VATIS Update Biotechnology . Nov-Dec 2005

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Biotechnology Nov-Dec 2007

ISSN: 0971-5622

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

Co-publisher: Biotech Consortium India Ltd
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India to host Asian biotech training centre

A US$7 million centre is being set up in India to provide biotechnology training and research opportunities for scientists from across Asia. The UNESCO-supported centre will also be a hub for biotechnology research, promoting South-South co-operation. In addition to holding biotechnology training courses, the centre will hold international conferences and workshops. It will also set up a central database of information on Asian biotechnology research. The centre will be run by the Department of Biotechnology, Government of India, and is likely to be located in New Delhi.

India is contributing core funding for the centre, but once it is set up, the government will seek additional funds from United Nations agencies and other international bodies. By promoting networking between researchers in different countries, the centre would aim to encourage collaborative research and development programmes between research centres in Asia.


China to hold international congress on plant biotech

The International Congress of Plant Tissue Culture and Biotechnology will be held in China in August 2006. The Congress will form an opportunity for Chinese plant biologists to learn about the recent international progress in biotechnology and to showcase Chinas current advances in the field. It would also help increase the countrys impact on plant molecular biology, genetics and agri-biotechnology and the application of agri-biotechnology.

The Congress will be held in Beijing from 14 to 18 August 2006. More than 2,000 plant biologists, including four Nobel Prize winners, are expected to attend the Congress to discuss hot topics like the industrial uses of transgenic plants, intellectual property in biotechnology, biosafety and genetically modified plants.

According to Dr. Xu Zhihong, chairman of the International Congress and president of Beijing University, China can develop genetically modified (GM) products on its own. The number of theses published annually by it in top research journals accounts for 10 per cent of the total. Lectures on GM organisms will be organized during the Congress to popularize agri-biotechnology among the public, clearing up some misunderstandings about GM food.


Indian state to set up biotech park

In India, the West Bengal Industrial Development Corporation (WBIDC), a state government agency, has signed an agreement with the Indian Institute of Technology (IIT) in Kharagpur to set up a biotechnology park at Kharagpur in West Bengal. The proposed facility would be established on 100 acres of land near IIT campus at a cost of US$22 million. The project would be developed through public-private partnership and focus on the areas of bioinformatics and industrial enzymes. The proposed park will have an infrastructure of international quality, including an incubation centre.

WBIDC will provide seed capital and plans to organize two investors meet at the end of 2005 to identify prospective financiers. It will then invite an expression of interest for selecting strategic partners with technical support and guidance from IIT. The strategic private partners selected will develop the park with technical help feom IIT, which would take the intellectual property patent of developing the park so that it could sell this theme in international market. The project would also offer reasonable discounts to private players interested in investing in modern healthcare, in vitro medicine, biometrics and industrial enzyme sectors.

Express Pharma Pulse, 29 September 2005

Little difference found in GM potatoes

There is little difference between genetically produced potatoes and conventional varieties, says scientists in Germany and the United Kingdom. The conclusion was reached by scientists at the Max Planck Institute of Molecular Plant Physiology in Potsdam, Germany, and their colleagues from the University of Wales in England. They say the two types of potatoes differ only in substances intentionally incorporated with gene technology.

The scientists compared genetically modified (GM) Desiree potatoes with five conventional varieties. The results of the study showed substances in the Agria, Desiree, Granola, Linda and Solara varieties exhibit a surprising range of variation. However, the GM lines from the Desiree variety lie within the same of range of variation except for a higher content of insulin polysaccharides. There was no evidence of any new, unexpected substances. The GM potato had two different genes for the formation of insulin sugars introduced into it since polysaccharides have a beneficial effect on human intestinal flora. The British Food Standards Agency financed the analyses of nearly 2,800 potato specimens.


India plans city clusters for stem cell research

The Government of Indias Department of Biotechnology (DBT) is planning to set up three Centres of Excellence for stem cell research to initiate focused and targeted programmes on human stem cell research. The research programmes would be structured to ensure the involvement of both basic researchers and clinicians. DBT is in the process of identifying the research programmes and the sites for the purpose. It has encouraged inter-institutional city clusters programmes by involving basic researchers, clinicians and the industry. This includes sharing of information, exploration of collaboration and discussion on emerging policy issues, etc. Such programmes have been conducted at Pune and Vellore and are planned also in Bangalore, Hyderabad and Delhi.

The initiative on stem cell research is part of the overall strategy of DBT to concentrate on developing R&D in emerging areas. The department has been conducting brainstorming sessions on stem cells to identify priorities and to examine the possibilities to enhance research in this area in the country. The main features of the strategy include promotion of stem cell research for therapeutic applications using adult and embryonic stem cells as well as other more readily available sources such as bone marrow, peripheral blood and umbilical cord blood cells.

Major initiatives have already been taken to develop research programmes for haematopoietic, limbal,neural, hepatic, cardiac, embryonic and human corneal stem cells and their preservation. Limbal stem cells are being used at L.V. Prasad Eye Institute, Hyderabad, to repair cornea surface disorders caused by limbal stem cells deficiencies. Under a programme supported by Christian Medical College, Vellore, a technology has been established for collection, purification and transplantation of haplo-identical haematopoietic stem cells. A study conducted at the National Centre for Cell Science, Pune, and the Indian Institute of Science, Bangalore, showed that banana lectins have stem cell preservation activities.

Chronicle Pharmabiz, 22 September 2005

Philippines close to cloning water buffalo

A team of researchers headed by Dr. Libertado Cruz, executive director of the Philippine Carabao Centre, said that it is close to creating the worlds first clone of carabao, the Philippine water buffalo, which could eventually help raise productivity levels for millions of impoverished farmers. The aim of the research is to replicate a super buffalo that would boost the genetic make-up and milk production of the native water buffalo.

Dr. Cruz informed that his team was now in the process of transferring the cloned embryos to a surrogate dam (mother). By the middle of 2006, some live animals could be born. Researchers at the centre had created the embryos by fusing genetic material from somatic cells taken from a Bulgarian water buffalos ear with the eggs of a local carabao. The Philippines has imported about 3,500 Bulgarian buffaloes, which are descendents of a high-yielding Murrah breed of India. The plan was to obtain enough sperm from cloned male super buffalo to start a widespread insemination programme in the Philippines that would create higher-yielding carabaos. There was no danger of the Philippine carabao being entirely replaced by a new breed of super buffalo since there were genetically pure pools of carabao that would be protected.


