VATIS Update Biotechnology . Nov-Dec 2006

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Biotechnology Nov-Dec 2007

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.

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Nobel Prize for discovery of RNA interference

Two United States scientists Dr. Andrew Fire from the University of Massachusetts Medical School and Dr. Craig Mello from Stanford University School of Medicine have won the 2006 Nobel Prize for medicine for their discovery of how to switch off genes, a potential road to new treatments for diseases from AIDS to blindness and cancer. Dr. Fire and Dr. Mello are among the youngest in recent history to win the prize of 10 million Swedish crowns (US$1.37 million). Their work, which was published in 1998, received very swift recognition.

Through experiments with worms, the two showed that a double strand of ribonucleic acid (RNA), the genetic messenger of the cell, can silence targeted genes through a process known as RNA interference (RNAi). RNAi has grown quickly into a hot area of research for pharmaceutical and biotechnology companies, who see it as a promising way of tackling a range of conditions. The discoveries may lead to methods to stop gene expression in diseases such as cancer, slowing tumour growth.


Gates Foundation pledges aid to Indian HIV/AIDS control efforts

The Bill & Melinda Gates Foundation, the United States, announced a pledge of US$23 million to strengthen the Indian governments capacity to fight HIV/AIDS in the country. The pledged amount is part of the total US$58 million committed to Avahan, the Gates Foundations India AIDS initiative, and would be disbursed during 2007-09.

Under an agreement signed by Mr. Prasanna Hota, Union Secretary for Health and Family Welfare, and Mr. Tadataka Yamada, President of the Gates Foundations Global Health Programme, the money would go towards programme management and technical capacity at the national and state levels. Avahan would provide support and training for staff of Indias National AIDS Control Organization (NACO) and the State AIDS Control Societies to boost their skills in project and financial management. Avahan also plans to help improve interventions among vulnerable populations such as injection drug users, male homosexuals, and commercial sex workers and their clients. Avahan and NACO plan to collaborate in order to establish a suitable implementation strategy.


Kenya approves a national policy on biotechnology

The National Biotechnology Development Policy 2006 approved by the Kenyan cabinet marks the green signal for the use of biotechnology in the country. The policy outlines the safety procedures for biotechnology in the context of research and development, technology transfer and commercialization of products that would result from research undertaken in Kenya.

The document recognizes the role that biotechnology could play in poverty reduction, enhancing food security, and conservation of the environment and biodiversity. It identifies industry and trade as key areas for using biotechnology. Priority is given to the provision of relevant infrastructure, framework facilities and other resources for the rapid and safe development and application of biotechnology in agriculture, environment, health, industry and research.

The policy, however, has taken a strong line on the ethical, environmental and biosafety concerns of biotechnology. It outlaws human cloning, terminator technologies and any other technology found to be entailing unethical scientific practice. The government also plans to create legislation to deal with genetically modified organisms, as they are developed, following an ongoing risk assessment. Any use of biotechnology in Kenya must receive the approval of the designated authority and meet the requirements of Kenyas Environment Management and Coordination Act of 1999.


Roslin to produce Europes first useable stem cell line

A US$3.7 million project that would position Scotland as a world leader in the commercialization and clinical use of stem cell technology is to be established in Edinburgh. Under the direction of internationally renowned scientist Dr. Paul De Sousa of University of Edinburgh, the Roslin Cells Centre (RCC) plans to create human stem cell lines from donated eggs and embryos for research and clinical use. These would be marketed to the international stem cell community to help speed up the process of translating laboratory research into effective clinical treatments of diseases such as leukaemia, Parkinsons disease and diabetes.

The centre, which was initially being funded by Scottish Enterprise Edinburgh and Lothian, would also act as the first step in a supply chain to support the development of the stem cell sector in Scotland, providing cells that could be used by academics, NHS Scotland as well as commercial companies.


Glaxo speaks to United Kingdom about bird flu vaccine

GlaxoSmithKline Plc, the United States, has discussed with the government of the United Kingdom about nation-wide bird flu vaccination after signing a similar deal with Singapore. Chief Executive Director Mr. J. P. Garnier met Prime Minister Mr. Tony Blair and Chancellor Mr. Gordon Brown to discuss the possibility of stockpiling tens of millions of doses of the firms H5N1 vaccine.

The firm was also close to signing a contract with France and had spoken to the United States government about the possibility of a mass vaccination programme although no imminent decision is on the cards. The Swiss Federal Office of Public Health has ordered 8 million doses of the vaccine to protect its entire population in the event of an influenza pandemic, which many experts fear might be triggered by bird flu. The vaccine has not yet won regulatory approval but Glaxo plans to file it with the European Medicines Agency by the end of 2006.


United States set to allow sale of cloned milk and meat

Three years after the Food and Drug Administration (FDA) of the United States first hinted that it might permit the sale of milk and meat from cloned animals and their offspring, the agency is poised to endorse marketing of mass-produced animals for public consumption. The decision, expected by the end of 2006, is based largely on new data indicating that milk and meat from cloned livestock and their offspring pose no unique risk to consumers.

The agency is not inclined to call for labelling of products from clones because it would be impossible to authenticate and distinguish clonal meat or milk from conventional products. There is a debate about integrating clones into the food supply due to the remarkable progress made since the 1996 birth of Dolly, the worlds first mammalian clone, created from the udder cell of an ewe. Since then, scientists have applied the technique successfully to cattle, horses, pigs, goats and other mammals. Each clone is a genetic replica of the animal that donated the cell from which it was grown.

Cloning could solve a number of long-standing farm problems. In the eyes of many in agriculture, cloning is simply the latest in a string of advances that have given farmers better control over animal production.

Funding for biomass genomics research in the United States

The United States Departments of Energy and Agriculture (DOE and USDA) have announced US$4 million funding for bio-based fuels research that will accelerate the development of alternative fuels. The departments issued a solicitation for research proposals for new plant feedstock genomics research projects.

