VATIS Update Biotechnology . Sep-Oct 2011

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Biotechnology Sep-Oct 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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Collaboration on biotech wastewater treatment solutions

The treatment of water to eliminate pollutants is crucial for human health and the environment. While there are several water treatment methods available, the potential of biotechnology (based on plants, micro-organisms or biochemical processes) for treating polluted water has not been fully exploited yet. India’s Department of Biotechnology (DBT) and the European Commission have come together to support the development of innovative biotechnological wastewater treatments to improve water recycling for agriculture and improve water usage. The objective of this pilot initiative is to support strategic cooperation between India, and the European Union and its member states for addressing more effectively global societal challenge in issues related with bioresources and water. The project will develop wastewater treatment applications, leading to a greater integration of research actors and activities from across India and the European Union. Through this programme, DBT aims to promote multi-institutional networked programme with cross-disciplinary partnerships.

The participation of industry, including small and medium enterprises (SMEs), is expected to contribute to bring a market-oriented innovation in this field in order to address the social dimension of the project. A wide coordination of research activities in the topic area between India and the European Union, which are both major players in these fields, will contribute to step up the India-European Union collaboration in scope and scale. The collaborative project includes the large-scale integrating project targeted at SMEs. However, the SME-targeted collaborative projects will only be selected for funding by DBT on the condition that Indian companies fulfil criteria as defined by the Biotechnology Industry Research Assistance Programme (BIRAP) of DBT. The European Union contribution to SMEs will be 25 per cent of the total estimated contribution for the project as a whole. With the total economical frame being about 12 million euros, the requested European Union contribution will not exceed 600,000 euros per proposal.

India and Canada to foster joint R&D projects

Under the Canada-India agreement for scientific and technological cooperation, the governments of Canada and India have agreed to foster joint research and development (R&D) projects by implementing Ontario/India Collaborative Research Fund (CRF). While the Indian side is being represented by Department of Biotechnology (DBT), Ministry of Science and Technology, Government of India, the Canadian side is represented by International Science and Technology Partnerships Canada (ISTP), a non-governmental organization selected by the Ministry of Research and Innovation (MRI), Government of Ontario, Canada. The programme is open to R&D projects in all areas of biotechnology including life sciences and medical devices.

The programme, aimed at fostering and supporting the development of collaborative R&D projects, would be bringing together companies, research organizations, academics and other collaborators for the joint development of innovative products or processes. It also aims to stimulate innovative R&D projects (engaging small to medium-sized companies and/or larger, well-established firms) that address a specific market need or challenge; demonstrate high industrial relevance and commercial potential; and aim to deliver benefit to all participants, and more broadly, to both nations. These projects help participants to become more competitive by developing global research-based alliances with the potential to foster increased or expanded international R&D collaboration.

National Centre for Systems Biology to be established

In the United States, the Medical College of Wisconsin has received a five-year, US$13 million grant to establish a National Centre for Systems Biology. Dr. Daniel Beard, a physiology professor and member of the Biotechnology and Bioengineering Centre, is the principal investigator for the grant. The first goal of the Centre is to create a computational model that will integrate data in the form of a virtual physiological rat (VPR) to help investigators understand and predict physiological function and disease. This will fill a major gap in the understanding of the multiple genetic and environmental causes of diseases. Scientists working on VPR will develop computational tools to decipher the underlying causes of diseases, including hypertension, renal disease, heart failure and metabolic syndromes. Computer simulations will be used to translate the findings from animals to yield new information about complex disease in humans.

The Centre will also utilize the findings of the VPR in real animal models; researchers will derive new strains of rats by developing new transgenic and knock-out strains of rat to test, validate and refine the discoveries of the virtual model. Knock-out rats are genetically engineered rats with a single gene turned off, or “knocked out”, to better understand the functions of particular genes. The first knock-out rats were developed at the Medical College in 2009. The Centre will also serve the research community by developing courses and workshops, training and recruiting scientists from underserved communities, and holding annual scientific meetings to present recent findings.

World’s first cloned human embryonic stem cells

More than seven years after a fraudulent claim on creation of the first cloned human embryonic stem cells (hESCs), the cells seem to have been made for real. There is one problem though: the cells contain an extra set of chromosomes, which means they could never be used to grow tissues for transplantation from a patient’s own cells – the ultimate goal. But having at last shown that there is no block to making cloned hESCs, biologists are optimistic that it should be possible to find a solution to the chromosome problem.

Mr. Dieter Egli and Mr. Scott Noggle of the New York Stem Cell Foundation Laboratory, the United States, and colleagues fused skin cells with unfertilized human eggs. When they removed the eggs’ own chromosomes, as is usual in cloning experiments, the resulting embryos all stopped developing at the 6-12 cell stage. However, when the eggs’ chromosomes were left in place, a fifth of the embryos developed further to form balls of cells called blastocysts. From 2 out of 13 of these embryos, the team isolated hESCs. One of the cloned cell lines came from a man with type 1 diabetes, the other from a healthy man.

Clinical trials of breakthrough gene therapy to treat HIV expected in 2012

In the United States, researchers at Calimmune, a stem cell company founded by Nobel Laureate Dr. David Baltimore, plan to start Phase I/II clinical trials of a revolutionary new gene therapy to treat HIV infections. About 1 per cent of people in Europe have a rare gene mutation that makes them immune to the dreaded human immunodeficiency virus (HIV) infection that has so far killed over 30 million people globally since 1981. Scientists have identified the gene that makes that 1 per cent of the population immune and have used that knowledge to develop a novel gene therapy to provide immunity to HIV patients. The researchers have sought the permission of the United States Food and Drugs Administration (FDA) to start Phase I/II clinical trials of their proprietary gene therapy that aims to remove the protein that is used by the HIV virus to infect a person.

