VATIS Update Biotechnology . Jan-Feb 2011

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Biotechnology Jan-Feb 2011

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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World’s largest video database on proteins published

After four years of conducting intensive calculations in the supercomputer MareNostrum at the Barcelona Supercomputing Centre, Spain, scientists led by Dr. Modesto Orozco at the Institute for Research in Biomedicine (IRB Barcelona) have presented the world’s largest database on protein motions. The new database, called MoDEL covers more than 1,700 proteins and is partially accessible through Internet to researchers worldwide. MoDEL has been developed to study the basic biology of proteins and to accelerate and facilitate the design of new pharmaceutical agents.

“Nowadays we design drugs as if the proteins against which they are to act were static and this goes a long way to explain failures in the development of new drug therapies because this is not a true scenario. With MoDEL, this problem is solved because it offers the user from 10,000 to 100,000 photos per protein, and these confer movement to these structures and allow a more accurate design,” says Dr. Orozco, Head of the Molecular Modelling and Bioinformatics Group at IRB Barcelona, Director of the Life Sciences Programme at Barcelona Supercomputing Centre and a professor at the University of Barcelona. At present, MoDEL covers more than 30 per cent of human proteins structures that are of pharmacological interest, and is expected to grow in future. According to the researchers, the focus is on relevant proteins in human diseases and MoDEL will cover 80 per cent of pharmaceutical targets in a period of two to three years.

New global partnership in rice science

One of the world’s largest global scientific partnerships for sustainable agricultural development has launched a bold new research initiative that aims to dramatically improve the ability of rice farmers to feed growing populations in some of the world’s poorest nations. The efforts of the Global Rice Science Partnership (GRiSP) are expected to lift 150 million people out of poverty by 2035 and prevent the emission of greenhouse gases by an amount equivalent to more than one billion tonnes of carbon dioxide.

GRiSP – an initiative of the Consultative Group on International Agricultural Research (CGIAR) and led by the International Rice Research Institute (IRRI) and its partners – was launched in Hanoi, Viet Nam, during the 3rd International Rice Congress. The global initiative will lead scientists to embark on the most comprehensive attempt ever to deploy rice’s genetic diversity. Cutting-edge research aimed at discovering new rice genes and deciphering their functions will feed into accelerated efforts to break the yield barrier in rice and to breed new generations of “climate-ready” rice with flooding tolerance and other traits that are essential for adapting production in the face of climate change.

The launch of GRiSP marks the beginning of a five-year, nearly US$600 million endeavour that will also promote revolutionary transformations in rice agronomy, processing and policy. The overall goal will be to serve farmers and consumers by increasing yields using improved seeds and agricultural practices and reducing post-harvest losses. The initiative is expected to boost rice supplies enough to reduce anticipated increases in rice prices by an average of at least 6.5 per cent by 2020, and at least 13 per cent by 2035.

Genome 10K Project announces genome sequencing plan

The Genome 10K Project (G10K) scientists and BGI (formerly the Beijing Genomics Institute) of Shenzhen, China, have announced a plan to sequence the genomes of 101 vertebrate species within the next two years. G10K is an international effort to gather specimens of thousands of animals from zoos, museums and university collections throughout the world, and then sequence the genome of each species to reveal its complete genetic heritage. The project aims to assemble a genomic zoo – a collection of DNA sequences for 10,000 vertebrate species (approximately one for every vertebrate genus) by 2015.

Dr. David Haussler – G10K co-founder and a professor of biomolecular engineering in the Baskin School of Engineering at University of California Santa Cruz, the United States – said the first 101 species to be sequenced were selected from the G10K database, which catalogues specimens suitable for sequencing from more than 16,000 vertebrate species, both living and recently extinct. The planned sequencing will take place at the BGI facilities, which have the largest number of advanced DNA sequencing machines under one roof of any institute in the world.

The sequencing project builds on a BGI project launched in January 2010, called the 1,000 Plant and Animal Reference Genome Project. The 101 vertebrate species chosen for this phase of the project were selected by a consortium of BGI scientists, their collaborators and sponsors, and the Chairs of G10K taxonomy groups for mammals, birds, amphibians, reptiles and fish. The selection aimed to capture phylogenetic diversity across the vertebrate radiations while avoiding overlap with public-sponsored, whole-genome sequencing projects. To meet G10K’s quality goals, every species must have a reference genome sequence with chromosome-scale contiguity suitable for display on a genome browser and accurate enough for genome-based research.

Bangalore set to be India’s nanotech hotspot

Bangalore, India’s information technology and biotechnology hotspot, is now emerging as the nanotechnology hub with the growing investments and interest in this area. In a bid to augment the growth of this promising sector, the government of Karnataka State has allocated 14 acres of land to set up the Indian Institute of Nano Science and Technology (IINST) in Bangalore. The proposed institute is expected to be functional by 2011.

The United States backs new drugs and vaccines

The United States of America has earmarked US$1.9 billion for new biotech initiatives that can fight off the biologic threats of the future. The government’s Biomedical Advanced Research and Development Authority has already handed out contracts worth more than US$100 million to help accelerate work on a range of drug and vaccine development technologies. The overall goal is to create a “nimble, flexible capacity to produce medical countermeasures rapidly in the face of any attack or threat,” says Ms. Kathleen Sebelius, Secretary of the Department of Health and Human Services (DHHS).

The lion’s share of the money, US$822 million, is being spent on vaccine technology with an eye to radically reducing the amount of time it takes to deliver large stockpiles of vaccines to ward off a pandemic. Ms. Sebelius points out that the old egg-based vaccine production system is quite outdated and far too slow. She is particularly interested in new technologies that can clear the research and development bottlenecks that develop for these countermeasures.

New collaboration in flu virus genetic research

Scientists from Singapore and the United States have designed an automated, sensitive and highly accurate approach to identify dangerous changes in the genome of the influenza virus. Available as a software package called Graph-incompatibility-based Re-assortment Finder (GiRaF), the method analyses large databases of influenza genomes and all eight segments of the genome to detect re-assortments. It resulted from a collaboration between Dr. Niranjan Nagarajan, Senior Research Scientist at the Genome Institute of Singapore, and Dr. Carl Kingsford, an Assistant Professor at University of Maryland, the United States.