The new funding continues a commitment, begun in 2006, to conduct fundamental research in biomass genomics to provide the scientific foundation to facilitate the use of woody plant tissue, specifically lignocellulosic materials, for bioenergy and biofuels. Developing lignocellulosic crops for energy fuels could use less intensive production techniques and poorer quality land, thereby avoiding competition with food production on better quality land.

The programme will take advantage of significant advances in breeding, molecular genetics and genomic technologies and build upon the existing knowledge base of plant biology to enable scientists to confidently predict and manipulate biological function for bioenergy resources of plants.



JK Agri Genetics signs accord with NBRI on Bt cotton

In India, JK Agri Genetics of Hyderabad and the National Botanical Research Institute (NBRI) of Lucknow have entered into an accord to commercialize their new Bt cotton technology using Cry 1EC gene in India. JK Agri Genetics had recently launched the first indigenously developed Bt cotton developed under collaborative research with BREF-IIT Kharagpur in the Indian market after obtaining clearances from the Genetic Engineering and Approval Committee (GEAC). The new gene (Cry 1EC) developed by NBRI would be pyramided with the recently released material carrying Cry 1AC gene. This elite Bt cotton would give broader insect-resistance coverage, particularly against Spodoptera (tobacco caterpillar), and is expected to provide season-long uniform protection from the target pests throughout the entire field. Current cotton varieties containing Bt do not offer acceptable control of Spodoptera. The new product is expected to help in delaying the resistance development in cotton bollworm complex.

JK Agri Genetics plans to complete the regulatory studies and launch this elite new generation product in a few years. Farmers who would plant this new product (Cry 1 EC + Cry 1AC) will be able to significantly reduce the use of externally applied expensive chemical insecticides, including organophosphate and synthetic pyrethroid products that are used to control these pests.


GTC and LFB collaborate on transgenic products

GTC Biotherapeutics, the United States, and LFB Biotechnologies, France, are collaborating on a venture, which will focus on recombinant plasma proteins and monoclonal antibodies (mAbs) to eventually develop a robust pipeline for treating conditions such as haemophilia. The agreement focuses on developing selected proteins and mAbs using GTCs transgenic production platform, which would generate a transgenic recombinant form of human factor VIIa (rhFVIIa). Factor VIIa is a clotting factor in the coagulation of blood. The application of transgenic technology might enable the production and pricing of rhFVIIa at appropriate levels for its broader utilization, such as its use in the treatment of many unmet needs of patients in developing countries and the treatment of other acquired bleeding conditions.

Under the terms of the agreement, GTC would be responsible for development of the production system for the products and would retain exclusive commercial rights to the products in North America. LFB Biotechnologies would be responsible for clinical development and regulatory review of the first programme of this collaboration, and would have exclusive commercial rights in Europe. GTC and LFB Biotechnologies will hold rights co-exclusively in the rest of the world to the products developed through their collaboration.


Biogen Idec and Alnylam join hands on RNAi therapeautics

Biogen Idec, Australia, and Alnylam Pharmaceuticals, the United States, are in collaboration to discover and develop RNA interference (RNAi) therapeutics for the potential treatment of progressive multi-focal leukoencephalopathy (PML). PML is caused by infection of the central nervous system with a virus called JC virus and could occur in certain immune-suppressed patients, including those receiving immunomodulatory therapies.

RNAi is a naturally occurring mechanism within cells for selectively silencing and regulating specific genes. Since many diseases are caused by the inappropriate activity of specific genes, the ability to silence genes selectively through RNAi could provide a new way to treat a wide range of human diseases. RNAi is induced by small, double-stranded RNA molecules, and can be activated by chemically synthesized small interfering RNAs (siRNAs), which are double-stranded RNAs that target a specific disease-associated gene. Natural RNAi machinery in cells use the siRNA molecules to cause highly targeted gene silencing.

Alnylam and Biogen Idec would initially conduct investigative research into the potential of using RNAi technology to develop therapeutics to treat PML. Under terms of the collaboration, Biogen Idec would fund all research and development activities and Alnylam would receive an upfront payment of US$5 million.


Spains Zeltia sets up gene silencing unit

Zeltia, a Spanish drug company, has set up a new biotechnology arm to investigate gene silencing, an area of medicinal research. The new unit, Sylentis, would start by looking at RNA interference (RNAi) gene silencing in ophthalmology and digestive systems. The company started experimenting with RNAi in 2002 and had its first positive result in 2004. According to Zeltia, Sylentis has collaboration deals with other laboratories and is in talks with international drug companies.


Biotech projects win Australian government funding

The Australian government has allocated about US$390 million over five years for investment in science infrastructure under National Collaborative Research Infrastructure Strategy (NCRIS), in addition to approximately US$499 million in cash and in-kind contributions from the state and territory governments, universities, the CSIRO and private institutions.

NCRIS is divided into nine different research capability areas. One of these, Integrated Biological Systems, will see the establishment of an Australian Phenomics Network of mouse production and phenotyping facilities, under the leadership of Monash University. Funds have been committed also to set up an online Atlas of Living Australia, a biodiversity search engine providing access to information held in biological collections museums and institutes across the country.

A national plant phenomics facility will be established at the University of Adelaide and CSIRO/ANU. BioPlatforms Australia, a new coordinating body, will get funds from NCRIS for genomics, proteomics, metabolomics and bioinformatics. The money will be used by existing facilities and programmes in these areas to build on research entities such as the Australian Genome Research Facility as well as the Australian Proteome Analysis Facility.



Gene mutation that regulates sensitivity to alcohol

Researchers led by Dr. Adrian Rothenfluh at the University of California-San Francisco (UCSF), the United States, have discovered a gene mutation in fruit flies (Drosophila) that alters sensitivity to alcohol. The findings might have implications for human studies seeking to understand innate differences in peoples tolerance for alcohol.