The therapy works as follows: HIV infects a person using a protein CCR5 that acts as the co-receptor for the virus to invade the T cells. Most people inherit two copies of the gene (one from each parent) that code for CCR5 protein. However, it was discovered that about 1 per cent of adult Europeans have a mutation in both copies of the gene and therefore do not produce the CCR5 protein. This makes them resistant to HIV infection because the virus cannot infect a person in the absence of this protein. Calimmune researchers have pioneered a blood stem cell therapy that uses several mechanisms such as RNAi interference to block the expression of the protein CCR5. Currently, HIV infections lead to the prevalence of acquired immunodeficiency syndrome (AIDS) over a period of time and prove fatal in most of the patients. These patients are given lifelong treatment of antiretroviral drugs. The annual treatment for each patient costs about US$25,000 or about US$750,000 on average for a patient’s lifetime.


Panacea Biotec pledges to support GAVI initiative

Panacea Biotec, India, became the first company in the world to introduce a fully liquid pentavalent vaccine, EasyFive, in 2005. EasyFive vaccine immunizes children against diphtheria, tetanus, whole-cell pertussis, hepatitis B and haemophilus influenza type B. Panacea is considered to be the largest vaccine producer in India and the third largest biotechnology company. The company has now pledged its support to the cause of the Global Alliance for Vaccines and Immunization (GAVI) by deciding to reduce the cost of EasyFive by 10-15 per cent in the coming years. This effort would increase the access of vaccines to millions of children. Following the introduction of EasyFive in developing countries in 2008, the price of pentavalent vaccines decreased by 18 per cent in 2010. The new vaccine price reductions are expected to help in donor support for GAVI and contribute towards reducing GAVI’s funding challenge.

GAVI, launched in 2000, is a global health partnership representing stakeholders in immunization from both private and public sectors, developing world and donor governments, philanthropists such as the Bill & Melinda Gates Foundation, the financial community, developed and developing country vaccine manufacturers, technical and research institutes, civil society organizations, as well as multilateral organizations like the World Health Organization (WHO), the United Nations Children’s Fund (UNICEF) and the World Bank.

Aventis Pharma to buy Universal Medicare’s nutraceuticals unit

In India, Aventis Pharma, a unit of Sanofi based in France, will acquire the nutraceuticals business of unlisted Universal Medicare to boost its consumer healthcare and wellness segment in the country. The transaction will involve transfer of about 750 employees of Universal to Aventis Pharma, the latter said in a statement. Aventis is close to buying the over-the-counter business of Universal Medicare for about US$109.5 million. Universal’s turnover of the nutraceuticals business comprises over 40 over-the-counter formulations. Its portfolio includes cod liver oil capsules, vitamin supplement tablets, eye care and skin care products, and pain relief gel. Universal will manufacture the products and supply them to Aventis Pharma on mutually agreed terms.

Franklin Templeton Private Equity Strategy invests in Symbiotec

Symbiotec Pharmalab Ltd., India, has received an investment of US$9 million from Franklin Templeton Private Equity Strategy (FTPES), a private equity portfolio managed by Franklin Templeton Asset Management (India) Private Ltd. and advised by Darby Asia Investors (India) Ltd., the private equity arm within Franklin Templeton Investments group. Symbiotec is engaged in research, development, manufacturing and marketing of research-based active pharmaceutical ingredients (APIs) for hormones and corticosteroids. It has an extensive product portfolio of over 40 corticosteroid and hormone APIs and supplies products to leading pharmaceutical companies in India and overseas. The funds raised from FTPES will be used for backward integration by setting up fermentation facilities, which is expected to improve the company’s competitive positioning and profitability. This is also expected to help the company to attract customers from highly regulated markets such as the United States, Europe and Japan.

Array adds US$713 million cancer drug pact with Genentech to deal roster

Array BioPharma, the United States, has added another high-profile pact to its roster of big-name collaborations. Genentech Inc., the United States, has stepped in with an upfront payment of US$28 million and a promise of up to US$685 million in milestones so that it can snag the rights to develop ARRY-575, a preclinical ChK-1 programme that will be combined with a similar programme of Genentech and pushed into Phase I. Genentech plans to match ARRY-575 with another Phase I compound, RG7602 or GDC-0475. Genentech will be responsible for the development costs and is also committed to a double-digit royalty stream on the early stage programme. The clinical goal of Genentech is to show that a pair of ChK-1 inhibitors will strip the body’s natural defences against DNA damage, thus allowing chemotherapy drugs to do their intended work without interference from the protein kinase.

Zymeworks inks deal with Merck on bi-specific antibodies

Canada-based Zymeworks has struck a deal to put its platform technology to work developing bi-specific antibodies for Merck, based in the United States. Zymeworks gets an unspecified upfront payment, US$187 million in potential milestones and tiered royalties on approved drugs. Zymeworks’ bi-specific antibodies are designed to bind to two different targets, making them effective against a pair of ailments such as cancer and autoimmune disorders. “Zymeworks’ technology platform has the potential to provide a unique solution for engineering novel antibodies,” said Mr. Richard Murray, Senior Vice President of biologics research at Merck. “This is an important validation of our scientific leadership in the field of structure-guided protein engineering,” Zymeworks’ CEO Mr. Ali Tehrani said.

NIBRT and GE Healthcare Life Sciences in joint research

The National Institute for Bioprocessing Research and Training (NIBRT), Ireland, and GE Healthcare Life Sciences, the United States, announced a joint research collaboration to drive advances in technologies for the development and functional analysis of therapeutic antibodies, which are being increasingly used to treat diseases like cancer, multiple sclerosis and rheumatoid arthritis. NIBRT and GE Healthcare are investing US$0.5 million each in the first year of this project, which is planned to run for two years. The goal of the collaboration is to develop robust and reproducible biochemical assays for the analysis of the biological activity of therapeutic monoclonal antibodies.

The collaboration will combine NIBRT’s leading expertise in glycobiology and novel bioanalytical techniques with GE Healthcare’s capabilities in protein-protein interaction analysis, particularly its Biacore SPR technology. The research will be led by NIBRT’s Principal Investigator and global leader in glycobiology, Prof. Pauline Rudd, and will involve researchers from GE Healthcare Life Sciences laboratories in Uppsala, Sweden.

