Southwest Association for Education in Biomedical Research - SwAEBR

Research Focus 2004:

Human Blood Stem Cells Repair Mouse Hearts

Regeneration of damaged hearts using blood stem cells now appears to be clinically promising, say researchers who have shown in mice that human stem cells use different methods to morph into two kinds of cells needed to restore heart function – cardiac muscle cells that contract the heart, and endothelial cells that line blood vessels found throughout the organ. Researchers used marker proteins to examine how human the new mouse heart cells were. Two months after mice with ailing hearts were treated with human stem cells, about 2% of cells in their heart showed evidence of a human genetic marker. Researchers showed, for the first time, how these human master cells use different ways to become two distinct kinds of cells needed in the heart. Human stem cells primarily fuse onto mouse cardiac cells to produce new muscle (myocyte) cells that have both human and mouse DNA. But to form new blood vessel cells, they differentiate or mature by themselves, presumably to patch damaged mouse blood vessels with human cells. These findings should help resolve debate as to whether stem cell transfer actually creates new types of cells that last within a heart. - Circulation, 21 December 2004

Understanding a Disease That Blinds Children

Leber congenital amaurosisis is a rare condition causing childhood blindness. There is no treatment. In a new study with mice, it has been shown that absence of the AIPL1 gene causes loss of light-sensitive rod and cone cells, closely mimicking the inherited human disease. This gives scientists a model that can be used for testing potential treatments, which are likely to involve gene therapy. They are now working to determine if they can prevent this disease by supplying the retinas of affected newborn mice with the missing AIPL1 gene. - Molecular Brain Research, 20 December 2004

Gene Implicated in Rett Syndrome

A new gene has been identified that may be involved in Rett syndrome, a neurological disorder resulting in autism, seizures and loss of speech, almost exclusively in girls under 18 months. Rett syndrome is caused by a mutation in the gene MECP2, encoding a protein thought generally to affect the expression of many other genes, several of which probably contribute to the disease. The search is on for MECP2 target genes that are relevant to the development of the syndrome. Work using mice has now shown that the gene DLX5 is a strong candidate. The authors found that DLX5 expression was altered in the brains of mice lacking MECP2. In humans, DLX5 is an 'imprinted' gene, and is expressed only from the copy received from one's mother. In cells from individuals with Rett syndrome, however, they found that the gene was expressed from both copies, resulting in an overproduction of the protein. DLX5 regulates the production of enzymes that synthesize a signaling chemical called GABA, which is linked to the development of other neurological disorders, suggesting that this pathway may have role in at least some of the features of Rett syndrome. - Nature Genetics, online DOI: 10.1038/ng149, 19 December 2004

Mouse Mimics Cancer Syndrome

Scientists have developed a new strain of mouse that closely resembles Li-Fraumeni Syndrome (LFS) in humans. LFS predisposes those affected to a broad range of cancers and is characterized by mutations in the p53 tumor suppressor gene. Most LFS patients develop cancer by age 65. The work could lead to a treatment not only for LFS, but also for other cancers. Although LFS is a rare genetic disease, affecting fewer than 400 families worldwide, the p53 gene is also very commonly mutated in tumors unrelated to LFS. Mutations in p53 are detected in over half of all human tumors, such as colon, breast, skin, bladder, and many cancers of the digestive tract. Consequently, the development of a therapy for LFS specifically targeted at p53 has the potential to be applied to a wide range of cancers. Previous attempts to create mouse mimics of LFS, by completely inactivating p53, were unsuccessful because the mice did not develop the wide range of tumors seen in human LFS patients. In this study, two different mutations in p53 that are commonly found in human tumors gave rise to more tumors and different types of tumors. - Cell , 17 December 2004

Gene Linked to Myelin Repair in the Brain

Scientists working with tissue from rodents from humans and with genetically modified mice have identified a genetic repair process in the brain that can re-coat nerves with myelin—the fatty 'insulation’—that is stripped away in multiple sclerosis. The gene Olig1, thought to aid the development of certain brain cells, is essential for the myelin-repairing process in adults with diseases like multiple sclerosis (MS). The Olig1 gene jump-starts a process that can restore, at least temporarily, the myelin coating of nerves damaged in MS. When the researchers induced demyelinating lesions in mice lacking Olig1,they found that although brain developed normally it could not repair the demyelinating lesions. The findings will not yield direct results in terms of finding treatment for MS, but they give new insight and direction for research, and it is hoped that therapeutic approaches focusing on the repair process will be available in the future. - Science, 17 December 2004

How Stem Cells Find Injured Tissue

New research using isolated cells and then mice suggests that stem cells use inflammatory signals to home in on brain damage. Researchers found that a molecule called SDF-1 alpha, secreted by injured or inflamed neural tissue, acts like an SOS signal and summons implanted human neural stem cells to the site of injury, where the stem cells can assume the function of missing neurons. Scientists tracked SDF-1 alpha and found that it triggered a series of intracellular processes associated with survival, cell proliferation, and migration—all steps required for stem cell mobilization, engagement, and repair. They then simulated stroke in mice and implanted human neural stem cells that had been incubated with a fluorescent dye. These cells traveled from where they were implanted to the site of injury and intertwined with the SDF-1 alpha-expressing cells. There was a positive correlation between the amount of SDF-1 alpha expressed and the number of stem cells present. SDF-1 alpha was only found in damaged areas—not on the opposite, normal side of the brain, which failed to retain the implanted neural cells. - Proceedings of the National Academy of Sciences, Early Edition DOI: 10.1073/pnas.0408258102, 17 December 2004

Insulin-like Protein Points to New Diabetes Drugs

Researchers studying mice have isolated a new compound produced by fat tissue that shares properties with insulin and may lead to the development of new diabetes drugs. They call the protein visfatin. Visfatin is produced in abdominal visceral fat of both humans and mice. The blood level of the protein increases during the development of obesity. Surprisingly, visfatin binds to and activates the insulin receptor. There are, however, important differences between visfatin and insulin. For example, visfatin levels do not change markedly with fasting or feeding, as is the case with insulin. It's known that obesity, and specifically the accumulation of fat in the abdomen around the visceral organs, is linked to the development of insulin resistance that can lead to overt diabetes. The researchers found that visfatin displays beneficial insulin-like effects in mice. High doses of synthetic visfatin lowered blood glucose levels in insulin-resistant or insulin-deficient animals. But much remains to be discovered about how visfatin, insulin and glucose are related.- Science Express DOI: 10.1126/science.1097243, 16 December 2004

Mice Think Outside the Box

Mice living in standard, barren cages may suffer stress and impaired brain development. But some researchers worry that building more stimulating environments might disrupt the reproducibility of results from mice in behavioral tests. Researchers using a large numbers of female mice have now found that introducing novelties such as tunnels, trapezes and tissues into the cage environment did not affect the performance of mice in common behavioral tests. The results cast doubts on the need to make mouse cages similar between laboratories, and many different types of animal study can incorporate a more interesting environment without loss of precision or reproducibility. - Nature, 16 December 2004

New Route to Parkinson's in Garbage Disposal

Researchers have known for a while that mutations in a key gene called parkin are a major cause of Parkinson's disease (PD). Parkin is part of the cell's garbage disposal system that rids the cell of unwanted proteins by degrading them. Now researchers studying rats have discovered a new mechanism by which the parkin gene can be compromised, a finding that they say could lead to new drugs for the disorder. They found that the protein produced by a gene called BAG5 inhibits parkin activity and the action of another protein, called Hsp70, a chaperone that works with parkin. Studies with rats found that BAG5 enhances the death of the dopaminergic neurons targeted by Parkinson's and that inhibiting the gene reduces such death. - Neuron, 16 December 2004

Oxidants Link Obesity to Diabetes

Individuals with metabolic syndrome, which is common in older people, are at risk of coronary heart disease, stroke, vascular disease, and type 2 diabetes. Although risk factors for this syndrome are known to include obesity, physical inactivity, and genetic factors, the role of obesity is not completely understood. Now, researchers have shown that fat cells of obese mice produce increased levels of toxic oxygen molecules known as reactive oxygen species (ROS) as well as the enzyme NADPH oxidase. These cells produce decreased levels of the enzymes that are responsible for destroying these toxic forms of oxygen. The researchers found that treatment of these mice with apocynin – an antioxidant that inhibits NADPH oxidase – reduced ROS production in fat cells, improved diabetes, and reduced the levels of fat present in the blood and liver. The results suggest that accumulated fatty tissue is a major source of ROS in obesity and acts as an early trigger of the metabolic syndrome - Journal of Clinical Investigation, 15 December 2004

How Platelets Help Cancer Invade Other Tissues

Malignant tumors have the ability to spread from one organ to another. Depleting the number of blood platelets, which can happen in several ways, by many mechanisms, has been shown to result in a reduction of secondary tumors in lung and bone in animals with transplanted tumors. This effect is attributed to the platelets’ capacity to enhance the survival of tumor cells, encouraging them to escape into surrounding tissue, and development of new blood vessels to support tumor growth. Now, studying mice with breast or ovarian cancer that spreads into bone, two additional roles of platelets have been found. These show that platelets act as a direct source of lysophosphatidic acid (LPA), which promotes tumor cell division; and are indirect activators of bone breakdown. - Journal of Clinical Investigation, 15 December 2004

Gene Therapy Reduces Skin Cancer

Researchers have successfully tested the first gene therapy for skin cancer, using mouse with the disease xeroderma pigmentosum, or XP. Their results show promise for similar gene therapy in children suffering from this rare disorder. XP is a debilitating disease in which patients must avoid the sun and all other sources of UV light. They have a 10,000-fold increase in cancer risk and many succumb to skin tumors at an early age. A mutation in any one of seven human genes involved in DNA repair is sufficient to cause XP. One of the commonest genes in XP patients is Xpa. Mice with Xpa mutations suffer from XP and develop cancerous skin lesions within three weeks of UV exposure. Researchers injected the normal version of mouse Xpa into the mutant mice and exposed them to UV light for a few hours over several days. Five months after the last exposure the treated mice merely had sunburn. The skin cells surrounding the site of the injection in the treated Xpa mutant mice were nearly identical to those of normal animals, indicating that the DNA repair mechanism had been restored by the addition of the normal Xpa gene. - Proceedings of the National Academy of Sciences, Early Edition DOI: 10.1073/pnas.0406304101, 14 December 2004

Finding the Cause of Psoriasis

Researchers studying mice may have discovered what causes psoriasis, a common and irritating skin ailment that affects 2 in 100 people. Their findings may open the way to an effective treatment. They developed a mouse that shows all the signs of the condition, studied it, and successfully treated it. They found that it takes a combination of a protein called STAT3 and an active immune system to cause psoriasis. Their finding suggests that psoriasis may start with an over-enthusiastic attempt by the body to heal wounds, and they made a skin cream that blocked this process in mice. Activated STAT3 is essential for wound healing. When the healing process is complete, normal STAT3 returns to its inactive form. But when it fails to turn off, the wound healing process continues and skin cells proliferate. Activated STAT3 is found in the skin of most psoriasis patients. - Nature Medicine, online DOI: 10.1038/nm1162, 12 December 2004

An Eye-opener for Narcolepsy

Results of a preliminary study with mice suggest a step forward in our understanding of the processes behind narcolepsy; there appears to be an underlying autoimmune process for people with a certain genetic profile. Narcolepsy is a chronic disorder characterized by excessive daytime sleepiness, which is caused by changes in hormone concentrations and nervous system activity. Scientists induced narcolepsy-like symptoms in smooth muscles of mice by injecting antibodies from blood samples of nine people with confirmed narcolepsy. Mice injected with antibodies from nine people who did not have narcolepsy (the control group) did not develop such symptoms. The findings suggest that the functional autoantibody is a sensitive and specific marker for human narcolepsy and might lead to a clinically useful assay for diagnosing narcolepsy. Identification of the target of the autoantibody and a better understanding of its long-term effects could open up new possibilities for diagnosis and management of this disabling disease. The scientists might have identified the missing link that connects an autoimmune process to selective loss of particular nerve cells and the development of narcolepsy. - Lancet, 11 December 2004

