VATIS Update Biotechnology . Jul-Aug 2004

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Biotechnology Jul-Aug 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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International plant genetic resources treaty enters into force

On 29 June 2004, the International Treaty on Plant Genetic Resources for Food and Agriculture entered into force, with 55 countries having ratified it. According to the Director-General of the Food and Agriculture Organisation (FAO), Dr. Jacques Diouf, the Treaty brings governments, farmers and plant breeders together and offers a multilateral framework for accessing genetic resources and sharing their benefits.

A unique and innovative aspect of the Treaty is its Multilateral System for Access and Benefit Sharing, that ensures the use of plant genetic resources based on the principle of easy access and exchange, and the fair and equitable sharing of the benefits. The System covers a list of 35 food crops and 29 forage crops. Plant breeders, farmers and public and private research institutions will be able to access these plant genetic resources under standard conditions and to use a wide range of them. The Multilateral System is expected to greatly reduce transaction costs for the exchange of plant genetic material between countries, as costly separate bilateral agreements with each source country would no longer be required.

Benefit sharing under the Treaty will include exchange of information, access and transfer of technology and capacity building. Those who commercialize plants bred using material from the Multilateral System will be required to pay an equitable share of the monetary benefits to a trust fund, which will be used to help developing countries improve the conservation and sustainable use of plant genetic resources. The level, form and manner of this payment will be determined by the Governing Body of the Treaty.

The worlds most important gene bank collection, around 600 000 samples held by the Consultative Group on International Agricultural Research (CGIAR), will be put under the realm of the Treaty. The Treatys funding strategy will be the Global Crop Diversity Trust, established by FAO and the International Plant Genetic Resources Institute on behalf of the CGIAR Centres. The Trust will set up an endowment fund of US$260 million to support gene bank conservation and capacity building in the developing countries.

Contact: Mr. Erwin Northoff, Information Officer, Food and Agriculture Organisation, Viale Terme di Caracalla, Rome, Italy. Tel: +39 (6) 5705 3105



EU funding for GM plant vaccines

European scientists have launched a consortium, called Pharma-Planta, to make pharmaceutically useful products like vaccines and pharmaceuticals for treatment of major diseases. Thirty-nine labs in 11 European countries will work together, with input from researchers in South Africa. The European Union has put 12 million euros into the project, which is expected to start clinical trials by 2009. Pharma-Planta expects that the technologies it would develop over the course of its initial five years of funding would eventually boost the global supply of treatments.

Candidate plants could include tobacco, maize, potatoes and tomatoes. The preference would be to use plants in which the desired protein products are expressed in high quantities in the seeds, which are easily harvestable. The first product, an antibody, is expected to be used in treating HIV. The second product would probably be a post-bite vaccine for rabies, which is still a significant killer in Africa and South-East Asia.

The projects aim is to focus on areas that would be of greatest benefit to developing nations, and any plant platforms that work particularly well are to be freely licensed in those countries. It also envisages cultivation of GM plants, and the processing necessary to remove the useful molecules from the plant tissues would be done locally. (BBC News, 12 July 2004)

India to develop meningitis vaccine

The international Meningitis Vaccine Project (MVP) has signed an agreement with the Serum Institute of India (SII), based in Pune, India, to develop a new conjugate meningitis-A vaccine at a cost of US$0.40 per dose. The vaccine will be used for the African meningitis belt, which stretches from Ethiopia to Senegal. MVP is run by the World Health Organization (WHO) and the international charity PATH.

To create the vaccine, SII has applied a new technology using hydrazine to conjugate a tetanus toxoid with a meningitis-A polysaccharide from a Dutch company, SynCo BioPartners. The technology was developed by Dr. Carl Frasch and Dr. Che-Hung Lee of the United States Food and Drug Administration. The existing polysaccharide vaccines cannot be used in children younger than two years and do not produce long-lasting protection. It is hoped that the new conjugate vaccine will overcome these problems.

The United States National Institutes of Health negotiated a technology license agreement with SII, for which the latter would pay US$2.4 million over 10 years.


Stem cell centre in the United Kingdom

The United Kingdom has founded a new US$30 million stem cell centre in Cambridge called the Cambridge Stem Cell Institute and headed by Dr. Roger Pedersen, professor of regenerative medicine at Cambridge University. The centre will focus on fundamental research on both human embryonic and adult stem cells as a precursor to the study of therapeutic applications.

According to Prof. Pedersen, scientists still dont understand stem-ness what it means to be able to differentiate to different cells and so far the identity of only a handful of adult stem cells in the body, such as blood and muscle, is known. However, embryonic stem cells by definition include all the other stem cells. Understanding them is therefore a vital first step.

Besides fundamental research, the centre will also address issues of clinical interest already identified by other laboratories, such as insulin-producing cells for the pancreas. The centre is backed by the Juvenile Diabetes Foundation, and diabetes and Parkinson disease will be the first clinical targets. Prof. Pedersen is hoping to conduct the first human trials of therapies within five years. He hopes that his new centre will attract a number of top stem cell researchers from the United States and elsewhere who are interested in human embryonic stem cell research.


First chemical genomics network centre in the United States

The National Institutes of Health (NIH), Maryland, the United States, has established a Chemical Genomics Centre, the first component of a nationwide network that would produce innovative chemical tools for use in biological research and drug development.

According to NIH director, Dr. Elias Zerhouni, the unprecedented opportunity would broaden the scope of biological exploration for the public sector researchers. Up to 10 pilot centres would be funded at academic institutions. These chemical genomics centres would coordinate to build a network in the academic research community for identifying a broad range of small molecules that have promising properties for biological research.

Chronicle Pharmabiz, 17 June 2004

Indo-Thai tie-up for biotech projects

Indias Department of Biotechnology (DBT) has tied up with Thailands Ministry of Science and Technology to develop joint programmes for the advancement of biotechnology in areas of genomics, and infectious diseases like tuberculosis and malaria, among others. Speaking at the Indo-Thai workshop on biotechnology in Pune, Dr. S. Natesh, Adviser to DBT, emphasized the importance of bilateral and multilateral collaborations and highlighted Indias cooperation with 25 countries in the field of science and biotechnology.

