Southwest Association for Education in Biomedical Research - SwAEBR

Research Focus 2001:

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

Milking Animals for Malaria Vaccine
A cheap malaria vaccine purified from milk produced by genetically modified mice has successfully protected monkeys against the disease. Only one of five immunised animals contracted the disease, but six out of seven unvaccinated monkeys had to be treated for malaria. Researchers created a strain of mice carrying a form of the gene for a surface protein from the malaria parasite, Plasmodium falciparum. The gene was designed to be switched on by cells lining mouse mammary glands, so the protein, called MSP142, would be secreted into the milk. The researchers also modified goats to produce the protein in their milk, raising the prospect of a cheap way to mass-produce a malaria vaccine to save millions of lives. They commented that one herd of goats could produce enough vaccine for the whole of Africa. The next step will be to find out whether the vaccine produced in goats' milk also protects monkeys. However, some have cautioned that the existing vaccine would probably have to be modified to include more proteins if it is to protect people living in areas where malaria is rife. - Proceedings of the National Academy of Sciences, early online edition, 18 December 2001

Blocking Tumour Growth
Researchers have identified a promising new target for cancer chemotherapy that could impact on tumour formation and the spread of secondary cancers by inhibiting cell growth. Tumour growth was blocked in the test tube and in laboratory mice by interfering with the cell's ability to supply itself with vital substances called polyamines. Cells depend on polyamines for growth, and there are normally two pathways to ensure an adequate supply. Cells produce their own internally, and they also gather circulating polyamines. The researchers showed that blocking a cell-surface sugar molecule called heparan sulphate stopped the cell's supply pathways for polyamines resulting in a dramatic reduction in tumour formation in mice. - Proceedings of the National Academy of Sciences, early online edition, 18 December 2001

New Light on Psoriasis
Scientists have discovered a critical protein involved in skin inflammation. The study, conducted on mice, sheds new light on the molecular mechanism of wound healing and identifies a potential new drug target in the treatment of skin disorders such as psoriasis. The skin is the first line of defence against injury and infection. Upon injury, specialised skin cells called keratinocytes receive signals that send them to the site of the injury, where they initiate the wound healing process. These signals actually prompt a gene called PPARbeta to produce a protein that in turn activates the genes responsible for keratinocyte action. Mice lacking PPARbeta do not heal wounds properly, and by studying these mice researchers have found the reason: the mice have too few keratinocytes at the injury site. - Genes & Development, 15 December 2001

Modelling Lung Cancer
Independent research groups have developed mouse strains that can control the timing and extent of lung cancer. These mice shed new light on the initiation and maintenance of the most prevalent form of this disease. Pulmonary adenocarcinoma is the most common type of lung cancer, in which the gene K-Ras will be mutated into an active, cancer-promoting form in about a third of cases. The role of K-Ras in cancer development is one of the most actively pursued cancer research topics. Both mouse strains present significant advantages over existing mice used to study lung cancer. In one strain a genetically modified virus, in the other an antibiotic, regulates activity of the K-Ras gene. These agents allow researchers to turn on the K-Ras gene at will and study the course of the disease. - Genes & Development, 15 December 2001

Gene Therapy Cures Sickle Cell in Mice
Sickle cell anaemia and thalassaemia are inherited haemoglobin disorders affecting people of African or Eastern Mediterranean descent. In addition to the resulting anaemia, misshapen red cells get stuck in blood vessels, leading to painful episodes and ultimately organ damage. A new gene therapy method corrects sickle cell disease in mice, and may suggest future therapies to treat the genetic disease in humans. The therapy counteracts the faulty gene that causes red blood cells to "sickle" or deform, by transferring an anti-sickling variant of the gene to bone marrow with a viral delivery system. Once there, the anti-sickling gene incorporates itself into the stem cells that give rise to red blood cells. In two mouse strains, the new gene was rapidly expressed in 99% of all circulating red blood cells, preventing sickling and other signs of the disease. - Science, 14 December 2001

