VATIS Update Biotechnology . Sep-Oct 2004

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Biotechnology Sep-Oct 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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Europe approves GMO seed for planting

The European Union (EU) on 8 September 2004 approved the first biotech seeds for planting and sale across EU territory. The European Commission authorized 17 different seed strains of maize engineered by Monsanto, the biotech giant from the United States, from a parent crop that won approval for growing just before the EU began its biotech ban in 1998 that lasted nearly six years. The Commission also dropped a proposal on how much GMO material may be tolerated without labelling in batches of conventional seed. Before this decision, the GMO seeds had only national authorizations issued by France and Spain and only farmers in these countries could buy and plant them. Under an established legal procedure, once an EU state allows a seed to be sold on its territory and assuming all EU legislations are complied with the Commission is obliged to extend that authorization to other EU states as well. The 17 seeds will now be entered into what is called the Common Catalogue, the EUs overall seed directory that includes all national seed catalogues. The parent maize seed, known as MON 810, has been engineered to resist certain insects.


Japanese panel permits human cloning for research

A new law, which prohibits reproductive cloning but allows cell nuclear transfer for the purposes of developing stem cells, has been passed by the Singapore parliament. Singapores Health Ministry introduced draft law in May this year, in a step-by-step approach to regulate biomedical research. The first step was the Human cloning and other prohibited practices bill, which imposes a fine of up to S$100,000 (US$58,700) or 10 years in prison, or both on violators.

The law prohibits the placing of any cloned human embryos in bodies of humans or animals. There are also prohibitions on the import or export of any cloned embryos and the commercial trading of human eggs, human sperm and human embryos. The law also forbids the developing of human embryos created by means other than fertilization for more than 14 days, and forbids researchers from developing human embryos outside the body of a woman for more than 14 days, which leaves plenty of time for the derivation of stem cells. According to stem cell researchers, 5-6 days after fertilization or nuclear transfer only is required for harvesting stem cells.


Mexico to open national genome institute

A 2.4-billion peso (US$196 million) National Institute of Genomic Medicine (INMEGEN) in Mexico City being set up by the Mexican Government is expected to open its first units by the end of 2004. The permanent 40,000-square meter building is scheduled to be fully ready by late 2006. Temporary 3,000-square meter facilities including six research labs, three high-technology units (genotyping, expression analysis and bioinformatics), and teaching facilities will open by the end of 2004. INMEGEN, which will be the 11th Mexican national health institute, will focus on research programmes devoted to the health problems of the Mexican population. Initial research will focus on metabolic diseases (diabetes and obesity), infectious and cardiovascular diseases, cancer, pharmacogenomics and population genomics.

According to Dr. Gerardo Jimenez-Sanchez, the INMEGEN Director, institute would focus on developing genomic medicine for the Mexican population so that it does not have to depend on importing technology and scientific knowledge.


Indias first ancient DNA laboratory opens shop

An Ancient DNA laboratory set up at the Centre for Cellular and Molecular Biology (CCMB), Hyderabad, India, was inaugurated by Dr. M.K. Bhan, Secretary of Department of Biotechnology, Government of India. It has been set up in a collaboration between the Department of Biotechnology and the Council of Scientific and Industrial Research. This laboratory is the first of its kind in India and projects have been started in collaboration with archaeologists and palaeontologists.

A recent study by CCMB had discovered skeletal remains of people belonging to 8th century AD in Roopkund Lake (also known as mystery lake), situated in the eastern part of Chamoli district in Uttaranchal. Researchers from Deccan College Post-graduate and Research Institute, Pune, India, collaborated with CCMB in this initiative, providing samples and theoretical support in the investigations. About 30 specimens are currently being analysed. Efforts to extract and amplify DNA from these remains have been successful and DNA sequencing and preliminary analysis have been performed.

Chronicle Pharmabiz, 8 July 2004

Germany pleased with results of stem cell law

A report on the first 18 months of regulations allowing the import and use of human embryonic stem cells for research purposes has been published by Germany. The report covers the period 1 July 2002 to 31 December 2003, during which seven applications for carrying out stem cell research were received by the Robert Koch Institute, which is responsible for reviewing applications. Five had been approved by the end of 2003. All approved applications involved the import of stem cell lines registered at the United States National Institute of Health. The research approved between 1 July 2002 and 31 December 2003 included a project that would procure neural and glial cells from human embryonic stem cell and investigating their development and regeneration potential in an animal model. A second project will involve differentiating between the human embryonic stem cells in heart muscle cells and characterizing these cells, while a third will develop an in vitro system for the analysis of neurotoxic effects on human embryonic stem cells.

According to Germanys health ministry sources, the new law has ensured high ethical standards and creation of safe conditions for research. The law permits Germanys scientists to conduct experiments using human embryonic stem cells for research considered to be important, to improve scientific knowledge in basic research, or to further medical knowledge of the development of diagnostic, preventive or therapeutic processes for the treatment of humans. Import and use must be approved by the Robert Koch Institute under the surveillance of an independent and central ethics commission on stem cell research.

The report states that the compulsory regulations on the conditions of allowing imports and the use of human embryonic stem cells for research purposes, the approval process and the setting up of an independent central ethics commission for stem cell research with the task of checking and assessing the approval conditions that are part of the authorization process have proved themselves valuable.

Chronicle Pharmabiz, 5 August 2004

Rapid way to make human SARS antibodies

A research team led by Dr. Elisabetta Traggiai and Dr. Antonio Lanzavecchia from the Institute for Research in Biomedicine, Bellinzona, Switzerland, have developed a new laboratory technique to mass-produce human antibodies that thwart the SARS virus in mice. The research was in collaboration with the National Institute of Allergy and Infectious Diseases (under the National Institute of Health), Bethesda, Maryland, the United States.

The new technique could become an important tool for developing a cocktail of SARS-specific antibodies that might help protect people recently exposed or at high risk of exposure to the SARS virus. The technique could also help develop similar approach to treat other illnesses, such as HIV/AIDS and hepatitis C, besides offering a potent frontline defence for health workers at high risk of exposure.