Iran hopes to cut imports with GM rice

Iran hopes to cut its imports of about 1 million tonnes of rice each year by developing higher-yielding varieties of genetically modified (GM) rice. Iran approved the commercial planting last year of a GM variety called Tarom molaii, an aromatic rice popular among Iranians but not classified among the higher-yielding varieties. The variety yielded an average of 2.2 tonnes per hectare, 10 per cent higher yield than a non-GM counterpart in Iran. According to Dr. Behzad Ghareyazie of the Agricultural Biotechnology Research Institute of Iran, which developed the GM variety, the area planted of GM rice was likely to rise in the following years after high acceptance among farmers and consumers of the variety.

The GM rice introduced in Iran is resistant to the stem borer pest, the main rice pest in the country, which normally infests up to 25 per cent of harvest each cropping season. Countries in Asia, like China, India and the Philippines that are pursuing research on other GM varieties, are closely watching developments of the GM rice in Iran. The GM rice released in Iran was commercialized after nearly 10 years of risks assessment, including field trials. The first GM variety came from Iran and scientists at the International Rice Research Institute in the Philippines helped to modify the rice to resist attack by insects.


Chronicle Pharmabiz, 22 September 2005

Half-animal, half-plant microbe flags evolution process

Scientists in Japan have found a mysterious marine microbe, half the cells of which eat algae like animals while the rest perform photosynthesis like plants. Professor Isao Inoue, a member of the University of Tsukuba research team, said that he believes the microbe demonstrates part of the process of single-cell marine microbes evolving into plants.

The scientists discovered the single-cell microbe, a kind of flagellate, on a beach in Wakayama Prefecture, and called it hatena (mystery). The microbe is originally green and is made up of algae. When it divides into two cells, one takes over the algae from its parent and remains green and the other turns colourless. The animal-type, colourless cell develops an organ like a mouth and uses it to eat algae, while the plant-type green one utilizes algae it has in its body to perform photosynthesis and produce energy. The research team believes that as the marine microbes evolve into plants, only the chloroplasts in algae they take in their cells develop, while the other organs degenerate.


Chronicle Pharmabiz, 22 September 2005

Another biotech park in India

The Department of Biotechnology, Government of Himachal Pradesh, is planning to set up a biotechnology park on about 134 acres of land near Solan with private participation. The total cost of the project is estimated to be US$33 million. The Government of India has already sanctioned US$2 million for incubator equipment and its share for land and core infrastructure.

The private investor is expected to contribute towards the remaining capital and recurring cost of the incubator facility, as well as make capital investment for infrastructure development in the Biotechnology-Industrial Park. The government is allotting the entire land on long-term lease after competitive bidding. The private investor would build, operate and manage the park on a long-term basis.

Chronicle Pharmabiz, 22 September 2005

Protection for bananas diversity

Efforts to conserve the genetic diversity of bananas economically the worlds fourth most important crop have been boosted by the creation of an international centre for research and training. The centre was set up in October at the Catholic University of Leuven in Belgium under an agreement between the university and the International Plant Genetic Resources Institute (IPGRI).

Bananas are a major crop throughout the developing world. But conserving the genetic diversity of different varieties is difficult because most are seedless and reproduce by sprouting directly from a parent plant. Therefore, samples of these varieties cannot be stored in conventional seed banks.

The agreement recognizes the expertise of the university in safely freezing plant material a technique it will pass on to researchers from developing countries, according to IPGRI. For two decades, the university has hosted the worlds largest collection of bananas with samples today of some 1,175 varieties. Scientists can use this resource to develop bananas with traits desired by both farmers and consumers.



GangaGen and Elanco tie up for anti-bacterial products

GangaGen Life Sciences India (GLSI), Bangalore, India, has entered into a collaborative research, licence and commercialization agreement with Elanco Animal Health, a division of Eli Lilly of the United States, to develop anti-bacterial products derived from bacteriophages. The tie-up will build on GLSIs phage technology expertise and Elancos commercial experience to jointly develop and commercialize phage-based products for the control of dangerous bacteria that pose problems for human and animal health.

The initial emphasis of GLSIs phage development would be on the control of the Escherichia coli O157:H7 pathogen, which causes serious food-borne illness in humans. GLSIs strategy is to eliminate pathogenic E. coli in cattle before the animal is processed for food. The company has already demonstrated in pre-regulatory trials with cattle that its phage product works to reduce the E. coli O157:H7 burden. There are currently no effective treatments to reduce bacterial pathogens in food animals prior to their slaughter. GLSI is also developing bacteriophage-based products for the prevention and treatment of bacterial infections resistant to antibiotics. It has developed proprietary technology for the production of phage products like the elimination of Staphylococcus infection, treatment of urinary tract infection and Pseudomonas aeruginosa infection in burns and wounds.

Chronicle Pharmabiz, 29 September 2005

Sinovac to commence trials for pandemic influenza vaccine

The China State Food and Drug Administration (SFDA) has approved the starting of human clinical trials for prototype pandemic influenza (H5N1, bird flu) vaccine made by China-based Sinovac Biotech Ltd. SFDAs regulatory agency for drug and biological products validation, the National Institute for the Control of Pharmaceutical and Biological Products, closely monitored and tested the new vaccine throughout the pre-clinical phase. Sinovac plans to start clinical trials soon.
Because of this vaccines uniqueness, the clinical trial process will be modified slightly, from three phases, to only two stages. Pre-clinical trial results showed that the companys pandemic vaccine safely induces a high-quality immune response (immunogenicity) in animals. Scientists will use clinical trials to examine immunogenicity and safety in humans, and to establish the ideal dosage and immunization schedule. Once initiated, preliminary testing for the first clinical stage is expected to take about three months to complete.

