Stop Food Cravings, Stop Obesity

Researchers have identified a hormone in mice that controls the desire to eat. A treatment based on the hormone could provide a natural remedy for obesity. The hormone PPY is released into the bloodstream after a meal, where it transmits a signal to the brain to stop eating. The hormone also helps clear sugar from the blood, which helps prevent type 2 diabetes. Researchers found that the action of the hormone is concentration-specific – when they genetically engineered mice to overproduce the protein, the mice lost weight and kept it off. It is unclear whether the hormone has such an impact in humans, but if so it could provide an alternative to surgery and other dramatic approaches to treating obesity. It could also help prevent type 2 diabetes. - Neuropeptides, online DOI: 10.1016/j.npep.2007.11.003, 27 December 2007

Mice Could Help Treat Dwarfism

Researchers have identified a protein in mice that encourages bone growth. The study could lead to treatments to help children with dwarfism. When the scientists first identified the protein, osteocrin, they thought about using it to treat osteoporosis. But in mice, they found that the protein is active only in growing bones, and not in the bones of adults. GM mice engineered to overproduce the protein had bones longer than normal and developed hunchbacks. A drug that mimics osteocrin could help trigger the growth of stunted bones in young adults with dwarfism, although any therapy is at least 10 years away. - Journal of Biological Chemistry DOI: 10.1074/jbc.M708596200, 14 December 2007

Gender Imbalance in Liver Cancer Explained

Males may be more prone than females to liver cancer because the disease affects the male and female genomes in different ways, research with mice suggests. Liver cancer is the fifth most common cancer in the world and the third-biggest killer. Liver cancer is far more common in males than females. The same is true in mice, and so researchers used the species to study the genetic changes occurring during the onset of the disease. The researchers infected mice with the Helicobacter bacteria that lead to human hepatitis B and C infection, which is associated with liver cancer. They found that the male mice were more prone to inflammation after infection, and in inflamed areas some masculine genes were turned off while others became more active. Because of the imbalance, the male mice could not maintain normal metabolic rates, and cancer emerged in many cases. Feminine genes represent the 'default' condition in mammals, and are more resistant in this case to inflammation, explaining why females are less prone to liver cancer following chronic hepatitis. - Cancer Research DOI: 10.1158/0008-5472.CAN-07-1479, 15 December 2007

Researchers have discovered a molecular switch that has a powerful impact on the inflammatory immune response in mice. Controlling the molecular switch could help treat lupus and other chronic autoimmune diseases. The scientists already know that GM mice lacking three receptors called TAM receptor tyrosine kinases develop a lupus-like condition. Now, they have discovered why the TAM receptors are important. Cytokines are chemical messengers that help coordinate an immune response to infection. But cytokines also activate the TAM receptors, which help to halt the immune response once the infection has been tackled. If the TAM receptors are absent, there is no brake on the immune response, and autoimmune diseases such as lupus develop. Lupus patients often have low levels of a blood protein that is necessary for the TAM receptors to function normally. Boosting levels of that protein in patients could help treat lupus. - Cell, 14 December 2007

Research with mice has identified an unexpected role for the immune system in brain development during childhood. Scientists know that there are many more brain cell connections in the young brain than there are in adulthood, with many connections pruned during adolescence. Now they have shown that the immune system protein C1q is important in the pruning process, in both the eyes and brain of young mice. The protein is normally turned off in adult mice, but in mice with glaucoma, a common disease of the retina, C1q is re-activated. The researchers think that reactivation causes the death of important nerve cells in the retina and leads to disease. Blocking C1q could prevent brain diseases before they emerge. - Cell, 14 December 2007

Cholesterol plays an important role in hearing, according to research with mice. Researchers know that cholesterol levels are lower in hair cells than in other body cells. They also know that hair cells in the ear pick up vibrations in the air and are important in the hearing process. The scientists studied the effects on hearing of different levels of cholesterol in the hair cells within their ears. They found that mice bred with excessively low levels of cholesterol in their hair cells had impaired hearing. Adding more cholesterol benefited hearing at first, but as levels of cholesterol rose, these mice also experienced hearing loss. Cholesterol levels in hair cells are determined early in life and don’t change much after birth, the researchers say, unlike cholesterol levels in blood which can vary depending on diet. - Journal of Biological Chemistry DOI: 10.1074/jbc.M705078200, 14 December 2007

Obese mice are more susceptible to bacterial gum disease than lean mice. Researchers infected obese and lean mice with Porphyromonas gingivalis, the bacteria that cause gum disease. After 10 days, all mice had lost some of the alveolar bone, the area of the jawbone containing tooth sockets. But obese mice had lost 40% more bone than lean mice. The obese mice also had impaired immune systems – they produced fewer of the messenger proteins that trigger an immune response, and had fewer macrophages, the white blood cells that ‘swallow’ and destroy bacteria. The researchers do not yet know precisely why obese mice are more susceptible to infection, but they think that alterations to the NF-kB signaling pathway, which helps coordinate an immune response, may be responsible. - Proceedings of the National Academy of Sciences, online DOI: 10.1073/pnas.0710335105, 12 December 2007

