SwAEBR - Research Focus

Southwest Association for Education in Biomedical Research - SwAEBR

Research Focus 2003:

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

Mouse Resists Diabetes

An engineered mouse, already known to be immune to weight gain from a high-calorie, high-fat diet, now seems able to resist the onset of diabetes. Type II diabetes is a chronic disease caused by a problem in the way the body makes or uses insulin. The discovery of a gene that seems influence both weight gain and glucose regulation is potentially significant for both conditions and their relationship. In mice engineered to lack the gene, SCD1, muscle cells were more sensitive to insulin, enabling the cells to absorb glucose and avoid hyperglycaemia. Elevated levels of glucose in the blood prompt the pancreas to produce more insulin, which tends to make cells even more resistant to the critical hormone. Because humans have SCD1 equivalents, the new finding helps explain why some people, who may lack the gene, remain lean and diabetes free, despite a rich, fatty diet. This new insight into the gene and its influence could herald the development of new drugs to prevent both diabetes and obesity as it may help scientists zero in on the underlying problems that lead to both conditions. - Proceedings of the National Academy of Sciences, 16 September 2003

Anti-inflammatory Could Help Children with Bone Disease

A drug commonly used as an anti-inflammatory medication could also help children with an inherited form of rickets to avoid complications from their disease, according to research using mice. Rickets, specifically X-linked hypophosphataemia, causes bones to soften and weaken because the kidneys waste phosphate, a mineral that combines with calcium to make bones and teeth. The disease is similar to osteoporosis but occurs in children with growing bones. In the mouse study, researchers found that the drug, Indomethacin, keeps the body from wasting needed phosphate without causing the potentially life-threatening complications of conventional therapies. Indomethacin is a drug similar to aspirin or ibuprofen and is commonly used to relieve pain, swelling and stiffness caused by gout, arthritis and other inflammatory conditions. Researchers injected Hyp mice, which have the same genetic mutation as people with X-linked hypophosphataemia, with Indomethacin twice a day for four days. They found that phosphate levels in the mice's urine were much lower than before the treatment. The study results were so promising that plans are already under way for a study in children. - Proceedings of the National Academy of Sciences, 16 September 2003

Dual Action Anthrax Vaccine More Effective

Researchers have created a vaccine that delivers a one-two punch to anthrax and could become a powerful defensive weapon against bioterrorism. The new vaccine prods the immune system to attack both the anthrax bacterium (Bacillus anthracis) and the toxins it makes. This dual action represents an improvement over the currently available vaccine, which targets only the toxins. In a test of the vaccine using mice, animals were injected first with the vaccine, then 10 days later with anthrax toxin. All the vaccinated mice survived the toxic challenge, while unvaccinated mice exposed to the toxin died within 24 hours. The researchers suggest that the new vaccine will also be an important tool for treating those already infected with anthrax as a so-called therapeutic vaccine. The vaccine will now have to be tested in animals infected with actual anthrax spores as opposed to the lethal toxin used in this study to replicate the natural disease process. - Proceedings of the National Academy of Sciences , 16 September 2003

Enzyme Inhibitors May Halt Tumour Growth - 1

Researchers have identified compounds that could wipe out an enzyme responsible for tumour growth. These compounds are the first 'drug-like' agents that have been shown to inhibit an enzyme called sphingosine kinase (SK). Since SK is known to be involved in growth regulation and other biological processes that are important in tumour growth, these compounds have potential for the treatment of many types of cancer. The research team screened about 16,000 compounds searching for inhibitors of SK. Four types of compounds were found to be very effective and were more potent than previous SK inhibitors. It was then necessary to determine if the new SK inhibitors do in fact promote anti-tumour activity in an animal. The researchers tested the effects of one inhibitor on tumours growing in mice. Tumours in treated mice showed between 50% and 85% less growth than tumours in untreated animals. Importantly, there were no significant change in the body weights of those animals treated with the SK inhibitor, suggesting that it was not toxic to the animals. - Cancer Research, 15 September 2003