Express Pharma Pulse, 22 July 2004

Bioserve to set up zebrafish facility at Hyderabad

Indias first Zebrafish Facility at Hyderabad will be set up shortly by the Hyderabad-based Bioserve Biotechnologies India Private Limited. The facility will bring down time spent on clinical trials as zebrafish can be a better substitute to mice, since studying the life cycle stages of the fish is much easier due to its faster growth. It also aids studying the mutants and the breeding cycle more conveniently. Such facilities already exist in countries like the United States, Germany and Singapore.

The company will also offer a variety of services, including Plasmid DNA extraction/purification, DNA cloning, DNA extraction services, cDNA library and allied services, RNAi synthesis, siRNA designing and validation services, protein purification, gene expression, competent cells and plasmid transformation, oligonucleotide synthesis with different modifications DNA sequencing, sequences-based HLA typing, gene walking, fragment analysis, high throughput genotyping, SNP analysis and molecular diagnostic kits, and services for infectious diseases.

Chronicle Pharmabiz, 29 July 2004

IIL gets govt approval for hepatitis B vaccine trials

Indian Immunologicals Ltd. (IIL) based in Hyderabad, a wholly owned subsidiary of Indias National Dairy Development Board (NDDB), has received an approval from the Genetic Engineering Approval Committee (GEAC) of the Government of India for conducting phase III clinical trials for human recombinant hepatitis B vaccine. Following this, IIL is preparing to launch the recombinant human hepatitis vaccine during the first half of 2005.

The company has set up a human vaccines plant and an R&D centre costing Rs. 50 crore (US$10.5 million) in Hyderabad. The new plant, which can produce about 200 million doses per year of each vaccine, has been designed to manufacture vaccines such as recombinant hepatitis B, hepatitis A, measles, diphtheria, pertussis and tetanus. IIL in association with the Indian Institute of Science, Bangalore, and the Department of Biotechnology is also developing the first indigenous DNA-based rabies vaccines, and plans to launch these during 2005.

Express Pharma Pulse, 12 August 2004


Syngene in research pact with Novartis Institute

Syngene International of Bangalore, India, has entered into an agreement with Novartis Institute of Biomedical Research Inc., the United States, to carry out research projects on new drug discovery and development.

Novartis joins the ranks of leading multinational pharmaceutical companies that form part of Syngene Internationals objective to conduct research for large pharmaceutical companies. According to Dr. Jeremy Levin, head of Novartis Institutes global strategic alliances, the institute intends to develop strong alliances with world-class scientific programmes in India, and the relationship with Syngene, and its parent Biocon, offers such an opportunity.

Express Pharma Pulse, 9 September 2004

FIZ finalizing collaboration with three Indian biotech companies

As a follow-up to its signing of a memorandum of understanding with the Karnataka Biotechnology Development Council (KBDC) of the Government of Karnataka State, India, and the International Technology Cooperation Network in July 2004, the Frankfurt Innovation Centre for Biotechnology (FIZ), Germany, has initiated a dialogue with two biotechnology companies in Karnataka and another in Pune for R&D collaboration.

The tie-ups will provide Indian companies the opportunity to expand their market horizon and will act as a catalyst to generate FIZs US$5 billion revenue target by 2010. The Indo-German MoU would serve as a gateway to Asia where FIZ is in the process of tapping business, such as in China, Singapore and Japan where it will attract talent, capital and technology to help the FIZ firms create new products and services. Funding to a tune of 40 per cent of the total project cost is available for Indian research firms keen to enter Germany and operate out of FIZ.
The two year-old FIZ, set up at an investment cost of 25 million Euros, is the first publicly funded research centre that has the advantage of combining biotech and pharma project platforms on a global level. At present, there are around 15 companies from the United States and the United Kingdom operating out of FIZ. The focus areas for research at FIZ are inflammatory drugs, central nervous system drugs, proteomics and bioinformatics. (Chronicle Pharmabiz, 2 September 2004)
As a follow-up to its signing of a memorandum of understanding with the Karnataka Biotechnology Development Council (KBDC) of the Government of Karnataka State, India, and the International Technology Cooperation Network in July 2004, the Frankfurt Innovation Centre for Biotechnology (FIZ), Germany, has initiated a dialogue with two biotechnology companies in Karnataka and another in Pune for R&D collaboration.

The tie-ups will provide Indian companies the opportunity to expand their market horizon and will act as a catalyst to generate FIZs US$5 billion revenue target by 2010. The Indo-German MoU would serve as a gateway to Asia where FIZ is in the process of tapping business, such as in China, Singapore and Japan where it will attract talent, capital and technology to help the FIZ firms create new products and services. Funding to a tune of 40 per cent of the total project cost is available for Indian research firms keen to enter Germany and operate out of FIZ.

The two year-old FIZ, set up at an investment cost of 25 million Euros, is the first publicly funded research centre that has the advantage of combining biotech and pharma project platforms on a global level. At present, there are around 15 companies from the United States and the United Kingdom operating out of FIZ. The focus areas for research at FIZ are inflammatory drugs, central nervous system drugs, proteomics and bioinformatics.

Chronicle Pharmabiz, 2 September 2004

Dragons erythropoietin gets market approval in Ecuador

Ecuadors Ministry of Public Health has approved for sales the recombinant erythropoietin (EPO) product manufactured by Dragon Pharmaceutical Inc., Vancouver, Canada. EPO is used for treating anaemia caused by renal failure and surgery.

In addition to China, India, Egypt, Brazil and Peru, Dragons EPO is now approved and marketed in six countries in Asia, South America and the Middle East. Additional regulatory submissions are in progress throughout world, and the company is preparing to enter the European Union market. Dragon has a cGMP facility in Nanjing, China, where EPO is produced.

Chronicle Pharmabiz, 29 July 2004

Strand-MediBIC venture to provide data mining solutions

Strand Genomics, Bangalore, India, and MediBIC, a Japanese pharmacogenomics and pharmaceuticals consulting firm, have formed a business collaboration to provide bioinformatics and data mining solution in Japan. Under the agreement, MediBIC and Strand will jointly develop products, technologies and customization services for their drug discovery and development customers, and provide consulting in the areas of genomics, proteomics, predictive ADME & toxicology, clinical studies and other pharmaceutical R&D areas. The combined effort of both companies would help in developing a truly in silico platform for the entire drug development pipeline.

