VATIS Update Biotechnology . Nov-Dec 2004

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Biotechnology Nov-Dec 2004

ISSN: 0971-5622

VATIS Update Biotechnology is published 4 times a year to keep the readers up to date of most of the relevant and latest technological developments and events in the field of Biotechnology. The Update is tailored to policy-makers, industries and technology transfer intermediaries.

Co-publisher: Biotech Consortium India Ltd
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Chicken genome sequenced

The International Chicken Sequencing Consortium has published an extensive analysis of the draft sequence of the chicken genome, the first bird genome to be sequenced. The consortium included 175 scientists from China, Denmark, France, Germany, Japan, Poland, Singapore, Sweden, Spain, Switzerland, the United Kingdom and the United States. According to Dr. Jerry Dodgson at Michigan State University, the United States, chickens and humans are, in some cases, infected by the same viruses, bacteria and parasites. Their research has shown that chickens and humans share more than half of their genes. The chicken genome sequence is expected to help uncover genes that enhance natural disease resistance in birds which can also be applied to humans.

Elucidating the genome sequence of chicken is expected to have implications for the commercial poultry industry also as it may allow high-laying animals or animals that have particular carcass characteristics to be identified. Researchers at the BBSRC-sponsored Institute for Animal Health (IAH), the United Kingdom, analysed the part of the chicken genome responsible for controlling tissue rejection, which influences the susceptibility of individuals to diseases. This line of work, led by Dr. Jim Kaufman, will aid breeding of healthier chickens and designing better veterinary vaccines.


Potential malaria vaccine in the offing

In Mozambique, trials conducted using Belgium-based GlaxoSmithKline Biologicals RTS,S/AS02A malaria vaccine have shown promising results. The vaccine protected a significant percentage of children from uncomplicated malaria, infection and even severe forms of the disease for at least six months. This largest malaria vaccine efficacy trial also reconfirmed the vaccines safety in 1-4 year old children. The vaccine is delivered in a three-dose regimen. A recombinant protein that fuses a part of the P. falciparum circumsporozoite protein with the hepatitis B surface antigen molecule, RTS,S, had been under development at GlaxoSmithKline for more than 15 years.

According to the study, which was approved by Mozambiques Ministry of Health and co-sponsored by PATHs Malaria Vaccine Initiative, the vaccines efficacy against clinical malaria attacks was 30 per cent. While efficacy against primary infection with Plasmodium falciparum was 45 per cent, efficacy against severe disease was 58 per cent. P. falciparum is the parasite that causes the greatest number of cases of malaria in Africa. Glaxo-SmithKlines vaccine is directed against the form of P. falciparum parasite that is injected by mosquitoes, which is known as the sporozoite. The antibodies and white blood cells produced after immunization prevent the sporozoite from surviving or developing further in the liver. Since further studies are essential, a licensed malaria vaccine is not expected to become available before 2010.


India-Denmark cooperation on biotech research

A Memorandum of Understanding (MoU) aimed to boost the development of long-term cooperation in the field of biotechnology has been signed by India and Denmark. The MoU envisages exchange of researchers, technicians, training of young scientists as well as joint execution of scientific R&D projects. Mr. Kapil Sibal, Indias Minister of State for Science and Technology, stated that India is poised to make a quantum jump in biotech business from the current level of US$500 million to US$9 billion over the next five years. Mr. Sibal called for greater partnerships between public and private institutions to take innovations from laboratories to the market place. According to the Danish representative Mr. Helge Sander, Denmark is about to set up a Hi-Tech Foundation for research and development in biotechnology, nanotechnology and information technology, for which about two billion Euros will be spent over seven years starting from 2005.

Chronicle Pharmabiz, 28 October 2004

Change in European outlook of GM crops

The regulatory quagmire in the European Union (EU) is slowly heading towards solid ground on the issue of genetically modified (GM) foods after years of being bogged down. Exporters of GM products are reaping the benefits of a more efficient approval process adopted by the EU in 2001. The European Commission, EUs executive arm, has already approved two GM corn applications under the new regime, one submitted by Monsanto and the other by Syngenta. Twenty-one other submissions are in the pipeline, including Monsantos GT73, a line of GM canola tolerant to Roundup herbicide.

According to the previous set of rules, a qualified majority of member states had to be in favour of an application. Under the new system, the European Commission is empowered to approve or reject applications when member states cannot reach an agreement on their own. According to the EUs ambassador to Canada, Mr. Eric Hayes, there is also an onus on biotech companies to revisit the priorities of their breeding programmes like taste, nutrition and cost since the present range of GM products do not offer tangible benefits to consumers.


National policies on biotech and bioinformatics

Indias first-ever National Biotechnology Policy will be announced in January 2005 by the central government, for which the Department of Biotechnology has already initiated the process. A joint team representing the ministries of Health, Science and Technology, and Environment are engaged in formulating the policy that addresses all issues of the biotechnology industry, including biotech parks, legal issues and monitoring procedures.

Also scheduled to be proclaimed in May 2005 is a Bioinformatics Policy, a first-of-its-kind initiative in the world. The first draft of the policy is ready. It was devised with inter-ministerial inputs from the Ministry of Communications Department of Information Technology and the Ministry of Science and Technology, and after close interactions with around 25 industry leaders. The Department of Biotechnology is coordinating with the Council of Scientific and Industrial Research, Department of Science and Technology and the Indian Council of Agricultural Research to speed up the task of framing guidelines for both the policies.

Chronicle Pharmabiz, 28 October 2004

New biopark in India

A world-class biotechnology R&D facility promoted by TIDCO at a cost of about US$14 million was inaugurated on 10 November 2004 at Chennai, India. The TIDCO Centre for Life Sciences (TICEL) Biopark, set up in technical collaboration with Cornell University of the United States, offers developed space for biotech companies to establish research facilities and a common Bio-Resources Centre (BRC) for testing and analysis.