The National Institute for Biological Standards and Control (NIBSC) of the United Kingdom provided Sinovac with a reassortant virus strain. This highly infectious H5N1 strain is reassortant of a human influenza virus strain, derived through reverse genetic technology, which is used to imitate the potential pandemic strain. NIBSC reported it conducted safety tests on mice, rats and ferrets, and the results showed the strain to be safe. It should not have biosafety problems while conducting R&D and clinical trials.


Glenmark files for trials on diabetes drug

The Indian pharma major Glenmark Pharmaceuticals has filed an application to commence the first phase of human trials on its prospective diabetes drug molecule GRC 8200 in the United Kingdom. Phase I of the study is expected to be completed in February 2006. The company has also put in place an aggressive clinical development plan for GRC 8200 to reduce the gap with other competing molecules under trial.

Glenmark Pharmaceuticals SA, the companys wholly owned subsidiary in Switzerland, has filed for phase I clinical trials for GRC 8200 with the Medicines and Healthcare products Regulatory Agency (MHRA) in the United Kingdom. Parexel UK, a clinical research organization, will conduct the trials using single and multiple oral doses on healthy volunteers. The study will assess the bio-availability and safety of GRC 8200 in humans. Glenmark plans to initiate a Proof of Concept study in South Africa in January 2006 on diabetic patients. Further, it has started various other non-clinical studies and expects to file an Investigational New Drug with the United States FDA by mid-2006 to begin Phase II.

Chemical Weekly, 11 October 2005

IBM to help accelerate cancer research and treatment

IBM, the United States, has entered into separate agreements with leading cancer hospitals in the country to help accelerate cancer research, diagnosis and treatment. IBM and Memorial Sloan-Kettering Cancer Centre (MSKCC) are building a state-of-the-art integrated information management system to improve the ability of clinicians and researchers to study long-term cancer-related illnesses, identify disease trends and determine success rates. Funded by a US$3 million grant from IBM, MSKCC will include a system to integrate its hospital data with text mining and related analytical capabilities into a unified information management system to facilitate predictive analysis and research. In addition, pathologists at MSKCC are working closely with IBM to create a searchable database for pathology reports.

IBM and the Molecular Profiling Institute (MPI) have partnered to harness new molecular profiling technologies to help diagnose ailments and access information to determine better treatment options. The technology being developed jointly will provide clinicians with diagnostic intelligence and analysis to assist them in making molecular distinctions when diagnosing and treating cancer patients.

IBM is working with CHU Sainte-Justine Research Centres Mother and Child University Hospital Centre to help develop an informatics infrastructure, based on IBMs Clinical Genomics Solution, to better define the genetic markers for acute lymphoblastic leukaemia. Advanced technologies will help the CHU researchers have real-time access to a body of quality data. Clinical data that was once manually extracted from the hospitals patient file will now be electronically transmitted and merged with genomic data to build a Medical Information Repository. This will reduce a query process from days to minutes and allow the development of personalized therapies for various patients.


Jubilant acquires stake in CRO

Jubilant Organosys Ltd., India, has acquired 10 per cent equity stake in Target Research Associates Inc. for US$33.5 million in cash. This is a major initiative that supports Jubilants plan to expand its contract research services globally and makes it the largest Indian contract research organization (CRO) having operations in India and the United States.

The acquisition of Target also enables Jubilant to increase its presence in the United States market, which has the highest concentration of biotech and pharmaceutical companies. It offers an opportunity to Jubilant to strengthen its position as a preferred outsourcing partner to pharma firms to reduce their drug discovery costs and time to market. The integration of Jubilant Clinsys, the Indian CRO of the group, is expected to further enhance business potential in the area of data management and clinical research services.

Target would be able to offer its United States-based clients the benefits of contracting clinical research services from India including high quality, cost competitive data management services and access to a large patient population. This will enable faster patient enrolment, thus reducing the time taken to complete clinical studies.

Chronicle Pharmabiz, 13 October 2005

Invitrogen enters into research collaboration with Chinese centre

Invitrogen Corporation based in California, the United States, has entered into a collaborative research agreement with the National Centre for Drug Screening (NCDS), Shanghai, Chinas only national centre specialized in screening for new drugs. NCDS is home to thousands of unique synthetic compounds and extracts from natural products that are at the core of traditional Chinese medicine.

The collaborative research agreement calls for the cooperative use of proprietary Invitrogen drug discovery technologies, such as GeneBLAzerTM and Polar ScreenTM, as well as development of new assays and techniques specific to the collaboration. These technologies and assays will focus on the high-throughput screening of unique compound libraries against nuclear receptors at the organization. According to Dr. John Printen, Director, Drug Discovery Solutions at Invitrogen, the collaboration would help evelop assays and screening technologies for nuclear receptors, a target disease class that has proven productive in drug development.



Novel cut-and-run gene regulation mechanism

At the Cold Spring Harbor Laboratory, the United States, scientists led by Dr. David Spector have found a new kind of messenger RNA (mRNA) molecule that is converted from non-protein coding status to protein coding status in response to cellular stress such as viral infection. The discovery reveals a cut-and-run mechanism that is likely to control the expression of many genes in humans and a variety of other organisms.

Dr. Spector and team found that under standard growth conditions, a particular population of mRNA molecules lingered in the nucleus indefinitely in structures called nuclear speckles and never reached the cytoplasm. They developed a method for purifying speckles, allowing the identification of not only the many different protein components of speckles but also the mRNAs that are the basis of the new study, which identified the first such mRNA: one transcribed from a mouse gene called mCAT2 that encodes a cell surface receptor.

According to Dr. Spector, the first clue came when they found that the mCAT2 gene encodes two different kinds of mRNAs; the standard protein-coding version that is exported to the cytoplasm as usual and an atypical version that remains in the nucleus. Further studies revealed that the mCAT2 receptor is involved in the production of nitric oxide, and that nitric oxide production is stimulated by various stress conditions including wound healing and viral infection. Based on this, the scientists hypothesized that when cells are stressed, the atypical messenger RNA is released from the nucleus, exported to the cytoplasm and translated into protein, thus circumventing the time-consuming process of producing new mRNA and providing a rapid response to viral infection or other stresses.