Compound J Tackles Tuberculosis

Tuberculosis kills two million people a year, but a promising drug may save some of them. The compound has a different mode of action from existing therapies, acts more quickly, and works on patients with drug-resistant infections. The new drug, currently called compound J, kills the bacterium, Mycoplasma tuberculosis, twice as effectively as standard antibiotics in mice. Therefore a course of pills would be shorter and easier to complete. The drug moves easily to the lungs, where it cripples a bacterial enzyme called ATP synthase. Initial studies in humans show that injections of Compound J are safe, at least for short periods of time. Trials in people with active disease are now under way, although it will be many years before the drug makes it to the market. - Science Express DOI: 10.1126/science.1106753, 9 December 2004

Improving Chemotherapy Survival

Seeking a way to lessen patients' vulnerability to deadly infections following chemotherapy, researchers have found a way to boost the immune function in mice following such treatments. Their approach involved increasing the pool of cells that give rise to neutrophils, a type of white blood cell that is critical for fighting bacterial and fungal infections but is particularly ravaged by chemotherapy. The team found that an infusion of a type of bone marrow cell – called myeloid progenitor cells - from a donor mouse yielded significantly more neutrophils in the mice a week after a dose of a typical chemotherapeutic agent. The procedure also increased the animals' ability to fight a deadly fungal infection. The condition in which neutrophils are lacking is known as neutropenia. It is the leading cause of death among cancer patients that is not related to their tumor. Because of the seriousness of the condition, doctors will reduce chemotherapy doses if they notice an infection developing in the early phases of the disease, which can decrease the efficacy of the cancer treatment. Additionally, resulting fevers and infections during neutropenia must be fought with antibiotics and antifungals, which can be toxic and spur resistance. - Blood, First Edition DOI: 10.1182/blood-2004-07-2676, 2 December 2004

Protecting Implants in the Body

Blocking a key molecule protects breast implants, permanent catheters, pacemakers, artificial joints, glucose sensors for diabetics, and other biomaterials from rejection and damage by the body, according to a study with mice. Implantation of biomaterials and tissue-engineered devices into tissues cause the development of a foreign body reaction that can lead to implant failure, and this reaction has been implicated in the malfunction and failure of numerous devices and implants. Where the foreign body and the implant are in contact, giant cells are formed from the fusion of recruited inflammatory cells that attack the implant. A protein called the CC chemokine ligand (CCL)-2, is believed to be responsible for the recruitment of foreign body giant cell precursors to the implant site. This study eliminated CCL2 in two different ways: by genetically engineering mice to lack the gene for it, and in other mice by blocking CCL2 function with of a protein decoy. They found that, when CCL2 was absent, the implant was protected from damage. The is a newly-discovered and more complex role for CCL2, and also paves the way for a therapeutic drug target to help sustain implants. - American Journal of Pathology, December 2004

Gene Vaccine for Alzheimer's

Researchers have found a way of stimulating the immune systems of mice to counter the amyloid proteins that cause the devastating brain plaques that are characteristic of Alzheimer's disease. Now, researchers have created a gene-based vaccine aimed at stimulating the immune systems of mice to fight off plaque-causing amyloid protein in the brain. Although prior studies of amyloid protein vaccination had shown some slowing in the plaque build-up, negative side effects also occurred in a handful of patients. Some had autoimmune responses that caused encephalitis. The key was finding another way to vaccinate patients without stimulating the body's own immune cytotoxic T cells. So researchers vaccinated mice with the amyloid gene rather than the amyloid protein, using a gene gun. The mice made lots of antibodies without stimulating cytotoxic T cells. The hope is that humans can make human antibodies against the amyloid. From mouse studies and in previous clinical trials of patients with Alzheimer's disease, immunization with amyloids slowed the build-up of plaque on the brain and appeared to slow cognitive loss. - Archives of Neurology, December 2004

Pinpointing the Genes for Lupus

Researchers using mice have found a gene family involved in determining the potential for acquiring lupus, a debilitating autoimmune disease that affects 200,000 people in the UK. The findings indicate genetic susceptibility to lupus results from imbalance between genes that increase and genes that suppress the immune system’s responsiveness. Individuals with increased risk for lupus may simply have the misfortune of expressing a 'bad' combination of versions of genes that are ‘good’ for resistance to infectious diseases. In the study of a mouse strain that develops autoimmunity similar to human lupus, researchers identified a cluster of genes, the SLAM/CD2 family, occurring in the same region of the human genome associated with genetic susceptibility to the disease. The genes played a crucial role in the disease’s development in the mice, but only when they were expressed in specific combinations with other genes. Researchers are currently working to expand analysis of these genes and their functions into humans with lupus, as well as individuals who may be at increased risk for developing the disease so they can be identified earlier. - Immunity, December 2004

Gene Therapy for Heart Failure

About one million Britons have heart failure. Other gene therapy in animals has been geared to over-expressing a gene, but this study used a gene that brought the heart’s protein level back to normal. S100A1 is part of a larger family of proteins called S100, which binds to calcium and is primarily found at high levels in muscle, particularly the heart. Previous studies by other researchers showed that the protein was reduced by as much as half in patients with heart failure. A few years ago, the same team put the human gene that makes S100A1 into a mouse, and found a resulting increase in contractile function of the heart cell. This time they used animals that had had heart attacks, and found the hearts worked better, had stronger beats, and used their energy supply more efficiently. The gene was carried in a modified form of a common-cold virus, and was injected into the coronary arteries. The team hope to learn more about the mechanisms behind S100A1’s actions, and eventually, develop gene therapy protocols in humans.
- Journal of Clinical Investigation, 1 December 2004

How Children Have Growth Spurts

The existence of growth spurts and growing pains in children may be glaringly obvious to parents, but their cause has lacked scientific explanation. A new study of lambs now sheds some light on this childhood phenomenon. In a five-year study, in which the leg bones were measured every three minutes, the research team found that growth occurred primarily when the animals were at rest. While the research does not provide a definitive link to nocturnal growth and the pain that some children experience, it does provide valuable new data and a possible explanation for growing pains. As the first study to demonstrate actual bone growth spurts, it presents a significant leap forward in documenting the process of normal growth spurts, and suggests that infants and children may also grow when they are at rest. - Journal of Pediatric Orthopaedics, December 2004

Clues about Cancer Genes

Scientists know that genes that preserve chromosome stability play an important role in protection against cancer. But understanding what controls them is a trickier matter. A new study using mice suggests that these genes act in concert with the p53 tumor suppressor gene. The scientists bred mice that lacked one copy of the p53 gene. They found that tumors in these animals were more likely to lack (or have a mutated version of) Fbxw7, a gene that is known to encode an enzyme implicated in maintaining chromosome stability - than those in animals with no p53 at all. In addition, mice deficient in Fbxw7 were more susceptible to radiation-induced tumors. The new findings shed light on the relationship between Fbxw7 and p53. - Nature, 9 December 2004

Chicken Genome Deciphered

Researchers have presented an extensive analysis of the draft sequence of the chicken genome, the first bird genome to be sequenced. This genetic information should prove useful for evolutionary, developmental and molecular biology as well as for agriculture. The International Chicken Sequencing Consortium sequenced approximately one billion base pairs in the genome of the red jungle fowl Gallus gallus, the wild ancestor of domestic poultry. They have also compared the differences between the red jungle fowl and three different strains of domestic chicken and provided a physical map of the chicken genome, which will help to fill in any gaps in the sequence and facilitate comparison with other species. The chicken has long been used by developmental biologists to study embryonic growth. Armed with the chicken genome sequence, biologists should be better able to pinpoint crucial genes that drive early embryonic development. The sequence might also enable farmers to breed more disease-resistant flocks. - Nature, 9 December 2004

Three Genes Control Prostate Cancers

A complex interplay between three different genes may determine how prostate cancer will progress, a new mouse study finds. Studies have shown that 5–10% of human cancers are hereditary; and genetic mechanisms are estimated to be responsible for half of cases that start before age 55. Six separate genes seem to be involved in prostate cancer and a research team had already studied two that suppress tumor growth. They are NKX3, a prostate-specific gene; and PTEN, which suppresses tumor growth. Now they have added a third gene to the mix, p27kip1, another tumor suppressor. The results are paradoxical. The mice with one normal p27kip1, gene showed faster progression of their prostate cancers. But cancer growth was inhibited in the mice with no p27kip1, gene activity. The study suggests that a better understanding of human cancer progression requires study of the interactions within groups of genes, rather than of single gene activity. - Proceedings of the National Academy of Sciences, Early Edition DOI: 10.1073/pnas.0407693101, 7 December 2004

How AIDS Is Transmitted Orally

Oral transmission of HIV is problematic, especially in developing countries where it is not practicable for HIV-infected mothers to bottle-feed their babies. Researchers have used monkeys to trace how the virus that causes AIDS may enter and spread throughout the body following an oral exposure. The virus cannot be transmitted via saliva, but breast milk is more infectious than previously thought. In the study, rhesus monkeys were infected with SIV administered onto the cheek pouch. They found that likely sites of infection included soft tissue in the mouth, esophageus and tonsils. SIV was not present in tissues below the esophagus until four days after infection, indicating that the stomach acids probably prevented the virus from entering through the stomach or intestines. At one day following oral exposure, the first lymph nodes infected were closest to the head and neck. Four days after infection, the virus could be detected in nearly all tissues. T-cells and macrophages probably played key roles in disseminating the virus. This may help to explain why antiviral therapies can effectively protect from HIV or SIV infection only if given within hours of exposure to the virus. - AIDS, 3 December 2004

Gene Therapy Shows Promise for Parkinson’s

Scientists have given novel treatments to rats that might one day lead to gene therapy treatment options for patients with Parkinson's disease. They have discovered that inserting a gene associated with the disease protected brain cells from degeneration. About 5-10 % of cases are inherited, and five genes have been implicated in patients with a family history of the disease. One form of inherited Parkinson’s is associated with mutations that cause overexpression of the alpha-synuclein protein. Another form typically strikes before age 40 and is linked to a mutation in the parkin gene. Both forms of the disease involve build-up of alpha-synuclein in the cell. The scientists injected Parkinson’s rats with a harmless virus containing the genes for parkin as well as a mutated form of the alpha-synuclein gene. The viruses successfully delivered the genetic material to about 30% of the rat brain cells. After six weeks, the researchers found that brain cells in animals injected with both parkin and mutated alpha-synuclein genes were still functioning. The presence of parkin protein appeared to protect the neurons from alpha-synuclein toxicity. -Proceedings of the National Academy of Sciences, 2 December

Too Much Iron a Risk Factor for Parkinson’s

Research with mice shows that excessive iron levels can increase the risk of developing Parkinson’s disease. Mice were fed varying amounts of iron to determine levels that led to or hastened the progression of Parkinson's-like symptoms such as tremors and balance problems, both in healthy rodents and, more markedly, where risk factors existed. In contrast, low levels of iron delayed onset of Parkinson's in mice with risk factors and slowed progress of the disease in those already infected. But the low iron news was mixed. The researchers warn against the dangers of self-medication with iron supplements. - Experimental Neurology, December 2004

Paralyzed Pets Walk Again

A successful method for healing spinal injuries in dogs has been developed, offering hope for treating human paralysis. Spinal injury is common in dogs, especially dachshunds. So pet dogs have been used to pioneer treatments, benefitting them and potentially humans, too. Scientists have developed a polymer called PEG that acts as a molecular sticking plaster on holes in nerve cells caused by spinal injury. It has to be administered as soon as possible and within 72 hours of injury. Scientists are now able to report that dogs have had the use of their back legs restored so that they are walking, with support, after four days, and are able to return home after 10 days. Follow-up shows they are still walking three years later. The scientists have yet to gain approval to test the drug on humans. - Journal of Neurotrauma, December 2004

Slowing Brain Tumors with Genetic Engineering

Glioblastoma multiforme is the most deadly of brain tumors, killing its victims within 6–12 months despite treatment. Now, researchers have found in rats that a small protein called hsFlt3L, delivered via a genetically engineered virus, increased the number of immune system T-cells cells in the brain and significantly slowed tumor growth, greatly prolonging survival of rats. The investigators found that 70% of the treated rats survived for over a year—more than half a rat’s lifetime— and that the treatment did not cause adverse immune reactions in the normal brain. In contrast, the rats treated with placebo substances died from their tumors within one week after the start of the treatment. This might lead to a new and better way of treating glioblastoma. - Molecular Therapy, December 2004

Real-time Images of How Lymph Nodes Work

Scientists studying mice have provided the first view, in real time, of the live actions of a network of dendritic cells, specialized components of the lymph nodes of the immune system. When microbes and other foreign invaders are detected, they travel to the lymph nodes. Here the spindly arms of dendritic cells inform other immune cells, the white blood cells called T and B cells, which then take action against the invader. Now scientists have found that another population of dendritic cells inform T and B cells what the body’s own tissues look like, so that they are safe in the case of a real immune system emergency. This immature but informative activity of dendritic cells is part of what immunologists call the steady state of the immune system. By making dendritic cells fluoresce, scientists have watched them work in real time. If this network is teaching other immune cells to recognize, or tolerate, the body’s own tissues, then the technique could led to advances in the treatment of cancer and autoimmune diseases. - Nature Immunology, December 2004

New Alzheimer’s Treatment?

