VATIS Update Biotechnology . May-Jun 2010

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Biotechnology May-Jun 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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Biotechnology makes agricultural production greener

Despite the current and predicted agricultural challenges posed by climate change and increased demands on arable land and natural resources, farmers around the world are able to practice Earth-friendly farming thanks to agricultural biotechnology, points out the United States-based Biotechnology Industry Organization (BIO).
Biotechnology provides tools and technologies that provide solutions to many of today’s global environmental challenges. Agricultural biotechnology provides environmental benefits through:

  • Increased yields, thereby reducing pressures to force more land into production;

  • Herbicide-tolerant crops that allow the use of no-till farming practices, enhancing soil moisture content, reducing erosion and limiting carbon dioxide emissions;

  • Crops that need fewer pesticide applications and that thrive in a no-till environment, greatly reducing on-farm energy consumption and associated environmental impacts; and

  • Reduced waste production from livestock feedlots and concentrated animal agriculture operations via biotechnology-improved feed products and biotech nutritional supplements for livestock.

In 2007, the 274 million acres of biotech crops resulted in a 14.2 million tonnes reduction in carbon dioxide emissions, which is equivalent to removing 6.3 million cars from the road for a year, said Ms. Sharon Bomer Lauritsen, BIO’s Executive Vice President for Food & Agriculture. Biotechnology is promising even more solutions to tomorrow’s challenges, such as: crops and trees that are more tolerant of frost, drought, floods and high-saline soils; crops that use soil nutrients more efficiently, reducing the need for fertilizers; and animals that use feed more efficiently and produce less manure. Biotechnology will continue to be one of the ‘greenest’ tools available to help farmers better provide the food, fuel and fibre to serve a growing population, asserts Ms. Bomer.

UNIDO launches biotech network for developing nations

Developing countries wanting to make more of their biotechnology resources are the target of a network launched by the United Nations Industrial Development Organisation (UNIDO). The International Industrial Biotechnology Network (IIBN) will help local universities and small-to-medium enterprises to develop and improve existing biotechnology products. It will also encourage further bio-prospecting.

Mr. George Tzotzos, IIBN Programme Coordinator, said the network would provide biotechnology support and access to high-level technologies for developing countries wanting to make better use of their existing biological resources. He said that a major hurdle for developing countries that wish to sell biotechnology products in Europe is meeting the European Union’s stringent safety standards and maintaining a high product quality, adding that IIBN could be of help in this regard through making connections and establishing mutually beneficial partnerships. Mr. Ivan Ingelbrecht, IIBN Project Manager based at Ghent University, Belgium, said the network would serve as a catalyst for establishing North-South and South-South partnerships.

IIBN – launched in Austria on 29 March 2010 – is supported by the Flanders/UNIDO Science Trust Fund for Industrial Biotechnology. It will receive core funding of US$1.66 million over the next five years from Belgium’s Ministry for Innovation, Public Investment, Media and Poverty Reduction. IIBN members will be asked to contribute as well. The network will be coordinated by the Institute of Plant Biotechnology for Developing Countries, Belgium, and supervised by a scientific and technological advisory panel and a steering committee.
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Innovative biotechnology sheds new light on complex diseases

Innovative biotechnology is leading to a greater understanding of complex diseases and better tools for diagnosing and treating conditions such as heart disease, cancer and diabetes. “The biotechnology revolution is helping create medicines that use unprecedented technologies, such as nano-sized particles that target cancer cells and ways to actually regenerate healthy muscle to replace damaged heart tissue, and gene therapy,” said Mr. Billy Tauzin, President and CEO of the Pharmaceutical Research and Manufacturers of America (PhRMA), the United States. “Such critical innovation is creating medicines with the potential to help millions of patients live longer, healthier and more productive lives,” he added.

New biologics are among the more than 600 biotech drugs currently in various stages of clinical development to treat a wide range of diseases. In 2007, biopharmaceutical research companies based in the United States accounted for 82 per cent of global biotech research and development.

Nanobiotechnology, a ā€œQuantum Scienceā€ approach in 21st century

Nanobiotechnology is the application of nano-scaled tools to biological systems as well as the use of biological systems as templates in the development of novel nano-scale products. Nanobiotechnology involves the creation and use of materials and devices at the level of molecules and atoms for the development of nanomedicine, nanosensors, nanofluidics, etc. Both nanotechnology and biotechnology have tremendous impact by themselves and therefore, when they complement each other, it results in biological systems with novel functionalities.

Nanomedicine, an offshoot of nanotechnology, refers to highly specific medical intervention at the molecular level for curing diseases or repairing damaged tissues, such as bone, muscle or nerve. It involves newer methods to deliver drugs at the right place, time and amounts in the body. Scientists and engineers have developed new systems where the human-body parameters are monitored using a techno-monitor (semiconductor chip) that is placed inside a human body. Recent nanomedicinal approaches include the application of nanoparticles for cancer imaging and therapy, drug delivery for prostate cancer, and nanowire devices for virus detection and cancer screening.

Nano sensors can be prepared by engineering the biomolecules, to recognize a wide variety of targets, including small molecules and specific proteins. Researchers have created DNA-based sensors for “nano-tongues” and “nano-noses”. Nanofluidics has significant applications, right from high-density data detection in DNA sequencing to improved taste and variety of fruits and vegetables. On the commercial front, nanotechnology has thus enhanced science, engineering and technology, thus giving high efficiency and profitability of human existence.

Biotech boosts environment

Biotech seeds are providing substantial environmental benefits, including reduced use of crop chemicals and lower soil erosion, according to a report released recently. The report, prepared by the Conservation Technology Information Centre (CTIC), the United States, examines the impact of biotechnology on the ability of farmers to improve their environmental performance.

“The adoption of biotech crops – especially soybeans – closely tracks the expansion of conservation tillage and no-till production,” according to the report. “Roundup Ready beans have helped facilitate a 68 per cent increase in full-season soybeans,” said the author of the report, Mr. Dan Towery of Ag Conservation Solutions, the United States. He talks about how biotech crops and other new technology are big parts of a sustainable future for modern crop production.

