VATIS Update Biotechnology . Sep-Oct 2006

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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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Europe challenges United States in stem cell research

A major research project that links the expertise of 20 leading organizations has been launched in Europe with the aim to keep Europe at the forefront of human embryonic stem cell research. The ESTOOLS consortium, led by the Centre for Stem Cell Biology at the University of Sheffield, United Kingdom, is a European Union Sixth Framework Programme Integrated Project, which will advance fundamental understanding and biomedical application of human embryonic stem cells, generating significant benefits in human healthcare.

The project plans to generate knowledge on the fundamental processes governing stem cell differentiation and permit greater standardization of research with human embryonic stem cells, not only in Europe but also throughout the world. It will include the development of robust internationally agreed standardized protocols, tools for growing and manipulating embryonic stem cell lines, and for monitoring their phenotypic, genetic and epigenetic stability. ESTOOLS also plans to train young researchers across Europe to gain expertise in the field of embryonic stem cells.


India announces launch of annual Asia biotech meeting

Noting that the biotechnology industry in Asia is still at a nascent stage, India has announced the launch of an annual Asia Biotech meet, bringing together scientists and biotechnology experts who will focus mostly on the needs of the people of the region. Mr. Kapil Sibal, Minister of Science and Technology, said that most of Asia was largely an agricultural community and therefore, agricultural biotechnology was necessary for food security. He announced launching of the annual meeting at the fourth ASEAN informal ministerial meeting on Science and Technology, held at Kuatan in Pahang state, Malaysia.

The meet was modelled on the lines of the Biotechnology Conference held annually in the United States. The Asia Biotech conference will be held in rotation across ASEAN plus six nations namely, China, Japan, Republic of Korea, India, Australia and New Zealand. The first conference will be held at New Delhi in November 2007.


Malawi to formulate a national biotech policy

According to the African News Dimension, Malawi is in the process of formulating its national biotechnology policy. Mr. Patrick Kachimera, Malawis Secretary for Science and Technology, said that it is imperative for Malawi as a developing nation to put much emphasis on biotechnology research and development.

Mr. Kachimera also said that a policy is already under development. The government wanted to ensure that caution is exercised, and that biosafety would be given utmost consideration. Malawis National Research Council is in the process of drafting the policy, which would regulate the use, import, export and research on biotechnology in the country.


Danforth Plant Science Centre gets a US$15 million gift

The Danforth Plant Science Centre, the United States, announced that it has received a US$15 million gift from Monsanto Co. to boost the non-profit Centres mission of bringing biotechnology to the developing world. The Centre has worked for seven years on cassava, a tropical crop that is the most important food security crop in Africa, one that keeps farmers from starvation when the main crop fails. In the last decade, however, a plant virus had swept across the eastern Africa and decimated the cassava crop. Researchers at the Danforth Plant Science Centre have engineered a virus-resistant cassava.

Plant biotechnologist Dr. Joel Cohen said that non-profit science centres have been going good at doing research but less adept at turning that research into humanitarian products for poor people. Mr. Rob Rose, spokesperson for the Centre, said that corn researchers would also get some of the gift money. Researchers are trying to make corn resistant to fungal diseases, which reduce yields and produce mycotoxins that can be a threat to human and animal health.


Australia funds hepatitis B vaccine project

The Australian government has provided approximately US$1 million grant to Vaxine Pty. Ltd. to assist the commercialization of its new hepatitis B vaccine. Mr. Ian Macfarlane, the Minister for Industry, Tourism and Resources of Australia, indicated during the announcement that Vaxines hepatitis B inoculation was expected to be less toxic, less painful and more potent than vaccines available at present.

Vaxines Chairman, Professor Nikolai Petrovsky, who developed the vaccine with Dr. Peter Cooper from the Australian National Universitys John Curtin School of Medical Research, indicated that early testing had demonstrated the vaccine to be safe. Prof. Petrovsky suggested that the natural ingredients in the vaccine booster might be the reason why this adjuvant is tolerated so well by the body. He said that Vaxines aim is to use the vaccine to immunize those people who were not exposed to hepatitis B and to protect them against the virus. He added that there is a good chance that the vaccine could also be used to treat infected people.


United States FDA forms task force on human tissue safety

The United States Food and Drug Administration (FDA) has announced the formation of a multidisciplinary task force on human cell and tissue safety. The FDA Tissue Task Force (HTTF), which will be led by senior FDA officials from within the Centre for Biologics Evaluation and Research (CBER) and the Office of Regulatory Affairs (ORA), was established as part of the agencys efforts to strengthen its comprehensive, risk-based system for regulating human cells and tissue.

The main priority of HTTF will be to assess the effectiveness of implementation of the new tissue regulations, which went into effect in 2005. A review of recently reported findings that some tissue recovery establishments are not following federal requirements for tissue recovery would be of particular interest. Dr. Jesse Goodman, Director of CBER said that the primary goal of the new task force is to identify whether any other steps are needed to further protect the public health while assuring the availability of safe products.

Chronicle Pharmabiz, 7 September 2006

Thailand sees GM as key to staying ahead

Thailand is likely to start developing genetically modified (GM) crops in order to maintain its competitive edge in the global food export business, said Professor Sakarindr Bhumiratana from the National Science and Technology Development Agency, Thailand. I dont think we can maintain this non-allowance of GM field trials for much longer because it will limit our development of seeds and more productive crops, said Prof. Sakarindr.

Thailand, the worlds leading exporter of canned tuna and frozen shrimp, is seeing a rising challenge from China in many of its biggest exports including rice, shrimp and pineapples. While the shrimp production of Thailand is now saturated, China is expanding in this sector by around 25 per cent this year. Thailand is also down in global rankings in rice exports and needs to increase its research into new technologies to improve productivity.


International Rice Prize 2006

Prof. Dr. Akihiko Ando of the Centre for Nuclear Energy in Agriculture (CENA), Brazil, won the Koshihikari International Rice Prize for 2006. Prof. Ando was chosen in recognition of his outstanding research, teaching and extension activities related to rice breeding using mutation induction for the last 40 years. The Koshihikari
International Rice Prize was established in 1997 to celebrate 50 years of development of one of Japans most popular rice cultivars, the Koshihikariin. The second winner of the 2006 prize is Dr. Moussa Si from the Africa Rice Centre (WARDA).