Sudden Heart Failure
Researchers have discovered a gene that may be linked to sudden heart failure. The single gene - called KChIP2 - was identified in mice, but humans are known to have a version. The gene controls the electrical currents that maintain even heartbeats. When KChIP2 is defective, the currents are less active than normal. External triggers such as exercise or caffeine, or the heart skipping a beat, can cause a dangerous heartbeat pattern. The gene can either be permanently defective or become switched off, and when this happens people are at increased risk of developing irregular heartbeats, which can lead to sudden death. The next stage is to identify the precise chain of events that causes the gene to be switched off. - Cell, 14 December 2001

Protecting Cells from Stroke Damage
An oxygen-carrying protein in brain cells may help protect them from the damaging effects of oxygen deprivation. Researchers say that the findings - from research with cultured cells and mice - could lead to ways to prevent brain damage following stroke. The protein, called neuroglobin, is similar to haemoglobin, the oxygen-carrier in red blood cells. But the function of neuroglobin has been unclear since its discovery about a year ago. The protein binds to oxygen and exists primarily in nerve cells, so the researchers examined whether neuroglobin acts when the brain is starved of oxygen. They found that oxygen deprivation caused nerve cells to churn out more neuroglobin, both in cultured cells and in mice with a stroke-like condition. Moreover, the cell experiments showed that this elevated neuroglobin protected nerve cells from damage, so it may be possible to treat stroke with a drug that would increase neuroglobin levels. But researchers first need to find out whether increasing neuroglobin prevents stroke damage in animals. - Proceedings of the National Academy of Sciences, online early edition, 11 December 2001

Regulating the Gut
A gene that governs development of nerve cells has now been shown to be involved in regulating differentiation of stem cells into secretory cells in the intestine. Researchers showed that the Math1 gene is necessary for the differentiation of three kinds of intestinal cells from stem cells. To pinpoint the gene's activity, the researchers studied genetically engineered mice without the gene. In these mice, three kinds of cells, normally present in the lining of the gut, were missing. These cells are responsible for secreting substances necessary for digestion and protection against microorganisms. This finding could eventually lead to new treatments for such diseases as irritable bowel syndrome and colon cancer, or to treatments to regenerate damaged intestinal tissue. - Science, 7 December 2001

Doubt on Growth of New Adult Brain Cells
The brains of mammals, including humans, have a neocortex which researchers believe is responsible for higher cognitive functions such as thought and planning. Recently, neuroscientists have been unable to find any evidence that adult primates are able to create new neurons in the neocortex. The results run counter to a widely publicised report two years ago when other researchers reported the first discovery of neurogenesis - formation of new neurons - in the neocortex of adult monkeys. Using similar techniques to the 1999 study, the researchers used molecular markers to track dividing cells in the monkeys' brains. Analysing the neocortex, the researchers looked for cells that carried both markers, indicating that a new cell had formed and secondly that it was a nerve cell. Although they found new cells in other regions of the brain, the researchers failed to find new cells in the neocortex. - Science, 7 December 2001

Obese Mice May Help Heart Patients
New treatments for heart disease and diabetes could result from research on obese mice. Scientists have found that blocking the activity of an enzyme in fat cells protects mice against high cholesterol levels, diabetes and heart disease, even if they are obese around the middle, which is known to raise the risk of these disorders. The findings suggest that similar techniques could be used to prevent all three conditions in humans. The team found that the hormone cortisol, a natural defence against stress, is one of the main reasons for heart disease and related disorders. Their work has also shown that an enzyme that stimulates cortisol production in fat cells, known as 11ßß HSD-1, is much more active in "apple-shaped" obesity, leading to an increased risk of high blood pressure, raised cholesterol levels, diabetes and heart disease. - Science, 7 December 2001

Spraying Away Bacteria
Researchers are planning clinical trials of a nasal spray which could be a powerful weapon against infection. The spray contains an enzyme taken from viruses which attack and kill bacteria. In tests on mice it wiped out one of the most notorious infectious bugs, Streptococcus pneumoniae. Unlike antibiotics, the "phage" enzyme does not create drug resistance. The new approach used an enzyme employed by the phage virus that kills bacteria by punching holes through cell walls. The phage enzyme, called Pal, killed 15 common types of Streptococcus pneumoniae, bacteria that can cause ear and throat infections, pneumonia and bacterial meningitis. They used the phage enzyme to eliminate the bacteria present in the nasopharynx, the area between the back of the nose and the throat, in laboratory mice. They also showed that it can kill penicillin-resistant strains of the bacterium. A nasal spray containing this enzyme would prevent infections before they start. - Science, 7 December 2001