The CTIC report shows that herbicide-tolerant soybeans and cotton helped cut the United States herbicide use by 47.4 million pounds of active ingredient in 2007. Insecticide-resistant cotton and corn varieties led to reduced applications of insecticides in that year by 8.67 million pounds of active ingredient, the report says. Conservation tillage and no-till are also credited with improving soil quality and enhancing wildlife habitat. Other benefits of reduced tillage brought about by the biotech trend include lower fuel consumption as well as reduced greenhouse emissions.

Fraunhofer opens development lab for future biotech production

Automation is becoming increasingly important in the field of biotechnology, and the only means of simultaneously testing thousands of substances on cells or of creating artificial skin models at competitive prices. The Biopolis testing laboratory, Germany, which was opened on 9 February at the Fraunhofer Institute for Manufacturing Engineering and Automation (IPA), is playing a part in these developments. At the laboratory, engineers and life scientists work together to create complex devices that fulfil specific requirements of biotechnology research.

Interdisciplinary cooperation is vital for the work of Biopolis, where biologists are benefiting from the experience of engineers. The first major project at the laboratory is a Fraunhofer development: a tissue factory that automatically makes three-dimensional dermal tissue constructs. Thanks to the relatively simply layered structure of the skin, the cultivation of issue in the laboratory has in recent years developed into the extremely successful application area of “tissue engineering”. Laboratory-reconstructed skin and cultured skin are two significant fields of application today: it is often the last resort for patients with severe burns and chronic wounds. The cosmetics and pharmaceutical industries use skin grown in the culture dish for testing new substances.

If all goes according to plan, three-dimensional and fully functional skin samples will be created at Biopolis fully automatically from just a small skin sample. When finished, the engineers are aiming at a capacity of 5,000 skin constructs per month, at a price of around US$43 each. These artificially produced skin samples could be used, for example, in the pharmaceutical industry.

Biopolis is not limited to the development of tissue production devices. The development of a device that would replace pipetting is in the final phase. Another prototype under further development at Biopolis takes over the complete cell culture passage process.


Researchers to benefit from imaging companiesā€™ merger

Leica Microsystems of Germany, a market leader in the field of microscopy, has acquired Genetix Ltd. of the United Kingdom, which has established industry standards in areas such as picking microbial colonies for genomic studies or screening and selection of mammalian cell lines. The integration of these two highly regarded manufacturers of imaging and microscopy systems is designed to provide the biomedical and biotechnical fields with the best options for imaging and intelligent image analysis.

Genetix will exist as a separate business unit within Leica Microsystems and will continue to market its products through existing channels. Customer services such as product ordering, applications support and instrument service will remain unchanged.

Duke, LabCorp combine forces to create The Biomarker Factory

In the United States, Duke University Medical Centre and Laboratory Corporation of America® Holdings (LabCorp) have formed a joint venture to commercialize new biomarkers. The new entity is designed to speed the translation of newly discovered biomarkers into widely available clinical tools that can measure individual therapeutic responses, predict disease progression and evaluate biological or disease-causing processes.

This innovative venture, known as The Biomarker Factory, combines Duke’s excellence in biomarker discovery and validation with LabCorp’s expertise in the development and commercialization of innovative diagnostic and laboratory tools. “The Biomarker Factory is at the intersection of translational medicine and personalized medicine,” said Dr. Victor J. Dzau, Chancellor for Health Affairs, Duke University, and CEO of Duke University Health System.

The Biomarker Factory will benefit from hundreds of thousands of biological samples contributed by Duke, as well as the infrastructure already in place in the Duke-led, large-scale epidemiology study known as MURDOCK, which is currently recruiting 50,000 people into a registry. It will also capitalize on the LabCorp biorepository being developed to discover and validate biomarkers in human disease.

Biotron ties up with ACLIRES for conducting drug trial

Biotron Ltd. of Australia – engaged in the research, development and commercialization of drugs that target significant viral diseases with unmet medical need – said it believes its alliance with ACLIRES clinical research group will be critical to its success. Dr. Michelle Miller, Biotron CEO, said: “ACLIRES is specialized in running clinical trials for both Hepatitis C and the HIV virus...ACLIRES also has access to large numbers of eligible patient populations. This really is critical to the successful completion of the trial, as one of the biggest risk factors for trials is access to sufficient suitable patients.”

Unlike other Hepatitis C drugs, Biotron’s drug, BIT 225, works by targeting the p7 protein, a viral protein essential to virus production and replication. The next stage of development is to determine how the drug works in combination with current approved treatments for these viruses – Interferon and Ribavairin.

McGill, Enobia Pharma partner for new bone-disease treatment

In Canada, Dr. Marc McKee, from McGill University’s Faculty of Dentistry and the Department of Anatomy and Cell Biology, is collaborating closely with Enobia Pharma to develop innovative treatments for serious genetic bone diseases. Dr. McKee’s research looks into the reasons why calcium phosphate mineral fails to crystallize properly to form strong bones and teeth. This field, known as biomineralization, involves nanotech research into the proteins, enzymes and other molecules that control the coupling of mineral ions (calcium and phosphate) to form nano-crystals within the bone structure.

The treatment, enzyme replacement therapy to treat hypophosphatasia, is currently undergoing clinical testing in several countries. Hypophosphatasia is a rare and severe disorder resulting in poor bone mineralization. In infants, symptoms include respiratory insufficiency, failure to thrive and rickets. Dr. McKee’s research is funded in part by the Canadian Institutes of Health Research.

Dendreonā€™s breakthrough cancer vaccine approved

The United States Food and Drug Administration (FDA) has approved Provenge, Dendreon Corporation’s breakthrough cancer vaccine that promises to extend the lives of prostate cancer victims by several months.