Researchers have shown that brief treatment of mice with a form of Alzheimer's using a compound called rolipram. Rolipram improves memory in long-term potential and contextual learning—two measurements of brain function. Production and accumulation of beta-amyloid (Ab), which is toxic in the brain, is a central cause of Alzheimer’s. Rolipram's protective effect is due to its ability to modify gene expression, making brain synapses more resistant to damage caused by the accumulation of Ab. The beneficial effect of rolipram treatment was found to extend for at least two months after the end of one course of the treatment. The beneficial effects were even greater in older mice, suggesting that this class of drug might not be limited to treatment in the initial phases of disease. Further studies are needed to determine how long improvements persist after a single course of treatment and whether it is better to give continuous therapy or successive courses. -Journal of Clinical Investigation, 1 December 2004

A New Way to Lower Cholesterol?

A new approach to preventing hardening of the arteries looks promising. Researchers reduced cholesterol levels in mice by homing in on a key group of proteins. Cholesterol-lowering drugs such as statins work by lowering cholesterol throughout the body, but some patients still have heart attacks. Researchers are now targeting cholesterol in macrophages scavenger blood cells that eat foreign substances, including cholesterol. Sometimes, these lipid-laden cells become inflamed and form lesions on vessel walls. A family of proteins known as PPARs are produced by cells in vessel walls and play a role in minimizing diabetes or lowering triglycerides. They might also have a more direct effect in lowering atherosclerosis by altering the cholesterol metabolism in macrophages.
Drugs are already available for diabetes or lowering triglyceride levels that act on the three kinds of PPARs—alpha, beta and gamma—which can then turn on and off genes that play a role in cholesterol metabolism. Alpha and gamma were shown in mice to lower cholesterol, while beta PPAR had no effect. People with cholesterol problems may be helped even more by a combination of the available cholesterol-lowering drugs and these newer agents that attack the problem on the cellular level. - Journal of Clinical Investigation, 1 December 2004

Progesterone Metabolite Reduces Stress

A steroid hormone released during progesterone metabolism reduces the brain's response to stress, according to research with rats. Scientists found evidence that the progesterone metabolite allopregnanolone reduces the brain's response to a peptide hormone called CRF that plays an important role in the stress response in animals. The finding could provide a new drug target for treating anxiety and depression in women. To test this hypothesis, the researchers gave progesterone to neutered female rats, and found they displayed significantly lower CRF-enhanced startle responses than untreated spayed rates. Allopregnanolone had the same effect on spayed rats. These findings correlate with clinical evidence that some women suffering from depression or anxiety have low allopregnanolone levels that return to normal after treatment with anti-depressant medications. - Journal of Neuroscience, 10 November 2004

Does Slimming Slow Alzheimer’s?

A restrictive diet in mice reduces the build-up of plaque we in the brain, which is typical of Alzheimer’s disease. With obese people generally considered to be at a higher risk for developing Alzheimer's, the research raises questions about whether the findings are potentially applicable to humans. Researchers used mice whose DNA had been altered with human genes from two families with early onset hereditary Alzheimer's. The mice were then split into two groups as young adults: one that could eat all they desired and one that had its food intake reduced by 40 percent over a four-week period (diet- restricted). In the diet-restricted mice, both the amount and size of plaque was about 50 percent less than in mice that ate as much as they wanted. The next goal is to find out why diet restriction has such profound and rapid effects. - Neurobiology of Aging, Articles in Press DOI: 10.1016/j.neurobiolaging.2004.09.01, 25 November 2004

A New Approach to MND Treatment

Motor neurone disease (MND or ALS) is a paralyzing disorder caused by the death of motor neurons in the spinal cord and brainstem. A new treatment approach has delayed the progression of the disease in rats. Researchers delivered recombinant VEGF, a growth factor known to promote neuron growth and survival, directly into the brains of rats with MND symptoms. The rats survived five times longer than untreated animals and the onset of paralysis was delayed. This is one of the greatest therapeutic effects reported with growth-factor treatment in MND. Direct delivery to the brain was particularly effective in rats suffering from forelimb-onset MND (the equivalent of human bulbar-onset MND cases), stimulating motor neuron survival in the brainstem. VEGF helped preserve the connections between motor neurons and muscles in these animals. This work may help revive interest in clinical trials using growth factors as a potential treatment for MND, and also establishes a new rat MND model that could be used to evaluate novel treatments. - Nature Neuroscience, online DOI: 10.1038/nn1360, 28 November

Minnow Throws Light on Cholesterol-lowering Drugs

The common sea-water minnow has helped provide an answer to why certain cholesterol-lowering drugs work better in some people than others. Researchers studying the genetic make-up of the fish found that normal differences in how their heart muscles process fats and sugars contain clues to this mystery. They found a set of genetic keys that explain why some people can eat fat and not suffer from heart disease, and why cholesterol-lowering treatments are more effective in some people than others. Surprisingly, the genes that matter most are not the same in each individual—in some, increases in certain genes affect the use of fats, while in others, they affect the use of sugars. This is an important first step in understanding why some of us can eat fatty foods and not suffer from cardiac disease and why some drugs or medical treatments work on some individuals but not on others. Ultimately, this work could point the way towards identifying the number and type of certain genes a person has. With this information, doctors could prescribe the most effective medication to treat high cholesterol or blood sugar, and have a clearer understanding of an individual’s propensity for heart disease. - Nature Genetics, online DOI: 10.1038/ng1483, 28 November 2004

Down Syndrome Protein Reduces Tumor Growth

Scientists have found that overexpression of a protein called Down Syndrome Critical Region 1 (DSCR-1) in mice blocks the formation of new blood vessels and thus reduces tumor growth. New cancer treatments may result. Many disorders of the circulation, including atherosclerosis, tumor growth and inflammation are caused by the activation and dysfunction of the endothelium. This layer of cells lines the inside of blood vessels and regulates many processes including new blood vessel formation, blood vessel diameter, blood clotting, the migration of circulating white blood cells, and the normal release of molecules involved in inflammation. Certain growth factors and enzymes cause endothelial cells to increase their expression of genes involved in proliferation, inflammation, and thrombosis. These substances also turn on a gene that produces Down Syndrome Critical Region 1 (DSCR-1), and that DSCR-1 then negatively feeds back on the substance and shuts off its production. Researchers discovered that when DSCR-1 is overexpressed in mice, it blocks the formation of new blood vessels and thereby reduces tumor growth. This connection between overexpression of DSCR-1 and a reduced risk for solid tumors and inflammatory states such as atherosclerosis may eventually be used for therapeutic gain patients with other conditions. - Journal of Biological Chemistry, 26 November 2004

Gastric Cancer Stems from Bone Marrow

The textbook explanation of the cause of common cancers may have to change following a discovery that links bone marrow cells to stomach cancer and probably lung, liver, cervical and other cancers. Researchers studying mice have found that stomach cancer arises from stem cells from bone marrow, probably those that give rise to bone and connective tissues, a striking and unexpected discovery. In mice with cancer, the bone marrow cells were recruited to the site of gastric inflammation caused by chronic infection. The implications of this study may lead to new methods of diagnosis and treatment of many cancers—particularly those that have been linked to chronic inflammation such as stomach, oesophagus, lung, pancreas and liver. - Science, 26 November 2004

Hope for Millions with Food Allergies

A team of scientists has developed vaccines that vastly reduce or eliminate dogs' allergic reactions to three major food allergens: peanuts, milk and wheat. The benefits lasted at least three months and this is the first reversal of life-threatening food allergies in an animal other than the mouse. Of the nine dogs in the study, four had peanut allergies and five had both milk and wheat allergies. Ten weeks after the dogs were vaccinated for the relevant allergenic foods, significantly greater amounts of the foods had to be used to generate a telltale allergic bump on the skin (called a wheal) in standard allergy skin tests. The peanut-allergic dogs went from developing symptoms to a single peanut to tolerating 57 or more. The milk-allergic dogs ceased to vomit when they were given milk, and showed a 60% reduction in diarrhoea. Food allergies affect a significant number of people and cause about 20 deaths a year, mostly in children and young adults, in the UK. At present the only treatment is avoidance. - Allergy, online DOI: 10.1111/j.1398-9995.2004.00711.x
16 November 2004

Improving Anthrax Vaccine

Scientists using mice have produced a vaccine against anthrax that, when combined with the existing vaccine, confers better protection. Anthrax is a particularly nasty bacterium because it produces a powerful toxin and can lie dormant for years. During anthrax infection, the bacterium multiplies and its outer capsule protects it from being swallowed up and killed by white blood cells. The toxins produced by the bacterium are thought to act mainly by damaging defensive cells called phagocytes, causing the immune system to malfunction. The efficacy of the current anthrax vaccine is based on an antigen to the toxin. Scientists have now produced a vaccine against the capsule. Vaccination of mice with either capsule or toxin provided some protection, but vaccination with both resulted in survival of 9 out of 11 mice. Scientists are now trying to finesse the vaccine in mice, to give full protection. - Vaccine, 15 November 2004

Why Mice Teeth Stay Sharp

The gene responsible for the formation of tooth enamel has been identified. The researchers believe they now have the key to understanding how the teeth of rodents stay so sharp while the rest of the tooth is worn down by gnawing. The answer lies in a gene that codes codes for a signaling module—bone morphogenetic protein (BMP)—that is critical to enamel formation. It is subject to a specific protein inhibitor, follistatin. These proteins ensure that the enamel is built up only on the outer side. Therefore, the outer surface is harder, wearing down more slowly, and a sharp edge forms at the point where the two surfaces meet.- Developmental Cell, November 2004

Antibiotic Fights Parkinson’s?

Researchers have shown in mice that rifampicin, an antibiotic used to treat leprosy and tuberculosis, can prevent the formation of protein fibrils associated with the death of brain cells in people with Parkinson's disease. The treatment is effective on cell cultures in test-tubes and is now being tested in mice. The researchers regard this as a potential preventive measure rather than a treatment. Deposits called Lewy bodies, composed mostly of alpha-synuclein fibrils, appear in affected nerve cells. There are two schools of thought: one is that the fibrils themselves are toxic, and the other is that smaller precursors of the fibrils formed earlier in the process are toxic and cause the neurons to die. The group found that rifampicin stabilized alpha-synuclein as a soluble form, thereby preventing the formation of fibrils. It also dissolved existing fibrils, and preliminary data showed these were non-toxic. The researchers had already shown this effect with a related compound, baicalein. Rifampicin is an already-approved drug and may also prevent the formation of the protein deposits that characterize Alzheimer's disease, which are composed of a different protein from alpha-synuclein. - Chemistry & Biology, November 2004

SARS Vaccine Damages Liver

A SARS vaccine triggered severe liver inflammation when tested in ferrets—an unexpected problem that should give pause to others working to develop a vaccine against the disease. The team stumbled upon the problem by accident when one of the scientists insisted on running unplanned blood chemistry tests on the vaccinated ferrets. The recombinant vaccine works by genetically modifying a pox virus to produce a protein, called the spike protein, which is made by the SARS coronavirus. The scientists chose the modified pox virus, called MVA, because it has been widely - and safely - used in development of other vaccines. Ferrets were used because they suffer disease similar to that experienced by humans. They developed antibodies, as expected, after vaccination, but now scientists are no longer certain that they are a good model for human SARS, and all future research on the vaccine will include checks for liver disease. - Journal of Virology, November 2004

Stem Cells Could Restore Vision

Stem cells taken from the retina at the back of the eye could eventually be used to restore normal vision in people with sight problems. Human retinal stem cells regenerated when they were transplanted into the eyes of developing mice and chicks. The cells' progeny migrated to the retina and turned into photoreceptor cells, the retina's light-sensing apparatus. The researchers discovered that cells taken from a wide age range of human subjects— from newborns to subjects in their 70s—can produce stem cells. Such cells could be used to tackle failing eyesight due to retinal degeneration in older people. - Proceedings of the National Academy of Sciences, 2 November 2004