Epilepsy-prone rats can be protected from developing the condition if they are treated with a medicine from an early age. Epilepsy is a neurological disorder characterized by seizures that result from excessive electrical activity in the brain. The researchers used a technique that measures brain activity to identify a protein that triggers seizures. They also discovered that treatment with a chemical called ethosuximide protected the rats from seizures. When the researchers treated young GM rats prone to epilepsy with ethosuximide, the rats experienced fewer seizures later in life. - Epilepsia, online DOI: 10.1111/j.1528-1167.2007.01458.x, 7 December 2007

GM mice with human liver cells can be protected from developing hepatitis C through a set of antibodies. Hepatitis C affects around one person in 30, and treatment often requires a liver transplant. Studying the disease is difficult because humans and chimpanzees alone are affected. Researchers developed GM mice with human liver cells and infected them with the hepatitis C virus. The mice quickly picked up the infection. But the researchers treated a second and third group of mice with experimental antibodies designed to fight two forms of hepatitis C. All of the mice treated with antibodies saw a delay in infection, and around half to three quarters of each group did not become infected. In the future, versions of the antibodies could be given to patients who think they have been exposed to the virus. - Nature Medicine, online DOI: 10.1038/nm1698

6 December 2007

The enzyme that makes humans feel the heat from chilli peppers modifies pain tolerance in mice.

When researchers studied the pain response in GM mice lacking the enzyme c-Kit, they found that the mice could stand a hot infrared beam for 40% longer than normal. The pain response occurs when nerve endings called ‘nociceptors’ in the skin fire signals through the nervous system. The researchers found that the infrared beam had to be 6oC hotter than normal before the nociceptors fired in the GM mice. The scientists say that c-Kit is the first example of a single gene being required for normal noxious heat sensitivity. - Neuron DOI: 10.1016/j.neuron.2007.10.040, 6 December 2007

A marijuana-like neurotransmitter could help reduce the symptoms of depression, according to research with rats. Scientists already know that rats show signs of depression when an enzyme called FAAH is inhibited in the brain. In its active state, the enzyme helps the brain to process anandamide, a marijuana-like chemical. The researchers tested whether it is the lack of anandamide that leads to depression. The researchers treated depressed rats with a chemical, URB597, to stop the breakdown of anandamide in the brain. As the level of anandamide in the brain rose, the rats showed fewer symptoms of depression. The researchers think that URB597 could help treat some forms of depression. - Biological Psychiatry DOI: 10.1016/j.biopsych.2006.12.001, 15 November 2007

Researchers have identified a marker molecule that allows them to track the movement of stem cells in the brains of rats and mice. Brain stem cells could be harnessed to repair the brain damage that results from diseases such as Alzheimer's, but scientists have been unable to track the movement of these cells until now. The researchers identified a molecule that is unique to the stem cells. The researchers could track the movement of brain stem cells in rats, mice, and humans by scanning for the marker molecule using magnetic resonance spectroscopy (MRS). When the researchers injected brain stem cells into rats’ brains, they used MRS to locate the stem cells. The finding could have a number of implications. Antidepressants work by raising the number of brain cells, which are normally formed by brain stem cells. The researchers will use their new technique to study whether depression is caused by a loss of the brain stem cells needed to grow new brain cells.- Science DOI: 10.1126/science.1147851, 9 November 2007

A green tea extract may help control severe cases of sepsis, a condition in which bacteria encourage the body’s own immune system to attack tissue. Sepsis occurs when bacteria infecting the body stimulate the immune system to release cytokines, which cause inflammation. Among the most important of these cytokines is HMGB1. Researchers found that a component of green tea, called EGCG, stops the production of HMGB1. When the researchers used the green tea extract to treat mice with severe sepsis, over three-quarters of the mice survived. Normally, only half of mice with severe sepsis survive. The researchers hope their results could encourage clinical trials soon.- PLoS One DOI: 10.1371/journal.pone.0001153, 7 November 2007

Research with mice suggests that fat cells can help increase the amount of insulin released from the pancreas. The finding could help researchers increase pancreatic efficiency, which could help in the treatment of type 2 diabetics. The pancreas responds to rising blood sugar levels by releasing insulin, but a number of other substances can also increase insulin release. Researchers found that fat cells in mice release a protein called Nampt. In the blood, the protein helps produce a compound called NMN that, when it arrives at the pancreas, ramps up insulin release. When the researchers bred GM mice with just one of the standard two copies of Nampt, the mice were unable to properly metabolize glucose. Giving the mice NMN helped reverse the condition. The researchers think that NMN could help treat type-2 diabetics by helping the pancreas to release more insulin. - Cell Metabolism, 7 November 2007

Researchers have discovered a gene mutation responsible for some forms of lung cancer. Mice lacking the gene die at birth because of poor lung development. Scientists studying the genetics of lung adenocarcinoma, a common form of lung cancer, identified a number of mutations not found in healthy tissue. They linked one third of the mutations to genes already known to play a role in lung cancer. The most important is NKX2-1, a gene that helps the development of alveoli, the tiny air sacs in the lungs that help transfer gases into and out of the blood. When the researchers bred GM mice to lack NKX2-1, the alveoli did not develop and the mice suffocated at birth. The scientists think that a mutated version of the gene could be responsible for a number of lung cancers.- Nature, online DOI: 10.1038/nature06358, 4 November 2007