Located on five acres of land, the biotech park can be expanded to two and half times the current size. Built to world-class design and standards conforming to cGLP, USFDA and Bio-Safety Level (BSL) 2/3 standards, the ground floor of the park hosts the BRC with wet lab for fermentation, microbiology, molecular biology, plant and animal tissue culture, downstream processing as well as analysis. The tenancy areas located from the first to fifth floors have a built-up area of 22,152 ft2 and lab area of 1,496 ft2, customized to satisfy tenants requirements. These labs are available in modules of 882 ft2, with BSL2/BSL3 standards. Common supplies of potable water, demineralized water, compressed air and vacuum, centralized AC, 100 per cent back-up power, treated waste collection and disposal, business centre, conference area, food court, parking area, etc. are available. In-house support services like IPR and technology transfer assistance will also be available at the site. About 28 per cent of the total lab space of 82,000 ft2 has already been allocated and it is expected that the park will reach 100 per cent occupancy within two years.

The TICEL Biopark has institutional partnerships with the Central Leather Research Institute (CLRI), Chennai, for animal tissue culture; Vimta Labs Ltd., Hyderabad, for molecular biology; and the Indian Institute of Science (IISc), Bangalore. A scientific advisory committee headed by a scientist from IISc will guide the park.

Chemical Weekly, 23 November 2004

California approves research involving stem cells

In the United States, 59 per cent of Californians voted for Proposition 71, the California Stem Cell Research and Cures Initiative, which will raise around US$300 million a year for a decade through bond sales. This corpus is intended to boost embryonic stem cell research that are not eligible for funding from the government since 9 August 2001. Conceived three years ago by a group of rich Californians whose families include diabetes sufferers, this initiative will create a new research entity the Institute for Regenerative Medicine to distribute funds and establish research guidelines. The state constitution would be amended to guarantee biologists right to conduct embryonic stem cell research and protect the institute from interference or supervision by the legislature.

By insulating the research funding against the vagaries of politics, crafters of Proposition 71 hope that researchers and companies will be drawn from around the country and the world to California. The resulting economic stimulus is expected to help pay off the bonds and could produce a significant return, depending on the success of the research.


Green tea stimulates nerve regeneration

Existing theories about green teas brain benefits have received strong support from scientists in Russia who say that an extract of the tea spurs nerve regeneration. Scientists from the Kuban State University, Kuban Research and Production Laboratory of Physiologically Active Substances and the Institute of Brain (Russian Academy of Medical Sciences) have been studying vegetarian concoctions as both preventative and treatment solutions for nervous system diseases. The team tested a dry, reduced-alcohol green tea extract on rat spinal ganglia, clusters of neurons, cultivated in a nutrient medium.

Experimenting with different concentrations of the extract, researchers judged the effectiveness of this approach by parameters like the neurons capacity for regeneration compared to controls and reported that the extract is highly stimulatory at a concentration of 0.004-0.006 per cent. On the second day of cultivation, the green tea extracts effects appeared to kick in, reached their peak by day four and by the fifth day, the effect disappeared. Lower concentrations had lesser effect while higher concentrations did not raise the benefits.



Life sciences incubator set up

ICICI Knowledge Park, India, has established a life sciences incubator to enable scientists to carry out research. The Department of Science and Technology funded about US$380,000 of the total investment of US$600,000. Of the eight labs, four are exclusively for biotech while the rest are for chemistry experiments. The incubator houses common facilities like wash autoclave and drying room. An instrumentation room is also included in the incubator. The biotech incubator will provide opportunities in the areas of enzymes, organic intermediates, antibiotics, recombinant proteins, biopharma products, primary and secondary metabolites, and biospecialities.

Chronicle Pharmabiz, 11 November 2004

SGS sets up pharma-biotech research unit in India

A US$5 million pharma-biotech preclinical and clinical research and testing facility is being set up in India at Tidel Park, Chennai, by Switzerland-based SGS, a global leader offering expertise, quality and integrity in inspection, verification, testing and certification services. The new facility is part of SGS expansion plans in India, which would largely depend on its main area of concern textile services apart from the new area of interest, preclinical pharma-biotech research.

The new entity, which will be equipped to undertake preclinical and clinical research as well as animal toxicity studies, would offer tough competition to domestic companies, who are into preclinical research, including Ranbaxy and Jubilant in North India, Quintiles and Acute test of Nicholas Piramal and Siro in western India. The company expects business worth US$2.5 million in the first year of its operation.

Express Pharma Pulse, 14 October 2004

Shreya launches recombinant vaccine

Shreya Life Sciences, India, has started marketing a recombinant human insulin under the brand name Recosulin. Manufactured using the technology licensed from Biotechnology General Corp. (BTGC) (now known as Savient Inc.) of the United States, Recosulin was developed using Advanced Technology in Second Generation rDNA Human Insulin. Previous technology for human insulin uses methionine as a linker molecule that requires 24 stage unit operations involving treatment with harsh chemicals like cynogen bromide. However, advanced technology from BTGC does not require methionine and uses lysine and arginine instead. With this technology, the manufacturer of Recosulin needs only 19 stage unit operations without any involvement of harsh chemicals. The technology is patented by Shreyas collaborator.

Shreya has introduced a complete range of insulin to suit individual patient requirements in both 40 IU/ml and 100 IU/ml, namely Recosulin M30 - Pre-mixed 30/70, Recosulin N - NPH and Recosulin R - Regular. The company plans to initially launch Recosulin by importing finished products from Bioton, Poland (manufactured employing BTGC technology). In the second phase, crystals will be imported and formulated at Shreyas manufacturing facility at Aurangabad.

Along with the launch of Recosulin, Shreya is also launching Recojet, which is considered to be the countrys first needle-free painless insulin delivery device. Shreya entered into an exclusive arrangement with Antares Pharma, the United States-based global leader in developing innovative technologies for delivering drugs across the skin, through its partner, Scigen of Singapore.

Chronicle Pharmabiz, 25 November 2004

Pact for manufacturing vaccine

Panacea Biotec, a pharma major based in India, has entered into a tie-up with the United Kingdom-based Cambridge Biostability Ltd. (CBL) to produce vaccines utilizing CBLs stable liquid technology. By making vaccines stable across a range of temperatures, the new technology allows vaccines to be used in extreme temperatures and remote areas, which means more children than ever before will have access to life-saving vaccination.