Nicotine Improves Survival in Sepsis

Nicotine improves survival in mice with septic shock. In septic shock there is an exaggerated inflammatory response that ultimately leads to multiple organ failure and death. Researchers found that a nerve signal called acetylcholine inhibits inflammation. This action of acetylcholine depends on a receptor that can also bind nicotine, and nicotine proved to be more efficient in stopping inflammation. Mice with septic shock given nicotine survived. The action of acetylcholine in stopping inflammation, and the more efficient action of nicotine, suggests that nicotine-like substances might be useful for the treatment of sepsis. - Nature Medicine, November 2004

Preventing Recurrent Miscarriages

Researchers have identified in pregnant mice a potentially valuable therapeutic pathway for preventing miscarriages in certain lupus patients. Their research on the recurrent pregnancy loss that afflicts systemic lupus erythematosus patients focused on antiphospholipid syndrome (APS), defined by thrombosis and recurrent pregnancy loss in the presence of antiphospholipid antibodies. Antiphospholipid antibodies occur in about a quarter of patients with lupus, and also in up to one fifth of patients with recurrent miscarriages who do not have lupus. The research suggests that the anticoagulant heparin, a common treatment to prevent miscarriages in these patients, does not work as previously understood. In a study involving pregnant mice treated with antiphospholipid antibodies from lupus patients, the investigators found that heparin works not as an anticoagulant but instead by blocking activation of the complement pathway, a series of inflammatory proteins previously found to play an essential role in pregnancy loss and placental injury. The results underscore the potential value of developing and testing targeted complement inhibitory therapy for patients with APS. Understanding how antiphospholipid antibodies cause pregnancy loss in APS patients could also lead to important insights into the general mechanisms of miscarriages benefiting non-lupus patients. - Nature Medicine, November 2004

Heart Drug with a Designer Antidote

In a discovery that could give physicians more control over the actions of medications, researchers studying pigs and mice have developed a novel drug pair - a potent anti-coagulant with a matched "antidote." On of the commonest problems that heart specialists face is giving a blood-thinning agent to patients without the accompanying risk of bleeding. When this happens, doctors have little choice but to wait for the blood-thinning drug to be cleared from the body. When such patients need emergency surgery they often face a life-threatening wait. Faced with this challenge, researchers developed a drug-antidote combination from scratch, targeting a clotting factor called IXa. Then they showed that it was an effective anti-coagulant in pigs, and injected the antidote. Most of the anticoagulant effect of the first drug was neutralized within 10 minutes. They then repeated it in mice that were bleeding from their tails, with equal success. The rationale for developing the drug could be used, the researchers say, for designing other drug-antidote pairs. - Nature Biotechnology, November 2004

Down Syndrome Rethink

The small group of genes long believed to cause Down syndrome are unlikely to be the real culprits, according to recent research in mice. The finding is bad news for those devising therapeutic strategies, whose job would be simplified if blame could be laid at the door of just a few genes. Down syndrome occurs when threeŻinstead of twoŻcopies of chromosome 21 are present in a fertilized egg. A region of this chromosome called the Down syndrome critical region was believed to contain genes responsible for many features of Down syndrome, including changes in the head and face. Scientists genetically engineered mice to have three sections of the Down syndrome critical region. They found that resulting facial changes were the opposite of what would be expected in Down syndrome. Their faces were longer and narrower than normal, but Down syndrome is characterized by shorter than normal facial bones. - Science, 22 October 2004

A Possible End to Allergy Misery?

The suffering of millions of people with allergies could one day be eased thanks to new research using mice. The problem is that the allergen triggers the release of histamine from blood cells called mast cells. Now, researchers have discovered that inactivating a key signaling molecule called p110delta reduced the effect of allergies in mice. Mice lacking the gene for p110delta also had a reduced response. It is hoped that this finding can be developed for use by people with allergies. - Nature, 21 October 2004

A Working Partnership of Anti-lung Cancer Drugs

Two different agents that have little individual effect on lung cancer when tested in low doses in the lab and in animals have a bigger impact when combined together, say researchers. The study, which used mice, tested an experimental targeted therapy, an inhibitor known as SCH66336 or lonafarnib, and a protein called IGFBP-3. The researchers found that even at a combined low dose, tumor size was reduced by half in mice implanted with human lung tumors. The scientists are already developing a treatment regime for patients and say that the two drugs are also being tested on animals with other types of cancer. - Circulation, 19 October 2004

Gene Therapy for Thalassemia Closer

The condition of mice with a genetic blood disease called beta-thalassemia improved significantly following treatment of their blood forming cells with a gene that enabled them to produce the type of hemoglobin normally found only in the fetus. Beta-thalassemia is a genetic blood disease in which the red blood cells have an abnormal form of hemoglobin. The team successfully treated the mice by using a newly developed vector—a biological ferry composed of DNA housed within a harmless virus—to shuttle a therapeutic gene into the stem cells that make red blood cells. The gene enabled the red cells to make gamma-globin, a protein that acted as a substitute for beta-globin, which is missing in thalassemia. If they used adult gamma-globin they risked provoking an immune response, but the fetal form does not do this. - Blood, 15 October 2004

Plant Extract May Treat and Prevent Skin Cancer
Researchers have demonstrated in mice that a compound derived from a common American wildflower can be used to treat and prevent the most widespread form of human skin cancer, called basal cell carcinoma or BCC. Oral administration of cyclopamine, derived from the corn lily, a poisonous plant, dramatically reduced tumor development in mice genetically engineered to be prone to BCC when exposed to ultraviolet light. Treatment with cyclopamine produced 90% fewer microscopic BCC tumors, and 50% fewer visible tumors. The dose used was not toxic to mice, so the therapy has great clinical promise. Because cyclopamine kills tumor cells by breaking only a single link in the chain of biochemical reactions leading to cancer, it should have far fewer side effects than more traditional chemotherapies. The same chemical pathway has also been implicated in prostate cancer, brain tumors, lung cancer and some types of breast cancer, so cyclopamine’s safety and effectiveness against BCC tumors raise hopes that it could find wider clinical applications - Cancer Research, 15 October 2004

Prozac Fights Cancer

Researchers have shown that the antidepressant drug Prozac (fluoxatine) can safely boost the effectiveness of cancer chemotherapy in mice. A common problem in cancer therapy is that tumors become drug resistant. This is called multi-drug resistance. There are compounds, called chemosensitizers, that increase tumor sensitivity but they are mostly too toxic for patients to tolerate. However, Prozac in the drinking water reversed multi-drug resistance in mice with human breast cancer grafts and secondary lung tumors. The discovery still requires clinical testing to verify the results, map out a treatment regimen and determine the ideal dose. - Cancer Research,
15 October 2004

Why Muscles Waste Away in Illness and Old Age

Researchers studying mice have discovered an important biochemical pathway for the muscle wasting that happens in cancer, diabetes, having a limb in plaster, and old age. The condition has long been a medical mystery, but now researchers have discovered the biochemical pathway involved and a simple treatment may result. They focused on a transcription factor called NF-kB, which is well known for its importance in immune cells but was previously not known to be a critical mediator of muscle wasting. They created two different strains of transgenic mice—MIKK mice, in which NF-kB was activated in muscle tissue, and MISR mice, in which NF-kB activation was inhibited in muscle. The MIKK mice appeared normal at birth, but as they matured, their muscles shrank. On the other hand, the MISR mice were normal, and their muscles were normal under the microscope. The researchers treated MIKK mice with aspirin-type drugs (salicylates), high doses of which are known to inhibit NF-kB activity. After six months’ treatment they had become nearly normal. When salicylate treatment was given to the mother mice during pregnancy, body weights and muscle mass of progeny were essentially normal throughout life. - Cell, 15 October 2004

Cholesterol Control That Fights Alzheimer’s

In a new study, researchers show that blocking a pathway that controls cholesterol distribution in cells dramatically reduced the number of amyloid plaques in the brains of mice. Some of the treated mice were much better at learning their way through a maze than were untreated mice.
Researchers were investigating a potential relationship between cholesterol metabolism and Alzheimer’s, since it was found that a particular variant of the gene for a protein called apoE, which transports cholesterol, significantly increased risk of the disease. In addition, some epidemiological studies have suggested that people taking statin drugs to control blood cholesterol have a reduced incidence of Alzheimer’s. They used a substance that inhibits the gene that produces ACAT, which controls whether cholesterol is stored in the cellular membrane or in intracellular droplets, and also appears to regulate the formation of amyloid-beta, the protein fragments that make up amyloid plaques. While the particular ACAT inhibitor used in this study is not yet appropriate for human trials, other ACAT inhibitors are in phase 3 clinical trials for cardiovascular disease. It is possible that they might prevent, reduce or delay Alzheimer’s as well as improve cholesterol metabolism. - Neuron, 14 October 2004

A Clue to Deafness

A protein synthesized deep in the ear is a key factor for normal hearing and could be used to help develop treatments for deafness, say researchers working with mice and zebrafish. Researchers have long sought this missing link in the ear's conversion of sound waves into electrical signals that the brain can recognize as distinct sounds. The gene for the newly identified channel is called TRPA1, and is an important addition to the list of three dozen genes linked to hearing loss. It may aid the search for treatments for some of 300 known forms of inherited deafness. The next step is to screen families with inherited deafness for defects in the TRPA1 gene. Although researchers suspected that the inner ear's hair cells contained such a link, its identification could mark the beginning of a new search for inherited deafness treatments. It could also prove revolutionary for mechanical engineering applications that require a similar conversion process. - Nature, online DOI: 10.1038/nature03066, 13 October 2004

New Therapeutic Weapon of Stem Cells

Scientists have used embryonic stem cells to repair a genetic defect in the hearts of unborn mice in an experiment that paves the way for correcting inherited diseases. This research offers the most definitive evidence yet that the versatile cells can help repair organs: by filling in damaged areas—the primary focus of stem cell research to date—and the unique finding that stem cells secrete potent chemicals to make tissues rejuvenate themselves. In the new study, pregnant mice were treated with stem cells and the chemicals these cells produced enabled their offspring to survive an inherited heart deformity that is usually fatal. The stem cells could not cross the placental barrier, but the drug-like chemicals did. Tests indicated that the chemicals prompted the animals' defective heart muscles to rebuild themselves—literally refashioning their mutated hearts into healthy pumps. Two of the chemicals, IGF1 and WNT5a, have been identified but the researchers believe there are others. The technique is unlikely to be tried in humans any time soon because of technical and ethical concerns. However, the embryonic stem cell compounds could help diseases of adulthood, too. Though adults have stem cells, the researchers doubted that they could make the same range of chemicals. - Science, 8 October 2004

Mice Unlock Mystery of Super-virulent Flu

Disease experts studying mice are a step closer to understanding the deadly secrets of the Spanish flu virus, which killed around 20 million people around the world from 1918 to 1919. It left many others permanently brain damaged, and some of these patients were the subjects of Oliver Sachs’s famous book, Awakenings. The sequence of genes that make up the virus were reconstructed in 1999 and 2000 using samples from preserved victims. Now, researchers have used a process called reverse transcriptase to reconstruct the genes, which they then used to infect mice. Mice don't normally get flu, but the virus caused lung disease with severe bleeding. One of the two genes bound the virus to host cells and injected the viral contents. This understanding might help health experts to contain future outbreaks of deadly flu, such as the new Asian bird flu, which has recently spread to humans and is a potentially worse flu than the Spanish flu. - Nature, 6 October 2004

Targeted Drug for Skeletal Disorders and Cancers

Scientists have prolonged the lives of mice with a rare blood disorder by using an experimental drug that blocks signals promoting runaway growth of blood cells. The researchers also tested the drug, PKC412, in a patient with the hard-to-treat disease, called myeloproliferative disease (MPD), and saw her symptoms improve. The drug reduced her dangerously high white blood cell count and shrank her enlarged spleen and lymph nodes. However, the disease wasn't cured and she underwent a bone-marrow transplant to treat the acute leukemia caused by her MPD. PKC412 acts similarly to the pioneering drug Gleevec, one of the first drugs to treat cancers by shutting down signals from an abnormal form of an enzyme called tyrosine kinase. Gleevec blocks these uncontrolled growth signals in chronic myelogenous leukemia and gastrointestinal stromal tumor. PKC412, like Gleevec, is a highly specific targeted drug that disables a switch in cancer cells that has become jammed in the on position because of a genetic mutation. The glitch allows a continuous stream of signals to prod blood cells into an uncontrolled frenzy of division and growth. - Proceedings of the National Academy of Sciences, 5 October 2004

