VATIS Update Biotechnology . Mar-Apr 2010

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Biotechnology Mar-Apr 2010

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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Roles of biotech, nanotech and synthetic biology in future food

Some say the world’s population will swell to 9 billion people by 2030 and that will present significant challenges for agriculture to provide enough food to meet demand, said animal scientist Mr. Rod Hill from University of Idaho, the United States. Along with Mr. Larry Branen, a University of Idaho food scientist, Mr. Hill had organized a symposium during a recent meeting of the American Association for the Advancement of Science to explore ways biotechnology could provide healthy and plentiful animal-based foods to meet future demands.

Synthetic biology, nanotechnology, genetic engineering and other applications of biotechnology – and the public’s role in determining their acceptable uses – were all addressed by panellists from various universities and organizations in the United States. The goal for the session was to encourage a dialogue among scientists and the public.

The Earth cannot continue to provide enough food without technological support, said Mr. Hill, who studies muscle growth in cattle. “Unaided food production is an unattainable ideal – current society is irrevocably grounded in the technological interventions underpinning the agricultural revolution that now strives to feed the world,” he said.

Nanoparticles may be used to target certain genes and thus play a role in genetic engineering of food animals, Mr. Branen said. “There is also no question that nanomaterials may help increase the shelf stability of food products and assure their safety.” Other panelists included University of Missouri’s Prof. Kevin Wells who believes genetically modified animals would have a future place on humanity’s tables, just as GM plants do now. Panelist Mr. Hongda Chen, who serves as the United States Department of Agriculture’s national programme leader for bioprocessing engineering and nanotechnology, will explore how scientific methods like nanotechnology may be applied to help meet the world’s growing demand for safe and healthy food. Synthetic biology, the use of novel methods to create genes or chromosomes, will be explored by panelist Ms. Michele Garfinkel, a policy analyst at the J. Craig Venter Institute. The public’s acceptance or rejection of new technologies that could determine future food supplies will be the domain of Ms. Susanna Priest, a professor at the University of Nevada Las Vegas.

Malacca plans biotech facility with Indian input

The government of the Malaysian state of Malacca intends to use an Indian firm’s help to develop a M$ 450 million (US$138 million) biotechnology research facility for the development and distribution of biotherapeutic products for medical use. The state’s corporate subsidiary Melaka Biotech Holdings Sdn. Bhd. will sign a joint venture agreement with the Vivo Bio Tech Ltd. of India and Vanguard Creative Technologies Sdn. Bhd. of Malaysia.

The Chief Minister Mr. Mohammad Ali Rustam, the Chairman of Vivo Bio Tech Mr. Vishwanathan Komplella and the Directors of the joint venture, Mr. Chandrakant Avalani and Mr. Sittampalam have already signed a memorandum of understanding. The Malaysian Prime Minister Mr. Najib Tun Razak described the project as a commendable venture with newly improved Malaysia-India economic ties.

The proposed research centre and eventual manufacturing plant is expected to provide facilities for the transfer of technologies in the areas of pre-clinical testing, toxicology and drugs development. Melaka Biotech Holdings will provide investment in the form of 11.7 ha of land for the project. The land will be leased to the joint venture for up to 30 years, with the option of buying it within five years.

Experts predict dramatic developments in malaria vaccine

Those interested in investing in the biotech industry may wish to consider the area of vaccine development, especially vaccines for widespread and deadly diseases such as malaria. This is the gist of a new report released by the healthcare market research publisher Kalorama Information, the United States. At least six major research groups are developing vaccines to prevent transmission of malaria, spurred by the commitment of the Bill and Melinda Gates Foundation, the United States, to contribute US$10 billion in grants to support malaria vaccine development.

The current frontrunner in the race for a malaria vaccine may be Mosquirix from GlaxoSmithKline, the United Kingdom, which is engaged in several large-scale Phase III trials in Africa. Initial studies of the vaccine in children under five have shown that it can reduce infections by as much as 63 per cent, though more often in the range of 50 per cent, with effects persisting for at least one year. Although most healthcare organizations are looking for 80 per cent results, the company is still hoping for marketing approval in 2012.

Overall, Kalorama predicts a US$100 million vaccine market from products like these by 2012, and growing to more than US$1 billion by 2017. “The attention on this disease comes at a time when pharmaceutical companies are positive about vaccines as part of their business model and searching for new targets,” said Mr. Bruce Carlson, publisher of Kalorama Information.

A centre to investigate complex biological systems

While the behaviours of individual cells and the functions and properties of tissues and organs have been extensively studied, the complex interactions of cell clusters have not been examined in great detail. The newly established US$25 million Emergent Behaviours of Integrated Cellular Systems (EBICS) Centre of the National Science Foundation (NSF) in the United States will study the complex interactions of cell clusters. The Massachusetts Institute of Technology (MIT), the University of Illinois, Urbana-Champaign, and the Georgia Institute of Technology will jointly run the Centre.

The EBICS Centre aims to advance research on complex biological systems, create new educational programmes based on this research, and demonstrate leadership in its involvement of groups traditionally under-represented in science and engineering. It is expected to enable scientists to create biological modules such as sensors that can be combined in various ways to produce different capabilities.

United Kingdom grants patent for iPS cells

A biomedical company from the United States, iPierian, has been granted the first patent issued outside Japan for the genetic reprogramming technology used to create induced pluripotent stem (iPS) cells. The decision by the United Kingdom’s Intellectual Property Office does not involve the work of Kyoto University’s Mr. Shinya Yamanaka, whom many consider to have invented the technology behind iPS cells, which have the ability to develop into any cell type in the body. Instead it credits the invention to a competing Japanese research group led by Mr. Kazuhiro Sakurada, who worked for an affiliate of Bayer Schering Pharma. iPierian, based in South San Francisco, acquired rights to the patent claims in 2008.

While various international research groups have filed more than 75 patent claims involving iPS cells, the only patents awarded until now have been issued by Japan for Mr. Yamanaka’s work. Crucially, iPierian contends that Bayer had filed its key claims for the use of iPS technology in human cells months ahead of any rivals, including Mr. Yamanaka. But Ms. Akemi Nakamura, a Kyoto University spokesperson, says the Yamanaka claim was filed prior to the Sakurada claim.

