VATIS Update Biotechnology . Jul-Aug 2006

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ISSN: 0971-5622

VATIS Update Biotechnology is published 4 times a year to keep the readers up to date of most of the relevant and latest technological developments and events in the field of Biotechnology. The Update is tailored to policy-makers, industries and technology transfer intermediaries.

Co-publisher: Biotech Consortium India Ltd
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United Nations commission to study HIV/AIDS in Asia-Pacific

UNAIDS, the Joint United Nations Programme on HIV/AIDS, has set up a commission to study the disease and its impacts on development in Asia and the Pacific. The ten-member commission is examining the state of the epidemic, including disease incidence and levels of awareness, prevention and treatment. It is also assessing the epidemics medium- to long-term socio-economic impacts, including its effects on national budgets and health systems.

Scientists have predicted a rapid growth of HIV infections in the next two to three years in China and Bangladesh China because they fear the governments are underestimating the epidemic and not implementing adequate strategies to control it. Dr. Tim Brown, Commission Member and Senior Research Fellow at the East West Centre in the United States said that there are many countries in the region that are not on the radar because of seemingly low prevalence but the epidemic could spread fast if unchecked.

The commission would not duplicate the work of existing agencies but would look at available data and assess how to close the data gaps, said its Chairman Dr. Chakravarthi Rangarajan, who also chairs the Indian governments Economic Advisory Council. Dr. Maire Bopp, founder of the Pacific Island AIDS Foundation, told that Asia and the Pacific were two vastly different entities and it would be a challenge to create a common framework of action for the region as a whole.


Africa seeks common stance on genetic modification

A high-level panel of experts in Nairobi said that Africa might be forced to consume genetically modified food products made in other continents in future if it fails to nurture its own research capacity on genetic modification (GM). The African Union set up the panel of 14 experts to make recommendations on whether the continent should adopt GM research, and argued that African leaders needed unbiased research on the benefits and disadvantages of GM research before making a decision.

Kenyan legislators said that they would be dismayed by any plans to make their nation rely on externally manufactured research material to be adopted for implementation without the due expert knowledge. An official of the African Agricultural Technology Foundation, Nairobi, said that the panel needs to recommend what Africa needs to do and they must keep building on what they have already done. African leaders will hold the first-ever scientific conference early next year to discuss the GM research before a full summit of the heads of state in January 2007.


A global health centre to fight against diseases

Johns Hopkins University, the United States, plans to launch a new centre for global health, which would coordinate efforts to fight against diseases such as HIV/AIDS, malaria, avian flu and heart diseases. The new centre would integrate the work of the Universitys medical school, nursing school and the Bloomberg School of Public Health.

Dr. Thomas Quinn an infectious disease expert who has been studying HIV/AIDS in Africa, Asia and Latin America for 20 years would head the centre. The centre will receive annual funding of US$800,000 from the three schools. The staff members of the centre plan to work with advisory committees to identify global health problems, draft solutions, address challenges and locate financial resources.


EU and the United States work jointly on biotechnology research

The renewal of an administrative arrangement for the European Union-United States Task Force on Biotechnology Research was signed by Dr. Janez Potoenik, European Science and Research Commissioner. Since 1990, this Task Force has been fostering the transatlantic dialogue of the European Commission with the United States government to underline Europes role as an important player in life sciences and biotechnology research. The core topics of the discussion included: new developments in life sciences and biotechnology creating added value in society; improvement in medical diagnosis, treatment and care; enhanced sustainability through optimal use of biological renewable resources; and reducing the adverse effects on agriculture, industry and aquaculture.

The transatlantic biotech Task Force brought together officials, scientific leaders and researchers in their early careers to forecast research challenges and promote better links between scientific communities. It addressed topics such as synthetic genomics, environmental biotechnology, plant science, and plant-based bio products, obesity, and emerging infectious diseases, like avian flu and SARS.


US$3 billion bid to boost biotech in Brazil

The Brazilian Forum of Biotechnology Competitiveness which includes government agencies, the private sector and academic institutions has announced a multi-billion-dollar strategy with the aim of making the country a world leader in biotechnology. It has identified research areas that have the potential to boost the competitiveness of Brazilian industry, increase Brazils participation in global trade, speed up its economic growth and create jobs. The plan entails creating new funding mechanisms, training and improving the infrastructure of research institutions.

The overall cost of putting the plan into action is estimated to be US$3 billion, which would be provided by the public and the private sectors. Of this, more than US$530 million is earmarked for health-related biotechnology, including the production of drugs and vaccines for neglected diseases and cutting-edge research in the fields of genomics, proteomics, nano-biotechnology and stem cell science. The document calls for an urgent, intense and integrated effort from the government, industry and academia to enable Brazil to appear, in 10-15 years, among the leaders in biotechnology industry, especially in the areas of human health, farming and cattle raising, and industrial biotechnology.


Funding boost for research into TB and malaria drugs

The Bill and Melinda Gates Foundation has provided US$104 million for tuberculosis research, according to an announcement by the Global alliance for TB Drug Development (TB Alliance), a public-private partnership that would undertake the work. The money will accelerate the development of 11 potential drugs, with the long-term goal of treating the disease with just 10 doses where the current TB drugs require up to 130 doses.

According to Dr. Peter Small, Senior Programme Officer at the Gates Foundation, new treatments could free patients from the gruelling 6-month regimen and, ultimately, save millions of lives. If patients dont complete their treatment, which could be due to drug supply interruption, there is a possibility of multi-drug-resistant forms of the bacterium emerging. Standard TB and HIV drugs cannot be combined easily but according to Dr. Maria Freire, Chief Executive Officer and President of TB Alliance, a package of new drugs would be able to treat people co-infected with HIV and those suffering multi-drug-resistant forms of the disease.