To test this idea, the researchers mimicked the effect of viral infection by treating cells with interferon. They discovered that the atypical mRNA in the nucleus was rapidly cleaved in response to the treatment, and that the protein-coding portion of the molecule was then quickly exported to the cytoplasm and translated into protein. This cut-and-run mechanism is a completely new paradigm of gene regulation, and studying it would have broad implications for biology and biomedical research.


A new target in fight against obesity and diabetes

A team of scientists led by Dr. George Thomas of Genome Research Institute and Department of Genome Science, University of Cincinnati, the United States, has identified a possible new target for treating obesity and diabetes. The new target, a molecule called hVps34, is activated by amino acids entering the cell. This molecule triggers the activation of an enzyme, S6 kinase 1(S6K1).

Normally turned on through a series of reactions initiated by the presence of insulin, S6K1 works to drive growth. But it also has a second regulatory function. When an organism overfeeds, S6K1 becomes hyperactive and signals insulin to stop bringing more nutrients into the cell. This hyperactive regulation results in insulin resistance. The researchers found that insulin and amino acids, both of which play critical roles in driving cell growth, work through independent pathways to trigger a molecule that turns on S6K1. Once S6K1 signals insulin to stop working, this enzyme would become inactive and its other function of promoting growth would also stop. But in laboratory studies, Dr. Thomas and his team noticed that mice on high-fat diets continued to grow, even after insulin quit performing its normal function, indicating the active state of S6K1. Learning that S6K1 can actually be turned on by more than one pathway is important, because it represents a potential target to regulate obesity and diabetes.

Chemical Weekly, 11 October 2005

Quaking gene is candidate to suppress tumour growth

In the United States, a team of researchers from the Northwestern University and the University of Wisconsin has shown that the quaking gene, first described as a mutation in mice that causes rapid tumour, is likely to suppress tumour growth. The team led by Dr. Philip Iannaccone postulates that the gene does this by inhibiting production of a protein associated with GLI1, a cancer-causing oncogene highly associated with severe birth defects and several childhood cancers.

Development occurs as a coordinated series of genetic control events that create proliferation of cells signals for further differentiation, proteins that define cellular function and programmed movement of cells into developing structures. These processes, known as pattern formation, are controlled largely by signal transduction pathways that receive signals from outside the cell in the form of protein interaction with the cell surface. A signal transduction pathway critical to early development of humans and animals involves the genes Sonic hedgehog (the signal) and GLI (the transcription factor). Mutations in this GLI family of three genes, first discovered in a human brain tumour, cause severe birth defects and devastating cancers in humans.

According to Dr. Iannaccone, while some cancers are explained by known defects in the regulation of the GLI1 gene, for many cancers the reasons for excessive GLI1 protein are not known. It is likely that the protein levels and activity of GLI1 are regulated at levels other than the gene. The form of regulation occurs after the gene makes messenger RNA (mRNA). The scientists showed that after the mRNA for GLI1 is made, it binds to the quaking protein and inhibits the translation event. This means that all controls that the cell has on the gene for GLI1 can be present and active and the GLI1 will still not be produced. The formation of these RNA protein complexes is a very ancient form of regulation of protein function.

Results of the study open a new research direction for issues ranging from cancer formation to environmental interactions in development and may point the way to similar mechanisms of control in other genes.


Rhythm gene discovered

Researchers led by Dr. Andres Villu Maricq, a professor from University of Utah, the United States, have found a gene that controls rhythmic events in a worms life swallowing food, laying eggs and excretion. If the gene is disabled, the worms cannot swallow, so they die; if the gene is partly restored so that the worms can swallow, they have trouble reproducing and get constipated.

The study deals with ultradian rhythms that control such body functions as heart rate, breathing, swallowing and contraction of the intestines. The gene that controls ultradian rhythms in worms is related to other genes that, when mutated, cause uncontrolled growth of mammalian cells a hallmark of cancer. Understanding how the working of the gene may help learn how to interfere with it a possible way to find new cancer drugs.

The researchers discovered in the worm Caenorhabditis elegans a gene they named vav-1. The gene is related to three similar human genes and controls the rhythmic contractions of smooth muscle in three parts of the worms body by regularly raising and lowering calcium levels in the muscle cells. The parts are: the pharynx, which is the worm equivalent of the throat and must undergo a wave-like expansion and contraction every one or two seconds so the worm can swallow; the gonadal sheath, a tube-like smooth muscle structure that contracts every seven seconds during ovulation, squeezing out eggs; and the intestines, which must pressurize and then release so the worm can defecate every 45 to 50 seconds.

The chain of molecular events begins when the vav-1 gene is used to make the protein vav-1. The protein activates other proteins made by Rho/Rac genes. Then the Rho/Rac proteins turn other genes and proteins on and off. The study found that when Rho/Rac proteins are turned on, levels of a chemical named IP3 increase in cells. IP3 attaches to receptors on the endoplasmic reticulum, a calcium-filled membrane bag inside each cell. IP3 makes the endoplasmic reticulum release calcium into the cell. Ups and downs in calcium levels control the rhythmic contractions responsible for swallowing, ovulating and defecating.

When the scientists disabled the vav-1 gene, the worms could not swallow food and died before the end of the first larval stage, or 10 to 12 hours into their normal two-week lifespan. When the researchers restored the vav-1 gene just in the pharynx to enable the worm larvae to eat, survive and grow to adulthood, the worms rarely were able to produce offspring and their 50-second defecation cycle became irregular, with the mean time between cycle increasing to 195 seconds.

According to Dr. Maricq, they have found a gene that is important for the control of fundamental rhythms in nematode worms and the same gene products that control the fundamental processes of life in mammals also are found in the worm. The study suggests this gene and related genes may have critical roles in controlling rhythmic behaviours in humans and other animals.


Model of genes that induce abnormality in skin cells

In the United States, Dr. Mary J. C. Hendrix, president and scientific director of the Childrens Memorial Research Centre, and colleagues have developed a three-dimensional model that shows how interacting with the microenvironment of metastatic melanoma cells induces normal skin cells to become similar to aggressive cancer cells that migrate and spread throughout the body.