VBI Vaccines buys Epixis, gains CMV and hep C vaccines

VBI Vaccines, the United States, has completed its acquisition of Epixis S.A. – a French biotech company developing its “eVLP” platform technology for a new generation of Virus-Like Particle (VLP) vaccines – for an undisclosed sum. The deal gives VBI rights to Epixis’ eVLP platform, and complements its thermostable vaccine development platform. The two companies were working together since 2010, on a research collaboration focused on cytomegalovirus (CMV). VBI has plans also to advance Epixis’ pre-clinical hepatitis C vaccine candidate. “Our proof of concept and pre-clinical findings have been extremely promising in both CMV and Hepatitis C and we believe clearly demonstrate the value of the eVLP platform,” noted former Epixis CEO Ms. Charlotte Dalba, who is now a senior consultant with VBI.

CLC bio building bioinformatics foundation

CLC bio, a Danish software firm, is working on making sense of the large volumes of molecular data collected in studies of prostate tumours, providing bioinformatics in support of a US$4 million project to research the cancers. With financial backing from the Danish Council for Strategic Research, the project aims to find new molecular markers that show which prostate cancers are wired to become deadly. CLC will develop the bioinformatics tools to support the project, which will involve samples from an extensive tissue bank, sequencing prostate cancer genomes and microarray analyses. The project hits on a worldwide problem that is affecting the care of prostate cancer patients.


Detailed map of gene activity in mouse brain completed

A new atlas of gene expression in the mouse brain provides insight into how genes work in the outer part of the brain called the cerebral cortex. In humans, the cerebral cortex is the largest part of the brain, and it is the region responsible for memory, sensory perception and language. Mice and people share 90 per cent of their genes; so the atlas, which is based on the study of normal mice, lays a foundation for future studies of mouse models for human diseases and, eventually, the development of treatments. The study by scientists from the National Human Genome Research Institute (NHGRI), the United States, and University of Oxford, the United Kingdom, describes the activity of more than 11,000 genes in the six layers of brain cells that make up the cerebral cortex.

To map gene activity in all six layers of the mouse cerebral cortex, the research team first micro-dissected the brains of eight adult mice, separating the layers of the cortex. They then purified RNAs, including messenger RNA (mRNA), from each cortical layer. The presence of an mRNA indicates that a gene is turned on, and the quantity of mRNA shows the extent to which the gene is active. To determine which genes were turned on and to what extent, the researchers used a relatively new sequencing technology called RNA-seq. The technique depends on two steps – RNA is first copy-processed into a form of DNA, and the resulting DNA is then sequenced on a second-generation, DNA sequencing instrument. The massive data set that results is then analysed by a cluster of computers to determine which genes have been turned on in the brain cells and to what extent. The researchers believe that by determining the gene activity in each layer, it will be possible to connect brain anatomy, genetics and disease processes with greater precision. The research team found that more than half of the genes expressed in the mouse cerebral cortex demonstrated different levels of activity in different layers. These differences point to the areas where specific genes play important roles.

Key gene discovery could streamline biofuels production

In the United States, a team of researchers at the Department of Energy’s BioEnergy Science Centre (BESC) has identified the single gene that controls ethanol production capacity in a micro-organism. This discovery could be the vital missing link in developing biomass crops that produce higher concentrations of ethanol at lower costs. The discovery of the gene controlling ethanol production in a micro-organism known as Clostridium thermocellum implies that scientists can now experiment with genetically altering biomass plants to produce more ethanol. Current methods to make ethanol from a type of biomass found in switchgrass and agricultural waste require the addition of expensive enzymes to break down the plant’s barriers that guard energy-rich sugars.

Scientists, including those at BESC, have been working to develop a more streamlined approach in which tailor-made micro-organisms produce their own enzymes that unlock the plant’s sugars and ferment them into ethanol in a single step. Although scientists have studied C. thermocellum for decades, the genetic basis for its ability to tolerate higher concentrations of ethanol had not been determined. Instead of using just one technique or one approach, the research team that made the discovery was able to draw upon a number of experts spanning several scientific disciplines to contribute a broader set of analyses because of the BESC partnership.

Researchers create the world’s most advanced genetic map

A consortium led by scientists at University of Oxford, the United Kingdom, and Harvard Medical School, the United States, has constructed the world’s most detailed genetic map. This genetic map specifies the precise areas in the genetic material of a sperm or egg where the DNA from the mother and father has been reshuffled in order to produce the single reproductive cell. The biological process whereby this reshuffling occurs is known as “recombination”. This new map is the first constructed from African-American recombination genomic data.

Recombination, together with mutation, accounts for all the genetic (and thus physical) variety we see within species. But while mutation refers to the errors introduced into single locations within genomes when cells divide, recombination refers to the process that stitches together huge chunks of chromosomes during sexual reproduction. But this stitching process only occurs at some specific locations. In a prior landmark set of papers, Mr. Simon Myers and his colleagues at the University of Oxford identified a DNA code, or motif, that attracted part of the recombination machinery, a gene called PRDM9. Knowing the motif, a string of 13 DNA letters, researchers could zero in on the locations where recombination typically occurred – the “recombination hotspots”.

The researchers discovered that the 13 base-pair motif that is responsible for many of the hotspots in Europeans accounts for only two-thirds as much recombination in African-Americans. They connected the remaining third to a new motif of 17 base pairs, which is recognized by a version of the recombinational machinery that occurs almost exclusively in people of African ancestry. These findings are expected to help researchers understand the roots of congenital conditions that occur more often in African-Americans (due to mutations at hotspots that are more common in African-Americans), and also to help discover new disease genes in all populations because of the ability to map these genes more precisely. The new map is very accurate because African-American individuals often have a mixture of African and European ancestry from over the past two hundred years.

Potato genome sequenced

A global effort has finally cracked the complex genome of potato (Solanum tuberosum), potentially opening up a new avenue for fighting blight. Being the world’s fourth most important food crop, potato is vital for global food security. Despite its importance, sequencing has been delayed because of the genetic complexity. Potato genome consists of more than 39,000 protein-coding genes, and it is a highly heterozygous autotetraploid – that is, it has four copies of every chromosome, and often with considerable variation among the corresponding four copies of each gene. This is in contrast to the two copies in most human cells. According to Mr. Glenn Bryan of the Scottish Crop Research Institute in Dundee, United Kingdom – one of the 26 research institutes from around the globe that formed the Potato Genome Sequencing Consortium – several factors made the sequencing possible. However, the key was finding a type of potato with a genome that could be adequately simplified.

