Using mice, researchers have determined the molecular machinery that triggers normal heart muscle growth and survival, and have linked defects in this machinery to an inherited form of human cardiomyopathy, a type of heart failure where the enlarged heart loses its ability to pump blood. In the studies with mice, researchers found that the expansion of heart muscle activates molecular pathways that preserve function and prevent injury to heart-muscle cells during periods of increased workloads. In humans, these increased workloads include high blood pressure, recovery from a heart attack, an overload of blood volume as a result of heart birth defects, or heart valve problems. The molecular pathway depends on a gene called muscle-specific LIM protein (MLP). MLP has been identified as playing a role in heart failure in previous studies in mice, but its precise mechanism of action in the heart was not known. This is an important part of the complex puzzle that should enable researchers to find additional triggers of heart failure. - Cell, 27 December 2002

Light on How Well Drugs Work

The process that makes fireflies glow bright in the night can also shed light on how well new medicines work, showing immediately whether the drugs are effective at killing cells or causing other effects. That's the conclusion of a team of scientists who inserted the gene for a firefly's glow-producing molecule, luciferase, into mice with cancer, and kept it from producing its telltale light until the cells started to die in response to cancer treatment. Using a highly sensitive camera, the researchers were able to immediately detect the faintest traces of the firefly light as it passed outside the bodies of the mice. The findings promise to give researchers a new way to get real-time information on whether new medicines are working. It could be used to speed up the testing of new drugs for cancer, stroke, AIDS, auto-immune disorders, blood diseases, heart attack damage, nerve-degenerative diseases like Alzheimer's disease, and other disorders where drugs are needed to kill cells, or to stop cell death. It could also be used to monitor other cell processes. - Proceedings of the National Academy of Sciences, 24 December 2002

Windows on the Mind

Two research groups have revealed a technique to watch nerve cells in the living brain. But they reach opposite conclusions as to how the cells are storing memories. Scientists have long debated whether connections between nerve cells physically grow and break when memories are formed and erased. Now they have imaged the tiny living protrusions called spines that receive signals from neighbouring nerve cells. Using genetically modified mice, whose nerve cells glow with green fluorescent protein, they sculpted small glass or bone viewing screens into mouse brains. One team concluded that, in 6-10-week-old mice, spines last for days or weeks - only 50% persist for a month or more. This turnover helps refine larger circuits underlying memories, they suggest. But another group argues that, in adult mice, 96% of spines remain for the lifetime of the animal. This could explain the persistence of long-term memories. The dispute may be accounted for by differences in the two experiments. But, whatever the case, the technique represents a breakthrough that will have far-reaching implications for neurobiology. - Nature, 19 November 2002

Cancer Gene Controls Blood Vessel Growth

Scientists have found a new target to squeeze off a tumour's blood supply. They showed how a common cancer-causing gene, Id1, controls the switch for tumour blood vessel growth known as angiogenesis. This is a factor in cancer progression because it provides the blood source for tumour cells. The new study concludes that the Id1 gene controls the angiogenesis pathway in certain cancers by turning off the production of a protein called TSP-1, a naturally occurring angiogenesis suppressor. The researchers found activation of the Id1 gene, which is highly expressed in melanoma, breast, head and neck, brain, cervical, prostate, pancreatic and testicular cancers, results in decreased expression of TSP-1 and increased tumour blood vessel formation. The researchers also found TSP-1 levels that were three- to five-fold greater in mice with Id1 gene function turned off than in mice with normal Id1. Control mice with normal Id1 showed well-developed blood vessels, but mice with a non-functioning Id1 gene showed little blood vessel growth when TSP-1 was activated. When the anti-TSP chemical was given to these mice, blood vessel growth resumed. - Cancer Cell, 17 December 2002

Gene Therapy Cures Cancer in Mice

Using a novel gene therapy approach that boosts the body's immune system, researchers have cured cancer in laboratory mice. In experiments researchers applied the gene therapy technique to render immune cells insensitive to transforming growth factor beta (TGF-beta), a powerful, naturally occurring substance in the body that enables cancer cells to evade surveillance by the immune system. The approach boosted the mice's immune systems, which virtually eliminated cancerous tumours in the animals' lungs and prostate glands. After inserting a mutated gene for the TGF-beta receptor into bone marrow cells, transplanting the cells into mice and then injecting the mice with melanoma cells, the researchers found that 70% of the animals survived and showed a virtual absence of secondary tumours in the lung. In another group of mice with the mutated TGF-beta gene that were later injected with prostate cancer cells, the gene-targeted approach resulted in 80% survival. All of the control mice that had not received the gene therapy died of secondary cancer. Tests showed that in the mice treated with the mutated TGF-beta receptor gene, infection-fighting immune cells had mounted a powerful response to kill cancerous tumours. These results strongly indicate that a gene therapy approach to inducing TGF-beta insensitivity in transplanted bone marrow cells may be a potent anticancer therapy. - Cancer Research, 15 December 2002

On the TRAIL of Gliomas

Researchers have combined a special protein that targets cancer cells with neural stem cells to track and attack brain tumours. Glioblastoma multiforme, or gliomas, are a particularly deadly type of brain tumour. They are highly invasive with poorly defined borders that intermingle with healthy brain tissue, making them nearly impossible to remove surgically without catastrophic consequences. Furthermore, cells separate from the main tumour and migrate to form satellites that escape treatment and often lead to recurrence. The current study used genetically engineered neural stem cells to deliver a protein called TRAIL that is known for its cancer-fighting properties. In the test tube the genetically engineered cells produced significant cancer cell death, maintaining their viability and strongly expressing TRAIL for as long as 10 days. Similar results were found when human glioblastoma cells in mice were treated with TRAIL-secreting stem cells. A week after treatment, strong secretion of TRAIL was visible in the main tumour mass and in secondaries, which decreased significantly in size. While the treatment was dramatically effective in killing glioma cells, it was not toxic to normal brain tissue. - Cancer Research, 15 December 2002