FAO/IAEA Plant Breeding and Genetics Newsletter, No. 17


Organon and NIBRT enter into research collaboration

The Irish National Institute for Bioprocessing Research and Training (NIBRT) and Organon, the human healthcare business of the Dutch group Akzo Nobel, have announced the formation of a research collaboration, which will focus on the control and understanding of glycosylation in CHO cell culture. The alliance is designed to combine NIBRTs academic resources with the existing manufacturing know-how of Organon to improve cell culture process. The research programme will study the regulation and expression of those enzymes active in cell cultures, which are highly relevant for their role in glycosylation. Using a combination of systems biology modelling and experimental validation in vitro, key optimization data will be generated under the collaboration, which will advance the understanding of enzyme expression, regulation and action related to glycosylation in production systems.

According to the company, this is the first industry research collaboration to be announced by NIBRT, which was incorporated early in 2006. The academic portion of the collaboration will be supported by Prof. Keith Tipton and Dr. Gavin Davey of the Systems Biology Group in the School of Biochemistry and Immunology, Trinity College Dublin (TCD). Experimental work will be carried out in TCD and later in collaboration with Prof. Pauline Rudds group (NIBRT) in Belfield. Scale-up work will be carried out in the NIBRT research facility, currently under construction. This collaboration is targeted as a multi-annual research programme with associated milestones and will be reviewed and directed by the programme team on a continual basis.


Eli Lilly and Suven enter CNS research deal

Drug giant Eli Lilly and Suven Life Sciences based in the United States have entered into a deal that will focus on pre-clinical research of molecules in the therapeutic area of central nervous system (CNS) disorders. The deal sees scientists from both parties pooling their knowledge to identify potent, oral compounds that selectively modulate the specified G-Protein coupled receptor for the target CNS disease. Mr. Venkat Jasti, Vice Chairman and CEO of Suven, said that this is their first true research collaboration with a global pharmaceutical company, thereby helping them realize the next step of their strategic plans.

Suven is no stranger to the market for CNS therapies and it is currently the second largest therapeutic category worldwide. It recently presented preclinical data of their 5-HT 6 antagonist compounds being developed for the treatment of mild cognitive impairment associated with Alzheimers disease or schizophrenia, Parkinsons and obesity diseases.


Vaccines drive Indian biotech market

Biologics form the most significant contributor to the Indian biotechnology market. Vaccines and recombinant therapeutics are the leading sectors driving the growth of biotechnology industry in India. According to industry estimates, major share of the revenues is generated through exports. With increasing consolidation of manufacturing and marketing capabilities by Indian companies, India has already achieved leadership position in global vaccines market and is all set to grab the market opportunity in the global recombinant therapeutics market. Prominent players include Serum Institute of India, Panasia Biotec, Indian Immunologicals, Aventis Pharma, Glaxo Smithkline, Shanta Biotechnics and others. Major initiatives in India, which are at the various stages of development, include vaccines for anthrax, HPV, typhoid, HIV meningitis, cholera, Japanese encephalitis and rotavirus, besides improved versions of tuberculosis vaccines.

The recombinant therapeutics market in India is growing rapidly. Prominent products in this segment include recombinant human insulin, recombinant human erythropoietin protein, granulocyte colony stimulating factor, interferon alpha and beta, human growth hormone, human FSH and recombinant streptokinase. According to industry estimates drugs worth more than US$70 billion are expected to come off patent over the next few years.

Chronicle Pharmabiz, 7 September 2006

Karo Bio and Wyeth extend research collaboration

Karo Bio, the United States, and Wyeth, the United Kingdom, have extended their atherosclerosis collaboration for an additional year until the end of August 2007. The primary objective of the extension is be to characterize back-up compounds and to further evaluate their additional clinical possibilities.

LXR is a nuclear hormone that is an important regulator of cholesterol metabolism in mammals. LXR has many features that make it an attractive drug development target for prevention and treatment for atherosclerosis and dyslipidemia. Modulation of LXR with small molecule compounds has been shown to enhance the efflux of cholesterol from cells in atherosclerotic disease blood vessels, resulting in reduction in progression of atherosclerotic disease in selected experimental models. Modulation of LXR has also been implicated in reducing vascular inflammation which, in addition to cholesterol, is an important mediator of atherosclerosis. It is believed that these features of LXR are of central importance for a new generation of drugs to treat as well as prevent atherosclerosis successfully.


Indo-American collaboration for anti-clot protein molecule

A pharmaceutical company in the United States has obtained worldwide licensing rights to carry out clinical development and commercialization of a novel clot busting therapeutic protein developed by a constituent laboratory of Council of Scientific and Industrial Research (CSIR), India. The Institute of Microbial Technology (IMTECH) in Chandigarh signed a technology licensing agreement with Nostrum Pharmaceuticals Inc., under which the latter will develop this therapeutic protein in association with Symmetrix Pharmaceuticals Inc., an affiliate of Nostrum.

The therapeutic protein licensed to Nostrum is known as clot specific streptokinase (CSSK), an engineered protein produced by recombinant DNA technology. It said, the common problem of blood thinning associated with streptokinase owing to general and widespread plasminogen lysis in the blood that can cause severe bleeding, and even death in some cases, will be avoided when CSSK is used. IMTECH has already obtained a European patent for this molecule, and the Indian and United States patents are pending.

Chemical Weekly 5 September 2006

GSK signs US$1.5 billion deal with ChemoCentryx

GlaxoSmithKline (GSK) and Chemocentryx, both based in the United States, have formed a partnership worth US$1.5 billion which will provide the company with access to selected targets from one of the broadest pipelines of chemokine-based therapeutics in the biotech industry. The deal reinforced an emerging trend of risk sharing and reward sharing alliances becoming popular with biotech and smaller pharma companies.

GSK had previously stated that that it wanted to make most of new approaches in targeting diseases by setting up long-term agreements with smaller pharma and biotech companies, which have proven very successful in developing innovative medicines using novel molecules in recent years.