The researchers used a variety of S. tuberosum referred to as DM. This differs only slightly from another variety that the researchers studied, RH, which more closely resembles that found in most supermarkets. DM, cultivated in South America, has a diploid genome, meaning that it has a more manageable two copies of every gene. Using this potato, geneticists selected one copy of each chromosome and duplicated these to produce a double-monoploid clone – in which the two genes that make up each pair are homozygous, or identical – that they can sequence almost completely. The most important finding of the consortium’s initial analysis is the identification of more than 800 disease-resistance genes, each of which has potential for use in fighting devastating diseases such as the potato cyst nematode and the potato blight pathogen Phytophthora infestans, famous for causing the Irish potato famine of the 1840s. Singling out these genes will make it easier to develop new varieties of potato. The tuber has been very difficult to improve through breeding because of its complex genetics.

Route for eliciting HIV-neutralizing antibodies mapped

Researchers have detailed how certain powerful human immunodeficiency virus (HIV)-neutralizing antibodies evolve, a finding that generates vital clues to guide the design of a preventive HIV vaccine. The discoveries were made by a team led by the Vaccine Research Centre (VRC) at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, the United States. The new findings build on an earlier discovery by VRC scientists of three HIV antibodies, two of which could stop more than 90 per cent of known global HIV strains from infecting human cells in the laboratory. Called VRC01, VRC02 and VRC03, these antibodies were found in blood donated for NIAID studies by an HIV-infected North American known as donor 45. Scientists report discovering antibodies similar to VRC01 in the blood of two HIV-infected Africans known as donor 74 and donor 0219. They also found that these VRC01-like antibodies bind to the same spot on HIV in the same way. This suggests that an HIV vaccine should contain a protein replica of this spot, known as the CD4 binding site, to elicit antibodies as powerful as VRC01. The CD4 binding site is one of the few parts of the continuously mutating virus that stays the same across HIV variants worldwide, and the virus uses this site to attach to the cells it infects.

The scientists previously found that the genes for VRC01-like antibodies undergo an unusually high number of mutations – 70 to 90 – between the first draft that codes for a weak antibody and the final version that codes for an antibody that can neutralize HIV. These genes lie in the DNA of immune cells called B cells. To guide B cells along this evolutionary pathway, the scientists turned to an existing technology to sequence the collection of B-cell genes that code for all antibodies that a person’s immune system creates. The scientists identified thousands of antibody genes that code for VRC01-like antibodies and then sorted these genes into family trees showing their evolution from their earliest stage into mature forms. The genes that coded for HIV-neutralizing antibodies grouped together on the same branches of the trees. The researchers then focused on the gene segment that codes for the part of the VRC01-like antibody that attaches to and neutralizes HIV. Examining this sequence in the genes of the new-found relatives of VRC01 revealed how the sequence changed step by step along one of a few clear paths from its original state into a mature form. The scientists found that a vaccine that elicits VRC01-like antibodies would need to coax the B-cell DNA of immature antibodies to evolve along one of these pathways.

New genes for diabetes in South Asians found

Scientists have found six new genes linked to a common form of diabetes among South Asians. The genes turned up in a six-country Genome Wide Association Study (GWAS) that is looking at variations in genes among individuals of a specific population. The study covers 58,587 South Asians in India, Mauritius, Pakistan, Singapore and Sri Lanka. A report of the study said South Asians, marked by high glucose levels in blood, have four-fold higher risk of developing Type 2 diabetes, which results from incorrect response to insulin.

Mr. Viswanathan Mohan, founder of the Madras Diabetes Research Foundation (MDRF), India, and chief diabetologist at the Indian Council for Medical Research’s Advanced Centre for Genomics of Diabetes, said that the identification of the six new genes will “perhaps lead to future therapies for diabetes.” Mr. Mohan, who was part of GWAS, said scientists did not previously know that five of the six genes were linked to diabetes. He said that it may take several years of follow-up and cutting-edge research to find application in society. Until then, simple methods such as a test to assess diabetes risk could help doctors make timely interventions.

Control gene for developmental timing discovered

Researchers from University of Alberta, Canada, have identified a key regulator that controls the speed of development in the fruit fly. When the researchers blocked the function of this regulator, the flies sped up their rate of development and reached maturity much faster than normal. The research team, led by molecular geneticist Mr. Kirst King-Jones, noticed a peculiar behaviour of DHR4, the protein they were studying – it acted as a sentinel to either allow or prohibit the production of steroid hormones by moving periodically between the cell nucleus and the cytoplasm.

In insects, these steroid hormone pulses control the development through the various stages of their life cycle. When the researchers blocked the function of DHR4 in the steroid hormone-producing cells, the maturation stage was reached 20 per cent faster than normal. In human terms this would mean that sexual maturity would be reached years earlier than normal. Mr. King-Jones says the new research defines a novel mechanism by which steroid hormone pulses are regulated.


New drug candidates for protein-folding diseases

In the United States, collaborating researchers at Stanford University and The Scripps Research Institute have identified chemical compounds that show promise as potential therapeutics for a set of medical conditions caused by the abnormal clumping together of a protein known as transthyretin (TTR). The compounds, which prevent the abnormal aggregation of TTR, function by holding the protein together in its functional form. These compounds hold the promise to be of help to people who have TTR-related amyloid diseases or are at risk for them, and may have advantages over other TTR-stabilizing drugs currently undergoing clinical trials. “These new compounds have structures that make them very effective at stabilizing TTR in its stable native tetrameric form in laboratory tests, and they also seem non-toxic in cell culture,” said Mr. Stephen Connelly, a senior Research Associate in the laboratory of Prof. Ian Wilson at Scripps.