New Approach to Parkinson's Treatment

Scientists using mice may have uncovered a cheap and easy way to treat Parkinson's disease. The treatment, which is currently used to help people with epilepsy, appears to restore impaired brain function and protect against neurological degeneration. Mice with Parkinson's disease were treated with infusions of the drug D-beta-HB. Researchers believe Parkinson's is caused by a depletion of the chemical dopamine in the brain. Researchers found the mice treated with the drug D-beta-HB had constant levels of dopamine in the brain while dopamine kevels dropped in those treated with a placebo. Thus D-beta-HB may offer straightforward neuroprotection for the treatment of neurodegenerative diseases such as Parkinson's disease. More research needs to be done to determine the effect of long-term use of D-beta-HB. Current small studies in humans show the treatment can be well tolerated and similar approaches have been used to treat epilepsy safely for more than 70 years. - Journal of Clinical Investigation, 15 September 2003

Enzyme Inhibitors May Halt Tumour Growth - 2

New inhibitors of the enzyme telomerase may slow tumour formation within weeks, researchers using human cells and mice have discovered. They could lead to treatments that slow or prevent recurrences of cancers. Telomerase is an enzyme that maintains telomeres –– repeating sequences of DNA at the end of each chromosome. The enzyme is found in most types of tumour cells but not in healthy cells, indicating the potential of telomerase inhibitors in chemotherapy. However, in earlier studies scientists found that months of treatment with an inhibitor were required before tumour growth was slowed. Researchers have now treated cultured human tumour cells with a unique compound that blocks telomerase activity, and cell growth slowed substantially after just a few weeks. Prostate cancer cells treated with the inhibitor barely formed tumours in mice and yielded very low levels of prostate specific antigen (PSA), a marker of prostate cancer. The researchers also discovered that when the telomerase inhibitor is combined with the standard cancer therapeutic agents carboplatin and cisplatin, there are additional anticancer effects. - Cancer Research, 15 September 2003

Cancer Drugs Halt Heart Failure

Experimental cancer drugs may help to prevent the development of a common cause of heart failure: cardiac hypertrophy - the enlargement of the heart muscle cells. Research using genetically modified mice showed that trichostatin A could block this cell enlargement. Cardiac hypertrophy can be a perfectly healthy response to exercise and training - heart cells grow larger like any other well-conditioned muscle. However, it can be result of an unhealthy cardiovascular system, or a genetic defect, in which case it can be fatal. The new research is based on the theory that some cases of hypertrophy are caused by over-production of a protein called Hop, which reacts with a substance called HDAC. Treatment of genetically modified mice that overproduce Hop with trichostatin A, an HDAC inhibitor, prevents hypertrophy. HDAC inhibitors are among the first known medications to prevent the condition. More experimental work needs to be done to determine whether these drugs consistently reduce cardiac hypertrophy, which is the heart's response to a wide variety of different events, and to ensure that they do not have unrelated side effects. - Journal of Clinical Investigation, 15 September 2003

Unhelpful Hedgehogs Cause Cancer

High levels of a protein known as Sonic hedgehog (SHH) may trigger certain forms of digestive tract tumour, according to two studies in mice. Treatment with cyclopamine - a drug that inactivates SHH -can cause some tumours to shrink. The Hedgehog signalling pathway specifies patterns of cell growth and development in a wide variety of embryonic tissues. High levels of activity are seen in many digestive tract tumours - including those originating in the oesophagus, stomach, biliary tract and pancreas. In one study, mice carrying human biliary duct tumours responded to treatment with cyclopamine. Their tumours shrank completely after 12 days of treatment. In a second study, scientists reported a similar effect of cyclopamine in mice with pancreatic tumours. Both studies highlight the importance of the Hedgehog signalling pathway in certain digestive tract tumours. The pathway may have an early and critical role in cancer formation. - Nature online DOI: 10.1038/nature01972, 14 September 2003

Easing Platelet Transfusion Shortages

A safe method has been developed, using mice and human platelets in test tubes, to chill blood platelets to prolong their shelf-life by a week or more. This would help to ease chronic shortages that endanger patients in urgent need of platelet transfusions. Platelets, the cell fragments in blood that help make clots to stop bleeding, must currently be stored at room temperature. If they are refrigerated, the platelets undergo a chemical change that makes them the target of macrophages, one of the body’’s immune cells. For this reason, platelets are stored at room temperature and become useless after five days, because they no longer function properly and the risk of bacterial contamination increases sharply. Researchers coated platelets with a naturally occurring sugar called galactose, which masked the chemical change that prompts macrophages to attack. This treatment was effective either before or after the platelets were refrigerated, and allowed transfused platelets to evade attack after 12 days’’ storage. When transfused into mice, about 30% more chilled, treated platelets remained in the blood after 24 hours than room temperature platelets. Untreated chilled platelets diminished rapidly after transfusion. - Science, 12 September 2003

New Way to Control Inflammation?