Mouse studies suggest that two genes that independently increase the risk of epilepsy can, together, lower the risk of seizures. Researchers know that a mutated version of the Kcna1 gene increases the risk of epileptic seizures in the temporal lobe region of the brain, a brain region involved in speech, sight and sound. A second gene, Cacna1a, increases the risk of "absence" epilepsy, in which the patient freezes and stares into empty space. Mice carrying just one of the defective genes can die suddenly, but GM mice carrying both effective genes had fewer seizures and did not die suddenly. The finding that two genes thought to have a negative impact can together have beneficial properties could lead to new treatments against epilepsy.- Nature Neuroscience, online DOI: 10.1038/nn1999, 4 November 2007

Researchers have discovered a protein that could help cancer patients and the obese to control their weight, following research with mice. The researchers found that cancer patients produce large quantities of a protein called MIC-1, which sends a message to the brain that the body is full and does not need to eat. The protein is produced within the cancer tumors, and as the tumors grow, so does the level of the protein. The cancer patient eats progressively less food, which helps speed their decline. The researchers found that when they injected a MIC-1 antibody into mice with cancer, it helped lower the levels of the protein and the mice regained lost weight. The MIC-1 antibody may have similar effects in cancer patients and could form part of an anti-cancer therapy. Because MIC-1 controls appetite, injections of the protein could help obese patients lose weight without the need for surgery.- Nature Medicine, online DOI: 10.1038/nm1677, 4 November 2007

Animals, like plants, respond to parasitic infection in one of two ways – either by learning to tolerate the infection or by building up resistance. Some animals have evolved to resist parasites, but scientists wanted to find out whether animals have also evolved tolerance. Using rodent malaria in different strains of laboratory mice, scientists studied weight loss, red blood cell count and levels of parasites in the mice and showed that different genetic groups of mice have different levels of resistance to infection. But the different mice strains became sick at different rates too. Some mice were still healthy – they lost little weight and maintained high blood cell counts – even when carrying high numbers of parasites. The researchers think these mice have evolved to tolerate infection. The researchers found that these two strategies for coping with infection are mutually exclusive; mice either try to resist malarial infection or they learn to tolerate it.- Science DOI: 10.1126/science.1148526, 2 November 2007

Researchers have found that a small region of the brain controls addictive impulses in rats. The finding could help treat a range of addictions. Scientists know that people who have experienced damage to the insula, a small region of the brain, don’t show addictive tendencies. To test whether the insula controls addiction, the researchers studied its activity in rats. They trained the rats to associate a white chamber with addictive amphetamines. When given the choice of a white or dark chamber, the rats head for the white chamber, even though wild rats naturally prefer dark conditions. Next, the researchers injected the rats with an anesthetic to numb the insula. Now, the rats preferred the dark chamber. Once the anesthetic wore off and the insula became active again, the rats again chose the white chamber. The study shows how important the insula is in controlling addiction, and provides researchers with a new target for therapy. - Science DOI: 10.1126/science.1145590, 26 October 2007

Obesity Connected to Reward Processing

Research with rats suggests that dopamine – a chemical associated with reward processing in the brain – has connections with obesity. Scientists looked at the number of dopamine receptors on the brain cells of obese rats. The rats had fewer receptors than expected. When the researchers restricted the rat’s food intake they found that the number of receptors increased. If the brain carries fewer receptors, it may not release as many rewarding chemicals that signal satisfaction after eating. The rat must overeat before enough dopamine is released. Increasing the level of dopamine receptors could help treat obesity. - Synapse DOI: 10.1002/syn.20468, 25 October 2007

Treating Stress

Research with mice may explain why some people react to traumatic situations with high degrees of stress. The result could help in the treatment of depression and post traumatic stress disorder. Researchers know that genetically identical mice can show a range of stress responses to the same situation. They now know that some mice are resilient to stress because of chemical activity in the brain. When the researchers subjected mice to a stressful experience, the mice released a chemical called dopamine, which in turn caused cells in a primitive pleasure centre in the middle of the brain called the VTA to release a growth factor called BDNF. When the BDNF signal from the VTA passed to another brain region, it caused the mice stress. But by blocking the signal from the VTA to the rest of the brain, the researchers could make the mice resistance to stress. A therapy to control the levels of BDNF could help treat stress. However, BDNF activity has beneficial effects in some parts of the brain, so a therapy would have to act only in the VTA. - Cell, 19 October 2007

Researchers have developed a mouse with a condition similar to childhood absence epilepsy (CAE). The mouse will help in the development of anti-seizure drugs. Researchers don’t know exactly what triggers epileptic seizures, but they have already identified a genetic mutation that leads to CAE in humans. They produced GM mice carrying the mutation. The mice are healthy at birth, but gradually develop epilepsy as they grow. By studying the mouse brain during development, the researchers should be able to pinpoint the changes that lead to epilepsy. Early results suggest there are defects in the brain cortex of the mice. The researchers hope that further studies will reveal all of the brain changes associated with CAE, and identify therapies to correct the damage. - Proceedings of the National Academy of Sciences, online DOI: 10.1073/pnas.0708440104, 18 October 2007