Viruses typically evolve by a gradual accumulation of mutations, but in some cases new influenza strains can emerge as a hybrid of two different strains. This re-assortment process represents a jump in the evolution of the virus. Influenza strains emerging from this process can acquire new skills, such as the ability to replicate faster or better evade the human immune system, which makes it particularly important to detect such viruses from the public health perspective. Re-assortments have been implicated in two out of three pandemics of the 20th century as well as in the 2009 H1N1 outbreak.


India’s asthma drug market to cross US$400 million in 2014

India’s asthma drug market will grow from US$ 246 million in 2009 to US$403 million in 2014, representing an annual growth rate of 10 per cent. According to the Emerging Markets report entitled “Asthma in India” by Decision Resources, one of the leading research and advisory firms for pharma and healthcare issues, this growth will be fuelled by improved access to medical care, a growing drug-treated population and a rising number of higher-income, brand-conscious asthma patients demanding more-efficacious agents.

Decision Resources Analyst Dr. Manashi Sherawat notes: “At US$246 million, India’s asthma market is close to some European Union countries in dollar terms.” According to the report, fixed-dosed combination drugs represent a major opportunity for multinational pharmaceutical companies. The use of combination therapy as maintenance treatment will increase as medical practice in India shifts from treating asthma on an as-needed basis towards treating it as a chronic disease that requires maintenance treatment. Specifically, Indian specialists anticipate that fixed-dosed combination therapies such as long-acting beta(2) agonist/inhaled corticosteroid will experience the highest uptake. “The Indian asthma market would benefit from new, more convenient therapies, which would boost patient compliance,” added Dr. Sherawat.

Antigen Express gets grants for cancer vaccine development

In the United States, Generex Biotechnology Corporation has announced that its wholly owned immunotherapeutics subsidiary, Antigen Express has received two Therapeutic Discovery Project grants, totalling US$488,958, under the Patient Protection and Affordable Care Act of 2010. The Antigen Express Therapeutic Discovery Projects are entitled: Ii-Key Her-2/neu Peptide Vaccine, for the treatment of breast cancer; and Ii-Key Her-2/neu Peptide Vaccine, for the treatment of prostate cancer.

The proprietary vaccine being developed by Antigen Express is an off-the-shelf product designed to reduce the risk of relapse in cancer patients. It is the subject of a controlled, randomized Phase II trial in patients with breast cancer which has yielded positive interim results. Based on positive results from a Phase I trial in prostate cancer patients, preparations for a Phase II clinical trial in prostate cancer patients are underway. In all studies, the self-potentiating vaccine has shown very low toxicity and good immune response.

Genzyme details market potential of its MS drug

Genzyme Corp., the United States, has provided an extensive briefing on the market potential of alemtuzumab for multiple sclerosis (MS). The company shared internal market research and key features of the alemtuzumab profile that may address the needs and physician and payer perspectives on the future positioning and uptake of alemtuzumab in the MS market. The company stated that, five-year follow-up data from the company’s completed Phase II trial – a large randomized trial against an active MS comparator – found that alemtuzumab-treated patients had significant reductions in relapses and disability. Over this period, the mean disability score for patients receiving alemtuzumab improved, but it worsened for those receiving the active comparator.

Pakistan to sign Bt cottonseed accord with Monsanto

The Pakistan government will sign an agreement with Monsanto, the seed producing company based in the United States, by the end of 2010. The Ministry for Food and Agriculture and Monsanto had signed a Memorandum of Understanding (MoU) in April 2010 for Monsanto providing Bt cottonseed to Pakistan. A high-level delegation of Monsanto had called on the Federal Minister for Food and Agriculture Mr. Nazar Muhammad Gondal in this connection.

The deal is expected to boost Pakistan’s cotton production to bridge the gap between supply and demand, and meet the growing demands from a sector that accounts for 60 per cent of the country’s exports. Bollgard-II cottonseed will be available to Pakistani farmers during the coming cotton season, according to Mr. Gondal.

Fledgling f-star in discovery deal with Boehringer

Boehringer Ingelheim, Germany, has signed a discovery pact with f-star Biotechnologische of Austria that will pay more than US$1.7 billion if all the stars align for seven different therapeutic antibody programmes. Boehringer is hitching a discovery ride on f-star’s Modular Antibody Technology platform, offering up to 180 million euros in payments, excluding royalties, for each of the seven drug candidates spanning a wide variety of therapeutic areas. Dr. Kevin FitzGerald, f-star CEO, says: “f-star has developed novel technology for the discovery of antibody-based products that are clearly differentiated from conventional antibodies and other protein-based drugs.” The technology allows the engineering of new antigen binding sites into “constant and variable” domains of antibodies. The company has touted the development of two molecular formats: Fcab and mAb2.

Avila and Sanofi-aventis in protein silencing cancer partnership

Sanofi-aventis, France, is paying Avila Therapeutics, the United States, US$40 million up front as part of an alliance to develop targeted covalent drugs against cancer cell signalling proteins. The partnership will involve the use of Avilomics™, Avila’s protein-silencing platform, to develop candidates against targets the firms say would be hard to address using traditional medicinal chemistry approaches.

Under the terms of the deal, Sanofi-aventis has exclusive worldwide rights to develop and commercialize resulting compounds, although Avila will have an option to retain the rights to one of the six collaboration programmes after the end of the initial three-year collaboration term. If the firm decides to partner out its retained project, Sanofi-aventis will have the first negotiation right. In addition to its up-front payment, Avila could potentially receive US$154 million in development and regulatory milestones per programme if approval is achieved in the United States, Europe and Japan. The company will also receive staged royalties and commercialization milestones.