The need for a cold chain is eliminated, resulting in savings of US$200 million a year. Also, the new vaccines have a very long shelf-life, thus saving US$100 million in wasted vaccines each year. Funds were provided by the Department for International Development (DFID) to Panacea for producing a pentavalent childhood vaccine that can be stored without refrigeration.

Express Pharma Pulse, 28 October 2004

New generation recombinant human insulin launched

In India, Bangalore-based Biocon Ltd. has set up a new facility to manufacture insulin. The company launched a new generation recombinant human insulin (rDNA) formulation, branded as Insugen, in the domestic market in November. Produced from human genes by cloning it with an yeast, Pichia pastoris, Insugen is a major landmark in Biocons foray into protein therapeutics. The firms research facility spent about US$17 million over four years to develop the formulation.

Insugen will also be launched globally, beginning with the Middle East, Southeast Asia and South America next year. Biocon has submitted a drug master file (DMF) to the United States FDA and is preparing one for the European market. The company has also entered into a marketing tie-up with Bristol-Myers Squibb Co. of the United Kingdom for exporting insulin in bulk form.

Chemical Weekly, 23 November 2004

Biocon, Vaccinex team up on therapeutic antibodies

An agreement has been signed between Indias Biocon Ltd. and Vaccinex Inc. of the United States to discover and co-develop at least four therapeutic antibody products. This collaboration combines Vaccinexs unique abilities to discover fully human monoclonal antibodies using its proprietary antibody discovery technology and Biocons expertise in clinical research and biologics manufacturing.

Both parties have agreed to identify promising antibody candidates and move them rapidly into clinical development for cancer, inflammation and autoimmune disease. As part of the collaboration, Biocon will also make an equity investment in Vaccinex. According to the spokespersons of these companies, this collaboration will allow Biocon and Vaccinex to accelerate introduction of new, high-value therapeutic antibody products in both India and western markets.

Chronicle Pharmabiz, 25 November 2004


Completed human genome sequence described

The scientific description of the now complete human genome sequence has revealed that the number of protein-coding genes is less than the estimated 35,000. Only 20,000-25,000 protein-coding genes can be found in the human genome, a surprisingly low number. The International Human Genome Sequencing Consortium is headed in the United States by the National Human Genome Research Institute (NHGRI) and the Department of Energy (DOE). Over 2,800 researchers are part of the International Human Genome Sequencing Consortium. The assembled human genome still has 341 gaps, compared with the 150,000 in the working draft announced in June 2000.

One of the central goals of the effort to analyse the human genome is identification of all genes, which are generally defined as stretches of DNA that code for particular proteins. Researchers have confirmed the existence of 19,599 protein-coding genes and identified another 2,188 DNA segments that are predicted to be protein-coding genes. It has also been confirmed that the finished sequence now covers more than 99 per cent of the euchromatic (or gene-containing) portion of the human genome and was sequenced to an accuracy of 99.999 per cent, which translates to an error rate of only 1 base per 100,000 base pairs 10 times more accurate than the original goal.


Bovine genome assembled

The National Institutes of Health, the United States, has announced that the first draft of the bovine genome sequence has been deposited into free public databases for use by biomedical and agricultural researchers around the globe. Researchers can access the sequence data through the following public databases: GenBank  at NIHs National Centre for Biotechnology Information, EMBL Bank ( at the European Molecular Biology Laboratorys Nucleotide Sequence Database and the DNA Data Bank of Japan

Work on sequencing the bovine genome began in December 2003. The breed of cattle selected for the sequencing project was Hereford, which is used in beef production. The initial assembly is based on 3.3-fold coverage of the bovine genome, which is similar in size to the genomes of other mammals and humans, containing approximately three billion DNA base pairs. Researchers are continuing sequencing and plan to have a six-fold draft of the bovine genome completed during the first half of 2005.

The team is also comparing the bovine genome sequence with readily available genomes of other organisms. Results of these analyses would be published in public databases shortly. In addition to helping medical researchers learn more about the human genome and thereby develop better ways of treating and preventing disease, the bovine genome sequence will serve as a tool for agricultural researchers striving to improve health and disease management of cattle and enhance the nutritional value of beef and dairy products.

Contact: Mr. G. Spencer, National Human Genome Research Institute, United States of America. Tel: +1 (301) 4020 911; Or Ms. R. Tomlin, Baylor College of Medicine, United States of America. Tel: +1 (713) 7984 710.


Genome of Cryptosporidium decoded

In the United States, the genomic sequence of Cryptosporidium hominis has been decoded by a multi-institutional team of scientists led by Dr. Giovanni Widmer at Tufts University School of Veterinary Medicine. The highly contagious parasite lives in the intestines of infected humans and is classified by the Centres for Disease Control and Prevention as a potential bioterrorist agent. Tufts is the first research institution capable of isolating and propagating this pathogen.

In 2000, Tufts applied to the National Institutes of Health (NIH) for funding to enable a consortium of researchers at Tufts University, Virginia Commonwealth University and the University of Minnesota to simultaneously sequence the genomes of two Cryptosporidium pathogens infectious to humans C. hominis and C. parvum. Apart from producing DNA from the C. hominis isolate TU502, scientists constructed a bacterial artificial chromosome library for this research project, which is crucial for building a scaffold of the genome, on which smaller sequence assemblies are aligned. The genome of Cryptosporidium will help determine underlying mechanisms of the organisms unusual resistance to antimicrobial agents, and enable researchers to develop preventive vaccines and/or pharmaceutical treatments for the parasite.


Researchers sequence genome of Haloarcula marismotui

The genetic assembly of Haloarcula marismotui, an archaeon that thrives in the Dead Sea, has been fully sequenced by researchers from the Institute for Systems Biology (ISB), the United States, in collaboration with researchers from National Yan Ming University in Taiwan and the University of Texas, the United States. Fifteen scientists collaborated on sequencing the 4.3 million base-pair genome. According to ISB, this investigation suggests that evolution of the first eukaryotic organism might have resulted from the fusion of genomes from a bacterium and an archaeon. Scientists believe that understanding this and other archaeal organisms might lead to applications in energy, bioremediation and health.