Stem Cells inks license pact with Canadian biotech company

Stem Cells Inc., the United States, has entered into a licensing agreement with Stem Cell Therapeutics Corp. (SCT) a Canadian biotechnology firm engaged in treating certain central nervous system (CNS) disorders by stimulating endogenous neural stem cells. According to the agreement SCT will pay Stem Cells upfront and license maintenance fees, as well as milestone and royalty payments.

The agreement also provides Stem Cells with access to SCTs intellectual property portfolio for use in drug discovery, screening and testing, and therapeutic use of cellular compositions.

Mr. Martin McGlynn, President and CEO of Stem Cells said that they are delighted to have SCT as their newest licensee in the neural stem cell field. He mentioned that their own basic approach to treat stem cell disorders of the CNS was through the direct transplantation into the brain of natural human neural stem cells.

Chronicle Pharmabiz, 7 September 2006


Completed genome set to transform the cow

An international consortium of research organizations, including Australias CSIRO and New Zealands AgResearch, has assembled the most complete sequence of the cow genome. The new bovine sequence contains 2.9 billion DNA base pairs and incorporates one-third more data than earlier versions. Differences in just one of these base pairs, known as single nucleotide polymorphisms or SNPs, can affect the functioning of a gene and mean the difference between a highly productive and a poorly performing animal.

Over two million of these SNPs, which are genetic signposts or markers, were identified as part of the project. CSIROs Dr. Ross Tellam said that the new map marked the end of the sequencing phase of the project, with the focus now on analysing the available data. He added that the information is very valuable to achieve a great improvement in cattle breeding and production. Cattle geneticists will use the bovine genome as a template to highlight genetic variation within and between cattle breeds, and between cattle and other mammalian species.

The researchers believe that this data would be very useful to identify the genes involved in key functions like lactation, reproduction, muscling, growth rate and disease resistance. For instance, once the complete set of genes that influence flesh tenderness is known, the scientists would be able to predict the particular type of pasture or grain that would lead to consistent production of meat of a specific standard of tenderness and marbling.


Scientists crack the code for DNA organization in nucleus

Scientists at the Weizmann Institute of Science in Israel, have proved that DNA sequence also encodes zoning information on where to place nucleosomes. They characterized this code and then, using the DNA sequence alone, were able to accurately predict a large number of nucleosome positions in yeast. The researchers examined around 200 different nucleosome sites on the DNA, seeking commonalities in their sequences.

Mathematical analysis did reveal such similarities and eventually uncovered a specific code word. The researchers found that this code word consisted of a periodic signal that appeared every 10 bases on the sequence and the regular repetition of this signal helped the DNA segment to bend sharply into the spherical shape required to form a nucleosome. To identify this nucleosome positioning code, they used probabilistic models to characterize the nucleosome-bound sequences, and then developed a computer algorithm to predict the encoded organization of nucleosomes along an entire chromosome.

The analysis of the DNA sequence-dependent conformational energy gave hints for the design of DNA-binding drugs that modify the DNA conformational state. Dr. Eran Segal and research student Mr. Yair Field said that since the proteins that form the core of the nucleosome are among the most evolutionarily conserved in nature, they believe the genetic code they identified should also be conserved in many organisms, including humans. Mutational processes may be influenced by the relative accessibility of the DNA to various proteins and by the organization of the DNA in the cell nucleus. They believe that the nucleosome positioning code they discovered may help understand the mechanisms underlying many diseases.


Asthma susceptibility gene found

A study undertaken by Dr. Miriam Moffatt and Professor William Cookson from the Wellcome Trust Centre for Human Genetics, United Kingdom, has led to the discovery of a gene causing susceptibility to asthma and atopy (hypersensitivity that causes allergies). This discovery has the potential to lead to better classification of asthma and to new treatments.

The newly found asthma gene, called PHF11, was located on chromosome 13, which was known to contain an asthma gene. The genetic variants predisposing to disease were most common in adults with severe asthma, but the gene might also be involved in milder forms of asthma and allergic childhood eczema. The gene appeared to regulate the blood B cells that produce immunoglobulin E, the allergic antibody. Although new treatments take years to develop, the gene potentially provides a target for drugs that could turn off immunoglobulin E and prevent allergic disease.


Gene variants may increase susceptibility to type 2 diabetes

Dr. Francis Collins, Director of the National Human Genome Research Institute (NHGRI), the United States, led a study that has identified a likely location for a type 2 diabetes susceptibility gene on chromosome 20.The team identified four genetic variants, called single nucleotide polymorphisms (SNPs), which were strongly associated with type 2 diabetes in Finnish and Ashkenazi Jewish populations. All four SNPs clustered in the regulatory region of a single gene, hepatocyte nuclear factor 4 alpha (HNF4A), a transcription factor that turns genes on and off in many tissues, including the liver and pancreas. In the beta cells of the pancreas, it influences insulin secretion in response to glucose.

Dr. Collins and his team found a common variation in this gene that appeared to raise the risk of type 2 diabetes by about 30 per cent. This variation didnt cause diabetes unless it was in combination with other yet to be identified genetic susceptibility factors and certain environmental influences, such as obesity and lack of physical exercise. The Finnish study identified ten SNPs within and near the HNF4A gene that were associated with type 2 diabetes. The most significant results were found in a region of DNA called the promoter, which regulates the genes expression in the insulin-secreting cells of the pancreas.

The other international research team, led by Dr. M. Alan Permutt of the Washington University School of Medicine, studied Ashkenazi Jewish adults in Israel. It found diabetes-related SNP associations in the same region of HNF4A and believe that these four variants mark a regulatory region that determine the expression level of HNF4A. The team will now examine if this region affects gene expression in some way. A mutation in the coding region of HNF4A causes MODY type 1, a rare form of diabetes that begins before age 25 in people of normal weight.


Human parasites genes help evade host detection

A team of scientists headed by Dr. Sara Melville, University of Cambridge, the United Kingdom, has shown that the parasite known to cause African sleeping sickness has evolved an unusual chromosomal structure as a result of environmental adaptation. The chromosomal sequences in this parasite are highly enriched in subtelomeric sequences that, in some cases, comprise 75 per cent of the total chromosome length and contain a large repertoire of genes involved in circumventing the human immune response.