The Yamanaka-Sakurada-iPierian relationship is complicated. Mr. Yamanaka was involved in the early founding of iPierian, which initially set up shop inside the Gladstone Institutes, an affiliate of the University of California, San Francisco. While he has no direct stake in iPierian, his Kyoto research laboratory collaborates with the company on efforts to refine methods of reprogramming cells. Mr. Sakurada briefly held the post of chief scientific officer of iZumi Bio, the company that became iPierian after it merged with Pierian, a start-up created by three Harvard stem-cell researchers. Mr. Ken Taymor, Executive Director, the Berkeley Centre for Law, Business and the Economy in the United States, says that patents are pertinent only in the countries where they are issued. But he acknowledged that the recent decision signals that at least one major patent office is taking the Mr. Sakurada’s claims seriously. “These are initial steps in defining the intellectual property landscape for this important technology,” he adds.


Goodwin Biotechnology announces collaboration with Macrocyclics

In the United States, Goodwin Biotechnology, a full service contract biomanufacturing company, and Macrocyclics, a manufacturer of customized chelating agents, have announced a collaborative agreement that will strengthen joint customer projects in nuclear medicine involving chelation, bioconjugation and good manufacturing practices (GMP).

“Clinical development programmes in nuclear medicine with biotargeted agents require combining chelation chemistry and bioconjugation chemistry to create a product,” said Mr. Garry E. Kiefer, Macrocyclics’ Chief Executive Officer. “In Goodwin Bio, we found a perfect collaborator to jointly advance diagnostic and therapeutic medicine,” he said. “Our integrated cGMP services combined with Macrocyclics’ chelation expertise will enhance clinical development programmes in nuclear medicine,” said Mr. Muctarr Sesay, Vice President of Process Development at Goodwin Biotechnology.

Galapagos picks up Argenta Discovery’s service business

Galapagos, Belgium, is paying 16.5 million euros in cash to take over the service business of Argenta Discovery, a contract research drug discovery company in the United Kingdom. Argenta’s respiratory development programmes will continue as a new privately held company called Pulmagen Therapeutics. Galapagos will have no ownership in Pulmagen.

Through the acquisition, Galapagos gains Argenta Discovery’s medicinal chemistry, computational chemistry, biology, and Absorption, Distribution, Metabolism and Excretion (ADME) activities, as well as the respiratory models and pharmacokinetics operations. The combination of Argenta with Galapagos’ service division BioFocus creates a drug discovery service organization with 390 employees. The combined service division, which will operate under the brand names of BioFocus and Argenta, is expected to bag 70 million euros in 2010 revenues.

Abbott in cancer research collaboration with Pierre Fabre

Abbott, a multinational pharmaceuticals health care company based in the United States, has signed an exclusive worldwide licensing agreement with Pierre Fabre, a multinational pharmaceutical and cosmetics company based in France, to develop and commercialize h224G11, a pre-clinical monoclonal antibody targeting the cMet receptor for the treatment of cancer. As per the agreement, both companies also intend to collaborate on research to explore next-generation cMet antibodies.

Under the collaboration and license agreement, Abbott will lead the development and commercialization of monoclonal antibodies targeting the cMet receptor. Pierre Fabre will receive an initial US$25 million upfront payment and research funding to support further discovery efforts for two years.

H224G11 works by specifically binding to cMet protein and interrupting the signalling pathway, which leads to cancer cell death and prevention of tumour growth. The antibody also inhibits cancer cell migration and angiogenesis.
Source: www.contract

Pall Corporation markets new biotech filtration system

Pall Corporation – a global leader in filtration, separation and purification based in the United States – has introduced the PallSep Biotech® system for the gentle separation of target molecules from complex biotechnology process fluids. The new system utilizes vibrating membrane filtration technology and encapsulated hydrophilic polyethersulfone membrane filter modules. This unique combination reduces the accumulation of retained species on the membrane surface, allowing for increased transmission of target molecule.

The PallSep Biotech system supports the production of high value products like therapeutic vaccines and antigen extracts. It permits the concentration, clarification and purification of feed streams with high levels of biomass particulates and viscosity, along with difficult-to-filter solutions such as fermentation broths and lysates.

“The new PallSep Biotech system expands processing options by allowing users to combine different process steps such as harvest and clarification within the same system, thus simplifying the process design,” said Ms. Nathalie Pathier, Tangential Flow Filtration (TFF) product manager, Pall Life Sciences. “The stable permeate flow and improved protein transmission we can achieve with this technology contribute to better process economics.”

Custom designed for specific requirements, the PallSep Biotech system can be operated manually or within an automated process. It includes all valves, pumps, sensors, vessel and piping elements. The system is suitable for installation in Good Manufacturing Practices (GMP) facilities for use in biopharmaceutical processes without any compromise on ease of use, flexibility, cleanability, safety or operating costs.

Lilly, Merck and Pfizer join forces to push cancer research in Asia

Three global pharmaceutical companies based in the United States – Eli Lilly & Co., Merck & Co. and Pfizer Inc. – have announced the formation of the Asian Cancer Research Group, Inc. (ACRG), an independent, not-for-profit company established to accelerate research and ultimately improve treatment for patients affected with the most commonly diagnosed cancers in Asia. The goal of ACRG is to improve the knowledge of cancers prevalent in Asia and to accelerate drug discovery efforts by freely sharing the resulting data with the scientific community.

Over the next two years, Lilly, Merck and Pfizer have committed to create one of the most extensive pharmacogenomic cancer databases known to date. This database will be composed of data from approximately 2,000 tissue samples from patients with lung and gastric cancer that will be made publicly available to researchers and, over time, further populated with clinical data from a longitudinal analysis of patients.

About 40 per cent of patients with lung cancer in Asia demonstrate a mutation (EGFR mutation) that is relatively rare in Western patients. This mutation has resulted in differences in response to some types of agents, suggesting that a different research approach is needed for developing treatments for certain patient populations. Gastric cancer, the second largest cause of cancer death in the world, has reached near epidemic proportions in some countries in Asia.