The scientists studied the behaviour of Drosophila exposed to alcohol. Ordinarily, at low doses of alcohol fruit flies increase their activity, while high doses has a sedative effect. The researchers found some fruit flies were much more resistant to alcohol sedation. These flies continued to move about much longer than typical fruit flies exposed to the same amount of alcohol. The scientists subsequently identified key differences in a particular gene associated with this behaviour. The mutation also altered sensitivity of the flies to cocaine and nicotine. This study described key molecular pathways and gene interactions that control alcohol sensitivity.

The researchers exposed fruit flies to vaporized alcohol and monitored their behaviour and motion patterns with sensitive tracking instruments. They isolated the flies that were less sensitive to alcohols sedative effects. By breeding subsequent populations of mutant flies, the scientists identified the particular genetic mutation and further showed that the white rabbit mutation disrupted the function of the RhoGAP18B gene. They also isolated a number of variants of RhoGAP18B, each of which had a distinctly different effect on the response to alcohol. By manipulating these genetic variants, the researchers generated flies with greater and lesser sensitivity to alcohols sedative and stimulant effects. The research team also detailed how signalling proteins encoded by the RhoGAP18B gene variants play an important role in reorganizing components of the adult fruit flys central nervous system, which in turn affected the flies behaviour. They concluded that the RhoGAP18B gene was closely involved in regulating behavioural responses to alcohol exposure.


Solexa announces sequencing of a human X-chromosome

Solexa Inc., the United States, has announced that its scientists, in collaboration with researchers at the Wellcome Trust Sanger Institute, United Kingdom, have sequenced a human X-chromosome. The initial results from this project demonstrated that the Solexa Genome Analysis System achieved the data quality, read length and coverage uniformity required for discovering and characterizing human sequence variation at genome-wide level. Solexa expects to be the first to deliver whole human genome sequencing at US$100,000 per genome. Scientists at Solexa and the Sanger Institute sequenced purified human X-chromosome DNA from an anonymous female and aligned 2.6 gigabases (billion bases) of high-quality data to the 155-megabase (million bases) reference sequence.

In addition to announcing its draft sequence of a human X-chromosome, Solexa also presented data from digital gene expression, small RNA analysis, and microbial resequencing and candidate region resequencing applications. The high quality and breadth of these applications data illustrated that the Solexa Genome Analysis System could effectively address a range of important genetic analysis applications. Solexa Inc. is in the process of developing and commercializing the Solexa Genome Analysis System, which would be used to perform a range of analyses including whole genome resequencing, gene expression analysis and small RNA analysis.


GM bacteria that naturally sweeten dairy

Scientists led by Prof. Oscar Kuipers from the University of Groningen, the Netherlands, have found a technique that could remove the need to add sweeteners to dairy products by adding a novel genetically engineered bacterial strain. The tests were performed on Lactococcus lactis strain NZ9000, constructed from the L. lactis strains LL108, LL302 and pORI280.

The researchers were able to delete genes that coded for glucose metabolism by the bacterium. This was achieved by disrupting the phosphotransferase system (PTS), which is the main sugar transport system. Lactose is a disaccharide, where a galactose molecule is bonded to a glucose molecule. It was possible to create a bacterium (NZ9000Glc-Lac+) that selectively fermented the galactose part of the lactose, but not the glucose part, by deleting certain genes in the lactose-PTS. The glucose then accumulated outside of the cell, in the dairy product. One of the genes deleted the glucose-PTS EII-cel (ptcBAC) was a recent discovery while the others glucokinase (glk) and EIIman/glc (ptnABCD) were known earlier.

The viability of the strain was tested both under synthetic laboratory conditions, as well as in skim milk with a lactose content of about five per cent. In both sets of tests, NZ9000Glc-Lac+ increased the glucose content and decreased the lactose content. The fermentation process was stopped when the pH of the milk fell to 4.2, as occurs in milk fermentation under natural conditions. L. lactis NZ9000Glc-Lac+ could be used to produce glucose from lactose, which could serve as a natural sweetener in fermented dairy products. This in situ produced glucose could replace, at least in part, the frequent addition of other sweeteners to dairy products, as the sweetness of glucose is about 60 per cent that of sucrose. The researchers believe that the technique could also impact on the taste of the final dairy product, since glucose production in combination with less acidification of the product would produce a milder taste.


Honeybee genome sequenced

Scientists from the University of Illinois, the United States, have decoded the genomic structure of the western honeybee, a finding that will give new insight into how these bees behave and where they came from. Honeybees are valuable to scientists as models for research organisms, said Dr. Robinson, Director of the Universitys Bee Research Facility. He added that in biology and biomedicine, honeybees are used to study many diverse areas, including allergic disease, development, gerontology, neuroscience, social behaviour and venom toxicology.
The regulation of genes in honeybees is more like the gene regulation of mammals, including humans, than it is like other insects, such as fruit flies. Now that the honeybee gene sequence is known, it might be possible to see how genes evolved to account for bee behaviour. For instance, honeybees have many more genes related to smell, compared with fruit flies or mosquitoes, but far fewer genes related to taste. The large number of odour receptors accounts for the honeybees ability to communicate within the hive and to find food and communicate the location of food to other bees. In terms of social behaviour, a form of bee social pressure can cause nurse bees to become foragers in response to needs of the hive. This shift involves changes in thousands of genes in the honeybee brain, the researchers noted.


Gene key to taste bud development identified

Scientists led by Prof. Brigid Hogan at the Cell Biology Department, the Duke University Medical Centre, the United States, have identified a gene that controls the development of taste buds. According to them the gene, SOX2, stimulates stem cells on the surface of the embryonic tongue and in the back of the mouth to transform into taste buds. Stem cells are immature cells that can develop into several different cell types depending on what biochemical instructions they receive. Taste bud cells, much like skin cells, continually slough off and are replaced by new ones. So the new findings provide insights into how stem cells continue to operate in adults.