Metastatic cancer cells show increased tumour cell invasion and migration, as well as an undifferentiated or plastic nature. The researchers hypothesized that this poorly differentiated cell type serves as an advantage to aggressive cancer cells by enhancing their ability to metastasize virtually undetected by the immune system. The current study tested the hypothesis that the microenvironment of metastatic melanoma cells could induce benign skin cells to become cancer-like.

They seeded a particularly aggressive form of human metastatic melanoma cells onto a three-dimensional collagen matrix and allowed the cells to precondition the microenvironment for several days. The malignant melanoma cells were then removed and the matrix was left intact. Normal human skin cells were seeded onto the matrix and allowed to remain for several days. The cells were later reprogrammed to express genes associated with a highly plastic cell type similar to the aggressive melanoma cells used in the study. Removal of the transdifferentiated skin cells from the melanoma microenvironment caused the cells to revert to their original appearance.

According to Dr. Hendrix, the findings offer new insights into the influence of the tumour cell microenvironment on the transformation of normal skin cells, as well as on genetic triggering mechanisms and signalling pathways that could well be targeted for novel therapeutic strategies to inhibit the spread of melanoma.



Global HIV/AIDS vaccine undergoing clinical test

The National Institute of Allergy and Infectious Diseases (NIAID), the United States, has announced the second phase of clinical testing of a novel vaccine targeted to multiple HIV sub-types found worldwide. The study investigators plan to enrol a total of 480 participants at sites in Africa, North America, South America and the Caribbean to test the safety and immune response to the vaccine. The trial marks an important step in the rapid development and effective candidate AIDS vaccine, according to Dr. Anthony Fauci, Director of NIAID.

The vaccine, developed by a team of scientists at the Dale and Betty Bumpers Vaccine Research Centre (VRC), combines synthetically modified elements of four HIV genes found in sub-types A, B and C of the virus the sub-types commonly found in Africa, the Americas, Europe and parts of Asia. These sub-types represent about 85 per cent of HIV infections worldwide. This is the first Phase II study of a vaccine candidate that is broadly relevant to the global AIDS pandemic because it combines components of HIV strains found all over the world. The Phase II study will test the safety and ability of the vaccine to generate an immune response in 480 healthy, HIV-negative adult volunteers aged 18 to 50 from populations particularly hard-hit by AIDS.

The trials will be testing a prime-boost strategy composed of two vaccine components given at different times. Both contain synthetic versions of four HIV genes: gag, pol, nef and env. The env gene codes for an HIV coat protein that allows the virus to recognize and attach to human cells; the other three come from HIV sub-type B, the primary virus found in Europe and North America. The vaccine incorporates modified env genes from sub-types A and C, common in Africa and parts of Asia, as well as sub-type B. The two vaccine components differ in how the genes are packaged. One contains only the naked gene fragments, which cannot reconstitute into an infectious virus. The other uses a weakened adenovirus as a vector to shuttle the non-infectious gene fragments into the body.


Gene therapy potential for treatment of pancreatic cancer

A Chinese research team at the Department of Gastroenterology, Ruijin Hospital, Shanghai, has found that a gene responsible for the production of a protein called vasostatin could open a new way to treat pancreatic cancer. Currently, the only viable treatment is surgery since radiotherapy and chemotherapy have little impact on the disease. The team investigated the potential of vasostatin to suppress the development of new blood vessels and pancreatic tumour cells both in test tubes and in mice with pancreatic cancer. Solid tumours, such as pancreatic cancer, are heavily dependent on a rich blood supply to enable them to grow rapidly and spread throughout the body.

The protein gene was incorporated into an adenovirus so that it would be able to penetrate the cells, acting as a vector. The test tube experiments showed that 72 hours after infection with the genetically modified virus, vasostatin was clearly active in the tissue and tumour growth in the mice was curbed. When compared with mice that had not been infected with the virus, the difference between the two groups was highly significant. The researchers then looked more closely at the pancreatic cells and the cell linings of the blood vessels. They found that though vasostatin seemed to have little impact on the pancreatic cells, it blocked the formation of new blood vessels, effectively cutting off the supply of nutrients to the malignant cells. This effect was seen in both the test tube and animal experiments. This type of gene therapy may be a new strategy to treat many malignant tumours.


Multiple sclerosis progression linked to immune-cell substance

Dr. Caroline C. Whitacre, professor of molecular virology, immunology and medical genetics and her team at the Ohio State University Medical Centre, the United States, have found that a substance made by immune cells plays a key role in the progression of a disease in animals that closely mimics multiple sclerosis (MS). The findings further suggests that blocking the molecule an immune-system signalling molecule known as macrophage migration inhibitory factor (MIF) might prevent the progression of the disease. The study was conducted using mice that develop EAE or experimental autoimmune encephalomyelitis, a disease that mimics MS, and these animals were compared with mice that lacked MIF.

The mice develop the disease after being inoculated with a myelin protein. After inoculation, the mice with the MIF gene showed progressive EAE. In contrast, the mice lacking the MIF gene had signs of early disease but recovered after about 20 days and showed no further sign of EAE progression. It was also found that MIF blocked the steroid hormone corticosterone; animals missing MIF had high levels of the steroid, while those with MIF showed very low levels. The level of the hormone, in turn, caused critical immune-system changes in the animals that were likely to affect the disease. For example, the mice with MIF (and low levels of the steroid hormone) showed high levels of immune-system cytokines or products that promote inflammation. Mice that lacked MIF (and had high levels of the steroid) showed high levels of immune-system cytokines or products that suppress inflammation. The study suggests that the inhibition of this steroid hormone by MIF has an important influence on the immune system and in determining the diseases progression.


Novel diabetes drugs developed

Researchers from the University of Ulster in the United Kingdom have discovered that by generating stable long-acting forms of GIP, which is a form a naturally occurring molecule produced by the body, two principal modes of anti-diabetic action could be achieved. GIP has been shown to have great potential as a highly effective, tumour-specific, non-toxic therapeutic for the treatment of a variety of oncological diseases, including non-small cell lung, hormone-dependent and hormone-independent ductile, glandular breast, prostate, colon, ovarian, skin and other cancer types.