Lilly completes Avid acquisition

In the United States, Eli Lilly and Company has completed the acquisition of Avid Radiopharmaceuticals Inc., a privately held company that is developing novel molecular imaging compounds intended for the detection and monitoring of chronic human diseases. Under the terms of the definitive merger agreement, Lilly acquired all outstanding shares of Avid for an upfront payment of US$300 million, subject to adjustment based on existing cash on hand at closing. Avid stockholders will also be eligible for up to US$500 million in additional payments contingent upon potential future regulatory and commercial milestones for florbetapir, a molecular imaging agent currently under research for detecting the presence of amyloid plaque in the brain.

Biogen scoops up CNS programmes in acquisition deal

After three years of partnering with Switzerland’s Neurimmune Therapeutics on antibody discovery programmes targeting the central nervous system (CNS), the United States-based Biogen Idec has signed a pact to acquire one of Neurimmune’s subsidiaries outright for up to US$427.5 million. The package kicks off with a US$32.5 million upfront payment and follows with up to US$395 million in milestone payments in exchange for worldwide rights to three pre-clinical programmes. The trio of therapies could have a future in the fight against diseases like Alzheimer’s, amyotrophic lateral sclerosis (ALS) and Parkinson’s. In its release, Biogen notes that the three pre-clinical candidates complement the existing research collaboration by targeting three different neurotoxic proteins – alpha-synuclein, tau and TDP-43 – the mis-folding of which is thought to be the cause of many neurodegenerative diseases.


Study shows great genetic variation in pancreatic cancer

A new study has detailed the complexity of genetic variation found in pancreatic cancer cells. The genetic changes behind pancreatic cancer are complex and varied, with tumour cells exhibiting a variety of genetic mutations. Scientists from Wellcome Trust Sanger Institute, the United Kingdom, and a few other institutions sequenced the DNA from primary and secondary tumours (metastases) of 13 patients in order to compare the mutations.

The sequencing revealed that 17 per cent of the genomic mutations were shown to cause what the researchers termed as ‘fold-back inversion’, a distinctive pattern of DNA rearrangement. This fold-back inversion is caused when a DNA region is duplicated following a breakage. These breaks can occur repeatedly during cell division, leading to an explosion of genomic instability.

This instability is found early on in the development of pancreatic cancer and can lead to the incorrect expression and deletion of genes. Given the random nature of mutations, there can be large genetic differences among cells in the same pancreatic tumour. Once a pancreatic tumour cell has gained the necessary mutations, it is able to move around the body, forming metastases. What this research showed is that the cancer cells continue to mutate even after they have left the pancreas, potentially enabling the tumour cells to survive in other organs, such as the lungs or liver.

Research confirms genetic link to obesity

A new study in the United Kingdom has provided the first direct evidence that over-activity of a gene called FTO (fat mass and obesity associated) leads to over-eating and obesity in mice. The findings suggest that the gene could be a promising target for developing anti-obesity drugs that decrease the gene’s activity.

A large genome-wide association study in 2007 had suggested that a genetic variant – a single change in DNA sequence that lay within the FTO gene – could be linked to increased likelihood of obesity. In the new study, the researchers – led by Prof. Roger Cox at MRC Harwell and Prof. Frances Ashcroft of the Department of Physiology, Anatomy and Genetics at the University of Oxford – set out to determine if it was differences in the activity of the FTO gene itself that were directly causing the increase in body weight.

Female mice with two extra copies of the FTO gene, when fed a standard diet, became 22 per cent heavier than normal female mice after 20 weeks. The difference in weight for male mice was 10 per cent. The researchers also showed that the difference came because mice with FTO over-activity consumed more food. At present, there is no suggestion that weight differences in humans with FTO variants are, or will be, nearly as large, or will necessarily affect the sexes in a similar proportion.

Gene therapy fixes memory problems in AD mice

Scientists at the Gladstone Institute of Neurological Disease (GIND), the United States, have discovered a new strategy to prevent memory deficits in a mouse model of Alzheimer’s disease (AD). Humans with AD and mice genetically altered to simulate the disease have abnormally low levels of an enzyme called EphB2 in memory centres of the brain. Improving EphB2 levels in such mice by gene therapy completely fixed their memory problems.

“EphB2 is a really cool molecule that acts as both a receptor and an enzyme,” said lead author of the study, Dr. Moustapha Cisse. “We thought it might be involved in memory problems of AD because it is a master regulator of neurotransmission and its brain levels are decreased in the disease.” To determine if low EphB2 levels contribute to the development of memory problems, the investigators used gene therapy to experimentally alter EphB2 levels in memory centres of mice. Lowering EphB2 levels in normal healthy mice disrupted neurotransmission and gave them memory problems similar to those seen in AD, suggesting that low EphB2 levels in AD brains contribute to the characteristic memory problems.

Increasing EphB2 levels in neurons of mice engineered to produce high levels of human amyloid proteins in the brain prevented neurotransmission deficits, memory problems and behavioural abnormalities, said Dr. Lennart Mucke, Director of GIND and senior author of the study. The scientists also found that amyloid proteins directly bind to EphB2 and cause its degradation, which helps explain why EphB2 levels are reduced in patients with AD and related mouse models.

New 3-D model of RNA ‘core domain’ of enzyme telomerase

Biochemists at the University of California Los Angeles (UCLA), the United States, have now produced a three-dimensional (3-D) structural model of the RNA “core domain” of telomerase enzyme. Because telomerase plays a surprisingly important role in cancer and aging, understanding its structure could lead to new approaches for treating disease, said Dr. Juli Feigon, UCLA Professor of chemistry and biochemistry and the senior author of the study. The critical telomerase RNA core domain is essential for telomerase to add telomere repeats onto the ends of chromosomes, the structures that hold our genes. The core domain contains the template that is used to code for the ends of the chromosomes.

The telomerase core domain consists of three pieces: a “pseudoknot” required for telomerase activity, at whose core three strands of RNA come together to form a triple helix; an “internal bulge loop”, which had been largely ignored but turns out to be quite significant; and a “helical extension” – all of which Dr. Feigon and her colleagues modelled using a new method they developed. The researchers put together the three pieces to create a 3-D model, determining the structures using state-of-the-art nuclear magnetic resonance (NMR) spectroscopy.