African sleeping sickness or trypanosomiasis is caused by the protozoan parasite Trypanosoma brucei, which is endemic to sub-Saharan Africa and is transmitted by tsetse flies. There are no vaccines against T. brucei, and most drugs to treat the disease have dangerous side effects or are scarce in the countries most heavily afflicted. T. brucei continually changes the expression of the proteins on its outer surface to avoid destruction by mammalian immune systems. These proteins are encoded by variant surface glycoprotein genes (VSGs). Some trypanosomes rapidly evolve and express new variants of VSG, thereby allowing the parasite to persist and spread through a population.

The current study demonstrated that T. brucei employed a strategy of chromosomal expansion to diversify its repertoire of VSG genes. Most of these VSG genes are concentrated in the subtelomeric regions, which in T. brucei are hemizygous. In contrast, the gene-rich cores of T. brucei chromosomes were diploid, meaning that the standard two copies were present. The study observed that the subtelomeres could dominate the chromosome to such an extent that a very small proportion of the chromosome was truly diploid. These huge subtelomeres were largely non-coding DNA, yet they contained contingency genes that the parasite multiplied and diversified for future use. The range of size variation observed in African trypanosomes far exceeded anything reported in any organisms till date and this, along with the potential size of the VSG repertoire in the huge subtelomeres suggested an unrivalled capacity of African trypanosomes for new immune-resistant strains.


Chemical signature of human embryonic stem cell DNA

Scientists from the Burnham Institute for Medical Research (BIMR) and Illumina Inc., the United States, in collaboration with stem cell researchers around the world, have found that the DNA of human embryonic stem cells is chemically modified in a characteristic, predictable pattern. This pattern distinguishes human embryonic stem cells from normal adult cells and cell lines, including cancer cells.

Embryonic stem cells are derived from embryos that are undergoing a period of intense cellular activity, including the chemical addition of methyl groups to specific DNA sequences in a process known as DNA methylation. The methylation and demethylation of particular DNA sequences in the genome are known to have profound effects on cellular behaviour and differentiation.

The researchers analysed 14 human embryonic stem cell lines from diverse ethnic origins, derived in several different labs and maintained for various times in culture.

They tested more than 1,500 potential methylation sites in the DNA of these cells and found that the embryonic stem cells shared essentially identical methylation patterns in a large number of gene regions. Furthermore, the methylation patterns were distinct from those in adult stem cells, differentiated cells and cancer cells. According to Dr. Jeanne Loring, co-director of the Stem Cell Centre at BIMR, these results suggest that therapeutic cloning of patient-specific human embryonic stem cells would be a huge challenge, because nuclei from adult cells would have to be epigenetically reprogrammed to reflect the specific DNA methylation signature of normal human embryonic stem cells. She said that this reinforced the need for basic research directed at understanding the fundamental biology of human embryonic stem cells before therapeutic uses could be considered.


Sequences reveal benign origin of deadly plant pathogens

An international team of researchers studied the genome sequences of two deadly plant pathogens Phytophthora ramorum and Phytophthora sojae. P. sojae causes severe damage in soybean crops, while P. ramorum causes the sudden death of oak trees. The sequences of both genomes, revealed a recent, large expansion and diversification of many deadly genes involved in infection of the plant hosts of Phytophthora.

The sequence information showed how the genus most likely evolved from a benign photosynthetic ancestor into a sophisticated, plant-killing machine. Phytophthora belongs to the kingdom Stramenopila, which also includes golden-brown algae, diatoms and kelp. Around 1,300 million years ago, some or perhaps all stramenopiles acquired the ability to harness light for their energy needs by assimilating photosynthetically competent organisms. Today, however, some of the stramenopiles, such as Phytophthora, are non-photosynthetic.

The genome sequences revealed that P. sojae and P. ramorum have a large number of genes compared with counterparts such as pathogenic fungi: 19,027 likely genes in P. sojae and 15,743 in P. ramorum. The sequences also clearly indicated a recently acquired, large armoury of proteins that enabled the pathogens to attack their plant hosts. This extraordinarily large and plastic array of pathogenicity genes provided a major insight into the basis for the success of their group of pathogens. A comparison of the genomes of the two Phytophthora species showed a rapid expansion and diversification of many protein families linked to plant infection, including toxins, protein inhibitors and enzymes that could break down cell walls. In particular, a group of genes encoding a large family of secreted proteins called the secretome evolved much faster than other protein-coding genes. Secreted proteins were intimately involved in the mechanism of pathogenesis.

The project to sequence the genomes of the two Phytophthora species started in 2002. The work has been funded by the the United States' National Science Foundation, Department of Agriculture's National Research Initiative and the Department of Energy, and has been carried out by an international team of scientists led by the Joint Genome Institute and the Virginia Bioinformatics Institute. Prof. Jeffrey Boore of the Joint Genome Institute remarked: This has been a ground-breaking, large-scale, collaborative project. As a resource for the entire scientific community, it is already having an immediate impact on plant pathogen research.



New gene therapy for melanoma

A team of researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, in the United States has demonstrated sustained regression of advanced melanoma in a study of 17 patients by genetically engineering patients own white blood cells to recognize and attack cancer cells. This is the first time gene therapy has been used successfully to treat cancer.

The researchers hope it will be applicable not only to melanoma, but also for a broad range of common cancers, such as breast and lung cancers. Autologous lymphocytes are a persons own white blood cells that have previously been used to treat metastatic melanoma. In a process called adoptive cell transfer, lymphocytes are first removed from patients with advanced melanoma. Next, the most aggressive tumour-killing cells are isolated, multiplied in the lab, and then reintroduced to patients who have been depleted of all remaining lymphocytes. While reasonably successful, this method can only be used for melanoma patients and only for those who already have a population of specialized lymphocytes that recognize tumours as abnormal cells.

NCI researchers, led by Dr. Steven A. Rosenberg, sought an effective way to convert normal lymphocytes in the lab into cancer fighting cells. To do this, they drew a small sample of blood that contained normal lymphocytes from individual patients and infected the cells with a retrovirus in the laboratory. The retrovirus acts like a carrier pigeon to deliver genes that encode specific proteins, called T cell receptors (TCRs), into cells. When the genes are turned on, the TCRs made lodge on the outer surface of the lymphocytes. These TCRs act as homing devices in that they recognize and bind to certain molecules found on the surface of tumour cells. They then activate the lymphocytes to destroy the cancer cells.