Improved method for capturing proteins

Producing antibodies suitable for research has often been a difficult, costly and laborious exercise. Mr. John Chaput and his colleagues at the Biodesign Institute at Arizona State University, the United States, have developed a new way of producing antibody-like binding agents and rapidly optimizing their affinity for their target proteins. Such capture reagents are vital for revealing the subtleties of protein function and may pave the way for improved methods of detecting and treating a broad range of diseases.

Antibodies are Y-shaped structures, capable of binding in two or more places with specific target proteins. Synthetic antibodies are simpler forms that attempt to mimic this behaviour. Affinity reagents with strong binding properties can be created by combining two weak affinity segments on a synthetic scaffold. A properly constructed affinity reagent can amplify the binding properties of the individual segments by two or three orders of magnitude. “This dramatic change in affinity has the ability to transform ordinary molecules into a high affinity synthetic antibody,” Mr. Chaput states. However, the chemistry used to make such reagents can be quite challenging a task. Mr. Chaput’s team managed to produce synthetic antibodies that do not require cell culture, in vitro selection or the application of complex chemistry. They call their reagents DNA synbodies.

The new production strategy, referred to as Ligand Interaction by Nucleotide Conjugates (LINC), uses DNA as a programmable scaffold to determine the optimal distance needed to transform two weak affinity binding segments or ligands into a single high-affinity protein capture reagent. The result is an artificial antibody, capable of binding to its antigen target with high affinity and high specificity. The process is rapid and inexpensive. It is also very flexible, as the distance between the two ligand components bonded to the short, double-stranded DNA scaffold can be fine-tuned for optimum affinity.

In the current study, the researchers made use of pre-existing ligands with documented affinity for various disease-related proteins. The method involved the use of well-characterized ligands as building components for high-quality DNA synbodies, eliminating the initial screening procedure and expanding the potential to tinker with the two-piece synbody to optimize affinity. The peptides of choice for the study were those with high affinity for growth factor receptor bound protein 2 (Grb2). The results for the best synbody in the study demonstrated a binding affinity five- to ten-fold stronger than commercially available antibodies for Grb2, despite the synbody’s comparatively primitive architecture.

New protein structure model to inhibit cancer development

Researchers at the University of Hertfordshire, the United Kingdom, have developed a structural model of a protein, which makes it possible to develop more effective drugs to target diseases such as cancer, heart disease and influenza. A research team lead by Dr. Andreas Kukol at the University’s School of Life Sciences, describes how they have developed a new 3D model of a protein that unleashes the inhibition of the growth of cells which, unless stunted, could lead to the spread of cancer or support infections such as influenza. “Our bodies are made up of proteins and therefore, they are important for the proper functioning of the body,” said Dr. Kukol. “Malfunction of the protein can lead to cancer. This happens when it becomes over active, so our task has been to identify inhibitors.”

Researchers led by Dr. Kukol developed a 3D model of the kinase IKK-ß enzyme, a protein that regulates other proteins. “This enzyme controls proteins like policeman controls traffic,” said Dr. Kukol. “If the policeman or the enzyme gets out of control, then there will be chaos.” The new 3D model can be used to find new inhibitors, such as organic molecules like aspirin that attach to the active site of the enzyme and make it less active thus stop the spread of cancer or influenza.

Protein switch for turning stem cells into heart tissue

Researchers at University of Oxford, the United Kingdom, have identified a protein that can direct stem cells to become either new heart muscle or blood vessels. The research, which was carried out in zebra fish, offers insight into how it might be possible to generate tissues to repair the human heart after damage inflicted by a heart attack. The scientists, based at the MRC Molecular Haematology Unit at Oxford, identified a protein called “fibroblast growth factor” (Fgf) as the controlling factor that determines whether developing heart cells become heart muscle or blood vessels.

According to Dr. Filipa Simoes, “Our study shows how having the correct concentrations of Fgf in the developing zebra fish heart ensures that the different cell types form properly. Crucially, we were able to convert blood and blood vessel cells into heart muscle cells by flipping genetic switches controlled by Fgf.” Prof. Roger Patient, who led the research at the University of Oxford, explains: “If we can manipulate these heart cells in fish embryos, in the longer term we can look to try and do the same in human hearts – even adult hearts – if we can identify the equivalent cells. This could bring significant benefit to heart attack patients or people with heart defects.” The researchers also propose that these cells in the fish, with the potential to make both heart muscle and vessels, may represent cells that played an important role in evolution. Over millions of years they may have been responsible for an increase the amount of cardiac muscle, enabling the heart to grow in size from two chambers in the zebra fish to four chambers in humans.

First evidence of plant evolution found in protein network

The eon-spanning clock of evolution – the millions of years that generally pass before organisms acquire new traits – belies a constant ferment in the chambers and channels of cells, as changes in genes and proteins have subtle ripple effects throughout an organism. Researchers at Dana-Farber Cancer Institute’s Centre for Cancer Systems Biology in the United States, along with an international team of colleagues, have captured the first evidence of evolution within networks of plant proteins. They used a new map of these networks to uncover how microbes like bacteria and fungi undermine plants’ defences against disease – by disrupting a small set of “virtuoso” proteins that play a variety of different roles within the cell.

The model for the two studies was Arabidopsis thaliana, which has a relatively simple genome of 27,000 genes. Despite decades of research involving the plant, however, scientists have yet to determine the roles of more than 60 per cent of those genes. To gain the first inklings of those roles, investigators used genetic blueprints to produce about 8,000 of the proteins normally made by the plant’s cells. They then mixed each of those proteins with each of the approximately 7,999 others to see which interact. The experiment gave a map of 6,200 interactions between 2,700 proteins – far more than had been shown in any previous map of the plant’s interactome. The scientists employed a newly developed mathematical algorithm to scour the map for “communities”, clusters of densely interconnected proteins likely to function together. They identified 26 such communities, many of which correspond to known processes but contain new proteins. The function of other communities needs investigation. Knowing which genes work together offers clues to their roles within the cell.