Widely seen as a likely blockbuster with a cost of around US$75,000 per patient, the approval comes after Dendreon braved a major setback at the FDA in 2007 and went ahead with a confirmatory Phase III study of the therapy. Betting that the agency would go ahead with an approval, Dendreon has invested hundreds of millions of dollars in the infrastructure that will be needed to supply the cancer vaccine, which is made with a patient’s own white cells.

The approval marks a transformative change for Dendreon, which is likely to vault into the top ranks of the world’s biotech companies as revenue from Provenge funds additional discovery work. The decision by the FDA is one of the most closely watched of the year.

Gentel launches detection kit for protein microarrays

Gentel Biosciences, a United States-based leader in proteomics discovery tools, has introduced the APiX View™ Detection Kits for ultra-sensitive chromogenic detection of protein microarrays, including reverse phase protein such as SomaPlex™ arrays from Protein Biotechnologies. This launch expands the applications of APiX technology to include not only antibody and protein arrays on clear glass slides, but also tumour lysate arrays on porous nitrocellulose surfaces.

APiX chromogenic technology provides for the detection of any biotinylated molecule, generating light grey-to-black spots that are visible to the naked eye and can be scanned with the Gentel Proteomics Multi-System. APiX is also compatible with a variety of secondary antibodies such as anti-mouse and anti-rabbit. APiX uses a proprietary gold-catalysed silver deposition and typically achieves measurably improved sensitivity when compared with fluorescence detection.

Tumour lysate arrays are a type of reverse phase protein microarray that contains a collection of up to several hundred tumour samples on slide. Antibodies or other probes are applied to the array to detect the abundance of specific protein biomarkers and rapidly measure expression across a large population of tumour samples. Array results are then compared with demographic and relevant clinical disease-specific data on the tumour collection to draw a conclusion.

Generex Biotechnology patents insulin administering method

Generex Biotechnology of the United States, a leader in drug delivery for metabolic diseases through the inner lining of the mouth, has received a United States patent for a “method for administering insulin to the buccal region”. This new patent increases the number of patents related to the company’s proprietary buccal drug delivery platform technologies to 158, with 22 of them being United States patents. Generex has a total of 105 patent applications pending in many jurisdictions around the world.

Biotech start-ups target microRNA and cardio drugs

A pair of biotech start-ups in the United States has kicked off their activities. In Seattle, Mirina Corporation announced that it had raised an undisclosed amount of money through the venture capital firm Versant Ventures to cover operations for the next 12-15 months. Mirina will use the fund to push the development of microRNA therapies. The deal underscores venture capital’s increasing interest in the field of microRNA. LipimetiX LLC, Boston, has launched its operations as developer of a series of peptides therapeutics that mimic the function of Apolipoprotein E for lipid-lowering treatments for high-risk cardiovascular patients.


New methods identify thousands of new DNA sequences

A person can have one or more copies, or no copy at all, of a particular DNA sequence, which may account for why these sequences were absent from the reference human genome. A large portion of the sequences are either missing, fragmented or misaligned when compared with results from next-generation sequencing genome assemblies on the same samples, said Dr. Evan Eichler, senior author of a study in the United States. Dr. Eichler – a professor of genome sciences at University of Washington (UW) and an investigator with the Howard Hughes Medical Institute – said, “These findings suggest that new genome assemblies based solely on next-generation sequencing might miss many of these sites.” Dr. Jeffrey M. Kidd, now a post-doctoral fellow at Stanford University, is lead author of the paper that describes the new techniques the research team used to find some of the missing sequences.

The reference genome assembly is a mosaic of DNA sequences derived from several individuals: but about 80 per cent of the reference genome came from eight people and one of them accounts for more than 66 per cent of the total, revealed Dr. Kidd. The researchers found that, in some cases, the number of copies of these sequences varied from person to person. If the donor sample was missing a sequence that many other people have, that sequence would not be represented in the reference genome. The new study used information from nine individuals, representing various world populations, to search for and fill in some of the missing pieces.

By looking at genomes of seven kinds of animals – chimpanzee, orang-utan, Rhesus monkey, house mouse, Norway rat, dog and horse – the research team was also able to show that some of the newly identified DNA sequences appear to have been conserved during the evolution of mammals and man. “Some of the sequences present in several mammals actually correspond to sites of variations in humans – some people have retained a particular sequence, and others have lost it,” Dr. Kidd said.

Novel tool for DNA research

Luminescent markers are an indispensable tool for researchers working with DNA. However, the markers are troublesome: some tend to destroy the function and structure of DNA when inserted, while some others emit so little light that they can barely be detected in the hereditary material. Mr. Soren Preus, a Ph.D. student at the University of Copenhagen, Denmark, has now developed a tool in collaboration with researchers at Chalmers Technical University, Sweden, that might address both problems.

Mr. Preus investigated the properties of the two luminescent DNA base analogues, tCnitro and tCO, to determine whether they could measure the structure of DNA without disrupting it. His scrutiny has shown that the function of DNA is unimpeded by the insertion of the molecular gauge. Further, one base analogue is very efficient at emitting light and the other very good at receiving it. As the transport of light energy between the two luminescent markers can be provoked, they are usable for a measuring technique known as Fluorescence Resonance Energy Transfer (FRET).

In brief, FRET measurements are performed by forcing two luminescent markers to transfer light-energy from one to the other, and then measuring the efficiency of the transfer. The two different markers are placed in the DNA-helix. When they are subjected to a light pulse, tCO emits part of the energy to tCnitro. This energy transfer can be measured, and by calculating backwards it is possible obtain exact information about the relative distance and angle of the two markers. This allows for calculations of distance and angle of all the natural base pairs in the DNA structure. With that, the researcher can put together a picture showing every twist and turn of the DNA structure. Because structure and function are closely related in DNA, the method holds the potential to reveal new insights into the workings of DNA.