The researchers decided to study the internal bulge loop’s structure and its dynamics. “What we found when we determined the structure was, first, it is quite unusual, with an unexpected fold that causes a large bend in the RNA. We then did biochemical studies that showed that the bend and its flexibility are important for telomerase activity. The internal bulge loop turns out to be really important in determining the topology of this domain, which was unpredicted,” Dr. Feigon said.

For telomerase to be active, it needs the telomerase RNA and a protein called human telomerase reverse transcriptase. The core domain includes the template which does reverse transcription. “Reverse transcriptases normally copy RNA to DNA but do not contain RNA; in this enzyme, the protein requires the RNA component to function,” Dr. Feigon said. Telomerase has its own internal piece of RNA that helps copy the DNA, but this template is only about 10 of the 451 nucleotides, she added.

Fly study suggests new genes can be essential

Genes that have sprung up relatively recently in the genome are just as likely to be essential as ancient, well-conserved genes, according to a new study. “The importance of a gene is independent of its age,” said Dr. Manyuan Long, an ecology and evolution scientist from University of Chicago, the United States, and senior author of the study. Dr. Long and his co-workers first compared the genomes of a dozen Drosophila fly species, narrowing in on several hundred genes that appear to have arisen relatively recently in fly evolution. They then used RNA interference to systematically block 195 different genes that have been added to the Drosophila genomes over the past 35 million years, showing that nearly a third of the new genes tested are essential. These findings hint that it could be important to understand the functions of genes that have arisen recently in specific lineages as well as ancient, conserved genes that are shared across many species.

Of the 195 young genes tested, the researchers found that 59 genes – more than 30 per cent – are required for Drosophila viability. Almost all of these genes are located on autosomal chromosomes, and roughly 95 per cent appear to have arisen through gene duplication and divergence, in some cases accompanied by retrotransposition. These new and essential genes don’t seem to cluster at any particular point in the fly’s phylogenetic tree and include genes that arose as recently as three million years ago. Similarly, when they tested the effects of knocking down 245 more ancient, conserved genes selected at random, the team found that 86 of these genes – about 35 per cent – were essential.

Based on their findings, the researchers concluded that new genes may be particularly prone to becoming essential if they contribute to these larval and/or pupal processes, and if they interact with more ancestral genes. New genes come in and quickly interact with older genes, and if that interaction is favourable by helping the organism survive or reproduce better, it gets favoured by natural selection and stays in the genome. After some time, the organism will not be able to live without the gene.

ADHD, developmental RD have common genetic influences

Attention Deficit Hyperactivity Disorder (ADHD) and developmental reading disability (RD) are complex childhood disorders that frequently occur together. However, the reason for this correlation is unknown. A new study in the United States has suggested that these disorders have common genetic influences. The researchers, led by Dr. Erik Willcutt from University of Colorado-Boulder, studied 457 pairs of twins. They compared groups of participants with and without RD and ADHD, using tests to measure general cognitive ability, processing speed, reading and language skills, and then analysed results from pairs of twins within those groups. The use of identical twins (who share all their genes) and non-identical twins (who share half their genes) allowed the scientists to distinguish between genetic and environmental influences on the participants’ cognitive abilities.

The findings showed that both RD and ADHD are influenced by many factors; ADHD on its own was associated with a reduced ability to inhibit responses to stimuli, while reading disabilities are associated with various weaknesses in language and memory. However, both disorders are associated with a slow processing speed, and the twin-analyses further revealed a significant genetic correlation between RD and ADHD – a participant with one of the disorders is more likely to show symptoms of the other. The researchers suggest processing efficiency to be a useful marker to look for in future studies of the connection between the two disorders.


Chemists concoct new agents to study critical cell proteins

Proteins are gateways through which critical signals and chemicals are exchanged between living cells and their environments. For the most part, however, little is known about the structure of these gateways and the way they work. They are notoriously difficult to study because extracting these proteins intact from cell membranes is tricky. A team of scientists from the University of Wisconsin-Madison (UWM) and Stanford University, the United States, and Imperial College London, the United Kingdom, has devised a technology to more easily obtain membrane proteins for study. “The proteins are embedded in the membrane to control what gets into the cell and what gets out,” explains Dr. Samuel Gellman, a UWM professor of chemistry and a senior author of the paper.

A primary obstacle has been getting proteins out of the membrane while maintaining their functional shapes. To that end, Dr. Gellman’s group has developed a family of new chemical agents, known as amphiphiles, that are easily prepared, customizable to specific proteins and inexpensive. “These amphiphiles are very simple,” says Dr. Gellman. “That is one of their charms. The other is that they can be tuned to pull out many different kinds of proteins.” The development of the amphiphiles was conducted in close collaboration with groups that specialize in techniques that help resolve the three-dimensional structures of proteins found in cell membranes.

X-ray crystallography reveals structure of thrombin precursor

Using state-of-the-art robotic and X-ray crystallographic equipment, researchers at Saint Louis University (SLU), the United States, have revealed for the first time the molecular structure of the zymogen, or inactive, form of the blood-clotting enzyme thrombin. The research provides a missing link between the inactive zymogen form of thrombin and the mature enzyme generated upon vascular injury, according to Dr. Enrico Di Cera, Chair of the Department of Biochemistry & Molecular Biology at SLU School of Medicine and lead researcher of the study.

Before thrombin becomes active, it circulates throughout the blood in the inactive zymogen form. When the active enzyme is needed, for example after a vascular injury, the coagulation cascade is initiated and the zymogen is converted into an active enzyme that causes blood to clot. When triggered in the wrong conditions, clotting can lead to debilitating or fatal conditions like heart attack, stroke and deep vein thrombosis.