Delivering Chemotherapy with Ultrasound

Cancer patients undergoing chemotherapy often endure painful side effects caused by the powerful drugs as they course through their entire bodies, damaging healthy tissue and tumours alike. Researchers are now reporting that they have successfully tested a new method in laboratory rats that would concentrate the impact of cancer drugs on specific cancerous tissues, thus sparing the rest of the body from harm. Their method combines two key innovations: packaging a cancer drug, doxorubicin, in tiny molecules of water-soluble plastic so that the drug would not interact while passing through a person's bloodstream, then using ultrasound to release the drug from its package at the specific part of the body affected by the cancer. Tests produced significant reductions of tumour size in rats. This method shows potential in offering controlled drug delivery, which could reduce the negative side effects that arise during chemotherapy and could localise the treatment at the tumour site, although human application is still several years away. - Cancer Research, 15 December 2002

Overcoming a Broken Heart

Injury to the mammalian heart in a heart attack leads to scar formation rather than regeneration of the damaged heart muscle. Researchers have now shown that the tiny zebrafish heart responds very differently. Two months after surgical removal of 20% of the ventricle, zebrafish exhibited complete restoration of the heart, apparently through multiplication of heart muscle cells. The work boosts efforts by many researchers to find ways to grow new, healthy cells to replace scarred heart tissue in cardiac patients, a goal still many years away. - Science, 13 December 2002

Set a Cell to Catch a Cell

Researchers have genetically engineered a type of white blood cell to seek out and destroy rogue cells responsible for an autoimmune disease in animals that resembles multiple sclerosis in humans. In multiple sclerosis, some of the body's white blood cells (T cells) become misdirected, attacking the nervous system they were designed to protect and leading to impairment of nerve function and debilitating disease. Researchers have found a way of selectively killing misdirected T cells that may work without side effects. By engineering disease-fighting T cells to recognise rogue T cells, the researchers succeeded in killing rogue cells in the culture dish and protecting animals with the mouse form of MS, experimental allergic encephalomyelitis (EAE). All mice survived that were treated with modified T cells after induction of EAE. In comparison, a half or more of mice receiving no treatment or non-modified cells succumbed to EAE. - Nature Biotechnology, December 2002

Tumour Vaccine Targets New Blood Vessels

Researchers have engineered a DNA-based oral vaccine that counteracts cancer in mice by choking the blood supply to tumours. Tumours need a blood supply to survive once they get more than a couple millimetres in size. This fact has propelled a great deal of interest in the design of treatments that prevent infusion of blood vessels into tumours. Such an approach also has the advantage of being potentially effective against a wide range of tumour types. In this study, the investigators targeted a protein produced in new blood vessels, called vascular endothelial growth factor receptor 2 or FLK-1. Animals treated with the FLK-1 vaccine showed reduced vessel growth and were able to fend off three different types of cancer. The vaccine induced no ill effects by several measures, including fertility. But the mice did have a slight delay in wound healing, consistent with the involvement of new vessel growth in this process. The FLK-1 vaccine protected mice even 10 months after their last dose. Such a vaccine has the greatest potential in preventing or delaying the onset of recurrent tumours, especially in cases of minimal residual disease after other treatments. - Nature Medicine, December 2002

Stem Cells Reach New Maturity

Transplanted neural stem cells are used to treat disorders such as Parkinson's disease, but a major obstacle to this therapy has been that only a few stem cells become nerve cells when placed in most brain areas. Now a new procedure produces stem cells that develop into appropriate cell types after being transplanted into many regions of the rat brain.  In previous studies, stem cells have mainly become glial support cells, rather than neurons, when transplanted into parts of the brain that are not producing new neurons. Only the few brain areas that normally add neurons in adulthood seemed to contain the appropriate signals to allow more than a small number of stem cells to mature into neurons. The new technique involves treating the stem cells in a culture dish with a cocktail of growth factors and other proteins for one day before transplantation. Such cells may lead to better treatments for neural injury and neurodegenerative diseases. - Nature Neuroscience, December 2002

Gene May Explain Aspects of Infertility

Researchers have uncovered an ovary gene whose absence from mouse egg cells produced severe pregnancy complications. The gene, Fmn2, produces the protein formin-2, which is similar in mice and humans and offers promise for understanding embryo loss, birth defects, and infertility in women. Humans produce a large number of eggs with abnormal number of chromosomes, which is the leading cause of pregnancy loss-about one in 100 women suffer from recurrent miscarriages, losing two or more pregnancies. In mice, the formin-2 gene is required to ensure the proper distribution of chromosomes to the egg and the same is likely to be true in humans. The researchers are now actively searching for mutations involving the formin-2 gene in women with reproductive loss and infertility. - Nature Cell Biology, December 2002

Disabling Bacterial and Viral Toxins

Many bacteria do their damage by making potentially lethal toxins, which are transported into cells by a substance called furin, which is located on the cell surface. Blocking furin could therefore stop toxins entering cells, and scientists have developed a compound that does this. The compound, a protein fragment called D6R, blocks furin and was effective against the Pseudomonas aeruginosa bacterium. This is an opportunistic pathogen, which means that it commonly lives on the human body, is usually harmless in healthy people but in people who are unwell it causes a variety of infections: in the urinary tract, respiratory system, skin, blood and soft tissues. Those most at risk are those with impaired immune systems related to cancer, HIV and severe burns. It is often difficult to treat because many of the common strains have become resistant to most antibiotics. D6R could also prove useful in treating infection from other viruses and bacteria whose toxins depend on furin. These include Ebola, clostridium, diphtheria, shigella, RSV, yellow fever, and the AIDS virus. - Infection and Immunology, December 2002