In another development, Novartis Institute for Tropical Diseases has announced that it would lead a new public-private partnership to find new drugs to treat malaria. The alliance involves the Welcome Trust, Singapore Economic Development Board and Medicines for Malaria Venture, which together will provide US$20 million in funding.



Biotech industry close to net profit

In the United States, a strategic collaboration was formed between Celera Genomics, an Applera Corporation business, and Medarex Inc. to discover and develop fully human antibodies for the potential treatment of multiple cancer indications. The collaboration would encompass the development of therapeutic antibodies against proteins identified by Celeras proteomic research discovery efforts as being over-expressed on the surface of tumour cells and validated through additional research at Celera. The collaboration combines Celeras ability to discover and validate novel targets for oncology with Medarexs expertise in the development of fully human antibody therapeutics.

Under the collaboration, Celera and Medarex plan to jointly select targets from Celeras portfolio of novel cancer targets. Medarex expects to generate fully human monoclonal antibodies against these targets using its proprietary UltiMab human antibody development system, and the two companies expect to jointly carry out initial validation studies. Celera and Medarex aim to alternate the selection of antigen-antibody research projects to further develop and commercialize the antibodies independently. The selecting party would have full development and commercialization rights to products that result from its selected research programmes, and the other party would be entitled to receive milestone payments, if milestones are achieved, and royalties on commercial sales of any such products. The selecting company might develop antibodies generated under this collaboration internally or through external partners.


Invitrogen and HUPO enter research partnership

Invitrogen Corporation, the United States, and the Human Proteome Organization (HUPO), Canada, have entered a scientific collaboration focused on advancing proteomic research through education initiatives, standardization of research protocols and development of advanced proteomic products. Under the terms of the collaboration, Invitrogen scientists would support efforts driven by HUPO and its members internationally to develop new proteomic standards, products and processes. Invitrogen will also support a number of global educational programmes and resources.

Dr. Gregory T. Lucier, Chairman and CEO of Invitrogen, said that their partnership with HUPO would enable their researchers to work closely with thought leaders in the field of proteomics. By collaborating with leading protein laboratories internationally, Invitrogen and HUPO plan to foster a set of industry standards to enable large-scale data generation and analysis, consistent with the mandate of HUPO to shape the next phase of disease research and drug discovery. HUPOs education and training initiative offers programmes to promote expertise in all areas of proteomics including sample preparation, protein separation, mass spectrometry, bioinformatics and experimental design.

Invitrogen has already developed a comprehensive technology portfolio for proteomic research. Highlighted by systems such as its ZOOM Benchtop Proteomics fractionation and electrophoresis products, SILAC mass spectrometry reagents and its flagship ProtoArray protein microarray, the company has introduced several innovative platforms as a part of its extensive offerings.


SemBioSys obtains rights to platform-enhancing technologies from Syngenta

SemBioSys Genetics, a biotechnology company in Canada developing a broad pipeline of protein-based pharmaceuticals and non-pharmaceutical products, has announced an agreement to acquire technology assets and in-license intellectual property related to the manufacture of biopharmaceuticals in safflower from Syngenta Crop Protection AG, Germany. The assets and intellectual property will allow SemBioSys to further increase its efficiency in transgenic safflower development.

Dr. Andrew Baum, President and CEO of SemBioSys Genetics, said that this technology would improve their productivity, expand their ability to make decisions early in the development process and allow them to accelerate new products into the clinic. The agreement specifically provides SemBioSys with a licence to Syngentas proprietary safflower transformation technology including all of Syngentas improvements to safflower transformation and propagation as they apply to plant-made pharmaceuticals as well as other products of SemBioSys. SemBioSys has also acquired information related to the genome sequence and structure of safflower.


EiRx therapeutics and bioMrieux announce collaboration

EiRx Therapeutics plc of Ireland has announced that it has entered into a collaboration agreement with bioMrieux SA of France to work together to validate the diagnostic and therapeutic potential of candidate tumour markers emerging from their respective cancer research programmes.

EiRx and bioMrieux both undertake research into the expression of genes and proteins within tumour samples from cancer patients, aiming to identify biomarkers associated with the development and progression of the disease. Biomarker technologies are expected to contribute to the improved diagnosis and treatment of cancer, and to accelerate the development and clinical evaluation of new medicines. As such, they are vital to the emerging science of personalized medicine and represent a major area of investment for the life sciences industry. During the collaboration, bioMrieux would explore the utility of proteins from EiRxs biomarker panel as components of new and improved diagnostic tests for colorectal cancer. At the same time, EiRx will employ its siRNA-driven functional validation platform to explore the utility of bioMrieuxs colorectal biomarker panel as targets for new drug therapies.


Novozymes acquires Delta Biotechnology

Novozymes, the United States, has signed an agreement to acquire Delta Biotechnology Ltd., United Kingdom, from the Aanofi-Aventis group. Delta Biotechnology is a small technology-driven company involved in the research, development, production and sale of microbially produced recombinant proteins. Delta Biotechnology has a strong position in the market segment of recombinant human albumin, an ingredient used in the biopharmaceutical industry as replacement for human serum albumin.

The companys sales amounted to about US$17 million in 2005 and have mainly been based on annual sales of Recombumin for the formulation of biopharmaceutical products. The company also has in its pipeline projects for other quality grades of recombinant albumin and recombinant transferrin, which may be used as ingredients for cell culture media in the future. Furthermore, Delta Biotechnology has developed a platform for producing recombinant proteins based on Albufusion technology. Novozymes took over Delta Biotechnology Ltd. as part of its strategy of acquiring businesses that could strengthen its market position.