Gene variants associated with late-onset Alzheimers identified

In the United States, genetic variants associated with late-onset Alzheimers disease have been identified by Celera Diagnostics, a joint venture between the Celera Genomics Group and Applied Biosystems Group of Applera Corp. These gene variants, also referred to as single nucleotide polymorphisms (SNPs), are present in the genes for an enzyme involved in glucose metabolism called glyceraldehyde-3-phosphate dehydrogenase (GAPD), which is also involved in neuronal apoptosis or programmed death of brain cells.

The initial association between these SNPs and Alzheimers disease was discovered in a genotyping study of 282 SNPs on chromosome 12 and the association with GAPD led scientists to analyse other genes in the GAPD family on four other chromosomes. They found a significant association between Alzheimers disease and another GAPD family member (GAPDS), and a compound genotype, or combined set of variants, from three genes on two different chromosomes. In order to minimize possible false associations, the candidate gene study employed three well-characterized sample sets collected independently in the United States and United Kingdom, which included genetic samples from a total of 1,089 participants with Alzheimers disease and 1,196 individuals without dementia. According to Dr. Thomas White, Chief Scientific Officer of Celera Diagnostics, The combination of their association of GAPD and Alzheimers disease together with recently published findings of GAPD and its role in neurotransmission may ultimately lead to better treatment methods and therapies for neurological disorders.


Research to map DNA topography gets NHGRI grant

Prof. Thomas Tullius, Chairman of the Department of Chemistry, Boston University, the United States, has received a three-year US$870,000 National Human Genome Research Initiative (NHGRI) grant to map the bumps, dips and turns characterizing the surface of naked DNA as part of the international research effort known as ENCODE (or Encyclopedia of DNA Elements). This research will give scientists a finely detailed picture of how the most fundamental aspects of naked DNA DNA without proteins bound to its surface influence its function. Prof. Tullius research has three goals build a database of patterns of the DNAs sequence and structure found using a special probe, develop computational methods that can predict these patterns in any sequence of DNA, and to employ these experimental and computational approaches to build structural maps of the genome.

A chemical probe called a hydroxyl radical will be used in Prof. Tullius study. The radicals can spot a particular hydrogen atom in deoxyribose, a part of DNA, and can cleave the DNA molecule at that point. The pattern of these cleavages provides a picture of the surface of DNA accessible to the probe. By applying this probe to the ENCODE-selected genome segment, experimental data will be recorded to help realize the second goal, development of a robust, computational model to predict cleavage patterns in any DNA sequence. The next step involves construction of maps of protein-binding sites and sequences critical to the folding of chromatin, the nuclear structure that condenses to form chromosomes during DNA replication. By applying both experimental and computational techniques chemical probes and pattern-discerning software Prof. Tullius will be able to build three-dimensional structural maps of naked DNA, thus providing researchers a detailed idea not only of where regulatory proteins bind to genomic DNA but also of how DNAs structure abets its function.


Platypus has five pairs of sex chromosomes

Dr. Willem Rens and his team from Cambridge University, the United Kingdom, and Dr. Frank Grtzner et. al. at the Australian National University in Australia have demonstrated that platypus has ten sex chromosomes, rather than the single pair usually found in mammals. The use of fluorescence in situ hybridization (FISH) has confirmed how the ten elements segregate. Five X chromosomes go into one cell and the five Y into another, resulting in two kinds of sperm half with XXXXX that determine female young and half with YYYYY that determine male young. According to Dr. Grtzner, the only way to ensure that five X chromosomes end up in one sperm and five Y chromosomes in another is for all of the sex chromosomes to assemble in a certain pattern X1Y1X2Y2X3Y3 X4Y4X5Y5 during meiosis. This was exactly what scientists found, a chain of alternating X and Y chromosomes. Dr. Rens team used FISH to visualize each chromosome and discover how sex is determined at the chromosomal level.

The most surprising finding was that the X at one end of the platypus sex chromosome chain had genes that were orthologous with those on the human X chromosome while genes on chromosomes at the other end are homologous with those on the bird Z chromosome. This suggests that sex determination systems in mammals and birds are not as different as thought previously. Prof. Marilyn Renfree, University of Melbourne, opines that mammalian sex chromosomes may have co-evolved with those of birds, and platypus may be the key to find out.



Vaccine against cervical cancer

Experts in the United Kingdom hope that a vaccine for preventing infections known to cause cervical cancer in women would be available in three years. Cervical cancer is the second most common cause of cancer deaths in women worldwide and guarding against the human papilloma virus (HPV) would save many lives. GlaxoSmithKline (GSK) and Merck Sharp and Dohme have developed vaccines against HPV and are in a race to get their products approved. The two vaccines are being tested on thousands of women around the world, in a bid to confirm the vaccines effectiveness and safety.

Dr. Anne Szarewski, who is trailing GSKs vaccine, reports that experts hope a three injections course given to girls before they are sexually active over six months would provide lifelong immunity. Trials have shown that the vaccine could offer 100 per cent protection against strains of HPV linked to about 70 per cent of cervical cancers. According to a spokesperson for GSK, an application would be submitted to the Medicines and Healthcare Products Regulatory Agency in 2006 and expects that its vaccine Cervarix would be available in 2007.


Dopamine neurons obtained from adult human stem cells

Dr. Lorraine Iacovitti and co-workers at Thomas Jefferson University, the United States, have found a way to transform bone marrow stem cells into becoming dopamine-producing neurons. Human adult bone marrow stem cells, also known as pluripotent stem cells, normally give rise to human bone, muscle, cartilage and fat cells. Researchers had previously demonstrated that by employing a potion of growth factors and other nutrients, it was possible to convert adult bone marrow stem cells into adult brain cells. In the new process, bone marrow cells are grown in suspension as neurospheres, groups of cells in the early stage of development, similar to the way neural stem cells are grown. The newly differentiated cells expressed traits of neurons and related cells called astrocytes and oligodendrocytes, cells derived from neural stem cells. The neurons produced tyrosine hydroxylase, an enzyme needed to make dopamine. The team also uncovered a second enzyme involved in dopamine production and an important molecule called the dopamine transporter. According to Dr. Iacovitti, if the differentiation of bone marrow stem cells can be appropriately directed, these cells could provide an abundant source of adult human neurons for use in the treatment of neurodegenerative diseases, e.g. Parkinsons disease, which is marked by a loss of dopamine-making cells in the brain.