Alleviating Muscular Dystrophy

Muscle build-up is moderated in normal animals by a protein called myostatin. When this is blocked, animals over-develop their muscles-this has been seen for 200 years in the Belgian Blue breed of cattle. The myostatin gene in mice was sequenced in 1997. Researchers have found that knocking out the myostatin gene in mice with a form of muscular dystrophy (MD) led to less physical damage to their muscles and an increase in strength compare to mice with MD and with the myostatin gene intact. Myostatin can be blocked with an antibody, and when this was given to mice with MD, their body weight and muscle mass increased and they showed less muscle degeneration. This strategy differs from gene therapy in that it doesn't try to replace a faulty gene but instead works around the problem by producing more functional muscle to compensate. Potentially, this approach may be useful in combination with other types of therapies to slow the progression of muscular dystrophy and other muscle wasting diseases. - Annals of Neurology, December 2002 and Nature, 28 November 2002

Vaccine Promises to Prevent Cervical Cancer

Cervical cancer kills almost as many women world-wide as breast cancer. A vaccine developed, in part, with rabbits has the potential to cut the toll steeply. In a study of 2,400 women, it seemed to give complete protection against a virus that causes most cases of cervical cancer. The vaccine will not be available to women for several years, as researchers continue work to ensure that the vaccine can deliver long-term blanket protection against the sexually transmitted human papillomavirus (HPV), believed to be responsible for most cases of cervical cancer. But the new study proves a long-debated point: viruses that cause cancer can be halted with vaccines, offering hope that one deadly cancer could be largely eliminated with simple injections. - New England Journal of Medicine, 21 November 2002

Early Promise Against Ewing's Sarcoma

Imatinib mesylate, also known as Gleevec, is showing early signs of promise in preclinical trials against Ewing's sarcoma, a bone tumour in children and adolescents. Gleevec has been used successfully in patients with chronic myelogenous leukemia and some gastrointestinal tumours. Treatment with the drug induced cell death in all Ewing's sarcoma cell lines tested, including those resistant to chemotherapy, and substantial tumour shrinkage in mice. Higher concentrations of imatinib were needed to kill Ewing's sarcoma cells than other tumour cells and such high concentrations may not be achievable in patients. However, identification of a similar treatment could lead to improved therapy for Ewing's sarcoma. - Journal of the National Cancer Institute, 20 November 2002

Targeting Bone Tumours

Most cancer patients are not killed by their primary tumours but succumb to secondaries. The most common human cancers - lung, breast, and prostate - frequently spread to bone, causing pain, fractures, and nerve compression syndromes. Scientists have now found that inhibition of the cells that specialise in breaking down bone, osteoclasts, not only decreases bone damage but also reduces bone tumours in mice. Preliminary results from human patients treated with bisphosphonates, a group of drugs also used to prevent and treat osteoporosis, suggest that the same might be true in humans. Direct inhibition of a protein called PTHrP, believed to play a critical role in starting the vicious cycle in most breast cancers that cause secondaries in bone, reduced bone breakdown, and compared favourably with bisphoshonates. The mode of action of the two classes of drugs is different, which suggests that the two drugs might be used successfully in combination. -  Journal of Clinical Investigation, 15 November 2002

Drugs Intefere with Bone Healing

Researchers have found that selective COX-2 inhibitors - a class of medications widely prescribed for painful inflammatory conditions such as osteoarthritis and rheumatoid arthritis - interfere with the healing process after a bone fracture or cementless joint implant surgery. Their findings suggest that patients who regularly take COX-2 inhibitors should switch to a different medication, such as acetaminophen or codeine derivatives, following a bone fracture or cementless implant. The study, conducted in rabbits, also suggests that physicians should consider changing prescribing patterns since many doctors commonly prescribe anti-inflammatory drugs including COX-2 inhibitors under the very circumstances in which the drugs should be avoided. - Journal of Orthopaedic Research, November 2002

Understanding Aggressive Childhood Cancer

Researchers have generated a mouse with an inactivated tumour suppressor gene that triggers rhabdoid tumours, rapidly advancing cancer that affects children. The discovery of the fast-onset cancers that result from inactivation of the gene, and the technique used to generate the model, are likely to prove useful in studying genes involved in other forms of cancer. The tumour suppressor gene, called SNF5, codes for a protein that helps to regulate the expression of genes. Mice that are deficient in SNF5 die very early in embryonic development, and mice that lack only one of the two genes show a relatively low prevalence of tumours, at about one year old. Scientists knocked out the SNF5 gene in some mouse cells but not in others. They were able to create mice whose tissues had a delicate balance of cells with normal and inactivated SNF5 genes: enough cells with normal SNF5 to allow the mice to live longer, but enough with inactivated SNF5 genes to give rise to cancers. Most of the mice developed malignant lymphomas, or cancers of the blood cells, while many also developed rhabdoid tumours. - Cancer Cell, November 2002

Firefly Light Illuminates Infection

Researchers are using a herpes virus that produces a firefly enzyme to illuminate the virus's course of infection in mice and to help monitor response to therapy. The technique enables them to follow an infection over time as it progresses and resolves, and do this repeatedly using the same animal. Normally, to study the progress of infections and the genes that control them, researchers have to kill infected mice each day and analyse their tissues to determine the level of virus present. The process is further complicated by the fact that individual mice respond differently to infection. This imaging method, known as in-vivo bioluminescence, enabled investigators to track changes in the viral population in the same animal day after day. They first added a gene for luciferase, an enzyme produced by fireflies, to a strain of herpes virus and injected the modified virus into mice. The mice were also injected with luciferin, a compound also produced by fireflies that emits light when exposed to luciferase. They were anaesthetised and photographed using a special camera. The image showed the location and amount of virus in the mouse as areas of colour. - Journal of Virology, December 2002

Sepsis Vaccine Proves Protective

A group of researchers has designed a vaccine that might be used to protect against severe sepsis, an acute and often deadly condition disease that is estimated to strike millions worldwide. Although the new vaccine has not yet been tried in humans, it has worked well in mice. Sepsis, also known as septic shock and systemic inflammatory response syndrome, is characterised by shock to the organs following poisoning with endotoxins - chemical components of certain bacteria. The best treatment is broad-spectrum antibiotics to quell the infection, but this is often too little, too late. The new approach involves active immunisation - used in measles, smallpox and polio vaccines - in which the patient is exposed to a substance resembling the pathogen. In this case, the researchers designed a synthetic compound that mimics a common bacterial endotoxin called lipid A. After vaccinating mice, they observed a 95% reduction in the inflammatory chemical TNF-alpha indicating that the vaccine had successfully controlled the response to infection. Significantly, the vaccine also seemed to raise a broad antibody response. This two-pronged approach may be the reason why the vaccine proved particularly protective. - Angewandte Chemie, 18 November 2002