Chronicle Pharmabiz, 12 August 2004


Genetic map of main tree genes outlined

Researchers in Sweden and in Oregon State University (OSU), Oregon, the United States, have publicly released a new database of many of the most important genes in a tree genome. This genes collection, which includes a large proportion of those expressed during tree growth, is among the best for any plant species. The database describes approximately 102,000 sequences of the most commonly expressed genes in the genus Populus, which includes cottonwoods and aspens. According to Prof. Steven Strauss from OSU, this is an important fundamental step towards doing the type of genetic and biotechnology research with trees which had been possible with only the most scientifically well-known plants.

The study also compared many of these gene sequences to those found in Arabidopsis, and found that nearly all the genes were functionally common between the two, even though they have been separated by about 100 million years of evolution and now look completely different. It also indicated that the large majority of transfers of genes between widely separated plant species via genetic engineering would not produce novel characteristics, but simply modify existing genetic characteristics. It is hoped that the new study will help scientists find specific genes in a matter of minutes using computational approaches.


New gene identified in breast cancer growth

In Canada, researchers at the Research Institute of the McGill University Health Centre at Montreal and McMaster University at Hamilton have identified a new gene, beta1-integrin, shown to be critical in the initiation of tumour growth and development in a mouse model of cancer.

The study by Dr. William Muller and his colleagues used breast-cancer-prone mice to demonstrate the role of beta1-integrin. They initially showed that removing this gene did not affect the normal mammary development of the mice. However, if this gene were to be removed from already growing tumours, the tumours would cease to grow. These findings show that blocking the function of this gene halts tumour proliferation and breast cancer, since tumour cells do not grow without beta1-intergrin. The next step is to look for therapeutics that block this gene in humans.


Data on Chromosome 5 final sequence made public

In California, the United States, the Department of Energy Joint Genome Institute (JGI) and the Stanford Human Genome Centre (SHGC) have finalized the sequence of Chromosome 5. As the new sequence reveals, this chromosome is a genetic behemoth containing key disease genes and a wealth of information about how humans evolved.

Chromosome 5 is made up of 180.9 million genetic letters the As, Ts, Gs and Cs that spell out the chromosomes 923 genes, including 66 genes that are known to be involved in human disease. Another 14 diseases seem to be caused by Chro-mosome 5 genes, but they have not yet been linked to specific genes. Other Chromosome 5 genes include a cluster that codes for interleukins, molecules that are involved in immune signalling and maturation and are also implicated in asthma.

According to Dr. Eddy Rubin, Director of JGI, besides the disease genes, other important genetic motifs scanned from vast stretches of non-coding sequence have been found on Chromosome 5. Comparative studies of these vast gene stretches have shown that these regions, conserved across many mammals, have powerful regulatory influence. Hidden in the Chromosome 5 sequence are clues to how humans evolved after branching away from chimpanzees. On average, the chromosome is more than 99 per cent similar in humans and chimpanzees, with the greatest similarity found in genes that cause diseases when mutated. Despite similarities in the overall sequence, the human and chimpanzee chromosomes compared have some structural differences, including one large section that is flipped backwards in humans. Such an inversion makes it impossible for the two chromosomes to pair up when the cell divides to create sperm and eggs. Over time, that incompatibility could have driven a reproductive wedge between the evolving populations. Further, about one-third of Chromosome 5 is similar to a chicken chromosome that determines the chickens sex, much like the X and Y chromosomes in humans. This finding backs up previous research suggesting that before mammals and birds split 300 million years ago, the sex chromosomes had not yet evolved. After the split, mammals and birds developed their own methods of creating males and females.

One duplicated region on Chromosome 5 could help explain how spinal muscular dystrophy is inherited. Researchers had known that the disease is caused by deletions in the gene for survival of motor neurons, but people with the same deletion can have more or less severe forms of the disease. The region contains many duplication and other rearrangements and varies considerably between people. With the sequence for this region in hand, the researchers can now study how variations in the number of deletions or repetitions influence the disease severity.


New mammalian clock gene discovered

A team of scientists led by Dr. Steve Kay and Dr. John Hogenesch from The Scripps Research Institute in La Jolla and the Genomics Institute of the Novartis Research Foundation (GNF) at San Diego, both in California, the United States, has discovered a new genetic component of the mammalian clock a protein known as Rora.

It has been known for years that many plants and animals, including humans, possess internal clocks that keep track of time and coordinate physiological, behavioural and biochemical processes in a rhythmic 24-hour cycle of day and night. The mammalian clock is composed of many separate clocks that maintain different circadian rhythms adapted to the various body tissues. Coordinating the activities of these different clocks is the master circadian oscillator, which is the suprachiasmatic nucleus. This small centre in the brains hypothalamus with about 10,000 neurons sits above the optic chasm. This master clock synchronizes different clocks that reside in peripheral tissues, and cycles every 24 hours.

This cycling involves the coordinated expression of many genes involved in feedback loops, in which the expression of one gene turns on the expression of a second gene, which turns off the first gene, which turns off the second gene, which turns the first gene back on, etc. Different tissues respond to the clock in their own ways, and reset their own clocks independently of one another. Understanding the intricacies of the mammalian clock required discovering the different genes that communicate the timing of the master clock with the circadian rhythms of the various tissues.

The scientists performed gene array experiments on different samples of mammalian tissue to determine which genes were cycling and which could be components of the clock. They looked at the expression of 10,000 different genes in various murine tissues in the liver, kidney, aorta, skeletal muscle and the suprachiasmatic nucleus of the hypothalamus every three hours over the course of two days and also looked for cyclic expression.

The results showed that about 10 percent of the genes cycled, but most showed little overlap from tissue to tissue. However, the overlapping cyclers those genes that cycled in all tissue types could be the ones that formed part of the master clock. The team found 50 genes that cycled at the same time throughout the day across all the various tissues. These included both known and unknown circadian rhythm genes. Some of these other genes could be part of the mammalian circadian clock, and they could interact with some of the known clock genes by controlling transcription.