Genome mapping technique speeds up gene spotting

A global team of scientists has demonstrated a specialized mapping technique that could speed work in genomic fields by quickly finding genetic associations that shape an organism’s observable characteristics. Using plants from 93 different Arabidopsis thaliana populations, a team led by the Gregor Mendel Institute of Plant Biology in Austria was able to find genetic associations among multiple phenotypes, or traits, suggesting that the same genes or closely related genes controlled those traits. Dr. David E. Salt, Professor of plant biology at Purdue University, the United States, and co-author of a paper on the study, said the ability to find these types of genetic links could speed up scientists’ ability to find and isolate genes and understand their function.

A traditional search for a gene responsible for a particular characteristic requires using plants that have been phenotyped, or identified by characteristics. They are then crossed with others and the offspring are phenotyped. The offspring’s genes with the desired trait are then checked for similarities. The process can be painstaking and time consuming because many thousands of individuals may need to be checked.

In this study, specific differences in DNA, called single nucleotide polymorphisms (SNPs), were compared at 250,000 sites across the genomes of many individuals. The genomes were matched against specific traits for each individual to find SNPs that are associated with the trait of interest, such as high seed yields, for example. The places where the genomes match in individuals with high seed yields are possible locations of sought-after genes. Genome-wide association mapping is a faster process because fewer plants – usually in the hundreds – need to be grown and phenotyped. Finding genetic associations among multiple phenotypes could reveal more information about how those characteristics might be connected.

New Alzheimerā€™s gene identified

Researchers in the United States examined gene variations across the human genome (full DNA sequence) of 2,269 people with late-onset Alzheimer’s and 3,107 people without the disease. This genome-wide association study found that about 9 per cent of those with late-onset Alzheimer’s had a specific variation in the gene MTHFD1L on Chromosome 6. Only about 5 per cent of those who did not have Alzheimer’s had the variant.

The primary known genetic contributor to late-onset Alzheimer’s is a variant of the gene APOE on chromosome 19. The Alzheimer’s-linked APOE variant occurs in about 40 per cent of people who develop late-onset Alzheimer’s. The influence of the MTHFD1L variation is not as strong as APOE, and the variation itself is not as common in the population, said principal investigator Dr. Margaret Pericak-Vance, Director of the University of Miami Miller School of Medicine’s John P. Hussman Institute for Human Genomics.

Previous research had found MTHFD1L to be involved with the metabolism of folate, which in turn can influence levels of homocysteine. Elevated homocysteine, which is often tied to folic acid deficiencies in the diet, has been shown to be a risk factor for coronary artery disease and late-onset Alzheimer’s. Previous genome-wide studies have also implicated another MTHFD1L variation in coronary artery disease. Taken together, the research hints at ways in which the gene variant might be linked to changes in blood vessel function in the brain that impact Alzheimer’s, Dr. Pericak-Vance said.

Scientists discover new genetic sub-code

In Switzerland, Prof. Yves Barral from the Biology Department at Eidgenössische Technische Hochschule Zürich (ETH Zürich) and computer scientists Dr. Gina Cannarozzi and Prof. Gaston Gonnet, from the Computer Science Department of ETH Zürich and the SIB Swiss Institute of Bioinformatics, joined in a multi-disciplinary study into possible sub-codes in genomic information. The study identified novel sequence biases, or genetic sub-codes, and their role in the control of genomic expression.

This information has several interesting implications. Firstly, it provides novel insights into how the cellular decoding machinery works. Secondly, and more pragmatically, it makes possible to read information about gene expression rates directly from genomic sequences, whereas up to now, this information could only be obtained through laborious and expensive experimental approaches, such as microarrays. “A cell must respond very quickly to injuries such as DNA damage and to potent poisons such as arsenic. The new sub-code enables us to know which genes are turned on quickly after these insults and which are best expressed slowly,” said Dr. Cannarozzi.

The new sub-code also provides insight into cellular processes at the molecular level. In every living cell, the translation allowing the production of proteins takes place at specialized factories, the ribosomes. This novel sub-code will therefore also provide more information about the functioning of these ribosomes. All the data gathered up to now indicate that the ribosomes recycle their own components, the tRNAs, to optimize the speed of protein synthesis. The discovery of a new way to regulate translation could potentially be exploited produce therapeutic agents and research reagents more efficiently.

Genome-wide approaches to schizophrenia

The psychiatric disorder schizophrenia has both environmental and genetic risk factors, and a high heritability. After over 20 years of molecular genetics study by researchers from Northshore University Health System Research Institute, the United States, new molecular strategies, primarily genome-wide association studies, have generated major tangible progress in the research on the disorder. The new data provide evidence for:

  • Several chromosomal regions with common polymorphisms showing genome-wide association with schizophrenia (the major histocompatibility complex, MHC, region at 6p22-p21; 18q21.2; and 2q32.1, while the associated alleles present small odds ratios and suggest causative involvement of gene regulatory mechanisms in schizophrenia;

  • Polygenic inheritance;

  • Involvement of rare (<1 per cent) and large (>100 kb) copy number variants (CNVs); and

  • A genetic overlap of schizophrenia with autism and with bipolar disorder challenging the classical clinical classifications.

The new findings now need to be translated into a better understanding of the underlying biology and into causal mechanisms. Further, a considerable amount of heritability remains unexplained. Deep resequencing for rare variants and system biology approaches are hoped to improve our knowledge of the genetic architecture and underlying biology of schizophrenia.


A protein that speeds growth of damaged liver

In a breakthrough that could help damaged livers repair naturally and quickly, scientists in Australia claim to have discovered a protein that could double the speed of liver cell growth, helping the organ to heal on its own. A team at the Western Australian Institute for Medical Research (WAIMR) has found that a protein, called TWEAK, significantly raises the growth rate of liver progenitor cells (LPCs), which are crucial in liver repair.

Lead author Dr. Janina Tirnitz-Parker said when the team set out to understand how TWEAK affected LPCs, they discovered it had a dramatic effect on cell growth. “LPCs grew twice as fast as they normally would. This means that there could be potential to use TWEAK to help damaged livers repair themselves by growing new healthy cells at a much faster pace,” she said.