Heart Drug Hope for MS

A relatively cheap drug, commonly prescribed to avoid heart disease, may be able to treat multiple sclerosis. Researchers have reported a powerful healing effect on mice with experimental autoimmune encephalomyelitis, which mimics the symptoms of MS. The experiments have yet to be replicated in humans, but the results in relapsing, remitting MS-type mice were dramatic. Those given the drug in their first MS-type attack did not get the full-blown disease. If in their second attack, the drug - atorvastatin - reversed the paralysis. Animals with the less common, chronic paralysis, form of MS had their symptoms eased. Atorvastatin - marketed under the trade name Lipitor - is a drug that lengthens lives by reducing cholesterol in the blood. Early signs that the statins, the class of drugs to which atorvastatin belongs, might help treat autoimmune diseases came in 1995, when it was found they eased acceptance of transplanted organs. Another widely-prescribed statin, simvastatin, marketed as Zocor, is undergoing trials on 32 patients with relapsing-remitting MS. - Nature, 7 November 2002

Heart Drug Builds BoneWidely used heart drugs called beta-blockers help build bone in mice, raising hopes that they may also strengthen weak bones in people with osteoporosis. A small study to test this hypothesis in people is already under way and preliminary results may be available within a year. While there are drugs to help stop the destruction of bone, new therapies that reverse osteoporosis are greatly needed. Previous research showed that mice lacking leptin, a hormone that helps regulate body weight, were not only more obese than other mice but they also had stronger bones. Similarly, it has been observed that obese people are less likely to develop osteoporosis than their leaner counterparts. The investigators have worked out how leptin affect bone. Experiments with mice revealed that a part of the nervous system known as the sympathetic nervous system is a key link between leptin and bone-forming cells known as osteoblasts. When leptin-dependent signals in the sympathetic nervous system act on osteoblasts, they are prevented from forming new bone. But beta-blockers, which are commonly used to treat high blood pressure, can inhibit that signalling. - Cell, 1 November 2002

Mini Brain Scanner Kinder to Mice

A miniature brain-scanner is sensitive enough to detect subtle differences in the brain chemistry of mice, scientists have shown. This opens up a new non-invasive way to study genetically engineered strains of mice that serve as models for human neurological diseases, such as Parkinson's and Alzheimer's. Positron emission tomography (PET) is an important tool for detecting and studying a wide range of diseases in people. Before 'microPET' was invented in 1997, the technique could not be used on lab animals at all. Instead, many animals had to be killed and dissected to investigate brain changes. MicroPET can be used with rats, and for observing structural changes in mouse brains. The new experiments demonstrate that it can be used to probe brain chemistry in genetically modified mice, now commonly used in medical research. Because microPET can be used on living animals, it could be used to study how neurochemical differences between strains of mice affect behaviour or disease progression over time. This should throw new light on the development of disease in people. - Journal of Nuclear Medicine, November 2002

Flaxseed Diet Helps Prostate Cancer

A diet rich in flaxseed seems to reduce the size, aggressiveness and severity of tumours in mice genetically engineered to develop prostate cancer, according to new research. And in a few of the mice, the flaxseed diet kept them from getting the disease at all. Previous human studies suggested that dietary fibre reduces cancer risk, and omega-3 fatty acids also have shown a protective benefit. Flaxseed is the richest plant source of omega-3 fatty acids and is high in fibre. It is also a source of lignan, a specific family of fibre-related compounds that appear to play a role in influencing both oestrogen and testosterone metabolism. Since testosterone may be important in the progression of prostate cancer, lignan could help inhibit the growth and development of the disease. Following the mouse research, a clinical trial in 160 men with prostate cancer is examining whether a low-fat diet, or flaxseed supplementation, or a combination of the two will be most effective in stopping prostate cancer cells from dividing. - Urology, November 2002

Bacterial Promise Against Cancer

Researchers have shown that combining components of harmful bugs can create a powerful weapon against melanoma in mice. For the last four decades, researchers have studied Escherichia coli and Listeria monocytogenes - sometimes deadly bacteria - to discover how they interact with the immune system, invade cells, rob them of nutrients, and grow within other cells to eventually shut down necessary bodily functions. They have now created a safe combination of components from both bugs that is a potential treatment for melanoma. Researchers infected mice with melanoma, and found that six of the eight mice whose immune system was primed with the E. coli/Listeria combination remained tumour free more than 90 days later. The remaining two mice showed significant delay in tumour growth compared to mice that did not receive the vaccination. The mice in the study's control group did not live past 16 days. These results suggest that doctors could utilise this killed bacterial formulation to prime the immune system against diseases such as cancer, or other harmful viruses and bacteria. - Gene Therapy, November 2002

Tumour Vaccine Targets New Blood Vessels

Researchers have engineered a DNA-based oral vaccine that counteracts cancer in mice by choking the blood supply to tumours. Tumours need a blood supply to survive once they get more than a couple millimetres in size. This fact has prompted a great deal of interest in the design of treatments that prevent growth of blood vessels into tumours. Such an approach also has the advantage of being potentially effective against a wide range of tumour types. Animals treated with the vaccine made from a protein produced in new blood vessels, called FLK-1, showed reduced vessel growth and were able to fend off three different types of cancer. The vaccine, which works by triggering an attack by the body's killer T cells on FLK-1, induced no ill effects except for a slight delay in wound healing. The FLK-1 vaccine even protected mice 10 months after their last dose. Such a vaccine has the greatest potential in preventing or delaying the onset of recurring cancers. - Nature Medicine, November 2002