There were three groups of patients in the study. The first group consisted of three patients who showed no delay in the progression of their disease. As the study progressed, the researchers improved the treatment of lymphocytes in the lab so that the cells could be administered in their most active growth phase. In the remaining two groups, patients received the improved treatments. Two patients experienced cancer regression, had sustained high levels of genetically altered lymphocytes, and remained disease-free over one year. One month after receiving gene therapy, all patients in the last two groups still had 9 per cent to 56 per cent of their TCR-expressing lymphocytes. There were no toxic side effects attributed to the genetically modified cells in any patient.


Landmark success for transdermal insulin delivery

Phosphagenics Ltd., Australia, announced that it has successfully delivered insulin through the skin using transdermal carrier technology. From one topical application of TPM-02/Insulin as a gel, insulin was shown to safely penetrate the human skin and then be delivered into the blood stream over a sustained period of time. The main objective of the trial was to know the tolerability and safety of TPM-02/Insulin, and this was achieved with no adverse reactions. It also demonstrated the ability of TPM-02/Insulin to deliver insulin into the blood stream at levels high enough to produce significant results. The trials were conducted at the Centre for Clinical Studies in Melbourne, in accordance with ICH GCP standards and under the guidance and supervision of Professor Leon Bach. Blood glucose, insulin levels and the insulin biomarker C peptide were all measured as secondary endpoints.


New findings could lead to vaccine for severe malaria

A joint study in Karolinska Institute, Sweden, and Makerere University, Uganda, has produced key findings on how the malaria parasite conceals itself in the placenta, as the most severe form of malaria hits pregnant women and children the hardest. Plasmodium falciparum is the most virulent of the four malaria parasites that infect man. It is particularly dangerous in that it also infects the placenta of pregnant women, with fatal consequences for both her and the foetus. Ms. Niloofar Rasti, a graduate student from Karolinska Institute explained that for some reasons, women in their first pregnancy lose the semi-immunity that is normally found in adults, and the placenta seems to be an anatomically favourable environment for a sub-population of the parasites. During one particular phase of its lifecycle, the parasite enters the human red blood cells, where it produces proteins that attach themselves to receptor in the wall of the blood vessels.

This causes the red blood cells to accumulate in organ capillaries, and gives rise to life threatening symptoms. Adults who have been infected many times can become partly immune, as their defence system gradually starts to recognize the parasites proteins. When the placenta is formed, however, a new environment is introduced with a different set of receptors. This means that a new growth niche is made available to a sub-population of the parasites.

Earlier studies had suggested that each protein from the parasite attached to only one specific receptor in the placenta. But the natural mechanisms were different from the laboratory studies and therefore the research team collected and analysed placentas on site in Uganda. According to the study, most of the parasites could bind to three different receptors in the placenta and this meant that a future vaccine couldnt be based on the principle of one protein one receptor, as was previously believed.


Research scientists successfully test new anti-obesity vaccine

Scripps Research Institute (SRI) scientists have developed an anti-obesity vaccine that significantly slowed weight gain and reduced body fat in animal models. In the study, mature male rats immunized with specific types of the active vaccine ate normally yet gained less weight and had less body fat, indicating that the vaccine directly affected the bodys metabolism and energy use. This finding may be especially important to stop what is commonly known as yo-yo dieting, the cycle of repeated loss and regain of weight experienced by many dieters. The new vaccine, which is directed against the hormone ghrelin, a naturally occurring hormone that helps regulate energy balance in the body, may mark the effectiveness of immunopharmacotherapy to combat this serious and growing global problem.

According to Dr. Kim Janda, Jr., a Chemistry Professor of Chemistry at SRI and Director of the Worm Institute of Research and Medicine, the United States, preventing ghrelin from reaching the central nervous system can produce a desired reduction in weight gain. Ghrelin promotes weight gain and fat storage through its metabolic actions, decreasing the breakdown of stored fat for energy as well as curbing energy expenditure. During periods of weight loss, such as dieting, the body produces high levels of ghrelin to slow down fat metabolism, encourage eating, and promote fat retention, changes that normally make it difficult to lose weight and keep it off.

The researchers developed three active vaccines (Ghr1, 2 and 3) to immunize adult male rats. During the study, the rats immunized with Ghr1 and Ghr3 ate normally but, once antibody levels increased, accrued less body weight and fat, indicating an increase in the bodys energy use, a finding supported by studies of genetically altered mice. The study did note, however, that the immunized rats were fed low-energy, low-fat and relatively less palatable chow diets. The study cuationed that whether active immunization against ghrelin would help prevent the development of obesity caused by high-fat Western diets or would facilitate weight loss once obesity is established remains uncertain.


H5N1 and human flu hybrid does not spread

Researchers from the United States Centre for Disease Control and Prevention created various combinations of the H3N2 human flu virus and H5N1 viruses from Hong Kong, Indonesia and Viet Nam. They tested the ability of the virus to replicate and transmit in ferrets, whose respiratory tract cells interacted with flu viruses similarly to those in humans. Researchers had previously suggested that if these two viruses were able to combine, it could become capable of easily infecting and spreading between people.

One study suggested that two proteins on the surface of H5N1 allowed it to attach to and infect bird cells, but were ineffective at attaching to human cells. This led researchers to suggest that H5N1 might need surface proteins more like on those on human flu to trigger a pandemic. The study showed that one virus had human flu proteins on its outer surface, but bird flu genes inside. It was poor at spreading from ferret to ferret though it was good at replicating. A virus with H5N1 external proteins and internal human flu genes replicated as much as normal human flu virus but could not spread between ferrets at all. The researchers said that while the amount of virus that a ferret produced in its nasal cavities might affect the chance of the virus being spread to a nearby animal, other factors in addition to the ability to trigger sneezes could be more important. In the study, ferrets with human flu virus or viruses that had external proteins belonging to the human virus sneezed consistently. Ferrets with any virus with H5N1s external proteins, however, sneezed rarely or not at all.