Research with mice has revealed the brain cells that help us wake in the morning. The study could help understand sleeping disorders such as narcolepsy. Researchers know that narcoleptics have few of the special brain cells that produce the protein hypocretin. To find out if the lack of hypocretin is responsible for sleep disorders, scientists studied its activity in mice. They used a virus to insert a light-sensing protein into the hypocretin-producing brain cells in mice. When the researchers shone light into the mouse brain using fibre optic technology, they could activate the brain cells and produce hypocretin. Mice treated this way woke faster than normal. Another set of GM mice lacking the gene for hypocretin were always slow to wake. The researchers think they could help insomniacs by reducing the production of hypocretin, while narcoleptics could benefit from more hypocretin. - Nature, advanced online publication DOI: 10.1038/nature06310, 17 October 2007

Research with zebrafish shows how the sleep control systems of fish differ from those of mammals. Researchers hope to use the study to construct an evolutionary tree of sleep. Zebrafish sleep at night just as mammals do, but if they are constantly disturbed during the night, they don’t catch up on lost sleep during the day. The scientists think that this is because the effect of daylight on the fish is so powerful that it keeps them awake even if they are tired. Mammals often sleep during the day after a restless night. The scientist produced GM mice lacking the gene for hypocretin, a protein important in controlling sleep patterns. Mammals lacking hypocretin develop both insomnia and narcolepsy, but the fish developed insomnia only. The research shows that fish rely on sunlight to stay awake during the day. Mammals have developed different mechanisms for staying awake. - PLoS Biology DOI: 10.1371/journal.pbio.0050277, 16 October 2007

Research with fish has identified a protein involved in blood vessel formation. Healthy blood vessels are essential for normal organ function, but the genetic processes involved in blood vessel formation are unclear. Now, scientists have identified an important role for the protein Birc2. GM zebrafish lacking the gene for Birc2 showed severe hemorrhaging, because a process of programmed cell death destroyed the developing blood vessels in young fish. The research could help understand how blood vessels form in humans. Inhibiting blood vessel formation in tumors may help treat a range of cancers by starving them of the oxygen they need to grow. - Nature Genetics, published online DOI: 10.1038/ng.2007.8, 14 October 2007

Researchers have discovered how to rejuvenate donated blood and increase its performance after transfusion. Dogs that received the treated blood fared better than expected. Scientists know that donated blood for transfusion loses its therapeutic benefit within days. Blood transfusions have been linked with a higher risk of heart attack, organ damage and death. The researchers think the link is down to the loss of nitric oxide from donor blood. Nitric oxide can help dilate blood vessels and ease blood flow. They infused old donor blood with nitric oxide and transfused it into dogs. The dogs benefited from the transfusions as if the blood was fresh. A treatment for humans could be developed within a few years, say the researchers. - Proceedings of the National Academy of Sciences, published online DOI: 10.1073/pnas.0707958104, 11 October 2007

Mice exposed to flu virus produce offspring that are more susceptible to developing schizophrenia, researchers have found. The flu virus is restricted to the respiratory tract, and so researchers think that the virus is only indirectly responsible for increasing the risk of schizophrenia. They gave pregnant mice a molecule to trigger an immune response similar to that produced by flu. The offspring tended to develop schizophrenia. The researchers concluded that the mother’s immune response was transmitting signals to the fetus that increased the risk of schizophrenia. Through trial and error, they found that an immune molecule called interleukin-6 was responsible. GM mice lacking interleukin-6 produced healthy offspring even if the researchers induced a strong immune response during pregnancy. Treatments to prevent interleukin-6 from damaging the developing foetal brain could help reduce the number of cases of schizophrenia. - Journal of Neuroscience DOI: 10.1523/JNEUROSCI.2178-07.2007, 3 October 2007

Research with mice shows that a compound found in mangos and grapes can help stop the spread of cancer in the neck and head. Cancers of the head and neck are difficult to treat and often spread to other tissues. Chemotherapy treatments are often ineffective because patients develop resistance to the therapy. Now, researchers have found that lupeol, a compound found in fruit and vegetables, can help treat resistant cancer. The researchers gave the compound to mice with head and neck cancers. Lupeol selectively induced death in the cancer cells without damaging surrounding tissue. The researchers say that lupeol is even more effective if combined with existing cancer therapies. They are continuing to research the compound in animals before beginning clinical trials in the near future. - Cancer Research DOI: 10.1158/0008-5472.CAN-07-0801, 15 September 2007

Research with mice has identified a target region for a potential Chlamydia vaccine. Chlamydia remains the most prevalent sexually transmitted bacterial infection in the world. The researchers took a strain of Chlamydia that lacked a plasmid, a small circular molecule of DNA found in bacteria, and injected it into mice. The mice did not develop the hallmarks of disease, such as damage to the oviduct. When the mice were later infected with normal Chlamydia, they had developed immunity to infection and did not become ill. The plasmid-deficient version of Chlamydia could form the basis of a vaccine against the disease in future. - The Journal of Immunology , 15 September 2007

New Breast Cancer Target

Research with mice has uncovered a gene that plays an important role in the development of breast cancer. The research could help explain the differences in individual responses to existing breast cancer treatments. Breast cancer cells grow in response to stimulation by the hormone estrogen. Standard cancer treatments interfere with estrogen signaling. Now, scientists have discovered that a transcription factor called TFAPC2 controls a number of pathways associated with estrogen signaling. Removing TFAPC2 from mice with breast cancer left the cancer cells unable to respond to estrogen and inhibited tumor growth. Existing breast cancer drugs such as tamoxifen target only one estrogen signaling pathway. The researchers suggest that some patients do not respond to tamoxifen treatment because estrogen still reaches the cancer cells through a different route. Targeting TFAPC2 could prove a more effective treatment because it controls a number of estrogen pathways. - Cancer Research DOI: 10.1158/0008-5472.CAN-07-2293, 15 September 2007

