VATIS Update Biotechnology . Jan-Feb 2006

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Biotechnology Jan-Feb 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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In search of a plant-based vaccine for avian influenza

Dow AgroSciences LLC, the Canada-based wholly owned subsidiary of Dow Chemical Co., is to team up with the University of Melbourne, Australia, in the pursuit of plant-made production systems for an avian influenza vaccine. This collaboration is the result of a Linkage Grant from the Australian Research Council. The Macfarlane Burnet Institute and Monash University also partner in this project. Linkage-Projects programme supports cooperative research projects between the industry and higher education researchers for programmes benefitting regional and local communities.

The project aims to provide proof-of-concept for the rapid production of plant-made vaccines for Australias poultry industry, shielding the industry from exotic influenza strains and guarding rural communities from the impact of stock losses. Plant-made production systems offer significant benefits over traditional vaccines as they do not contain any components of animal origin. This feature also makes plant-based vaccines an attractive technology for the future development of swine and human influenza vaccines.


Indian agency seeks funding to boost the biotech sector

In India, the Department of Biotechnology (DBT) has recommended a US$222 million package to provide additional impetus to the countrys biotech sector. According to a five-year biotech development strategy, more emphasis would be placed on promoting innovation, creating a world-class scientific pool and establishing about 50 centres of excellence. The wide range of initiatives mooted by the strategy include fresh infusion of funds and interventions to provide world-class, customized human resource for the industry. The key area of focus is on improving quality in human training and education.

The Indian biotech industry accrued US$1.07 billion revenues in 2004-05, with exports accounting for 42 per cent of this figure, as per a sector survey released in June 2005. DBT has put forward a proposal to set up four technology transfer centres in the country as technology management is a big problem, according to Dr. M. K. Bhan, Secretary of DBT.


Regional biotechnology centre on the anvil in Viet Nam

A biotechnology centre is scheduled to be set up in Ho Chi Minh City, Viet Nam, in the next five years (2006-2010). The facility will enable basic and applied research of scientific themes related to biotechnology, serving agriculture, health and the environment. The centre will receive and transfer, as well as provide, consulting services related to modern biotechnology for manufacturing biological products, train human resources and market goods pertaining to biotechnology. The first phase of construction will be completed in 2008 and the second in 2010.

Chronicle Pharmabiz, 5 January 2006

GM food farm in China

In China, Shanghai province is scheduled to set up its first outdoor experimental farm to test security procedures for growing genetically modified (GM) crops. Expected to be completed by the end of this year, the GM farm would be established in Qingpu district and is anticipated to become a major base for tests on locally developed GM plants and food crops, including corn and fruits. The farm will be isolated from other crop areas to prevent pollen or seeds from being introduced into the food chain.
Different government departments as well as the Shanghai Science and Technology Commission have appropriated about US$500,000 to support this project. The effort was endorsed earlier by the Ministry of Agriculture and is considered a key project by the local government. The new facility will provide valid information, as the crops will be exposed to nature for which the security test period could last from one to several years. Moreover, the entire process of growing GM plants would be closely scrutinized to keep tabs for any negative side effects as the primary concern is that GM plants from the facility may affect vegetation in surrounding areas.


United States EPA to investigate GM food allergies

In the United States, the Environmental Protection Agency (EPA) plans to develop new methods for assessing the potential allergenicity of genetically engineered food, as part of its Science to Achieve Results programme. EPA is issuing a request for applications for research on appropriate methods, either within or outside the framework of the current decision tree, primarily to assess human allergenicity of proteins in genetically engineered foods. A secondary aim is to improve the understanding of the basic mechanisms underlying food allergy and susceptibility to food allergy, as it pertains to genetically engineered foods. EPA is expected to provide around US$3 million for allergy related studies on genetically modified foods in 2006.

Currently, the United Nations Food and Agriculture Organization and World Health Organization have proposed a decision tree to be used in assessing the potential allergenicity of novel dietary proteins. However, many of the components recommended in this decision tree have not been sufficiently developed or validated. Ideal technologies would improve hazard identification and enhance the ability to estimate the potency of unknown proteins relative to known allergenic and non-allergenic proteins in a logistically feasible and cost-effective manner.


Cloning pigs with Alzheimers

Scientists at Foulum Research Centre, Denmark, are trying to clone pigs suffering from Alzheimers disease in a bid to test the several Alzheimers medications readily available. According to Prof. Gabor Vajta, scientists have good reasons to expect that some of the sows pregnant with cloned egg cells would succeed in producing Denmarks first cloned pig in spring. At present, eight nations have successfully produced cloned pigs. However, Denmark is the first place in the world where identical pigs will be used in an attempt to crack the code behind brain diseases like Alzheimers and Parkinsons. By begetting pigs suffering from Alzheimers, and when the ailment becomes apparent in the year-old pigs, scientists can commence testing some of the medicines that are ready for trial.



Antibody for cancer therapy

In the United States, Agensys Inc., a cancer biotechnology company, has formed a global alliance with Merck and Co. Inc. to jointly develop and commercialize AGS-PSCA, Agensys fully human monoclonal antibody (MAb) for prostate stem cell antigen (PSCA). The agreement grants Merck worldwide rights to AGS-PSCA and an exclusive licence to PSCA, a proprietary Agensys target, and rights to other therapeutics and diagnostic products developed under the alliance.
The parties will co-develop and jointly fund AGS-PSCA for prostate cancer and other indications through phase II. Agensys has initiated phase I clinical trials of AGS-PSCA in individuals with advanced prostate cancer at Memorial Sloan-Kettering Cancer Centre and the Johns Hopkins Kimmel Cancer Centre. Merck is responsible for leading the succeeding worldwide clinical development programme, with significant participation by Agensys. Merck has primary responsibility for both marketing and commercial manufacture. Agensys has an option to participate in phase III development and commercialization in the United States. In preclinical studies of human prostate, pancreatic and bladder cancers, AGS-PSCA has consistently demonstrated significant inhibition of tumour growth and metastases, thus increasing survival rates.