Long-lived CFGene Therapy

Using mice, researchers have developed a novel system of gene therapy for cystic fibrosis (CF), involving a natural compound found in our lungs which 'conditions' lung airways to allow cells to take up the therapeutic gene. Our lungs have developed highly effective ways to protect us from allergens, irritants, dust, viruses and other foreign particles. But these defences also hinder effective gene therapy in our lungs. Using mice with CF, the researchers developed a system to briefly overcome these defences. After a single dose of a detergent found naturally in our lungs, cells readily took up the gene needed to treat CF. The airway cells showed substantial recovery from the cystic fibrosis defect for at least 110 days. As airway cells are replaced every three months, some of the therapeutic gene must have been passed on from parent stem cells to daughter cells. This showed, for the first time in a living animal, that long-lived gene therapy for CF is possible. Researchers now need to find the most effective dose and timing for the detergent, and make rigorous safety checks on the virus particle used for the gene transfer. - Science, 1 November 2002

Immune Defence May Improve Cancer Vaccines

Working with both mice and laboratory cell cultures, researchers have discovered that a molecule best known for its anti-microbial properties also has the ability to activate key cells in the immune response. This suggests that the molecule, a protein fragment called ßß-defensin 2, may be useful in the development of more effective cancer vaccines. Defensins are known to be an important component of the body's immediate response to infection. ßß-defensin 2 attacks and destroys a broad range of bacteria as part of the innate immune system, the body's first line of defence against such infections. The new finding links ßß-defensin 2 to the second arm of the immune system, adaptive immunity. Unlike innate immunity, the adaptive immune system develops specifically in response to an infection, changing as needed to ward off each invader. When they administered ßß-defensin 2 to mice, researchers observed a robust response among cells involved in anti-tumour immunity. They hope to harness this property by incorporating ßß-defensin 2 into cancer and AIDS vaccines. - Science, 1 November 2002

Cancer Pain Control with Gene Therapy

By programming a herpes simplex virus to deliver a pain-blocking protein, researchers have been able to significantly reduce cancer-related pain in mice with tumours. Although there are already many powerful medications to treat pain, the unwelcome side effects of these drugs include excessive drowsiness, constipation and difficulty urinating, limiting relief of the most severe painful conditions. Using the virus to deliver the natural painkilling compound may help in those cases. The investigators plan to begin a clinical trial in patients with severe pain resulting from secondary cancers next year. The researchers created an inactivated herpes simplex virus that carries the human gene for proenkephalin, a naturally occurring painkilling substance. Mice with tumours in a leg bone that received injections with the altered virus showed a substantial and significant reduction in pain-related behaviour. - Annals of Neurology, November 2002

Diabetes Drug Shrinks Cushing's Tumours

Most cases of a hormonal disorder called Cushing's Syndrome are caused by non-cancerous pituitary tumours that secrete too much of a particular hormone resulting in high cortisol levels. However, the disorder can ultimately lead to an early death for many patients whose tumours cannot be removed surgically. Now, researchers have found that pituitary tumours produce an excess of a specific protein receptor called PPAR and that treatment with a common diabetes drug was effective in shrinking tumour size and reducing hormone production in Cushing's pituitary tumours in mice. A human trial will begin soon to test the effectiveness of TZD type antidiabetic drug in patients with Cushing's syndrome who have pituitary tumours. - Nature Medicine, November 2002

New Look at Alzheimer's Vaccine

Trials of a promising new therapy for Alzheimer's disease were abruptly halted earlier this year when several patients developed inflammation in the brain. But two new studies raise the possibility that, with modifications, the basic approach may still effectively counteract Alzheimer disease. One of the studies provided the first detailed data on the patients themselves, the other took a closer look at the vaccine in mice. The researchers found that the vaccine worked effectively if mice were injected with only a small portion of A-beta, raising the possibility that a more refined vaccine such as this could bypass the inflammatory side effects in humans. The findings also open the door to generating small-molecule drugs that mimic the effects of the vaccine. - Nature Medicine, November 2002

Treatment for Ewing's Sarcoma

Research scientists and doctors have used a mouse to demonstrate an innovative therapeutic approach to Ewing`s sarcoma: the combination of human interferon and a common anti-tumour agent, ifosfamide. Their results point to the development of a less intensive and more effective therapeutic strategy for Ewing`s sarcoma, a severe bone cancer occurring in children and adolescents. Previous experiments had demonstrated the activity of various interferons against cells derived from Ewing`s sarcoma. This was confirmed by observing the activity of the interferons in so-called nude mice (immunosuppressed) with Ewings sarcoma. The researchers also evaluated the activity of ifosfamide, which blocks DNA replication and hence cell proliferation. Using interferon and ifosfamide resulted in extended survival of the tumour-bearing animals. These observations are highly encouraging, especially as survival is poor in the advanced stages of the disease. A new therapeutic strategy would combine interferon and ifosfamide to treat patients resistant to conventional treatments. - Oncogene, 31 October 2002

Model for Common Lymphomas

Scientists have developed the world's first animal with mature human B-cell lymphoma, a development that may uncover the genetic mutations that cause these types of cancer. Mature B-cell type lymphomas account for about 85% of all lymphomas. The research team had previously identified an abnormality in a gene called TCL1 in patients with B-cell lymphomas, prevalent in those suffering from AIDS. They wondered what would happen if they developed a mouse with abnormally expressed TCL1 - would the mouse develop cancer? In fact, mice with abnormally regulated TCL1 developed three different types of lymphoma. The next step for the research team will be to develop molecules that block the action of TCL1, to try to discover what cell pathways are being used by cells destined to become malignant. They also are working to discover if TCL1 is abnormally expressed in other human cancers. - Proceedings of the National Academy of Sciences, 29 October 2002