An experiment found that a family of genes called the retinoic acid receptor-related orphan receptor-a (Rora) cycled and could control transcription. Rora was a gene that produced a transcription factor and it activated the transcription of a gene that encodes another transcription activator known as Bmal-1, which is one of the known circadian genes. Bmal-1 drives the transcription of a protein called cryptochrome, which subsequently inhibits the ability of Bmal-1 to activate cryptochromes own transcription. This feedback loop is what keeps the body entrained to a 24-hour day. Since Bmal-1 is so crucial to keeping the bodys clock entrained, finding something like Rora, which alters Bmal-1s expression, is significant and suggests that Rora is also part of the mammalian clock. The scientists observed a mutant murine model called staggerer that has a defective Rora gene, which causes a characteristic loss of coordination, and also had a defect in its ability to regulate its circadian clock. It was seen that staggerers have aberrant circadian rhythms and a shortened clock that is only 23.2 hours long.

According to Dr. Kay, the overlapping made the clock more robust and resilient to change which meant that there was more than one cycle in which changes to clock genes could affect changes to other genes, and therefore the clock could be reset more easily. Further, knowing that Rora was a component of the mammalian clock it may be a valuable target for the development of compounds to correct sleep disorders, many of which are related to circadian rhythms, and for countering the most common circadian problems the jet-lag one feels after overseas flights or fatigue when working night shifts.


Gene plays role in formation of cancer cells from stem cells

Scientists from the Netherlands Cancer Institute in Amsterdam and University of Zurich, in Switzerland have identified, by investigating the common link between the cancer cells and stem cells, a gene that plays a crucial role in the formation of cancerous cells from stem cell in childrens brain.

They found that the gene, BM11, was needed for multiplication of stem cells in brain and the genes overexpression results in enormous growth of stem cells leading to formation of medulloblastomas, the most common form of brain cancer in children. Overexpression of BM11 was found in 8 of the 12 such cancers studied. The gene determined the stem cells identification, as it ensured whether a stem cell remained a stem cell or not and did not differentiate.

Chemical Weekly, 13 July 2004

Database of genes linked with cancer drug resistance

Scientists at the National Cancer Institute (a part of the National Institutes of Health), Bethesda, Maryland, the United States, have created a database of information about a group of genes linked with multi-drug resistance in cancerous tumours. The research details the gene expression of a 48-member family of proteins called ABC transporters, wherein the associations between expression of individual ABC transporters in cancer cells and resistance to specific drugs have been identified. ABC transport proteins are embedded in the cell membrane and regulate traffic of many molecules including hormones, lipids and drugs in and out of the cell. Since they transport toxic materials out of cells, many of these 48 proteins confer resistance to cancer drugs in humans.

The researchers led by Dr. Jean-Philippe Annereau and Dr. Gergely Szakacs studied the ABC transporters in a group of cancer cell lines called the NCI-60 cells which includes leukaemias, melanomas, and ovarian, breast, prostate, lung, renal and colon cancers using real-time polymerase chain reaction to detect and quantify the expression of ABC transporter genes as messenger RNA in these cells. They found statistical correlations between tests of the cell lines sensitivity to cancer drugs and these cells expression of ABC transporters. Further tests, such as measuring changes in cell growth to evaluate the cells response to the drugs, supported the statistical correlations. The analysis of 68,592 ABC gene and drug relationships yielded 131 strongly inverse-correlated pairs; that is, in these 131 cases, the ABC gene expression of the cells was strongly correlated with decreased sensitivity to the drug. According to the scientists, these results indicate that some of the ABC transporters whose function remains unknown can influence the response of cells to cancer treatment.

The data generated could be used to find commonalities in compounds transported by MDR1, one of the ABC proteins most strongly associated with multi-drug resistance. With this information, a drug could be developed to reduce MDR1s ability to transport drugs out of the cell, as part of the effort to develop novel therapies designed to evade or exploit the action of ABC transporters.



Probable link between hypertension and diabetes

A team of researchers at Mount Sinai School of Medicine, New York, the United States, has identified the molecule that binds to a receptor in the brain and is known to regulate blood pressure and release of insulin. The researchers also discovered that this molecule acts as a neurotransmitter and excessive accumulation of this molecule in the pancreas will impair insulin release. Thus, it is possible that this molecule is the long searched for link between these two disorders. It was known that when a particular receptor in the brain is over-stimulated, blood vessels constrict and pressure rises. According to Dr. George Prell, Associate Professor of Pharmacology and Biological Chemistry at Mount Sinai School of Medicine, the identity of the molecule that binds to this receptor to trigger the reaction was not known. With the identification of this substance, scientists can begin to look at ways of blocking its action.

It was found that imidazole-4-acetic acid-ribotide binds to imidazol(in)e receptors, which are widespread throughout the brain and are abundant in the brainstem in areas critical to blood pressure regulation. When this molecule binds to the receptor, it leads to elevated blood pressure and when an antagonist is given, imidazole-4-acetic acid-ribotides hypertensive effect is inhibited. Further, it stimulates another group of imidazol(in)e receptors that regulates insulin release. However, while low concentrations of the ribotide stimulate insulin release, much larger concentrations block release, a condition that produces diabetes.

According to Dr. Prell, many drugs used to treat hypertension act by displacing imidazole-4-acetic acid-ribotide from these imidazol(in)e receptors, thus blocking the ribotides hypertensive effect. However, these drugs act at multiple receptors and thus have many side effects. With the identification of the endogenous molecule that binds to imidazol(in)e receptors, it may be possible to custom-design drugs that can specifically target the ribotide-receptor interactions to reduce blood pressure and diminish the onset of diabetes while avoiding other side effects.


Diarrhoea rotavirus entry into cells imaged

A team of scientists in the United States has used crystallography and electron microscopy to construct high-resolution images, which reveal the molecular rearrangements that rotavirus the most common cause of severe, dehydrating diarrhoea and vomiting in children use to break into cells. The team led by Dr. Philip Dormitzer at the Laboratory of Molecular Medicine, Childrens Hospital Boston, Massachusetts, determined the geometric structure and working parts of one of the virus surface proteins, called VP4.