Efficacy of green tea in treating genetic disorder and tumours

A compound found in green tea shows great promise for the development of drugs to treat two types of tumours and a deadly congenital disease. The discovery resulted from a study in the United States led by Dr. Thomas Smith at the Donald Danforth Plant Science Centre and his colleagues at the Children’s Hospital of Philadelphia. Glutamate dehydrogenase (GDH) is found in all living organisms and is responsible for the digestion of amino acids. In animals, GDH is controlled by a complex network of metabolites, absent in species belonging to the other kingdoms. Using atomic structures to understand the differences between animals and plants, Dr. Smith and his colleagues discovered that two compounds found naturally in green tea are able to compensate for this genetic disorder by turning off GDH in isolation and when the green tea compounds were administered orally. The Smith lab also used X-ray crystallography to determine the atomic structure of these green tea compounds bound to the enzyme. With this atomic information, they hope to be able to modify these natural compounds to design and develop better drugs.

Two other research groups have validated and extended these findings to show that blocking GDH with green tea is very effective at killing two different kinds of tumours – glioblastomas, an aggressive type of brain tumour, and tuberous sclerosis complex disorder, a genetic disease that causes non-malignant tumours to grow on a number of organs. While these compounds from green tea are extremely safe and consumed by millions every day, they have a number of properties that make them difficult to use as actual drugs.

Researchers unveil method for detecting lung cancer

Nanotechnology sensor could lead to earlier diagnosis for lung cancer, the world’s deadliest form of cancer. Lung cancer often spreads silently into more advanced stages before being detected. Researchers at University of Missouri (UM), the United States, say their discovery could provide a much earlier warning signal. “We have developed highly sensitive technology that can detect a specific molecule type in the bloodstream when lung cancer is present,” said Dr. Michael Wang, Assistant Professor of pathology and anatomical sciences.

UM researchers used blood plasma samples to detect a change in a microRNA molecule that is often elevated in lung cancer patients. They put an extract of blood plasma through a protein-based nanopore, which is a tiny hole in a thin membrane that is just big enough for a single molecule to pass through. By applying an ionic current to the nanopore, the scientists measured changes in the current that occur when the microRNA molecule associated with lung cancer is present. The altered current serves as a signal for lung cancer. “Our new nanopore sensor is selective and sensitive enough to detect microRNAs at the single molecular level in plasma samples from lung cancer patients,” Mr. Li-Qun Gu, a UM Associate Professor of biological engineering said. “This technology could possibly be used in the future to detect other cancer types as well as other types of diseases with specific DNA or RNA in the blood,” he added.

Early evidence suggests that TB jab could help fight cancer

Scientists have found a new potential mechanism to stimulate the body’s own ability to fight cancer using Bacillus Calmette-Guerin (BCG) – the germ commonly used to inoculate against tuberculosis (TB). The researchers, Dr. Wai Liu and Prof. Angus Dalgleish from St. George’s, University of London, the United Kingdom, say that new data suggests a mechanism by which vaccines could enhance the anti-cancer activity of currently available therapies. In laboratory-based experiments conducted with human tumour cells outside of the body, they showed that BCG can instruct white blood cells to produce chemicals called cytokines, which make tumour cells more likely to be detected by the body’s immune system.

“Cancerous cells are known to camouflage themselves as healthy cells. This means our blood cells responsible for immunity aren’t able to recognize the cancerous cells as being a problem and so the disease is able to continue to spread,” explains lead researcher Dr. Liu. The new study found that a small quantity of BCG – similar to the amount that is administered in a TB inoculation – can help the immune system recognize the cancer cells as ‘foreign’. The immune system can then fight them in the same way it would any other infection.

The cytokines produced as a consequence of the BCG jab set off a chain of events that begins with the hijacking of the tumour and forcing it to switch off its camouflage. This renders it visible to the body’s immune system, and the white blood cells now get targets to attack. The researchers tested the BCG injection on human cells from lung, breast, colon, pancreatic and skin cancer. Their research showed that in three of the cancer types – lung, breast and colon – the restoration of their visibility to immune cells was increased. Within the limits of the laboratory-based study, those cancer cells with reduced camouflage were then successfully targeted by white cells.

Discovery opens door for new influenza drugs

In the United States, researchers from Rutgers University and the University of Texas at Austin have determined the 3D structure of a complex between an influenza B virus protein and one of its human protein targets, resulting in suppressing the cell’s natural defences to the infection and paving the way for the virus to replicate efficiently. The discovery could help the development of drugs to fight seasonal influenza epidemics caused by the common influenza B strain. The discovery also helps explain how influenza B is limited to humans, and why it cannot be as virulent as A strains that incorporate new genes from influenza viruses that infect other species. Understanding features of influenza B virus will help scientists better understand how influenza A strains are able to cross species.

According to Prof. Gaetano Montelione, a lead author of the study and professor of biochemistry and molecular biology at Rutgers’ School of Arts and Sciences, “Our study shows the basis by which non-structural protein 1 of influenza B, or NS1B, binds to a human host protein, immobilizing it to prevent it from fighting the virus.” That human protein, known as interferon-stimulated gene 15 protein or ISG15, is an essential part of the defence mechanism that human cells use to protect themselves from viral infections. Chemicals that block the binding of NS1B to ISG15 may have antiviral potential against influenza B virus. The study also reveals why NS1B cannot bind ISG15 molecules in other species, such as dogs or mice. Only human and non-human primate ISG15 proteins have the unique molecular sequence in a small part of the protein that makes it possible to bind to the NS1B protein. “The 3D structure of the NS1B-ISG15 complex, which we determined using X-ray crystallography, has given us a clear understanding of the molecular basis for this species specificity,” said Prof. Robert Krug, co-lead author and Professor of molecular genetics and microbiology at University of Texas.

Treatment for cancer of the immune system

Infection with Epstein-Barr (EB) virus means that the B cells – the primary memory cells of the immune system – are hi-jacked. When the virus has penetrated, researchers have noted an excess of a special bio-antenna, a receptor known as EB12, suddenly sprouting from the surface of the B cells. But why they do so remained a mystery. While researchers know that the B cell EB12 receptors play a part when the cell visits the lymph glands, the immune system’s Central Station, the exact role of the receptor was not known.