Two distinct therapeutic products have been developed from GIP, which is released into the blood following eating based on earlier research done by the team. Pre-clinical studies revealed that both therapeutic products exhibit potent glucose-lowering actions mediated by either increasing circulating insulin or enhancing insulin action. GIP-based therapies are new approaches that offer advantages over existing and emerging diabetes/obesity therapies. It currently has two GIP drugs in its pipeline Incretide and Metalog whose actions are regulated by circulating levels of blood glucose.


Genetic switch involved in cells response to camptothecin

A research team led by Dr. Allan Chen, assistant professor of radiation oncology at the UC Davis Cancer Centre, the United States, has found that a gene involved in DNA repair has a major role in deciding how cells respond to radiation therapy. Ku86 acts as a switch: when turned off, it makes cells significantly more vulnerable to the radio-sensitizing property of the anti-cancer drug camptothecin. The discovery may help researchers design new anti-cancer agents that enhance the effectiveness of radiation therapy with less toxicity than currently available radio-sensitizing drugs.

Ku86 had no effect on the radio-sensitizing abilities of other anti-cancer agents such as etoposide, cisplatin and vinblastine. Ku86 also had no effect on camptothecin toxicity. The researchers concluded that Ku86 uniquely affects radiosensitization, but not cytotoxicity, induced by the drug. They began by identifying which enzymes affect radiosensitivity and cytotoxicity and then found a way to control such enzymes. The investigation focused on the enzyme DNA topoisomerase I, which is responsible for cutting single DNA strands so that the DNA molecule can rotate and unwind during transcription and replication. Camptothecin stops DNA topoisomerase I during the unwinding process, ultimately killing the cell.


Cancer virus can infect human cells

Dr. Francoise Rouault and colleagues from the Christian-Doppler Laboratory for Gene Therapeutic Vector Development at the Veterinary Medicine University, Vienna, Austria, have demonstrated that a virus that causes mammary cancer in mice can infect human cells. The study provides valuable data on the role of Mouse Mammary Tumour Virus (MMTV) and opens up several important avenues for future research. It also attempts to shed light on the debate whether a virus-like agent is involved in human breast cancer.

The scientists developed recombinant MMTVs carrying an inserted fluorescence gene. These MMTVs were able to infect human cells of diverse origin such as breast or cervix tumour-derived cells multiply and infect further cells. The study revealed that the efficiency of infection of human cells was, in the best case, comparable to that obtained during infection of mouse cells and, in the worst case, only ten times lower. Infection requires intact MMTV envelope proteins and is blocked by heat inactivation or specific anti-viral neutralizing antibodies.

Some scientists maintain that the presence of MMTV DNA is more due to contamination than infection, as MMTV does not have the necessary key to successfully infect human cells. Even if this turns out to be true, the data are important since MMTV can also be engineered as a means of efficiently delivering therapeutic genes and may prove particularly useful in the future treatment of breast cancer.


Stem cells to grown into cartilage

Scientists at the Imperial College, London, the United Kingdom, have successfully converted human embryonic stem cells into cartilage cells. The research involved growing human embryonic stem cells together with cartilage cells in Petri dishes in a specialized system that encouraged the stem cells to change into cartilage cells. When compared with the human embryonic stem cells grown alone, the stem cells and cartilage cells mix was found to have higher levels of collagen, the protein constituent of cartilage.

The cells were implanted in mice on a bioactive scaffold for 35 days. When they removed the scaffold, the cells were found to have formed new cartilage, showing that they can be successfully transplanted in living tissue. The scientists believe this technique could be used in plastic surgery. When removing head and neck cancers, cartilage parts are often cut away and then grafts taken from other parts of the body. This new technique would enable doctors to take stem cells from the patient, culture them and then transplant them after the surgery.



Protein in heart and adrenal gland critical in heart failure

Dr. Walter Koch, director of the Centre for Translational Medicine at Jefferson Medical College, Thomas Jefferson University, the United States, and his co-workers have found that GRK2, a protein that plays an important regulatory role in heart failure, also exerts powerful effects on the adrenal gland and is a potential drug target for heart failure. The team had earlier shown that in heart failure, GRK2 (G-protein coupled receptor kinase 2) is increased in the heart. It shuts off beta-adrenergic receptors, desensitizing them. When the heart is failing, the bodys sympathetic nervous system goes to work, releasing catecholamines hormones such as epinephrine and norepinephrine in an attempt to stimulate the heart.

Catecholamines are released from two sources: nerve terminals and the adrenal gland. Dr. Koch and team examined adrenal glands from mice in heart failure and found GRK2 increased. When catecholamines are released, a feedback system that works through alpha 2-adrenergic receptors is the brake on the system. They found that mice in heart failure had high levels of GRK2 in the chromaffin cells in the adrenal gland, which caused the down-regulation and desensitization of alpha 2-adrenergic receptors. Catecholamine release was also high in adrenal cells in heart failure. When the scientists reduced GRK2 levels using an inhibitory peptide, ARKct, catechomine release went down and the alpha 2-receptor function was restored. It appears that the increased GRK2 is a mechanism for catecholamine release, and contributes to the high catecholamines in heart failure. The findings show that not only is GRK2 a target in the heart for heart failure but also in the adrenal gland.


RNA splicing occurs in nerve-cell dendrites

Researchers led by Dr. James Eberwine from University of Pennsylvania School of Medicine, the United States, have discovered that nerve-cell dendrites have the capacity to splice messenger RNA (pre-mRNA), a process once believed to only take place in the nucleus of cells. By uncovering this capability in dendrites, the investigators hope to relate this capacity to memory and learning, as well as cognitive dysfunction.

During pre-mRNA splicing within the cell nucleus of a mammalian cell, a gene is copied into pre-mRNA, which possesses both exons (mature regions destined to code for proteins) and introns (non-coding regions). The splicing works by cutting out introns and merging together the remaining exon pieces, resulting in a final mRNA capable of being translated into a specific protein.

Dr. Eberwines lab was successful in showing that splicing can occur in dendrites through the detection and quantification of pre-mRNA splicing as well as the translated protein in single isolated dendrites. Since the splicing machinery is present in dendrites, when activated, pre-mRNA present naturally in the dendrite may be spliced and translated, giving rise to many different proteins. The regulation and timing of the protein expression is what make the central nervous system function. Failure in protein regulation or proper expression in neurons may give rise to cognitive dysfunction. By revealing the capacity of pre-mRNA splicing in dendrites, the researchers hope to understand its role in cognition and dysfunction.