Chronicle Pharmabiz, 24 November 2005

Bharat Biotech teams up with Acambis for JE vaccine

The United States-based Acambis has entered into a manufacturing and marketing agreement with Bharat Biotech International Ltd. (BBIL), India, for ChimeriVax-JE investigational vaccine against Japanese encephalitis (JE), a virus transmitted to humans by mosquitoes. JE is the leading cause of childhood encephalitis and viral encephalitis in Asia. As per the agreement terms, BBIL will be responsible for end-stage fill / finish processing of ChimeriVax-JE. Once the vaccine is approved, BBIL will market and distribute the vaccine in India and neighbouring nations. The five-year term of the agreement is open for extension.

Bulk vaccines will continue to be manufactured at Acambis Canton, Massachusetts facility, where material for phase III testing has already been produced following technology transfer and scale-up to commercial-scale manufacture. Acambis is preparing to commence pivotal phase III trials of a single-dose regimen of its ChimeriVax-JE vaccine candidate, having completed phase II clinical testing. The vaccine is likely to be launched in India this year. Acambis plans to target the vaccine at markets in non-endemic regions like the United States, Australia and Europe, as well as in endemic regions like China, Japan, Taiwan, the Philippines, Malaysia, India, Bangladesh and Sri Lanka.

Chronicle Pharmabiz, 24 November 2005

Pursuit for excellence in stem cell research

Stem Cell Sciences (SCS), the United Kingdom, has inked an exclusive agreement with Chemicon International, the United States, for the manufacture and marketing of SCS embryonic stem (ES) cell growth media for the research and drug discovery market. SCS would receive an upfront licence fee, milestone payments related to technology transfer and scale-up, and trademark and royalty payments based on product sales. The total value of this pact is expected to provide a multi-million dollar income stream to SCS in the next 3-5 years.

The new ES cell culture media products offer substantial improvements over animal serum-based media available in the market. According to Dr. Peter Mountford, CEO of SCS, CultiCellTM will change the convenience and reproducibility of growing mouse embryonic stem cells. The media will facilitate large-scale cell production, enabling wider application of stem cells in the discovery of new medicines for central nervous system (CNS) diseases, such as Parkinsons and Alzheimers.

Genetic Engineering News, Vol. 25, No. 20, 15 November 2005

IGK-YM Biosciences agree on developing EGFr inhibitor

Canada-based Cimym Inc., the majority owned subsidiary of YM Biosciences Inc., has joined hands with Singapores Innogene Kalbiotech Ltd. (IGK) to expand the development programme for its humanized, EGF receptor-targeting monoclonal antibody, nimotuzumab. IGK is the biotech subsidiary of P.T. Kalbe Farma Tbk (JK KLBF), a public company based in Indonesia with revenues exceeding US$300 million.

Terms of the licence include an upfront payment of US$1 million, undisclosed milestones and a royalty on sales. The licensed territories include Singapore, Taiwan, Thailand, Indonesia, Malaysia, the Philippines and South Africa, in addition to a number of other emerging markets. IGK will be responsible for development costs in its territories and also proposes to undertake the registration in its territories of all other indications developed by Cimym and its licensees elsewhere and those of other licensees of Cimab SA, YMs partner in Cimym Inc.

Chronicle Pharmabiz, 1 December 2005

Collaboration to develop test for early detection of lung cancer

The United States-based Cangen Biotechnologies Inc. has announced the expansion of its ongoing research collaboration with Olympus Corp., Japan, to develop a hybrid DNA-based and protein-based diagnostic test for use in the early detection of lung cancer. The expanded collaboration includes funding for a prospective clinical study. The goal of this research collaboration is the establishment of a blood-based molecular diagnostic test for early detection of lung cancer. The identification of specific DNA markers is under way. Several key DNA markers with 70-80 per cent accuracy have been identified from resected samples obtained by Cangen from Hyundai Hospital, the Republic of Korea, during 2005. The identified markers can easily be employed as a hybrid with protein-based markers to improve sensitivity and specificity. Olympus and Cangen are aiming for FDA approval after approximately two years.

Cangen has commenced patient recruitment for the study at clinical sites in Asia and will receive funding from Olympus in support of the study and ongoing research and clinical development efforts regarding lung cancer detection. Cangen will oversee the study from its Asia Clinical Trial Centre in Seoul, the Republic of Korea. Dr. Chul So Moon, CEO and Chief Science Officer of Cangen Biotechnologies, expressed that in cooperation with counterparts at Olympus, dramatic progress has been achieved over the last six months in the development of the test and platform for the early detection of lung cancer. This additional commitment by Olympus to reinforce clinical development of lung cancer detection technology underscores the viability of the technology as a key tool in saving human life.

Mr. Richard A. Silfen, President and Chief Financial Officer of Cangen, stated that this opportunity to expand Cangens collaboration with Olympus into the clinical development setting would accelerate efforts to commercialize the lung cancer diagnostic product. Contact: Mr. Richard A. Silfen, Cangen Biotechnologies Inc., United States of America. Tel: +1 (240) 6440 245; Or Mr. Ayako Nagami, Olympus Corp., Japan. Tel: +81 (3) 3340 2052.


Bharat Biotech sets up manufacturing facility in Malaysia

Bharat Biotech International Ltd. (BBIL), India, has entered into a Memorandum of Understanding (MoU) with Perak Development Corporation (PDC), as well as Remco Engineering and Consultancy, for setting up its first overseas unit in Malaysia. BBIL will extend its technical expertise while Remco would build the plant; PDC owns the land. This plant is expected to help BBIL in penetrating into Middle East and Asian markets, specially Indonesia. The new facility, expected to start commercial production by June 2007, will manufacture hepatitis B vaccine initially and take up production of other vaccines later. BBIL will be investing about US$13 million in the new manufacturing facility and R&D.
Development of a rabies vaccine by BBIL is in an advanced state and the vaccine is anticipated to hit the market by the first quarter of 2006. The companys candidate Rotavirus vaccine is ready for clinical trials, which are likely to be completed by 2008-09. BBILs work on malarial vaccine is also in progress, with its first candidate ready for phase I trials. More vaccines, including a couple of combination vaccines, are in the pipeline. ADPT + hep B + Hib combination vaccines are also planned. In due course, therapeutic products and vaccines will account for equal proportion of BBILs offering. Probiotics is another potential area as are growth factors.