Professor George Yeoh, Head of WAIMR Laboratory for Liver Disease and Carcinogenesis and co-author of the study, said: “This is a key finding for liver disease, because we now know what tickles liver cell growth – it could have huge benefit for patients with liver conditions by helping to regenerate their existing liver faster and possibly ruling out the need for transplants. If this phenomenon can be harnessed it might be possible to increase or inject TWEAK onto a patient’s liver in order to help the organ repair itself naturally, and much faster.

Molecular structure of key fluorescent proteins found

Scientists at Albert Einstein College of Medicine of Yeshiva University, the United States, have determined the crystal structures of two key fluorescent proteins – one blue, one red – used to “light up” molecules in cells for research. The finding allowed them to propose a chemical mechanism by which the red colour in fluorescent proteins is formed from blue. The researchers now have the first roadmap for rationally designing new and differently coloured fluorescent proteins.

Many fluorescent proteins of various colours have been found in other marine organisms such as jellyfish and corals. But the molecular nature of these colours remained a mystery, hindering the development of new imaging probes. Scientists seeking new fluorescent probes first had to fuse the genes for known fluorescent proteins to bacteria, and then expose millions of these microbes to radiation, in the hope of producing random genetic mutations that lead to new and useful fluorescent proteins.

The new discovery will allow fluorescent proteins to be created in a much more systematic and rational way. “Knowing the molecular structures of the chromophores – the part of fluorescent protein molecules that gives them their colour – we can now do hypothesis-based designing of new probes, instead of relying on random mutations,” says principal investigator Dr. Vladislav Verkhusha, Associate Professor of Anatomy and Structural Biology and member of the Gruss Lipper Biophotonics Centre. Using the new information, Dr. Verkhusha’s laboratory has already designed a variety of new fluorescent proteins that can glow in colours ranging from blue to far-red. An expanded fluorescent protein palette would be a big help to researchers.

Variant of gene-regulating protein in embryonic stem cells

The journey from embryonic stem (ES) cell to a fully developed liver, heart or muscle cell requires not only the right genes, but genes that are turned on and off at the right time – a job that is handled in part by the DNA-packaging proteins known as histones. New research from the United States shows that minute variations between histones play an important role in determining how and when genes are read. The findings hint at an unimagined complexity of the genome and may open a new avenue of investigation regarding the mysterious causes of the human genetic disease known as ATR-X syndrome.

Chemical modification of histones is one of the mechanisms that cells use to establish and maintain the activation or silencing of specific genes. In addition, histone variants, which differ from other histone proteins by just a handful of amino acids, can be inserted at specific locations in the genome to provide a cell with another mechanism for fine-tuning gene regulation. To track one such variant – histone H3.3 – and distinguish it from other histone proteins, researchers from Rockefeller University’s Laboratory of Chromatin Biology and Epigenetics collaborated with scientists at Sangamo Biosciences. Together, they designed and used a DNA-cutting enzyme called a zinc finger nuclease to chemically tag histone H3.3. They then used ChIP sequencing technique to produce the first genome-wide maps of H3.3 localization, first in mammalian ES cells and then again after the cells had differentiated to become neurons. In collaboration with bioinformatics experts at the Albert Einstein College of Medicine, they found that the location of H3.3 throughout the genome changed with ES cell differentiation.

Most scientists believed that a factor known as HIRA was responsible for controlling the localization of H3.3. The new research partly confirmed this, but found that H3.3 was still present in many other specific areas of the genome even without HIRA. The researchers went on to identify several additional proteins associated with H3.3. Two of them, ATRX and Daxx, had never before been linked to H3.3. ATRX is particularly interesting, because mutations in the gene that codes for this protein in humans causes the genetic disease called alpha-thalassaemia, and X-linked mental retardation syndrome.

New understanding of proteinā€™s role in brain

A team of researchers headed by Dr. Nahum Sonenberg from the Department of Biochemistry and Goodman Cancer Centre of McGill University, Canada, has discovered that brains in mammals modify a particular protein in a unique way, which alters the protein’s normal function. This finding represents an important step in understanding how human brains work. When memories are being formed, neurons communicate with each other through electrical impulses at specialized connections. To strengthen these connections, the neurons require new proteins. The protein in question, 4E-BP2, controls the process of producing new proteins in the nervous system.

Before the team’s discovery, no one knew 4E-BP2 could be chemically altered or that this could have an effect on neuron function. Dr. Sonenberg’s team included researchers from the Université de Montréal, the Montreal Neurological Institute, the University of Toronto, Baylor College of Medicine in the United States, and the University of Bergen in Norway.

Protein jab mends broken bones

Proteins that are known to boost the growth of the skeleton have now been used to heal broken bones in mice – with the help of tiny capsules that shuttle the healing protein to the site of injury. Dr. Roel Nusse and his colleagues at Stanford School of Medicine in Palo Alto, the United States, found that injecting mice with a family of proteins called Wnts – packed inside lipid bubbles, or liposomes – triggers new bone growth within a few days.

Wnt proteins are known to stimulate bone formation and tissue regeneration, but scientists have not managed to turn them into drugs because the proteins are not very stable, and they tend to clump together instead of migrating to injuries. Inspired by methods used to deliver drugs to tumours, Dr. Nusse and his colleagues previously found that encasing purified Wnt proteins inside liposomes enhances the activity of the proteins in healthy mice. Now they have tested the protein-delivery system in injured animals for the first time.

In mice, the scientists inactivated a gene called Axin2, which usually dampens Wnt signalling, to create a prolonged, amplified Wnt signal in the mice and found that immature bone cells started to mature faster than in normal mice. When they drilled tiny holes into the leg bones of these mice lacking Axin2, they noticed that cells in injured areas multiplied and matured more quickly than cells in intact tissue or in normal mice. As a result, bones in these mice started to regrow within a few days – faster than broken bones in normal mice, which can take several weeks to heal. The team next injected the injured mice with the Wnt capsules and found that bones started to regrow within a few days, and the skeletal defects healed faster than mice injected with empty vesicles alone. Because Wnt proteins can repair a range of tissues, Dr. Nusse says that the technique might be able to treat not only fractures and osteoporosis, but also diseases of the skin, heart and brain.