HIV efficacy from frog secretions

A team of scientists led by Dr. Derya Unutmaz, associate professor of microbiology & immunology at Vanderbilt University Medical Centre, the United States, has discovered that compounds secreted by frog skin could be used as a successful treatment in the fight against HIV infection. The findings take a unique approach that could lead to topical treatments for preventing HIV transmission.

The scientists focused on the specialized granular glands in the skin that produce and store packets of peptides, small protein-like molecules. In response to skin injury or alarm, the frog secretes large amounts of these antimicrobial peptides onto the surface of the skin to combat pathogens like bacteria, fungi and viruses. The scientists screened 15 antimicrobial peptides from many frog species for their ability to block HIV infection of T cells, immune system cells targeted by HIV.

The Australian red-eyed tree frog, Litoria chloris, had the highest levels of peptides that block HIV infection. The peptides appeared to selectively kill the virus, with the researchers theorising that the peptides inserted themselves into the HIV outer membrane envelope, creating holes that cause the virus particle to fall apart. The antimicrobial peptides did not harm the T cells at concentrations that are effective against the virus, since HIVs outer membrane is derived from, and therefore essentially identical to, the cellular membrane. The researchers propose that the peptides act selectively on the virus in part because of its small size relative to cells.

In further tests, the researchers allowed cultured dendritic cells to capture active HIV, incubated the HIV-harbouring dendritic cells with antimicrobial peptides, washed the peptides away, and added T cells. It was found that normally the dendritic cell passes the virus to the T cell, and a very efficient infection of the T cell take place. However, when the dendritic cells were treated with peptides, the virus was gone. The investigators currently are using imaging technologies to test the hypothesis that HIV is actually cycling to the dendritic cell surface.


DNA enzyme target exhibits great dexterity

Scientists from the Howard Hughes Medical Institute, the United States, have demonstrated that the helicase enzyme, which normally crawls along the length of a DNA strand during its function in replication and other processes, exhibits flexibility when it meets an obstacle. The enzyme snaps back to its original position on the DNA strand to begin the process again. The discovery could help those with Bloom syndrome a helicase-related disease who show an increased propensity for many types of cancer. The helicase involved in this disorder appears to play a role in the general maintenance of genomic integrity.

In their test tube experiments, the scientists concentrated on the engine component of a helicase called Rep from the bacterium E. coli. They followed Rep engines motion along the DNA strand by tagging it with a green fluorescent dye and also attatching a molecule of a red fluorescent dye to the destination end of the DNA strand. As Rep approached a blockaded end of the DNA strand, the researchers expected to see a gradual reduction in the red signal and an increase in the green signal. However, the protein did not stop at the blockade and fall off the DNA, but moved back where it began on the DNA. Then it repeated its gradual movement towards the barrier again and repeated the snap-back movement. Once it reached the blockade, it stretched out to grab the DNA strand near its starting point, formed a loop in the DNA and then released its stopping point to bring it back to its beginning. The results suggested that the repetitive shuttling could prevent the accumulation of unwanted proteins on the single-stranded DNA that could prove toxic to the cell.


Herb protein suppresses HIV-1 gene expression

A research team of headed by Dr. Kamel Khalili, Director of Centre for Neurovirology (CNV), the United States, has discovered that a novel protein, p27SJ, extracted from a callus culture of the plant St. Johns wort (Hypericum perforatum) suppresses HIV-1 expression and inhibits its replication.

The researchers were examining extracts from the plant cultured in the laboratory to see if they had any effect on cell growth or the behaviour of brain cells in vitro. During the study, they also looked to see whether these plant extracts isolated from the callus culture had any anti-viral activity and found that the plant extract inhibited HIV-1 gene expression and replication in infected cells. Next, the team sought to isolate the protein from the plant extract responsible for the observed anti-viral activity. After identifying the protein, the group cloned the gene, which they realized was a novel protein and named it p27SJ.

The researchers were able to identify the molecular mechanism by which the protein is able to suppress HIV-1 gene expression and replication. It is the expression of the viral gene and the replication of its genome that lead to the development of AIDS in HIV-infected individuals. The study found that p27SJ is able to inhibit expression of the HIV-1 gene by interacting with both cellular and viral proteins, and block viral replication by interfering with the proteins recruited by HIV-1 to increase viral gene expression.



New pathway into plant cells

At Oregon State University, the United States, Dr. Lynda Ciuffetti and co-researchers have used a pathogen of wheat to discover a new pathway into plant cells. The scientists have identified for the first time a protein that can cross plant cell membranes, where it functions as a toxin to kill the cell. It had been known that viruses and bacteria can penetrate cell wall barriers and disrupt plant cells, but never before has a protein been found that could do this by itself.

The biological mechanism discovered here bears striking similarity to the way proteins can function in mammalian cells scientists say they may have found a characteristic that has been preserved for more than 600 million years, when plants and animals diverged from a common ancestor on their separate evolutionary paths. The process of proteins getting inside of cells and affecting their behaviour is common in animal cells. However, the same process had not been known to exist in plant cells. The research was conducted using a pathogenic fungus that affects wheat by producing multiple toxins that attack wheat plants, reducing yields and ruining wheat used as seed.

According to Dr. Viola Manning, co-author of the study, how the protein produced by this fungus causes disease was not known earlier. None had ever shown before that a protein could move, without a pathogens assistance, from outside a plant cell to the inside. The current study has shown that the protein does penetrate the cell membrane and interact with chloroplasts, finally leading to cell death. The scientists say that this mechanism probably will be found in other cells besides wheat and with other proteins, and it may lead ultimately to some way to help address some plant diseases.


Rice for allergy relief

A research team at Japans National Institute of Agrobiological Science is developing a new variety of rice that could provide relief from sneezing and other symptoms to people who suffer from such allergies. The team has been working with a genetically modified strain of rice that incorporates an allergy-causing protein, which acclimates and thus immunizes the body against the allergen. A test group of mice that was fed the modified grain for four weeks showed fewer allergy symptoms than a control group fed normal rice. According to the Institutes Dr. Fumio Takaiwa, the modification would also be effective in other grains such as corn. The research team, which also includes members from Tokyo and Shimane universities, will next test the rice on monkeys before considering human tests.