Rotavirus itself is a large, soccer ball-shaped, 20-sided particle with three layers. From the outer layer project 60 spikes, each consisting of a cluster of VP4 molecules. Dr. Dormitzers team trimmed the VP4 protein down to two sub-components that make up the spikes head and body. They crystallized these pieces and used X-ray diffraction to determine their three-dimensional structures down to the atom. Comparison of the crystal structures to electron microscopy images suggests that VP4 undergoes two consecutive shape changes that allow it to breach the membrane of the cell it is trying to infect. First, digestive enzymes in the intestine cause two of the three VP4 molecules in each cluster to form a rigid spike, priming the virus to attack the cell and positioning the spike head to bind to the surface of the target cell. Then, in a second rearrangement, the spikes fold back, and VP4 takes on a folded-umbrella structure with three panels. It could be this folding motion that causes the spikes body to break a hole in the cell membrane for the virus to enter.

The key finding for vaccine development is that the head and body portions of the VP4 protein contain many of the targets that the immune system recognizes when it attacks the virus and protects against infection. According to Dr. Dormitzer, vaccines made from live viruses or killed viruses can present safety concerns and be unstable without refrigeration. In contrast, the head of the VP4 protein is very stable at room temperature and easy and relatively cheap to produce. He believes the same is true of the body. A vaccine based on these proteins could be very practical, especially for developing countries where rotavirus causes the most serious illness.

This research is a major advance in the understanding of how viruses cause infection, and shows how vaccine development can be made smarter by probing the physical architecture of viruses and finding the minimum parts needed to prime the immune system, without having to use a whole virus to make a vaccine. Component vaccines are generally considered safer than whole virus vaccines.

Contact: Mr. John Lacey, Office of Public Affairs, Harvard Medical School, 22 Shattuck Street, Boston, Massachusetts, MA02115, United States of America. Tel: +1 (617) 432 0442


Harvard Medical School News Release

Secret weapon of flesh-eating bugs revealed

Researchers led by Dr. David Ginsburg at the University of Michigan, Michigan, the United States, have found that bacteria can use our own clot-busting system to spread around the body. It is known that infections like sore throat caused by group A Streptococcus (GAS) are common, but occasionally these bacteria manage to spread rapidly, and when they do, it can lead to death in more than a quarter of cases. The body responds to GAS by building up blood clots around the infected area, corralling the bacteria. But the bacteria retaliate with an enzyme, called streptokinase, which causes the body to break down the clots, allowing the bacteria to escape resulting in possibility of patients developing necrotizing fasciitis, also called the flesh-eating disease.

The University of Michigan researchers have now worked out exactly how streptokinase does this. The bacterial streptokinase triggers the release of a protein called plasminogen, which is normally stored by the body until it is needed, starting a chain reaction that makes blood clots more soluble.

This discovery also explains why laboratory mouse is normally so resistant to GAS. Mouse plasminogen is different from the human form, and is not targeted by the streptokinase. GAS causes only localized infections when injected under the skin of a mouse, because its enzyme cannot make blood clots break down. In order to test this, the researchers took genetically engineered mice that relied on human plasminogen for clot control and injected them with GAS. The bacteria soon spread through the mice, killing most of them. The experiment was then repeated in which scientists used GAS with streptokinase removed. This time, the mice suffered only localized infections and none died. This showed the interaction between streptokinase and human plasminogen as the root of the bacterias spread. This could lead to a vaccine that blocks streptokinase and stops the bacteria spreading, and thereby prevents certain types of infections becoming fatal.


Chemical in betel leaf may cure leukaemia

A potential cure for a form of leukaemia has been discovered in the common betel leaf by scientists at the Indian Institute of Chemical Biology (IICB) in Kolkata, India. Locally known as paan, the leaf is widely chewed as an aid to digestion. The compound, known as chlorogenic acid, discovered in the leaves of the betel plant (Piper betel), kills cancerous cells in chronic myeloid leukaemia (CML) but leaves non-cancerous cells unharmed. CML attacks white blood cells.

Following the discovery, experiments were conducted using the compound on cancer cells obtained from Europe, Japan and the United States. Later, blood cells from patients with chronic leukaemia were treated with chlorogenic acid. In all these studies, the cancerous cells were totally destroyed. Studies using live mice with CML also showed the same results all cancerous cells were killed. IICB is in talks with the Indian Council for Medical Research about clinical trials on humans. If proven effective, this discovery could lead to an affordable treatment for leukaemia patients, especially in poorer countries, as betel plants grow abundantly in South Asia.


Stem cells stop mice going blind

Dr. Martin Friedlander at The Scripps Research Institute in California, the United States, and his colleagues used an injection of stem cells that saved the sight of mice, which would otherwise have gone blind. The research team focused on a group of eye diseases called retinitis pigmentosa, in which cells in the retina break down over time, causing gradual loss of vision and sometimes blindness.

Retinitis pigmentosa has many different underlying causes, so it is difficult to find a drug that works for all cases. There is currently no good treatment for the condition, which affects around one in 3,500 people. The scientists extracted a pool of stem cells from the bone marrow of adult mice and injected them into the eyes of newborn mice with a version of retinitis pigmentosa, before their retinas had begun to break down. The treatment appeared to halt some of the deterioration, particularly that of the cones, which are responsible for colour and fine vision. The team had earlier shown that stem cells could help stop blood vessels in the retina breaking down, probably by integrating into them. But some stem cells could lodge in the eye and manufacture some type of molecule that helps both blood vessels and cones survive. The treated mice were also able to detect light shone into their eyes, whereas a group that did not receive treatment went totally blind. The study raises the prospect that some forms of human blindness might be treated with cells from a patients own bone marrow.


Pioneering the basics for new kind of cancer vaccine

A new approach to cancer vaccines that purposely kills healthy skin cells to target the immune system against tumours has been successfully tested by scientists at Mayo Clinic in the United States. The approach and results were promising because multiple rounds of treatment eradicated skin cancer in all the mice studied.

In conventional chemotherapies for cancer, the destruction of healthy cells is undesirable. To test the idea that killing normal cells might target a specific immune system response, the team chose normal skin cells called melanocytes that are involved in the highly lethal cancer malignant melanoma.