Bigger Brains Not Better
Researchers have discovered that a gene previously implicated in several forms of cancer is also a key regulator of nerve stem cell proliferation. Understanding how the protein expressed by the gene PTEN affects the multiplication of these stem cells could aid efforts to use stem cells in treating neurological disorders. Understanding how knocking out PTEN in adult animals triggers cancers could also lead to drug therapies for cancers. PTEN is the second most frequently deleted tumour suppressor gene, giving rise to human cancers including brain, breast, prostate, and endometrial cancers. There is also evidence that the PTEN protein plays a normal role in neural development. The researchers discovered that deleting Pten in mouse embryos appeared to hyper-activate signals that that regulate cell proliferation and cell death in the brain. There was a significant increase in brain size in the mutant animals, and an increase in the size of the brain cells themselves. - Science, 7 December 2001

SOD Reduces Joint Disease
The painful inflammation and debilitating joint damage characteristic of rheumatoid arthritis may be reduced or prevented with a new approach using small-molecule 'enzyme mimetics'. A study in rats showed that a compound mimicking superoxide dismutase (SOD) substantially reduced the erosion of cartilage and bone, as well as chronic inflammation. The compound, called M40403, also markedly reduced levels of immune system signalling molecules that increase inflammation and are known to be involved in the development of arthritis in humans. In the study, researchers evaluated the effects of daily doses of M40403 on the development and progression of arthritis in rats. They found that M40403 halved inflammation and reduced joint damage by at least 70%. These promising compounds are highly stable and do not appear to provoke an immune response in the body. Furthermore, the chemical structure of the compounds can be easily optimised for application to different diseases and conditions such as pain, inflammation and cancer. - - Arthritis & Rheumatism, 10 December 2001

Gene Link to Lung Cancer
A gene has been identified that may help scientists understand the biology of lung cancer. Studies in mice showed that when the gene, known as Dutt1/Robo1, is missing during foetal development the lungs grow abnormally. When the gene was deleted from a group of mice, 63% died at birth. Those that survived went on to develop pre-cancerous abnormalities in their lungs similar to those which herald lung cancer in humans. The researchers believe that when the gene is defective it may open the door for cancer triggers such as tobacco tar. Further work is expected to lead to better ways of investigating the link between genetic mutations and lung cancer. - Proceedings of the National Academy of Sciences, early online edition, 4 December 2001

 Clues to Wasting
Cancer, AIDS and other types of chronic diseases are often accompanied by wasting caused by a drop in albumin levels. Patients with wasting become progressively weaker and may even die. Now, researchers using mice have unravelled some of the causes of wasting syndrome, which may shed light on ways to treat and prevent it. The team studied mice specially bred to produce high levels of a substance called TNF-alpha, which they knew played a role in causing wasting syndrome. They also treated liver cells directly with TNF-alpha. They found that the abnormalities caused by TNF-alpha were similar to those seen in the livers of cancer patients with wasting syndrome, the end result being a block on albumin production. Importantly, they found they could prevent these abnormalities by treating the mice with antioxidants and another substance that blocked the cascade of events caused by TNF-alpha, suggesting possible therapies for wasting syndrome. The next task will be to assess other medications to see if they can prevent the biochemical changes observed, first in the animal model and eventually in patients. - European Molecular Biology Organization Journal, 3 December 2001

Optic Nerve Regenerates
Neurologists have found a way to reconnect severed optic nerves to the brain so that they once again transmit normal electrical signals. The achievement is a first in mammals, and may hint at ways of reversing some types of blindness in people. It may be possible to use a version of the technique to treat people with spinal cord injuries. Researchers got severed nerves to regrow up to 14mm - more than three times as far as anyone has managed before. They anaesthetised rats and severed their optic nerves, then they sutured the two cut ends back together, finally they released proteins called crystallins, known to inhibit apoptosis - the mechanism by which cells self-destruct. Three months after the surgery, about 30% of the nerve fibres had regenerated. Just 10% is sufficient for residual sight. The regenerated nerves also carried normal electrical signals, suggesting that they had rewired themselves into the brain, although the connections were a bit scrambled. The team is currently studying the rats` behaviour to assess how their eyesight. - - Experimental Neurology, 1 December 2001