Key Role for Blood Formation Gene

Research with mice has shown that one gene plays a vital role in blood cell production. If the gene is removed, the bone marrow stops producing blood cells within 14 days. The research could lead to new treatments for childhood leukemia. Researchers know that the Mixed Lineage Leukemia (MLL) gene is involved in forming embryonic blood stem cells, but it is unclear what role it plays in normal blood cell formation. They used GM mice in which they could turn off MLL with chemicals. Within two weeks of impairing MLL function, the mice had developed bone marrow failure. The research shows that MLL is needed throughout life. MLL is commonly mutated in childhood leukemia and is a therapeutic target. But scientists working on therapies for childhood leukemia will need to make sure that MLL is still present to avoid further health problems. - Cell Stem Cell , 13 September 2007

The Importance of Good Timing

Treatments against viral infections are most effective if administered more than three days after infection, research with mice shows. Researchers infected mice with the LCMV Armstrong virus and then treated them with an antibody that stimulates an immune response by activating a molecule called CD137. Whether the mice survived the infection depended on when the antibody was administered. Some mice received the antibody within the first day of infection. The mice produced a normal immune response, but by Day 8 the immune system collapsed. But mice given the antibody more than three days after viral infection produced a better immune response and cleared the virus. The results show that CD137 treatments can have different effects – either inducing the death of important immune system cells or enhancing viral immunity – depending on the timing of treatment. This may be important for future vaccine development. - The Journal of Clinical Investigation DOI: 10.1172/JCI32426, 13 September 2007

Skin Color Explained

Researchers may have discovered how skin cells become pigmented, following a study with mice. The research could have implications for skin cancer research and a range of cosmetic therapies. Scientists know that special cells called melanocytes produce melanin, a pigment that colors the skin. But they do not know why some cells take up melanin and other cells do not. The Foxn1 gene is expressed in some skin cells, and the researchers investigated its role in pigmentation. When they produced GM mice with Foxn1 activated in cells that do not normally express the gene, they found that those normally colorless cells became pigmented with melanin. The research shows that Foxn1 makes cells into pigment recipients. It is Foxn1 that instructs the melanocytes where to deposit melanin. A better understanding of this process could impact on therapies for skin disorders such as vitiligo, in which pigment is lost from skin patches, and may even help restore pigment to grey hair. - Cell , 7 September 2007

New Role for HIV Drug

A drug used to treat HIV may be effective at combating cancer too, new research with mice suggests. New drugs are costly to develop in terms of both time and money, and so researchers often try to find new uses for existing treatments. HIV protease inhibitors are effective because they inhibit the Akt molecule. Akt is also emerging as a cancer target, and so researchers tested the effect of the HIV therapies on cancer cells. The scientists found that HIV therapies in concentrations known to be safe in people were effective against breast cancer cell cultures. They also tested the HIV therapies on mice with lung cancer. The mice responded well to treatment, particularly involving the drug nelfinavir. Because nelfinavir is already known to be safe for human use, a clinical trial involving cancer patients has already begun. - Clinical Cancer Research DOI: 10.1158/1078-0432.CCR-07-0161, 1 September 2007

Fish Model of COX Deficiency

Researchers have developed a zebrafish model for COX deficiencies. Such deficiencies can block the function of mitochondria, the energy-producing structures within cells, potentially leading to fatal metabolic disorders. COX deficiencies are difficult to study because it is hard to find a suitable animal model. GM mice with a similar condition appear to be as badly affected as humans, often miscarrying before birth which makes it hard to obtain data. The researchers developed a new zebrafish model by reducing the expression of a protein involved in the formation of COX. Because zebrafish develop in eggs outside the female and young fish are transparent, the researchers could track changes in the early stages of development. COX deficient fish showed defects in tissue development, reduced heart function, and swimming problems. The scientists can now study specific effects of COX deficiency, which should lead to improved therapies to treat mitochondrial diseases in humans. - The Journal of Biological Chemistry DOI: 10.1074/jbc.M703528200, 30 August 2007

Researchers have transferred human gut bacteria into mice to better understand how they affect metabolism. The study could lead to new treatments for metabolic disorders such as diabetes and obesity. Gut bacteria (microbes) work with the body to help digestion and maintain general health. Scientists took microbes from humans and placed them in the guts of mice. They found that some microbes impacted on the ability to digest fats. Fats are broken down by bile acids, which are produced by the liver. The microbes affect the process because they metabolize bile acids. Everyone carries a different array of microbes in the gut, and some may be responsible for metabolic disorders such as diabetes and obesity. By transplanting microbes into mice, the scientists think they can better understand the role played by the different microbes and identify those responsible for harmful disorders. They will also be able to develop treatments, including probiotics, to improve the condition of patients with metabolic disorders. - Molecular Systems Biology, published online DOI: 10.1038/msb4100153, 22 May 2007