This new approach is significant for two reasons. First, it turns the death of healthy cells into a therapeutic advantage by inflicting a stress known as inflammatory cell death on skin cells to which the researchers attached a protein involved in heat shock. Researchers were able to trigger a healing immune response aimed at the skin cancer tumours. The response was strong enough to eradicate the tumours. Second, the researchers avoided triggering autoimmune attacks, which are a common disabling side effect of most cancer vaccine attempts. In autoimmune attacks the body attacks and injures itself, instead of cancer. The new approach appears to breach a major obstacle to advancing cancer vaccine research from the laboratory into human trials.

Express Pharma Pulse, 12 August 2004

Vanilla may have a future in sickle cell treatment

In addition to its popular role in flavouring ice cream, fudge and cake frosting, vanilla may have a future use as a medicine. The results of a study, led by research haematologist Dr. Toshio Asakura of The Childrens Hospital of Philadelphia, the United States, have indicated the strong possibility that a form of vanilla may become a drug to treat sickle cell disease.

Specially bred mice were subjected to low oxygen pressure, a condition that causes their red blood cells to form the hazardous sickle shape. The mice that had received a compound, which turns into vanilla in the body, survived five times longer than mice that did not receive the chemical.

That vanillin protects red blood cells with sickle cell disease from assuming the sickle shape, which obstructs blood vessels, had been known for 30 years. However, this effect occurred only in test tubes because vanillin breaks down in the digestive tract before reaching the bloodstream. Scientists at Medinox, a biotechnology company based in San Diego, California, the United States, developed a variant of vanillin called MX-1520, chemically modifying it to resist degradation by the digestive system. MX-1520 is a prodrug a compound that becomes an active drug (in this case, vanillin) in the body. Dr. Asakura and his team tested MX-1520 using transgenic sickle mice animals with red blood cells containing human sickle haemoglobin, similar to the defective blood cells in people with sickle cell disease. The researchers found that most of the MX-1520 turned into vanillin in the mice, where it interacted with sickle haemoglobin and inhibited the formation of rigid sickle cells. The results of Dr. Asakuras research indicate that further study of the vanillin prodrug MX-1520 is warranted.



Computer program builds novel drugs

The Austrian company Inte:Ligand has developed a new software package for modern drug design, providing pharmaceutical companies with a tool to speed up the entire drug development process. The software, known as iLib Diverse, is a flexible tool for creating libraries of drug-like organic molecules suitable for rational lead structure discovery in a fast and efficient way. Apart from creating molecules, which exhibit the required features for the target medicine, the technology allows the user to check the computer-generated molecule for its ability to cross the blood-brain barrier and its oral administration.

iLib Diverse uses algorithms to extend known chemical building blocks, and subsequently combine them to develop new drugs with improved properties. This enables researchers to enhance the effects of drug candidates by using the software platform to develop new medicines for specific application areas. Depending on filter settings, up to 15,000 compounds can be generated per minute on a standard PC. Besides the option to fully customize fragment and filter settings, exporting libraries in SMILES or SDF file format, the generated molecules can be used in most existing drug discovery software packages. iLib Diverse is suitable for pharmaceutical companies of all sizes, biotech start-ups and research institutions.

Contact: Inte:Ligand, Software-Entwicklungs und Consulting, Clemens Maria Hofbauer-G. 6, A-2344 Maria Enzersdorf, Austria.



Tool developed for toxicological studies

Ocimum Biosolutions Ltd. of Hyderabad, India, has developed software for toxicological studies. Toxchek is a multi-platform and multi-user integrated module following Good Laboratory Practices (GLP) stipulated by the United States Food and Drug Administration. It has an in-built reporting engine that allows researchers to generate comprehensive study reports having all the information recorded during the study execution, along with statistical analysis. It manages, compares and tracks data from general toxicology studies like chronic, sub-chronic, acute and long-term teratology studies. The database is secure, password-protected procedures ensuring privileged entry and maintenance of long-term integrity. An administration module enables security and access control to the system, besides mapping the organizational structure and workflow in the laboratory.

The study design and scheduling module helps in designing in vivo and in vitro studies with the user specifying the animals and group information, test compounds and dosage information using built-in randomization algorithms. Furthermore, the user can specify investigations and schedule data collections for different timelines as required.

Toxcheks study library module records information containing toxicology investigations, standard operating procedures and clinical symptoms. The reference data library defines accepted standards of values for parameters specific to various species and strains. The inventory management and tracking system tracks parameters such as location, price and shelf-life of specimens, while the animal inventory maintains a list of animals sorted and grouped by species and strains along with their age groups. Auto-identification of inventories, staff, consumables, animals, samples, etc. enables the system to easily keep a tab on expired containers and reorder levels.

Contact: Ocimum Biosolutions, 404 Reliance Classic, Road No. 1, Banjara Hills, Hyderabad 500034, India. Tel: +91(40) 55627200


The Financial Express, 12 August 2004


Newly discovered protein plays key role in cancer progression

Researchers led by Prof. Pier Paolo Pandolfi Head of the Molecular and Developmental Biology Laboratory at Memorial Sloan-Kettering, New York, the United States have discovered the biological function of the cytoplasmic form of the promyelocytic leukaemia protein (PML), and identified it as an essential factor in maintaining TGF-b signalling. Many cancers including leukaemia and that of colon and prostate continue to grow unchecked because they do not respond to a signal from transforming growth factor-beta (TGF-b) to die and stop proliferating. The cause of this signalling disruption of the normal cell cycle has not been fully understood.

TGF-b is a protein that can suppress tumour development by signalling a cell to stop growing and the unresponsiveness to TGF-b signalling has been associated with a variety of human cancers. The researchers found that cytoplasmic PML (cPML) also has a key role in cancer development, besides affecting the nucleolar network for tumour suppression, and in regulating the function of a gene crucial to the suppression of the genesis of cancer. It is needed for the formation of a signalling complex that is an essential factor in activating TGF-b signalling.