“ACRG is about sharing information for the common good,” said Dr. Kerry Blanchard, Lilly’s Vice President and leader of drug development in China and who represented Lilly in ACRG formation. “This company will aid researchers around the world to develop diagnostics, tailor current treatments and develop novel therapies to improve outcomes for affected patients with lung, gastric and perhaps other forms of cancer,” he added.

PPD continues its Asian expansion

PPD Inc., a leading global contract research company based in the United States, has announced the opening of offices in Manila, the Philippines, and Bangalore, India, expanding its Phase II-IV clinical development services in response to growing client demand in the Asia-Pacific region. PPD will provide clinical management services in key therapeutic areas from both locations. The offices strengthen PPD’s full range of drug discovery and development services and continue to position the company to capitalize on the tremendous growth of the outsourcing market in Asia-Pacific. PPD recently expanded in this region through its acquisitions of Excel, the market leader, and BioDuro, a drug discovery outsourcing company in the United States.


Part of human genetic material comes from a virus

About eight per cent of human genetic material comes from a virus, according to researchers. The research showed that the genomes of humans and other mammals contain DNA derived from the insertion of Borna Disease Viruses (BDVs), RNA viruses whose replication and transcription takes place in the nucleus. Prof. Cédric Feschotte from University of Texas at Arlington, the United States, wrote on the research led by Prof. Keizo Tomonaga at Osaka University in Japan, that this virally transmitted DNA may be a cause of mutation and psychiatric disorders such as schizophrenia and mood disorders.

The assimilation of viral sequences into the host genome (endogenization) occurs when viral DNA integrates into a chromosome of reproductive cells and is subsequently passed from parent to offspring. Until now, retroviruses were the only viruses known to generate endogenous copies in vertebrates. But the scientists have now found that non-retroviral BDVs have been endogenized repeatedly in mammals throughout evolution.

BDV owes its name to the town of Borna, Germany, where a virus epidemic in 1885 wiped out a regiment of cavalry horses. BDV infects a range of birds and mammals, including humans. It is unique because it infects only neurons, establishing a persistent infection in its host’s brain, and its entire life cycle takes place in the nucleus of the infected cells. Prof. Feschotte said that this intimate association of BDV with the cell nucleus prompted researchers to investigate whether BDV may have left behind a record of past infection in the form of endogenous elements. They searched for sequences that are similar to that of BDV in the 234 known eukaryotic genomes (the genomes that have been fully sequenced).

The researchers unearthed a plethora of endogenous Borna-like N (EBLN) elements in many diverse mammals. They were also able to recover spontaneous BDV insertions in the chromosomes of human cultured cells persistently infected by BVD. Based on these data, Prof. Feschotte proposes that BDV insertions could be a source of mutations in the brain cells of infected persons.

Gene that improves quality of reprogrammed stem cells

Scientists at the Genome Institute of Singapore (GIS) report that a genetic molecule called Tbx3, which is crucial for many aspects of early developmental processes in mammals, significantly improves the quality of induced pluripotent stem (iPS) cells, the stem cells that have been reprogrammed from differentiated cells. By adding Tbx3 to the existing reprogramming cocktail, GIS scientists successfully produced iPS cells that were much more efficient in recapitulating the entire developmental process.

“With this new knowledge, we are now able to generate iPS cells which are, or approach, the true equivalent of embryonic stem cells (ESCs),” said Dr. Lim Bing, lead author of the study and Senior Group Leader at GIS, one of the research institutes of Singapore’s Agency for Science, Technology and Research (A*STAR).

Converting adult cells to stem cells such as iPS cells represents one of the most astounding breakthrough technologies in biological research. These cells look and behave like normal ESCs that can generate all other tissue types. Previous studies had demonstrated how scientists can make iPS cells by using different genetic cocktails, as well as improve this efficiency by adding chemical supplements. However, not all iPS cells generated with different cocktails resemble true ESCs; that is, the quality of the iPS cells is highly varied.

“The new study by Bing Lim and colleagues shows that the inclusion of Tbx3 as one of the reprogramming factors significantly improves the quality of iPS cells. These iPS cells were superior since viable adults composed entirely of these iPS cells could be generated,” said Dr. Azim Surani, Physiology and Reproduction Professor at the Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, the United Kingdom. These iPS cells also showed superior ability for contribution and transmission through the germ line, a critical criterion for assessing the quality of iPS cells.

Heart rhythm gene revealed in new research

A gene that regulates the rhythm of the heart is revealed in new research published in Nature Genetics. The authors of the study, from Imperial College London, the United Kingdom, say their discovery helps them to understand how the body’s heartbeat is controlled and could ultimately help scientists design more targeted drugs to prevent and treat certain heart problems. The gene identified in the study is linked to serious heart rhythm disturbances, which cause more than half of the heart disease deaths, and reveals a new mechanism that controls the heartbeat.

A person’s heartbeat is controlled by electrical signals, which start in one central place and travel around the heart muscle. This electrical signal is transmitted by specialized proteins in heart muscle cells called ion channels. The new study reports the discovery of an ion channel in the heart called SCN10A, which directly influences heart rhythm disturbances and a person’s risk of cardiac arrest caused by ventricular fibrillation. The mutation identified in the SCN10A gene is common and, at an individual level, has a modest effect on a person’s risk of having heart rhythm problems.

The researchers – led by Dr. John Chambers from the School of Public Health and Prof. Jaspal S. Kooner from the Division of Epidemiology, Public Health and Primary Care – analysed the genetic make-up of about 20,000 people to look for genetic factors influencing the heartbeat. They studied the electrocardiogram of each person, and measured the time taken for electrical signals to travel to different parts of the heart. They discovered that variation in the gene that encodes the ion channel SCN10A was associated with slow and irregular heart rhythms, including risk of ventricular fibrillation. The researchers then identified the protein in human and mouse heart muscle cells.