While researchers have an understanding of the structure of active thrombin, very little was known about its zymogen form. In the new study, the researchers used X-ray crystallography to gather data about the molecular structure of the protein. The structure of the zymogen form of thrombin provides crucial details about the activation mechanism that sheds light on the way the mature enzyme works. Future research can capitalize on these new findings to define better strategies for therapeutic intervention. “We now know that the zymogen form of thrombin is very different from the mature enzyme, in ways that open new opportunities for therapeutic intervention, Dr. Di Cera explained.

Cellular communicators for cancer virus identified

A new discovery at University of North Carolina (UNC), the United States, describes how cells infected by the Epstein-Barr virus (EBV) produce small vesicles or sacs called exosomes, changing their cellular “cargo” of proteins and RNA. This altered exosome enters cells and can change the growth of recipient cells from benign to cancer-producing. In this way, virus-infected cells can have wide-ranging effects and potentially manipulate other cells throughout the body.

Dr. Nancy Raab-Traub, Professor of microbiology and immunology at UNC Lineberger Comprehensive Cancer Centre, said: “Exosomes may be the Trojan Horse through which EBV gains control of cells that are not even infected. Importantly, the production of exosomes may provide a new therapeutic target that can be blocked to reduce cancer growth.” EBV is perhaps the world’s most successful virus, as it cannot be eliminated by the immune system and is constantly secreted into saliva where it is effectively transmitted. Infection with the virus rarely causes disease; however, in several major cancers, EBV proteins hijack the cell’s growth regulatory mechanisms to induce uncontrolled cell growth.

Through exosomes, a protein called latent membrane protein 1, which is considered the EBV oncogene, can be delivered to uninfected cells. Significantly, EBV also changes the entire contents of the exosomes to deliver cellular proteins that are also activated in cancers. This surprising finding reveals that one infected cell can have wide-ranging effects and induce the unchecked growth of its neighbouring cells. The study also showed that the cells that produce blood vessels – the process called angiogenesis – readily take in the altered exosomes and are potentially induced to grow.

Scientists identify synthetic activator of two critical proteins

Scientists from the Florida campus of The Scripps Research Institute, the United States, have identified a new synthetic activator of a pair of proteins that belong to a protein family playing key roles in human metabolism and immune function. “This new compound is particularly important because it works in vivo, and it is selective for certain receptors,” said Dr. Tom Burris, Professor in the Department of Molecular Therapeutics and leader of the study. “These two properties give it significant potential as a possible therapeutic compound.” The discovery could provide new and potentially more effective therapeutic approaches to diseases ranging from diabetes to osteoporosis.

The new discovery represents the very first synthetic ligand (binding partner) that functions as an agonist (activator) of retinoid-related orphan (ROR) nuclear receptor. Although scientists do not know the full therapeutic significance of the new synthetic ligand, its potential usefulness is clear, Dr. Burris noted. “For example, loss of ROR alpha in animal models renders them resistant to weight gain,” he said, “while ROR gamma has been shown to be involved in development of cells that are implicated in autoimmune diseases, and loss of ROR gamma results in animals that are resistant to these types of disease.” ROR alpha has also been shown to be required for normal bone development.

Dr. Burris and his colleagues used a compound known as T1317, an inverse agonist that binds to the same site as an agonist but induces the opposite action of an agonist, as a molecular scaffold to synthesize an array of compounds and assess their activity against a number of receptors, including ROR alpha and ROR gamma. One compound – SR1078 – displayed a unique pharmacological profile that indicated it had a high potential for use as a chemical probe for assessing ROR receptor function in general. “When we treated cells with SR1078, we got a significant increase in ROR alpha transcription. Similarly, with ROR gamma, SR1078 treatment resulted in a stimulation of ROR gamma dependent transcription activity. Basically, it produced more of these receptor proteins, significantly so,” said Dr. Burris.

A milestone in fight against deadly disease

In the United States, researchers at the Seattle Structural Genomics Centre for Infectious Diseases (SSGCID) and the Centre for Structural Genomics of Infectious Diseases (CSGID) have reached a major milestone in the effort to wipe out some of the most deadly diseases on the planet. They have experimentally determined 500 three-dimensional protein structures from a number of bacterial and protozoan pathogens, which could potentially lead to new drugs, vaccines and diagnostics to combat deadly infectious diseases. Some of the structures solved by them come from organisms like the H1N1 flu virus.

The SSGCID scientists solved the first protein structure from Rickettsia – a genus of bacterial pathogens carried by many ticks, fleas and lice – that causes several forms of typhus and spotted fever. Scientists at CSGID determined the structure of a vital enzyme in the shikimate pathway of Clostridium difficile, which is the most serious cause of antibiotic-associated diarrhoea in humans and can lead to a severe infection of the colon. The shikimate pathway is essential for plants and bacteria like C. difficile, but is not present in animals, making this enzyme an attractive antibiotic target. CSGID researchers have also determined the structures of numerous proteins from other pathogens such as Bacillus anthracis (anthrax), Vibrio cholerae (cholera), Salmonella enterica (salmonellosis), Yersinia pestis (plague) and Staphylococcus aureus (staph infections).

Mapping the structures of drug-resistant bacteria is also a priority for the two centres. The structures solved by these centres are immediately made available to the international scientific community through the Protein Data Bank, providing a “blueprint” for development of new drugs, vaccines and diagnostics. The centres are on track to ultimately identify nearly 500 more structures by the end of 2012.

New technique to identify cancer biomarkers

In Belgium, Targetome, a spin-off company of the University of Liège, is marketing a new technique used to identify biomarkers, which are specifically over-expressed in certain cancers and cancerous metastases. Based on the research carried out by the University’s Applied Geno-Proteomics Centre (GIGA) and Cancer Metastasis Research Laboratory, led by Professor Vincent Castronovo, this new technique is the first stage in the development of a new type of diagnosis methodologies and anti-cancer therapies, enabling early detection, efficient localization through imaging of malign lesions and their selective destruction.