The researchers made their discovery in mice and they believe the same process occurs in humans. They combined the SOX2 gene with another gene, derived from jellyfish, and inserted the combination into mice chromosomes. They selected the added gene for its capacity to produce a special protein, called enhanced green fluorescent protein that glows green when exposed to ultraviolet light. In their work they used this fluorescence marker as a tool for tracking the activity of SOX2 in the oesophagus, among other sites. As they worked with the mice, they noticed that specific areas on the tongue and in the back of the mouth lit up, in addition to areas in the oesophagus. Additional studies confirmed that SOX2 was present in high amounts during the development of taste buds.

In another set of experiments the team used a different variant of the mouse strain in which the SOX2 gene was altered to produce only low levels of SOX2. In these animals, the stem cells in the tongue were not transformed into taste buds. Instead, the cells became the scaly cells found on the surface the tongue that help to direct food to the back of the mouth. The new findings could lead to a better understanding of developmental disorders of the gut caused by mutations in the human SOX2 gene.


Researchers identify a key regulator for stem cells

A research team led by Dr. Elaine Fuchs at the Howard Hughes Medical Institute, the United States, has found that by turning a single gene, they could prevent skin stem cells from maturing into the three types of adult skin cells, namely the epidermal, sebaceous and hair cells. Tcf3 is a transcription factor, a protein that controls the activity of a collection of genes in order to coordinate their action. In earlier studies, they found that the gene for Tcf3 was activated in a region of the adult hair follicle called the bulge, where stem cells were expected to be present. They also knew from other studies that a relative of Tcf3, called Tcf4, appeared to be important for the development of the intestine.

The researchers reasoned that if Tcf3 played a role in maintaining adult follicle cells, it would also be present in embryonic skin, which consists mainly of stem cells.

When they analysed the epidermis of embryonic mice, they found that theTcf3 gene was active in the embryonic skin stem cells. The researchers next sought to pinpoint which genes Tcf3 controlled. They genetically engineered a mouse in which they could switch on at will the Tcf3 gene in skin cells. They then used DNA microarrays to analyse which genes were affected when Tcf3 was activated. They found that Tcf3 repressed members of a gene family called PPAR, which themselves produce key transcription factors that promote skin stem cells to differentiate into sebaceous and epidermal gland cells.


DNA structure being uncovered

A team of biochemists led by Dr. Martin Egli from the University of Vanderbilt, the United States, has revealed the reason behind the incorporation of five-carbon sugars into the backbone of DNA and RNA when six-carbon sugars, like glucose, might have been more common. The scientists studied the X-ray crystal structure of homo-DNA, an artificial analogue of DNA in which the usual five-carbon sugar was replaced with a six-carbon sugar.

The homo-DNA structure showed several similarities with DNA apart from being more stable. It looked more like a slowly writhing ribbon than the tightly twisted ladder of DNA. The structure also showed that homo-DNA had more flexibility in how the bases bind. The bases in normal DNA adhere to a somewhat strict binding scheme where guanine (G) binds with cytosine (C) and adenine (A) binds with thymine (T). In this Watson-Crick base pairing, the G:C bonds are much stronger than A:T or any other bonds. The findings suggest that fully hydroxylated six-carbon sugars would not have produced a stable base pairing system capable of carrying genetic information as efficiently as DNA.


Antibiotic inhibits cancer gene activity

Scientists led by Dr. Andrei Gartel at the University of Illinois, the United States, have found that a little known antibiotic could function as an anti-cancer agent, inhibiting a gene found at higher than normal levels in most human tumours. They targeted a gene believed to be over-expressed in cancer cells to screen for promising anti-cancer agents. The FoxM1 gene is responsible for turning on genes needed for cell proliferation and turning off genes that block proliferation. Uncontrolled proliferation is characteristic of cancer cells.

The scientists developed a new screening system, based on the fluorescent protein luciferase, to identify small molecules that inhibit proteins that turn genes on and off. Using this system, they identified an antibiotic, siomycin A, which specifically targets FoxM1 without affecting other cell functions. In further experiments in tissue cultures, they found that siomycin A induces cancer cells, but not normal cells, to commit apoptosis. The antibiotic will now be tested against other cell lines in the laboratory and in preliminary animal experiments before human trials are planned.



Effective anti-malarial agent

Biochemists led by Dr. Utpal Tatu of the Indian Institute of Science, India, have found that the anti-cancer drug and the inhibitor of heat shock protein 90, Geldanomycin, was an effective anti-malarial agent. They found that the drug inhibits transitional changes of the parasites in human erythrocyctes (red blood cells) leading to the conclusion that the heat shock protein 90 was needed for the growth of Plasmodium falciparum in human erythrocytes. The discovery was an outcome of the study of several fibrile episodes on the growth of the malarial parasite P. falciparum on patients suffering from malaria. The Biochemistry Department has also developed an ancillary proteomic tool for identification of proteins in P. falciparum.

Explaining the phenomenon, researchers said that the plasmodium thrives at around 25C and when it enters the human body, it has to cope with human body temperature of 37C. When humans develop fever, it has to thrive in temperatures up to 43C. Thus, the plasmodium experiences heat shock wherein its proteins undergo some changes. During its asexual life cycle in the vertebrate host, the parasite resides in the erythrocytes. As a part of its survival strategy, the parasite trafficks a variety of proteins at different destinations within the erythrocyte host. Some proteins are even secreted out of the erythrocytes, researchers said.