Study finds potential ovarian cancer stem cells

Researchers from the Massachusetts General Hospital, the United States, have identified potential ovarian cancer stem cells, which might be behind the difficulty of treating these tumours with standard chemotherapy. According to Dr. Paul Szotek, MGH Pediatric Surgical Research Laboratories, these stem like cancer cells might be resistant to traditional chemotherapy and could be responsible for the ultimately fatal drug-resistant recurrence that is characteristic of ovarian cancer. Recent studies have identified tiny populations of tumor cells that appear to act as stem cells, driving the tumours ability to grow and spread. If some of these specialized cells escaped destruction by chemotherapy or radiation, the tumour would be able to recur quickly, often in a form resistant to chemotherapy. Similar cancer cells have been previously identified in leukemia and breast cancer and in cell lines of central nervous system and gastrointestinal tumours.

The MGH researchers first examined two mouse ovarian cancer cell lines and identified cells with characteristics of the cancer stem cells found with other tumours. They then observed a small percentage of stem-like cells in human ovarian cancer patients. When mouse ovarian tumour stem-like cells were injected under the skin of mice, they led to the formation of new tumours much faster than did injections of regular tumour cells. Although the potential ovarian cancer stem cells were less responsive than regular tumour cells to in vitro treatment with chemotherapy drug Doxorubicin, the stem-like cells remained sensitive to repeated treatment with Mullerian-inhibiting substance. This protein, important in the normal development of sexual organs, might play a key role in new therapeutic approaches owing to its ability to inhibit the proliferation of tumour cells.


Allergies linked to Parkinsons disease

Researchers from Mayo Clinic, the United States, have discovered that allergic rhinitis is associated with the development of Parkinsons disease later in life. Dr. James Bower, neurologist and lead investigator, said that the association with Parkinsons disease is increased to almost three times that of someone who does not have allergic rhinitis.

Previous studies had shown that regular takers of non-steroidal anti-inflammatory drugs, such as ibuprofen, were less likely to develop Parkinsons disease. This prompted Dr. Bowers team to look further into the links between diseases characterized by inflammation and Parkinsons. They studied 196 people who developed Parkinsons disease, matched with people of similar age and gender who did not develop Parkinsons. The researchers examined these groups to determine if those who developed Parkinsons disease had more inflammatory diseases. They found that those with allergic rhinitis were 2.9 times more likely to develop Parkinsons. They did not find the same association with Parkinsons disease in patients with asthma. The investigators theorized that a tendency towards inflammation was the key link between the diseases.

According to Dr. Bower, people with allergic rhinitis mounted an immune response with their allergies, so they might be more likely to mount an immune response in the brain as well, which would produce inflammation. The inflammation produced might release certain chemicals in the brain and inadvertently kill brain cells, as seen in Parkinsons. The study did not prove that allergies caused Parkinsons disease; instead, it pointed to a link between the two diseases. Thus, allergic rhinitis would now be considered one among many possible risk factors for development of Parkinsons disease.



Defects in crucial brain protein implicated in memory loss

A research team led by Duke University Medical Centre, Singapore, has discovered that the ability to recognize familiar objects and companions is lost when levels of a protein crucial for recycling a chemical messenger in the brain are reduced, mimicking some of the symptoms of Alzheimers disease. The protein recycled a chemical called acetylcholine that carried messages between nerve cells. Normally when the signal needs to travel through the brain neurons release acetylcholine to transport the signal across the gap, or synapse, between neurons.

Acetylcholine is stored in tiny hollow spheres, called vesicles that bud off the end of the neurons. A protein pump, called a transporter, located in each neuron controls the storage and release of acetylcholine from these vesicles, recycling the neurotransmitter back to the nerve cell vesicles in preparation for the next burst of signal. It is this acetylcholine transporter protein that the researchers targeted by disrupting the gene that controlled its production.

In the study, the researchers took advantage of a built-in trait of the animal models mice are innately curious and tend to explore new objects and companions extensively by sniffing and touching. The scientists ran mutant mice with defective acetylcholine transporter gene through a series of tests to evaluate their performance in behavioural tasks. They ran normal mice through the same tests to serve as a control group. The first test assessed the mices ability to discriminate unfamiliar objects and in the second test of memory a new mouse was introduced in the cage of the test subjects. In contrast to the mutant mice, the normal mice extensively explored the intruder mice but they showed less and less interest over time. To validate this theory, they treated the mice with drugs called cholinesterase inhibitors that increased the levels of acetylcholine in the brain. The mutant mice treated with drugs, when run through the same tests, recognized the intruder mice after several meetings, confirming that the defects stemmed from the reduced amounts of acetylcholine.


How cells decide whether to grow or die

Researchers at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, have discovered how a signalling pathway controlled the life and death of cells in the fruit fly (Drosophila). The breakthrough came as Dr. Barry Thompson from Dr. Stephen Cohens group at EMBL looked at a recently discovered signalling pathway called Hippo. According to him Hippo acted as a switch between cell division and death.

Using sophisticated genetic techniques, Thompson and Cohen established that a microRNA called bantam makes the link between the signals that led to cell growth or death. Without bantam, tissues grow too slowly and remain smaller than normal. Thompson says that bantam is an unusual type of RNA molecule: unlike other RNAs that went ahead to make proteins, bantams job was to regulate other RNAs by attaching itself to them and blocking their expression to proteins. Normally, those proteins would shut down cell division. With bantam around, the break was off, and they continued to divide. Dr. Cohens lab is studying microRNAs like bantam because of their pivotal role in many vital processes across species.


Researchers discover HIV dependence on a human protein

In the United States, Mayo Clinic virologists have discovered a specific human protein that is essential for HIV to integrate into the human genome. The researchers led by Dr. Eric Poeschla showed that when HIV inserts itself into a chromosome, a key step that helps it to establish a safe haven, it needs a specific protein called LEDGF/p75 (p75). This protein forms a molecular tether between chromosomes and HIVs integrating protein (integrase). The team also found that p75 protected HIV integrase from the cells protein-degrading machinery.