Researchers have discovered a genetic switch that can drastically reduce fatty deposits in the coronary arteries of mice while regulating the inflammatory process involving immune cells called macrophages. The scientists believe that the switch, a protein called PPAR-delta, could be a target for drugs to control inflammation in a variety of diseases, including cancer, neurodegenerative diseases, inflammatory joint and bowel diseases and immune disorders. The researchers fed both normal and PPAR-delta-deficient mice a fatty diet and compared the formation of atherosclerosis in both strains of mice. In earlier studies, they found that knocking out PPAR-gamma made the arteries narrow much more rapidly, but to their surprise they found the opposite result with PPAR-delta. The deposits almost failed to develop at all, so these mice had very clean arteries. The researchers also found that PPAR-delta controls inflammation by a previously unknown pathway. This has far-reaching implications, in part because it can now be studied in detail and also because it can be controlled by an orally active drug. The researchers are now exploring the protein's role in an array of other cells, including fat cells and muscle cells. - Science Express DOI: 10.1126/science.1087344, 11 September 2003

Yellow Mice Help Pin-point Mutations

A new genetic technique helps pin-point mutations on specific chromosomes. The method has revealed 88 new mutations on mouse chromosome 11. Researchers hope that it will help us to understand human gene function, and the role of genes in disease. Scientists used tricks from fruitfly genetics to develop their new screen for mice. The method allows researchers to track down mutations in a particular region of a particular chromosome. Offspring with a mutation have yellow fur. Using the strategy, the team spotted a variety of mutations hidden on mouse chromosome 11 affecting skin, nervous system, blood cells, head and face, and fertility. This vastly simplifies the breeding and maintenance of mutant strains - no complicated tools such as molecular genotyping are required, only the ability to follow coat colours. - Nature, 4 September 2003

Chronic Wasting Disease Spreads Horizontally

Chronic wasting disease, a BSE-related disease that affects mule deer, can spread efficiently from animal to animal. This horizontal route of transmission, rather than maternal transfer - where the disease is passed from mother to unborn foal - may account for the epidemic affecting deer populations in central USA. Researchers studied the transmission of chronic wasting disease (CWD) within two populations of captive Colorado mule deer. One group was born to mothers that had contracted the disease. Animals in the second group were born to disease-free mothers, but joined the first group when they were 3-4 months old. All of the former and almost all of the latter contracted CWD over a four-year period. Because the incidence of CWD in the two groups was similar, the research suggests that maternal transmission does not contribute to disease transfer. Instead, horizontal transmission is more likely to be important in sustaining CWD epidemics. This could happen directly or indirectly - concentrating deer in captivity or transporting infected animals may facilitate transmission. - Nature, 4 September 2003

Search-and-destroy Flushes HIV Out

Scientists have devised a new technique to switch on and drive latent HIV from its hiding places in the body. The research suggests a possible therapy to kill the hidden virus so people who are HIV-positive could eventually stop taking antiretroviral medications, which can have serious side effects. These drugs kill HIV, often depleting the virus to undetectable levels in the blood of patients. But latent HIV still hides in resting T-cells and when an HIV-infected person discontinues medication, this small reservoir of latently infected T-cells can rekindle the spread of HIV infection throughout the body. The researchers used mice specially bred without immune systems. They implanted the mice with human thymus tissue and then infected the tissue with HIV. The mice responded by producing human T-cells infected with latent HIV. The researchers then used a two-step approach to expose and destroy latent HIV. First, they stimulated the T-cells strongly enough to prompt the cell to express latent virus but not to trigger other functions. This revealed the hidden HIV. Second, they used an immunotoxin - an anti-HIV antibody genetically fused with a toxin - to target and kill the HIV-infected T-cells. - Immunity, September 2003