Researchers at University of Copenhagen, Denmark, made a map of the bio-antenna molecule by molecule and then, as the first in the world, made a blueprint of a tiny molecule they thought could bind to the B cell EB12 receptor. “When we know what receptors react to, it tells us more about the part they play, and our tiny molecule, a ligand, blocks the EB12 receptor, preventing it from doing its job,” said Mr. Mette Rosenkilde, a professor of pharmacology at the Department of Neuroscience and Pharmacology. “In time, this block may be able to help transplant patients. If we can restrain EB virus reproduction when the immune system is being medically suppressed, we may well be able to avoid cancer,” said Mr. Tau Benned-Jensen, a post-doc researcher at the Faculty of Health Sciences. “On the other hand, the EP virus also appears to play a part in other immune diseases such as autoimmune disease, where the ability to adjust the immune system would be beneficial,” explained Mr. Rosenkilde.

New discovery paves way for cancer treatment

Researchers at A*STAR’s Institute of Molecular and Cell Biology (IMCB), Singapore, have made a landmark discovery in the battle against the rapid spread of aggressive cancers associated with PRL-3 oncoprotein. Contrary to the current accepted theory that antibodies can only bind to cancer proteins found on the cancer cell surface, the IMCB team led by Dr. Zeng Qi has discovered that antibodies can directly target intracellular oncoproteins like PRL-3 that reside within the cancer cells to arrest cancer growth successfully. This breakthrough finding can pave the way for more targeted solutions for cancer treatment and cancer prevention. PRL-3, which stands for “Phosphatase of Regenerating Liver 3”, is a key protein linked to cancer metastasis, the rapid and often fatal spread of cancer cells from the primary tumour to other parts of the body. PRL-3 is commonly overproduced in many types of aggressive lung, liver, kidney, bone and breast cancer.

The new study using mouse models suggests that cancers could be effectively treated through the direct introduction of antibodies to target the PRL-3 oncoprotein inside the cancer cell. Likewise, vaccination with PRL-3 antigen to prevent cancer can induce the body’s immune system to produce antibodies that will directly target the PRL-3 within the cancer cell. Direct introduction of PRL-3 antibodies resulted in 70-90 per cent reduction of tumours caused by PRL-3 expressing cancer cells.

Scientist develops virus that targets HIV

In a major step towards treating human immunodeficiency virus (HIV), a chemical engineering professor at Viterbi School of Engineering, University of Southern California (USC), the United States, has created a virus that hunts down HIV-infected cells. Dr. Pin Wang’s lentiviral vector latches onto HIV-infected cells, flagging them with what is called “suicide gene therapy” – allowing drugs to later target and destroy them.

Like a precision bombing raid, the lentiviral vector approach to targeting HIV has the advantage of avoiding collateral damage, keeping cells that are not infected by HIV out of harm’s way. Such accuracy has not been achieved by using drugs alone, Dr. Wang said. So far, the lentiviral vector has only been tested in culture dishes and has resulted in the destruction of about 35 per cent of existing HIV cells. While that may not sound like a large percentage, if this treatment were to be used in humans, it would likely be repeated several times to maximize effectiveness. Among the next steps will be to test the procedure in mice. While this is an important breakthrough, it is not yet a cure, Dr. Wang said.

Fish oil reduces effectiveness of chemotherapy

Researchers at University Medical Centre Utrecht, the Netherlands, have found that the allegedly healthy fish oil has a uniquely adverse effect on nearly all types of chemotherapy. The basis of the research was the observation that chemotherapy seems to get less effective over time. It appears that chemotherapy is made ineffective by two fatty acids that are made by mesenchymal stem cells in the blood. Under the influence of cisplatin chemotherapy, stem cells secrete fatty acids which induce resistance to a broad spectrum of chemotherapies. These fatty acids – called platinum-induced fatty acids (PIFAs) – are also found in commercially produced fish oil supplements containing omega-3 and omega-6 fatty acids as well as in some algae extracts. The researchers studied the effect of PIFAs in mice that had tumours under the skin. They found that the tumours became insensitive to chemotherapy after administration of normal amounts of fish oil, prompting the scientists to recommend that PIFA products should not be used by people who are on chemotherapy.


New genome sequence could improve food and oil crops

An international team of scientists, funded in the United Kingdom by the Biotechnology and Biological Sciences Research Council (BBSRC), has sequenced the genome of a Chinese cabbage variety of a plant called Brassica rapa, a close relative of oilseed rape. The research could help improve the efficiency of oilseed rape breeding, and that of a host of other major food and oil crops. The project was conducted by an international consortium involving researchers working across four continents, with the majority of the data generated in China. Researchers at the John Innes Centre and Rothamsted Research, both in the United Kingdom, were part of the project team.

Oilseed rape is an unusual hybrid that contains the entire genomes of two other plants: B. rapa and another closely related species B. oleracea. By sequencing B. rapa, researchers are able to access half of oilseed rape’s genes without having to wrestle with its large and complex genome. The B. rapa sequence was produced using a technology that breaks the DNA into small segments before reassembling the complete genome. Throughout its evolution B. rapa has triplicated its genome meaning that the task of assembling the final picture posed a particular challenge to the scientists and the technology.
Source: http://www.

Breeding ozone-tolerant crops

United States Department of Agriculture (USDA) scientists, working with the University of Illinois at Urbana-Champaign, found that future levels of ground-level ozone could reduce soybean yields by an average 23 per cent. Dr. Randy Nelson, geneticist and research leader with the USDA Agricultural Research Service (ARS) Soybean/Maize Germplasm, Pathology and Genetics Research Unit, and Dr. Lisa Ainsworth, a molecular biologist with the ARS Global Change and Photosynthesis Research Unit, are screening soybean varieties for ozone tolerance and sensitivity in Soybean Free Air Concentration Enrichment (SoyFACE) experiments. SoyFACE involves testing plants in open-air field conditions under atmospheric conditions predicted for the year 2050. At that time, ozone concentrations are expected to be 50 per cent higher than today’s concentrations.