Researchers identify how hormone regulates iron

In the United States, a team of researchers at the University of Californias David Geffen School of Medicine and University of Utah has discovered the functioning of a hormone called hepcidin, which regulates the uptake of iron from the diet and its distribution in the body. The hormone hepcidin controls ferroportin, an iron-transporting molecule on the surface of specific cells that contain iron. Hepcidin signals ferroportin not to release iron into the blood stream.

The team found that in case of insufficient hepcidin to regulate ferroportin, too much iron is taken up from the digestive system, which can lead to haemochromatosis, a major genetic disorder. If too much hepcidin is present in the body, which can occur in patients with infections or inflammatory diseases like rheumatoid arthritis or inflammatory bowel disease, inadequate amounts of iron is released into the blood stream, causing chronic anaemia. In a cell culture, researchers added hepcidin to cells and found that hepcidin attaches to ferroportin, thereby causing the latter to be swallowed and destroyed by the cells. Without ferroportin on the surface to release iron, the mineral remains trapped inside the cell.

According to researchers, a form of hepcidin could be developed that people with haemochromatosis could inject to help reduce the amount of iron taken up by the body. For patients with anaemia associated with too much hepcidin, development of drugs to block hepcidin from binding to ferroportin might help release more iron into the body. Thus, this discovery has helped better understand diseases caused by excess as well as insufficient iron content.


Immune protein linked to survival of melanoma patients

In the United States, Dr. David W. Mullins et. al. at the University of Virginia Health System have demonstrated that immune responses to prevent or delay the spread of melanoma, a deadly form of skin cancer, could prolong survival in patients if their immune cells carry a special kind of marker on the surface. The team correlated the presence or absence of the protein with the survival of 52 patients having advanced metastatic melanoma and found that survival increased by 50 per cent in patients whose T lymphocytes (immune cells that kill tumours) carried a particular protein, or chemokine receptor, called CXCR3. Increased survival was observed in patients with Stage III metastatic melanoma, but no increased survival was noticed in patients with Stage IV, stressing the importance of early detection and treatment. Researchers can now target vaccines to certain lymph nodes in the body that they know will generate T cells with the appropriate chemokine receptor like CXCR3, a homing feature that allows these killer cells to find and eradicate tumours.


Lag-3 gene dampens immune responses

In the United States, researchers from St. Jude Childrens Research Hospital and Johns Hopkins Kimmel Cancer Centre, have uncovered that Lag-3 gene acts as a brake to prevent immune system responses from running out of control. Regulatory T cells, which carry the Lag-3 protein on their surfaces, interfere with the action of effector T cells or warrior cells, which orchestrate attacks on specific targets in the body such as cancer cells and micro-organisms. Both the effector and regulatory cells arise from CD4+ T lymphocytes. Dr. Dario A.A. Vignali, the lead researcher, states that braking action of regulatory T cells prevents the destructive effects of autoimmune diseases, e.g. diabetes type 1, which occurs when effector T cells mount an attack on pancreatic cells that produce insulin.


New antibiotic target could mean the end of pneumonia

Scientists headed by Dr. Thomas Leyh at Albert Einstein College of Medicine, the United States, have stumbled on a molecular Achilles heel in the organism that causes pneumonia, thereby providing a target for developing new antibiotics that could eventually eradicate the disease. Streptococcus pneumoniae takes the lives of some 3,700 people daily, the majority being children below the age of five. Decades of antibiotic use have produced drug-resistant strains of S. pneumoniae that are capable of evading even the so-called last-line-of-defence antibiotics, e.g. vancomycin.

The virulence of S. pneumoniae requires a properly functioning channel called isoprenoid biosynthetic pathway. The team discovered an intermediate in the pathway diphosphomevalonate, or DPM which can inhibit the first enzyme, effectively shutting down the whole process. If this pathway is switched off, the normally pathogenic organism cannot survive in mouse lungs and its virulence is severely attenuated. However, the human enzyme is not influenced by the inhibitor which means that S. pneumoniae in human lungs or blood would be inhibited without any negative effect on human metabolism. DPM binds to its own pocket on the enzyme and therefore cannot be dislodged by the enzymes natural substrates. Researchers now plan to use DPM as a template for developing novel antibiotics to cure pneumonia and other streptococcal diseases, like meningitis.


Vitamin E fights cancer cells

Vitamin E has attracted interest for its beneficial effects, although researchers have recently linked high doses to an increased risk of death. Most research has focused on alpha-tocopherol, one of eight known forms of the vitamin. Dr. Qing Jiang and colleagues at Purdue University, the United States, report that gamma-tocopherol, which occurs naturally in such foods as walnuts and pecans, inhibits the proliferation of lab-cultured human prostate and lung cancer cells. Gamma-tocopherol was found to interrupt synthesis of fatty molecules called sphingolipids, which are important components of cell membranes, while leaving healthy human prostate cells unaffected.

The team states that this is the first time gamma-tocopherol has been shown to induce death in lab-grown human cancer cells while leaving healthy cells alone. This discovery could bring hope for cancer patients if the effect can be reproduced in animal models. Since most nutritional supplements contain only alpha-tocopherol, a different form of vitamin E that alone does not have these anti-cancer properties, it may be better to supplement the diet with mixed forms of vitamin E.


Stem cells repair heart

Researchers headed by Dr. Edward Yeh at Texas Universitys M. D. Anderson Cancer Centre, the United States, have found that regenerating damaged hearts with blood stem cells is clinically promising. The team reports to have gained new insights into the way stem cells become two kinds of cells required to restore heart function cardiac muscle cells, which contract, and endothelial cells, which line blood vessels throughout the organ.