Chicken Embryo Research Tunes into Inner Ear

Biologists have learned how to control the development of stem cells in the inner ears of embryonic chickens, a discovery that could improve the ability to treat human diseases that cause deafness and vertigo, including Meniere’’s disease. The researchers set out to determine the function of a family of genes found in many embryonic cells. Wnt genes influence the development of organs from the brain to muscles. The researchers knew that Wnt genes were present in the ears of embryonic chicks, and used a modified retrovirus to deliver a souped-up version to make more cells experience the Wnt signal. This instructed the embryonic cells to develop into different adult cells. Instead of forming the tiny hairs that the inner ear uses to detect sound waves, the stem cells matured into tissue with a different kind of hairs –– the sort used to keep balance. This ability to guide the choice of cell types could help understanding of the inner ear and its disorders. - Developmental Biology, 1 September 2003

First Line of Defence Against Meningitis

Researchers using an experimental blood brain barrier and mice have found out how the first line of defence used by the human blood-brain barrier works against bacterial meningitis, and why it sometimes fails. The blood-brain barrier effectively blocks the vast majority of circulating bacteria from entering the brain. To understand how group B streptococcus (GBS) bacteria affect the blood-brain barrier immune response, researchers developed mutant strains of GBS without a surface coating. Their hypothesis that the coating decreases the ability of the white blood cells and blood-brain barrier cells to recognise the bacteria as foreign proved correct. The mutant was more easily recognised by the blood-brain barrier, which triggered a protective immune response. In a second test, the researchers developed a GBS mutant that lacked a potent cell-damaging toxin. Mice infected with these mutant bacteria developed less meningitis than mice given normal GBS bacteria. After the GBS bacteria reach high concentrations in the blood-brain barrier, a toxin breaks down the barrier and provokes the inflammation that is the hallmark of bacterial meningitis. - Journal of Clinical Investigation, 1 September 2003

Green Tea Compound Blocks Bladder Tumours

Injection of a chemical found in green tea blocks the growth of bladder tumours in rats. The chemical, called epigallocatechin-3-gallate (EGCG), has never been studied as an anti-cancer agent injected directly into the bladder. Although EGCG has been shown to have anticancer properties, studies examining green tea use have yielded conflicting results. In one study, green tea consumption was actually tied to an increased risk in bladder cancer. However, in another study, drinking more than five cups per day seemed to protect against the cancer. In the new study, researchers examined the anti-cancer effects of EGCG in the test tube and in rats with bladder tumours. An EGCG dose was identified that could kill all cancer cells after two hours of incubation. They then tested EGCG on rats implanted with tumour cells. Thirty minutes after tumour cell injection, some of the animals were treated with EGCG, others were not. Two thirds of the animals treated with EGCG were tumour free three weeks later. In contrast, all the untreated animals showed tumour growth. - Journal of Urology, September 2003

First Mouse Model for Kidney Stones

Scientists have found a strain of mouse that suffers from cystinuria type I, a disease commonly known as kidney stones. They discovered that the mouse had raised levels of urea in the blood, a hallmark of impaired kidney function, and stones in the urinary tract. The mouse had a mutation in the Slc3a1 gene: mutations in the human Slc3a1 gene have long been associated with cystinuria. This mouse should aid understanding of the processes involved in the formation of kidney stones. - Human Molecular Genetics, September 2003

Anthrax's Line of Attack Questioned

Researchers using mice have challenged the accepted wisdom about the way that anthrax strikes. The bugs were generally thought to produce a toxin that attacks immune-system cells called macrophages, causing them to release a lethal pulse of molecules called cytokines. But mice that have macrophages resistant to anthrax toxin were still killed by it, and any cytokines they made vanished before the animals died. The researchers also disputed the idea that anthrax victims die of septic shock, caused when the effects of cytokines shut the body down. The mice died because fluid built up around their lungs and, starved of oxygen, their livers failed. This study used only the toxin, so should be repeated using whole anthrax bacteria. Doctors have a crude vaccine and antibiotics to use against anthrax. But they want to find antidotes to the toxins - because even if antibiotics kill the bugs, they can leave fatal levels of poisons behind. Many scientists are already working on ways to block lethal toxin from entering cells, or prevent it working. Now they have to figure out which cells the lethal toxin targets. - Journal of Clinical Investigation, 1 September 2003