Primary cells from PML-null mice were resistant to TGF-b-dependent growth arrest, induction of aging and cell death. When PML function was added back to these cells, this defect was corrected and TGF-induced activity restored normal cell functions. These findings explain the link between these two proteins in the development of cancer and suggest that restoring their activity may provide a possible treatment for human cancers.


First glimpse of DNA binding to viral enzyme

The first molecular-scale images of DNA binding to an adenovirus enzyme a step believed essential for the virus to cause infection has been produced by scientists at the United States Department of Energys Brookhaven National Laboratory, New York, and Albert Einstein College of Medicine, New York, the United States. The team was led by Dr. Walter Mangel at the National Laboratory and Dr. Mark Chance from the Albert Einstein College of Medicine.

Adenoviruses cause respiratory and other infections, and in patients with compromised immune systems such as those infected with human immunodeficiency virus (HIV) an adenovirus infection can be deadly. During infection, adenovirus makes an enzyme called a protease, which cleaves or degrades viral scaffolding proteins to complete the maturation of newly synthesized virus particles.

The scientists used a technique called synchrotron footprinting, which provides structural information on the contact points regions providing critical communication in the cell of biological molecules. The footprinting approach provided data on the DNA binding region of the adenovirus protease that was not available by other techniques. The scientists bombarded different solutions of the adenovirus protease and DNA with X-rays and characterized the changes occurred on the surface of the protein. Based on the changes in accessible surface area, the team was able to deduce the location of the DNA binding site.

The discovery that the viral DNA interacts with the protease was unprecedented and led them to characterize the interaction in detail. The scientists now believe that inside the virus particle the protease uses the DNA as a guide-wire, sliding along the genetic material to remove the internal scaffolding proteins, all located near the DNA. Extensive contact was found happening between the enzyme and the DNA, which wraps around more than half the enzyme molecule, like a strap, holding two parts of the protease together. The long DNA binding site offers numerous locations along it that could be used as targets for drugs to block the interaction and act as antiviral agents.


Largest virus proteome unveiled

A record number of proteins for one of the largest and most complex viruses, the highly infectious and stealthy human cytomegalovirus (HCMV), has been reported by a team of scientists from the Pacific Northwest National Laboratory (PNNL), Washington, and the Oregon Health & Science University, Oregon, both in the United States. The identified proteins include the viral and host proteins that compose the HCMV virion. HCMV, a member of the herpes virus family, is the leading viral cause of birth defects and poses a serious threat to patients with a compromised immune system.

The scientists used proteomics instruments and approaches unavailable elsewhere that combined the high-resolution separations of proteins with their identification at the same time, using a powerful mass spectrometer developed at PNNL. The team discovered 71 proteins in mature HCMV, double the number previously known. It is believed that HCMV may express as many as 200 proteins at various points in its life cycle.

It was found that when a cell is infected, the HCMV incorporates into itself a huge number of the host cells proteins, some of which are as abundant as viral proteins, demonstrating the complexity of this common virus. According to the scientists, the prevalence of host proteins in the virus may also suggest how the virus avoids detection by the immune system by using the bodys own cellular proteins as camouflage.

Contact: Mr. Bill Cannon, DOE Pacific Northwest National Laboratory, Washington, United States of America. Tel: +1 (509) 375 3732



Protein is key for digestive function of the pancreas

Dr. Wanjin Hong and colleagues from the Institute of Molecular and Cell Biology in Singapore have identified a protein that is necessary for secretion of digestive enzymes by the pancreas. The digestive enzymes secreted by pancreatic acinar cells are packaged into units called zymogen granules, which upon stimulation with hormones like cholecystokinin (CCK), are emptied through a process called exocytosis into ducts leading to the small intestine.

In some pathological conditions, the digestive enzymes are abnormally secreted backwards into the blood, damaging the pancreas and leading to a condition called pancreatitis.
The scientists examined a protein called VAMP8 that has been implicated in the process of exocytosis and is present on zymogen granules. They genetically engineered mice that were missing VAMP8 and found that the mice had pronounced pancreatic defects. Pancreatic acinar cells lacking VAMP8 had many more zymogen granules than control acinar cells, and CCK did not stimulate exocytosis in VAMP8-deficient acinar cells. This suggests that VAMP8 could play a role in regulated enzyme secretion in pancreatic acinar cells.

The researchers then administered stimuli known to induce pancreatitis and measured levels of digestive enzymes in the blood in the pancreases of normal and VAMP8-deficient mice. Compared with normal mice, mice lacking VAMP8 had substantially reduced blood levels of digestive enzymes and demonstrated partial resistance to pancreatitis. This suggests that VAMP8 may be involved in the abnormal secretion of digestive enzymes associated with pancreatitis. A direct link between VAMP8 and pancreatitis still needs to be established.


Scientists disrupt key HIV proteins interactions

A team of scientists led by Dr. Gregory Weiss at the University of California, Irvine, the United States, has successfully targeted an HIV protein called Nef, which is responsible for accelerating the development of acquired immunodeficiency syndrome (AIDS). Certain small molecules synthesized by them disrupted Nefs interaction with other proteins.

Using phage display technique, Dr. Weiss and team attached the Nef protein to the surface of a harmless virus, and created synthetic molecules that could target and dislodge the protein. The scientists invented a system for identifying guanidine alkaloids, which are small molecule inhibitors of protein-protein interactions. The Nef protein was attached to the surface of a bacteriophage, which provided a handle that could be tracked by the researchers to determine whether Nef was binding to three cellular proteins, as is Nefs function. They then searched for a mechanism that would disrupt binding by Nef and found that their synthesized molecules and Nef both competed to bind with the cellular proteins. Each time the molecules succeeded, Nef was dislodged from binding to the three proteins and thus inhibited. Dr. Weiss is now seeking to dislodge Nef without causing collateral damage.



Mystery of sterility of garlic plant solved

A team of scientists from Hebrew University of Jerusalem, Israel, has been able to restore fertility to a sterile garlic plant, thus opening the way to wide-ranging scientific research that could lead to improved yields and quality. Garlic plants commercially cultivated today are totally sterile and are propagated only asexually. The reasons for this as well as the means to restore the plants fertility have remained unknown.