“We are moving towards selective immunotargeting treatments, which will have the advantage of sparing the healthy tissues in order to focus on the cancerous cells,” said Prof. Castronovo. The originality of the technique that he developed – in vitro method for screening accessible biological markers in pathologic tissues – lies in the fact that, unlike previous techniques, it enables the identification of biomarkers that have three essential qualities: they are in abundant in the cancer lesions, they are specific and, above all they are accessible (reachable by high affinity ligands such as antibodies). This approach is unique, as it identifies potential therapeutic targets through the same path that will, in the end, be used for the administration of the targeted therapy, in other words the bloodstream pathway.


New approach to blocking malaria transmission

At University of Illinois Chicago (UIC), the United States, researcher Dr. John Quigley has proposed a promising new approach to blocking malaria transmission. The research focuses on potential targets to inhibit transmission of the Plasmodium parasite that causes malaria. Previous studies have shown that mosquitoes with increased oxidative stress in their mid-gut (where Plasmodium reproduces) are resistant to the parasite’s transmission. Dr. Quigley and his team hypothesize that if they can disrupt the function of a cell-surface transport protein called FLVCR that pumps haeme out of the cell, it will increase the oxidative stress in the mosquito gut and hamper Plasmodium at a crucial point in the parasite’s life cycle.

The researchers isolated the FLVCR gene from two common malaria-transmitting mosquitoes and showed that the gene encodes a protein that exports haeme and protects cells from oxidative stress. Using gene-silencing techniques, they were able to significantly reduce levels of FLVCR in the mosquito gut. “If disruption of the function of the protein inhibits parasite transmission, then we can potentially use parts of the protein as an antigen to try to stimulate a vaccine in people,” said Dr. Quigley, an assistant professor of medicine at the UIC College of Medicine and senior author of the study. The antibody blocks FLVCR and increases oxidative stress, and the parasite is not able to complete its life cycle, thus preventing the spread of malaria, he explained. The research, he says, may be applicable to all blood-eating insects that cause a variety of diseases, such as dengue fever and leishmaniasis.

Faster-growing E. coli strain for gene therapy or vaccine use

A metabolic engineer from University of Illinois Urbana-Champaign, the United States, has improved an Escherichia coli strain, making it grow faster. Dr. Yong-Su Jin, an assistant professor of microbial genomics, and his colleagues have developed an E. coli strain that is suitable for mass production of high-quality DNA that could be used in vaccines or gene therapy.

Dr. Jin worked with E. coli DH5 alpha, a laboratory strain that had excellent potential but grew very slowly. When scientists began to use this strain in research years ago, they handicapped it, causing some of the genes to mutate so that it would meet the requirements of molecular biology experiments. There was a trade-off, though – the strain’s slow growth in minimal media, commonly used in laboratory and industrial fermentations.

Because scientists had used random mutagenesis, they were not sure where the mutation that caused the slow growth had occurred. Dr. Jin and his colleagues were able to locate and fix the problem. “We learned that the scientists had unintentionally weakened a key enzyme in a gene in the nucleotide biosynthesis pathway. When we reversed this mutation, the modified strain grew as quickly as other types of E. coli used in industry while retaining the traits that make it useful in scientific experiments,” he said. The beauty of the new strain lies in the purity and abundance of the DNA that it contains, which makes it a candidate for use in important biotechnological applications, such as DNA vaccine production and gene therapy.

Nano-engineers aim to grow tissues with functional blood vessels

In the United States, nano-engineers at University of California San Diego (UCSD) won a grant from the National Institutes of Health (NIH) to develop the tools to manufacture biodegradable scaffolds around which heart tissues – functional blood vessels included – will grow. Developing methods for nurturing tissues that mimic nature’s fine-grained details, including vasculature, could lead to breakthroughs in efforts to grow replacement cardiac tissues for people who have suffered a heart attack. The work could also lead to better systems for growing and studying cells, including stem cells, in the laboratory.

“We are creating biomaterials with nanostructures on the inside,” said research leader Prof. Shaochen Chen from the UCSD Department of Nano Engineering. The researchers plan to add new levels of precision and functionality to the scaffolds produced by the biofabrication platform that they invented. The improved biofabrication platform will allow them to produce scaffolds with precisely designed systems of nanoscale pores and other micro-architectural details that control how cells interact with each other and with the environment.

The researchers also plan to create scaffolds with tubes, and then seed those tubes with the cells that line blood vessels – endothelial cells – in order to try to generate functioning vascular systems. The lack of blood vessels in most tissue regeneration systems results in cell death and loss of function, and limits the maximum size of regenerated tissues. In addition, the chemical properties of the new scaffolds will change from top to bottom, which will create chemical gradients that drive cell growth. The scaffolds will be based on natural materials such as hyaluronic acid, a key component of the “extracellular matrix” that provides structural support, wound healing, and a range of other functions to human and other animal tissues.

Redeeming role for a common virus: ability to kill cancer

Researchers at Lombardi Comprehensive Cancer Centre of Georgetown University Hospital, the United States, are collaborating with other institutions to look for an answer by conducting a Phase II clinical trial of a reovirus-based therapy for people with advanced or recurrent non-small cell lung cancer with a specific tumour profile.

“With reovirus, we are able to accentuate the positive and attenuate the negative,” says the lead investigator of the study Dr. Deepa Subramaniam, Interim-Chief of the Thoracic Medical Oncology Programme. The researchers genetically altered the virus to ensure that it will not replicate in a healthy cell. “What is left is a virus in search of a host, and reovirus loves the environment inside a specific kind of cancer cell,” explains Dr. Subramaniam. That specific kind of cancer cell is the one with malfunctioning machinery called KRAS or EGFR mutation, which leaves the cancer vulnerable to a viral take-over. Once it is in, the reovirus exploits the cell’s machinery for its own replication. As a result, the cell is filled with virus particles causing it to literally explode, she explains.

Volunteers in the clinical trial will receive the reovirus in addition to the chemotherapy drugs paclitaxel and carboplatin. The physicians will watch to see if the cancer shrinks while also seeing if this combination of drugs causes serious side-effects. “This trial represents an attempt to seek and destroy cancer by choosing a treatment based on specific tumour characteristics. Preliminary data from the study should come quickly,” says Dr. Subramaniam.