Dr. Natesh pointed out the importance of investments in the areas of healthcare, agriculture, medicines and human genome, and towards bio-industrial development. He outlined the various internationally compatible regulatory structures that had been set up for risk assessment and management of recombinant DNA products. He identified aquaculture, marine biotechnology, agriculture, food and fermentation biotechnology as the areas that would be covered under the Indo-Thai joint biotechnology programmes.

Chronicle Pharmabiz, 24 June 2004


Interleukin Genetics receives patent for asthma tests

Interleukin Genetics Inc. in Massachusetts, the United States, was awarded a patent by the United States Patent and Trademark Office for methods and kits that use specific genetic markers to assist in the diagnosis and management of an obstructive airway disease, such as asthma. This patent was based on studies by Interleukin and collaborators that showed that specific gene variations might be used as part of a medical assessment to predict an individuals response to different asthma drugs (pharmacogenetics), and to identify those who were likely to develop severe asthma.

Interleukin Genetics demonstrated that certain variations (SNPs) in the Interleukin genes (IL-1 and IL-13) produce lifelong tendencies to have more inflammation or qualitative differences in inflammatory mechanisms. These variations represented an important new tool for the physician charged with early patient diagnosis and treatment selection. The patent includes specific variations in the inflammatory gene for IL-13 and represents part of the companys expanding coverage of inflammation genes outside the IL-1 gene cluster. In addition to providing predictive genetic tests for asthma, the expanded gene coverage allows for selection and/or development of therapeutics based on the specific underlying biological mechanism involved in the disease state.

Chronicle Pharmabiz, 24 June 2004

Biocon expands product base

Bangalore-based Indian company Biocon Biopharmaceuticals, a subsidiary of Biocon Ltd., has added two additional monoclonal antibodies and three cancer vaccines to its product portfolio.

The company, a joint venture with CIMAB of Cuba, currently produces a humanized anti-epidermal growth factor (EGF) receptor called h-R3 that targets monoclonal antibody for a variety of cancers including head, neck tumours and brain tumours, and non-small cell lung cancer a recombinant granulocyte stimulating factor and erythropoietin. A phase II clinical trial is about to commence to evaluate the efficacy of h-R3 in squamous cell carcinoma of solid head and neck tumours. Following the outcome of this trial, the effect of h-R3 on other cancers would also be evaluated through a series of clinical trials.

The new products would include: h-T1, a humanized anti-CD6 targeting immuno-suppressive monoclonal antibody for T-cell lymphoma, rheumatoid arthritis and psoriasis; q-T3, a chimeric anti-CD3 targeting immuno-suppressive monoclonal antibody for organ transplant; an EGF cancer vaccine; a TGFa cancer vaccine; and a HER 1 cancer vaccine.

Express Pharma Pulse, 24 June 2004

Themis to enter biotech sector with erythropoietin and interferon

In India, the Mumbai-based Themis Medicare is planning to enter the biotech market with products like erythropoietin, interferon alpha, human growth hormones and plant hormones. It would start manufacturing the products at the manufacturing facility of its subsidiary Themis Biotech in Hyderabad. The plant has been upgraded for manufacturing fermentation-based products such as lovastatin, simvastatin, gentamycin and sisomycin.

Themis Medicare has tied up with companies in Italy, China and Argentina for technology transfer and sharing of intellectual and financial expertise in the field of biotechnology.

Chronicle Pharmabiz, 27 May 2004

Patent for Introgens adenoviral product portfolio

The Board of Regents of the University of Texas System, Austin, Texas, the United States, has been awarded a patent covering adenoviral vectors with the tumour suppressor p53 in pharmaceutical compositions. Introgen, Texas, has obtained the exclusive licence.

According to Dr. David Parker, Introgens vice-president of Intellectual Property, the patent covers adenoviral p53 constructs for use in therapeutic applications and is not limited to Introgens Advexin adenoviral p53 product. Advexin therapy uses the adenovirus delivery platform, a very important and frequently used tool in the fields of tumour suppressor therapy and vaccines. Unlike other viral delivery systems, adenoviruses do not mix with a patients DNA. Rather, they are genetically altered to be unable to replicate in humans and to have important properties that lend themselves readily to commercial-scale manufacture.

Introgens Advexin therapy is protected by up to 13 United States patents covering differnt aspects. However, the present patent is unique because it gives Introgen protection for close to 10 years longer than some other patents in the portfolio.

Chronicle Pharmabiz, 24 June 2004

Shantha Biotechnics to widen product range

Shantha Biotechnics, Hyderabad, India, is all set to widen its product portfolio from the existing two products to at least six by 2005, notching an overall turnover of about US$15 million. Erythropoietin, the drug used for maintaining red blood cell level, and streptokinase, the clot-busting drug, would hit the market in the present year. These drugs enjoy a market size of about US$15 million and US$8.6 million, respectively. By early 2005, the company plans to roll out a combination vaccine (hepatitis and DPT) and alpha feto protein (therapeutic product used for genetic disorders). The company is also considering an initial public offer of its shares worth approximately US$21.6 million in 2005.

Chemical Weekly, 22 June 2004

Indo-Swiss seminar to promote Indian biotech firms

The Government of India, in cooperation with the Swiss government, is planning a major biotechnology promotion event in Switzerland. A conference-cum-workshop would project the capabilities of Indian biotech companies in Europe. It is a part of the bilateral trade agreements between the two countries, signed during the Switzerland President Mr. Pascal Couchepins visit to India in November 2003, on intensifying cooperation in the field of life sciences and technology. Most Swiss firms look at the United States for business partnerships, except for Novartis and Roche, which have biotech projects in India. The event would highlight Indias capabilities in biotechnology on manufacturing quality products at competitive rates.

Chronicle Pharmabiz, 24 June 2004


Kangaroo hops in line for genome sequencing

The National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH) in the United States, announced a partnership with the Melbourne-based Australian Genome Research Facility Ltd. (AGRF) to sequence the DNA of one of Australias best-known animals a member of the kangaroo family known as the tammar wallaby (Macropus engenii). Researchers are studying the tammar wallaby to gain insights applicable to human reproduction and development, evolution, anatomy and physiology of mammals and disease susceptibility. The kangaroo would be the second marsupial to have its genome sequenced, after grey short-tailed, South American opossum (Monodelphis domestica).