The team induced heart attacks in immune-deficient mice and treated them with human CD34+ stem cells. Two months later, some of the mice were examined and heart cells sorted based on their expression of marker proteins. Among the markers sought for were markers of human cells, markers of cardiac muscle cells and markers of endothelial cells. It was found that 1 per cent of the cells had markers of both human and cardiac muscle cells, which according to Dr. Yeh is a high frequency of new cells after only two months. In total, 2 per cent of cells expressed human markers, meaning that 1 per cent were endothelial cells.

Further analysis confirmed findings about human markers. A majority of the cardiac muscle cells expressing human markers (73 per cent) contained both human and mouse DNA, which suggested that the CD34+ stem cells fused with existing mouse muscle cells while those without mouse DNA either differentiated or lost mouse DNA when dividing. For the endothelial cells expressing human markers, most (97 per cent) had no evidence of mouse DNA, meaning that they came directly from differentiated stem cells. The stem cells can persist for up to a year, which is a long time in the life of a mouse. The study also explains why stem cells can help a heart heal.



Mutation database aids study of inherited diseases

A team of researchers at Cardiff University, the United Kingdom, has built up a unique database comprising almost 50,000 human gene mutations associated with inherited diseases. The Human Gene Mutation Database (HGMD), maintained by the Institute of Medical Genetics, is freely offered together with the Frequency of Inherited Disorders Database (FIDD) as services to the scientific community. Expanding at over 5,000 new entries every year, HGMD provides a unique resource to those working in the field of medical genetics. The comprehensive database of inherited lesions in human genes lists information about the nature, location and context of the mutations as well as names and chromosomal locations of the related genes.

Advances Wales, Issue 45, Winter 2004

Algorithm helps detect changes in cancer genomes

At the Courant Institute of Mathematical Sciences, New York University, the United States, Prof. Bud Mishra and his team have developed an algorithm that can lead to more accurate detection of cancer genes than previous versions. The new algorithm can detect genetic differences between normal cells and cancer cells. It can reveal excess and missing copies of DNA segments associated with various forms of cancer, ultimately pointing to locations of both oncogenes and tumour suppressor genes. In addition, the algorithm can be used to account for varied genomes present across the human population.

An earlier version of the algorithm, including many other competing algorithms, were capable of dealing with only cancer data or only polymorphism data. They were not able to separate variations in cancerous and non-cancerous genes in a single framework. The algorithm runs through Valis, a software environment that would be made available on-line in mid-December. A part of the funds for this research was provided by the Armys Prostrate Cancer Research Programme.



Researchers isolate protein that could banish allergies

Allergies are essentially inappropriate responses by the immune system to allergens such as pollen, dust, insects and animals. These result in the activation of immune cells, known as mast cells, which release inflammatory agents. In the United Kingdom, Dr. Bart Vanhaesebroeck and his team at University College London branch of the Ludwig Institute for Cancer Research (LICR), together with collaborators from Novartis Respiratory Disease Centre headed by Dr. Peter Finan, found that inactivating p110delta in mast cells of mice substantially reduces the allergic response observed in mice. In mice lacking the gene for p110delta, the allergic response was reduced substantially whereas in normal mice that had been treated with an experimental drug inhibiting p110delta, the allergic response was stopped completely.

Mr. Khaled Ali, lead author of the study, opines that by targeting p110delta, the activation of mast cells can be stopped directly. This is in contrast to current therapies for treating allergies, which are mainly non-specific, targeting the symptoms rather than the mast cells. Efforts by the LICR group also focused on their findings that p110delta could play a role in certain tumours, like leukaemia, and that targeting the p110delta pathway may one day be useful in the treatment of cancer.


New protein suggests novel tumorigenic pathway

In Japan, Dr. Tomohiko Maehama et. al. at the Tokyo Metropolitan Institute of Medical Science and Tokyo Metropolitan University have discovered a new protein, named PICT-1 (protein interacting with the carboxyl terminus 1), which is involved in regulating PTEN, the second most commonly mutated tumour suppressor in human tumours. Mutations in the PTEN tumour suppressor are found in a variety of human cancers, including breast and prostate cancers. Approximately 20 per cent of the mutations are located in a segment of 70 amino acids at the C-terminus of PTEN and these mutations lead to rapid degradation of PTEN in cells, indicating that this region is critical for ensuring PTEN stability.

Studies have shown that cells add phosphate molecules to specific serine and threonine residues within the C-terminal segment to stabilize PTEN. In order to identify the proteins involved in this stabilization, Dr. Maehamas team screened a library of human brain cDNA to find proteins that interact with PTEN and identified a new protein that binds to the C-terminus of PTEN and named it PICT-1. They discovered that PTEN molecules with mutations in their C-terminus are unable to bind to PICT-1, and that PICT-1 stabilizes PTEN by regulating the phosphorylation of a serine in the C-terminal segment. They hypothesized that PICT-1 may affect phosphorylation by activating a kinase or inhibiting a phosphatase.

According to Dr. Maehama, this discovery indicates that cells with impaired PICT-1 function may become cancerous because of the resulting instability in PTEN. This would represent a new tumorigenic pathway that was not due to a defective PTEN gene but rather a loss of PTEN function caused by PICT-1. If this was the case, then this new type of tumour may be treated with rapamycin or related drugs that are often used in cancers resulting from PTEN loss of function.


Human protein chokes cancer

In the United Kingdom, Dr. Dave Bates and colleagues from Bristol University have established the function of the protein VEGF 165b (vascular endothelial growth factor), which works on blood vessels present in human body. Using VEGF 165b would be a more natural approach to fighting cancer, as the protein is produced by the body under normal circumstances. This protein, can stunt the growth of cancerous tumours by inhibiting the growth of new blood vessels that supply them with nutrients. Tumours need to maintain a blood supply so that they can continue to grow.

By better understanding how VEGF 165b works, researchers believe that it would be possible to prevent tumour growth using the protein. According to Dr. Bates, it is important to try this protein in models of other diseases where blood vessel growth is necessary, such as diabetes, age-related macular degeneration and arthritis. This cancer-fighting protein could be used as a non-invasive therapy to attack and destroy tumours.