Regenerative stem cell therapy offers hope for CVD treatment

Physician researchers at Northwestern University Feinberg School of Medicine, the United States, are revolutionizing treatment of cardiovascular disease (CVD) by utilizing patients’ own stem cells to regenerate heart and vascular tissue. In some patients, the CVD is so advanced that a standard treatment is not an option. “Regenerative cardiovascular medicine strives to redevelop cardiac and vascular tissue and stimulate new blood supply to areas like the heart and legs by using stem cells already present in the patient’s body,” said Dr. Douglas W. Losordo, Director of the Feinberg Cardiovascular Research Institute.

Dr. Losordo’s limb preservation study examined the effectiveness of stem cell therapy in limb preservation for patients with critical limb ischemia (CLI), which develops in patients with severe arterial obstruction that limits blood flow to the extremities. The trial tested the ability of CD34+ cells to stimulate new blood vessel formation in ischemic limbs, which can improve perfusion and salvage function. The Phase II trial had a total of 28 patients randomized at 18 sites. The patients enrolled were in the later stages of peripheral artery disease and at heightened risk for amputation. Patients in the randomized group had CD34 injected at eight locations in the ischemic limb and were followed for 12 months. Treatment showed a 50 per cent reduction in the total amputation rate compared to control. Although further study is needed, these results evidenced that CD34 cell therapy is an effective treatment for CLI.

Novel compounds hold promise in treatment of neuro-degenerative diseases

In the United States, researchers at Southern Methodist University (SMU) and University of Texas (UT) Dallas have discovered a family of small molecules that shows promise in protecting brain cells against neuro-degenerative diseases such as Parkinson’s, Alzheimer’s and Huntington’s. Dallas-based start-up biotechnology and therapeutics company EncephRx Inc. was granted the worldwide licence to the jointly owned compounds. EncephRx will develop drug therapies based on the new class of compounds as a pharmaceutical for preventing nerve-cell damage, delaying onset of degenerative nerve disease and improving symptoms.

The researchers developed and tested more than 100 compounds for neuroprotective efficacy and toxicity over four years before making the discovery. SMU researchers will assist EncephRx in optimizing the primary compound, while the UT Dallas team will support testing and analyses.

Scientists unveil new method to create bio-artificial organs

Spanish scientists have presented a new technique to create bio-artificial organs for transplant using stem cells which they say will vastly reduce the risk of rejection of the donated organ. The technique involves “stripping” a donated heart, liver or other organ, which is deemed unsuitable for donation of their cells, leaving just a “scaffold”, Dr. Francisco Fernandez-Aviles, Chief Cardiologist at Madrid’s Gregorio Maranon hospital revealed.

Stem cells from the patient are then applied to this framework to re-grow the organ, which will share their DNA, thus making it more acceptable to their body. Doctors will be able to carry out transplants involving organs that have been re-generated using this technique in five years time at the earliest, said Dr. Fernandez-Aviles. “This will put an end to two problems – the lack of donors or organs suitable for transplant and the rejection of transplanted organs by the patient,” he said.


Gene discovery suggests way to engineer fast-growing plants

Tinkering with a single gene may give perennial grasses more robust roots and hasten the timeline for creating biofuels, according to scientists at the Duke Institute for Genome Sciences & Policy (IGSP), the United States. Perennial grasses, such as switchgrass and miscanthus, are important biofuels crops and can be harvested repeatedly, said Dr. Philip Benfey, Director of IGSP Centre for Systems Biology. But before that can happen, the root system needs two to three years to get established.

Dr. Benfey’s team appears to have found a way to do that. They took a directed genomic approach aimed at identifying genes that become active when cells stop dividing and start taking on the characteristics of the mature, adult cell they are to become. “We systematically looked for those genes that come ‘on’ precisely when cells transition from proliferation to differentiation and then turn ‘off’ again just as quickly,” Dr. Benfey said.

The genome-wide search in the roots of the familiar laboratory plant Arabidopsis and subsequent screening of mutant lines turned up a single gene, which the researchers call UPBEAT1 (UPB1). Further study showed that UPB1 controls the gene expression of peroxidase enzymes. They then showed that these peroxidases control the balance of free radicals between the zone of cell proliferation and the zone of cell elongation where differentiation begins. When the researchers disrupted UPB1 activity in the plant root, it altered the balance of free radicals such that cells delayed their differentiation and continued growing. Those plants ended up with faster-growing roots, having more and larger cells. When UPB1 activity was increased, the growth of plant roots slowed.

Interestingly, UPB1 appears to act independently of plant hormones that play well-known roles in the balance between cell division and differentiation. From an engineering perspective, the prospect of enhancing growth by taking a gene away, as opposed to adding one, is particularly appealing, Dr. Benfey notes. The findings might also lead to new ways to produce stronger and bigger plants with the capacity to sequester more earth-warming carbon dioxide from the atmosphere, he says.

Breeding potatoes with improved properties

It is possible to breed potatoes in such a way that they produce new types of starch for use as a new and improved plant-based raw material in the construction, paper, glue, fodder and food industries. These results are described in Mr. Xingfeng Huang’s Ph.D. thesis at Wageningen University, the Netherlands. Using genetic modification, Mr. Huang managed to develop potatoes with larger starch granules, a higher capacity to retain water after several cycles of freeze/thaw, and have a stronger capacity to form gels.

Some bacteria contain enzymes that have a Starch Binding Domain and are involved in the breakdown of starch. If potatoes were able to produce these enzymes, which have a slightly different function than the enzymes already present in the potato, that would probably result in starch granules with new characteristics. This could make the potato an even better source for plant-based and sustainably produced raw materials.

When Mr. Huang introduced the gene for amylosucrase enzyme of the Neisseria polysaccharea bacterium, it changed some important characteristics of the starch granules in potato. The granules, for instance, were about twice as large and the starch was more capable of ‘binding’ fluids. This means that smaller amounts of starch can produce the same viscosity in, for example, sauces and desserts. It was also shown that the new starch granules were better at retaining water, which is highly relevant to frozen food products.