Blind Mice See Again

Researchers have used gene therapy to restore sight to mice with a rare hereditary form of blindness. The research could lead to new treatments to treat a variety of forms of blindness in the future. Researchers identified the genetic defect that causes achromatopsia. This affects the cells in the eye important for central vision and color discrimination; cone photoreceptors. They delivered fully-functioning versions of the gene to the mouse eye using a harmless virus. Two months later, 19 of the 21 treated eyes had responded well, and 17 showed responses similar to normal mice. The research is the first to show that gene therapy targeting the cone cells is possible, and could open the way to treat other forms of blindness that affect the cone cells. - Nature Medicine, advance online publication DOI: 10.1038/nm1596, 21 May 2007

Protection Against Bioterrorism

Researchers have produced a protein that protects rabbits against enterotoxin B, a potential bioterrorism agent. Staphylococcus aureus bacteria release a toxin (enterotoxin B) that can cause food poisoning. But if enterotoxin B is produced during infection or is inhaled, it can elicit a fatal immune response by binding to T-cells in the immune system and causing the release of inflammatory compounds (cytokines). Now, scientists have engineered a protein that binds with enterotoxin B and prevents it from attaching to T-cells. They exposed rabbits to enterotoxin B and then treated them with the protein. None of the rabbits became seriously ill. The protein is cheap to make and is far smaller than an antibody, and so can penetrate deep into tissue for more effective treatment. However, the scientists also suggest that an antibody to fight enterotoxin B would be useful, because the new protein survives in the body for only a few hours, whereas an antibody remains active for weeks. - Nature Medicine, advance online publication DOI: 10.1038/nm1584, 21 May 2007

Malaria Vaccine

Researchers are close to producing a vaccine for malaria following a successful trial with mice. The new vaccine is based on antibodies collected from a small population of Gambians with a natural immunity to malaria. To refine the vaccine, scientists tested it in mice. Unfortunately, mice do not become ill when infected by the malaria parasite, so the scientists had to produce a mouse model of the disease before they could test the vaccine. They used a related parasite that does cause disease in mice and genetically modified it so that the human antibodies would detect it as they do malaria. When they injected mice with the GM parasite, they succumbed to infection and died. But if the mice had received a vaccine containing the human antibodies before being exposed to the parasite, they fought off the infection and survived. The scientists hope to begin clinical trials shortly. - PLoS Pathogens DOI: 10.1371/journal.ppat.0030072, 18 May 2007

New Model Will AID Burkitt Lymphoma Research

Researchers have developed a mouse model for Burkitt lymphoma and related autoimmune problems, potentially leading to better treatments for these conditions. Activation-induced cytidine deaminase (AID) is an enzyme of the immune system (despite the name, it has no connection with AIDS) produced by B cells. B cells produce antibodies to attack viruses and bacteria. When B cells detect a foreign invader, they migrate to the lymph nodes, tonsils and spleen to divide and replicate in order to fight the infection. Part of this replication process involves the AID enzyme, which encourages the antibody genes within B cells to randomly mutate, producing new varieties of B cell. Although some of these mutations will help destroy foreign cells, others can lead to unwanted side effects – these are usually destroyed before they can harm the body. When they are not removed they cause autoimmune disorders and Burkitt lymphoma, a cancer of the B cells. The new mouse model involved attaching a fluorescent molecule to AID, allowing scientists to visualize AID activity in living mice. By cross breeding the new GM mice with strains of mice pre-disposed to develop Burkitt lymphoma, the researchers will be able to study how AID contributes to the onset of the disease. - The Journal of Experimental Medicine DOI: 10.1084/jem.20061952, 14 May 2007

Sheep Provide Insights into Teenage Pregnancy

Studies with sheep may help improve the health of babies born to pregnant adolescents, according to researchers. Teenage pregnancies are becoming more common globally, but because teenage girls have not finished growing, nutrients necessary for the fetus' healthy development may be diverted elsewhere. The scientists demonstrated this by underfeeding adolescent ewes during pregnancy. The under-nourished sheep did not produce enough blood vessels to supply the developing fetus with nutrients. This was a non-reversible process; even if the pregnant sheep were returned to a healthy diet later in the pregnancy, they could not properly nourish the fetus because too few placental blood vessels had been produced early in the pregnancy. The results show how important adequate nutrition is to pregnant adolescents in the first two trimesters to reduce the chance of damage to the fetus. - Biology of Reproduction, papers in press DOI: 10.1095/biolreprod.107.061457, 2 May 2007

New Treatments for Parkinson’s

Research with monkeys has revealed that implanting dopamine generators in the brain can relieve the symptoms of Parkinson’s disease. Parkinson’s disease is characterized by muscle rigidity caused by a decrease in the level of the chemical dopamine in the brain. Increasing this level can relieve symptoms. However, dopamine cannot cross the blood-brain barrier, and so cannot be given as a drug. The researchers induced Parkinson’s-like symptoms in monkeys. They then took small fragments from the monkey’s carotid body, an area at the base of the brain that releases dopamine, and implanted them into areas of the brain that control movement. The monkeys’ condition improved. The scientists think that the implanted cells release substances (trophic factors) that induce the surrounding tissue to produce more dopaminergic cells, the cells that release dopamine. One such trophic factor is GNDF, and the scientists could also improve the condition of monkeys with Parkinson’s by injecting GNDF into the brain instead of implanting dopamine generators, meaning GNDF and similar trophic factors could help relieve the symptoms of Parkinson’s. - Brain DOI: 10.1093/brain/awm061, May 2007