GlaxoSmithKline and Galapagos enter into alliance in osteoarthritis

GlaxoSmithKline (GSK) UK Ltd., United Kingdom, and Galapagos NV, Belgium, have announced the creation of a worldwide, drug discovery and development alliance in the field of osteoarthritis. GSK, through its recently established Centre of Excellence for External Drug Discovery, and Galapagos will collaborate to deliver disease modifying drugs with clinical proof of concept to GSKs global research and development organization. This alliance builds upon Galapagos internal target and drug discovery programmes in the area of osteoarthritis.

The aim of this turnkey agreement was for Galapagos to expand its portfolio of novel validated targets in the field of osteoarthritis, to conduct compound screening, identify tractable hits, pursue a number of hit-to-lead programmes, and develop the resulting leads into candidate selection compounds through to a successful proof of concept in clinical research Phase IIA. GSK will have exclusive options to further develop and commercialize these compounds on a worldwide basis. On the other hand, Galapagos will have the right to further develop and commercialize compounds for which GSK does not exercise its option.



A gene predisposing to pituitary tumours identified

A recent Finnish study identified a low-penetrance gene defect, which predisposes carriers to intracranial tumours called pituitary adenomas. It was found that individuals carrying the gene defect were particularly susceptible to such tumours, which secrete growth hormone. Excess of growth hormone results in conditions called acromegaly and gigantism. The research group, lead by Prof. Lauri Aaltonen of University of Helsinki and Dr. Outi Vierimaa of Oulu University Hospital, provided the initial observations leading to the investigations, aimed at unravelling the genetic basis of susceptibility to pituitary adenomas. Pituitary adenomas are common benign neoplasms, accounting for approximately 15 per cent of intracranial tumours.

Most common hormone-secreting pituitary tumour types over-secrete prolactin or growth hormone, which together with local compressive effects account for their high morbidity. The researchers detected three clusters of familial pituitary adenoma in northern Finland. They suspected that a previously uncharacterized form of low-penetrance pituitary adenoma predisposition (PAP) could be contributing to the disease burden in the region. The researchers had previously characterized a population-based cohort diagnosed with growth hormone secreting pituitary adenoma in the Oulu University Hospital. These data were linked to the pedigree information, to identify additional affected distant relatives.

The PAP phenotype, a very low-penetrance susceptibility to somatotropinoma and prolactinoma, did not fit well to any of the known familial pituitary adenoma syndromes. Low penetrance indicated hereditary predisposition, which relatively rarely lead to actual disease but might cause much more effect on population level than high-penetrance disease susceptibility. The results suggested that inherited tumour susceptibility might be more common than previously thought. The identification of the PAP gene showed that the new DNA chip-based technologies could identify causative genetic defects in low-penetrance conditions even without a strong family history.


Gene therapy for cancer found effective in mice

An ovarian cancer study led by Dr. David Barlett at the University of Pittsburg Medical School, the United States, has suggested a new route for treating the deadly cancer. Most ovarian cancer patients survive four years or less after they are diagnosed. The study revealed that the current treatments for ovarian cancer were fairly harsh while gene therapy represented a potent, nontoxic alternative for treating the deadly disease.

At a meeting of the American Society of Gene Therapy, the United States, Dr. Barlett and colleagues said that they injected mice with ovarian cancer cells and treated some of the mice immediately with a virus genetically engineered to carry cytosine deaminase, a so-called suicide gene that helps cancerous cells self-destruct. Some other mice were treated with gene therapy 30 or 60 days later, while a third group was not given any treatment. Tumours did not grow in the mice that were treated immediately with gene therapy, and those treated a month or two later had tumours that grew only very slowly. The untreated mice either died or had to be euthanized because of their quick cancer progress.

The team from University of Pittsburg used gene therapy to deliver a compound called manganese superoxide dismutase-plasmid liposome to mice, and then exposed it to radiation. The compound is known to protect cells from the effects of radiation. Untreated mice irradiated at higher doses lost weight and died fairly rapidly owing to bone damage. But mice treated with the gene therapy lost no weight, had little bone-marrow damage and lived longer. This treatment has been shown to be most effective when administered before exposure to radiation.


IVF could cause errors in genetic imprinting

Researchers investigating genetic imprinting in mouse embryos had shown that certain culture media and concentrations of oxygen altered the expression of several imprinted genes. Imprinting is a process by which some genes are activated or inactivated depending on whether they have been inherited in chromosomes from a parent.

A team led by Prof. Paolo F. Rinaudo, a scientist at the Centre for Reproductive Sciences, California, the United States, found that the culture of mouse embryos in the laboratory is sufficient to alter the expression of many imprinted genes and that this effect can be modified by the composition of the culture medium and oxygen concentration. The expression of one gene, H19, was reduced regardless of the culture conditions. Prof. Rinaudo and his colleagues cultured mouse embryos in four media with 5 per cent oxygen. Two of the four media were also used with 20 per cent oxygen, making six different cultures in total. As a control some embryos were left to mature in the mice (in vivo).

The researchers identified 38 imprinted genes, most of which showed no difference in expression after in vitro culture compared to the in vivo embryos. Fives genes showed statistical differences with the control. The expression of one gene, H19, which is associated with Beckwith Wiedeman syndrome, was reduced regardless of the culture conditions. Emerging evidence shows that some neurological and behavioural abnormalities are associated with assisted reproductive techniques. Beckwith Wiedeman syndrome and Angelman syndrome in humans were found to be associated with aberrant genomic imprinting.