Delayed Treatment, Better Recovery?
Rats given an experimental therapy several weeks after spinal cord injury showed dramatically greater regrowth of nerve fibres and recovery of function than rats treated immediately after injury, a new study shows. This suggests that the window of opportunity for treating spinal cord injury may be wider than previously thought. The researchers used a combination therapy of foetal spinal tissue transplants and nerve growth factors, or neurotrophins. Earlier studies in animals have shown that foetal tissue transplants and neurotrophins can improve regrowth of injured nerve cells in the adult spinal cord, and that some injured nerves can regrow even after long periods of time. However, the new study is the first to show that spinal cord regeneration is actually improved when treatment is postponed until most of the initial injury-related changes in the rat spinal cord and the surrounding environment have stabilised. - Journal of Neuroscience, 1 December 2001

Clues about Breast Cancer GenesScientists have discovered a link between p53, a gene that is often defective in cancer, and BRCA2, a gene known to play a role in about one third of all hereditary breast cancer cases. Working with mice, they studied the effects of the cancer-promoting gene p53 on the breast cancer gene BRCA2. Mice genetically engineered to have defects in both copies of the BRCA2 and p53 genes were much more likely to develop tumours than mice that only had defective BRCA2 genes. The study supports the idea that BRCA2 and p53 boost each other as suppressors of mouse mammary-gland tumour formation. The genetically engineered mice could be used to test strategies for preventing and treating breast cancer. - Nature Genetics, December 2001

Replacing Damaged Eye Cells
Researchers have found a potential way to replace damaged rod and cone cells in the eye's retina. Their research on rats showed that photoreceptor-like cells could be created from the iris, which is not normally reactive to light. The genetic technique, in which cells are taken from the iris, modified in the laboratory and transplanted back into the retina, could some day prevent blindness from degenerative diseases of the retina such as macular degeneration and retinitis pigmentosa. - Nature Neuroscience, December 2001

Gene Protects Nerve Fibres
Scientists have discovered a mutant protein in mice that slows down the degeneration of nerve fibres after injury. Although the same protective protein is unlikely to be found in humans, studying the protein in mice may lead to ways to protect nerve fibres in people. Normally, axons, the long connections between nerves, degenerate within 48 hours of being cut. But in a particular strain of genetically engineered mice, this degeneration goes into slow motion, taking several weeks. Why axons are protected in these mice was unknown, but now a team has identified a gene in the mice that contains the instructions for an axon-protecting protein. This discovery not only opens new therapeutic possibilities through the use of the protein itself, but also may help scientists to determine how the nerves are protected, by looking at the functions of the protein. - Nature Neuroscience, December 2001

Rapid Reaction Force
How do our bodies know when a virus is lurking? In mice a specialised immune surveillance cell has been identified that responds to the presence of viruses by rapidly releasing massive amounts of interferon-alpha, which induces an anti-viral state throughout the animal. Interferon-alpha-producing cells (IPCs) were shown to be the major producers of interferon-alpha, which plays a crucial role in limiting early virus spread and activates cellular mechanisms to interfere with viral replication. Finally identifying this cell in mice provides a system to test for the optimal means of inducing IPCs when needed. - Nature Immunology, December 2001

Route for HIV Vaccines
Mucosal surfaces, such as the lining of the mouth and anus, are a way into the body for HIV infection, particularly since they lead to the intestine, which provides the best conditions for the virus to replicate. Thus, developing a vaccine that would prevent HIV entry through mucosal surfaces is paramount to fighting the AIDS epidemic. A team of researchers has compared the protective ability of a vaccine given subcutaneously and via the rectum to macaque monkeys. The vaccine was a combination of parts of the HIV virus known to stimulate the body's defences. The scientists found that when they administered the vaccine at the mucosal surface of the rectum it was more effective at preventing infection with simian/human immunodeficiency virus (S/HIV) than when the same vaccine was given subcutaneously. - Nature Medicine, December 2001