Rats, Genes and Internet Advance Spinal Cord Repair

A study of the changes in gene expression at and around the site of a moderate spinal injury in rats, has identified identified several promising avenues for new clinical treatments. The project looked at four time points, spanning from three hours after injury to a more chronic state 35 days later. An international network of neuroscientists is studying how to optimize the intrinsic capacity of the adult nervous system to repair and remodel itself as well as how to elicit robust regenerative responses after injury. The network is working with a company that organizes and hosts online and onsite programming competitions to create a high-quality, web-based application to disseminate the microarray data from this study to the scientific community. This interactive platform, which will allow users to see how thousands of genes behave after injury, will be available online so that data are easily accessible to all scientists. - Experimental Neurology, October 2004

Protein Link in Multiple Sclerosis

Research using human patients, isolated cells and mice has revealed that the trigger for the destructive process involved in multiple sclerosis (MS) may come from astrocytes, a normally supportive cell type. Although the exact cause of MS is unknown, the symptoms appear to arise from an abnormal autoimmune and inflammatory response that selectively destroys oligodendrocytes, the cells that form the myelin sheath around nerve axons in the central nervous system. In individuals with MS, astrocytes express abnormally high levels of a protein called syncytin. The researchers only saw over expression of the protein in astrocytes and microglia associated with damaged oligodendrocytes. Producing syncytin in astrocytes in culture resulted in the production of compounds that were toxic to human oligodendrocytes. Mice producing syncytin showed loss of oligodendrocytes and motor impairments similar to MS. Treatment with an antioxidant compound reversed these effects. - Nature Neuroscience, online DOI: 10.1038/nn1319, 26 September 2004

Embryonic Stem Cells Set the Pace

Cells derived from human embryonic stem (ES) cells can impart a new rhythm to pig hearts. The pacemaker activity of the transplanted human cells shows that they integrate functionally in the recipient pig hearts and underscores the potential of human ES cells for cardiac repair. Before human ES cells can be applied in regenerative medicine, scientists must determine whether these cells (or their progeny) can heal injured tissues in animals. Researchers generated heart cells from human ES cells in a culture dish and transplanted them into the hearts of pigs. The pigs had an abnormally slow heart rate that was induced surgically. The transplanted human heart cells partially corrected the abnormality in the pig hearts, like a biological version of an electronic pacemaker. Ultimately, such cell therapies may be used as an adjunct to conventional mechanical pacemakers. - Nature Biotechnology, online DOI: 10.1038/nbt1014, 26 September 2004

Rolling Back Rheumatoid Arthritis

An experimental agent blocks the progression of rheumatoid arthritis in mice with a form of the disease. The treatment appears to be more effective than any other existing therapy. Rheumatoid arthritis is an autoimmune disease, where the body turns on itself and destroys the joints. Drugs such as glucocorticoids, which suppress the immune system, slow disease progression, but have serious side effects. The disorder affects roughly one percent of the population, many of whom live with debilitating pain. The new treatment binds to the CD137 protein on the surface of immune cells and modulates the cells' function. The end result is a decrease in the production of destructive antibodies directed against components of the joint. - Nature Medicine, online DOI: 10.1038/nm1107
26 September 2004

Immune Memory Doesn't Need Reminding

New research in mice shows that the body remembers how to fight a parasitic infection long after the parasite has been cleared from the body. The success of vaccines relies on the assumption that the body's immune memory can last a long time. But exactly how long-term memory is maintained is far from clear. Prevailing dogma says the immune system can only sustain long-term resistance to parasites such as Leishmania major if low levels of parasites are maintained in the body. This is bad news for vaccine development as it suggests that it might be difficult to develop a non-live vaccine against chronic infections. The latest research shows that immunity to Leishmania major is mediated by two different populations of T cells. The group of T cells that clear the parasite from the body do need the presence of the parasite. But a second population-dubbed central memory T cells-can persist long after the parasites have been eliminated. Transferring these central memory cells from infected mice into new mice protected the new mice from subsequent infection with Leishmania. - Nature Medicine, online DOI: 10.1038/nm1108, 26 September 2004

Boosting Utrophin Protects Against Muscle Wasting

Researchers have developed report a novel strategy for stimulating the production of utrophin – an important muscle protein in young mice – for muscular dystrophy therapy. The investigators gave mdx mice (the mouse model for Duchenne's muscular dystrophy) heregulin, a small molecule to turn on the production of utrophin in their muscles. A threefold increase in utrophin levels improved muscle function in the mdx mice. The researchers noted an improvement in the quality of mouse muscle tissue, the biomechanical properties of muscles, and biochemical indices of dystrophy in the muscles. Utrophin is made in large amounts in fetal muscles, after which dystrophin takes over throughout adult life as one of the main muscle-membrane-associated proteins. This approach reawakens the body to make utrophin again. It doesn't preclude possible gene-therapy treatments for muscular dystrophy but is a parallel strategy with great potential of being used in combination with other approaches. - Proceedings of the National Academy of Sciences, 21 September 2004

Blood Cells an Asthma Drug Target

White blood cells could be good targets for future asthma drugs. Two studies found white cells called eosinophils play a role in causing asthma in mice and the same could be true in humans. Their findings contradict earlier research suggesting these cells are the result, rather than a cause, of asthma and re-establish the importance of the eosinophil as a potential therapeutic target in asthma. Both studies used mice lacking eosinophils. In the first, scientists found that eosinophils were essential for asthma to develop. Mice without these cells developed no symptoms when exposed to known allergic triggers of asthma. The second study found eosinophils were important in one of the long-term parts of the asthma disease process that affects the structure of the lungs. Targeting eosinophils may well provide effective therapy for some asthma patients. - Science, 17 September 2004

New Way to Protect Brain from Stroke Damage

Researchers using isolated cells and rodents have uncovered a new culprit behind the brain injury suffered by stroke victims. Their new study links brain cell damage to a rise in brain acidity following the oxygen depletion, or ischaemia, characteristic of stroke. The results may lead to new therapies designed to avert the often debilitating effects of stroke, for which successful treatments are currently lacking. Experiments linked specific proteins that form channels though cell membranes so-called acid-sensing ion channels (ASICs) to the influx of calcium in nerve cells starved of oxygen and subjected to acidic conditions. That calcium overload sets off a cascade of events toxic to cells. Rats injected with agents known to block ASICs including the venom of a tarantula spider had reduced brain damage from ischaemia. Mice lacking a functional copy of the ASIC gene were similarly resistant to stroke damage. The new study pinpoints a new target underlying toxic levels of calcium in the brain. Blockers of ASIC1a, either alone or in concert with other neuroprotective methods, might prove useful for stroke therapy. - Cell, 17 September 2004

Unexpected Discovery on Male Infertility

Scientists have made a surprise finding about the molecular basis of male infertility. Their discovery came during research into cancer using mice. The team were studying a molecule called JAM-C in relation to the formation of new blood vessels around tumors. The team wanted to find out what the normal function of JAM-C was, so they looked at what happened when the gene that codes for the molecule was disrupted in mice. They found that the male mice unable to produce JAM-C were infertile and had round instead of elongated sperm cells. Research on maturing stem cells showed that that JAM-C is essential for sperm cells to mature in mice and key in determining which end becomes the head and which the tail. - Nature, 16 September 2004

Understanding Type 2 Diabetes

A new study sheds light on the key mechanisms by which new pancreatic beta cells normally form in response to insulin resistance. These findings may help researchers devise ways of staving off full-blown diabetes. Insulin resistance is a condition in which the body needs increasing amounts of insulin to function properly, and keep blood glucose levels in the normal range. It is a major contributor to type 2 diabetes and obesity. For years, the body compensates for insulin resistance by forming more insulin-producing beta cells within the pancreas. Researchers studied this compensatory growth in two different genetically modified mice with insulin resistance. The results suggested beta-cell growth in insulin-resistant states occurs by a mechanism in which cells take on a more primitive form and begin replicating. It is possible that the response originates from potential beta-cell stem cells, a more primitive cell that has yet to differentiate into a beta cell. They also showed that insufficiency of a protein called PDX-1, which is critical for the development of pancreatic islets that contain beta cells, limited beta cell growth in insulin-resistance suggesting that PDX-1 may play an important regulatory role. - Journal of Clinical Investigation, 15 September 2004

Drug Combo Attacks Tumor Development

Researchers have long suggested that new, targeted, drugs may work best against cancer when paired with other therapies. In a new study using mice and cell lines scientists have shown that two different types of drug do seem to work better together. The early results are so promising that preliminary testing of the drug combination in humans is now being planned. Anti-angiogenesis drugs, which inhibit blood vessels that feed tumors, have thus far failed to make the anticipated dramatic impact on targeted tumors when used singly in human clinical studies. Previous evidence suggests that a new class of drugs called HDAC inhibitor, which helps normalize how DNA is wrapped around a scaffolding of proteins called histones, also affects blood vessel development. An anti-angiogenesis drug combined with an HDAC inhibitor reduced the number of blood vessel cells in culture dishes by half. In mouse models, the combination controlled 60% of new blood vessel formation compared to 50% using the agents individually. Tumour growth in mice with prostate cancer was reduced 85% using the combination of drugs, in mice with breast cancer by 80%. - Cancer Research, 15 September 2004

Stem Cells Stop Mice Going Blind

An injection of stem cells has saved the sight of mice that would otherwise have gone blind. The study raises the prospect that some forms of human blindness might be treated with cells from a patient's own bone marrow. The research team focused on a group of eye diseases called retinitis pigmentosa, in which cells in the retina break down over time, causing gradual loss of vision and sometimes blindness. There is currently no good treatment for the condition, which affects around one in 3,500 people. They extracted a pool of stem cells from the bone marrow of adult mice and injected them into the eyes of newborn mice with a version of retinitis pigmentosa, before their retinas had begun to break down. The injections appeared to halt some of the eye's deterioration, the team found, particularly that of the cones, which are responsible for color and fine vision. The treated mice were also able to detect light shone into their eyes, whereas a group that did not receive treatment went completely blind. - Journal of Clinical Investigation, 15 September 2004

Smo Suppression Smothers Brain Tumors Safely

The eradication of brain tumors in mice following treatment with a novel drug suggests that certain cancers might one day be cured without the use of toxic chemotherapy and radiation. The type of tumour successfully treated—medulloblastoma—is the most common malignant brain cancer in children. Researchers treated the mice with oral doses of HhAntag, a compound known to block the function of a molecule called smoothened (Smo). The suppression of Smo also suppressed several genes that are critical to triggering and driving tumour growth. The compound inhibited cell proliferation and led to the death of tumour cells, resulting in regression of the medulloblastoma. The Smo protein is part of a biochemical cascade of reactions called the Sonic Hedgehog pathway (Shh). The Shh pathway triggers normal growth of the cerebellum in the fetus, but abnormal activity during infancy and early childhood causes medulloblastoma. The hedgehog pathway does not work in tumour cells cultured in dishes: only animal studies could show that HhAntag can halt and reverse an otherwise fatal cancer. - Cancer Cell, September 2004

Switching off the Leukemia Gene

Researchers have eliminated leukemia in mice by shutting off a molecule necessary for the cancer cells' survival. The experiment confirms that cancer calls cannot remain malignant in the absence of the molecule, known as BCL-2, which fights cell death. Scientists had suspected, but hadn't confirmed, that cancer cells need BCL-2 to survive. Genetically modified mice highly susceptible to developing leukemia were also modified so that BCL-2 could be switched off by adding an antibiotic to the animals' water. Within three days, the treated mice had fewer leukemia cells; within 10 days, their white blood-cell counts were normal. Five of the mice lived for more than 200 days, and one lived more than a year. By contrast, all of the untreated mice died in just over 100 days. Scientists already are looking to develop new therapies that would kill cancer by targeting the BCL-2 gene. - Cancer Cell, September 2004