Species split more recent, human and chimp genomes reveal

According to a new study by scientists at the Broad Institute of MIT and Harvard, and at Harvard Medical School, the United States, the evolutionary split between human and chimpanzee was much more recent and more complicated than previously thought. The results in the paper published in Nature showed that the two species split no more than 6.3 million years ago and probably less than 5.4 million years ago.

Dr. David Reich, the senior author of the paper and an assistant professor at Harvard Medical School, said that the study gave unexpected results about how humans separated from their closest relatives, the chimpanzees. The researchers found that the population structure that existed around the time of human-chimpanzee speciation was unlike any modern ape population.

While the previous studies focused on the average genetic difference between human and chimpanzee, the new study looked at the complete genome sequence to reveal the variation in evolutionary history across the human genome. The genome analysis revealed that the speciation occurred in an unusual way that left a striking impact across chromosome X, according to Dr. Eric Lander, Director of the Broad Institute. Possible hybridization followed by interbreeding and then final separation explained the strange phenomenon seen on chromosome X.


Down syndrome gene identified

Researchers at the Stanford University School of Medicine and Lucile Packard Childrens Hospital, the United States, identified one possible cause of mental retardation in Down syndrome a gene that, when over-expressed, causes neurons responsible for attention and memory to shrivel and stop functioning normally. Most of the people with Down syndrome also develop Alzheimers disease by the age of 40. The researchers tried to correlate one of the most troubling symptoms, cognitive dysfunction, with one particular gene. While it was not the only gene involved, its presence in three copies made a major difference.

This is the first time that mutations in the App gene get linked directly to degeneration of a specific group of neurons in the brains of those with Down syndrome. The breakthrough confirmed an idea suggested by previous research: neuronal degradation in people with Down syndrome results from an interrupted conversation between nerve cells in a specific part of the brain. A signalling neuron needs feedback to thrive. It releases neurotransmitters towards its neighbour and the target cell fires back such molecules as nerve growth factor, or NGF. Researchers used a mouse model, in which only about 140 genes including App were present in three copies, to follow NGFs journey from the membrane to the cell body of the signalling cell. They found that although NGF retrograde transport was severely compromised in the mouse, it was markedly increased when the third App copy was deleted. According to researchers, the App gene clearly influenced the transport of NGF in Down syndrome, though its functioning at the molecular level still needs to be elucidated.



New potential drug target in tuberculosis treatment

In Germany, scientists at the Hamburg Outstation of the European Molecular Biology Laboratory (EMBL) and the Max Planck Institute for Infection Biology in Berlin have obtained structural image of a protein that the tuberculosis bacterium needs for survival in human cells. This image revealed features of the molecule that could be targeted by new antibiotic drugs. Mycobacterium tuberculosis is dangerous because it hides and persists in the immune cells of our bodies. According to Dr. Matthias Wilmanns, Head of EMBL Hamburg, it can only persist there because of the activity of some key molecules.

A protein called LipB is essential for the organism because it activates cellular machines that drive the bacteriums metabolism. The researchers discovered that LipB was highly active in acutely infected cells, particularly in patients infected by multi-drug-resistant forms of M. tuberculosis. They saw in these cells a 70-fold increase in the production of LipB when compared with other cells. This strongly indicated an involvement in pathogenesis and made it an interesting target where traditional drugs had lost their efficacy. A structural picture of the protein yielded important clues about its activity. EMBL scientists purified LipB and obtained crystals of the molecule. Using the high-energy synchrotron radiation beamlines, they created an atom-by-atom map of the proteins structure. A high-resolution picture of the active site of LipB bound to a lipid inhibitor helped them to determine the function of the enzyme.

Unlike other organisms, M. tuberculosis has no back-up mechanism that could take over LipBs role. Therefore, an inhibitor blocking its active site would shut down key processes the bacterium needs to survive and replicate. As a very effective strategy for a drug, the scientists will now search for compounds that can do so. At the same time, they are continuing to look for other proteins as drug targets. They are now focusing on structures of molecules that help M. tuberculosis to persist in its dormant state and could become drug targets.


Asthma drug effectiveness dependent on genes

Researchers from the University of Dundee, the United Kingdom, have found that a specific genetic variant, known as the Arg/Arg-16 variant, renders the asthma drug salmeterol ineffective. Salmeterol is part of a group of drugs known as beta-agonists. These medicines are bronchodilators, or muscle relaxants, not anti-inflammatory drugs. They are used to help control moderate to severe asthma and to prevent night-time symptoms. The genetic status of Arg/Arg-16 variant is reasonably common.

The researchers studied a number of children and adolescents with asthma in Tayside, Scotland. Results indicated that, while most patients had their asthma well controlled using salmeterol, those with the Arg/Arg-16 variant had almost double the number of asthma attacks compared with those with the other forms of this gene. Dr. Somnath Mukhopadhyay of the University said that some patients with asthma could be failing to respond to inhaled salmeterol, but they have identified a likely cause for as the patients genetic status. If asthma is poorly controlled on salmeterol, then alternatives, rather than additional treatments, may be more useful.


Central nervous system beckons attack in MS-like disease

Researchers at Washington University School of Medicine, the United States, have shown that cells in the central nervous system (CNS) could sometimes send out signals inviting attacks on immune system. In mice, this resulted in damage to the protective covering of nerves, causing a disease resembling multiple sclerosis (MS).
The researchers found that they could prevent destructive immune cells from entering nervous system tissue by eliminating a molecular switch that sends come here messages to immune cells. Normally, flipping that switch causes immune cells to rush to the vicinity of the cells that sent the signals and destroy whatever they consider a danger, including nerve cell coatings. But in the mice in which the switch was removed, the researchers saw that immune cells previously primed by the scientists to attack the CNS did not enter the CNS, and the mice stayed healthy. In contrast, normal mice treated with the same hostile immune cells had numerous immune cells in their CNS tissue and developed MS-like symptoms.