The Mayo team then developed a highly effective version of RNA interference (RNAi) technique to strip all detectable p75 from human chromosomes. Without its p75 partner, HIV was highly impaired. An intriguing irony was their use of a crippled version of HIV itself, a virus with proven skill in accessing the human genome, to deliver the RNAi. As a result, human T cells that HIV mainly targets became resistant to HIV. Adding back p75 made them vulnerable again and adding a dominant-negative piece of p75 to the mix further impaired the virus. The Mayo team showed that the virus needed surprisingly little p75 to integrate.

Each time HIV reproduced itself, it used its integrase protein to insert a copy of its genome into a chromosome. That copy became a permanent archive of the genetic programme of the virus, like a tiny file burned onto a computer hard drive. While patients kept healthy when those copies were suppressed with antiviral medicines, they were never cured. Stopping the medicines, even briefly, let HIV repopulate the body with many millions of copies, like a computer virus spreading around the world from a single infected computer.


Key fat and cholesterol cell regulator identified

Researchers at the Harvard Medical School and the Massachusetts General Hospital Cancer Centre, the United States, have identified a key protein that acts together with a family of molecular switches to turn on cholesterol and fat production. High levels of cholesterol and lipids are linked to many interrelated medical conditions and diseases, such as obesity, type 2 diabetes, fatty liver and high blood pressure. After a meal, a family of proteins called sterol regulatory element binding proteins (SREBPs) act as switches to turn on cholesterol and fat production. Between meals, the production of cholesterol and lipids is turned off. However, excess intake of food, coupled with lack of exercise, appear to disturb the normal checks and balances that control the SREBPs, resulting in overproduction of cholesterol and lipids.
The researchers, led by Dr. Anders Nr, showed that a protein called ARC105, which binds to the SREBPs, is essential to controlling the activity of the SREBP family of proteins. They found that after initially removing ARC105 from human cells by a process called RNAi, SREBPs were no longer able to activate cholesterol and lipid biosynthesis genes. To validate these findings in a physiological setting, they used the microscopic worm Candida elegans. The team showed that when the function of either SBP1 or MDT15, the homologues of SREBP and ARC105 in C. elegans, was knocked out, the worms lost their ability to properly store fat, lay eggs and move normally. The removal of ARC105 in human cells by RNAi also negatively affected the same key SREBP target gene as identified in C. elegans. The team found a flexible tail on the SREBP molecule that fits into a specific groove on a region of ARC105 called KIX. It believes that this specific interaction between the two proteins might be a target for small molecule drugs.


Evidence to show how proteins fold into their critical shapes

Researchers at the Scripps Research Institute, the United States, found evidence that supported a long-held theory of how proteins fold to create their characteristic shapes and biological functions. The theory is that proteins start to fold in specific places along an amino acid chain that contains non-polar groups, or groups of molecules without charge, and continue to fold by aggregation, when several individuals of these non-polar groupings combine. Using the same principle that separates oil and water, these hydrophobic molecules avoid water and associate with each other. The theory proposes that there are sites along the polypeptide chains where hydrophobic groups initially fold in on themselves, generating small hydrophobic pockets that are protected from water.

The theory was based on two methods to show that initial folding sites occur among non-polar groups in a polypeptide chain. Dr. Jane Dyson and Dr. Peter Wright at the Scripps Institute used an experimental nuclear magnetic resonance procedure to validate the predicted results of the two theoretical methods. The first method used supercomputers to calculate the energy required to convert a polypeptide chain into a collapsed hydrophobic pocket. The folds occur in places that need the least possible energy to maintain. By finding these places where the non-polar groups exist, the researchers better grasp where folding occurs along a linear polypeptide chain. The other method mapped a folded protein by tracing the three folding steps required to arrive at the proteins native structure. The two methods were used together in this study to pinpoint where the initial folding took place and then propagated to the final folded form.



Plant extracts better than synthetics as meat preservatives

Grape seed and pine bark extracts as additives in cooked meats perform better than synthetic preservatives in oxidation and microbial effects, say the results of a study that could be readily acceptable to consumers seeking ready-to-eat meat products with natural preservatives. The lead researcher Dr. Juhee Ahn from Ohio State University explained that in recent years, natural antimicrobial and antioxidant compounds are preferably used in meats because of their potential health benefits and safety compared with synthetic preservatives, such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).

The new study found that grape seed extract (ActiVin) and pine bark extract (Pycnogenol) performed better that BHA and BHT in retarding the microbial contamination of freshly ground beef by E. coli, Listeria and Salmonella. The same extracts also performed better than the synthetic alternatives after nine days at reducing oxidation of the beef. The antioxidant activity of grape seed extracts has been linked to boosting cardiovascular health by limiting oxidation of LDL (bad) cholesterol, while Pycnogenol has been claimed to have beneficial effects on a wide range of medical conditions from diabetes to asthma, from boosting male fertility to improving the memory (of mice). It was found that E. coli populations on the meat decreased by only five per cent for the BHA/BHT additive, but decreased by 33 and 35 per cent, respectively, for the meat with added ActiVin and Pycnogenol. No change in Salmonella populations were seen for the BHA/BHT meats, while ActiVin and Pycnogenol reduced the bacterial population by 19 and 23 per cent, respectively.

The study showed that Pycnogenol and ActiVin are promising additives for maintaining the quality and safety of cooked beef. The extracts also had a profound effect on the colour of the meats. However, the researchers noted that use of such extracts in high concentrations might impact detrimentally on the organoleptic properties of meat products and called for further research to find a balance.


New study may help reduce the global dependence on fertilizers

A team of researchers managed to trigger nodule formation in legumes without using Rhizobium bacteria. The discovery opened up the possibility of inducing nodule formation even in non-leguminous crops, which would revolutionize global farming and food production by dramatically reducing the dependence on nitrogen fertilizers.

Nodule formation in legumes is triggered by a molecule called the Nod factor, present in Rhizobium, which activates a gene called DMI3. The scientists from John Innes Centre, the United Kingdom, and the Washington State University, the United States, used the legume Medicago truncatula for their experiments. They found that when a similar gene called CCaMK, found in lily, was used to replace DMI3 in M. truncatula, the new plant was still able to develop nodules in the presence of nitrogen-fixing bacteria. The team then created a mutant version of CCaMK by knocking off a part of the gene and then introducing the remainder into M. truncatula. The plant produced nodules even in the absence of Rhizobium bacteria. This led the researchers to conclude that the part of CCaMK removed was inhibiting nodule formation.