The scientists, led by Prof. Haim Rabinowitch, found that in its growth process, the garlic plants bulbing and flowering occur simultaneously in the spring and both the processes were regulated by temperature and day length. During generations of cultivation, farmers selected those plants that displayed early ripening and large bulbs. The rapid growth of the bulbs drew most of the nutrient and energy resources of the plant, leaving little for blossoming, resulting in abortion of the floral bud at a very early stage of development, and hence complete sterility. In those cases in which the plant succeeded in producing a floral stem, the developing flower buds were strangulated by the bulbs at the top that were developing fast under conditions of lengthening days. The scientists experimented with growing garlic plants under controlled temperature and daylight. They succeeded in delaying the bulb growth in favour of flowering, regaining fertility and production of seeds. This work opens the possibility for new physiological and genetic research on one of the most important vegetable condiments in the world.


Researchers identify chlorophyll-regulating gene

Researchers led by Prof. Peter Quail of the College of Natural Resources at the University of California, Berkeley, the United States, have identified a critical gene for plants that start their lives as seeds buried in soil. They have described how a gene called phytochrome-interacting factor 1, or PIF1, affects the production of protochlorophyll, a precursor of the chlorophyll used by plants during photosynthesis. While a seed germinates under soil it is producing a controlled amount of protochlorophyll for its debut above ground. Once they are exposed to light for the first time, protochlorophyll needs to be converted into chlorophyll quickly.

Since the PIF1 gene binds to phytochrome, a protein that is triggered by light and controls a plants development, the researchers disabled it in Arabidopsis thaliana, and compared the mutant seedlings with a control group of normal plants. The seedlings were grown in the dark to mimic conditions beneath the soil, with groups being brought out into the light at different time points throughout a six-day period. The scientists found that mutated plants had twice the levels of protochlorophyll than normal, wild plants, suggesting that phytochrome acts as a negative regulator for protochlorophyll. The mutated seedlings failed to switch off production of protochlorophyll throughout the germination period. The longer the seedlings stay in the dark, the more toxic the levels of protochlorophyll become, and the more likely they would die when exposed to light.

According to the researchers it is an unbound form of protochlorophyll that is toxic. Normal plants produce enough of an enzyme, called protochlorophyllide oxidoreductase, to bind with typical levels of protochlorophyll. But not enough enzyme is produced to handle the overabundance of unbound protochlorophyll churned out by the mutant seedlings. The finding may also have implications for agricultural biotechnology.


Genetic modification of linseed produces healthier PUFA

Dr. Ernst Heinz and colleagues at the University of Hamburg, Germany, have succeeded in producing genetically modified linseed plants that accumulate significant levels of very long chain poly-unsaturated fatty acids (PUFAs) in seed. Very long-chain PUFAs such as those found in fish oils are increasingly recognized as important for a healthy human diet as their consumption has been linked to a to a variety of other health benefits, including protection against heart disease, inflammatory diseases (such as arthritis, irritable bowel syndrome and some cancers) and the pro-motion of healthy brain and eyes in infants.

Oilseed crops such as canola, safflower and linseed typically accumulate in their seed a high proportion of C18 PUFAs such as linoleic acid and alpha-linoleic acid. Once consumed, they may be metabolized into very long chain (C20 and C22) PUFAs in the human body. However, this process is slow and inefficient compared with the direct consumption of C20 and C22 PUFAs that may be obtained from fish oils. Oilseed crop species contain all of the proteins and enzymes necessary for the biosynthesis of the range of fatty acids present in seed oil, but they lack certain fatty acyl desaturases and elongases necessary for the biosynthesis of very long chain PUFAs.

The researchers produced linseed (Linum usitatissimum) and tobacco (Nicotiana tabacum) plants that synthesize very long chain PUFAs in their seed by introducing genes for fatty acyl desaturases and elongases. First, protein sequences for fatty acyl desaturases and elongases were analysed from a variety of organisms nematode, fungus, alga, plant, etc. that produced very long-chain PUFAs. The DNA coding sequences for these genes were then introduced into the plants, and expression of the proteins directed into the seed with the use of seed-specific gene promoter sequences. The best results were obtained with the use of the plant and algal gene sequences. These transgenic plants accumulated significant levels of very long chain PUFAs in their seed.


Gene chips research could lead to superior cottons

Dr. Jeff Chen, a scientist at the Texas Agricultural Experiment Station under the Texas A&M University, the United States, is collaborating with Dr. Jonathan Wendel, project leader of the Cotton Evolution Genome Project at Iowa State University, the United States, to develop a high-quality DNA microarray resource accessible to the cotton community. DNA microarrays have applications in studying changes in gene expression and genomic structure in many biological contexts, including genetics, physiology, development and environment. The microarrays will eventually include all favourable genes from cotton researchers so that they can be used in cotton breeding and field applications, and could lead to cotton varieties with superior traits and improved fibre quality.



Biotechnology Present Position and Future Developments

This book focuses on biotechnology applications, describing the technologies involved, explaining the progress made to date and outlining 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.

Detailed treatment is given to developments in new platform technologies including genomics, proteomics and bioinformatics, along with the implications of high throughput analytical techniques including microarrays. New developments in imaging and optical biology are discussed, besides biosensors, bioelectronics and bionetworks. The authors highlight the key factors that make biotechnology particularly relevant to the Agri-Food sector. They also examine the contributions it can make on medicine and health care, in providing improved approaches to the diagnosis, treatment and prevention of disease.

Contact: Teagasc, 19 Sandymount Avenue, Ballsbridge, Dublin 4, Ireland. Telephone: + 353 (1) 637 6000; Fax: + 353 (1) 668 8023


Applied Genetics of Leguminosae Biotechnology (Focus on Biotechnology, V.10B)

Divided into two volumes, this 344-page work presents an up-to-date analysis of in vitro and recombinant DNA technologies for the improvement of grain, forage and tree legumes. Volume 10B presents the current state and future prospects of in vitro regeneration and genetic transformation expression and stability of transgenes modification of traits in almost all the important legumes.

Contact: Kluwer Academic Publishers, P.O. Box 989, 3300 AZ Dordrecht, The Netherlands. Tel +31 (78) 657 6050; Fax +31 (78) 657 6300



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