The data generated by the kangaroo genome project would prove to be extremely valuable for medical research, as well as agricultural research, around the globe. Comparing the human genome sequence with that of kangaroo would enable scientists to identify regions of similarity and difference that could provide clues about the structure and functions of genes vital to human health and development. AGRF expects to begin sequencing the kangaroo genome in 2004 and complete its part of the effort in approximately two years.

Chronicle Phramabiz, 17 June 2004

Hope of cure for sufferers of Huntingtons disease

Dr. Beverley Davidson and her colleagues at University of Iowa, the United States, have shown that gene therapy could be helpful in treating brain-wasting diseases like Huntingtons disease, which affects around 250,000 people in the United States alone. The approach involves trying to correct genetic abnormalities by injecting an animal or person with corrective sequences of DNA or RNA.

The researchers tested their therapy in mice with a disorder that mimicked a disease called spinocerebellar ataxia type 1, which leaves its sufferers progressively less able to walk. The therapy eliminated pockets of damaged brain tissue from the mice and corrected the physical symptoms of the disease. This was the first time that gene therapy was shown to cure a disease like spinocerebellar ataxia. The finding was also significant because it was the first time that gene therapy had been used to cure a so-called dominant progressive brain disorder. Such diseases occur in cases where a patient inherits a defective copy of a gene from just one parent. Most gene therapies involve replacing a missing gene sequence. In all dominant disorders, however, it is the mutant sequence itself that causes the problem. Therefore, any therapy needs to actively block a sequence rather than just replacing one.

To do that in the mice, the researchers used a technique called RNA interference. They isolated pieces of genetic material that bound to and blocked the mutant gene. The pieces were packaged into stripped-down virus particles and injected into the mice. The virus used was an adeno-associated virus that did not cause disease in mice or humans. After the injections, the proteins created by the mutant gene disappeared and the mice improved.


Genome of sudden oak death bug cracked

In the United States, scientists led by Dr. Brett Tyler of the Virginia Bio-informatics Institute, Virginia, and Dr. Dan Rokhsar, at the Joint Genome Institute, California, have successfully sequenced the genome of Phytophthora ramorum, the fungal pathogen that causes the sudden oak death. The completion of the sequence coincided with heightened worries over the spread of the sudden oak death in the country following the discovery that an infected California nursery had spread the disease nationwide through plant shipments.

P. ramorum is the first member of the Phytophthora family to be sequenced. Scientists revealed the 65 million-long sequence of DNA base pairs that made up 15,000 genes of the organism. The researchers hope that the map of P. ramorums genetic code would pinpoint genes and their proteins that would allow them to detect, track and treat the disease.

P. ramorum causes the death of several species of oak and beech by invading plants through the bark and cutting off the flow of food from the leaves to the roots, eventually leading to death of roots and upper tree. It can infect at least 40 other species, including shrubs like rhodedendron and camelia.

In the short term, the scientists hope the gene sequence would lead to a diagnostic tool for P. ramorum, based on proteins released by it. Currently, it is impossible to detect the pathogen until a tree shows symptoms a year or more after infection. In the longer term, they hope to develop a selective treatment.


Worms reveal intron insights

Dr. Kenneth Wolfe and Dr. Avril Coghlan, two researchers at the Trinity College Dublin in Ireland, have discovered 122 novel introns that appeared in the genomes of Caenorhabditis elegans and C. briggsae since the two species diverged 80-120 million years ago, shedding light on how new introns arise and are subsequently spread among genes. The genomes of both worms contain approximately 100,000 introns, of which more than 6,000 are unique to one species or the other. The researchers identified 81 new introns in C. elegans and 41 new introns in C. briggsae. Of these, 13 are found in genes involved in pre-mRNA processing.

The researchers used actual sequence data to infer the process by which introns were gained, rather than relying on phylogenetic arguments, the conventional approach to studying intron evolution. They used Basic Local Alignment Search Tool (BLAST) to identify orthologous genes across all the species (animal and nematode), and by comparison of all genes, they were able to find intron sites present in one of the nematodes, but absent in all other species, thus inferring that the gained introns must be less than 100 million years old.

The novel introns had settled in the worm genomes in a stretch of DNA called an exon splice site consensus sequence. With the new introns, the consensus sequence was stronger than the consensus sequence around any of the other introns, thus suggesting that the splice site was the target site the new introns were inserted into.

So far, similar studies in mammals have failed to detect evidence of any new introns. Bacteria, on the other hand, lack introns altogether, leading scientists to wonder if they were lost from bacteria early on in their evolution.

Two unusual findings in the study were the discovery of copies of introns elsewhere within the same genome and duplicate copies of an intron within the same gene. The scientists attributed the anomalies to a process called reverse splicing, whereby an excised intron somehow inserts into a different site within the same mRNA template. Reverse transcription of the mRNA then gives rise to DNA containing the reinserted intron becoming part of the genome. The results represented two major findings, one being that introns are changing a lot, both in terms of gain and loss. The second and more novel part was how one intron could give rise to another.


Scientists decipher odour code

Working with the fruit fly as a model, Dr. John Carlson and graduate student Ms. Elissa Hallem in the Department of Molecular, Cellular and Developmental Biology at Yale University, Connecticut, the United States, discovered how odours are encoded by the olfactory system into the complex messages sent to the brain. They systematically tested the odour receptor proteins in the fruit fly antenna and recorded which odours they detected. The study provided new insight into the process by which animals sense and distinguish odours, a process that is essential to identifying food, mates and predators.

The antennae of insects contain several odour receptor proteins, but it was previously not known how the entire collection of receptors acted together to encode olfactory information. The scientists used a mutant fruit fly to determine the individual odour sensitivities of each of the 32 odorant receptors of each normal fruit fly antenna. The antenna of their mutant fruit fly had an empty neuron, which had lost its original odour receptor and did not respond to any odours.