The researchers determined that the astrocytes, the specialized cells that provide nutrients to neurons, were among the cells most active in sending signals to attract lymphocytes. The researchers found that astrocytes in mice produced chemokines as a response to activation of their TNFR molecules, which were found to be the molecular switch that sends calls to the immune cells. The research team will now study various regions of the brain to determine the types of signals sent to and from different areas of the CNS to the immune system.


New source of multi-potent adult stem cells in humans

Researchers at the University of Pennsylvanias School of Medicine, the United States, isolated a new source of adult stem cells that appear to have the potential to differentiate into several cell types. If their approach to growing these cells can be scaled up and proves to be safe and effective in animal and human studies, it could one day provide the tissue needed by an individual for treating a host of disorders, including peripheral nerve disease, Parkinsons disease and spinal cord injury. Using human embryonic stem cell culture conditions, the research team isolated and grew a new type of multi-potent adult stem cell from scalp tissue obtained from the National Institute of Healths Cooperative Human Tissue Network.

The multi-potent stem cells grow in what the investigators call hair spheres. After growing the raw cells from the hair spheres in different types of growth factors, the researchers were able to differentiate the stem cells into multiple lineages, including nerve cells, smooth muscle cells and skin pigment cells (melanocytes). The differentiated cells acquired lineage-specific markers and showed appropriate functions in tissue culture, according to each cell type. For example, after 14 days, 20 to 40 per cent of the cells in the melanocyte media took on a web-like shape typical of melanocytes. The new cells also expressed biomarkers typical of pigment cells and when placed in an artificial human skin construct, produced melanin and responded to chemical cues from normal epidermis skin cells. After 14 days, about 10 per cent of the stem cells in the neuronal cell line grew dendrites, the long extensions typical of nerve cells, and about 80 per cent of the stem cells grown in the muscle media differentiated into smooth muscle cells. The researchers thus showed that human embryonic stem cell media could be used to isolate and expand a novel multi-potent adult stem cells from human hair follicles.


Statins stop replication of hepatitis C virus

Statins typically used as anti-cholesterol medications can inhibit the replication of the hepatitis C virus (HCV), reports a study by researchers from Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan. Statins could replace ribavirin in combination therapy with interferon. Combination of interferon and ribavirin is effective only in 55 per cent of patients whereas the remaining 45 per cent risk the disease progressing to cirrhosis and liver cancer. Using the OR6 cell culture assay system, the researchers evaluated the anti-HCV activities of five statins: atorvastatin, fluvastatin, lovastatin, pravastatin and simvastatin. When the statins were tested alone, all except pravastatin inhibited HCV replication. Fluvastatin had the strongest effect, atorvastatin and simvastatin had moderate effects while lovastatin had a weak effect. While pravastatin exhibited no anti-HCV activity, it did work as an inhibitor for HMG-CoA reductase, suggesting that the anti-HCV activities of the other stains are not due to the direct inhibition of HMG-CoA.

The researchers determined that the anti-HCV activities of statins were not related to cytotoxicity but because of their ability to inhibit the replication of HCV RNA via a specific antiviral mechanism. The finding that the addition of both mevalonate and geranyl geraniol restored HCV RNA replication in the statin-treated cells supports the theory that statins block HCV RNA replication by inhibiting certain proteins. Trials also showed statin-interferon combinations as having stronger inhibitory effects on HCV RNA replication than statin used alone.



Molecular mechanism of a diabetes vaccine revealed

A team of researchers led by Prof. Irun Cohen from the Department of Immunology of the Weizmann Institute of Science, Israel, has revealed the molecular mechanism of a vaccine for Type 1 diabetes. Type 1 diabetes is an autoimmune disorder in which the immune system mistakenly attacks the bodys own insulin-producing pancreatic cells, reducing and ultimately eliminating the production of insulin. Several years ago, Prof. Cohen and colleagues developed a vaccine that arrests the progression of Type 1 diabetes in laboratory animals. A particular protein called HSP60, or even only a small particular fragment of it, the peptide designated p277, is able to shut down the autoimmune response causing this disorder.

The scientists discovered that p277 directs the activity of the immune system in two ways. First, it steps up the activities of a different type of T cell that regulates the amount of potentially harmful T cells available. In addition, T cells treated with p277 cause the delinquent T cells to secrete anti-inflammatory substances instead of the usual inflammation-causing ones that lead to autoimmune disease. This double action of the peptide weakens the damaging activities of the immune response further. The scientists also showed that in order to activate this response, p277 must be bound to the receptor TLR-2, which is found on the cell walls of the regulatory T cells. Dr. Cohen said that by identifying the molecular activity of p277 with such precision, they could copy natures own system in regulating the immune system and therefore, help to boost the immune system in preventing the destruction of insulin-producing pancreatic cells.


New molecule that targets leukemia and lymphoma cells

Researchers at the University of California Davis Cancer Centre, the United States, have developed a novel peptide, LLP2A, that binds to the surface of leukemia and lymphoma cells with extremely high affinity, specificity and stability, and demonstrates remarkable promise as a tool to help image tumours and deliver anti-cancer drugs. According to Dr. Kit Lam, Professor and Chief of Hematology and Oncology, this peptide has great potential for becoming a new, effective imaging and therapeutic agent for patients with lymphoid cancers.