Chronicle Pharmabiz, 5 January 2006


Breakthrough reported in plant stem cell research

Totipotent stem cells allow plants to build new organs throughout their whole life. Researchers led by Dr. Jan Lohmann at the Max Planck Institute for Developmental Biology in Germany have uncovered a feedback mechanism, involving a growth-enhancing hormone and a regulatory protein, which controls the number of stem cells the plant produces. This breakthrough has helped demystify the role of hormones and genetic factors in preventing plants from having growth that is either stunted, or uncontrolled and tumour-like.

All above-ground parts of a plant leaves, stem, flowers and seeds are ultimately derived from cells of a small tissue at the tip of the shoot, biologically known as apical meristem. This part contains totipotent stem cells that are active throughout the life of the plant. However, it is crucial that the plant finds the right balance with regard to the number of its stem cells since stunted growth would be the result if either the number of meristematic stem cells increases too quickly or the stem cell pool shrinks rapidly. To date, two regulatory mechanisms have been found to play an important role in maintaining a healthy ratio of meristematic stem cells. The first involves growth-promoting hormones such as auxin and cytokinin while the second involves genetic factors. The latter mechanism was found by researchers at the University of Tabingen who reported that a gene called WUSCHEL has a key influence on how many cells in the apical meristem actually stay as stem cells. Contact: Dr. Jan Lohmann, Max-Planck Gesellschaft, Germany.



Website: www.medilexicon.con

Fungus genomes sequenced

A team of researchers headed by microbiologist Dr. William Nierman at the Institute for Genomic Research (TIGR), the United States, report to have sequenced Aspergillus fumigatus genome. A. fumigatus is a mould that lurks across forest compost to forest greenery. It is the most common mould that causes infection, triggering allergic reactions, asthma attacks and even fatal infections among people with weakened immune systems. Dr. Nierman expressed that the genome sequence would be crucial for developing tools to effectively manage A. fumigatus infections as they become more prevalent in the ageing population.

The A. fumigatus genome is 28 MB in size and comprises eight chromosomes bearing a total of almost 10,000 genes. The fungus can tolerate temperatures up to 70C and becomes a human pathogen as it is perfectly comfortable at body temperature (around 37C). By altering ambient temperatures in the lab, TIGR scientists tracked gene activity, documenting different A. fumigatus genes that turned on and off, as the environment warmed. Suspect genes encode proteins involved in central metabolic pathways, cell signalling, cell wall biosynthesis, pigment biosynthesis and secondary metabolite production. Researchers plan to systematically knock out or disable, genes that may make A. fumigatus infectious, which could lead to better therapies for serious asthma, allergy and other conditions.


Genetic code for control of gene expression

At the University of Helsinki, Finland, a team of molecular biologists, developmental biologists and computer experts reports to have achieved significant progress in cracking the code for how gene expression is controlled. It is evident that genes are expressed in tightly controlled spatial and temporal patterns. However, scientists were not aware of the code by which the expression was regulated.

Researchers led by Prof. Jussi Taipale have defined the binding specificities of several transcription factors, DNA-binding proteins that are required to activate gene expression. The team designed a software called enhancer element locator (EEL) to search genomic sequence for regions where many transcription factors bind DNA side by side. Finding the same region with high frequency of transcription factors in several species indicates that the DNA element regulates gene expression. The team even showed that the predicted regulatory elements direct organ-specific expression of a marker gene in transgenic mice. Experimental and computational methods enabled genome-wide analysis of regulatory elements in several species.


Role of microRNA identified in thyroid cancer

It has been known that some people inherit a predisposition to developing papillary thyroid cancer (PTC), the most common form of thyroid cancer representing around 80 per cent of all cases. Although changes in key cell signalling systems and gene translocations are sometimes evident in thyroid tumours, no specific gene mutations have yet been identified that are directly linked to the predisposition of this type of cancer.

In the United States, a team of researchers led by Dr. Huiling He at the Ohio State University Comprehensive Cancer Centre, investigated the role of microRNA (miRNA) in thyroid cancer. miRNAs, genetic material not longer than 22 or so nucleotides in length, can latch on to part of the messenger RNA and scramble its ability to properly carry out the original coding instructions. The team examined samples of malignant tissue from 15 patients diagnosed with PTC and compared them with normal tissue adjacent to the tumours. It found 23 miRNAs that were significantly altered in the cancerous tissue when compared with the normal samples, with three of the miRs miR-146, miR-221 and miR-222 dramatically over-expressed, registering 11-19 fold higher levels of expression in the tumours than in the unaffected tissue nearby. Further studies revealed that two more miRs, miR-21 and miR-181a, when coupled with the three that showed over-expression, formed a signature that clearly predicted the presence of malignant tissue.

It was also discovered that miR-221 expression found in all of the apparently normal tissue of the patients with PTC was significantly over-expressed in a subset of three of the samples, suggesting that increased activity of miR-221 may be one of the earliest signs of carcinogenesis. Scientists believe miRNAs act like oncogenes, molecules that promote cell growth, and they also feel they may be tumour and tissue specific. For example, in many other forms of cancer, miRNA activity is suppressed, but in PTC, researchers found just the opposite 17 of the 23 miRNAs they discovered were over-expressed. The team is hopeful that these findings could help point the way towards new options in diagnosis and treatment for this disease.


More light on transcription-induced chimerism

Transcription-induced chimerism (TIC) is a widespread phenomenon in the human genome wherein two adjacent genes produce a single, fused RNA transcript. Dr. Roderic Guigs group from the Centre de Regulaci Genmica , Spain, in collaboration with a group led by Dr. Stylianos Antonarakis from Geneva University, Switzerland, and Dr. Rotem Soreks team from Israel, have independently derived estimates that at least 2-5 per cent of genes in the human genome are involved in TIC.