New Avenue for Preventing Colon Cancer

Researchers have provided the first evidence that blocking a cellular receptor can inhibit the development of pre-cancerous colon polyps in mice. The research suggests a new avenue for stopping or preventing colon cancer. The receptor, called PPARdelta, plays an important role in development, wound healing and fat metabolism. Studies have linked the development of colorectal cancer to the cyclooxygenase-2 (COX-2) enzyme. COX-2 is a major target for drugs that relieve the pain and inflammation of arthritis, and generates several potent, hormone-like substances called prostaglandins that play a role in a wide variety of physiological functions. One of them, prostaglandin E2 (PGE2), has been specifically linked to the development of colon polyps. The current study tested the effect of PGE2 in mice with the mutation that made them susceptible to polyps. Administration of the prostaglandin dramatically increased the number of intestinal polyps. The animals were then crossed with mice without the PPARdelta gene. When PGE2 was given to these mice, there was no increase in polyps. This suggests that PPARdelta is a critical in PGE2-stimulated promotion of colorectal tumour growth. - Cancer Cell, September 2004

Mice Aid Anxiety and Stress Studies

Mice have been produced lacking two enzymes, MAO A and MAO B, which have been linked to both violent criminal behavior and Parkinson’s disease. Mice lacking both enzymes should provide an excellent way to study their specific roles in anxiety and stress-related disorders. MAO A and MAO B are involved in breaking down nerve signaling proteins. Higher or lower than normal amounts of these enzymes result in irregular signals, causing abnormal behavior. Realizing the connection between these signaling proteins and behavior, psychiatrists routinely use MAO A inhibitors as antidepressants and MAO B inhibitors for Parkinson’s disease. The MAO A/B knockout mice should provide scientists with a good model in which to study the combined actions of the enzymes, as well as examine the roles of the signals they control in anxiety- and stress-related disorders - Journal of Biological Chemistry, 17 September 2004

Distinguishing Lethal from Localized Prostate Cancers

Researchers have discovered a possible way to distinguish lethal secondary-forming prostate cancers from those restricted to the walnut-size organ. Their very thorough study involved the use of mice, cell lines and cancers taken from men who had died from the disease. Most prostate cancers grow slowly, making watchful waiting a common alternative to immediate surgical removal of the prostate. However, there's no sure-fire way to tell whose cancer will stay put in the gland, and whose will be aggressive and spread - a development that despite aggressive treatment is usually fatal. The researchers found that a cellular signaling molecule called Hedgehog, which drives normal development and regeneration of prostate tissue, is greatly activated in aggressive prostate cancers. If doctors could use Hedgehog activation – perhaps measured by detecting some marker in the blood –they distinguish between the lethal form and the localized form and treat them accordingly - Nature, online DOI: 10.1038/nature0296215, September 2004

Cancer Drug May Reduce Kidney Disease in Lupus

A drug that is already being tested as an anticancer agent, especially in lymphoma, may also reduce the kidney disease that is a result of systemic lupus. The drug, SAHA (suberoylanilide hydroxamic acid), inhibited the onset of lupus-related kidney disease in mice with lupus. In systemic lupus, the normally protective immune system attacks the body's own organs, damaging kidneys, heart, lungs, brain, blood or skin. Most people with lupus have achy or swollen joints, frequent fevers and prolonged or extreme fatigue. The mice in the study had a defective gene and spontaneously developed lupus, including lymph node swelling and increased spleen size. Besides preventing kidney disease, SAHA decreased the size of the spleen and at the same time decreased the production of certain T-cells (a type of white blood cell) that are a key to the autoimmune disorder, when compared to mice with lupus that didn't get the drug. It also decreased excess protein in the urine. SAHA caused no adverse effects in the animals. Researchers hope to start a clinical trial of SAHA in lupus patients next year. - Journal of Immunology, 15 September 2004

New Therapy for Newborn Lungs

Inhaled nitrite, a salt commonly used to counteract the effects of cyanide poisoning, can be used to treat the narrowing of blood vessels in the lungs of newborn babies. Neonatal pulmonary hypertension is a life-threatening condition characterized by the constriction of lung blood vessels, resulting in poor blood oxygenation throughout the body. The researchers tested the effect of inhaled nitrite in newborn lambs with pulmonary hypertension, and found that it reduced pulmonary hypertension for long periods with no apparent side effects. The action of nitrite seemed to depend on the production of the gas nitric oxide, which has well-known relaxing effects on blood vessels and is absent in cases of pulmonary hypertension. The results of this study indicate that nebulized nitrite could be a simple and cheap therapy for neonatal pulmonary hypertension. - Nature Medicine, online DOI: 10.1038/nm110912, September 2004

Redefining Fetal Heart Development

Congenital cardiovascular defects, such as congenital heart disease (CHD), are present in about one in 100 live births and are the most common malformations in newborns. Researchers using genetically modified mice have been investigating how the heart develops with the hope of learning why some hearts don't develop correctly. The latest finding may redefine current models of how the heart develops in mammals. During normal embryonic development in mammals, pre-cardiac cells form the bilateral cardiac primordia –two symmetrical, tube-shaped regions located on both sides of the early embryo. As cardiac development progresses, these two regions fuse, forming one large tube, which, in turn, further develops into the four-chamber heart. In mice, the researchers successfully inactivated the Foxp4 binding protein, which resulted in the inability of the bilateral tubes to fuse. The mouse embryos developed two, four-chambered hearts exhibiting most aspects of advanced heart development. Eventually these embryos succumbed due to the lack of correct blood flow with two hearts pumping into the same set of blood vessels. This work may be crucial in determining what gene mutations might lead to congenital cardiovascular defects. - Science, 10 September 2004

Misfolded Proteins in Lysosomal Storage Disease

Researchers have discovered how accumulation in brain cells of a fat molecule called GM1-ganglioside (GM1) disrupts the folding of newly assembled proteins into their proper shapes, triggering nerve degeneration and mental retardation in children. The disease GM1 gangliosidosis disrupts the normal function of brain cells and causes them to self-destruct. The latest discovery in mice offers strong evidence for the cause of GM1 gangliosidosis in children. GM1 gangliosidosis is a lysosomal storage disorders, an inherited disease in which one or more enzymes in the lysosomes are defective. Lysosomes are the cell's recycling centres, where proteins, fats and other molecules are broken down into their basic building blocks, which are then reused to make new molecules. The discovery identifies for the first time the endoplasmic reticulum, the cell's protein processing factory, as the location of biochemical reactions leading to brain cell death in children with this disease. Now that researchers have a better understanding of what causes the damage, they may be able to design treatments that specifically remedy this problem. The finding may also hold true for other lysosomal storage diseases. - Molecular Cell, 10 September 2004

New Protein Plays Key Role in Cancer Progression

Many cancers, including colon, prostate, and leukemia, continue to grow unchecked because they do not respond to a signal to stop proliferating from a protein called transforming growth factor-beta (TGF-b). The cause of this signaling disruption of the normal cell cycle has not been fully understood until now. Scientists using genetically modified mice have discovered the biological function of promyelocytic leukemia protein (PML), and identified it as an essential factor in maintaining TGF-b signaling. Their findings explain the link between these two proteins in the development of cancer and suggest that restoring their activity may provide a cancer treatment. - Nature, 9 September 2004

Common Cold Virus Can Cause Polio

Virologists have discovered that, under the right conditions, a common cold virus closely related to poliovirus can cause polio in mice. They injected a cold virus called Coxsackievirus A21 into mice that were engineered to be susceptible to this particular virus. However, instead of developing a cold, the mice unexpectedly displayed paralytic symptoms characteristic of polio. Administering the virus directly into muscles, instead of the virus's normal home in the nasal cavity, was critical for development of polio. Until now, it has been widely accepted that Coxsackievirus and poliovirus cause distinct illnesses because they bind to different docking sites, called receptors, on host cell surfaces. The current study turned that belief on its head. The mice were genetically engineered to have only the Coxsackie A21 receptor, called ICAM-1, and they did not have the poliovirus receptor. Still, when the mice were injected with Coxsackievirus into their muscles, it initiated infection through the ICAM-1 receptor. Following the injection, the mice began to display symptoms of polio, including an abnormal gait, dropfoot, and slight paralysis of the lower hind limb. - Proceedings of the National Academy of Sciences, Early Edition DOI: 10.1073/pnas.04039981017 September 2004

Blood Vessel Close-up

A new method has been developed to visualize tissue and its associated blood vessels in a living organism, in this case mice, with greater detail than had previously been achieved. The method provides a promising tool for diagnostic and therapeutic studies. Researchers experimented with a prototype volumetric computed tomography (VCT) scanner that is designed for high-resolution three-dimensional imaging. Using this technique, they analyzed the structure of human cancers transplanted into mice, and visualized their architecture with much greater detail than other available techniques such as magnetic resonance imaging. They even succeeded in observing small tumour vessels with a diameter 200 times smaller than a millimeter, and could clearly distinguish between living and dead tissue. The development of this technique substantially improves imaging of blood vessels and other structures, and offers a promising tool for the study of tumors and therapies that are aimed at interfering with their blood supply - Nature Medicine, online DOI: 10.1038/nm1096 7 September 2004

Proteins Slow the Progress of Parkinson's

Two proteins may halt Parkinson’s disease, experiments with rats have shown, and work towards a potential human therapy has already begun. The proteins prevented brain cell loss in the vital dopamine-producing region. The researchers used a genetically engineered deactivated virus to carry the two proteins – Sonic Hedgehog and Gli-1 – to substantia nigra cells in the brains of adult rats. One week after the proteins had been injected, a drug that induces Parkinson’s disease was given to the rats. Four weeks later, the control group that had not received the proteins had lost 80% of neurons in the substantia nigra. Rats that received the injected proteins only suffered 20% to 30% brain cell loss. These results establish for the first time that viral transfer of Sonic Hedgehog and Gli-1 – two proteins that are involved in early brain development, but are no longer present in the adult brain – may provide a new strategy to prevent progressive degeneration of the nerve cells in the brain that causes Parkinson’s disease. Transferring the therapy from rats to humans would mean overcoming several problems, including the body’s immune system, which attacks the virus carrying the proteins. - Molecular Therapy, September 2004

Novel Gene Therapy for Bladder Cancer

Gene therapy that causes the bladder to act like a bioreactor to produce and secrete the anti-cancer agent interferon-alpha has shown dramatic benefits in mice. This gene therapy strategy holds much promise for treating aggressive cancers of the human bladder wall; a clinical trial is being planned. Human bladder tumors growing in experimental mice substantially decreased in size after two treatments with the novel gene-based therapy. There was little or no evidence of cancer cells remaining in the bladder in many of the mice after treatment. Also, every kind of bladder cancer cell line tested in the laboratory responded, even cells known to be resistant to the interferon-alpha protein. Bladder cancer is a leading cancer, and "superficial" bladder cancer - cancer confined to the lining of the bladder wall - is the most common type. Although some patients with this cancer can be cured with the standard biological therapy, the use of BCG, tumors will reappear in about half of patients, and up to one third of them will die from disease. - Molecular Therapy, September 2004

Protein Is Key for Digestive Function of the Pancreas

Scientists have identified a protein in mice that is necessary for secretion of digestive enzymes by the pancreas. The research enhances the understanding of the normal physiology of the pancreas and provides some insight into abnormal processes that may lead to pancreatic disease.  Not only does the pancreas produce the hormone insulin that regulates blood sugar, it also produces digestive enzymes that are secreted into the gut and break down the food we eat. These enzymes can also turn on the pancreas itself, causing the painful and sometimes life-threatening condition pancreatitis. The process by which these harsh digestive enzymes are released into the gut is not entirely understood. Mice that were genetically designed to be missing a protein called VAMP8, that has been implicated in the process, had pronounced pancreatic defects. Compared to normal mice, mice lacking VAMP8 had substantially reduced blood levels of digestive enzymes and demonstrated partial resistance to pancreatitis. Thus VAMP8 may be involved in the abnormal secretion of digestive enzymes associated with pancreatitis. - Developmental Cell, September 2004

Cancer Prediction Gene

Researchers at have identified a Jekyll and Hyde cancer gene that could help predict who is likely to develop cancer years before the onset of the disease. For the past two decades, scientists have focused on two genes: one that promotes cancer growth and one gene that blocks its growth. Now they have discovered a third type of cancer gene that can switch between blocking cancer and promoting it. The research focused on colorectal cancer in mice. The gene – called DCC, for deleted in colorectal cancer - works like a lock with a key. When there is no key, the gene's cancer development is locked down and cells are not able to grow to produce a tumour. But when there is a key present - in this case a growth protein known as netrin-1 - the gene can support tumour growth. In the study, mice were genetically engineered to overproduce netrin-1. They not only had a slightly higher frequency of pre-cancerous growths, but aggressive full-blown cancers as well when combined with another mutation that typically produces only benign tumors. -Nature, 2 September 2004

Anti-inflammatories for Cancer?