The peptide binds to a receptor found on the surface of lymphocytes and is attracted specifically to malignant lymphocytes, not healthy ones. It is intended to work like a monoclonal antibody but a peptide is much smaller than an antibody and has potential to infiltrate cancer cells more successfully. Three monoclonal antibodies rituximab, ibritumomab tiuxetan and tositumomab have already been approved by the FDA for the treatment of T-cell lymphoma. But these antibodies bind to healthy lymphocytes along with malignant ones. Besides, as they do not bind to T cells, they cannot be used to treat T-cell lymphoma. In contrast, LLP2A binds to both B-cell and T-cell lymphoid cancer lines, and has low affinity for normal T or B lymphocytes. The researchers have already used LLP2A to successfully image lymphoid tumours in living mice. More research has to be done before LLP2A is being used as a lymphoma imaging agent in patients.


New hybrid method sequences genome quicker and cheaper

The ability to achieve genomic sequencing faster and cheaper than ever before is set to become the solution to an increasing demand for genome-sequencing methods. The newer method known as 454 pyrosequencing that emerged in the past year, uses real-time, light-based observations of gene synthesis to reveal genomic information. It produces genomic information up 100 times faster than the old technology, report scientists from the J. Craig Venter Institute, the United States, and the University of New South Wales, Australia. They found that combining the advantages of the two sequencing methods in a hybrid approach produced better quality genomic information. The scientists, using the genomes of six ocean bacteria, evaluated the utility and cost-effectiveness of the old and new methods to demonstrate that hybrid method was better than either method on its own.

The traditional method known as Sanger sequencing works best at sequencing large segments of the genomes, while the newer method is more adept at sequencing smaller, more difficult sections. The hybrid sequencing approach enables the scientists to more easily close sequencing gaps between genome fragments compared with previous techniques. The new hybrid method gave exceptional results for several marine microbes and it is expected to kick-start other genome projects that were previously constrained by economic concerns.


Scientists identify protein with a crucial role in cell death

The PARL proteins function has been discovered by researchers from the Flanders Interuniversity Institute for Biotechnology, Belgium, in collaboration with Dulbecco-Telethon Institute hosted by the Veneto Institute of Molecular Medicine in Padua, Italy. By studying mice that are unable to produce PARL a protein thought to interact with Presenilin, a major player in Alzheimers disease the researchers have discovered the significance of this protein in controlled cell death. Mitochondria are the powerhouse of the cell and hence it has been suspected that poorly functioning mitochondria can, among other things, lead to brain cell disturbances and thus contribute to Parkinsons disease.

Dr. Bart De Strooper, who has extensive experience in Alzheimers disease research, and Dr. Luca Scorrano, who specializes in the functioning and effect of mitochondria, got together to study PARL. Previous research had indicated that the link between PARL and Presenilin is negligible. It was understood that PARL is important to the cells mitochondria, but the proteins specific function has remained unknown for a long time. To obtain insight into PARLs function, the researchers used knock-out mice that were no longer able to produce PARL. These mice deteriorated very rapidly losing muscular strength after only 4 weeks, which greatly reduced their capacity for breathing, and died after 8-12 weeks. Thus, lack of PARL leads to weakening of muscle cells, a phenomenon that also takes place in the normal ageing process. From the research of Dr. Strooper and Dr. Scorrano, it turns out that PARL is a key to initiating apoptosis in the mitochondria. Although the mitochondria of the knock-out mice have a normal development and are able to convert oxygen into energy, they have apparently lost their protection against apoptosis, and so the cells die off more quickly. The study concluded that PARL plays a crucial role in cellular apoptosis and probably in the origin of age-related diseases, like Parkinsons disease.


The role of transcription factor protein in cell death

Researchers at the University of Pennsylvania School of Medicine, the United States, discovered that a protein called Elk-1 interacts with mitochondria suggesting that this protein, which is typically active in the nucleus, could play a role in cell death, neurodegeneration and schizophrenia. They found that mRNA and protein encoding Elk-1, a transcription factor, were localized in the dendrites of intact rodent neurons. Dr. James Eberwine, Professor of Pharmacology said that it was unique to find a transcription factor in the dendrite.

To find the role of Elk-1 in the dendrites, the investigators first characterized some of the proteins with which Elk-1 interacts, and found that it associates with mitochondria proteins. Mitochondria are distributed throughout cells, including in the dendrites, and are important in maintaining the energy stores and regulating viability and death of the cell. They over-expressed Elk-1 in rat neurons and found that there was a decrease in the cell viability. Conversely, when they knocked down the Elk-1 expression, the survivability of neurons increased, indicating that Elk-1 plays a role in neuron viability and that Elk-1 could play a key role in neurodegeneration and schizophrenia.

Researchers developed a method, called phototransfection, to focally introduce Elk-1 RNA into the dendrite. The introduction and translation of Elk-1 mRNA in dendrites caused cell death, while introduction and translation of Elk-1 mRNA in the cell soma did not produce cell death. The Elk-1 proteins translated in the dendrites were transported to the nucleus and cell death depended on subsequent transcription. According to Dr. Eberwine it was the first formal proof that RNA can be translated and made into protein in an intact neuronal dendrite. The studies showed the importance of dendritic environment in modifying proteins after they have been made.


Unusual mechanism keeps repair protein accurate

Cancer researchers in the United States have discovered that a newly identified protein, critical for repairing damaged genes, uses an unusual mechanism to keep its repairs accurate. While other DNA-repair proteins ensure their accuracy with the help of proofreading regions or accessory molecules, this protein maintains its accuracy using an otherwise ordinary looking portion of its molecular structure.

Dr. Zucai Suo, an assistant professor of biochemistry and a researcher at the Ohio State University Comprehensive Cancer Centre, led the study. According to him, the DNA was constantly attacked and damaged by a variety of agents but the body must properly repair that damage, or it could lead to cell death or to cancer, birth defects and other diseases. There are six families of DNA polymerases and the newly identified protein was the first polymerase that used this mechanism to maintain its accuracy when making new DNA.