Dr. Soreks team systematically identified over 200 cases of TIC involving 421 human genes. The team found that genes involved in TIC events often reside closer together than other gene pairs in the genome. Furthermore, intergenic sequences of TICs were processed via the same standard eukaryotic splicing machinery that removes introns from RNA transcripts. Following a similar whole-genome survey of splicing events, Guigs lab focused on the ENCODE regions, a set of DNA sequences, representing 1 per cent of the genome, that have been selected by a large research consortium for more rigorous, in-depth analyses. When focusing on these regions, researchers identified six TIC events (involving 3.6 per cent of tandem gene pairs), only one of which was identified during the whole-genome survey. This indicates that future investigations of specific regions may reveal a greater prevalence of TIC events genome-wide.

The team unravelled an interesting gene fusion event involving genes called PIP5K1A and PSD4, which reside side by side on human chromosome 1. These genes produce a fusion product that, during the course of evolution, inserted into a different site in the human genome (chromosome 10), becoming a new gene which is actively transcribed in a variety of tissues. According to Dr. Sorek, these findings might have applications in drug development. Recombinant engineered fused proteins are currently being developed as therapeutic proteins by several companies and institutes. However, the problem is that these proteins often elicit an immune response and therefore are toxic and cannot be used as efficient drugs. The understanding that some gene pairs are naturally produced as fused proteins might lead, in the future, to the development of non-toxic engineered fused proteins that could be used as drugs.


Fertility genes discovered

In the United States, researchers at the State University of New Jersey have discovered two genes required for fertilization to occur, named egg-1 and egg-2. The team was led by Dr. Andrew Singson and Pavan Kadandale, a graduate student. The proteins encoded by these genes are similar to low density lipoprotein (LDL) receptors, known from cholesterol and fat metabolism but never before specifically implicated in fertilization. The team also found that in the absence of these two genes, the vital process of fertilization is halted.

Fertilization can be a paradigm for gaining insights into how cells interact over the life and development of multi-cellular organisms because it is one of the most basic of cell-cell interactions. The underlying cell biology is going to be universal with applications even in infectious diseases, such as AIDS, where the virus passes its genetic material to the cells it infects just as fertilization transmits sperm DNA to the egg. Genetic tools such as RNA interference (a way of removing gene function) and gene knock out mutants were used to see what would happen if worms lacked the function of egg-1 or egg-2 genes. The results were that the worms became sterile because fertilization had failed to occur. Normal sperm could no longer get into the eggs produced by egg-1 and egg-2 mutant hermaphrodites.

Dr. Singsons group picked the two egg genes as an educated guess based on research that Dr. Singson had previously conducted with a group of sperm genes. Mutations in sperm genes prevented the sperm from fertilizing normal eggs. The hope was that the sperm genes, together with the newly discovered egg genes, would be the lock and key that mediate normal fertilization. For a sperm to enter an egg, the sperm has to recognize the egg and ignore other sperms/cells in the environment. Then there are interactions needed to get the surface membranes of both the sperm and egg to fuse, a critical initial step in fertilization. Results confirm that along with the previously identified sperm genes, egg-1 and egg-2 encoded molecules are a key component of the cellular machinery required for successful fertilization in worms.


Genes fine-tune muscle development process

A group of scientist headed by Dr. Da-Zhi Wang at the School of Medicine, the United States, has isolated genes that fine-tune the muscle development process. These genes are part of a recently discovered group of genes known as microRNAs (miRNAs). Though miRNAs were first identified in worms about a decade earlier, they have been recognized as essential gene regulators only in the past few years.

Muscle tissue is generated when myoblasts, or pre-muscle cells, stop proliferating and instead undergo irreversible changes (differentiation) that cause them to become myotubes, or mature muscle cells. Dr. Wangs group studied two miRNAs miR-1 and miR-133 found exclusively in muscle cells. As their genes are located very close to one another, miR-1 and miR-133 are always expressed together, yet they carry out opposing tasks. Dr. Wang expressed that this was the first case wherein two miRNAs are co-expressed together but perform different functions.

Investigations revealed that both the miRNAs are instrumental in determining if myoblasts proliferate or differentiate. It was found that increasing the amount of miR-1 caused myoblasts to differentiate into mature muscle cells, but prevented their proliferation. To the contrary, raising the amount of miR-133 caused myoblasts to proliferate even more, but precluded them from going through differentiation. Similar experiments carried out in developing frog embryos confirmed these findings. Increasing miR-1 caused more muscle tissue overall and fewer myoblasts, while increasing miR-133 led to more myoblasts but less muscle overall in the frog embryos. The miRNAs, however, are not a blueprint for making protein.



Bacteria in yoghurt block HIV infection

Researchers in the United States report to have genetically altered some friendly bacteria found in yoghurt to release a drug that blocks HIV infection. Dr. Bharat Ramratnam, an HIV specialist at Brown Medical School, and his colleagues modified the genetic make-up of the bacterium Lactococcus lactis so that it generates cyanovirin, a drug that has prevented HIV infection in monkeys and human cells. Cyanovirin binds to sugar molecules attached to the HIV virus, thereby blocking a receptor that HIV uses to infect cells. According to Dr. Sean Hanniffy, a molecular biologist at the Institute of Food Research, Norwich, the United Kingdom, It is basically passive immunization.

L. lactis produces lactic acid and is utilized to manufacture cheese and yoghurt. It is also found in some parts of the human anatomy, including the gut and vagina, where the acid it produces dampens the growth of harmful bacteria. The team opines that since lactic acid bacteria live naturally in the vagina, a single application of the bacterial group should see the modified bugs thrive there for at least a week. Hence, the next step might be to use other bacteria that can survive even longer. Although the bacteria have only been tested in a lab dish, the team is optimistic that the technique could provide a cheaper and more effective way of delivering drugs to fight the spread of AIDS, by getting the bugs to live right where the drugs are required.