The Economic times, 27 October 2006

Hormone resistance of pituitary tumours explained

Researchers led by Dr. Jacques Drouin, Clinical Research Institute of Montral (IRCM), Canada, have unravelled the mechanism of hormone resistance in pituitary tumours of Cushing disease patients. Cushing disease is caused by pituitary tumours that produce excessive amounts of hormone because the tumour cells have become resistant to negative feedback control by a class of steroid hormones called glucocorticoids. In Cushing disease, this excessive hormone production can lead to hypertension, obesity, diabetes and osteoporosis.

Through detailed molecular investigation of the mechanism of this negative feedback, the IRCM researchers identified two essential components (proteins) of this feedback mechanism. Extrapolating from these basic studies, they showed that approximately half of the pituitary tumours from Cushing disease patients were deficient in the expression of either of these proteins, thus providing a molecular explanation for the hormone resistance that was the hallmark and the first event in the formation of these tumours. Knowledge of the basic mechanism of hormone resistance could lead to the rational design of therapeutic approaches for the better management of Cushing disease patients and help understand other forms of hormone-resistant cancers.


Breakthrough discovery in the genetics of childhood blindness

Dr. Robert Koenekoop and colleagues at the McGill Ocular Genetics Centre, Canada, have made a breakthrough discovery in the genetics of childhood blindness. The new study identified the gene most often responsible for Leber Congenital Amaurosis (LCA), the commonest form of congenital blindness. LCA causes blindness from birth or during the first few months of life.

Discovery of the CEP290 gene and a single mutation found in 20 per cent of LCA patients would significantly speed up the genetic testing process for blind children. Prior to Dr. Koenekoops discovery, LCA had been linked to mutations in eight genes. These mutations together account for about 45 per cent of cases. By studying members of a Quebec family affected by LCA, the researchers were able to identify a mutation in CEP290. This mutation was detected in 21 per cent of unrelated cases, making it one of the most common causes of LCA identified.


Monoclonal antibody reduces asthmatic exacerbations

Dr. Trevor Hansel and collegues of the National Heart and Lung Institute at the Royal Brompton Hospital, London, have found that patients with symptomatic moderate asthma who were treated with anti-tumour necrosis factor alpha, an anti-inflammatory monoclonal antibody, experienced significantly fewer disease exacerbations than individuals taking a placebo.

The team infused 14 patients with infliximab, a monoclonal antibody that bound and neutralized tumour necrosis factor alpha (TNF). Eighteen patients received placebo during the eight-week double-blind study. The researchers said both structured and inflammatory cells in asthmatics can release TNF, which is an intercellular messenger protein, a cytokine, produced by white blood cells. Of the patients on placebo, 13 out of 18 (72 per cent) experienced exacerbations, as compared with only 4 out of 14 patients (29 per cent) on infliximab therapy. All patients in the study cohort continued to use inhaled corticosteroids for their asthma. Study protocol required them to be symptomatic during a two- to four-week run-in period. After the run-in phase, infusions of either infliximab or placebo were administered at weeks zero, two and six. Treatment with infliximab reduced the number of exacerbations in patients with asthma, as monitored using an electronic spirometer.

The infliximab therapy did not show significant efficacy for the primary endpoint of monitoring peak expiratory flow (PEF), but it did produce a significant decrease in the diurnal (during the day) variation in the PEF rate. The researchers noted no adverse events associated with using the monoclonal antibody for treatment. Given that infliximab therapy was well tolerated and reduced the incidence of asthma exacerbations, anti-TNF therapy merited further study in larger clinical trials in patients with severe asthma, the researchers concluded.


Killer B cells provide new link in the evolution of immunity

Scientists from the University of Pennsylvania School of Veterinary Medicine, the United States, have discovered a unique evolutionary link between the most primitive innate form of immune defence, which has survived in fish, to the more advanced adaptive immune response present in humans and other mammals. The finding represents an evolutionary step for the mammalian immune system and provides a potential new strategy for developing the needed fish vaccines.

In the adaptive immune system in mammals, B cells produce antibodies to fight infection. In the more primitive innate immunity in fish, the scientists found that B cells took part in a process known as phagocytosis, by which immune system cells ingest foreign particles and microbes.

In modern mammals, the B cell is a highly adapted part of the immune system chiefly responsible for the creation of antibodies that tag foreign particles and microbes for destruction. The scientists determined that these attack B cells accounted for more than 30-40 per cent of all immune cells in fish, whereas phagocytic cells made up only a small portion of the total number of immune cells in mammals.
Their findings also have agricultural implication. Vaccines currently given to farmed salmon, for example, appeal to the fishs adaptive immune response, which this research has now shown to be a small part of the overall fish immune system.


Jumping gene could help provide non-viral therapy

Dr. Joseph M. Kaminski and colleagues at the Medical College of Georgia Cancer Centre, the United States, say that jumping gene first identified in a cabbage-eating moth can provide a safer, target-specific alternative to viruses for gene therapy. The team compared the ability of the four best-characterized jumping genes, the transposons, to insert themselves into a cells DNA and produce a desired change, such as making the cell resistant to damage from radiation therapy.

The scientists found the piggyBac transposon to be 5-10 times better than the other circular pieces of DNA at making a difference in several mammalian cell lines, including three human ones. The piggyBac transposon, which has close relatives in the human genome, is widely used to genetically modify insects. For this study, the researchers used transposons to deliver a gene resistant to antibiotics. They found that while the piggyBac transposon might not work as efficiently as a virus, it puts Sleeping Beauty, another transposon, to shame when it comes to making cells antibiotic-resistant. Another clear benefit is that transposons are cheaper to produce and probably safer than viruses.

One of the next goals of the scientists is to use transposons to deliver manganese super oxide dismutase, a radio-protective gene, to potentially protect normal tissue from radiation damage.


Curcumin might help in Alzheimers disease

Researchers led by Dr. Milan Fiala, David Geffen School of Medicine at UCLA, the United States, found that curcumin, a chemical found in turmeric, might help the immune system clear the brain of amyloid beta, which form the plaques found in Alzheimers disease.