Stuttering linked to defective genes

Stuttering could be caused by defects in three genes, according to a landmark study. A team of researchers from the National Institute on Deafness and Other Communication Disorders (NIDCD), the United States, analysed the genes of 123 Pakistanis who stutter and 96 who do not, along with the genes of 550 people from the United States and the United Kingdom, around half of whom stuttered. Some of the Pakistani participants had been part of an earlier study that found that people who stutter had a mutation in a gene known as GNPTAB. The new study, led by geneticist Dr. Dennis Drayna, found that those who stutter also had mutations in two other genes called GNPTG and NAGPA. People who did not stutter did not have the mutations.

The three genes play their role in steering enzymes to a cell structure called the lysosome where the enzymes break down and recycle cellular components. Mutations in GNPTAB and GNPTG are already known to play a key role in two forms of mucolipidosis, a rare disorder where improperly recycled cell components accumulate in the lysosome and cause joint, skeletal, heart, liver, spleen and motor-system problems, along with developmental and speech problems. For the first time, this study has linked NAGPA, which is also linked to the lysosome, with a disorder in humans.

The study opens up the possibility that in future, enzyme replacement therapy could be used to correct stuttering. This will reassure parents of children who stammer, as well as adults who stutter, and help to remove the stigma associated with the speech problem. Researchers at the University of Punjab, Pakistan, the Hollins Communications Research Institute, the United States, and other research institutes that are part of the United States National Institutes of Health also took part in the study.

Second dose of gene therapy for inherited blindness proves safe

Gene therapy for a severe inherited blindness, which produced dramatic improvements last year in 12 children and young adults who received the treatment for Leber’s congenital amaurosis (LCA) in a clinical trial, has cleared another hurdle. The same research team in the United States that conducted the human trial now reports that an animal study has shown that a second injection of genes into the previously untreated eye is safe and effective, with no signs of interference from unwanted immune reactions following the earlier injection.

The 10 animals – four monkeys and six dogs – that received the gene therapy twice had improved vision, and showed no toxic effects from the gene therapy. The study was conducted by scientists at the University of Pennsylvania School of Medicine, the Children’s Hospital of Philadelphia and two other institutions. Their findings suggest that human patients who benefit from gene therapy in one eye may experience similar benefits from treatment in the other eye for LCA. Researchers had exercised caution by treating only one eye in the human trial.

Single-cell imaging method to identify gene interactions

Scientists in the United States have developed a method of interpreting data from single-cell images to identify genetic interactions within biological networks, offering a glimpse into the future of high-throughput cell imaging analysis. With the ability to collect large imaging datasets, researchers from Massachusetts Institute of Technology (MIT) and Harvard Medical School (HMS) recognized an opportunity to explore the cellular networks that regulate cell morphology. MIT researcher Dr. Bonnie Berger and colleagues devised a novel computational model to identify genetic interactions using high-dimensional morphological data. Their model integrates prerequisite knowledge of a pathway to map potential interactions within a network by looking for similar morphological features upon genetic perturbation.

The group demonstrated the method by analysing the Rho-signalling network in fruit flies, a network that regulates cell adhesion and motility in eukaryotic organisms. The researchers knocked down components of the Rho-signalling network using RNA interference and then imaged thousands of fly cells, gathering measurements of cell perimeter, nuclear area and more than 150 other morphological features for each cell. The data were then passed through the computational framework to get a set of reliable interactions, confirmed by previously known interactions. The group found that by making combinatorial knock-downs of Rho network components, their computational method was able to infer Rho-signalling network interactions more accurately than when using data from single knock-downs.


A protein that helps heart muscle to contract

Researchers at the University of California San Francisco (UCSF), the United States, have discovered that a protein called B1N1 is necessary for the heart to contract. The findings shed light not only on what makes a heart beat but also on heart failure, a condition where cardiac cells are not able to contract and pump blood through the body.

Each contraction of a heart cell depends on tiny calcium channels in specialized pockets of membrane known as T-tubules. Correct positioning of these channels on the T-tubules is vital. Scientists have known for decades why the channels need to be on T-tubules, but were perplexed how they got there.

Dr. Ting-Ting Hong, lead author of the study and post-doctoral fellow in the Laboratory of Dr. Robin Shaw, an author of the study and a cardiologist in UCSF’s Heart Failure and Transplantation Service, had a mental image of calcium channels being carried on highways (known as microtubules) directly to membrane docking stations in the T-tubules. Dr. Hong confirmed her hypothesis of directed delivery of the channels and identified the protein docking station as BIN1.

The study involved human heart cells and non-muscle cells that allowed researchers to recreate the delivery process using only the highways, channels and docking station. When the team mutated the docking station (BIN1), it confirmed the cascade of signalling events necessary for heart contraction become dysfunctional, as in heart failure. Understanding how the heart cell organizes itself paves the way for investigators to understand what happens to the heart during heart failure.

New protein function discovered

Mr. Philip R. LeDuc of the Carnegie Mellon University, the United States, and his collaborators have discovered a new function of a protein that could ultimately unlock the mystery of how these workhorses of the body play a central role in the mechanics of biological processes in people. Until now, researchers have been mainly focusing on a protein called Integrin to study cell functions, but Mr. LeDuc’s team found that another lesser known protein called Syndecan-4 is extremely important in cell behaviour in a field called MechanoBiology – a field linking mechanics and biology. “Syndecan-4 is known to play an essential role in a variety of diseases like cancer,” Mr. LeDuc said.

Essentially what the new research does is take a look at how a protein’s shape and form determines how it functions in the human body from a mechanics perspective. The long chains of amino acids in proteins can form bonds with other molecules. These twist and fold into complicated, three-dimensional shapes, such as helices or densely furrowed globular structures. These folded shapes are very important because they can define a protein’s function in the cell, said Mr. LeDuc.

Research by Mr. LeDuc found that some protein shapes fit perfectly into cell receptors, turning chemical processes on and off, like a key in a lock. With mechanics changing the shape of proteins, the key might no longer fit into the lock, and serious consequences in the body can occur when proteins fail to assume their preordained shapes or fail to connect properly. “Misguided proteins have been linked to disease such as cancer, arthritis and wound healing, among others,” Mr. LeDuc explained. “Our research is looking at how protein shapes affect cells and how cell biomechanics impacts the entire process.”