Tamil flu-resistant strain of bird flu discovered

Researchers from the University of Tokyo, Japan, and the University of Wisconsin-Madison, the United States, report to have identified a mutated form of H5N1 bird flu that is resistant to Tamiflu, the drug being stockpiled around the world to counter a feared influenza pandemic. Led by Dr. Yoshihiro Kawaoka, the team brought to light this disturbing finding while investigating a case in Viet Nam involving a 14-year old girl who may have caught the flu from her brother rather than directly from infected birds. By sequencing the virus, it was exposed that the virus had a mutation that made it resistant to oseltamivir, the lab name for Tamiflu. However, tests on lab animals showed that the resistant virus is sensitive to another drug known as zanamivir, commercialized as Relenza. These findings raise the possibility that it might be useful to stockpile zanamivir and oseltamivir in case of an H5N1 influenza pandemic.

Chemical Weekly, 22 November 2005

Safer stem cell medium

Dr. Teneille Ludwig and Dr. James Thomson at WiCell Research Institute in the United States have developed a new culture medium for growing human stem cells. Free from animal products, this culture medium offers a cleaner and safer environment for performing the cutting-edge technology. Furthermore, this breakthrough has the potential to allow for therapeutic-use stem cells to be transferred directly to human subjects. The presently used animal-based culture media, which employs materials such as calf serum, carry the risk of contaminating viruses or prions, such as those that cause mad cow disease.

Researchers replaced the calf serum with human serum albumin, but were not successful. Therefore, the team supplemented the medium with lipids and five separate factors human TGF-, human FGF, GABA, pipocholic acid and lithium chloride, which activates an important metabolic pathway called WNT. Even human insulin and transferrin were included, and ion concentration and pH changed to achieve very good results. The medium was used to get two new embryonic stem cell lines from embryos less than a week old and successfully support the stem cell lines for seven months.


Tobacco plants yield effective and safe anthrax vaccine

A research group led by Dr. Henry Daniell at the University of Central Florida, the United States, has found a safe and effective method to produce large quantities of anthrax vaccine. Mice immunized with the vaccine obtained by genetically engineering tobacco plants survived lethal doses of anthrax several times stronger than the amounts to which humans have been exposed to. This breakthrough production method has the potential to assist government and health care providers avoid supply shortages as an acre of plants can produce 360 million doses in a year. The present production method involves an expensive fermentation process that can cause harmful side effects such as inflammation, flu-like symptoms and rashes.

Dr. Daniells team inserted the vaccine gene into the chloroplast genome of tobacco cells, partly because tobacco plants grow much faster than carrots, tomatoes and coffee. The cells were cultured for several weeks in the lab. Tests have shown that the vaccine taken from the plants was just as potent as the one produced through fermentation, but without the bacterial toxin that can cause harmful side effects. Dr. Daniell is also developing a new technology that would allow for vaccines to be administered orally and allow effective and less expensive treatments to be more accessible worldwide. Dr. Daniell believes that fruits and vegetables like tomatoes and carrots are the keys to figuring out a way for people to take anthrax vaccines orally in capsules of dried plant cells containing correct dosages of the protective antigen.


How do stem cells become brain cells?

Researchers at Oregon National Primate Research Centre (ONPRC), the United States, report to have gained new insights into how stem cells become various kinds of brain cells. The team has identified a key gene that appears to control the transition process. According to Dr. Larry Sherman, an associate scientist at the Division of Neuroscience, ONPRC, in the early stages of brain development prior to birth, brain stem cells, also known as neural stem cells, differentiate into neurons. In later stages, the same stem cells suddenly start becoming glial cells that perform several functions, including supporting neurons.

Investigations pertaining to the key gene, called brahma-related gene-1 (Brg-1) that is found in both mice and humans, revealed that Brg-1 is a critical signal that keeps stem cells from converting into neurons at the wrong time. This fact was ascertained by breeding mice lacking the gene in the nervous system to obtain embryos with smaller brains containing neurons but virtually no glial cells. As such, Brg-1 expression in stem cells can be manipulated, which allows for generation of neurons that could be used to replace cells lost in a variety of diseases and conditions that affect the brain and spinal cord. Dr. Sherman expressed that as the process involves a single gene, it would be highly amenable for the development of drugs targeted at promoting stem cell differentiation in the adult nervous system.


Genetic change raises susceptibility to tuberculosis

Dr. Pedro Flores-Villanueva and his colleagues at the University of Texas Health Centre, the United States, have identified a small genetic change that increases the chances of developing active tuberculosis (TB). Studies involving patients in the Republic of Korea and Mexico revealed that individuals who carry this genetic alteration were more prone to develop the disease when exposed to TB-causing bacteria.

The team demonstrated that the culprit behind the increased susceptibility to TB was a small change in the gene that encodes a protein called MCP-1. The MCP-1 gene resides on chromosome 17. Though the genetic modification was a tiny one, with the DNA sequence differing by only a single nucleotide, it leads to increased production of MCP-1 protein. The modification was five times more prevalent in individuals with active TB than in those who were infected but remained healthy. MCP-1 is a protein that helps attract immune cells to sites of infection. However, extremely high levels of MCP-1 can be dangerous as they inhibit the production of another immune protein called interleukin-12, which is required to activate immune cells that fight off the infection once they arrive.


Mechanism behind diabetes caused by high-fat diet identified

A team of researchers headed by Dr. Jamey Marth, at the Howard Hughes Medical Institute, the United States, have uncovered a molecular link between a high-fat, western-style diet and the onset of type 2 diabetes. Studies on mice have shown that a high-fat diet disrupts insulin production, resulting in classic signs of type 2 diabetes. The team found that knocking out a single gene encoding the enzyme glycosyltransferase (GnT-4a), which attaches sugar-like molecules called glycans to proteins in a process known as glycosylation, disrupts insulin production. Importantly, a high-fat diet suppresses the activity of GnT-4a and leads to type 2 diabetes due to failure of the pancreatic beta cells. Furthermore, the team uncovered a mechanistic explanation for beta cell failure in response to a high-fat diet and obesity, a molecular trigger that begins the chain of events leading from hyperglycaemia to insulin resistance and type 2 diabetes.