Proteins implicated in multi-drug resistant ovarian cancer

As with other cancers, resistance to anti-cancer drugs is a major obstacle to successful treatment of ovarian cancers, with frequent occurrence of multi-drug resistance (MDR). The mechanism of MDR is not clearly understood, although a number of factors are believed to be at the core. In an attempt to provide more information on the molecular basis behind MDR, Chinese scientists have undertaken a proteomics study of ovarian cancer. Dr. Da-Zhi Zhang and co-workers from Chongqing Medical University and Central South University, Changsha, examined ovarian cancer COC1 cell cultures and the cisplatin-resistant cells COC1/DDP. These have been shown to develop cross-resistance to anti-cancer drugs such as adriamycin and 5-fluorouracil.

Proteins from both cell cultures were extracted and digested with trypsin. The resultant peptides were isotope-labelled with different tagging and quantification reagents. Peptides from the parent cells were treated with the 115 reagent and those from the drug-resistant cells were labelled with the 117 reagent. The two sets of samples were then combined and purified. The peptides were analysed by liquid chromatography tandem mass spectrometry with electrospray ionization. Each peptide was labelled with the 115 or 117 reagent and their relative abundances determined from the mass spectrometric peak area ratios. The proteins corresponding to peptides of interest were then identified by database searching against a human protein database.

The scientists found 28 proteins present in different quantities between the two cultures, 11 being reduced in the drug-resistant cells and 17 increased in abundance. Of these, two proteins were particularly affected. Pyruvate kinase isoform M2 (PKM2), a metabolic enzyme, was significantly low in the drug-resistant cells and the chaperone heat shock protein 60 (HSPD1) was markedly high. Further experiments prompted the research team to conclude that PKM2 was involved in MDR of the cisplatin-resistant cells. Experiments with HSPD1, which folds key proteins after import into mitochondria, suggested that high levels of this protein are involved with the inhibition of cisplatin-induced cell death.


New Alzheimerā€˜s target discovered

Researchers in the European Union-funded Neuro GSK3 project have determined that neuron loss in course of Alzheimer’s disease is caused by the brain’s own immune cells, the microglia. When the team, under Dr. Jochen Herms of the Ludwig-Maximilians University (LMU) Centre of Naturopathy and Prion Research in Germany, analysed neuron loss in an Alzheimer model over a period of one month using two photon in vivo imaging, they found an increased number of microglial cells around lost neurons. In addition, microglia migration to the lost neuron stopped after neuron elimination and migration velocity around lost neurons was significantly higher. Knock-out of the microglial receptor Cx3cr1 which binds the signal molecule fractalkine prevented neuron loss. “We may be able to make use of these results to develop novel agents that can slow the rate of neuron loss by interrupting communications between the two cell types,” Dr. Herms stated.

RNA interference delivered on target using nanoparticles

A multi-institutional team of researchers and clinicians in the United States has published the first proof that a targeted nanoparticle can traffic into tumours, deliver double-stranded small interfering RNAs (siRNAs), and turn off the production of an important cancer protein using RNA interference (RNAi). Moreover, the team showed for the first time that this new type of therapy, infused into the bloodstream, can make its way to human tumours in a dose-dependent fashion – a higher number of nanoparticles sent into the body leads to a higher number of nanoparticles in the tumour cells.

These results, published in Nature, demonstrate the feasibility of using both nanoparticles and RNAi-based therapeutics in patients, and open the door for future “game-changing” therapeutics that attack cancer and other diseases at the genetic level, says lead researcher Dr. Mark E. Davis at the California Institute of Technology and the Nanosystems Biology Cancer Centre. What makes RNAi such a potentially powerful tool, Dr. Davis says, is the fact that its target is not a protein, the typical target for anti-cancer drugs. The vulnerable areas of a protein may be hidden within its three-dimensional folds, making access to them difficult for therapeutics. Instead, RNAi targets the messenger RNA (mRNA) that encodes the information needed to make a protein in the first place.

“In principle,” adds Dr. Davis, “that means every protein now is druggable because its inhibition is accomplished by destroying the mRNA. And we can go after mRNAs in a very designed way given all the genomic data that are and will become available.” He and his team had worked on ways to deliver nucleic acids to cells via the blood stream. They eventually created a four-component system, featuring a unique polymer called cyclodextrin, which self-assembles in the presence of RNA into a targeted, siRNA-containing nanoparticle. These nanoparticles are able to take the siRNAs to the targeted site within the body. Once they reach their target, in this case, the cancer cells within tumours, the nanoparticles enter the cells and release the siRNAs.

The siRNA delivery system is currently under clinical development by Calando Pharmaceuticals. Investigators from the Jonsson Compresensive Cancer Centre, the University of California–Los Angeles, South Texas Accelerated Research Therapeutics and the City of Hope Comprehensive Cancer Centre also participated in this study.

Full-size jaw bone grown from adult stem cells

In a pioneering experiment, scientists have grown a complex, full-size jaw bone from human adult stem cells. A team, led by Prof. Gordana Vunjak-Novakovic of Fu Foundation School of Engineering and Applied Science of Columbia University, the United States, has claimed that it has grown the temporomandibular joint (TMJ) from stem cells derived from bone marrow. As the TMJ is such a complex structure, it is not easily grafted from other bones in a patient’s body.

Prof. Vunjak-Novakovic’s technique for turning stem cells into bone was inspired by the body’s natural bone-building process. Her team started by analysing digital images of a patient’s jawbone, to build a scaffold into the precise shape of a TMJ joint. The scaffold was made from human bone stripped of living cells. The team then seeded the scaffold with bone marrow stem cells and placed it into a custom-designed bioreactor. The reactor, filled with culture medium, nourished and physically stimulated the cells to form bone.