Gene splicing and dicing protein

Scientists from the National Cancer Institute (NCI) and the University of Texas Health Science (UTHS) Centre in the United States and the University of Toronto in Canada have made a novel finding that offers a clue as to how genes can have what you might call multiple personalities. This discovery reveals that the protein MRG15, which previously had been known to affect cell growth and aging, also directs the gene-splicing machinery. As people or animals age, this gene-splicing machinery can go awry, producing nonsense proteins rather than the proper ones. These aberrant proteins can damage cells, possibly leading to diseases.

“We have known for three or four years, from other analyses, that this protein was also involved in splicing, but we needed the expertise of Dr. Misteli’s lab,” said Dr. Olivia Pereira-Smith, a professor in the Department of Cellular and Structural Biology and the Sam and Ann Barshop Institute for Longevity and Aging Studies at the UTHS Centre, has studied the function of MRG15 for more than 10 years. The study’s lead author is Dr. Reini F. Luco from the laboratory of senior author Dr. Tom Misteli at NCI and the leader of the splicing studies in the project.

An evolutionary protein link between plants and humans

Inserting a human protein important in cancer development was able to revive dying plants, showing an evolutionary link between plants and humans and possibly making it easier to study the protein’s function in cancer development, a study at Purdue University, the United States, has shown. The aminopeptidase M1 protein (APM1), is critical for root development in plants. Arabidopsis plants lacking the protein will die, but can be rescued if the protein is restored.

During experiments, Ms. Wendy Peer, a research assistant professor of horticulture, found that inserting a similar protein found in humans, called insulin responsive aminopeptidase (IRAP), also rescued the plants. “APM1 and IRAP are in the same group,” said Ms. Peer. “M1 aminopeptidase activity is such a fundamental process that it has been conserved evolutionarily. This protein has changed very little over time.”

The finding could advance the understanding of this class of proteins because it might make it possible to conduct studies with plants instead of animals, offering researchers more control and options. Humans with altered function of the equivalent proteins often have one cancer or other. “If humans have changes in these peptidases, they are very sick. Understanding how these proteins work in plants will help us understand how they work in humans,” Ms. Peer said.

APM1’s function is not entirely understood in plants. M1 aminopeptidases are thought to remove amino acids from proteins, thereby either activating or deactivating those proteins. M1 aminopeptidases also break down accumulations of proteins related to Alzheimer’s disease. Ms. Peer wants to understand which proteins APM1 targets and how it changes those proteins, thereby affecting changes in a plant’s development. She is working to discover which amino acids in APM1 are necessary for it to function.

BBS proteins shown to run an export business to protect cilia

A protein complex mutated in human disease removes excess signalling molecules to prevent them from damaging cilia, say researchers from University of Massachusetts Medical School, the United States.

Defective cilia cause a range of diseases including Bardet-Biedl Syndrome (BBS), a rare, multi-tissue disorder linked to mutations in 12 different proteins. Seven of these form a complex, called BBSome, but the function of this protein assembly in cilia and flagella is unclear. In worms, the complex glues together the intraflagellar transport (IFT) machinery that assembles and maintains cilia by hauling cargo back and forth along the organelle’s microtubules. But most mammalian cell types can still form cilia in the absence of BBS proteins, suggesting that the BBSome is not essential for IFT.

Mr. Karl Lechtreck and his team turned to the green alga Chlamydomonas, and found that BBS proteins were only present on a subset of IFT particles in each of the alga’s two flagella. Strains lacking components of the BBSome showed normal rates of IFT and proper flagellar structure, but could not steer away from bright light like wild-type cells could. Mutant flagella accumulated several signalling-related proteins, which the researchers think may disrupt the alga’s response to light. The researchers speculate that a similar build-up of disruptive proteins causes cilia dysfunction in BBS patients; the BBSome may remove excess signalling proteins from flagella by linking them to a subset of IFT particles undergoing retrograde transport out of the cilia. Mr. Lechtreck says that the next step is to fluorescently tag the signalling proteins and compare their movements to BBS and IFT proteins.

Biomarker for Alzheimer’s disease in healthy adults

Researchers at New York University (NYU) School of Medicine, the United States, have found that elevated levels of phosphorylated tau231, P-tau231, in cerebrospinal fluid may be an early diagnostic biomarker for Alzheimer disease in healthy adults. The study shows that high levels of P-tau231 predict future memory decline and loss of brain grey matter in the medial temporal lobe.

Prior studies found the medial temporal lobe to be the most vulnerable brain region in the early stages of Alzheimer disease, accumulating damaged tau proteins in the form of neurofibrillary tangles. The NYU team evaluated 57 cognitively healthy older adults and studied the relationships between baseline cerebrospinal fluid biomarkers, longitudinal memory performance, and longitudinal measures of the medial temporal lobe gray matter using MRI. Two years later, researchers found that 20 out of 57 healthy adults showed decreased memory performance. The group with worsened memory had higher baseline levels of P-tau231 and more atrophy in the medial temporal lobe. The higher P-tau231 levels were associated with reductions in medial temporal lobe grey matter.

“Our findings suggest that P-tau231 has the potential to be an important diagnostic tool in the pre-symptomatic stages of Alzheimer disease,” reports lead author, Dr. Lidia Glodzik, Assistant Research Professor, Department of Psychiatry at the Centre for Brain Health and Centre of Excellence on Brain Aging at NYU School of Medicine.



Nano version of a chemotherapy drug developed

A group of researchers in India has developed a nano version of carboplatin, used in chemotherapy treatment. Unlike the existing molecule, the nano version allows a higher concentration of the drug to attack the cancerous cells and thus increase the chances of survival of a patient. In addition, it will reach the cancerous cells at a faster pace and reduce toxicity levels of the chemotherapy drug. Carboplatin is a chemotherapy drug used against some forms of cancer, especially against cancers of brain and central nervous system.