Bacterial Protein Kills Tumours

The use of live bacteria to treat cancer goes back a hundred years. But while the therapy can sometimes shrink tumours, the treatment usually leads to toxicity, limiting its value in medicine. Now, researchers have isolated a protein secreted by bacteria that kills cancer cells but appears to have no harmful side effects. Tested in mice injected with human melanomas, the protein shrank the malignancies, but, in contrast with other studies using whole bacteria, caused no deaths or adverse reactions in the laboratory animals. The protein is a well-studied molecule called azurin that is involved in the everyday process cells use to generate energy. It appears to work by stabilising the p53 protein, known as a tumour suppressor because it prevents the formation of cancers through a cascade of molecular events that either stops cells from dividing or induces a process of programmed cell death. - Proceedings of the National Academy of Sciences, 29 October 2002

Pig Sperm Carry Human Genes

Researchers have created a strain of pigs that carry human genes in their hearts, livers and kidneys, an advance that could provide organs for transplanting into humans. They mixed swine sperm with human DNA to transfer a gene called decay accelerating factor, or DAF. The modified sperm was then used to fertilise pig eggs and produce litters of pigs carrying the human gene, obtaining, at high efficiency and low cost, genetically modified pigs expressing the human protein. More than 200 piglets in 20 litters were produced using the modified sperm technique and the human genes were present in up to half of the young. Tests showed that the human genes were present in the animals' central organs and that the genes would be passed along to later generations of pigs. - Proceedings of the National Academy of Sciences, 29 October 2002

Preventing Cell Death in Stroke

Researchers have successfully prevented many brain cells from dying in rats that have had strokes, perhaps pointing the way to a new technique that would preserve more brain function in human patients after stroke. The researchers gave rats a treatment that interrupted a signal within affected nerve cells that would otherwise tell them to die. This treatment allowed the rats to preserve two thirds more brain tissue after stroke than they would have otherwise. In subsequent experiments, rats that received the new treatment completed behaviour tests better than the rodents who were not given the treatment. Nerve cells often rely on a chemical known as glutamate to communicate with each other, and the chemical is also involved with learning and memory. However, when a stroke occurs, cellular structures called receptors become overstimulated by glutamate, triggering a process that leads to nerve cell death. The treatment developed is a protein fragment that blocks an early step in this process, thereby impeding cell death while preserving the useful functions of the glutamate receptor. - Science, 25 October 2002

New Compound Builds Bones Safely

A new man-made compound holds out the hope of safer hormone replacement therapy that can reverse bone loss without increasing cancer risk. Scientists studying mice found that the synthetic hormone, estren, was better at combating osteoporosis than the natural hormone oestrogen. But, unlike oestrogen, estren has no effect on the reproductive tissues and does not lead to an increased risk of breast and uterine cancer. Estren could also be helpful to men undergoing hormone treatment for prostate cancer, which leaves them vulnerable to osteoporosis, and may provide other anti-ageing benefits, such as protecting blood vessels and nerve cells. - Science, 25 October 2002

Stem Cells Seek, Destroy, Brain Tumours

Stem cells modified to produce a cancer-killing immune chemical can track and destroy difficult-to-treat brain tumours, researchers have found. They hope the work in mice could lead to new treatments for people with gliomas. Standard glioma treatment involves surgery, followed by radiotherapy or chemotherapy. But tiny groups of glioma cells often spread deep into healthy brain tissue, so even if the main tumour is wiped out, the risk of recurrence of the cancer is high. Life expectancy after diagnosis is normally about one year. The scientists took neural stem cells from mouse fetuses and genetically engineered them to produce interleukin 12. This is an immune stimulating chemical known to kill gliomas. They then injected the modified stem cells into implanted gliomas in the brains of mice. Treated mice lived significantly longer than controls. Almost one third even developed long-term immunity to brain cancer. This approach represents a promising new treatment for malignant brain tumours. - Cancer Research, 15 October 2002

Stem Cells from Cord Blood Show Promise

Scientists have reported that they can significantly increase the number of stem cells from umbilical cord blood by exposing the blood to a particular molecule, a finding that could have important implications for stem cell research. The ability to regenerate tissues from stem cells could have major implications for the treatment of many diseases, such as Alzheimer's disease, Parkinson's and cancer. The scientists exposed cord blood in the laboratory to a protein molecule called Delta-1. Although it remains unclear exactly how the molecule works, it somehow increased the number of immature stem cells in a sample of cord blood 100-fold. It also increased the number of haematopoeitic stem cells, which are cells that can evolve into any type of cell found in blood. The researchers next tested their newly harvested cells in mice with deficient immune systems. The animals' immune systems resembled those of leukaemia patients who have undergone radiation therapy prior to a bone marrow transplant. Study results showed the enhanced stem cells were more potent in the mice compared with non-cultured stem cells or stem cells not exposed to Delta-1. - Journal of Clinical Investigation, 15 October 2002

Promise for Lupus and Related Diseases

A chemical cousin of anti-anxiety benzodiazepine medications such as Valium has significantly reduced kidney inflammation in mice that develop a disease resembling human systemic lupus erythematosus. The research also revealed the novel mechanism by which the compound works, a discovery that could lead to safer and more effective drugs for managing lupus and other autoimmune disorders. Lupus affects about one person in every 3,500 in the UK. The mainstays of treating lupus-related kidney inflammation - the major cause of illness and death in lupus patients - are drugs developed many years ago to kill cancer cells. When given to lupus patients these agents kill immune cells but they also kill healthy cells, resulting in serious side effects. And they are not effective in some patients. The team gave the new medication, called Bz-423, to mice with lupus. Only one in six of the treated mice developed lupus-related kidney disease, and they showed none of the side effects caused by currently available lupus drugs. There is evidence that Bz-423 may also be useful in treating some cancers, as well as other autoimmune diseases. - Journal of Clinical Investigation, 15 October 2002