Dr. Marth and co-researchers focused on the function of GnT-4a, in part, because it is highly expressed in the pancreas. GnT-4a was known to maintain glucose transporters such as Glut-2, which play a crucial role in allowing the beta cell to sense how much glucose is present in blood, on the surface of beta cells in the pancreas. Transport of glucose across the cell membrane into pancreatic beta cells triggers insulin secretion. New studies have shown that in the absence of sufficient quantity of GnT-4a enzyme, Glut-2 lacks an attached glycan that is needed for it to be expressed at the cell membrane. Without the glycan, Glut-2 leaves the cell surface and becomes internalized, where it can no longer transport glucose into the cell. In turn, this failure impairs insulin secretion, causing type 2 diabetes in mice. The researchers are now testing to see whether over-expression of the GnT-4a gene in transgenic mice makes them resistant to diabetes induced by a high-fat diet or by transcriptional factor mutations that cause mature onset diabetes of the young.


Stem cell-based gene therapy: A cure for sickle cell disease?

Researchers at the Memorial Sloan-Kettering Cancer Centre (MSKCC), the United States, have devised a novel strategy that uses stem cell-based gene therapy and RNA interference to genetically reverse sickle cell disease (SCD) in human cells. According to Dr. Michel Sadelain, lead researcher based at the Immunology Programme, MSKCC, SCD can be cured only by transplanting healthy blood-forming stem cells from another individual. However, in most cases this option is not viable owing to the difficulty in finding a compatible donor. On the other hand, gene transfer technology always allows for a donor match because the patients own stem cells are used to treat the disease.

To treat SCD, MSKCC scientists devised a novel engineering strategy combining RNA interference with globin gene transfer by creating a therapeutic transgene, consisting of the gamma-globin gene and small interfering RNA specific for beta S-globin, the globin mutant chain that causes SCD. This new gene, which harbours an embedded small iRNA processor, had two functions produce normal haemoglobin and suppress the generation of sickle shaped haemoglobin S. The therapeutic gene was engineered into a lentiviral vector and introduced into haematopoietic stem cells. After the cells received the treatment, they made normal haemoglobin. This demonstrated the researchers hypothesis that one can simultaneously add one function and delete another in the same cell, thereby achieving synergistic genetic modifications within a single cell.


Plant-derived vaccine against deadly plague

Researchers led by Dr. Luca Santi at the Biodesign Institute, Arizona State University, the United States, report to have successfully transformed tobacco plants into vaccine production factories to combat the deadliest form of plague. Plague, caused by a rod-shaped bacterium called Yersinia pestis, is currently treated effectively with antibiotics. However, it has been discovered that some strains of the bacterium are resistant to antibiotics, raising concerns, especially, if plague could be used as a biological weapon. The plant-based vaccine is a result of innovative breakthroughs in plant biotechnology and vaccine design. The vaccine elicits a protective immune response in guinea pigs.

Researchers devised a new plant-based system that ensured rapid and stable production of high levels of proteins, called antigens, which conferred immunity against plague. Current vaccines are severely limited from widespread adoption owing to problems associated with high adverse reaction rates and side effects. The concept behind any recombinant sub-unit vaccine is that one can pick and choose selective antigens that can confer protection and limit the potential for adverse reaction. Hence, the team modified tobacco plants to make high levels of the plague antigens F1, V and a combination of these two, a so-called F1-V fusion antigen. All are known to be important for the plague bacteria to produce its toxic effects. The antigens were purified from the plants and injected into guinea pigs. Over half the vaccinated animals survived the challenge with all forms of the antigen. Guinea pigs vaccinated with V antigen alone had the highest survival rates.

As such, it can be concluded that the new system produces really high levels of antigens in relatively short periods of time and in a native form that allows for an appropriate immune response against bacterial pathogens. Additionally, like most crops, producing vaccines in tobacco plants primarily revolved around issues of speed, low cost and high yield. The major advantage of the vaccine is the rapidity of the system. In a matter of 10 days, scientists can go from infecting the plants to harvesting. From there, they purify the antigens in another 1-2 weeks to create the vaccine. This approach also eliminates the typical year-long lag time necessary to establish and characterize genetically modified or transgenic plants. The beauty of this system is its potential versatility that can be adapted to fight against other pathogens as well. The research teams next step is to refine their methods to achieve large-scale commercial production of the vaccine.



New protein may help treat deadly E. coli infection

At Queen University, Canada, a team of scientists led by Dr. Zongchao Jia and Mr. Michael Suits, a graduate student, have opened the door to more effective treatment of a deadly strain of E. coli bacteria with the discovery of a previously unknown protein. The newly identified protein allows E. coli 0157:H7 to obtain the iron it needs for survival in the body. E. coli 0157:H7 is responsible for a fatal illness known as Hamburger disease and is most commonly transmitted through undercooked meat, non-pasteurized milk and infected water sources.

Iron is a catalyst for bacterial growth. When a human body detects bacterial invasion, it produces proteins that bind tightly to and restrict iron to limit bacterial growth. On their part, bacteria have evolved other methods to acquire iron, including detecting and using human heme within proteins like haemoglobin that transports oxygen from the lungs. According to Dr. Jia, the recent breakthrough paves the way for studying the function of heme iron in E. coli O157:H7, and may lead to an understanding of how to therapeutically isolate the protein to keep the bacteria from flourishing.

Chronicle Pharmabiz, 17 November 2005

Molecule promoting prostate cancer identified

Researchers led by Dr. Shelton Earp, a Professor of Cancer Research, Pharmacology and Medicine, at the University of North Carolina, the United States, have identified a molecule that stimulates the aggressive growth of prostate cancer. Ack1 stimulates tumour formation, in part by signalling prostate cells to rid themselves of a tumour-suppressor protein. Normally, this suppressor protein would inhibit rapid cell growth by signalling the cell to destroy itself.