Using blood samples from six Alzheimers disease patients and three healthy control patients, the researchers isolated macrophages, the immune systems PacMen that gobble up waste products, including amyloid beta.

The researchers treated the macrophages with a drug derived from curcumin for 24 hours in a cell culture and then introduced amyloid beta. Treated macrophages from three out of six Alzheimers disease patients showed improved uptake or ingestion of the waste product compared with the patients macrophages not treated with curcumin. Macrophages from the healthy controls showed no change with curcumin treatment. That the patients whose immune cells responded were younger and had higher scores on a Mini-Mental State Examination suggested that curcumin might help those with less advanced dementia.



Protein as potential tactic to prevent tumours

Researchers from Mayo Clinic, the United States, have found that a protein that initiated a quality control check during cell division also directed the cell suicide (apoptosis) of those cells damaged during duplication. This knowledge represents a potential source for targeting anti-tumour drugs.

The researchers, led by Dr. Haojie Huang, examined a protein called cyclin-dependent kinase 2 (CDK2), which worked as a quality control inspector. As normal cells divide, they pause in the replication process when they find inaccurate genetic code embedded in their DNA. The health of offspring cells depend on accurate genetic code transfer from one generation of cells to the next.

The researchers showed that when genes have irreparable errors, CDK2 modifies another cellular protein FOXO1 to send a signal that results in the death of the cell. CDK2 infuses high energy into FOXO1, switching it on as the initial link in a signal that tells the cell to set itself up for apoptosis. It adds phosphorylation to specific serine residue on the chain of amino acids that make up FOXO1. In case of robust errors found in the genetic code, CDK2 signals FOXO1 to explicitly call for the cell to produce a set of proteins leading to its death. These protein-to-protein relationships allow targeted drug intervention to control unregulated growth of cancer cells.


Most complex protein knot ever seen discovered

A research team led by Dr. Leonid Mirny, in the MIT-Harvard Division of Health Sciences & Technology, the United States, has discovered the most complicated knot ever seen in a protein called human ubiquitin hydrolase. The team believes that it might be linked to the proteins function as a rescue agent for proteins marked for destruction.

Knots are rare in proteins less than 1 per cent of proteins have any knots and most are fairly simple. The researchers analysed 32,853 proteins, and all those that had knots were enzymes. Most had a simple three-crossing or trefoil knot, a few had four crossings, and the most complicated, a five-crossing knot, was found in only ubiquitin hydrolase. This knot might hold some protective value for ubiquitin hydrolase, whose function is to rescue other proteins from destruction. When a protein in a cell needs to be destroyed, it gets labelled with another protein called ubiquitin. Once this death mark is applied, proteins are shuttled to a cell structure called a proteasome, which pulls the protein in and chops it into pieces. If ubiquitin hydrolase intervenes and removes the ubiquitin, the protein is saved.

The same knot was found in ubiquitin hydrolase in humans and in yeast, supporting the theory of a connection between the knot and the proteins function. The researchers also found examples of proteins that are closely related and structurally similar except for the presence or absence of a knot. Two versions of the enzyme transcarbamylase, from humans and certain bacteria, catalyse different reactions, based on whether or not there is a knot. The researchers speculate that somewhere along the evolutionary line, the sequence that allow a protein to form the knot was added or deleted.


The shape of the Na/K pump

Led by Prof. David Gadsby, a team of scientists from the Laboratory of Cardiac and Membrane Physiology at Rockefeller University, the United States, has described the structure of one of the most important cellular membrane pumps. Many of the residues in an ion pump have an electrical charge that works to either draw in or repel ions that approach, allowing only those with the correct charge to flow through to their destination. Using a lethal marine toxin, researchers disabled the gates of the Na/K pump and used the patch-clamp amplifying technique to measure ion flow through individual protein pumps. Once the channel gates were unlocked, the researchers attached molecular markers to amino acids in the channel and then sent charged chemicals through it to see whether interactions between the molecules impacted the ion stream.

The scientists studied two of the proteins amino acids that reacted with digoxin, a cardiac drug known to target the Na/K pump. By altering the two residues it bound to and measuring the resulting change in the ion stream, the scientists were able to determine where those residues were located in a wide opening near the mouth of the channel. The scientists used the same residue-altering technique to further untangle the shape of the ion pathway. The results showed that two adjacent residues have a vastly different effect on ion flow: altering one of them slows the current, while altering the other stops it completely. Deeper in the narrow neck of the funnel is a filter, made of negatively charged residues, that selects for positively charged ions. By altering just a single residue to reverse its charge, the researchers were able to switch the selectivity of the filter.


Protein key to production of haeme in haemoglobin

Dr. John Schuetz and colleagues at St. Jude Childrens Research Hospital, the United States, have discovered that a protein called ABCB6 plays a central role in the production of a molecule that is key to the ability of red blood cells to carry oxygen, liver cells to break down toxins, and cells to extract energy from nutrients.

The investigators showed that ABCB6 is lodged within the outer membrane of the mitochondria and it ferries into a type of molecule called a porphryin. Inside the mitochondrion, porphyrins are converted to haeme. The researchers said the discovery of the location and function of ABCB6 solved the long-standing riddle of how porphyrins get into mitchondria so that they could be used to make haeme. Porphyrins are negatively charged and so is the inside of mitochondria. It was not clear how a negatively charged molecule could get into a negatively charged environment when it should have been repulsed like two negative poles of a magnet pushing each other apart.

The work showed that ABCB6 circumvent the problem by simply grabbing porphyrin molecules and pulling them in. It was found that the increase in ABCB6 in mitochondrial membranes causes the cells to make more porphyrin, the building block of haeme. The work helps understand of how disruption of the haeme production pathway could cause serious diseases.


