mice, one of which had unlimited access to a running wheel throughout the experiment whilst the other had limited access and formed a control group. Both groups were made to perform simple memory tests. Results showed that the mice with unrestricted access to the wheel exercised more, and performed twice as well in the memory tests as the mice in the control group. Afterwards, tissue samples from the brain were taken and showed a significant increase in the growth of new brain cells in the active mice. These samples were obtained from the dentate gyrus part of the brain which is one of the few regions of the adult brain capable of growing new matter. Scientists suggest that the growth may be due to increased blood flow and hormones released during exercise. Exercise is also known to reduce stress which can stop new brain cells growing due to the release of the hormone cortisol. The team believes this study explains how exercise improves memory and why it may deteriorate with age. They hope to conduct more research into the area to increase our understanding of the link between exercise and healthy brain function. - Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.0911725107,18 Jan 10

Examining patients eye cells and ability to smell may help detect Alzheimer's disease earlier on, research on mice suggests. In the past it has been difficult to diagnose the disease as the symptoms do not appear until considerable neurological damage has occurred. In Alzheimer's disease many neurons die leading to the destruction of cells in the eye and loss of smell. Now teams of scientists are developing ways to identify symptoms earlier and possibly even reverse some of the damage. Eye cells affected by the condition undergo two types of death. One is named apoptosis, where cells ‘commits suicide', the other necrosis, where the cells ‘explode'. In the early stages of Alzheimer's some eye cells will undergo apoptosis, however as the disease progresses, more cells go through necrosis. Using mice, researchers were able to identify the eye cells dying and work out how they were dying by tagging them with a fluorescent protein. The proteins were different colors - green for apoptosis and red for necrosis. They saw many green cells in the back of eye earlier on in the disease compared to red ones. By identifying the dying cells, scientists were able to administer the Alzheimer's drug memantine to reverse the effects of apoptosis. Other research on mice has shown that plaques form on the part of the brain devoted to smell, when the disease begins to develop. After the plaques form a loss of smell usually ensues. Scientists hope through conducting olfactory (smell) tests on patients, they could be able to identify Alzheimer's earlier. Both these methods of testing will be inexpensive and efficient, say researchers although more studies are needed to support their findings further. - Eye: Cell Death and Disease / Smell: Journal of Neuroscience, DOI: 10.1038/cddis.2009.3 / 10.1523/JNEUROSCI.4622-09.2010, 14 Jan 10

Stroke victims could regain near complete restoration of movement thanks to a new drug, research on rats has shown. Stroke is the third most common cause of death in the UK. There are two types of stroke (ischemic and hemorrhagic) and both cause damage to the brain, often resulting in paralysis. It is thought that smoking, lack of exercise and a diet rich in fat which ‘furs’ up blood vessels can increase the risk. However stroke can affect anyone of any age, background or lifestyle. People who survive strokes have varying debilitating effects including loss of speech and physical paralysis. Recently researchers have developed a special drug which reverses 99% of these effects. The drug named TGF alpha, is a protein naturally occurring in humans. When injected into the brains of rats, TGF stimulated stem cells to divide, creating new ones which turned into functioning cells, replacing those that were damaged. Rats given the injection were able to complete tasks involving motor function, regaining nearly all movement within a month. In comparison, rats which did not receive the treatment reversed only 30% of the damaging effects. The drug can also be administered through the nasal passages and rats treated this way had a 70% restoration. Scientists believe this breakthrough to be important as it shows the brain is like any other organ and can regenerate. Further research is needed to see if the drug will be as effective in humans. - Neuroscience, DOI: 0.1016/j.neuroscience.2009.02.029a, 13 Jan 10

Rays of light act as a potential trigger for migraine attacks, a study on rats has found. Migraine sufferers believe that their condition worsens upon exposure to light. Even those who are legally blind (not able to form images but still sensitive to light) have been known to find their migraine worsen with light intensity. This effect of light even in the visually impaired led scientists to hypothesize that migraines may be caused by non image-forming pathways of neurons in the body. Now scientists are able to reveal the role of light when an attack occurs. They studied the neural pathways of rats using techniques to detect and record neural activity stimulated by light. From this the scientists were able to map the neural response and link it to previously identified pathways involved in migraines. The research confirms that migraines can be made worse by light exposure and it is this specific non image forming pathway which is responsible. Scientists hope drugs could be developed to block this pathway and help stop migraines. Meanwhile sufferers could avoid exposure to light for a short period of time to alleviate the pain when an attack occurs. - Nature Neuroscience, DOI: 10.1038/nn.2475,11 Jan 10

Recent studies show zebrafish to be a useful animal model in studying mental illness and neurological diseases. Zebrafish are a tropical freshwater species used to study vertebrate development and gene function. In 2008, the UK used approximately 605,000 fish for research purposes, an 85% increase on the previous year. Their importance and usage is increasing because scientists are finding more ways in which the species can help in the understanding of disease, and even replace higher animals in research. Now researchers have revealed that zebrafish can be used to investigate treatments for mental and neurological diseases. Zebrafish have a similar brain chemistry to humans which has made them useful in testing responses to new medicines. One team tested many different compounds on zebrafish embryos and studied their response to light and movement. Another team investigated the effects of medication on sleep-wake cycles of zebrafish larvae. Both groups found that each medicine had a unique behavioral effect like a ‘fingerprint'. Similar fingerprints, producing the same type of behavior, used the same biological pathways. Because of the chemical similarities between the brains of zebra fish and humans, these findings suggest the animals make good models to study how these medicines would affect the human brain. The anatomy of zebrafish is simple and therefore easy to study. The embryo is uncomplicated and develops quickly. Once mature they can breed within 2-3 months and a female can produce as many as 200 eggs per week. They are particularly useful in genetic studies as their DNA has many similarities with the human genome, despite being half the size and reproducing so fast. Scientists hope to use zebrafish models to further study diseases such as Alzheimer's disease and sleeping disorders using chemicals they identified as possibilities through this research. -Nature Chemical Biology, DOI: 10.1038/nchembio.307, 8 Jan 10

Radiation Benefits for Alzheimer's Mice

Mobile phone radiation has been found to decrease the severity of Alzheimer's disease in mice, according to new research. Alzheimer's is a progressive disease that affects approximately 417,000 people in the UK. Symptoms include confusion, memory loss, mood swings and a loss of confidence, and can be partly attributed to an increased number of plaques made up of the protein beta-amyloid, in the brain. Now researchers have found that mice exposed to EMF (electro-motive force) radiation from mobile phones show improved memory function, and mice with Alzheimer's symptoms show a decreased number of plaques in the brain, when compared with mice that had not been exposed. Research also showed that the plaques fragmented or shrunk in older Alzheimer's mice. The team studied three groups of mice. The first two had Alzheimer's at different stages, one group of mice were 2 months old while the others were examined at 4 months when the disease had progressed further. A control group of healthy mice were also used in the same proximity and all three were exposed to EMF radiation for an hour daily over nine months. All the mice were periodically made to complete a ‘memory maze task' where they had to remember an escape route. Results showed that all the exposed mice had developed improved memory function. Although the results are exciting, scientists highlight the limitations of this study being applicable to humans. Alzheimer's in mice is different to that of humans as the latter experience the death of nerve cells. Also the mice received full body radiation, rather than specified and concentrated in an area such as the brain, so the results would be of a different dosage compared to what humans would generally receive. The scientists are looking to repeat and refine the study and hope they will be able to find the exact radiation dosage needed for mice to improve. - Journal of Alzheimer's Disease, DOI: 10.3233/jad-2009-1228, 6 Jan 10