Gene Therapy for Heart Failure

Researchers have reversed heart failure in rats using gene therapy. The scientists used a rat model of heart failure and treated some with a therapeutic gene (S100A1) that improves calcium signaling, important for strong heart pumping. They delivered the protein directly to the rat heart using a small and harmless virus. After two months, the rats treated with S100A1 had improved heart health and better heart pumping ability. Patients with heart failure are often treated with beta-blockers. When rats with heart failure were treated with beta blockers, the drugs stopped the progression of heart failure. But the gene therapy actually reverses the damage caused by heart failure and so is more effective. - Circulation, published online DOI: 10.1161/CIRCULATIONAHA.106.671701, 30 April 2007

Understanding the Action of Anti-depressants

Research with depressed mice may finally explain how fluoexetine (Prozac) works on the brain, and may lead to new and more effective medicines to combat depression. Depression results from an imbalance in the levels of serotonin, the brain’s ‘happy’ chemical, which transmits messages between brain cells. Fluoexetine, a standard treatment against depression, works by indiscriminately increasing the levels of serotonin. But it is unclear exactly how this helps relieve the symptoms of depression. Now, scientists have developed a chemical, EDMT, with a highly specific function. Serotonin transmits messages between brain cells by acting on seven different cell receptors. EDMT activates just one of those receptors, called 5-HT6. When the researchers compared the brain chemistry and the behavior of depressed mice on either fluoexetine or EDMT, they found few differences. Because fluoexetine and EDMT have similar effects on mice, it is possible that fluoexetine also acts on the 5-HT6 receptor. This information may lead to the development of new anti-depressant drugs acting specifically on the 5-HT6 receptor, which may be more effective than fluoexetine. - Journal of Neuroscience DOI: 10.1523/JNEUROSCI.3110-06.2007, 11 April 2007

Scientists have identified human pancreatic cancer stem cells, following research with mice. The discovery promises improvements in therapeutic strategies against pancreatic cancer, which has the worst survival rate of any major cancer. Cancer growth and propagation is controlled by a small subset of cells, which have been dubbed cancer stem cells. If cancer treatments can target and destroy these cells, it is less likely that the cancer will spread. Cancer stem cells have been found in a number of human cancers, but so far not in pancreatic cancer. That has now changed. In the study, scientists took samples of human pancreatic cancer and transplanted them into GM mice with impaired immune systems. The mice developed cancer. The researchers identified a subpopulation of cells that shared similar markers on their surface and which were responsible for the most rapid growth of tumors. As few as 100 cells injected into a healthy mouse resulted in tumor growth. Now they have a method of identifying pancreatic cancer stem cells, scientists may be able to develop new therapies to target these cells, and improve survival rates for pancreatic cancer. - Cancer Research DOI: 10.1158/0008-5472.CAN-06-2030, 23 February 2007

Motherly care is enough to alter the genetic code of young rats and make them less fearful in later life. Scientists found that rats exposed to licking and grooming after birth had enhanced levels of a nerve growth factor, NGFI-A. That growth factor binds to genes in the hippocampus that make glucocorticoid, a hormone produced in response to stress. In this bound state, NGFI-A attracts enzymes that attach to the gene DNA. These DNA modifications enhance the production of glucocorticoid in the young rats. Because the rats produced more glucocorticoid, they were better able to cope with stress. Modification to genes after birth is called epigenetics, and can help animals adapt their genetic code to the immediate environment. There is even evidence that epigenetic changes can be inherited in the sense that baby rats which grow up less fearful as a result of grooming will then groom their own offspring, encouraging the same epigenetic changes. - Journal of Neuroscience DOI: 10.1523/JNEUROSCI.4164-06.2007, 14 February 2007

Some people may have a degree of immunity against bird flu, according to new research with mice. The modern bird flu virus contains a version of the protein hemagluttin which is not found in human flu viruses. Hemagluttin is the ‘H’ in H5N1. However, both bird flu viruses and human flu viruses have broadly similar versions of a second protein, neuraminidase (the ‘N’ in H5N1). Scientists tested whether controlled exposure to the neuraminidase in human flu (H1N1) offered any immunity against H5N1. They inoculated mice with human N1 and exposed them to a number of flu viruses. The inoculation offered some protection against small doses of H5N1, although large doses of the virus were still fatal. The results show that human N1 can partially protect against H5N1. Because H1N1 is relatively common in the population, those who have been exposed to it in the past may be better able to cope with infection by H5N1. This may explain why most human H5N1 fatalities have involved the young. Older sufferers are more likely to have been infected with H1N1 at some point, and may be better able to fight H5N1. - PLoS Medicine DOI: 10.1371/journal.pmed.0040059, 13 February 2007