Ack1 belongs to a family of growth-promoting tyrosine kinase genes. According to Dr. Earp, tests demonstrated Ack1s profound effect on tumour growth in experimental systems. It was revealed that Ack1 activity could be inhibited by geldanamycin, an experimental drug developed by the National Cancer Institute, via interference with the cells molecular interactions, offering a target for treatment.


How rickettsial pathogens break into cells

Researchers from France and the United States report to have discovered the mechanism through which Rickettsia conorii, the Mediterranean spotted fever pathogen, enters into cells. Headed by Dr. Pascale Cossart, at the Pasteur Institute, France, the team has identified both the bacterial and host receptor proteins that enable R. conorii, to enter cells. Dr. Cossarts team demonstrated that the Ku70 protein on the surface of host cells is critical for R. conorii to enter the cell, making it the first Rickettsial receptor ever identified.

According to Dr. Cossart, this receptor is a sub-unit of a protein complex present mainly in the nucleus, but is also found in the cell cytoplasm and at the cell membrane. R. conorii specifically binds to Ku70. Binding and recruitment of Ku70 at the surface of the host cell are important events in R. conoriis invasion of mammalian cells. In addition, since Ku70 has previously been shown to control cell death, the new findings suggest that Rickettsia, which like several other intracellular parasites prevent cell death in order to multiply inside living cells, may also utilize this property of their receptor for successful infections.


Insights into protein synthesis and hepatitis C infections

In the United States, a study undertaken by Dr. Jennifer Doudna and Dr. Eva Nogales has unveiled key information that will aid in understanding the crucial first step in protein synthesis. Protein synthesis is the process by which genetic code, harboured within DNA and copied into RNA, is translated into the production of proteins. In their investigation, cryo-electron microscopy (cryo-EM) was used to create a 3-D model of the protein complex called eukaryotic translation initiation factor 3 (eIF3). The model demonstrated that eIF3 employs the same structural mechanics in loading either human or viral RNA to ribosomes. This discovery even helps explain how viruses like Hepatitis C are able to hijack protein synthesis machinery in humans to suit their own purposes.

According to researchers, this is the first insight into how the initiation mechanisms of protein synthesis work specifically for humans and is yet another step in understanding, at the molecular level, what happens when a viral infection occurs. A better understanding of these mechanisms could open the door to new and improved therapies for viral infections. By using cryo-EM, scientists can reconstruct images of the entire protein ensemble to investigate the molecular machinery behind the protein synthesis process.

Contact: Website:


Structure of viral harpoon protein unravelled

In the United States, a group of scientists led by Dr. Theodore Jardetzky and Dr. Robert Lamb from Northwestern University has solved the structure of a molecule that controls the ability of viruses of the paramyxovirus family to fuse with and infect human cells. The paramyxovirus family includes viruses that cause measles, mumps and many human respiratory diseases. Ascertaining the structure of this molecule and its role in the viral fusion mechanism may aid in the development of drugs and vaccines that target such viruses.

The large protein, called F, studs the surfaces of certain RNA viruses that are encased in a membrane envelope. As soon as such a virus comes in contact with a cell it can infect, the F protein changes shape and extends like a harpoon into the outer membrane of that cell. Then the protein goes through a conformational (shape) change and collapses upon itself, pulling the virus against the host cell and fusing the viral membrane with the target cells membrane. This fusion unleashes the viral RNA into the cell, which then hijacks the cells machinery to make and spread more viruses.


Scythe protein balances life and death during development

In the United States, a team of researchers led by Dr. Peter McKinnon has discovered that a protein called Scythe determines which cells live and which die during the growth and development of the mammalian embryo. Scythe plays a critical role during the development of mammals through selectively regulating when and where specific cells either proliferate or undergo apoptosis, the process by which cells self-destruct.

According to Dr. McKinnon, there is a balance between life and death in the embryo as the various parts of specific organs get sculpted out of the growing mass of cells and some are eliminated. However, cells in certain organs of models lacking both copies of the Scythe gene (Scythe-/-) either failed to receive or failed to respond to signals triggering proliferation or apoptosis. The resulting organs were malformed and unable to function properly.


New look at gene regulation

At the University of North Carolina, the United States, a team of researchers headed by Dr. Yi Zhang, have purified a novel protein that is capable of altering gene activity by reversing a molecular modification previously thought permanent. Studies revealed that the protein called JHDM1A can remove a methyl group from histone H3, one of four histone proteins bound to all genes.

Human genes are so tightly compacted within the nucleus that if the DNA of a single cell were unwound and stretched, it would be a line of about 2 m in length. As such, histones are necessary to package the DNA so that it fits inside a cells nucleus. Since they are so intimately associated with DNA, even slight chemical alterations of histones can have profound effects on nearby genes. Depending on the precise location and how many methyl groups are added, their presence can either switch affected genes on or off.

Researchers devised a biochemical strategy to isolate proteins that could remove methyl from histones inside a test tube. This resulted in the identification of a novel protein, JmjC histone demethylase 1A (JHDM1A). A similar protein exists in bakers yeast and has the potential to remove trimethyl groups. JmjC is only a section of the entire JHDM1A protein, but is required for its demethylase activity. Disruption of JmjC prevents JHDM1A from removing histone methyl groups.



Double line of defence!

Researchers at the Max Planck Institute for Plant Breeding Research, Germany, have uncovered the molecular components of non-host resistance. Non-host resistance means that the plant is unable to host a pathogen, which is a durable type of immunity to parasites. Although, in nature, non-host resistance stops almost all types of parasitic attacks, it has been the subject of little research.

PEN (penetration) gene identified by the team has been recognized as an important component of non-host resistance. In tests using arabidopsis mutations, which are partially susceptible to powdery mildews, it was found that when PEN2 is removed the plants become more susceptible to grass powdery mildew fungi and also other pests e.g. pathogens causing late potato blight. However, if PEN2 is missing, the plant is not totally helpless against fungal diseases. There is still another line of defence, which the invaders have to get through! In the absence of PEN2, the plant takes a drastic step the cell dies together with its attacker, thereby protecting the neighbouring plant tissue from infection. In this deadly line of defence, very different proteins play a key role, which identify molecular traits only present in parasites by using immune receptors both on the cell surface and inside the cell. Only if this second mechanism also fails can the originally non-virulent grass powdery mildew fungus colonize the plant.