Growing sorghum for biofuel

Researchers at Iowa State University, the United States, have examined 12 varieties of sorghum grass grown in single and double cropping systems to assess the efficiencies and environmental impacts of growing sorghum for ethanol. The experiment was designed to test the efficiency of double cropping sorghum grass to increase its yield for biofuel production. Dr. Ben Goff, the author of the report, found that using sorghum from a single-cropping system was more effective for the production of ethanol. He suggests that corn may not be able to meet the energy needs of the United States. According to the study, only 15 to 25 per cent of the energy requirements would be fulfilled using corn or starch-based ethanol.

Dr. Goff states that from a production standpoint, growing sorghum as a sole crop is more efficient for ethanol production. While certain genotypes of sorghum from the double-cropping system yielded total biomass equal to those in the single-cropping study, all of the sorghum varieties in the single-cropping system had consistently higher ethanol yields. Dr. Goff theorizes that the altered chemical compositions of sorghum could be attributed to the different cropping systems. He recommends that further study on double-cropping systems for ethanol production should focus on efforts to maximize production of sorghum, such as incorporating a winter crop that matures earlier in the season.

DNA technique to aid crops from deadly ‘honey fungus’

An international team of scientists has developed a new technique to aid crops at risk from a devastating agricultural parasite commonly known as the ‘honey fungus’. The development allows crop to be screened for natural resistance by adding DNA with fluorescent genes to the fungus before being planted out. The work – a joint effort by the Agricultural Research Service (ARS) of the United States Department of Agriculture and the University of Bristol, the United Kingdom – helps transform and genetically manipulate the plant-pathogenic fungus Armillaria mellea by artificially introducing DNA into it. DNA was introduced using Agrobacterium, a bacterium that is commonly used to genetically modify plants.

This powerful technique is very important in pinpointing how pathogens enter and spread through plants and, then, developing control practices that prevent or minimize infection. Dr. Kendra Baumgartner, an ARS specialist in vine and tree crop diseases, said: “Efforts are already under way to identify rootstocks of grapes, walnuts, and stone fruits that are naturally resistant to infection. The improved screening that is enabled by using transformed strains of Armillaria should allow more rapid identification of resistant plant materials.”

Being able to transform the fungus also helps with investigations into its population structure. These species are unusual as they can produce new genetic types without going through a conventional sexual cycle. When two individuals meet, there is the chance that nuclei from one strain can invade and recombine with nuclei in the other fungus, giving rise to new genotypes with new and novel traits.

New disease-resistant food crops in prospect

Researchers have uncovered the genetic basis of remarkable broad-spectrum resistance to a viral infection that, in some parts of the world, is the most important pathogen affecting leafy and arable brassica crops including broccoli, cabbage, cauliflower, kale, swede and oilseed rape. They have tested resistant plants against a range of different strains of the virus taken from all over the world and so far, no strain has been able to overcome the resistance.

Dr. John Walsh of the University of Warwick, the United Kingdom, and his team identified the major gene involved in resistance to turnip mosaic virus (TuMV) and discovered that the way in which it creates resistance is completely new. Using this knowledge, they found that it was possible to identify plants with an inherent resistance that could be used to speed up the breeding process and develop commercial varieties that are resistant to TuMV. The researchers are now working to breed resistance into Chinese cabbage. They hope in future to do the same with other crops.

Detection of barley pigment genes may help improve yields

Scientists in the United Kingdom have identified the genes that encode important visible differences in barley. The breakthrough is a major step forward in unravelling the genetic determinants controlling traits such as yield, quality and disease resistance. The DNA variants identified control a range of characters, from the eye-catching variations in barley awn-pigmentation to the shape and the structure of the ear, fundamental to differences in yield. In one case, the scientists were able to show that the absence of the purple pigment, anthocyanin, in the plant is probably controlled by a natural mutation within a gene thought to regulate the pigment’s biosynthetic pathway.

The collaborative investigation between scientists at National Institute of Agricultural Botany (NIAB), the Scottish Crop Research Institute and the University of Birmingham, as well as interested commercial partners, established and characterized a comprehensive set of the country’s barley varieties using state-of-the-art DNA profiling techniques. The NIAB research team pinpointed stretches of barley DNA code associated with observed variations in characters using statistical techniques pioneered in human genetics called ‘association mapping’..

The researchers were fortunate to have access to a treasure trove of distinctness, uniformity and stability (DUS) varietal measurements accumulated since NIAB began variety trials as far back as 1919. This database extends to complicated multi-site and multi-season measurements including yield, disease, agronomic and quality characters of barley and other major arable crops.


Genome Profiling for Genetic Marker Discovery

This book – part of the Studies in Mechanobiology, Tissue Engineering and Biomaterials Series –gives a complete and quantitative description of the fundamental mechanical properties of neural tissues, and their responses to both physiological and pathological loading. It reviews the methods used to characterize the non-linear viscoelastic properties of central and peripheral neural tissues, and the mathematical and sophisticated computational models used to describe this behaviour. Mechanisms and models of neural injury from both trauma and disease are reviewed from the molecular to macroscopic scale.

Contact: Springer GmbH, Haberstrasse 7, 69126, Heidelberg, Germany, Tel: +49 (6221) 345 4301; Fax: + 49 (6221) 345 4229; E-mail:

Translational Medicine and Drug Discovery

This publication focuses on the new discipline of translational medicine as it pertains to drug development in the pharmaceutical and biotechnology industries. It outlines general strategies, biomarker development, imaging tools, translational human models, and examples of their application to real drug development. The latest thinking on the subject is presented by researchers from many of the world’s leading drug development companies, such as Pfizer, Merck, Eli Lilly and Abbott, as well as academic institutions and public-private partnerships that support translational research. This book is essential for anyone interested in the filed of translational medicine from a variety of backgrounds – university institutes, medical schools, pharmaceutical companies, and drug development researchers and decision-makers.

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