The protein named DNA polymerase delta was found to have four distinct regions or domains. Region One had a predicted structure that allowed it to dock with other proteins. Region Two was found to be rich in the amino acid proline, but its function was not known. To study proteins role, the researchers made in the laboratory only the parts that did the repair work, Region Three and Region Four, and when they tested it they found that it made up to a 100 times more mistakes than DNA polymerase beta, which is a repair protein. This error rate was too high. They then made the entire protein and found that it could repair DNA as accurately as the comparison protein. The researchers also tested a version of the protein that lacked the docking region, and found that this shortened molecule could make DNA accurately. They thus concluded that the proline-rich domain was responsible for the repair proteins high fidelity.


New oestrogen receptor opens up drug possibilities

A study led by Dr. Thomas Deuel at the Scripps Research Institute in the United States suggests that the oestrogen receptor might play a signalling role in other oestrogen target tissues, including breast, uterus and prostate tissues. Oestrogen has long been linked to the development of breast cancer, through both stimulation of breast cell growth, which can lead to mutation, and oestrogen metabolism, which can interfere with apoptosis and DNA repair.

By researching the oestrogen and anti-oestrogen signalling pathways mediated by this new receptor, they could explain why some breast cancers grow worse or resistant to anti-oestrogen therapy specifically the drug tamoxifen, which blocks oestrogen signalled responses through ER-a66 in breast tissue. Tamoxifen is an oral selective oestrogen receptor modulator, which is used in breast cancer treatment. The study showed that the new receptor, hER-a36, unlike other oestrogen receptors, was situated on the cell plasma membrane that surrounds the cell cytoplasm. This receptor stimulates cell growth by oestrogens and anti-oestrogens through activation of the MAPK/ERK signalling pathway, which is involved in cell differentiation and growth. The results of the experiments showed that the presence of hER-a36 strikingly inhibited both oestrogen-dependent and oestrogen-independent trans-activation functions, which resulted in protein production mediated by ER-a66.

The scientists were surprised that anti-oestrogen treatments stimulate cell growth and that the anti-oestrogens appear to have a stronger and a more prolonged activation of the MAPK/ERK signalling pathway than the oestrogens tested. The study supported the conclusion that tamoxifen functions as both agonist and antagonist of oestrogen signalling and that the expression of hER-a36 may be involved in the development of human breast cancer resistant to tamoxifen.



Plantibody breakthrough for hepatitis vaccine

Cubas Biotechnology and Genetic Engineering Centre (CIGB) has developed the first monoclonal antibody from transgenic plants called plantibody to make a human vaccine. Antibodies used in therapeutic vaccines for humans are conventionally obtained from fermentation of mammalian cells, a time-consuming and costly method that generates very small quantities. In contrast, using plantibodies has created a breakthrough not only in dramatically reducing costs but also in boosting the yield of antibodies, making it easier for vaccines to be produced.

The antibody, CB-Hep.1, was from an ancestor of the tobacco plant. It was used to replace an antibody obtained from mice while manufacturing the hepatitis vaccine. CB-Hep.1 is reported to be the first plantibody used anywhere in the world for manufacturing a vaccine. Dr. Carlos Borotto, Deputy Director at CIGB said that the plantibody had won approval from Cubas medication quality control agency. According to him, the approval of the first CIGB plantibody has cleared the way for many potential uses of this alternative in manufacturing molecules important in the fight against devastating diseases. The ancestral tobacco plant in question was a non-commercial variety, with thicker leaves, grown in an inert environment, without soil, and hence ensured biosecurity.


Plant antibodies show anti-cancer activity in research

A number of therapeutic antibodies actually help kill cancer cells. They do this by binding to antigens expressed on the surface of cancer cells, which triggers a cell death process leading to the eradication of abnormal cell types. For instance, one monoclonal antibody called BR55-2 recognizes an antigen, called the Lewis Y antigen (LeY), over-expressed in cancers of breast, lung, ovary and colon. Demand for such antibodies is growing quickly, but production methods can manufacture only limited quantities and at high cost. Scientists are therefore exploring plants as possible antibody factories. Dr. Robert Brodzik and colleagues at Thomas Jefferson University, the United States, and University Medical Centre, The Netherlands, have reported that plant-derived anti-LeY monoclonal antibody exhibited biological activities for efficient immunotherapy against human cancer cells. Their article described the production of BR55-2 in transgenic low-alkaloid tobacco plants.

The subunits of BR55-2 were expressed separately, and subsequently assembled in plant cells of tobacco plants. Researchers grew the plants, isolated the transgenic BR55-2 and assayed its activity. They found that:
  • Antibody expression was high in the transgenic plants;
  • Like mammalian-derived antibodies, plant antibodies bound specifically to both breast cancer and colorectal cancer cells, and also initiated cancer cell death; and
  • Plant-derived BR55-2 inhibited tumour growth in immunosuppressed mice.

Together, these findings show that plant-derived antibodies have the potential for efficient immunotherapy.


Killer tomatoes target human diseases

Researchers at the Siberian Institute of Plant Physiology and Biochemistry, Russia, used the soil bacterium Agrobacterium tumefaciens to shuttle a synthetic combination of HIV and HBV DNA fragments into tomato plants. These included fragments of genes for various HIV proteins and the gene for an HBV protein called HBV surface antigen. The tomato plants then manufactured the proteins and, when the tomatoes were eaten, these proteins prompted the body to create antibodies against the viruses.