Mouse Resists Diabetes

Anti-inflammatory Could Help Children with Bone Disease

Dual Action Anthrax Vaccine More Effective

Enzyme Inhibitors May Halt Tumour Growth - 1

New Approach to Parkinson's Treatment

Enzyme Inhibitors May Halt Tumour Growth - 2

New inhibitors of the enzyme telomerase may slow tumour formation within weeks, researchers using human cells and mice have discovered. They could lead to treatments that slow or prevent recurrences of cancers. Telomerase is an enzyme that maintains telomeres – repeating sequences of DNA at the end of each chromosome. The enzyme is found in most types of tumour cells but not in healthy cells, indicating the potential of telomerase inhibitors in chemotherapy. However, in earlier studies scientists found that months of treatment with an inhibitor were required before tumour growth was slowed. Researchers have now treated cultured human tumour cells with a unique compound that blocks telomerase activity, and cell growth slowed substantially after just a few weeks. Prostate cancer cells treated with the inhibitor barely formed tumours in mice and yielded very low levels of prostate specific antigen (PSA), a marker of prostate cancer. The researchers also discovered that when the telomerase inhibitor is combined with the standard cancer therapeutic agents carboplatin and cisplatin, there are additional anticancer effects. - Cancer Research, 15 September 2003

Preventing Diabetes

Researchers have added to their earlier discovery of a link between Type 1 diabetes and diseases in which the immune system attacks the nervous system, such as multiple sclerosis (MS). This research, using mice, has identified possible new ways to prevent diabetes and develop tests to detect those at risk. The researchers traced the link between Type 1 diabetes and nervous system autoimmunity to nervous tissue surrounding insulin-producing beta cells in the pancreas. They unexpectedly found that it is these nervous system structures that are first destroyed in the earliest stages of diabetes, with autoimmunity subsequently veering off to attack insulin-producing cells. Modification of the early nervous tissue attack prevented diabetes in mice prone to the disease. This research may also open a new door for understanding a mystery in autoimmune diseases: why does the immune system attack its own tissue? It now seems possible that the nervous system and cells that separate nervous system from other tissue in the body may play an unsuspected, critical role in this process. - Nature Medicine, February 2003

Carbon Monoxide Benefits

Exposing rats to low levels of carbon monoxide (CO) prior to aorta transplantation prevents clogging of arteries associated with organ rejection and can also suppress blockage after balloon angioplasty. These findings suggest that carbon monoxide may be used to protect against injury to blood vessels. Currently the best available treatment for clogged arteries is balloon angioplasty or bypass surgery. But these have their limitations and significant failure rates. If you could pre-treat patients with CO it might result in a better long term outcome. The research suggests that the protective effect of CO relies on its ability to block attack by white blood cells and multiplication of muscle cells. CO may prove to be beneficial in the treatment of a broad range of diseases affecting blood vessels. In the study, there were no observed negative effects of the CO exposure on the animals, and studies are currently underway in pigs. - Nature Medicine, February 2003

Counter Attack

Bone marrow (BM) transplantation offers the hope of a complete cure for patients with immune deficiency diseases or certain forms of cancer, such as leukaemia. Yet such procedures often carry the risk that the transplanted cells may recognise the patient's tissues as foreign and begin an attack that, if unchecked, can be lethal. This is known as graft-versus-host disease. With the help of mice, researchers have now identified critical sites in the gut, called Peyer's patches, where these aggressive immune cells are first activated and then travel throughout the body to attack multiple tissues. Importantly, in mice that lacked Peyer's patches, graft-versus-host disease was avoided when donor immune cells were introduced. These results illustrate that a particular environment in the body is required to initiate graft-versus-host disease, and raise the possibility of a new therapies for bone marrow transplant patients. - Nature Immunology, February 2003

Stunning Views of Limb Regeneration

Employing a new high-tech type of scan called digital X-ray microtomography (microCT), scientists have discovered the way in which newts form new bone and cartilage during limb regeneration. Newts are a type of salamander, the only vertebrates capable of rebuilding lost structures such as limbs throughout their lifetimes. Researchers showed that bone formation in a regenerated forelimb combines elements of embryonic development and of adult wound healing. Results of their research, which have not been observed before in other studies, may have implications for replacement of limb parts missing from injury or birth defects, and, ultimately, for growing new tissue from parts of organs such as livers. MicroCT shows promise for detecting and characterising soft tissue structures, skeletal abnormalities and tumours in live animals, providing high-resolution images and rapid data acquisition. Now researchers can watch the process of rebuilding a limb over time in one living animal, and see what genes are doing and how they instruct the growth of new structures such as cartilage and bone. - Developmental Dynamics, February 2003