Designer pectins to shine in food ingredients future

At the University of Leeds, the United Kingdom, Dr. William Willats and colleagues have opened the door to obtain from different sources designer pectins with tailored functionalities. Pectin is widely used as gelling agent in jams, confectionary and bakery fillings, and as stabilizer in yoghurts and milk drinks.

A variety of pectins from plant, bacterial and fungal sources that had been digested with pectin methyl esterases were tested with the aim for producing pectins with the greatest stabilization capacity at the lowest concentration. Lime pectin with long contiguous stretches of unesterified galacturonic acid residues was found much more effective at preventing sediment than a range of other pectins.

Another area beginning to be explored is the transgenic approach, which would allow scientists to manipulate the structure of the pectin in plants. By manipulating the expression of certain genes in specific plants, plant scientists should be able to control pectin functionalities and quality in the plants even before extraction begins, said the researchers. The identification and characterization of plant acetyl transferases and esterases might in the future lead to production of pectin with improved functionality from transgenic sugar beet.


Protein that helps chickenpox and shingles virus spread

A research team led by Dr. Jeffrey I. Cohen at the National Institute of Allergy and Infectious Diseases (NIAID), the United States, has identified a human protein that helps varicella-zoster virus the cause of chickenpox and shingles spread from cell to cell within the body. It is a surface protein of varicella-zoster virus that attaches to a cellular protein called insulin-degrading enzyme, using it as a receptor to enter and infect cells.

The researchers found that when they deleted a molecule called glycoprotein E on the surface of the virus, the virus lost its ability to infect human cells. This led them to reason that glycoprotein E was involved in the virus infectivity, and it gave them a way to search for its receptor. The team used glycoprotein E as a sort of hook to fish out a human protein to which it binds.

They found that curtailing the expression of insulin-degrading enzyme within cells greatly reduced the infectivity of the virus and blocked its cell-to-cell spread. Genetically altering mouse and hamster cells to express human insulin-degrading enzyme rendered these cells more susceptible to varicella-zoster virus infection. Cells from hamsters and mice are normally resistant to the virus, which in nature only infects humans.

The scientists also found that they could block the virus cell-to-cell spread by adding compounds that prevented glycoprotein E from binding to the insulin-degrading enzyme. The finding suggests that the new receptor might be a valid target for new shingles and chickenpox treatments.


Clumping protein linked to return of ovarian cancer

In the United States, Johns Hopkins scientists have discovered that women treated for ovarian cancer are at increased risk of a rapid and potentially fatal recurrence if their tumor cells have high levels of NAC-1, a binding protein that triggers abnormal growth and slows down cell death, both hallmarks of malignancy. The research also suggests that drugs that block NAC-1 activity may be a useful strategy in preventing and treating recurrences as well. Because recurrent cancers are often what really kill patients, and most ovarian cancer gets diagnosed when it is already advanced, the findings offer women a better chance of catching or preventing recurrent disease early and increasing survival.

When the investigators compared levels of NAC-1 among primary and recurrent tumour samples taken from 338 ovarian cancer patients from two hospitals, they found that levels of NAC-1 were significantly higher in recurrent tumours compared with primary tumours taken from the same patient. Women whose primary cancers had high levels of NAC-1 were more likely to suffer a recurrence within one year.

The researchers genetically modified cells to make both NAC-1 and N130, a component of the protein found at the ends of natural NAC-1 and a binding site. In the modified cells, N130 capped off NAC-1 proteins disrupting their ability to bind with each other. This action can prevent tumour formation and kill cancer cells in experimental mice. In the future, drugs that mimic N130 can be used to treat cancer.



Scientists develop natural food colour from algae

At the Universidad de Jaen, Granada, scientists led by Dr. Bermejo Ruperto have developed a method of extracting the B-ficoeritrin protein, a natural red colorant from the microalga Porphyridium cruentum, which could prove useful in a number of food and beverage applications. The protein known as ficoerithrin confers a reddish colour to the micro-alga.

B-ficoerithrin is described as very fluorescent and its colour is similar to that of strawberries milkshake, according to researchers. The colorant could therefore eventually be used as a natural replacement of existing colorants. The scientists are now looking into the spectroscopic features of B-ficoerithrin. This will provide vital information on the possible structural changes of the protein when it is subjected to extreme conditions during the production process of foodstuff. The scientists have also set in motion an R&D project with a technological innovation company that works on the treatment and commercialization of microalgae aimed at the preparation of functional foods. A number of commercialized products already use pigments produced from microalgae.


Beta carotene-rich maize boosts vitamin A in rodents

Dr. Julie Howe and Dr. Sherry Tanumihardjo from the University of Wisconsin, the United States, have found that maize, bred to contain high concentrations of the pro-vitamin A carotenoid, beta-carotene, did increase the vitamin A status in gerbils, and could be used to tackle vitamin A deficiency. The human body converts beta-carotene in the diet into vitamin A.

The researchers set about testing whether feeding beta-carotene-rich maize to Mongolian gerbils with vitamin A deficiency would improve the vitamin A status of the rodents. Forty gerbils were fed a standard diet of white maize (low beta-carotene content) for four weeks before starting the experiments. The gerbils were divided into four equal groups and fed an oil control, 60 per cent high-beta-carotene maize, and beta-carotene or vitamin A supplements (matched to high beta carotene maize) for four weeks.

The researchers reported that concentrations of vitamin A in the liver of the gerbils that ate the high-beta-carotene maize group was 150 per cent that of the control group (0.25 versus 0.10 micromoles/g, respectively), and equalled that of the group receiving the beta-carotene supplements. The vitamin A supplemented group had higher liver concentrations of the vitamin than the other groups (0.56 micromoles/g). It was found that bioconversion of the beta-carotene to retinol (vitamin A) was about 3 g of beta-carotene to 1 g of retinol (1.5 mol beta-carotene to 1 mol retinol). The concentrations of beta-carotene in the livers of the gerbils that ate the high-beta-carotene maize was almost double that of the beta-carotene supplement group. The researchers concluded that biofortified maize adequately maintains vitamin A status in Mongolian gerbils and was as effective as beta-carotene supplementation.