Down To Earth, 15 August 2006

Bean gene works for CMV resistance in other plants

To protect themselves against pathogen invasion, plants make use of specific resistance (R) genes. Studies showed that the R proteins interact with pathogen elicitors, triggering a cascade of defence responses that eventually lead a pathogen to be confined within the initial zone of infection. This localization of infection protected a plant from further damage. Dr. Young-Su Seo and colleagues of University of California Davis, the United States, have reported that a viral resistance gene from common bean functioned across plant families and was up-regulated in a non-virus-specific manner.

Researchers identified viral response genes in common bean undergoing defence response to viral infection, and selected a gene designated as RT4-4 for further analysis. They introduced RT4-4 to Nicotiana benthamiana, and screened transgenic plants for resistance to bean dwarf mosaic virus (BDMV), cucumber mosaic virus (CMV), bean common mosaic virus (BCMV), bean yellow mosaic virus (BYMV) and tobacco mosaic virus (TMV). They found that most plants, whether transgenic or non-transgenic, developed disease symptoms typical to BDMV, BCMV, BYMV or TMV. However, transgenic plants developed systemic necrosis, a resistance response, when infected with seven strains of CMV from pepper or tomato, but not a CMV from bean. They traced the response to RT4-4 activity by detecting resistance responses in CMV-challenged leaves of transgenic tobacco plants. They also identified the CMV 2a gene product as the elicitor of the necrosis response. The researchers said that their approach would provide insights into the mechanisms by which plants activated pathogen-resistance responses.


Water-tolerant gene transferred to commercial rice varieties

Scientists have identified a gene present in hardy varieties of rice that enables the crop to tolerate flooded conditions. The researchers from International Rice Research Institute in Manila, the Philippines, and the University of California Davis, the United States, have successfully introduced the gene into commercial varieties like IR-64 and Swarna and are studying if the transgenic plants could survive submergence. Most rice varieties die if fully submerged for more than four days. Submergence cuts off oxygen supply and prevents photosynthesis. But the gene Sub1A-1, found in varieties grown in Sri Lanka and India enables these plants to withstand complete submergence for 10-14 days.

Rice varieties containing Sub1A-1 respond differently to stress like switching from aerobic to anaerobic respiration or growing above the water level but renew growth when the water level subsides. The gene controls hormonal changes related to cell elongation and carbohydrate consumption. The genes related to flood resistance or tolerance were found to be present on chromosome number 9 of the 12 rice chromosomes. The identification of Sub1A-1 is one of the significant achievements after the complete genome sequencing of rice was done almost a year ago.

Down To Earth, 15 September 2006

Flavanoid-rich GM tomatoes could boost heart health

Tomatoes genetically modified to have high flavonoid content reduced the levels of a protein in a mouse that is associated with inflammation, diabetes and heart disease in humans. Dr. Dietrich Rein from BASF Plant Science Holding, Germany, said that this is the first time a specific fruit has been shown to reduce human C-reactive protein (CRP) and that transgenic over-expression of specific flavonoids further reduced this important cardiovascular risk marker. The research team inserted Petunia chalcone isomerase (CHI) and Gerbera hybrida flavone synthase (FNS) genes into tomato plants to raise the flavonoid content in the tomato, and obtain the final transgenic plant, Lycopersicon esculentum cv.

Feeding the peel of transgenic tomatoes to mice genetically engineered to express human CRP enabled the researchers to study the potential human health effects of these flavonoid-enriched tomatoes (flTom). CRP, produced in the liver, is a known marker for inflammation. Increased levels of CRP are a good predictor for the onset of both type-2 diabetes and cardiovascular disease.

Dr. Rein and his team fed the CRP mice with a diet supplemented with 4 g/kg of flTom peel or wild tomato (wtTom). The amount of tomato fed to the mice was equivalent to a human daily intake of 2.3 g of peel or about 230 g of fresh tomato. After seven weeks of feeding, they measured levels of general health and cardiovascular risk, such as plasma CRP and cholesterol levels. It was found that consumption of either tomato peels resulted in a marked decrease in the levels of human CRP, with flToms effect being significantly higher. Levels of HDL-cholesterol were also up. The CRP levels in the flTom-fed mice went back to baseline levels after a two-week washout period.

According to the researchers results showed that genetically engineered fruit with enhanced flavonoids levels could have anti-inflammatory effects that exceeded the effects of its wild type counterpart. They propose that it was the effect of these flavonoids on the signalling of the nuclear factor-kappa B (NF-kB), a pro-inflammatory protein that is also said to activate a variety of human cancers, which could be behind the benefits.



Regulation of Gene Expression

The publication is appropriate both as a graduate textbook and a standard laboratory reference, and provides the essential groundwork for an advanced understanding of the various mechanisms that may result in altered activity of a specific cell protein. Part I focuses on approaches for studying control of mRNA expression and determining target genes for a given transcription copy. Part II outlines the methods for determining how proteins can regulate each other through synthesis, degradation, protein-protein interactions, and posttranslational modification. Part III explores how gene-targeting techniques in mice can provide insight into protein functions.

Contact: Humana Press, 999 Riverview Drive, Suite 208, Totowa, NJ 07512, United States of America. Tel: +1 (973) 256 1699; Fax: +1 (973) 256 8341


Biotechnology - Present Position and Future Developments

This book focuses on the applications of biotechnology, describes the technologies involved, explains the progress made to-date and outlines the future of the technology for each application. The main areas covered include crop production, animal biotechnology, the environment, industrial biotechnology, and animal and human health.

Extensive treatment is provided to developments in new platform technologies including genomics, proteomics and bioinformatics, besides the implications of high throughput analytical techniques. New developments in imaging and optical biology are dealt with in detail, and the impact of biosensors, bioelectronics and bionetworks are looked into. The questions of enormous public interest, such as the safety of genetically modified organisms (GMOs) in food, and the effects of GMOs on the environment, are also examined.

Contact: Teagasc, Oak Park, Carlow, Ireland. Tel: +353 (59) 917 0200; Fax: +353 (59) 918 2097


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