Antibodies Critical for Fighting West Nile Virus

Researchers have found that immune cells called B cells and the antibodies they produce play a critical early role in defending the body against West Nile Virus. Mice that lacked B cells and antibodies were completely unable to combat the virus. They developed serious brain and spinal-cord infection and ultimately died. These findings may help explain why the elderly and others with weakened immunity are most likely to develop serious disease when infected by the virus. West Nile Virus first emerged in eastern USA in 1999 and has spread steadily westward, reaching the West Coast last year. It is carried by mosquitoes and causes encephalitis, a brain inflammation. The virus affects mainly birds, especially crows and jays, but it also can cause disease in horses, humans and other mammals. In humans, West Nile Virus causes serious illness in a small proportion of infected people. Last year, doctors reported more than 3,500 cases of infection, with 5-10% of those resulting in serious illness or death. - Journal of Virology, February 2003

Red Dye Helps Huntington's

Researchers have successfully rid mice of a condition similar to Huntington's disease using a laboratory dye that dissolves clumps of abnormal proteins in the brain. This finding confirms that neurological diseases can result from protein clusters in the brain, but the dye is unlikely to end up as a treatment for humans. A similar procedure would be difficult in humans, because the dye - Congo red - does not cross the blood-brain barrier, which shields the brain from contact with body substances. Researchers administered Congo red to mice using a pump system that would be too difficult for humans. The mice were killed soon after they received Congo red, but if they had lived longer the protein clumps would probably have returned in their brains, and they would have needed another dose of Congo red. In future, medical science may develop a treatment that performs the same function as Congo red, and can cross freely from the blood into the brain. - Nature, 23 January 2003

Gene Required for Long-term Immunity

Scientists have shown that a gene called SAP is required to generate long-term immunity. By measuring the immune responses of mice genetically modified to lack SAP, researchers found that the gene's absence impairs the immune system's memory, namely its ability to recognise and react to infection. This finding has implications for research into vaccines, which by definition must engender long-term immunity. SAP was identified recently as the gene responsible for a lethal human genetic disease, X-linked lymphoproliferative disease, so this gene is clearly important for immune responses. The latest work shows that the SAP gene is a central player in long-term antibody responses, and indicates that manipulation of SAP may have therapeutic benefits in generating better antibody responses. - Nature, 16 January 2003

Leptin May Contribute to MS

The hormone leptin, primarily produced in fat cells, helps regulate food intake, metabolism and reproduction. It has also been shown to promote and sustain the body's immune response by binding to T lymphocytes - the frontline cells that protect against infection. The disease experimental autoimmune encephalomyelitis (EAE) in mice is currently used by researchers to mimic human multiple sclerosis (MS). Researchers now report that just prior to developing the symptoms of EAE, mice experience a significant burst of leptin which correlates with a reduction in food intake and weight loss. Subjecting mice to acute starvation, which prevents the production of leptin, was found to delay the onset and reduce the severity of disease. Modulating leptin concentration through diet, and/or the administration of drugs, may have potential in the treatment of MS and other autoimmune diseases. - Journal of Clinical Investigation, 15 January 2003

BID Towards Understanding Leukaemia

Scientists have discovered that mice lacking a gene called Bid develop the mouse equivalent of a type of adult human leukaemia. This finding shows that the BID protein, which encourages cell death, functions as a tumour suppressor, helping to maintain the delicate balance between cell survival and cell death in the bone marrow. BID-deficient mice succumbed to a form of leukaemia closely resembling human chronic myelomonocytic leukaemia (CMML): by 27 months of age, three quarters of the BID-deficient mice developed CMML. Human CMML generally affects older adults, but it can also occur in childhood. It is characterised by the uncontrolled growth of white blood cells called myelomonocytes. These cells crowd out and destroy other normal blood cells, like red blood cells and platelets, in the bone marrow of CMML patients. Over time, such alterations cause paleness, bruising, bleeding, and ultimately - without treatment - death. This discovery highlights potential roles for BID and similar proteins in tumour suppression and human disease. - Genes & Development, 15 January 2003