Mice were fed a solution containing the tomatoes in powdered form. It was found that they developed high levels of antibodies in their blood to both viruses. The researchers also found antibodies on mucosal surfaces, where the viruses could gain entry to the body through sexual contact. Dr. Rose Hammond of the United States Department of Agricultures Agricultural Research Service, an agency which is collaborating with the Russian researchers, said that it is the mucosal surfaces where more protection is required. The fact that there is no need to refrigerate the vaccine or to inject it with needles could make it very useful in poorer countries. Researchers at the International AIDS Vaccine Initiative in New York said that if the oral vaccine happens to work then it would be inexpensive and easy to make and administer.


Hepatitis B antigen expressed in potato root

About two billion people in the world are infected by the hepatitis B virus. Although a vaccine has already been developed, it is difficult to store and ship, and is therefore expensive for developing countries, where most hepatitis B infections occur. Scientists are currently engineering plants to produce hepatitis B antigens, which would lead to the development of plant-based, orally administered vaccines. Potato has been extensively studied as a potential vaccine production system. Hairy roots are an attractive system for the production of recombinant proteins due to their genetic stability, fast growth and ability to grow in hormone-free media.

In India, Dr. G.B. Sunil Kumar and his team from the Bhabha Atomic Research Centre and scientists from Shantha Biotechnics Limited have used an Agrobacterium to introduce the hepatitis B surface antigen (HBsAg) gene into an Indian potato cultivar called Bahar. After inducing hairy-root growth, they verified the presence of the transgene and its product by PCR and ELISA. Scientists noted that HBsAg was expressed in potato plants, microtubers and hairy roots. Plants regenerated from hairy roots also exhibited similar levels of HBsAg expression to that of transgenic plants. The researchers said that the expression levels could be enhanced by using root-specific promoters in future gene constructs.


Plants yield key to silencing HIV genes

Scientists have shown that humans use a process of immune defence that is common in plants and invertebrates to battle a virus. The new finding that human cells can silence an essential part of HIVs genetic make-up could have major implications for the treatment of people infected with the virus. The research was led by Dr. Kuan-Teh Jeang of the National Institute of Allergy and Infectious Diseases (NIAID) in the United States. Dr. Anthony S. Fauci, NIAID Director, said that the research suggested a novel approach to HIV therapy targeting a stable component of HIV.

The phenomenon, called RNA silencing, was first detected in plants and later in insects. Silencing leads to the destruction of viral RNA. Viruses, however, are not permanently defeated because they have evolved ways to suppress the silencing action. Dr. Jeang and colleagues set out to determine if RNA silencing contributes to human cells defence against HIV. The most unexpected finding, according to Dr. Jeang, was the way HIV used one of its proteins, called Tat, to suppress the silencing efforts of the cell. HIV could not evade the newly discovered sequence-specific siRNA attack by mutation. Instead, it required a virally encoded protein to blunt the assault. Dr. Jeang believed that Tat might be shielding a rare HIV Achilles heel, a genetic sequence that, for functional reasons, the virus cannot change in order to escape siRNA attack. This novel siRNA sequence discovered by the team might lead to the development of new RNAi-based drugs to which HIV would not be able to develop resistance by simple mutation.


Rice gene makes tobacco disease-resistant, salt-tolerant

When exposed to various environmental stresses, plants respond by regulating their signalling pathways, or expressing certain stress tolerance genes or proteins. The ethylene-responsive element binding proteins (EREBPs), a family of transcription factors involved in abiotic stress responses, are important in these pathways. One such protein is present in rice, and encoded by the OsBIERF3 gene. It has been shown to be expressed at high concentrations in rice infected with blast fungus, or facing extreme stress conditions such as salt and cold. In China, Dr. Yifei Caoa and colleagues at Zhejiang University found that over-expression of the rice EREBP-like gene OsBIERF3 enhanced disease resistance and salt tolerance in transgenic tobacco with transferred the rice gene.

Researchers introduced the OsBIERF3 to tobacco by transformation with Agrobacterium. They then measured transgene expression levels, and conducted assays for disease resistance and salt tolerance in both transgenic and wild type control plants. Researchers found that the transgenic plants had enhanced resistance against infection by the tomato mosaic virus and the bacterial wild fire pathogen, Pseudomonas syringae pv. tabaci, and increased tolerance to salt stress. This suggested that OSBIERF3, when over-expressed in plants, could regulate abiotic and pathogen stress responses.


Scientists to get to the root of plant cell fate

Researchers at the Salk Institute for Biological Studies, the United States, have determined the cause for the development of an extra root in place of a shoot in plants with a defective TOPLESS gene. Their findings suggest that it is possible to engineer a plant cell to develop in ways that better suit the agricultural needs. Dr. Elliot M. Meyerowitz, at the California Institute of Technology led the study and specifically focused on understanding mutations in the TOPLESS gene, which was previously identified in Arabidopsis thaliana, the first flowering plant to have its genome sequenced and a popular model organism for many aspects of plant biology.

Like animals, plants too develop along a polar axis, but with a root on one end and a shoot on the other. A defective TOPLESS gene, however, causes plant embryos to develop into a seedling with two oppositely oriented root poles. The researchers discovered that the TOPLESS gene encodes a protein (TOPLESS) that is a transcriptional co-repressor. The normal function of this protein is to silence genes required for root development in the shoot half of a plant embryo. However, in plants that have a mutant TOPLESS, genes that should be kept off in order to produce a shoot do not get switched off. In plants, the polarity could be changed much later in embryogenesis and their TOPLESS mutants could survive very well. This suggests that the actual polarity in the embryo is not fixed until quite late in development, and that provides an opportunity to change the fate of the plant structure.



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