Gene linked to greater risk of heart disease in type 2 diabetes

In the United States, Dr. Alessandro Doria and his team at Joslin Diabetes Centre, Harvard University, have found variations in a gene which help explain why people with type 2 diabetes are more prone to coronary artery disease, a leading cause of death for this group. People with diabetes are two to four times more likely to have cardiovascular disease, and are prone to stroke, blindness, kidney disease and nerve damage.

In the two-part study, researchers focused on a gene governing a protein called CD36, which is found in the membrane of several types of cells, including the walls of blood vessels. Previous studies had shown that, among other functions, CD36 is involved in transporting free fatty acids into cells and is also a scavenger of oxidized bad cholesterol LDL at the arterial wall. In the first part of the study, researchers mapped the structure of CD36 gene and looked for variants in this sequence that were associated with increased risk of heart disease. Investigations involving 585 people who did not have diabetes revealed five different CD36 variations that were associated with increased levels of free fatty acids and triglycerides. When all five variants were factored together, a strong link emerged, indicating that the highest levels of fatty acids and triglycerides occurred in people with a specific variant combination.

Using this new knowledge as the basis, the team studied 518 people, in both the United States and Italy, who all had type 2 diabetes. In addition, nearly half of these subjects also had heart disease, as indicated by heart catheterization indicating more than 50 per cent blockage of at least one coronary artery whereas others did not have any visible heart disease. Researchers mapped each persons CD36 gene variations, then compared those results with the presence of known heart disease and again found that there was a strong link. People with that specific variant combination in the CD36 gene were 60 per cent more likely to have heart disease.


Cell enzyme may help suppress cancer development

In the United States, a team of scientists led by Dr. Samson T. Jacob at Ohio State University Comprehensive Cancer Centre has shown that an enzyme known as PTPRO (protein tyrosine phosphatase receptor-type O) that normally alters the activity of other protein molecules in cells may also help prevent cancer. When the gene responsible for producing PTPRO is silenced, as can happen in lung cancer, for example, the amount of enzyme is lowered, allowing the cells to grow when they should not. PTPRO removes phosphate groups from the amino acid tyrosine present in specific proteins whereby some proteins become activated and some get inactivated. It is likely that the silencing of PTPRO alters the phosphate levels of some of these proteins and helps initiate processes that lead to cancer.

Researchers showed that the PTPRO gene is silenced gradually by a process called methylation and as methyl units accumulate on a gene, the gene becomes less active and fewer copies of its protein are made. In this case, silencing of the PTPRO gene causes a drop in the level of PTPRO enzyme. That, in turn, affects certain proteins that PTPRO acts on, furthering the cancer process thus indicating that PTPRO is a tumour-suppressor gene. By examining the PTPRO gene for methylation in 43 primary human lung tumours and their matching normal adjacent tissue, 51 per cent of the tumour samples were heavily methylated, while the gene in the adjacent normal tissue was essentially methylation-free. When researchers modified laboratory-grown human lung cancer cells to overproduce the PTPRO enzyme, the cells proliferated more slowly and more often died from apoptosis, or programmed cell death. In addition, when a chemical was used to remove the methylation in a cancer cell line, it slowed the growth of cells, again suggesting that the presence of PTPRO gene and its enzyme slowed the development of cancer. Taken together, these evidences strongly suggest that PTPRO gene is a tumour suppressor. Measuring the degree of methylation of this gene in a patients tumour would indicate the level of danger posed by that tumour or the treatments efficacy.


Gene linked to enlargement of proteins processing factory

Researchers from St. Jude Childrens Research Hospital, the United States, and Kyoto University, Japan, have discovered that the part of a cellular mechanism that regulates the folding of new proteins into their proper shapes also includes a genetic response that enlarges the factory where both protein folding and packaging of proteins occurs. Led by Dr. Joseph W. Brewer, the team found that the cell makes a molecule known as XBP1 in response to an increased demand on the protein-folding machinery. This rise in demand for folded proteins triggers the so-called unfolded protein response (UPR), as well as the expansion of the factory where proteins are folded and packaged so they can be secreted from the cell. The UPR also prompts the cell to make molecules called chaperones, which perform the actual task of protein folding. XBP1 triggers the cell to make phosphatidylcholine, the major building block of the rows of membranes that make up much of the factory, called the endoplasmic reticulum (ER). Membranes in the ER serve as envelopes to package the folded proteins. After leaving the ER, the envelope fuses with the inside face of the membrane cell and then the envelope pops open, ejecting the protein out of the cell. By linking the production of chaperone with the synthesis of phosphatidylcholine, XBP1 coordinates the processes of building and equipping new ER to raise the cells capacity for folding and shipping proteins.

Researchers made their findings in mouse cells called fibroblasts. They inserted the gene for XBP1 into a virus and used the genetically modified virus to transfer the gene into the fibroblasts. XBP1 gene triggered an increase in the activity of key enzymes involved in membrane production and because it is already known that UPR triggers activation of the XBP1 gene, findings of the current study suggest that XBP1 links the expansion of ER to the increased ability to fold and package newly made proteins for secretion. The need for close coordination of protein processing and packaging is especially critical in the case of antibody production. Cells that make and secrete antibodies, the B cells, have to synthesize, fold and release thousands of these proteins per minute in response to an infection.



Aflatoxin-resistant GM groundnut

Scientists at the International Crops Research Institute for the Semi-Arid Tropics (ICRISAT), India, have developed groundnut varieties incorporating chitinase genes from rice varieties resistant to Aspergillus flavus, the aflatoxin-producing fungal pathogen. The genes were introduced in popular local varieties like TMV-2 and JL-24. These transformed varieties have undergone the T-2 stage of glasshouse laboratory trials. Scientists are yet to seek approval from the Indian Department of Biotechnologys Review Committee on Genetic Manipulation (RCGM) for conducting contained greenhouse field trials from the next kharif season.