New Protective Role for Interleukin

An investigation of interleukin-6, a hormone inside cells often considered a 'bad actor' of the immune system because of its association with inflammation injuries and malignant diseases, shows that it also plays a therapeutic role in mice: it protects brain cells. Interleukin-6 - called IL-6 for short by researchers - may, in fact, be a 'white knight' for mouse brain cells, or neurons, as brain cells also are called. These results on genetically modified mice may be promising for humans as well. Every part of the brain is connected by neurons. Yet both the ageing process and many diseases - from Alzheimer's disease to multiple sclerosis to Parkinson's disease - are a steady assault on neurons. So identifying any factor that protects neurons or promotes their survival is an important step toward improving health as we age. This protective response holds considerable therapeutic significance since scientists already know how to make IL-6 in the laboratory. It may, therefore, be an appealing candidate for researchers to refine into an easily administered drug, although much basic science remains to be done. - Journal of Neuroscience, 15 January 2003

Cause of Rare Ageing Disease, Cancer

A rare and fatal genetic syndrome, Dyskeratosis Congenita (DC), may hold the key to understanding a mechanism that causes premature aging and cancer. Recreating DC in genetically altered knockout mice, researchers proved that the disorder was caused, by mutations in the DKC1 gene. Unexpectedly, they also showed that DC was caused by disruption to components in cells called ribosomes that manufacture proteins, and not due to shortened telomeres (at the end of chromosomes) as previously thought. This may have implications for development of drugs that kill cancer cells by specifically targeting ribosomes, in a similar way to some antibiotics for specific bacterial infections. In this study, mutant mice were generated that were an accurate model of the human disease, proving that mutations to the DKC1 gene cause DC with its premature aging, bone marrow failure and cancer. In fact, half the Dkc1 mice developed malignant tumours with the most common sites for these cancers being lung and breast, he added, noting that this suggests ribosome malfunction is important in the genesis of cancer and may have clinical implications for the identification of new molecular targets for cancer drugs. - Science, 10 January 2003

Gulf War Chemicals Can Damage Testes

A combination of chemicals given to protect Gulf War soldiers against deadly diseases and nerve gas may have inadvertently damaged their testes and sperm production, according to research using rats. The new study could explain why some veterans have experienced infertility, sexual dysfunction, and other genitourinary symptoms. Three protective chemicals were given to soldiers: the insect repellent DEET, the insecticide permethrin, and the anti-nerve gas agent pyridostigmine bromide. In a study designed to mimic the same conditions, researchers gave rats equivalent doses. When given together, the chemicals caused extensive cell degeneration and cell death in various structures in the testes. It appears that moderate stress, combined with the three chemicals, caused the most severe deterioration in testicular structure and sperm production, and these conditions were likely to have been experienced by some Gulf War soldiers in the combat environment. Now the task is to find the mechanisms to provide the soldiers with maximum protection and the least risk of chemical induced injury. - Journal of Toxicology and Environmental Health, 10 January 2003

Key to Normal Heart Development

Scientists who peered into the beating hearts of zebrafish embryos say that certain blood flow patterns in the organ are key to developing a healthy, normal heart. The same is probably true for human embryos. The researchers took advantage of the transparent nature of the zebrafish embryo and used a high-tech microscope to look through the embryo and into the beating heart. After measuring the velocities and patterns of blood flow, the team calculated the expected forces imposed on the heart chamber walls by the flowing blood. They surgically blocked the incoming or outgoing blood flow and found that diminished flow, and thus diminished forces on the heart wall, resulted in drastically altered development in the chambers, valves and orientation of the heart. Many of these changes were similar to those seen in cases of congenital heart disease and in zebrafish lacking key developmental genes. Although fish and humans are not closely related, they are both vertebrates, and therefore the findings are relevant to human heart development. The same processes occur in fish, amphibians, reptiles, birds and mammals during early heart development. - Nature, 9 January 2003

Second Serotonin Enzyme

Scientists have identified a second enzyme that is involved in making serotonin, a brain chemical associated with depression. And the genetic hardware of this newly identified enzyme is detected primarily in the brain, according to a study using genetically modified mice. The findings suggest that all past efforts to identify genetic reasons for mental disorders linked to abnormal serotonin production have focused on the wrong gene, and the discovery may lead to new diagnostic and therapeutic approaches. Serotonin synthesis occurs in a handful of extremely important brain cells and in some cells of the gut. It was believed for decades that only one enzyme controls the rate at which serotonin is made in all tissues. The discovery that a second enzyme is the source for serotonin in the brain opens a door to a completely new research area, and to better understanding of the biosynthesis of a compound related to a multitude of mood-controlling effects. - Science, 3 January 2003