Dr. Debraj Shome, Facial Cancer Expert from Apollo Hospitals, Hyderabad, and the leader of the five-member research team, said, “We realized that in many cases, large molecule carboplatin drugs could not penetrate and reach the cells in the eyes and the brain. We then thought why not come out with a nano version of this same drug which would be an answer to many shortcomings.” The reduced size of the drug makes it easy for the molecules to penetrate through the pores of the outer portion of the eye and directly target the cancerous cells. This was proven through an experiment conducted on rats. The nano version of the drug enters cells up to 75 per cent more than the normal generic version of the drug.

If successful in human trials, which is under way, this nano drug will mainly target children below the age of two years who are suffering from retinoblastoma (eye cancer) and children and young adults suffering from other round cell tumours. The researchers hailed from Indian Institute of Technology (IIT), Mumbai, LV Prasad Eye Institute, and Apollo Hospitals, Hyderabad, and Tata Memorial Hospital, Mumbai.

Biologists wake dormant viruses and uncover survival mechanism

It is known that viral “squatters” comprise nearly half of our genetic code. These genomic invaders inserted their DNA into our own millions of years ago when they infected our ancestors. But just how we keep them quiet and prevent them from attack was more of a mystery until researchers at the Ecole Polytechnique Federale de Lausanne (EPFL), Switzerland, revived them.

The reason we survive the presence of these endogenous retroviruses – viruses that attack and are passed on through germ cells – is because something keeps the killers silent. Research work by Dr. Didier Trono and his team from EPFL, in Switzerland, provide insights into evolution and suggest potential new therapies in fighting another retrovirus – human immunovirus (HIV).

By analysing embryonic stem cells in mice within the first few days of life, Dr. Trono and team discovered that mouse DNA codes for an army of auxiliary proteins that recognize the numerous viral sequences littering the genome. The team also demonstrated that a master regulatory protein called KAP1 appears to orchestrate these inhibitory proteins in silencing would-be viruses. When KAP1 is removed, for example, the viral DNA “wakes up”, multiplies, induces innumerable mutations, and the embryo soon dies.

Because retroviruses tend to mutate their host’s DNA, they have an immense power and potential to alter genes. During ancient pandemics, some individuals managed to silence the retrovirus involved and therefore survived to pass on the ability. Dr. Trono explains that the great waves of endogenous retrovirus appearance coincide with times when evolution seemed to leap ahead.

The discovery of the KAP1 mechanism could be of interest in the search for new therapeutic approaches to combat AIDS. The virus that causes AIDS can lie dormant in the red blood cells it infects, keeping it hidden from potential treatments. Waking the virus up could expose it to attack.

3-D structure of bullet-shaped virus could help fight diseases

Vesicular stomatitis virus (VSV) has long been a model system for studying and understanding the life cycle of negative-strand RNA viruses, which include viruses that cause influenza, rabies and measles. More importantly, VSV has the potential to be genetically modified to serve as an anti-cancer agent, exercising high selectivity in kVesicular stomatitis virus (VSV) has long been a model system for studying and understanding the life cycle of negative-strand RNA viruses, which include viruses that cause influenza, rabies and measles. More importantly, VSV has the potential to be genetically modified to serve as an anti-cancer agent, exercising high selectivity in killing cancer cells while sparing healthy cells, and as a potent vaccine against HIV. For such modifications to occur, however, scientists must have an accurate picture of the virus structure. While three-dimensional (3-D) structural information of VSV’s characteristic bullet shape and its assembly process has been sought for decades, efforts have been hampered by technological and methodological limitations.

Now, researchers at the University of California Los Angeles (UCLA), the United States, and colleagues have not only revealed the 3-D structure of the trunk section of VSV but have deduced the entire architectural organization of the bullet-shaped virion through cryo-electron microscopy and an integrated use of image-processing methods.

“The special shape of VSV – a bullet head with a short, helical trunk – has lent to its evasion from 3-D structural studies,” said study author Dr. Z. Hong Zhou, UCLA professor of microbiology, immunology and molecular genetics. The team proposed a model for the assembly of the virus, with its origin at the bullet tip. Their data suggest that VSV assembles through the alternating use of several possible interaction interfaces coded in viral protein sequences to wind its protein and RNA chain into the characteristic bullet shape. VSV was shown to be a highly ordered particle, with the nucleocapsid surrounded by, instead of surrounding, a matrix of M proteins. The findings could help lead to advances in the development of VSV-based vaccines for HIV and other deadly viruses, according to the researchers.

Key interaction that controls telomeres discovered

Scientists at the University of Michigan Comprehensive Cancer Centre, the United States, have traced another step of the process that stops cells from becoming cancerous. It starts with the enzyme telomerase that affects telomeres, or the caps at the end of a chromosome. Telomeres shorten over time, but telomerase prevents this from happening, making the cell immortal. If cancer is triggered in the cell, the presence of telomerase leads to the growth of the cancer. Telomerase is kept in control by the protein TRF1, which keeps the telomeres operating correctly. But another protein, Fbx4, can bind to TRF1 and degrade it, causing the telomeres to lengthen. Researchers have now discovered that a third protein, TIN2, can step in and override Fbx4 by binding to TRF1 first and preventing Fbx4 from attaching to it. This finding paves the way for developing a drug that acts like TIN2, keeping everything in check and stopping the first domino from falling.

Senior author Dr. Ming Lei, assistant professor of biological chemistry at the University of Michigan Medical School, says the researchers found that the location in the molecule where Fbx4 binds to TRF1 overlaps with where TIN2 binds to TRF1. Where both Fbx4 and TIN2 are present, the TIN2 wins out and binds to the TRF1 first. This blocks Fbx4 from binding to the TRF1, thereby stabilizing TRF1 and keeping the telomere length in control. The researchers are now looking at peptides that mimic TIN2’s binding to TRF1, in order to block Fbx4. The work is still in preliminary stages and no new therapies are being tested in patients. Currently, molecularly targeted therapies address a pathway or gene that is involved in only specific types of cancer. But as telomerase is involved in all types of cancer, if a drug is discovered, it could have an impact on all cancer types.
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Promising candidates for malaria vaccine revealed

Researchers in Australia, have uncovered a group of proteins that could form the basis of an effective vaccine against malaria. These new findings support the development of a vaccine against the blood-stage of malaria. Dr. James Beeson, Dr. Freya Fowkes and Dr. Jack Richards from the Infection and Immunity Division of Walter and Eliza Hall Institute, along with Dr. Julie Simpson from the University of Melbourne have identified proteins produced by malaria parasites during the blood-stage that are effective at promoting immune responses that protect people from malaria.