Research with mice has shown that cleft palate is the result of growth imperfections that occur in a small two-day window during embryo development. It is already known that the protein GSK-3 beta plays an important role in biological development. Now, researchers have found that GM mice lacking the gene for this protein develop cleft palate. The scientists have also identified the precise point during development that the protein is needed to prevent cleft palate. They used mice with an engineered version of the gene that produces an unstable version of GSK-3 beta. Because the protein breaks down rapidly, the GM mice did not develop properly and had cleft palate. However, in the presence of a drug (rapamycina), the modified protein is stabilized, restoring its function. By administering the drug at precise points during embryo growth, the researchers found that GSK-3 beta is needed only during a specific two-day period to prevent cleft palate in mice. The research offers a potential cure for cleft palate, but much remains to be done. Scientists will need to identify those mothers most at risk of having cleft palate babies, establish a treatment to restore the function of GSK-3B in humans, and identify the precise window during human foetal development to apply the treatment. - Nature advanced online publication DOI: 10.1038/nature05557, 11 February 2007

Scientists have discovered a powerful anti-cancer gene, following research with mice. The discovery of cancer genes proceeds by trial and error; researchers analyze tumors and look for variations in their genetic makeup to identify the genes responsible for tumor growth. As a result of this body of research, it is known that many human cancers are associated with the deletion of genes in a specific region of chromosome 1. This suggests that a gene in that region ordinarily suppresses tumor growth. However, identifying this anti-cancer gene has been difficult. Now, researchers think that they have found the elusive gene, which they call CHD5. When the researchers deleted CHD5 in GM mice, all of the mice developed cancer. But when the researchers added an extra copy of CHD5 to the mouse chromosome, it gave the mice additional protection; any cancer cells stopped dividing or committed suicide (cell apoptosis). Further studies showed that human glioma, a form of brain cancer, is also associated with deletion of CHD5, suggesting that the gene is as important in humans as in mice. In future, researchers could develop anti-cancer drugs that mimic the activity of CHD5 in patients missing the gene. - Cell, 9 February 2007

Scientists have discovered a method of gene therapy that can increase bone density in mice. The research may lead to new treatments for osteoporosis. Cells called osteoblasts produce bone. The longer the osteoblasts remain active, the greater the bone density. A number of growth factors enhance osteoblast survival by activating an enzyme called PI3K. But a second enzyme, Pten phosphatase, inhibits PI3K. The scientists produced GM mice lacking Pten, the gene that produces the inhibiting enzyme. The mice remained similar in size to normal mice, but grew progressively denser bones through life. The results show the important role that the Pten gene plays in controlling osteoblast cells. If the researchers can translate these findings to humans, they may be able to find ways to prevent bone loss, or even increase bone density in humans as they age. - Proceedings on the National Academy of Sciences, online publication DOI: 10.1073/pnas.0604153104, 7 February 2007

Disrupting nerve signals to the liver can prevent the onset of high blood pressure and diabetes in mice. Glucocorticoid, a steroid, is used commonly in medicine to treat asthma and arthritis. Unfortunately, steroids often lead to high blood pressure, or to insulin resistance and the development of diabetes. It is already known that the protein PPAR alpha must be produced in the liver for glucocorticoid to cause insulin resistance. Now, researchers have found another component in the development of diabetes and high blood pressure. The vagus nerve, which stretches from the base of the brain to the intestine, sends out nerve signals that appear to interact with PPAR alpha to encourage insulin resistance. Using GM mice that produced PPAR alpha, scientists disrupted the vagus nerve and the mice did not develop insulin resistance or high blood pressure, even if they were given steroid treatment. Surgical implants that are already used as a therapy for seizures could be modified to interfere with vagus nerve signals. These implants could benefit those at risk of developing hypertension or diabetes. - Cell Metabolism, 7 February 2007

Scientists have identified genes that are turned off in mice with B-cell non-Hodgkin's lymphoma (NHL). The same genetic defects may be responsible for NHL in humans. It is already known that human NHL sufferers often have a mutated version of the TCL1 gene. GM mice with the same mutation develop NHL. But the disease is not caused by TCL1 mutation alone. Now, some of the additional gene defects that lead to NHL have been identified. The researchers used a technique called ‘restriction landmark genomic scanning’ to identify the genes that work together with TCL1. They found that a number of those genes are inactivated in NHL mice. The next step is to find out if the same genes are inactivated in human NHL. If scientists can identify a genetic cause for NHL, it could lead to more effective treatments against the disease. - Oncogene advanced online publication DOI: 10.1038/sj.onc.1210211, 29 January 2007

A common blood pressure drug, losartan, is an effective treatment for muscle wasting disease in mice. Muscle can repair itself when damaged because signals sent to muscle stem cells encourage them to proliferate and attach to existing muscle fibers. This does not occur in patients with muscle wasting diseases, such as Marfan syndrome or Duchenne muscular dystrophy. These patients have excessive levels of a growth factor, TGF-beta, in their muscles, which is known to inhibit growth of muscle stem cells in the test tube. Now, researchers have shown that blocking TGF-beta can prevent muscle degeneration in animals. GM mice with a condition that mimics Marfan syndrome had poor muscle growth. But when the mice were given the drug losartan, muscle growth returned to normal. Losartan reduces high blood pressure by blocking a molecule called angiotensin II, but it also works against TGF-beta. Because of the encouraging results with the Marfan syndrome mouse model, the researchers also tested losartan against a mouse model of Duchenne muscular dystrophy. Again, the drug reversed muscle wasting. Losartan is already known to be safe for humans, so clinical trials involving Marfan syndrome sufferers will begin shortly. - Nature Medicine advanced online publication DOI: 10.1038/nm1536, 21 January 2007