Aflatoxin contamination is perceived by exporters as a significant non-tariff barrier, especially in the European Union, which does not permit imports of groundnut with aflatoxin contamination above 6 g/kg. It is expected that the new aflatoxin-resistant GM groundnut will hit the market within the next five years.

Agriculture Today, November 2004

Plant enzyme protects against multiple infections

Dr. Natasha Raikhel and colleagues from the University of California, the United States, have identified one of the key enzymes, VPEg (vacuolar processing enzyme), that trigger programmed cell death, an important process plants undergo in fighting off bacterial, fungal or viral infections. This key plant protein contributes to the defence against bacterial, fungal and viral pathogens in plants by activating programmed cell death (PCD) pathways. Mutants not having this protein are susceptible to pathogens.

PCD is the regulated destruction of cells that takes place during the course of development, as well as in response to bacterial, fungal and viral infection. Caspases are a family of proteases, or enzymes that degrade proteins, which play an essential role in initiating and carrying out PCD in animals. In plants, the genes controlling VPEg activities have not been identified, yet. Dr. Raikhel opines that since PCD plays such a central role in a wide variety of physiological processes, the VPE pathway for controlling PCD likely has a huge impact on this process in plants. The new enzyme holds out hope for improving crop yields, which are dependent on plants being able to fend off multiple types of pathogens.


Clues to the puzzle of talking root cells

In the United States, scientists led by Mr. Philip Benfey at Duke University have attempted to uncover the mystery of how one root cell conveys its molecular instructions to another in the development process. The team have found hints that the channels by which such molecules move between plant cells may also be mirrored in animal cells.

In their studies, the researchers sought to understand details of how a protein made by a gene called Short-Root travels from one cell to another in the developing plant root. Short-Root is named so because genetic mutations that generate a non-functional protein produce plants with stunted roots. The Short-Root protein is a transcription factor, a protein that acts as a master controller of a multitude of genes. It has been previously established that the Short-Root protein is one means by which one root cell talks to another to instruct it to develop in a certain way. The team studied Arabidopsis plant, a widely used model in plant biology research.

Scientists theorize that the protein moves from cell to cell through channels called plasmodesmata that exist between plant cells. Once it reaches its target cell, the protein migrates to the cells nucleus and it exerts its effects. Similar channels, called nanotubes have only recently been discovered in animal cells. Researchers used a tracer molecule to pinpoint the Short-Root protein in living root cells. These studies indicated that in the cells from which the protein moves, it exists in the cytoplasm not associated with any molecular complex. However, the tracer did not reveal that the protein was moving from one cell to another. The team also found that they could disrupt normal movement of the protein by genetically mutating its gene at a single point. This discovery implies that the protein needs a transport machinery to move between cells and the mutation presumably disrupted its ability to dock with that machinery.

According to Mr. Benfey, they have shown that there is an active process that recognizes signals and while cytoplasmic localization is essential for movement, it is not sufficient. The latest finding represents only the earliest hints of a mechanism by which the protein moves from cell to cell. It offers a promising pathway for further exploring that machinery.


GM strains mitigate development of bugs

A team of scientists led by Dr. Barry Pittendrigh of Purdue University, the United States, has found that plants modified with protectant genes designed to eliminate resistant insects can delay the development of pesticide-resistant bugs. A specific problem that researchers attacked is that insects susceptible to the high-toxicity genetic protectant used in the main field crops can survive, breed and reproduce in the refuge, or buffer zone, outside the field. Using a computer model they found that within a refuge, one can add a moderate plant protectant, which kills 30-50 per cent of insects which carry a rare resistance gene that can delay development of new resistant insects that in turn could attack the main crop.

When susceptible insects from the refuge breed with each other or with resistant insects, the high-toxicity genetically protected plants in the main fields still eradicate most of the insects offspring. The moderately effective genetically engineered protectants used in plants in the refuge could play a major role in insect control. These specially designed refuge-area protectants give rise to a phenomenon called negative cross-resistance as the moderate-toxicity protectant kills insects that are resistant to the primary protectant. In case moderately effective negative cross-resistance compounds could be discovered in a refuge and used, it eliminates many of the genetically resistant insects that otherwise might invade the main crop.


Animal genes help tomatoes

In the United States, Dr. Marilyn Roossinck, Dr. Ping Xu and Dr. Stephanie Rogers report that two animal anti-apoptotic genes protect tomatoes from cold temperatures and infection. Tomatoes are very sensitive to cold and have no known natural resistance to the cucumber mosaic virus (CMV). The team discovered that D satRNA, a molecular parasite of CMV, is capable of inducing programmed cell death (PCD) in tomatoes. However, little is currently known about the proteins participating in plant PCD pathways. Researchers expressed the worm ced-9 and human bcl-xL gene in tomato plants. This slightly affects plant growth and seed development, but on infection with CMV/D satRNA, the plants exhibited few or no symptoms of infection.

In another set of experiments, the team found that ced-9 and bcl-xL expressing plants were more tolerant of chilling at 4C, with no necrotic lesions forming in these plants. At 7C, ced-9 and bcl-xL plants were still able to bear fruit, while non-transgenic plants could not. This research suggests that cell death regulators from animal systems can be exploited for improving tolerance of certain crop plants to viral diseases and low-temperature stress.


Drought-tolerant wheat

A new variety of wheat developed by a team of scientists led by Dr. Ahmed Bahieldin at the Agricultural Genetic Engineering Research Institute (AGERI), Egypt, can be irrigated by a substantially low quantity of water. The drought-tolerant wheat was produced by transferring a gene from barley into a local wheat variety. In fact, the wheat could be cultivated with rainfall alone in some desert areas. The HVA11 gene from barley enables plants to tolerate low water levels for longer periods.

Following laboratory tests, the GM wheat was tested in greenhouse and field trials conducted for three seasons starting 2001-02. It was found that the GM plants were taller and yields were higher when compared with non-modified plants. The AGERI team plans to develop their technique and address biosafety issues to commercialize the transgenic wheat seeds as the first genetically modified (GM) product on the Egyptian market. According to Dr. Bahieldin, the gap between supply and demand makes GM drought-tolerant wheat very important in areas with sub-optimal conditions like water deficit or salinity.



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