Plant cells as miniature factories

At the United States Department of Energys Ames Laboratory at Iowa State University, researchers working for the Mass Spectrometric Imaging of Plant Metabolites project have discovered a gene that allows plants to package and store materials in their cells. The finding may open the door to producing new types of plastics from plants. The researchers would now study the chemical processes that take place within the cells of plants. Understanding of plant metabolism could result in harnessing plants to, for example, efficiently produce biomass, chemicals or industrial materials.

Before they can study the chemical makeup within plant cells, the researchers need new analytical instruments capable of identifying molecules in such minute quantities. They have turned to mass spectrometry, which works by measuring the mass of individual ions. The ability to sort and detect ions at cellular-scale quantities is what the team hopes to fine-tune in instrumentation. Once the equipment is ready, the team will look at the chemical content in Arabidopsis thaliana cells.

Chemical Weekly, 27 September 2005

Using GM plants to clean up heavy metals

Researchers led by Dr. Ru Binggen of the Peking Universitys College of Life, Beijing, have successfully used genetically modified (GM) tobacco and a species of algae to remove toxic heavy metals such as mercury from soil and water. As a cheap and effective way of eliminating heavy metal pollution from the environment, these GM plants carry ample health and economic benefits.

By inserting a rat gene into tobacco and the algae, Dr. Rus team made the plants produce metallothionein, a protein produced in mammalian liver, which binds easily to heavy metals. GM tobacco produces the protein in its roots and can absorb several hundred times more heavy metal ions from soil than normal tobacco. The plants can then be burnt and the heavy metals safely isolated from the ash. The tobacco plants under trial died before they could reproduce. Even so, the method is still much cheaper than using a chemical process to remove heavy metal pollution.

A different method was used with the GM algae: the algae were pasted onto a nylon membrane, which was then lowered into polluted water. After absorbing the heavy metals, the algae-covered membranes were taken out of the water and the heavy metals extracted from them in the safety of a laboratory.


Maize that can weather drought

Dr. David A. Lightfoot and colleagues at Southern Illinois University, Carbondale, the United States, have developed a transgenic maize (corn) that can weather a drought while yielding roughly 10 per cent more than the maize that lacks the SIUC gene, which was obtained from a common soil micro-organism. According to Dr. Lightfoot, this would be a very sensible technology to apply in those locations that are consistently dry.

The genetically modified maize can not only survive but can capture 10 per cent more of the nitrogen in ammonium-based fertilizers than unmodified maize and also can tolerate Liberty, a popular weed killer. It is not as strong a resistance as in the commercial one, but it uses a different mode of action. Ability to make super-resistant crops will matter increasingly in the future as the weeds resistant to herbicides start to spread. In addition, because of a small change in its amino acids, the modified maize may be slightly more nutritious. Maize containing the SIUC gene could go on the market in the next three to five years.


Rice yield breakthrough

At the Shanghai Institute of Plant Physiology and Ecology, China, scientists have found and incorporated in rice a key genetic code responsible for salt tolerance. Dr. Lin Hongxuan and more than a dozen researchers and students spent the past five years completing the project, which is considered a notable achievement in the countrys agricultural development. Researchers from the University of California, the United States, supported the efforts of Dr. Lin and his team, as they traced the genetic material in six generations of a specially grown hybrid rice. Each generation took around half a year to grow. By a technique called precise location, they finally found and cloned the SKC1 gene, which is responsible for salt tolerance in rice. According to Dr. Lin, it would normally take several years for agricultural experts to utilize the discovered gene to optimize rice species and to lift rice yields.


Crops use day-length to trigger flowering

Scientists have known for a long time that plants use cues from their environment to control flowering. Many crops, such as barley, react to the length of the day (day-length) and use this to determine their flowering time. Scientists led by Dr. David Laurie from John Innes Centre in Norwich, United Kingdom, have reported a breakthrough in understanding how crop plants use day-length by describing a gene called Ppd-H1, part of a genetic pathway that controls barleys response to day-length.

Plants, like humans and many other organisms, have an internal clock. In barley, this clock regulates the daily activity of a gene, called constans (CO), so that CO activity increases to a peak and then decreases on a daily cycle. Peak CO activity coincides with the plants exposure to daylight only if the length of the day is long enough. When this happens, CO activates a gene called flowering locus T (FT), which incites flower formation. The Ppd-H1 gene affects the timing of CO expression during the day. A variant of the gene found in late flowering barley causes the peak of CO expression to be shifted to later in the day. This requires a longer day length to enable the FT gene to be expressed and so delays flowering until longer days. This should help breeder breed new varieties.



Biotechnology Research in an Age of Terrorism

An examination of biological research from the point of national security concerns is justified in light of recent happenings. This new book by the National Research Council, the United Sates, recommends that governments expand existing regulations and rely on self-governance by scientists instead of adopting intrusive new policies. One key recommendation of the report is that there should be no attempt to regulate scientific publishing, and that scientists and journals be trusted to screen their papers for security risks. A new International Forum on Biosecurity should encourage the adoption of similar measures around the world. The book identifies seven types of risky studies including making an infectious agent more lethal and rendering vaccines powerless that would require approval, by mechanisms like the Biosafety Committees at several institutions in the United States that oversee recombinant DNA research.

Contact: The National Academies Press, 500 Fifth Street NW, Lockbox 285, Washington, DC 20055, United States of America. Tel: +1 (202) 334 2451.

Biotechnology 1996-2000: The Years of Controversy

Since 1996, biotechnology has been the focus of wide-ranging public controversy and deliberation in the developed world. The debates have been intensified by dramatic developments, such as expanded commercial exploitation of genetically modified (GM) crops and foods and boycotts of GM ingredients in Europe. Biotechnology 1996-2000 includes a time-series analysis of public attitudes interpreted in the context of media coverage and policymaking.

Contact: The Science Museum, Exhibition Road, South Kensington, London SW7 2DD, The United Kingdom. Tel: +44 (870) 870 4771


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