Anti-inflammatory drugs may be effective in preventing liver cancer, according to researchers studying mice. Liver cancer kills more than a thousand people a day around the world, and the vast majority of liver cancer cases are associated with long-term inflammation. One fifth of all cancer cases are believed to develop as the result of long-term inflammation. The researchers identified a protein called NF-kkappaB that increases the probability of producing cancer cells. They studied laboratory mice that spontaneously developed liver cancer as a result of chronic liver inflammation. With genetic engineering, they were able to inhibit the activity of the protein, reducing the number of cancer cells produced. The researchers also identified the signal that comes from the inflammatory cells and is responsible for activation of the protein. They then used an antibody directed against this signal and were able to boost the body's natural defense mechanisms that fight pre-malignant cancer cell production. The team are now investigating whether long-term medication against this signal will prevent the occurrence of cancer in mice, and, if so, will go on to test this approach in humans. - Nature, 2 September 2004

Protein May Halt Alzheimer's

In a finding that may cause a dramatic shift in the search for a therapy for Alzheimer's disease, researchers using mice have discovered that increased expression of a protein called transthyretin in the brain appears to halt the progression of the disease. The new research sought to discover why most mice genetically modified to get Alzheimer’s don’t show all the signs of the disease. The surprising answer could completely alter the way researchers think about treating Alzheimer's disease. The level of two specific proteins, transthyretin and IGF-2, is raised dramatically in these mouse strains. Since transthyretin had been shown in test tubes to bind to toxic beta-amyloid protein, the researchers hypothesized that in the mice, the transthyretin was preventing the beta-amlyoid protein from interacting with brain cells, thereby preventing tangle formation and brain cell death. Introducing an antibody into the mouse brain prevented transthyretin from binding with beta-amyloid protein, and the mice developed early signs of neurofibrillary tangles and brain cells died. A reliable method to deliver transthyretin into the brain, or increasing transthyretin expression in the brain might form the basis of new therapies for Alzheimer’s. - Journal of Neuroscience, 1 September 2004

New Approach to Combat Drug-resistant Staph Infections

A team of international researchers studying rats has shown that coating implanted medical devices with a key peptide known as RIP can prevent the occurrence of bacterial colonization, biofilm formation and consequent drug-resistant Staphylococcus aureus infection - a leading cause of illness and death among hospitalized patients. RIP acts by preventing bacterial cell-to-cell communication. This is the first direct demonstration that inhibiting cell-to-cell communication can prevent staphylococcal infections. RIP has been shown to inhibit any strain or species of staphylococci so far tested, including antibiotic-resistant strains, and no resistance to RIP has so far been observed. RIP has also been shown to be synergistic with antibiotics, so it can be used in combination therapy. RIP prevents the bacteria from being virulent by inhibiting a target protein (TRAP). No rats with RIP-soaked grafts showed evidence of graft infection, indicating complete protection. In addition, none of the animals showed evidence of drug-related adverse effects. - Journal of Infectious Diseases, 15 July 2004

Lupus-like Condition Prevented in Mice

Lupus is an autoimmune condition that causes arthritis, prolonged fatigue, skin rashes, kidney damage, anemia and breathing pain. Now, removal of an immune system signaling protein has prevented the development of a lupus-like condition in mice. If additional studies in other animals and humans confirm that SLAM-associated protein (SAP) is a primary contributor to lupus, it may be an ideal target for the development of new drug treatments. Normal immune system functions were still largely intact in the experimental mice that lacked SAP. Other immune system proteins are potential targets for new autoimmune disease treatments, but they all affect large portions of the immune system, making weakened immune function a potential side effect of any new drug. Targeting SAP for treatment may avoid that risk. The researchers plan to study how SAP removal or suppression affects other animals with lupus, and to test if SAP is present at unusually high levels in human patients with lupus.- Journal of Experimental Medicine,
15 July 2004

Making Human SARS Antibodies Quickly

Human antibodies that thwart the SARS virus in mice can be mass-produced quickly using a new technique. It could become an important tool for developing SARS-specific antibodies to protect people recently exposed to the SARS virus or at high risk of exposure. Currently, there is no specific effective treatment for SARS. A similar approach to prevent or treat other illnesses, such as HIV/AIDS and hepatitis C, might be possible using the same technique. Beginning with B cells from a recovered SARS patient, the researchers added a short stretch of synthetic DNA that mimics DNA found in bacteria and viruses. This switched many of the B cells back on, enabling them to churn out SARS antibodies at a fast pace. In only a few weeks, the researchers screened hundreds of antibodies and obtained 35 that could neutralize the SARS virus. Injecting one of the neutralizing antibodies into mice stopped the SARS virus from multiplying in the lungs, which can lead to pneumonia. Researchers will need to test the antibodies for their effectiveness in other laboratory animals, such as monkeys, as well as in human clinical trials. -Nature Medicine, online DOI: 10.1038/nm1080, 11 July 2004

Gene Fault Linked to Depression

A genetic variation may determine whether people are prone to depression. Scientists found mice had two versions of an enzyme which controls levels of the brain chemical serotonin. Humans may have many more versions of the enzyme, explaining why some get depressed and others not. A genetic test may predict who is likely to benefit from medication. Serotonin is a chemical used to transmit messages between nerve cells in the brain. Levels of the chemical have been linked to conditions including depression, anxiety, post-traumatic stress disorder and attention deficit hyperactivity disorder. Scientists discovered last year that the enzyme Tph2 (tryptophan hydroxylase-2) played a role in controlling serotonin levels in the brain. In this latest research, they were surprised to find two different versions of the gene for the enzyme. The enzyme variants had a major effect on the amount of serotonin brain cells produced. Mice with one variant produced 50 to 70% less serotonin in their brains than did mice with the other variant. These findings could lead to new insights into the role of the enzyme, and the gene that controls it, in animal behavior and human psychiatric disorders. - Science, 9 July 2004

Double Life of Cancer Gene

Research into the action of a key cancer gene has unexpectedly uncovered its vital role in nerve growth. The gene regulates a protein called c-Jun, which is found at high levels in many different forms of cancer, including skin cancer, liver cancer and Hodgkin's lymphoma. Learning more about this important protein could help to develop treatments for people with spinal injuries, as well as increase our understanding of cancer. Damage to nerves, such as from accidents, elicits a standard response – the 'axonal response' – that culminates in the re-growth and recovery of the nerve. The scientists examined the axonal response in mice that did not have c-Jun in their central nervous systems. Following injury, nerve cells lacking c-Jun showed severely impaired nerve regrowth compared to normal mice, suggesting that c-Jun is a major regulator of the axonal response. These results could have far-reaching consequences for understanding nerve regeneration. -Neuron, 8 July 2004

Tracing a Killer's Path in MND

New research in mice has shed light on how a rogue enzyme kills nerve cells motor neurone disease (MND), ultimately resulting in paralysis and death. The culprit is a mutant form of the enzyme superoxide dismutase (SOD1), which normally protects cells from harmful reactive oxygen. However, about 3% of people with MND have a mutant form of the enzyme. Experiments in mice showed that the mutant SOD1 protein selectively migrates to the powerhouse inside spinal cord neurons – the mitochondria - where it links itself to the mitochondrial membrane and kills the cells. - Neuron, 8 July 2004

Study Signals Promise for New HIV Therapy

A new approach to treating HIV infection is to block an enzyme called integrase, which is crucial to the melding of HIV genes with patients' own DNA. This step is vital to HIV's sneakiest trait - its ability to hide inside cells so it can rebound after therapy. But years of attempts at targeting integrase have failed. Now, an integrase inhibitor dramatically protected monkeys when the drug was given early in infection. The drug also provided some benefit to the very sick. Researchers gave their candidate, code-named L-870812, to six monkeys newly infected with a combination monkey-human version of HIV. The animals experienced only a mild decrease in crucial immune cells called CD4s, and four had their virus drop to undetectable levels. Some integrase inhibitor candidates are being studied in a few patients to see whether they seem safe and to check for early signs of viral suppression. Results, due early next year, will determine whether larger studies should be performed on the prospective drugs. The results with monkeys suggest this new mode of attack might finally be possible. -Science Express DOI: 10.1126/science.1098632, 8 July 2004

Gene Knockout Prevents Epilepsy in Mice

Epileptic mice have been treated by shutting off genes involved in the condition, a step towards treatments aimed at preventing the development of epilepsy in humans. The research offers the hope of drugs that could prevent epilepsy. Current anti-seizure drugs inhibit seizures in people with epilepsy, but they don't prevent the disease from developing. Researchers knocked out two genes in mice for proteins - BDNF and TrkB - involved in the development of epilepsy. BDNF is a protein found in the neurons of the central nervous system, TrkB is a receptor activated by BDNF. Epilepsy was then induced in the mice, but contrary to the researchers' expectations, knocking out the BDNF gene in the mice only slightly reduced their susceptibility to epilepsy. Despite the virtual absence of BDNF, the TrkB receptor was activated. When the researchers knocked out the TrkB gene, epileptic tendencies were extinguished. The TrkB receptor could represent an excellent target for drugs to prevent epilepsy. Researchers will explore whether knocking out TrkB in other animals prevents the development of epilepsy. -Neuron, 8 July 2004

Gene Therapy Alternative to Blood Pressure Drugs

Using guinea pigs, scientists have developed what is believed to be the first successful gene therapy that mimics the action of calcium channel blockers, agents widely used in the treatment of heart disease, including angina, arrhythmias, hypertension and enlarged heart. Their findings may lead to a gene therapy alternative to calcium channel blockers and their sometimes severe side effects, but also further interest in the development of gene therapies unique - as in this case - to one particular organ. Researchers increased production of a key protein involved in heart conductivity, called G-protein Gem, by injecting a virus carrying the gene that codes for the protein into the animals' heart muscles. Increased levels of Gem decreased calcium current densities – the chemical action of calcium channel blockers – by up to 90%, when compared to a control group. Indeed, when heart muscle was electrically stimulated to reproduce the effects of an irregular heartbeat, Gem infusion helped steady the heartbeat, returning it to a normal rhythm, just like calcium channel blockers do. No adverse side effects were observed. -Circulation Research, online DOI: 10.1161/01.RES.0000138449.8532, 8 July 2004

RNA Interferes with Brain Disease

Researchers have shown for the first time that gene therapy delivered to the brains of living mice can prevent the physical symptoms and neurological damage caused by an inherited neurodegenerative disease that is similar to Huntington's disease (HD). If the therapeutic approach can be extended to humans, it may provide a treatment for a group of incurable, progressive neurological diseases called polyglutamine-repeat diseases, which include HD and several spinocerebellar ataxias. Researchers used a stripped-down virus to deliver small fragments of genetic material (RNA) to critical brain cells of mice with a disorder that mimics the human neurodegenerative disease spinocerebellar ataxia 1 (SCA1). The genetic material suppressed the disease-causing SCA1 gene in a process known as RNA interference. Mice with the SCA1 gene that were treated with the gene therapy had normal movement and coordination. The gene therapy also protected brain cells from the destruction normally caused by the disease and prevented the build-up of protein clumps within the cells. - Nature Medicine, online DOI: 10.1038/nm1076, 4 July 2004

Putting the Brakes on Allergy

When suffering through an allergy attack, you can place the blame squarely on your mast cells. These cells have a hair-trigger response to release many irritating chemicals as soon as they sense the presence of allergens such as pollen. Although we know how the release is triggered, little is known about how to turn mast cells off. Scientists have identified a protein in mice - RabGEF1 - that dampens the allergic response of mast cells. The scientists generated mice lacking RabGEF1. Mast cells taken from these mice released more chemicals associated with allergic responses than did normal mast cells. Mice lacking RabGEF1 developed severe skin inflammation, and this correlated with increased numbers of activated mast cells in the skin. These data show that RabGEF1 normally puts the brakes on allergic responses and could potentially prove useful in therapy to dampen allergy symptoms. -Nature Immunology, online DOI: 10.1038/ni1093, 4 July 2004