UGA scientists engineer root-knot nematode resistance

Prof. Richard Hussey and colleagues at University of Georgia, the United States, have studied a worm-shaped parasite too small to see without a microscope, finding a way to halt the damage caused by one of the worlds most destructive groups of plant pathogens. Root-knot nematodes invade plant roots and, by feeding on the roots cells, cause the roots to grow large galls, or knots, damaging the crop and reducing its yield. They attack nearly every food and fibre crop grown.

The scientists developed resistant plants that prevent the nematode from feeding on the roots. Using a technique called RNA interference, they effectively turned the nematodes biology against itself. They genetically modified Arabidopsis plant to produce double-stranded RNA to knock out the specific parasitism gene in the nematode when it feeds on the plant roots. This disrupts the patho-gens ability to infect plants. The research efforts have been directed primarily at understanding the molecular tools the nematode use to infect plants. This is a prerequisite for bioengineering durable resistance to these nematodes in crop plants.


Genetically enhanced flavonoid tomatoes

Researchers led by Professor Uwe Sonnewald, University of Erlangen, Germany, have found that genetically modified tomatoes containing a higher level of flavonoids substantially reduce C-reactive protein (CRP) in mice. CRP is linked to inflammatory processes in mice as well as human beings and is associated with higher risk of heart and vascular diseases, as well as with type-2 diabetes.

Flavonoids are plant metabolites known for their anti-oxidant activity. To compare the effects of flavonoid-enriched and conventional tomatoes, scientist daily fed two groups of mice 12 mg of genetically enhanced and conventional tomato peel, respectively. To a human adult, this was equivalent of a daily consumption of approximately 230 g, or three fresh tomatoes. After seven weeks, the level of CRP was reduced considerably in both groups of mice. However, the level was significantly lower in the group of mice fed with genetically modified tomato peel. The biological mechanisms by which fruits and vegetables reduce human CRP and thus exert their benefits on human health are not fully understood and are likely to be numerous.


GM groundnut is enriched with vitamins

Dr. Kiran K. Sharma and colleagues at the International Crop Research Institute for the Semi Arid Tropics (ICRISAT), India, have announced a genetically modified (GM) groundnut (peanut) with betacarotene genes, which is rich in proteins and pro-Vitamin A. This GM groundnut has an advantage over rice since the pro-Vitamin A betacarotene-rich Golden Rice being developed by scientists has only 22-37 g/g betacarotene content, while the GM groundnuts potential betacarotene level is significantly more. The researchers are aiming at 500-600 g/g betacarotene content. Bioavailability would be tested on the rodent gerbil, which has been shown to have the same bioavailability rate as humans. Betacarotene molecule conversion to vitamin A varies from 1:2 to 1:32, depending on how betacarotene is consumed together with other foods.


GM techniques turn a plant parasite into a potential saviour

Prof. John Mansfield and colleagues at Imperial College London, the United Kingdom, have found a way to turn the bacterium Agrobacterium tumefaciens, famous for causing crown gall disease, into a potential saviour of rice producers. This parasite usually lives a fairly innocent existence in the soil surrounding the root, surviving on excess nutrients that naturally leak from the plant.

A. tumefaciens has a separate piece of genetic material, in the form of circular DNA, which provides it with all the tools it needs to invade a plant. Once the bacterium is inside the plant, a section of this circular DNA, called transfer-DNA (T-DNA), is snipped out. The T-DNA then invades plant cells, where it is incorporated into the genome, and causes the cells to produce the proteins coded for by the bacterial T-DNA. Infected cells grow unusually large and replicate rapidly, causing the galls on the plant. This neat trick also causes the cells in the galls to act as food factories, pumping out nutrients for the bacteria to feast on.

The scientists have devised a way to use this transfer of DNA between organisms of different kingdoms as a vehicle to introduce other foreign genes. They inserted a gene of interest into the T-DNA of A. tumefaciens, making it possible to instruct plant cells to produce the protein coded for by the gene. The researchers are now modifying cultivars of rice found in Bangladesh using Agrobacterium, aiming at increased food production, and development of salt tolerance.



Circulating Nucleic Acids in Plasma and Serum IV

The focus in this book is on three major applications of the circulating nucleic acids detection method: cancer, foetal medicine, and diseases such as diabetes, stroke and myocardial infarction. In addition, there are reports on the biology and origins of circulating DNA and RNA and on improved methods for the detection of nucleic acids in plasma and serum.

Contact: The Eurospan Group, 3 Henrietta Street, Covent Garden, London WC2E 8LU, United Kingdom. Tel: +44 (20) 7240 0856; Fax: +44 (20) 7379 0609


Biotechnology in Agriculture

The publication outlines the relevance of plant biotechnology to agriculture and the importance of regulatory and biosafety issues before public acceptance of genetically modified food. It also addresses the benefits and risks, as well as economic and intellectual property right implications of transgenic research.

Contact: Akhil Books Pvt. Ltd., 4675/21 Ganpati Bhawan, Ansari Road, Daryaganj, New Delhi 110 002, India. Tel: 91 (11) 65700698


Biotech 2006Life Sciences: A Changing Prescription

This book looks at the last 20 years of biotechnology progress, and contains interviews with biotech leaders who have influenced the development of the industry, besides an analysis of key activities taking place in various industry sectors such as healthcare, diagnostics, nutraceuticals, agri-biotechnology and industrial biotechnology.

Contact: Burrill & Company, One Embarcadero Centre, Suite 2700, San Francisco, CA 94111, United States of America. Tel: +1 (415) 591 5400; Fax: + 1 (415) 591 5401



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