During 2007 and 2008, USDA scientists tested 10 Midwestern soybean varieties. They found that exposure to 82 parts per billion (ppb) ozone reduced soybean yields by an average 23 per cent across all 10 varieties. They also found significant differences in ozone tolerance among the varieties. This shows the potential for breeding more ozone-tolerant varieties. Since ozone concentrations have been rising for decades, the scientists initially thought that varieties developed more recently would be more ozone-tolerant. But no significant improvement in ozone tolerance was noted in soybean varieties released since the 1980s.

Lowering harmful cyanogens and raising protein in cassava

Scientists at the Donald Danforth Plant Science Centre, the United States, have made another advancement in their efforts to improve the root crop cassava. A study by Dr. Narayanan N.N. and Dr. Uzoma Ihemere, research scientists working in the lab of Dr. Richard T. Sayre, have developed an approach that not only accelerates the reduction of cyanogen during food processing, resulting in a safer food product, but also lead to increased root protein levels and enhanced nutritional value. Cassava has many properties that make it an important food source across much of Africa and Asia. It also has many limitations – both leaves and roots contain potentially toxic levels of cyanogenic glucosides and the roots, although starchy and calorie-dense, provide the lowest sources of dietary protein among the major staple food crops (less than 30 per cent of the minimum daily requirement).

Hydroxynitrile lyase (HNL) is a natural cassava protein that contains 50 per cent essential amino acids and is found in the leaves of the plant. It can be eaten by humans with no allergic side effects. Dr. Narayanan and his colleagues showed that transgenic roots expressing HNL had a 53-74 per cent reduction in root cyanogen levels, and resulted in a nutritionally enhanced cassava that contained three times as much protein and twice as much total amino acids compared with wild type cassava. They also proved that over-expression of HNL reduced the time required to process and remove life-threatening cyanogens in the tuberous roots from days to minutes. Significantly, HNL is heat-stable and tolerates cooking for 15 minutes, which is helpful in variety of food preparation methods.

Virus-tested seeds sweet potato proven to increase yield

Sweet potato is vegetatively propagated and hence, viruses and mutations can accumulate readily, leading to plant decline. To maintain the integrity of commercial seed stock, sweet potato foundation seed programmes in the United States provide virus-tested foundation seed to commercial producers. While low incidence of re-infection with viruses were noted during the production of foundation seed, “little information was available to evaluate how rapidly seed productivity and quality declined on farms, where older generations of sweet potato are also grown and could serve as sources of inoculum for reinfection of new seed,” explained Mr. Christopher Clark, a faculty member at Louisiana State University (LSU), the United States, and lead author of a study to evaluate changes in seed quality among farms.

G1 seed (seed grown one year after virus therapy in the foundation seed production field at the Sweet Potato Research Station, LSU Agricultural Centre) was used as reference to compare the yield and virus incidence of growers’ generation 2 (G2) and generation 3 (G3) seed roots (grown one or two years following the year of foundation seed production). “Although yields of plants grown from G2 and G3 seed were 86.3 per cent and 86.1 per cent for United States No. 1 and 83.3 per cent and 86.0 per cent for total marketable, respectively, compared with the yields from G1 seed they were not significantly different,” the scientists reported. Yield and virus incidence data suggested that seed quality may vary from year to year and from location to location. Mr. Clark said that study results suggest that producers are indeed realizing yield benefits by incorporating virus-tested foundation seed into their production schemes.

A better test for a potato pest

A United States Department of Agriculture (USDA) scientist has created a new weapon in the war being waged against the potato cyst nematode – a diagnostic test that identifies the nematode type infesting a farmer’s field. Dr. Xiaohong Wang, a molecular biologist working with the Agricultural Research Service (ARS) Robert W. Holley Centre for Agriculture and Health, developed the monitoring tool in part by cloning and sequencing key genes. There are two potato cyst nematode (PCN) types: the golden nematode (Globodera rostochiensis) and the pale cyst nematode (G. pallida). Being able to tell one from the other is important because breeders have developed potatoes that can resist the golden nematode, but not the pale cyst nematode.

Traditional methods of distinguishing between the two PCN species have relied on time-consuming morphological analyses and polymerase chain reaction (PCN) assays. They also require relatively large samples of nematode cysts. But Dr. Wang and her colleagues cloned the parasitism gene the nematodes use to produce a protein, known as chorismate mutase, that plays an important role in the infection process. They then sequenced the chorismate mutase genes, compared the sequences, and identified unique regions in each sequence. They then developed a probe capable of recognizing the unique regions in each nematode’s DNA. The diagnostic test is reported to be a thousand times more sensitive than other similar systems.


Stem Cells and Revascularization Therapies

Significant advancements in the biology and engineering of stem cells have enabled progress in their clinical application to revascularization therapies. Some strategies involve the mobilization of endogenous stem cell populations, and others employ cell transplantation. This book – from the Biotechnology and Bioprocessing series – looks at the fundamentals and applied studies in stem cell biology, and provides perspectives associated with the development of revascularization strategies.

Contact: CRC Press, 6000 Broken Sound Parkway, NW, (Suite 300) Boca Raton, FL 33487, United States of America. Tel: +1 (800) 2727 737; Fax: +1 (800) 3743 401; E-mail:; Website:

Nanotechnology in Regenerative Medicine: Methods and Protocols

In this manual, expert researchers in the field provide an overview of a very wide range of currently used technologies and methods that involve nanotechnology principles that are applicable to tissue regeneration. This book focuses on particular areas such as the use of nanotechnology as a means to produce efficient platforms and structures for tissue engineering, delivery systems and biosensors, as well as the use of some techniques to study materials surfaces and the interactions between cells, biomolecules and surfaces at the nanoscale. Part of the Methods in Molecular Biology series, the book provides introductions to topics, lists the necessary materials and reagents, details laboratory protocols, and provides tips on troubleshooting and avoiding known pitfalls.

Contact: Humana Press, 999 Riverview Drive, Suite 208, Totowa, NJ, 07512, United States of America. Tel: +1 (973) 2561 699; Fax: +1 (973) 2568 341; Website:


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