Using genetic engineering, they created a series of mutant flies, each with a different fruit fly odour receptor in the previously empty neuron. They then tested the engineered neuron in each fly for the odour sensitivity of the receptor and found that some receptors responded strongly to many of the tested odours, while others responded in strength to only one or none. Some odours activated many receptors, while some others activated only one.

The researchers were able to create a map of which odour receptor was expressed in which type of neuron. This receptor-to-neuron map was the first map of its kind of the olfactory system. Dr. Carlson hopes that this map in the fruit fly would serve as a model for the olfactory systems of insects, such as mosquitoes, as well as for more complex organisms, including humans.


Access to DNA secrets yields better understanding of genes

Chromatin array, a new technology for examining DNA, was developed by Dr. Harold Garner and his colleagues at University of Texas (UT) Southwestern Medical Centre, Dallas, the United States. It gives a detailed picture of which genes have the propensity for activation, offering a new tool for understanding how genes function and possibly for diagnosing disease.

Various pieces of DNA are constantly being compressed and expanded as a cell responds to its changing needs. When the DNA expands, proteins called transcription factors gain access to the genetic code to read its instructions for making RNA, which in turn makes other proteins that carry out lifes essential functions. When DNA is highly compacted, it is not as accessible to transcription proteins, and cannot make RNA. According to the researchers, one of the advantages of the chromatin array is that it sorts through lots of pieces of DNA and gives information about each segment all at once, something that is not possible with other techniques. They could get information on a much larger number of genes and whether or not the genes were in a state in which they could make RNA, using this technique than by using traditional RNA microarrays.

Using the chromatin array, the UT Southwestern researchers could detect the relative compactness of several stretches of DNA at a time with very high resolution, allowing them to determine which genes had the propensity for making RNA. They found that for many genes, but not all, the more open the DNA was, the more RNA was produced.

Exactly what controlled compaction and expansion of DNA is still unclear, but Dr. Garner and his team intend to apply various drugs, such as those used in cancer therapy, to cells in order to understand if and how these drugs affect DNA compaction. The researchers would also investigate whether certain compaction and expansion states might be indicative of cancer or any other disease. Dr. Garner stressed that the current study described the platform technology necessary to try to understand larger questions. The next step would involve using the technique to investigate different types of cancer cells to see whether this type of assay could be a diagnostic tool.


Scientists zero in on cancers genetic core

Scientists led by Dr. Arul Chinnaiyan and Dr. Daniel Rhodes at the Comprehensive Cancer Centre of University of Michigan (U-M), the United States, have discovered that, of the approximately 35,000 genes in the human genome, activity from just 67 is required to change normal human cells into cancer. These 67 genes form cancers meta-signature a core set of essential genes, which somehow triggers the transformation from normal cells to cells that are neoplastic, or growing abnormally.

Oncomine, the cancer microarray database used in the study, was developed by Dr. Chinnaiyan, Dr. Rhodes and colleagues in the U-M Medical School, Johns Hopkins University School of Medicine in Maryland, the United States, and the Institute of Bioinformatics in Bangalore, India. The scientists used a statistical analysis method called comparative meta-profiling to examine 40 datasets from other scientists showing specific patterns of genetic activity associated with one of 12 types of cancer.

The researchers also identified another 69-gene meta-signature showing a common pattern of genetic activity in aggressive, invasive undifferentiated cancers. The pattern was different from the one found in well-differentiated cancers that grew slowly and were easier to control. The researchers tested the meta-signature validity by looking for the same patterns of genetic activity of 12 other gene expression databases, which were not available when the study began.

Express Pharma Pulse, 17 June 2004


Gene therapy to protect bone marrow during chemotherapy

In the United States, research on employing gene therapy to help protect the bone marrow cells of cancer patients undergoing chemotherapy is progressing steadily. Encouraging results have been reported by Dr. Stanton Gerson and his research team at the Centre for Stem Cell and Regenerative Medicine and the Case Comprehensive Cancer Centre at Case Western Reserve University, Ohio, and scientists at the Ireland Cancer Centre at University Hospitals of Cleveland, Ohio.

Dr. Gersons team studied the gene mutant MGMT that was able to protect stem cells from chemotherapy. In animal studies, they found that the gene could provide stem cells with very high levels of survival advantage (more than 500 fold) compared with normal stem cells without the gene.

Based on the pre-clinical animal results, they began clinical trials in patients with advanced cancer. Blood stem cells were collected from patients and exposed to a retrovirus containing the gene, which inserted the gene into the cells. Patients were then infused with their own genetically modified cells and treated with combination chemotherapy. Because stem cells had the new gene, they were resistant to the debilitating effects of chemotherapy and helped the patients to maintain greater strength following chemotherapy.

No complications were found in the five patients who were tested thus far, and transfer of the protective gene to the bone marrow or blood stem cells was found to be up to 41 per cent. According to Dr. Gerson, the novel approach could help in developing new therapies for treatment of cancer.

Express Pharma Pulse, 17 June 2004

Virus robs addicts of their high

Dr. Kim Janda and her colleagues at the Scripps Research Institute, California, the United States, have developed a novel method to clean up cocaine in the brain that produces euphoric sensation. The proposed cure for cocaine addiction is based on the premise that the addicts would be less inclined to keep taking the drug if they did not get that sensation. It is reported to be superior to the approach of inactivating cocaine once it is in the body by injecting addicts with antibodies, which then get bound to the drug and counteract its powerful effect. As the antibodies are unable to get into the brain, the effect of this approach is limited.

The new method uses a virus that invades the brain to deliver the antibodies. The virus is safe, as harmful gene sequences had been removed and genes for the appropriate antibodies had been inserted into the viruss genome.

The researchers gave eight rats nasal injections of the virus twice a day for three days and compared them with eight rats that did not receive the treatment. On the fourth day, they gave both groups a dose of cocaine. The untreated rats behaved in a characteristic way after receiving the drug sniffing, standing up on their hind legs and rocking backwards and forwards whereas the rats that received the virus showed much less severe behaviour, indicating less of the characteristic euphoric feeling.