Dr. Fowkes and Dr. Beeson identified these proteins by reviewing and synthesising data from numerous scientific studies that had looked at the relationship between antibodies produced by the human immune system in response to malaria infection and the ability of these antibodies to protect against malaria. “A malaria vaccine that stimulates an efficient immune response against the proteins that malaria parasites use to burrow into red blood cells would stop the parasite from replicating and prevent severe illness,” Dr. Beeson said.

Dr. Fowkes said the review of existing studies had illustrated how little was known about blood-stage malaria proteins and their suitability for use in vaccine development. “Only about six blood-stage malaria proteins have been well studied out of a potential 100 proteins,” she said.

Hacking into cells’ communication system could lead to new drugs

Cells rely on several signalling systems to communicate with each other and to control their own internal workings. Scientists from the European Molecular Biology Laboratory (EMBL), Germany, have now found a way to hack into a vital communications system, and raising the possibility of developing new drugs to tackle disorders like neurodegeneration, cancer and cardiovascular disease. The scientists have pieced together the first snapshot of what two of the system’s components look like while interacting.

One way these signalling systems work is by triggering a flood of calcium ions inside the cell. These get picked up by a protein called calmodulin, which turns this calcium signal into action by switching various parts of the cell’s machinery on or off. Calmodulin regulates a set of proteins called kinases, each of which controls the activity of specific parts of the cell, thus altering the cell’s behaviour.

Using high-energy X-rays produced by the European Synchrotron Radiation Facility (ESRF), in France, and by the German Synchrotron Radiation Centre (DESY), Mr. Matthias Wilmanns and his colleagues at EMBL revealed the molecular structure of one of these kinases, a protein called Death-Associated Protein Kinase (DAPK), when bound to calmodulin. The structure showed how calmodulin binds to a particular section of DAPK, switching the kinase on so that it can go and change the function of its targets. The team then worked out which of DAPK’s amino acids were crucial for calmodulin to bind. Faulty versions of DAPK are involved in the development of some cancers. Furthermore, DAPK has physical similarities to many of the other kinases controlled by calmodulin. Therefore, being able to see the three-dimensional structures of these proteins, how they clip together and alter each other’s behaviour means researchers can devise ways to manipulate this interaction with drugs.

Linkage between inflammation and lipid metabolism

Researchers at Karolinska Institute, Sweden, have discovered a protein that is crucial in mediating the anti-inflammatory actions of nuclear lipid receptors. The study identified GPS2, a protein that directly interacts with receptors, as a key component of a protein network, or a “genomic positioning system”.

Numerous nuclear receptors are known as master regulators of lipid metabolism and homeostasis. Recent research indicates that these receptors also play important roles in the control of inflammation, but the mechanisms had not been revealed. Dr. Eckardt Treuter and his team set out to elucidate this pathway. They specifically studied how the nuclear lipid receptors LRH-1 and LXR inhibit inflammatory gene expression in the liver during the acute phase response.

The investigators found that GPS2 was a crucial part of this network. It determines where and when these lipid receptors can control anti-inflammatory processes. The identified pathway connects metabolism and inflammation and is therefore relevant for the understanding of metabolic diseases such as diabetes and atherosclerosis. The researchers suspect even broader roles of related pathways in different tissues linked to metabolic diseases and to cancers.

“We are now closer to understanding at the molecular level how dys-regulation of individual components of these pathways causes alterations in gene expression that contribute to the development of metabolic diseases linked to inflammation,” Dr. Treuter remarks. This knowledge could open up novel pharmacological interventions. For instance, drugs that stabilize receptor interactions with GPS2 might trigger the anti-inflammatory pathway.


Sunflower genome holds the promise of sustainable agriculture

Genomics of Sunflower, a US$10.5 million joint project of Canada, France and the United States, will use next-generation genotyping and sequencing technologies to sequence, assemble and annotate the sunflower genome and to locate the genes responsible for agriculturally important traits such as seed-oil content, seed-dormancy, flowering and wood producing-capacity. “The intent is to have the basis for a breeding programme within four years,” says project leader, Dr. Loren Rieseberg from the University of British Columbia, Canada.

One of the potential applications of this research includes a hybrid variety of sunflower, grown as a dual-use crop. The wild Silverleaf species of sunflower, known for its tall, woody stalks that grow 10-15 feet tall and up to 4 inches in diameter in a single season, could be crossbred with the commercially valuable sunflower plant that produces high quality seeds, capitalizing on the desirable traits of both species.

“The seeds would be harvested for food and oil, while the stalks would be utilized for wood or converted to ethanol. As a dual-use crop it would not be in competition with food crops for land,” says Dr. Rieseberg. In addition, this fast growing annual crop will be highly drought resistant, thanks to desirable traits from the Silverleaf variety, and would therefore be suitable for use in subsistence agriculture in places like Sub-Saharan Africa, as well as in much of North America.

Dr. Nolan Kane, University of British Columbia, is one of the co-investigators on the project and together with colleagues at INRA in France, is doing much of the bioinformatics for the genome project. Dr. Steve Knapp from University of Georgia, the United States, is another co-investigator on the project, whose work includes genetic mapping for desirable traits such as wood formation, as well as the development of germplasm for breeding. “The complete sequence will give us a full draft of the genome and eliminate the arduous one at a time process that we have been using up until this point,” he says.

Biotech soybeans promise heart benefits

Genetically modified (GM) foods have been con-troversial ever since they were introduced. But a new variety of GM soybean nearing commercialization promises to deliver health benefits that could change how people think about agricultural biotechnology. The seed and biotech giant based in the United States, Monsanto, is on the verge of introducing GM soybeans that is claimed to produce substantial amounts of omega-3 fatty acids.