Bone tissue develops best when it is bathed in fluid flowing around it. Prof. Vunjak-Novakovic and her team looked into the exact flow rates one needs for optimal effects. After five weeks, they had a 4 cm high jawbone that was the precise size and shape of a human TMJ. Although the technique can be applied to other bones in the head and neck, Prof. Vunjak-Novakovic started with the TMJ because, “We thought this would be the most rigorous test of our technique. If you can make this, you can make any shape.” The team’s next step is to develop a way to connect the bone graft to a patient’s blood supply to ensure that the graft grows with the person’s body.

New discovery gives a boost to cancer research

A team of scientists led by the University of East Anglia (UEA), the United Kingdom, has discovered a brand new group of molecules which could help fight the spread of cancer and other diseases. The new molecules, which are synthetic derivatives of a natural product known as UDP-Galactose, block the activity of a group of enzymes called glycosyltransferases that the cells use to turn simple sugars into elongated sugar chains and branched structures.

Many biological cells – including cancer cells and bacterial cells – are literally covered by a coating of sugar. This sugar coating influences the way cells communicate with their environment and with each other. For example, when a cancer spreads through the body or when a bacterium infiltrates its human host, many of the contacts the rogue cells make with other cells are through these sugars on their cell surface. To form these complex sugar structures that decorate their surface, cells rely on gylcosyltransferases to join individual sugar building blocks together. As synthetic UDP-Galactose derivatives block these enzymes effectively, the UEA researchers have found, these molecules can be potentially used to interfere with harmful biological processes such as cancer metastasis and bacterial infection.

“Our results also provide a general strategy for how to design and improve such inhibitors in the future. The ‘snapshots’ we have taken of one of these enzymes, together with the new inhibitor itself, can provide very valuable guidance for the development of new anti-cancer and anti-infective drug candidates,” said the lead author of the study Dr. Gerd Wagner of UEA. The work was carried out in collaboration with the Carlsberg Research Centre in Denmark.

Deeper insights into how body repairs itself

Researchers in the United States have discovered how cells communicate with each other during times of cellular injury. The findings shed new insights into how the body repairs itself when organs become diseased and offers hope for tissue regeneration. Lead author Dr. Jason Aliotta, a physician researcher at Rhode Island Hospital, and his colleagues focused their work on the particles known as microvesicles. These particles are several times smaller than a normal cell and contain genetic information such as messenger RNA (mRNA), other species of RNA and protein.

The study revealed a novel mechanism by which the cells communicate with each other through these microvesicles. During times of cellular injury or stress – or with specific diseases such as cancer, infections and cardiovascular disease – these particles are shed and then taken up by other cells in the body. The genetic information and protein in the microvesicles help to reprogramme the accepting cell to act more like the cell from which the particle was derived.

What is unique to the research is the finding that this process occurs in other organs as well, like the heart, liver and brain. “These microvesicles can change the basic nature of adjoining cells, and that presents a world of possibilities in tissue restoration efforts,” stated Dr. Peter Quesenberry, Director of haematology/oncology at Rhode Island Hospital, who is a co-author on the paper. Among the practical implications of the findings is an understanding of the tissue repair process and determining whether microvesicles can be used in a therapeutic fashion. Based on their findings, the researchers also theorize that microvesicles could potentially be mediators of cancer metastasis.

Link between weight loss and immune function

Many overweight or obese people suffer from diseases such as cardiovascular disease (CVD) and Type 2 diabetes. Many of these problems are caused by the immune system’s response to excess fat. It has been known for some time that excess body fat, particularly abdominal fat, triggers the production of pro-inflammatory immune cells, which circulate in the blood and can damage the body. Dr. Alex Viardot and Dr. Katherine Samaras at Garvan Institute of Medical Research, Australia, have found that even modest weight loss of only 6 kg as a result of restricted-calorie diet led to an 80 per cent decrease in the number of pro-inflammatory T-helper cells. Weight loss also led to reduced activation of other circulating immune cells (T cells, monocytes and neutrophils) and decreased activation of macrophages in fat.

The scientists conducted their study on 13 obese individuals suffering from Type 2 diabetes, and placed them on a calorie-restricted diet – from 1,000 to 1600 calories a day for 24 weeks – along with gastric banding at 12 weeks. They suggest that the best way to maintain good health and to stave off disease is not to take dietary supplements and antioxidants in the hope they will have anti-inflammatory effects. Simply lowering body weight to a healthy level will have a far greater health impact.

Another interesting finding of the study suggests the activation levels of immune cells found in fat predicted the amount of weight individuals would lose following the diet, with those having more activated immune cells lost more weight. “It is the first time this has been described and is important because it helps us understand why some people lose weight more easily than others, and that inflammation is involved in regulating the response to bariatric surgery (reducing the size of the stomach through surgery),” said Dr. Samaras.


Bringing life back into dehydrated plants

Drought can take a serious toll on plants and animals alike. When cells are deprived of water, they shrink, collapsing in upon themselves and, without water as a medium, chemicals and enzymes inside the cells may malfunction. However, some plants, like the “resurrection fern” (Polypodium polypodioides), can survive extreme water loss, even as much as 95 per cent of their water content. How do the cells in these desiccation-tolerant plants remain viable?

A collaboration in the United States between Dr. Ronald Balsamo, Associate Professor of Biology at Villanova University, and Dr. Bradley Layton, Associate Professor of mechanical engineering and mechanics at Drexel University, studied P. polypodioides on the premises that the ability to survive very low water levels must be occurring at the cellular and molecular level. The scientists took a multi-pronged approach using: western blotting, a technique that can detect relative levels of different proteins over a time; immunolocalization, a technique that can “light up” spatial regions of plant tissue where a particular protein may be lurking; and atomic force microscopy that can resolve individual proteins and sometimes individual atoms.

What they found was novel and a bit controversial. They found that not only is a particular class of proteins, called dehydrins, more prevalent during dry conditions, but it was also prevalent near the cell walls. Dehydrins earned their name for their ability to attract, sequester and localize water because of their negative charge. The finding led the researchers to the conclusion that these water-surrounded dehydrins may actually allow water to act as a lubricant either between the plant cell membrane and the plant cell wall or between individual cell wall layers.