According to Dr. Janda, addicts who wanted to quit could eventually be given the treatment for the weak moments when they experience the desire for cocaine. The virus lingered in the brain for around two weeks and so, although the addicts might relapse once, the absence of any euphoric feeling would then discourage them from taking the drug again.


GM bacterium boosts cancer therapy

Researchers led by Prof. Peter Selby at the Cancer Research UK Clinical Centre in St. Jamess University Hospital, Leeds, the United Kingdom, have genetically engineered a designer bacterium to bolster the bodys immune response to tumours. They added a gene to a strain of Mycobacterium smegmatis, which is harmless despite being related to M. tuberculosis that causes tuberculosis. The extra gene made the bacterium produce a molecule that boosted the immune systems ability to identify and kill cancer cells.

In mice with bladder cancer, the modified bacterium worked much better than existing treatments against tumours in the bladder, leading to a reduction in the size and number of tumours. Eight out of 10 of the animals had no tumours by the end of the treatment. The researchers took M. smegmatis and added a gene to produce the protein called Tumour Necrosis Factor alpha (TNFa). TNFa is a part of the immune system, with a crucial role in killing unwanted cells, such as cancer cells. It is produced in response to BCG, the bacterium best known as a vaccine against tuberculosis. Current treatments for bladder cancer include BCG, but it does not work in about a third of patients, and could also causes significant unwanted side effects.

Using the patients own immune system to fight cancer in this way is an increasingly promising approach. Only the safety of the bacteria would need to be formally verified before they could be tried in humans.


Mutation helps virus evade the first line of immune defence

Dr. Wayne Yokoyama and his research associates from Washington University School of Medicine, Missouri, the United States, collaborated with research scientists from the Max von Pettenkoffer-Institute, Munich, Germany, and the University of Rijeka, Croatia, to uncover the first evidence that a virus could mutate to evade the bodys first line of immune defence. The researchers found that the mouse version of cytomegalovirus (MCMV) could mutate and thereby evade natural killer (NK) cells, the component of the immune system that attacks infections first. The discovery might help explain why people with AIDS or with compromised immunity suffer severe infections from viruses that they would otherwise defeat.

The researchers exposed mice lacking an acquired immune system, but with NK cells, to MCMV. Although the mice survived initially, they died within several weeks of infection, raising questions about what the virus was doing during that period. Subsequent analysis revealed that the viruses that grew out three to four weeks after infection were not the same genetically as the ones that were put in. The MCMV virus that eventually overcame the innate immunity of the mice had developed mutations in the gene for m157, rendering the virus invisible to NK cells.

When the researchers infected mice with a viral culture that did not contain mutant m157, there were different m157 mutations in each mouse. This suggested that mutations were independently developing in each infected mouse, allowing the viruses to escape detection by NK cells.

The results of the study strongly support the idea that there are mutations that occur in the course of a single infection and these mutants escape immune control as a result of selection pressure. According to Dr. Yokoyama, this is a new concept because such viral escape had been described before only in RNA viruses, which had a high propensity for mutation. The researchers are now trying to extrapolate their findings to human CMV to determine whether the virus is undergoing the same type of mutation to evade the innate immune system. Such findings in humans could lead to new treatment strategies to combat viral infections.


Genetic modification lowers cholesterol and homocysteine

A team of scientists led by Dr. Dennis Vance from University of Alberta, Edmunton, Canada, has reported that mice, which were genetically altered to lack either of the two different pathways through which humans and animals provide lipids for high density and low density lipoproteins (HDL and LDL), do not appear to suffer any ill effects. Scientists from Columbia University, New York, the United States, and Memorial University of Newfoundland, Canada, were part of the research team, which found that animals from both the groups had significantly lower levels of cholesterol in their blood stream. Alteration of one of the pathways also halved blood levels of homocysteine. The results suggest a unique therapeutic approach to lower LDL cholesterol and homocysteine levels, both known risk factors for cardiovascular diseases.

The study focused on the two methods or pathways, one called CT and the other called PEMT, by which the liver makes phosphatidylcholine (PC). PC is the key building block of cell membranes in humans and other animals, and an important component of the HDL and LDL lipoproteins that carry fat and cholesterol in the blood stream. The CT pathway contributes about 70 per cent of the PC in the liver and the PEMT pathway contributes the remaining. When the researchers genetically altered the mice to lack either the CT or the PEMT pathway in the liver, the mice appeared normal and bred normally. But in each case, whether the CT or the PEMT pathway was missing, levels of lipoproteins were decreased by as much as half.

The study suggests that pharmacological inhibition of the manufacture of PC in the liver may be a useful approach to lower LDL (bad cholesterol) in the blood stream since the pathways work similarly in humans. The animals altered genetically so as not to have a PEMT pathway for the creation of PC also showed a 50 per cent decrease in homocysteine, which helps LDL to build fatty plaques in the coronary arteries. Thus, this would help in lowering the risk and incidence of cardiovascular diseases.


Triple-vaccine strategy stimulates HIV-specific immune response

Scientists at The Wistar Institute and the University of Pennsylvania, both based in Pennsylvania, the United States, have reported success of an innovative triple-vaccine strategy in monkeys for creating an effective anti-HIV vaccine regimen. In a test of the new approach, the scientists sought to maximize the immune response to a truncated HIV gene called Gag and succeeded in dramatically stimulating the production of CD8+ T cells responsive to Gag. They believe that CD8+ T cells, which reduce viral load though they do not prevent infection, would be an important key to creating an effective HIV vaccine.

Many current vaccine development programmes rely on human adenoviruses engineered to include elements from disease-causing agents, as adenoviruses are easier to manipulate in the laboratory and readily enter a wide variety of cells, including cells of the immune system, to stimulate a strong and long-lasting immune response. However, an unaddressed problem with this approach is that many people are exposed to adenoviruses in their childhood. The antibodies that they carry could neutralize the viruses, thus interfering with the effectiveness of any vaccine based on them.