Fusion-free Marrow to Blood

Membrane, or epithelial, cells derived from bone marrow cells can be a result of differentiation, not fusion. Researchers transplanted marrow-derived cells from male mice into female mice. They followed the fate of the male marrow-derived cells by detecting the Y chromosome. Epithelial cells formed by cell-to-cell fusion expressed green fluorescent protein (GFP), those formed by differentiation produced beta-galactosidase. Under normal circumstances, the green fluorescent protein was not expressed, which meant that no fusion had occurred and that the marrow cells can become non-blood cells without fusing. When the tissues were damaged, there were some cells that expressed GFP and therefore were derived from donor cells fusing with recipient cells. Several years ago the researchers showed that bone marrow stem cells can differentiate into liver, lung, kidney, skin, muscle and other cells. Later studies by other researchers suggested that the bone marrow derived cells had actually fused with epithelial cells. - Science, 2 July 2004

Bird Flu Becoming More Dangerous

The bird flu virus is mutating and becoming more dangerous to mammals, say researchers working with chickens, mice and ducks. The discovery reinforces fears that a human pandemic of the disease could yet occur. Avian flu hit the headlines in 1997 when a strain called H5N1 jumped from chickens to people, killing six people in Hong Kong. The country's entire chicken population was slaughtered and the outbreak was controlled. Since then new strains of virus have killed a further 14 people. As yet, no strain has been able to jump from person to person, but if this happened widespread outbreaks could affect millions of people. The researchers isolated viruses from ducks, which are immune, between 1999 and 2002. Of the animals inoculated with the virus samples, both chickens and mice fell sick and the effect in mice was more severe with the later virus samples. A virus that has acquired the ability to infect mice could also infect humans. -Proceedings of the National Academy of Sciences, Early Edition DOI: 10.1073/pnas.040321210, 2 July 2004

Triple-vaccine Strategy Hits HIV

Researchers report the success in monkeys of an innovative triple-vaccine strategy aimed at creating an effective anti-HIV vaccine regimen. In a test of the new approach, the scientists sought to maximize the immune response to a truncated HIV gene called Gag and succeeded in dramatically stimulating the production of CD8+ T cells responsive to Gag. Many scientists believe that CD8+ T cells will be an important key to creating an effective HIV vaccine. The researchers created three vaccines, each with a different adenovirus as a backbone but all containing the same truncated HIV gene, Gag. Two of the vaccines were based on chimpanzee adenoviruses, and the third was based on a human adenovirus. The vaccines were administered to eight macaque monkeys and sparked high frequencies of CD8+ T cells against Gag that remained remarkably stable over time. For eventual clinical use, vaccines incorporating more elements of HIV would be needed to elicit sufficiently broad T-cell responses to be fully effective. -Journal of Virology, July 2004

Newly Grown Kidneys Sustain Rats

Because of the shortage of organ donors, most kidney patients die before an organ becomes available. Now scientists have shown that kidneys grown from embryonic tissue transplants can be used to sustain life in rats. The eventual goal is to use embryonic pig tissue transplants to help patients with renal failure live longer. Prior to insertion, scientists soaked the transplant tissue in a solution that included several human growth factors, proteins and hormones. One of the rats' original kidneys was removed. Three weeks after the transplant, researchers connected the new kidneys to the bladder and administered a second dose of growth factors. Rats with no new kidneys lived for two to three days, and rats with new kidneys disconnected from their bladders lived no longer. However, rats with new kidneys connected to their bladders lived seven to eight days. In addition to excretion and filtration, the new kidney also has to reabsorb salts, water and key nutrients, and the researchers showed that the new kidneys can reabsorb both water and the nutrient phosphorus. - Organogenesis, July 2004

PPAR for the Course

Diabetes is often stimulated in obesity by higher concentrations of free fatty acids in the blood. The understanding of how this process works is currently very limited. Free fatty acids are generated when glycerol is broken down in the liver or in fat tissue, and factor thought to be involved in increasing free fatty acids is the PPAR gene family. Researchers are now beginning to understand this process with a series of studies on PPAR in mice.
The researchers blocked PPAR gene family action. In doing so, they were able to separate specific roles for different members of the PPAR gene family in different tissues. Specifically, they showed a direct role for PPAR alpha in the metabolism of glycerol metabolism in the liver, while another member of the PPAR gene family, PPAR gamma, controls glycerol metabolism in fat tissue. These data will aid in understanding the complex interactions of genes, small molecules, and proteins that are involved in mechanisms underlying diseases such as diabetes. - Journal of Clinical Investigation, 1 July 2004

Key to Neuropathic Pain?

The lipid lysophosphatidic acid (LPA) is crucial in triggering the debilitating, burning pain that is commonly associated with nerve injury, reports a study in mice. Although much is known about the cellular mechanisms that mediate neuropathic pain, what elicits the pain in the first place remains a mystery. Because LPA is released after tissue injury, researchers tested its involvement as a potential trigger. They found that in mice, when the LPA receptor is either missing or where signaling downstream of the receptor is blocked, the mice do not experience neuropathic pain after nerve injury. Conversely, direct injection of LPA to normal mice triggers behavioral reactions similar to those seen with neuropathic pain. The identification of LPA and its receptor as initiators of neuropathic pain open new possibilities for the development of analgesics to manage this debilitating condition. - Nature Medicine, July 2004

Disease Might Respond to Neurosteroids

Scientists studying mice have identified a possible strategy for slowing a rare, fatal childhood neurodegenerative disease known as Niemann-Pick type C, in which brain cells accumulate fat and die. The disease, which also causes enlargement of the liver, occurs in about 1 in 150,000 children. The finding could also have implications for treating other neurodegenerative disease. The team discovered that the synthesis of neurosteroid hormones in the brain - a process known as neurosteroidogenesis - is severely disrupted in mice that naturally develop the disease. They then found that replenishing the depleted neurosteroid hormone allopregnanolone significantly delayed the onset of the disease, and doubled lifespan. The treatment was particularly potent when administered early in the animals' life. While the treatment did not target the cause of the disease - a mutation in one of two genes that disrupts the transport of cholesterol within all cells of the body - nor cure it, the therapy substantially delayed the onset of weight loss, motor coordination, mobility and death. It also significantly delayed the accumulation of fats in cortical cells, and the death of some neurons in the brain. - Nature Medicine, July 2004

Cancer Patient, Heal Thyself

Anti-cancer immune cells are found in cancer patients, but these cells fail to reject tumors; a failure that may be due to a series of different immune cell priming or suppressing mechanisms. Now researchers have found a way to make these cells, taken from cancer patients, more effective in mice with tumors. The researchers isolated immune cells from patients’ bone marrow and stimulated them to become effective killer cells in the test tube. Mice that had been previously implanted with tumors were injected with these activated cells. In contrast to cells that were not anti-tumour-specific, the cell-culture activated T cells were now very effective at infiltrating tumour transplants and in reducing tumour size. By reactivating anti-tumour-specific T cells that already exist in the patient’s own body, it may be possible to create immunotherapy tailored for each patient. - Journal of Clinical Investigation, 1 July 2004

PAF-way to Bone Loss

Many women after menopause suffer from the bone disease osteoporosis, where there is an increase in bone re-absorption back into the body creating a high risk of bone fracture. One gene that has been implicated in bone resorption diseases is platelet-activating factor or PAF. Now researchers have provided a potential new arena for treating such bone diseases inhibiting PAF function in mice. Mice with and without the PAF gene had their ovaries removed. The researchers found that mice without the PAF receptor had greatly improved bone mineral density as well as bone volume compared to ovariectomized mice that still had PAF gene function. Further studies in these mice showed that osteoclasts (the bone cells that responsible for the breakdown of bone material) are responsible for PAF's mechanism of action. In addition, when mice were treated with a molecule that inhibited PAF receptor function, bone resorption was also reduced. These results indicate that inhibiting PAF may form the basis of treatment for osteoporosis and other bone resorption diseases. - Journal of Clinical Investigation, 1 July 2004

GM Bacteria Boost Cancer Therapy

Bacteria have been genetically engineered to bolster the immune response against tumors in mice. Current treatments for bladder cancer include BCG, the bacteria best known as a vaccine against tuberculosis. A neutralized strain of the bacteria is injected close to the tumors, and is thought to stimulate the local immune system, which then kills both cancer cells and the bacteria. However, BCG does not work in about a third of patients with bladder cancer - despite being the most effective immunotherapy yet developed against any form of cancer. It can also cause significant unwanted side effects.  Researchers inserted a gene to produce a protein called tumour necrosis factor alpha (TNFa) into a related strain of bacteria, Mycobacterium smegmatis. In mice, the modified bacteria worked much better against tumors in the bladder than the existing treatment, leading to a reduction in the size and number of tumors. Eight out of 10 of the animals had no tumors by the end of the treatment. This enhanced bacterial strain could become a safer and more effective therapy for bladder cancer. -International Journal of Cancer, Early View DOI: 10.1002/ijc.20442, 30 June 2004

Customizing Alzheimer's Vaccine

Scientists have taken an important step toward creating a vaccine against Alzheimer's disease, customizing the response of the immune system with unprecedented precision. Using a harmless form of the herpes virus, they carefully crafted the immune response of mice, preventing the type of toxic side effects seen in a previous study in people of a vaccine against Alzheimer's. This study demonstrated a level of control over an Alzheimer's vaccine that was previously unattainable. In the human trial, other researchers showed that a potential vaccine designed to protect against Alzheimer's was apparently effective in some people – but the vaccine caused severe inflammation in the brains of several participants. In the recent study, while a vaccine most like the previous form proved lethal to four out of six mice, a modified form of the vaccine proved much safer while still causing a 20% decline in the amount of damaging amyloid plaque in the brain. The additional antigen tweaked the immune response in a way that muted the original vaccine's harmful side effects. - Neurobiology of Aging, online DOI: 10.1016/j.neurobiolaging.2004, 25 June 2004

Making Blind Zebrafish See

Scientists have restored the sight of blind zebrafish whose eyes failed to develop due to a genetic mutation. The findings are exciting first steps on a long road to understanding eye diseases in humans. The researchers first identified a family of eyeless fish. They then discovered the gene that controls initial development of eye tissue (retinal homeobox 3 or rx3) and that mutations in this gene resulted in the eyeless fish. When they introduced a normal copy of the rx3 gene into fish embryos that had inherited the mutated version of the gene, they discovered that this treatment restored normal eye development. Recent studies have shown that mutations in the human form of this gene cause anophthalmia, a disease in which eyes also fail to form. -Developmental Biology, 15 June 2004

Mouse for Pediatric Eye Cancer Tests

The development of a mouse strain that closely mimics the human eye cancer retinoblastoma gives researchers a way to test new therapies for this disease in the laboratory for the first time. Retinoblastoma is the third most common cancer in infants after leukemia and neuroblastoma (nerve cancer). Retinoblastoma that has spread outside the eye is among the deadliest childhood cancers, with an average survival rate of less than 10%. Until now, researchers had no reliable animal in which to test new drugs that might improve the outcome of retinoblastoma in children. A key genetic defect in both children and the retinoblastoma mouse is the lack of Rb1, the first tumour suppressor gene identified in humans. Researchers eliminated the gene Rb1, as well as two other cancer-suppressing genes, p107 and p53. Using this mouse strain and two others, researchers have already tested effective new drugs and drug combinations that will be used in future retinoblastoma treatments - Cell Cycle, July 2004

Signal Tells Stem Cells to Become Fat Cells

Researchers have found a key signal in mice, called BMP4, that tells stem cells to commit to becoming fat cells. Such mouse master-controller proteins are likely to have human counterparts, since both species have very similar proteins and developmental pathways. Researchers have long known about signals that direct muscle and bone stem cells, but little about the initial switch from stem cell to pre-fat cells. BMP4 is the first proven fat-cell producing signal for these stem cells. BMP4-treated stem cells implanted under the skin of mice developed into fat tissue that was indistinguishable from the animals' natural fat tissue. BMP4 is a protein that controls genes involved in cell function and growth. Identifying which genes are affected by BMP4 is likely to hold more clues to how stem cells commit to a more specific cell fate. Once scientists know the detailed mechanism of BMP4-signaling in fat cells, they can create drugs that interfere with the generation of stem cells, and may be able to create drugs that interfere with the generation of fat cells in both cell culture and in live animals. - Proceedings of the National Academy of Sciences, 29 June 2004

Promise for SARS Vaccine

Evidence for the effectiveness of experimental SARS immunization has come from studies in monkeys and ferrets. Although further research is required, these preliminary results show the potential for the development of a human SARS vaccine. Researchers immunized African green monkeys, with a single dose of an intranasal vaccine derived from an experimental pediatric parainfluenza vaccine engineered to express a major protective antigen of the SARS coronavirus, and infected them with SARS coronavirus one month later. The monkeys produced a