Stem Cell Master Switch

In the search to understand the nature of stem cells, researchers have identified a regulatory gene that is crucial in maintaining a stem cell's ability to self-renew. According to their findings in genetically modified mice, the Foxd3 gene is a required factor for pluripotency - the ability of stem cells to turn into different types of tissue - in the mammalian embryo. Stem cells represent a unique tissue type with great potential for disease therapy, but if we are to use stem cells then we need to know how they develop. To study the function of the Foxd3 gene, the research team generated mice with an inactivating mutation in the gene, and then analysed those mice to determine the role of the Foxd3 protein. They found that Foxd3-deficient embryos do not survive very long. Without Foxd3, the mouse embryos simply could not maintain enough stem cells to survive a crucial point in their development. These findings implicate Foxd3 as one of the few genes serving as a master switch of the developing embryo. - Genes & Development, 15 October 2002

Oestrogen May Worsen Alzheimer's

The results of a new study in rats suggest that oestrogen replacement therapy may hinder - not help - memory in older women with Alzheimer's disease. Many animal and laboratory studies had suggested that oestrogen might protect the brain from memory loss, but it is not clear if this is true for oestrogen replacement therapy (ORT). In the new study, rats had their ovaries removed - putting them into a low-oestrogen state similar to menopause - and were given a drug to stimulate brain inflammation, which occurs in patients with Alzheimer's disease. The researchers found that these rats actually fared worse on memory tests when they received steady doses of oestrogen. The findings add to a growing body of research demonstrating potentially negative effects of ORT, long thought to protect women against certain age-related changes. While oestrogen may protect certain women from memory loss, it may not be beneficial for those with brain inflammation, which occurs in patients with Alzheimer's disease. - Behavioral Neuroscience, October 2002

Gene Therapy for Parkinson's

Following successful tests using rats, doctors are to begin the first ever trial using gene therapy to treat Parkinson's disease. The technique uses gene therapy to re-set a specific group of cells in the brain that have become overactive, using the GAD gene, which makes a small molecule called GABA. This is released by nerve cells to inhibit, or dampen activity. Scientists deliver this directly to the overactive cells by using a modified virus to carry the GAD gene into the brains of rats. Tests on the rats showed the GAD gene was present and producing GABA as anticipated. Behaviour tests showed they had retained more normal function and did not develop further signs of Parkinson's compared to rats that had not been given the therapy. In addition to work in rats, tests on monkeys showed the therapy was safe and non-toxic. - Science, 11 October 2002

Parkinson's Affects Brain Connections

Researchers have discovered critical clues that may explain why parts of the brain damaged by Parkinson's disease aren't repaired by dopamine replacement therapy. The research indicates that the loss of dopamine seems to cause connections in the brain to reorganise. This affects the brain's ability to communicate effectively with body parts, for example, the ability to respond to stimuli from the body to control body movements. The research team studied rats and produced a new type of functional map of the brain. This showed that clusters of nerve cells shrank when deprived of dopamine. It was not the individual nerve cells that were shrinking or moving closer together, but rather the nerve cells around the edges of clusters became less responsive. The result is that the brain is unable to process some signals, affecting many different body parts. These kinds of permanent changes in connections would make curing Parkinson's disease difficult or impossible, making research into prevention all the more important. - Journal of Comparative Neurology, 7 October 2002

Vaccine for Sjöögren Syndrome

Using a mouse that naturally develops autoimmune Sjöögren syndrome, researchers have identified the protein (ICA69) that triggers the autoimmune response. They developed a candidate vaccine that dramatically reduced the progression of tissue damage in mice even relatively late in the disease. Sjöögren syndrome is an autoimmune disease in which the body's immune system mistakenly attacks its own moisture producing glands - for example, the salivary (mouth) and lacrimal (tear duct) glands. By removing the gene that produces the ICA69 protein, mice that normally develop Sjöögren syndrome had no tear gland disease and much reduced salival disease. The prototype vaccine was able to stop disease progression. Sjöögren syndrome affects approximately one per cent of the population and commonly occurs with other disease such as rheumatoid arthritis. The primary symptoms of Sjöögren syndrome are dry eyes and dry mouth. It may also cause dryness of other organs, affecting the kidneys, the gut, blood vessels, lung, liver, pancreas, and the central nervous system. Many patients experience debilitating fatigue and joint pain. There is currently no effective therapy for the syndrome. - The Lancet, 5 October 2002

Body Clock Gene May Suppress Tumours

A gene involved in regulating the body's internal clock may also serve to prevent cancer, new research suggests. The findings are based on animal studies and need to be confirmed in humans, but they raise the possibility of fighting cancer by manipulating the body's internal clock. Compared to normal mice, mice lacking the gene Period2, which controls circadian rhythms, were more likely to develop tumours. Likewise, the absence of the Period2 gene seemed to interrupt cells' response to DNA damage caused by radiation. The implication of the study is that the circadian clock works as a guardian to defend against cancer. The researchers suspect that the absence of Period2 leads to the overexpression of a gene called c-myc, which has been linked to cancer. The next step is to see whether circadian genes also suppress tumour development in humans. If this proves to be the case, it might be possible to manipulate the circadian clock to improve cancer treatment. - Cell, 4 October 2002

Faulty Signals Stop Tumours

The c-myc gene is commonly activated in a variety of human tumours, and scientists are gaining a better understanding as to why. Using genetically modified mice, they discovered that the c-Myc protein is essential for tumour development, as it regulates factors necessary for the growth of blood vessels into tumours. To study the role of c-Myc, scientists developed strain of mice that are deficient in the gene. The c-myc-deficient mice die as embryos due to cardiac and neural defects, but also display marked defects in the formation of blood vessels and red blood cells. The researchers found that these defects in the mice arise from faults in signals that coordinate blood vessel formation during development. They went on to show that c-Myc plays a similar role in orchestrating blood vessel formation during tumour formation. This provides strong evidence to suggest that the disruption of c-Myc may prove successful in treating cancer by stopping blood vessel formation. - Genes & Development, 1 October 2002