To address this difficulty, the research team, led by Dr. Hildegund C.J. Ertl of The Wistar Institute, used sophisticated bioengineering technologies and developed a series of vaccine vectors based on chimpanzee adenovirus strains that possessed the immunological strengths of human adenoviruses without their drawbacks. The scientists then created three vaccines, each with a different adenovirus as a backbone but all containing the Gag gene. Two of the vaccines were based on chimpanzee adenoviruses and the third was based on a human adenovirus. These were administered to two groups of four rhesus macaques each. One group received the human adenovirus vaccine first, followed by the two chimpanzee adenovirus vaccines. The other group received one of the chimpanzee adenovirus vaccines first, followed by the other chimpanzee adenovirus vaccine and then the human adenovirus vaccine.

Both triple immunization regimens sparked high frequencies of CD8+ T cells against Gag that remained remarkably stable over time, showing the potential of the new strategy. An advantage of the triple-vaccine approach was that it avoided generating pre-existing immunity to the vaccine backbone, which was new to the immune system at each stage of the regimen.


Software identifies promising ingredients for new drugs

Researchers at Rensselaer Polytechnic Institute in Troy, New York, the United States, have developed a software capable of quickly identifying molecules that show promise for future medicines.

According to the scientists, the trick with drug discovery is to have the drug molecule fit like a key in a lock, because shape affects its performance. To find the most likely molecules, the new software makes use of two shortcuts that enable the computer to search a vast molecular database quickly. The first shortcut rapidly describes in terms of numbers the molecule, its shape and its chemistry, using a technique to calculate electronic properties on the surface of a molecule. The second shortcut identifies which molecules have the right chemistry for a specific therapy. Using advanced pattern-recognition techniques (kernel methods), the software analyses a small sample database to identify molecules with the right chemical features. Once the key features are identified, the software can quickly screen large databases, accurately predicting the molecules that show potential.



First Internet server to search for genetic diversity

Pipeline Diversity Analysis (PDA), the first international server that allows the user to analyse genetic diversity on a large scale and in turn research the genetic basis of hereditary diseases, has been developed by researchers from the Universitat Autonoma de Barcelona in Spain.

Genetic variations, for example, in human beings are the key to understanding whether a person has a higher or lower risk of getting a certain type of cancer. They thus provide very valuable information for studying illnesses with a genetic origin. PDA enables biologists around the world to search for small variations in the genomes of different individuals and species using the data stored in large public genome databases, such as Genbank.

The web service consists of a set of programs that automatically search for genetic sequences in large public DNA databases. The sequences are grouped and the genetic diversity measured in different regions, searching for what scientists call nucleotide polymorphisms, which are small variations in the DNA molecule. The server PDA is available for use for the scientific community at the Internet address Website:

Designing enzymes from proteins

A group of scientists led by Dr. Homme Hellinga at Duke University Medical Centre, North Carolina, the United States, used a computational design to transform a protein with no catalytic abilities into a highly active enzyme, thereby presenting a valuable method to design from scratch enzymes with the desired properties. The scientists transformed ribose-binding protein (RBP) into an enzyme highly active as a triose phosphate isomerase (TIM).

TIM is an important enzyme of glycolysis, catalysing the inter-conversion between the ketose dihydroxyacetone phosphate (DHAP) and the aldose glyceraldehyde-3-phosphate (GAP). TIMs catalytic abilities have their origins in the precise orientation of three critical amino acid residues glutamate, histidine and lysine in its active site and in the controlled movements of the protein chain during catalysis. To transform RBP into TIM, the research team used algorithms to predict mutations that altered RBPs layer of residues so that it could bind GAP and DHAP. Catalytically active residues were then introduced into this receptor design, after defining the most favourable geometrical orientations of key interactions contributing to catalysis, identifying positions for the residues that satisfy these geometrical constraints, and using the receptor design algorithm to optimize the potential active site.

Fourteen RBP variants were designed, produced and assayed for TIM activity. Just like TIM, the RBP variants had a mechanism to close the active site after the substrate was bound, except they used a hinge-bending mechanism. The most active variant was much less thermostable than native RBP and was stabilized with computational design by adding mutations to the protein matrix, correcting interactions with the binding surfaces it surrounded. The resulting RBP variant NovoTim1.2 catalysed the TIM reaction at a rate 100,000- to 1,000,000-fold more efficiently than uncatalysed reactions. It also proved to be biologically active, supporting the growth of Escherichia coli under gluconeogenic conditions just like regular TIM.



Fujitsu and Idenken collaborate on worlds fastest bio-database

In Japan, the National Institute of Genetics, also known as Idenken, in Shizuka and Fujitsu Limited in Tokyo announced their agreement to collaborate on the development of a next-generation database system. The system would be based on Fujitsus Interstage Shunsaku Data Manager Enterprise Edition XML database engine. A prototype developed proved to be 100 times faster than Idenkens existing database system. It would be installed at Idenkens Centre for Information Biology and DNA Data Bank of Japan (CIB-DDBJ), and is scheduled to be publicly unveiled by the end of 2004. With this, CIB-DDBJ plans to position itself as an international leader in Bioinformatics.

Interstage Shunsaku is the first of its type developed in the world. This path-breaking technology would be able to handle massive amounts of biotechnology data and a huge volume of genome searches, all while delivering the worlds fastest search performance, enabling instantaneous responses to users varied search requests.

Once completed, the system would allow more thorough research than ever before to be conducted, operating at the level of the body, organs, tissues, cells and molecules. It would also open the way to develop personalized medicine based on the latest research, which might be the key to curing cancer, high blood pressure, diabetes and other such diseases, as well as shortening the development cycle for new drugs.


New database to help develop AIDS drugs

The National Institute of Standards and Technology (NIST), the United States, has released for public use an online database of AIDS-related protein structures. This new resource would be available to researchers who are either developing drug treatments for AIDS or studying the virus that causes the disease.

The HIV Structural Reference Database (, developed in collaboration with the National Cancer Institute, will receive, annotate, archive and distribute structural data for proteins involved in making HIV, as well as molecules that inhibit these activities. The new database contains data from both the published literature and from direct contributions by industrial and other laboratories. NIST scientists would annotate the structural data with information from various sources and index the entries so that users can reliably find particular structures. They would also help develop a new technique for indexing HIV protease inhibitors, enabling scientists to rapidly and reliably get data on all enzyme-inhibitor complexes such as a mutant strain that is resistant to a particular drug.