Lowering Beta-amyloid in Blood

Agents that alter blood levels of beta-amyloid protein in mice with Alzheimer's disease may ultimately be used to treat the illness in humans. Beta-amyloid protein is a component of the amyloid plaques that accumulate in the brains of people with Alzheimer's disease. If agents that do not need to enter the brain can treat Alzheimer's disease effectively, pharmaceutical companies may be able to develop targeted drugs that have few effects on the central nervous system. In the new study, researchers injected the beta-amyloid binding agent gelsolin into the peripheral bloodstreams of mice bred to develop Alzheimer's disease. The brains of mice that received gelsolin had significantly less beta-amyloid protein than those that didn't. Use of gelsolin also led to a significant decrease in the number of brain plaques. The scientists saw similar results when they used another beta-amyloid binding agent, ganglioside GM1. They do not advocate using these particular agents as treatments for Alzheimer's disease in humans. Rather, they see this as an initial step in the development of compounds that may be more flexible, more reliable and less likely to cause side effects in long-term administration than vaccines. - Journal of Neuroscience, 1 January 2003

Bringing Oxygen to Active Brain Cells

When a brain region is active, blood vessels in the area expand to increase blood flow and deliver more oxygen to hard-working cells. This response, which is the signal detected by functional magnetic resonance imaging (fMRI), may be triggered by specialised supporting cells called astrocytes, which can detect nerve activity and signal nearby blood vessels to expand. Researchers stimulated nerve cells in slices of rat brain, causing nearby blood vessels to expand, and found a parallel increase in activity within astrocytes that were in close proximity to both the nerve cells and the blood vessels. When the researchers prevented the astrocytes from responding, blood vessel expansion was blocked. Directly stimulating the astrocytes mimicked the vessel expansion effect. In anesthetised rats, administering a drug that blocked activation of the astrocytes could reduce increased blood flow in the brain induced by stimulating a forepaw. These new findings indicate that astrocytes are important in linking neural activity to increased blood flow. - Nature Neuroscience, January 2003

T Cell Activation Induces Immunodeficiency

One of the hallmarks of infection with HIV is a reduction in the number of certain immune system cells - CD4 T cells - to dangerously low levels. How this depletion occurs, whether by direct killing of the CD4 T cells or long-term activation of the immune system, was not understood. Scientists have now shown, using mice, that persistent immune activation, even with no viral infection, can indeed lead to immunodeficiency. They generated mice in which T cells are constantly activated - mimicking the immune system during a persistent infection with HIV. Chronic activation of the immune system induced a progressive depletion of T cells that was reminiscent of HIV-induced immunodeficiency. After six to eight months the mice succumbed to opportunistic infection, again mimicking HIV's effects on humans. This study therefore shows that persistent immune activation can cause lethal immunodeficiency. Damping down a chronically activated immune system could perhaps benefit HIV-infected individuals. - Nature Immunology, January 2003

Cell-based Vaccine Counteracts AIDS Virus

AIDS virus researchers may have edged closer to vaccine against HIV in experiments on macaques. Macaques develop AIDS after infection with SIV (simian immunodeficiency virus), a virus related to HIV. Researchers now report that a vaccine based on immune cells achieved dramatic reduction of levels of SIV in the blood. Moreover, the numbers of CD4 T-cells increased, another good indication of a robust immune response against the virus. The vaccine was constructed by treating immune cells called dendritic cells from an individual animal with chemically inactivated virus. The inactivated virus binds, fuses and enters dendritic cells in culture, but the virus's life cycle is halted before it begins to reproduce itself. After incubation with inactivated virus the cells were then injected back into the animal. The results must be verified in other types of primates - for example, the current study used Chinese macaques, whereas most studies so far have been performed on Indian macaques. How long the effect of the vaccine lasts also remains uncertain. But if the approach is confirmed in monkeys and successfully adapted in humans, it may represent a major new therapeutic approach to HIV-1. - Nature Medicine, January 2003

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Revised 8/3/04