Omega-3 rich GM soybeans could change the emphasis in agri-biotechnology from productivity to human health because soybean oil is practically ubiquitous in Western processed foods. It is in everything from breads and granola bars to salad dressings. Mr. Roy Fuchs, who heads soybean research at Monsanto, says one could get the full daily quota of one type of omega-3s just by eating three products made with the new soybean oil.

While few would argue that a food rich in omega-3 fatty acids would be a healthful addition to any diet, sceptics aren’t convinced that Monsanto’s GM soybean is the best source for those nutrients. Furthermore, questions remain about possible health risks from the GM soybean oil itself. The United States Food and Drug Administration (FDA) recently gave its approval to Monsanto’s soybean oil, and Monsanto expects their omega-3 soybean oil to hit the market in the next few years.

A wild oat helps in the fight against crown rust

Scientists from the United States Department of Agriculture’s Agricultural Research Service (ARS) are tapping into the DNA of a wild oat, considered by some to be a noxious weed, to see if it can help combat crown rust, the most damaging fungal disease of oats. Crown rust reduces oat yields up to 40 per cent and shows a remarkable ability to adapt to varieties bred to genetically resist it. ARS researchers and colleagues have inserted individual resistance genes into oat varieties that produce proteins believed to recognize strains of crown rust and trigger a defence response against them. “Multiline” cultivars with several resistance genes also have been developed.

Crown rust is caused by Puccinia coronata, a fungus that reproduces both sexually and asexually and has enough genetic flexibility to overcome resistance genes, usually in about five years, according to Mr. Martin L. Carson, research leader at the ARS Cereal Disease Laboratory in Minnesotta. To address this, Mr. Carson has turned to a wild variety, Avena barbata, for new genes with effective resistance. The slender oat grows wild in South Asia, much of Europe and around the Mediterranean region.

Mr. Carson inoculated A. barbata seedlings with crown rust. After several crosses, he found seedlings highly resistant to a variety of crown rust strains. In ongoing studies, he is crossing them with the domestic oat, A. sativa, to try to develop the right blend of resistance and desirable traits, such as high yield and drought tolerance. The goal is new plant lines that will effectively fight off crown rust.

Scientists sequence genome of grass as a biofuel model crop

Researchers from the United States Department of Agriculture (USDA) and their colleagues at the Department of Energy Joint Genome Institute have announced the complete sequencing of the genome of a kind of wild grass that will enable researchers to shed light on the genetics behind hardier varieties of wheat and improved varieties of biofuel crops.

The grass, Brachypodium distachyon, can be used by plant scientists as a model organism that is similar to but easier to grow and study than important agricultural crops, including wheat and barley. The research also supports the USDA priority of developing new sources of bioenergy; the Brachypodium genome is similar to that of the potential bioenergy crop switchgrass. But the smaller genome of Brachypodium makes it easier to find genes linked to specific traits, such as stem size and disease resistance.

Brachypodium is also easier to grow than many grasses, takes up less laboratory space, and offers easy transformation, which means scientists can insert foreign DNA into it to study gene function and targeted approaches for crop improvement in the transformed plants, said Mr. John Vogel, a lead author and molecular biologist with USDA’s Agricultural Research Service (ARS).

A major stumbling block in using switchgrass or any perennial grass as a biofuel crop is the difficulty in breaking down its cell walls, an essential step in producing ethanol from cellulosic biomass. Brachypodium may hold the key to finding ways to produce plant cell walls that are easy to break down, said Mr. Vogel, who developed a method with a very high success rate for inserting genes into Brachypodium.

Genetic analysis helps spot sugarcane rusts

Scientists from the United States Department of Agriculture’s Agricultural Research Service (ARS) have analysed rust fungi from more than 160 sugarcane samples from 25 countries to provide a valuable resource for plant breeders and pathologists who are searching for genetic resistance to the deadly orange and brown rusts. These diseases are a major concern for the sugarcane industry. Hence, correctly diagnosing which rust is present is key, according to Ms. Lisa Castlebury, a mycologist at the ARS Systematic Mycology and Microbiology Laboratory, and doing this by appearance alone is difficult.

The study has led a scientific team to genetically analyse and compare DNA sequences from sugarcane rust fungi. In the study, now in its third year, samples have been also analysed with light microscopy to spot the subtle differences between the two rusts. Ms. Castlebury and mycologist Mr. John McKemy identified the new orange rust found in a sugarcane-growing area in Florida. Now the study has turned into a global analysis of rust fungi affecting sugarcane cultivars, in collaboration with ARS research plant pathologist Mr. Jack Comstock and research molecular biologist Neil Mr. Glynn. Most of the sugarcane samples were received from the Americas, Asia and Australia. The results of the scientific team’s genetic sequences have been added to the GenBank, the National Institutes of Health’s genetic sequence database, for use by plant pathologists and plant breeders.


Plant MicroRNAs: Methods and Protocols

As a volume in the highly successful Methods in Molecular Biology series, this publication presents the fundamentals of plant miRNA biology, including pathways and approaches used for their discovery and investigation. It covers a broad range of molecular approaches to the study of small RNA, from basic to advanced experimental and computational techniques. The methods by which the expression of miRNAs and their impact on mRNA levels are characterized, including deep sequencing methods for miRNAs and target RNAs, are detailed. The publication enables molecular biologists to design and perform experiments on the biology of plant miRNAs and small RNAs, including their detection, quantification and localization, and covers approaches to data analysis.

Genetics and Genomics of Populus

Populus – with over 30 species and wide geographic distribution – has developed into a prime model system for tree research. Genetics and Genomics of Populus provides indepth description of the genetic and genomic approaches and tools for Populus, examines the biology that has been elucidated using genomics, and looks to the future of this unique model plant. This volume is designed to serve both experienced researchers and newcomers to the field. Contributors to the volume are a blend of researchers, some of who have spent most of their research career on this genus. The genetic and genomic strategies and tools developed by the Populus community, and showcased in this volume, will hopefully provide inspiration for researchers working in other, less well developed, systems.
For the above two publications, contact: Springer Customer Service Centre GmbH, Haberstraße 7, 69126 Heidelberg, Germany. Tel: +49 (6221) 3450; Fax: +49 (6221) 345 4229; Website: www.


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