The database is expected to be useful in developing strategies for inhibiting the activities of the HIV protease that is essential for maturation of HIV. In addition, it would also assist scientists to understand and circumvent the problem of mutations that make HIV resistant to certain drugs.



RNA enzymes act like protein enzymes

In the United States, Dr. Nils Walter and associates at the University of Michigan, Michigan, and his colleagues at Harvard University, Massachusetts, have studied how changes in ribozyme (RNA enzyme) molecules affect their activity, in order to understand how evolution had shaped ribozymes to function and to find ways of manipulating them for useful purposes.

Walters group combined a technique called single-molecule fluorescence resonance energy transfer (FRET) with mathematical simulations to study a ribozyme involved in the replication of a tobacco-infecting virus. Like protein enzymes, ribozymes accelerate chemical reactions inside cells. Just as a protein enzyme is not a static structure, a ribozyme also changes shape, cycling back and forth between its compact, catalytically active form and its inactive, extended form. Single-molecule FRET allowed the scientists to directly observe and measure how quickly the ribozyme switched forms and how these rates changed when various parts of the molecule were altered.

The researchers observed that the modifications made anywhere on the molecule, even far from the site where the chemical reaction occurred, affected the rate of catalysis. Thus, the study gave the evidence for the first time that ribozymes behaved like protein enzymes and that there was a network of motions that made a ribozyme act as a whole, just like a protein enzyme. According to Dr. Walter, information on how ribozymes work is important for answering fundamental questions of biology and the work may also lead to practical applications.


A single protein makes stem cells into fat cells

A team of researchers led by Dr. Qi-Qun Tang and Dr. Tamara Otto at Johns Hopkins University, Maryland, the United States, has found a key signal in mice that could make stem cells to become fat cells. The team discovered that adding a single protein called bone morphogenetic protein 4 (BMP4) induced mouse stem cells to become adipocytes (fat cells). A very similar signal was likely to be involved in humans too.

The stem cells that the Hopkins team studied had the ability to become fat, muscle, bone or cartilage, but how they commit to these fates was unclear. Apart from the muscle- and bone-inducing signals, which directed this type of stem cell to a particular fate, not much was known about the initial switch from stem cell to labelled pre-fat cell. To see if BMP4 could direct stem cells to become fat cells in culture dishes, the researchers treated cells with this suspected, but not yet proven, fat-commitment protein. They discovered that the treated stem cells, when pushed a little more, uniformly became fat cells. Furthermore, BMP4-treated stem cells implanted under the skin of mice developed into fat tissue, which was indistinguishable from the animals natural fat tissue. The results showed that BMP4-treated stem cells could be used to study and produce fat cells.

Express Pharma Pulse, 1 July 2004

Cows without prions immune to mad cow disease

Researchers at Kirin Brewery, Tokyo, Japan, and Hematech, South Dakota, the United States, have genetically engineered bovine embryos that cannot produce the protein responsible for bovine spongiform encephalopathy (BSE). Without it, the animals would be immune to mad cow disease.

The BSE-causing protein, called a prion, is present also in healthy cattle; it is only when it twists out of shape that it causes problems. When normal prion protein comes into contact with the disease-causing version, it can flip into the malignant form and cause rogue prions to spread through the brain. The researchers aimed to bypass the problem by creating genetically engineered cows that do not produce prions at all. They identified a target sequence within the gene that encoded prion protein, created an artificial DNA segment that inserted itself into the sequence and stopped the gene from functioning. This artificial DNA was injected into cow cells, and cloned embryos were created by fusing these cells with egg cells that had had their nuclei removed. Finally, the embryos were implanted into surrogate mothers. A handful of the BSE-free cows would be born early 2005 and the calves would be tested with a small dose of mad cow protein to see whether they were truly resistant to the disease.


Human protein reduces potency of chemotherapy

In the United States, researchers led by Dr. John Tainer and Dr. Douglas Daniels at The Skaggs Institute for Chemical Biology at The Scripps Research Institute, California, and Dr. Anthony Pegg at the Pennsylvania State University College of Medicine, Pennsylvania, have solved the structure of a human protein called AGT, which was known to interfere with the action of certain chemotherapy drugs. The fine details of the X-ray structure of AGT could help scientists find ways to fight certain cancers, such as brain tumours, which expresses high levels of AGT that make them resistant to chemotherapy. The structure provides a solid foundation for the development of better drugs and resistant proteins to improve cancer therapies.

Chemotherapy drugs, such as alkylating agents, inhibit the growth of cancer cells by damaging their DNA. However, the human repair protein O6-alkylguanine-DNA alkyltransferase (AGT), which is one of the bodys natural defences against DNA damage, inadvertently protects cancer cells from these agents. AGT repairs the bodys DNA very rapidly but cancer cells use AGT to escape chemotherapy by up-regulating or expressing excess amounts of AGT. When the cancer cells do this, they are rendered resistant to alkylating agents.

In order to understand how AGT repair worked at the molecular level, the researchers solved the structure of AGT bound to DNA. The model that they suggested was one of twist and grab. AGT recognizes a piece of damaged DNA and binds to that DNA. Then it twists out the phosphate backbone of the DNA, exposing the damaged base, repairs the base by grabbing the offending alkyl group and transferring it onto itself, and releases the now repaired section of DNA. In doing so, the protein is used up. The structure proved useful for designing inhibitors to interfere with AGTs actions. Researchers have already made such inhibitors of AGT, and some of these are currently being tested in clinical trials as an adjuvant for chemotherapy.



GM blue flowers created

The worlds first genetically modified blue rose has been created by Tokyo-based major Japanese brewer Suntory, which expects the flower to hit markets within four years. Suntory spent approximately US$27.8 million to create the blue rose, blue carnations and other genetically modified blue flowers. It teamed up with Calgene Pacific, an Australian biotech venture, in 1990 for the project and created the blue rose after 14 years of research by implanting the gene that leads to the synthesis of blue pigment in pansies. The colour of the blue rose comes from the pigment delphinidin, which does not exist in natural roses.