They also observed that the fern’s vascular tissue, found near the centres of individual fronds, does not deform greatly, highlighting the importance of keeping this tissue intact once water becomes available again. If dehydrin gene could be localized and transferred to other species, it could possibly confer the ability to resist drought to plants. The researchers are currently investigating similar hypotheses as they relate to other agricultural crops.

Doubled haploid technology for developing inbred corn lines

Agronomists at Iowa State University (ISU), the United States, are offering doubled haploid technology that allows corn breeders to more quickly produce inbred lines for research or private use. Dr. Thomas Lübberstedt, Associate Professor in agronomy and Director of the R.F. Baker Centre for Plant Breeding, has launched a Doubled Haploid Facility at ISU that can develop pure, inbred corn lines in less time than traditional methods.

Inbred corn lines have two copies of the same genome. They are sometimes called pure lines because after self-pollination, all offspring are an exact replica of the single parent plant. They are hence valuable for research or commercial use. These are homozygous plants with two identical copies per gene, while heterozygous plants, such as hybrids, frequently have two different copies per gene.

ISU’s Doubled Haploid Facility will allow development of pure, inbred lines in only two generations, taking about one year. “With the doubled haploid process, you start from the same place, but by a biological trick, the offspring do not contain two genomes as usual, but only one. Then you have a chemical treatment, and after that, plants have two identical genomes, so you can get to the inbred lines much faster,” said Dr. Lübberstedt.

High-yielding salt-tolerant wheat line developed

In a major breakthrough for wheat farmers in salt-affected areas, researchers at the Commonwealth Scientific and Industrial Research Organisation (CSIRO), Australia, have developed a salt-tolerant durum wheat that yields 25 per cent more grain than the parent variety in saline soils. Recent field trials proved that durum wheat varieties containing new salt-tolerant genes outperform the other varieties in saline soils.

The CSIRO Plant Industry research team responsible for the breakthrough recently isolated two salt tolerance genes (Nax1 and Nax2) derived from the old wheat relative Triticum monococcum. “Both genes work by excluding sodium, which is potentially toxic, from the leaves by limiting its passage from the roots to the shoots,” says the leader of the project, Dr. Rana Munns. Through traditional, non-genetically modifying breeding methods aided by molecular markers the team was able to introduce the salt exclusion genes into durum wheat lines.

Reducing yield loss for crops under stress

Plant researchers in the United States are taking a long look at stress in order to improve crop productivity, especially when faced with issues of climate change. Understanding and eventually curbing crop susceptibility to certain stresses could allow for higher yields during drought years in the agricultural areas of the world. It may also allow drier areas of the planet to support sustainable yields and profitable crops, says Dr. Stephen Howell, Professor of genetics, development and cell biology at Plant Sciences Institute of Iowa State University.

Dr. Howell, along with post-doctoral researcher Dr. Jian-Xiang Liu, recently released research results that outline new features about plant stress response mechanisms in Arabidopsis. “The system protects plants from adverse environmental conditions, but these responses slow or delay growth,” explains Dr. Howell. “So there is a trade-off.” The scientists have determined how special molecular indicators stationed inside the cell, but outside the nucleus, respond when stress warning bells go off. These sensors pick up on cues that appear as misfolded proteins. “Correct folding is very important to the function of a protein. Incorrectly folded proteins or unfolded proteins will malfunction,” says Dr. Howell. “But protein folding is a very finicky process and can mess up when environmental conditions are bad, as during a period of intense heat. Under these conditions, unfolded proteins accumulate and alarm bells are set off in the plant cell.”

When the alarm bells go off inside the plant cell, sensor molecules, called molecular-associated transcription factors, are unleashed. They enter the cell’s nucleus and turn on specific genes that send out reinforcements to help the protein-folding process. When coupled with a previous study from this group, the paper describes how there are actually two sets of factors involved. One set specializes in activating genes in response to salt stress. The factor in this study responds to heat stress and the accumulation of unfolded proteins. Together they help plants withstand a variety of stresses.

Teaching corn to fix its own nitrogen

Nitrogen fertilization is essential for profitable corn production. It also is a major cost of production and can contribute to degradation of the environment. Dr. Kaustubh Bhalerao, an assistant professor in agricultural and biological engineering, University of Illinois at Urbana-Champaign, the United States, believes it may be possible to “teach” corn to fix its own nitrogen, thus eliminating the need for nitrogen fertilizer applications.

Dr. Bhalerao is leading a multi-disciplinary study with collaborators from the University of California (San Francisco), Stanford University, University of Cambridge and New Castle University aimed at building systems that enable bacteria to spatially organize and communicate with and control plant cells. Dr. Bhalerao’s research focuses on building systems in which bacteria behave like amplifiers. “The bacteria sense the presence of an amino acid in their environment and produce a protein in response. A positive feedback mechanism in the gene circuit amplifies the production of that protein,” he said. By using bacterial amplifiers, the systems become more sensitive. The bacterial biosensors can thus detect concentrations much lower than possible otherwise.

A specific application being investigated is the design of a system that enables nitrogen fixing bacteria to communicate with the root systems of corn plants. According to Dr. Bhalerao, soybean fixes its own nitrogen by sending a message to a bacterium that encourages it to colonize in the plant’s roots. Once the right environment has developed, the bacteria start fixing nitrogen for that plant, helping soybeans to be naturally high in nitrogen.


Analytical Biotechnology

Analytical Biotechnology introduces is structured to take the reader in a logical step-by-step approach from basic principles though to the state of the art. Topics covered by the book include: the use of biomolecules as analytical reagents, chromatography and its use within analytical biotechnology, immunochemistry and immunosensors, sensors and biosensors, nucleic acids and their use within genomic, proteomic and metabolomic techniques, biotechnology as applied to forensic science, and market economics of the analytical biotechnology sector. The book covers all of the most widely used bio-analytical tools, besides discussing emerging techniques.

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Biophysics of DNA-Protein Interactions

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