New Clues to Cause of Stomach Cancer

Using mice, scientists have discovered a vital clue to the causes of stomach cancer and inflammatory bowel disease. Stomach cancer is the fourth most common form of cancer death in Australia and the second most common in parts of South Asia including Japan and Korea. Until now, little was known about what caused this disease, which is difficult to treat and usually incurable. The team's discovery has identified possible targets for the development of drugs to treat these diseases. The scientists found the clue when they made specific mutations to a molecule found on the surface of cells that is traditionally involved in helping regulate the body's immune system. The receptor molecule called, gp130, acts as a molecular 'antenna', to transmit instructions to individual cells from messenger molecules called cytokines found in the circulation and body fluids. This message service is what tells the cell how to respond to its environment. They were surprised when the mice carrying mutations in gp130 developed cellular changes and other symptoms that mirrored those of gastric cancer and bowel inflammation in humans.  - Nature Medicine, October 2002

Clot-busting Attack Cells from Within

Researchers have identified new compounds - protein fragments called pepducins - that inhibit blood clotting. Blood clots can lead to heart attacks and strokes, and this has driven interest in clot-busting agents. In mice, the new compounds prolonged the length of time that the animals bled, and in a test tube, the new compounds inhibited aggregation of human platelets, which is necessary for the formation of a blood clot. The compounds, which work in a unique way, have not yet been tested in people. But if they work as well as they do in a test-tube and in mice, they have the potential to add to the arsenal of drugs that keep the blood thin. - Nature Medicine, October 2002

Sleeping Through Surgery

Undergoing anaesthesia seems similar to being asleep in many ways. The resemblance extends to the brain region underlying the two states, according to research on rats. A small area of the brain known to be critical in controlling sleep/wake states turns out to be a target for some commonly used anaesthetics. The research team found that two anaesthetics, pentobarbital and propofol, act specifically within this brain region to produce their sedative effects. Research on the mechanisms of anaesthesia action has progressed rapidly at the molecular level, and this new work places the molecular work into a broader, whole animal context. - Nature Neuroscience, October 2002

Rib Nerves May Restore Leg Movement

Grafting tiny nerves from the rib cage mixed with a powerful growth inducer has significantly reversed paralysis from spinal cord injury in rats. The study suggests that nerve cells can be inserted and stimulated to grow through damaged areas of the spinal cord. Regeneration is considered very difficult because the damaged area apparently inhibits growth of new nerve-cell connections, but this study got close to arriving at the right combination of growth factors, nerve cells and physical stimulation to overcome these inhibitions and successfully treat spinal cord injury. Scientists found that grafting nerves from the rib cage and adding the growth stimulator, a molecule called aFGF, partially restored hind leg movement in rats that had their spinal cords severed. The growth factor aFGF is normally produced in the spinal cord by nerve cells, but scientists suspect that it is stored and only used when nerve cells are damaged. Previous studies have shown that adding aFGF can stimulate growth in individual nerve cells in the laboratory. - Journal of Neurotrauma, October 2002

Stem Cells Boost Motor Skills

Neural stem cells transplanted into injured brains survive, proliferate, and improve brain function in mice according to new research. These findings suggest that stem cells could provide therapy to treat traumatic brain injuries, the leading cause of long-term neurological disability in children and young adults. Mice that had neural stem cells injected into their brains shortly after a brain injury experienced significant improvement in motor skills. The cells appeared to travel directly toward the site of injury. Not only did the cells form neurons, but they also formed the glial cells that support neurons. Although the cognitive, or mental, abilities of the mice did not improve after treatment, their motor skills did get better. The next step is to follow mice for longer than three months to monitor the long-term effects of treatment and to see how long the window of opportunity for treatment lasts after injury, to determine if the cells could help people who suffered traumatic brain injuries months or years ago. - Neurosurgery, October 2002

Delivering Drugs to the Brainstem

Tumours in the brainstem are called brainstem gliomas and account for more than 10% of brain tumours in children. Current drug treatments of brainstem tumours are largely unsuccessful, because the drugs often fail to bypass the blood vessel lining protecting the brainstem. Now, researchers have effectively delivered drugs to the brainstem of rats and monkeys and monitored how the drugs spread inside the brain. The study provides hope for improved treatment of brainstem tumours and other brain diseases. In the new study, researchers used a technique called convection-enhanced delivery (CED) to deliver a tracer molecule to the brainstem of rats and monkeys. They then used magnetic resonance imaging (MRI) to track the tracer's movement throughout the brain. No neurological abnormalities resulted, and the brainstem tissues appeared normal, except for a small amount of scar tissue near the site of infusion. Drug delivery imaging with CED may ultimately improve outcomes for children with brainstem gliomas. If proven safe and effective, the technique might also be used to treat other neurological diseases, such as Parkinson's disease, other tumours, epilepsy, and pain disorders. - Journal of Neurosurgery, October 2002

Lipid Link to Motor Neurone Disease

Abnormal accumulation of two common lipids - the building blocks of fats - in motor nerve cells could play a critical role in the development of motor neurone disease (MND), according to studies in mice with a form of the disease. The finding could help scientists develop drugs to slow the disease's progression. In addition to drugs, scientists are investigating whether changes in diet might have an impact on an individual's susceptibility to MND. Scientists unearthed several new clues to the disease through a complex, multi-step investigation. They discovered that levels of various lipids were significantly raised in the spinal cords of people with MND. To test whether these elevated levels of lipids cause motor neuron degeneration, the investigators studied genetically modified mice that mimic MND. Analysis of the spinal cords of these animals, and of motor neurons exposed to damaging free radicals, again revealed increased levels of the lipids. - Annals of Neurology, October 2002

Possible Cure for Gluten Intolerance

Researchers have discovered the cause and a potential treatment for coeliac disease, an autoimmune condition that leads to an inability to digest gluten, a major protein in wheat, rye and barley products. Working with rats, researchers identified a fragment of gluten called gliadin that is responsible for the intestine-damaging inflammatory response experienced by coeliac patients. They also reported the use of a dietary enzyme made by a bacterium that can break down the fragment into harmless bits in the test tube and in rats. - Science, 27 September 2002

Hope for Rare Species