According to Dr. Takaharu Tanaka, head of the Institute for Advanced Technology, the modified rose appears to be more violet than blue, thus more work is necessary to create roses with bright blue colour. However, the results were better than the conventional breeding technology that created blue roses, which were usually purple or grey, rather than blue, as their colours came from red or orange pigments and not delphinidin.

According to company officials, it would take at least two and a half years for testing and inspections before the GM plant is deemed safe to breed for the environment. Suntory hopes to merchandise the blue rose in 2007 or 2008 and grow the global market for the genetically modified blue flowers to be worth US$270 million.


Genetically engineered health-promoting crops

Dr. Colin Lazarus and colleagues from Bristol University, the United Kingdom, have successfully put genes for three fatty acids into Arabidopsis, to produce health-promoting substances usually found in fish. Two of the genes come from algae and the third from a fungus. As the plants grow, the genes turn themselves on to produce omega-3 and omega-6 fatty acids, which are known to have significant health benefits. The researchers say this could lead to a new generation of food crops able to reduce the risk of heart disease and other medical conditions.

Omega fatty acids reduce the risk of heart disease and relieve symptoms of inflammatory conditions such as rheumatoid arthritis. There is also some evidence that they are effective against diabetes and are therefore a prominent ingredient of many health foods. They are found most commonly in oily fish. However, with fish stocks declining and prices escalating in some parts of the world, there is a growing demand for other sources of fatty acids and it is hoped that biotech crops could provide a rich source of these valuable omega fatty acids. According to the scientists, these genes could, in principle, be added to many different agricultural plants.

BBC News, 17 May 2004

Scientists discover new role for tiny RNA in plant development

In the United States, scientists from Rice University in Houston, Texas, and the Whitehead Institute for Biomedical Research at the Massachusetts Institute of Technology, Boston, have discovered that miR164 one of the plant microRNAs plays a vital role in the proper development of the stem, leaves and flowers of Arabidopsis. Arabidopsis is the first plant in which microRNAs were discovered; about 100 microRNAs have been identified in the species.

MicroRNAs are tiny strands of RNA that regulate gene expression in plants and animals. Hundreds of microRNAs are believed to exist in each species of plant and animal, but the function of only a few is understood. MicroRNAs are typically only about 20 nucleotides long and they down-regulate the production of certain proteins by interfering with messenger RNA in several ways. It is known that the miR164 gene is present in some flowering plants and in rice, which is an indication that it has been conserved for more than 250 million years of evolution, according to Dr. Bonnie Bartel at Rice University.

The research involved experiments on three strains of Arabidopsis: one normal, or wild-type strain, and two mutant strains created in the lab. In one of the mutants, miR164 was over-expressed, or produced in far greater quantity than normal. The other mutant expressed an miR164 target gene that was resistant to regulation by miR164, allowing the researchers to observe the consequences of a loss of miR164 regulation.

The researchers found abnormal development of leaves and flowers in both mutants. When miR164 regulation of a target gene was absent, plants produced the wrong number of organs. For example, flowers tended to contain too many petals and too few sepals. When too much miR164 was present, organs tended to fuse. Sepals never fully separated, for example, and stamen grew together in a mass.

By studying the function of microRNAs in specific species, scientists hope to answer basic questions about how and why they evolved, as well as gain an understanding that can be used in new medical and agricultural technologies.

Contact: Jade Boyd, Rice University, Houston, Texas, TX 77251, United States of America. Tel: +1 (713) 348 6778



Gene that regulates cell death in plant embryos identified

A team of scientists headed by Dr. Peter Bozhkov and Dr. Sara von Arnold from the Department of Plant Biology and Forest Genetics at the University of Agricultural Sciences, Sweden, has for the first time in the world isolated a novel gene that regulates cell death in plant embryos. The research has been conducted in collaboration with Durham University, England, and the Karolinska Institute, Stockholm.

Programmed cell death is a natural and important process during the life cycle of multi-cellular organisms. Among other purposes, it regulates the form of organisms during certain developmental stages and removes superfluous or damaged cells. Therefore, cell death is a kind of suicide that is regulated by a death gene. These genes are crucial to the functioning of the body. When the balance between production of new cells and cell death is disturbed, diseases like cancer and several neurological disorders arise. This has been studied extensively in animal cells. Compared with animal cells, plant cells have developed totally different mechanisms to regulate programmed cell death.

According to Dr. Arnold, this basic research on plant development would be useful in plant breeding and in forestry. The new knowledge about how programmed cell death is regulated can be exploited to increase production and bolster resistance in plants.



2003 Biotechnology VC Directory

In the search for venture capital, the first step is to find appropriate firms to approach. The Biotechnology VC Directory is designed specifically to facilitate this goal. For the United States/Canada edition of the book, BioAbility identified more than 560 venture capital firms, believed to be involved in the biotechnology industry, to assemble data. Using surveys and other analyses, it put togther a database of 440 distinct venture capital firms at 506 sites and 1,255 contacts. Each listing presents the firms locations, contact data including E-mail addresses, biotechnology company portfolio, and stages funded. Companies that could not be included owing to insufficient information and those that are no longer investing in biotechnology are listed. Indexes of VC firms, company contacts, VC companies by state, and biotech companies and their investors are also included.

Contact: BioWorld, 3525 Piedmont Road, Building 6, Suite 400, Atlanta, Georgia 30305 United States of America. Tel: +1 (404) 262 5535; Fax: +1 (404) 262 5474.

Biotechnology and Development: Challenges and Opportunities for Asia

This book brings together perceptions of eminent experts from the Asian region on some important issues like trade in GMOs, impact of genetic engineering on environment and human health, biosafety management and ethical aspects. The volume draws lessons from the experiences of Asian developing countries and revisits some of the concerns mentioned above. The contributors to the volume draw policy lessons from country experiences in capability building in Asia, in particular on the role of regional cooperation.

Contact: Academic Foundation, 4772-73/23, Bharat Ram Road, Darya Ganj, New Delhi 110 002, India. Tel : + 91 (11) 23245001-04; Fax : +91 (11) 2324 5005



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