Unique genes hold secret to better grain yields

Cereals are an important nutrition source for humans and livestock. The three main cereals are rice (23 per cent), wheat (17 per cent) and maize (10 per cent). A group of Japanese and Chinese researchers, headed by Dr. Motoyuki Ashikari from the Bioscience and Biotechnology Centre of Nagoya University, Japan, and Dr. Hitoshi Sakakibara of the Plant Science Centre, China, investigated the quantitative trait loci (QTLs) for plant growth and grain number. Agriculturally important traits such as growth height or grain number are often ruled by the number of genes located on QTLs.

To run a QTL analysis, researchers used two rice varieties. One was short with many grains and the other was tall with few grains. By crossing these two varieties, the team managed to identify five QTLs concerning grain number (Gn) and four concerning plant height (Ph). The most effective QTLs Gn1 and Ph1 were chosen for further research. Finally, the group succeeded in identifying the two main genes of these QTLs, a gene called semi-dwarf 1 (sd1) and another called OxCKX2. It was found that when sd1 is inactivated, plant height decreases by about 20 per cent. OsCKX2 codes for the enzyme Cytokinin Oxidase and if this enzyme loses its function, the grain yield is increased by about 44 per cent. If both genes are shut down, the rice variety produces 23 per cent more grains than a normal plant. Increase in grain yield by inactivating OsCKX2 compensates for the loss of yield due to a smaller plant from the inactivation of sd1.

Contact: Dr. Motoyuki Ashikari, Nagoya University, Japan.



GM maize in the fight against iron deficiency

Too little dietary iron is the main cause of anaemia, which can stunt childrens development and cause chronic fatigue in adults, especially women. The team led by Dr. Eva Stoger of Aachen University, Germany, have genetically modified (GM) maize to tackle iron deficiency in developing countries.

The team modified maize by adding genes to its DNA from both soybean and Aspergillus niger fungus. The soybean gene produces a protein that binds to iron that plants take up from the soil. Once in the maize kernel, however, the iron may get locked away in such a way that people would not be able to benefit from eating the enriched maize. This is where the fungal gene comes in; it unlocks the iron, making it available to humans. Moreover, it was shown that cells from the human intestine absorbed three times more iron from the GM maize than from unmodified maize as iron uptake is a complicated procedure that can be affected by other nutrients. However, further studies are required to assess potential side effects of the modification.


Drought-resistant tomatoes

In the United States, biotechnologists led by Dr. Kendal Hirschi have discovered that tomato plants that over-express the gene AVP1 yields stronger and larger root systems, which in turn results in the plant roots making better use of limited water. During trials, it was found that regular or control tomatoes suffered irreversible damage after five days without water while transgenic tomatoes, which began to show signs of damage after 13 days, rebounded as soon as they were watered.
According to Dr. Roberto Gaxiola, a plant biologist at the University of Connecticut, this technology could ultimately be applied to all crops because it involves over-expression of a gene found in all plants. This breakthrough could revolutionize agriculture and improve food production worldwide by addressing an increasing global concern water scarcity.


Growing crops to cope with climate change

A team of scientists headed by Dr. David Laurie at the Biotechnology and Biological Sciences Research Council (BBSRC), John Innes Centre, the United Kingdom, has identified a gene that could lead to the development of new crop varieties capable of coping with the changing world climate. The gene, isolated from barley, controls the way in which the plant responds to seasonal changes in the length of daylight. This is deemed crucial to understanding how plants have adapted their flowering behaviour to different environments.

The team discovered that Ppd-H1 gene in barley controls the timing of the activity of another gene called CO. When the length of the day is long enough, CO activates one of the key genes that triggers flowering. Naturally occurring variation in Ppd-H1 affects the time of day when CO is activated. This shifts the time of year that the plant flowers.


Safflower with health benefits progresses to field trials

In the United States, Arcadia Biosciences has developed safflower plants with seeds containing more than 35 per cent gamma linolenic acid (GLA) oil, an omega-6 fatty acid with health benefits that are similar and complementary to those provided by omega-3 fatty acids. Studies undertaken by a team of researchers, led by Dr. Ruth Lupu and Dr. Javier Menendez, have uncovered that GLA inhibits the action of Her-2/neu, a gene responsible for almost 30 per cent of all breast cancers. The team demonstrated that treating cancer cells that over-expressed Her-2/neu with GLA not only suppressed protein levels of the oncogene, but also resulted in 30-40 fold increased response in breast cancer cells to the drug Herceptin (trastuzumab), a monoclonal antibody used for the treatment of breast cancer.

The two main sources of dietary GLA are evening primrose oil and borage oil, which contain about 10 per cent and 20 per cent GLA, respectively.

Contact: Mr. Jeff Bergau, Arcadia Biosciences, United States of America. Tel: +1 (312) 2170 419



Dextran-producing transgenic potato tubers

Researchers from the Wageningen University, the Netherlands, and their colleagues from the Stanford University and Columbia University in the United States have investigated the production of dextran in potato tubers and its effect on starch biosynthesis. Dextran is used as an ingredient in food processing, as a moisture-retaining ingredient in cosmetics, as a vaccine adjuvant in immunology and as a blood plasma volume expander in haematology.

For the studies, two potato genotypes, cv. Kardal and the amylose-free (amf) mutant, were used for transformation. A binary plant expression vector was constructed containing a mature dextransucrase DsrS gene isolated from Leuconostoc mesenteroides. The pPFS binary vector was transformed into Agrobacterium tumefaciens using electroporation. Results were analysed for 30 independent transgenic potato clones. Five plants of each transgenic clone were grown in the greenhouse. Transformants KDD15, KDD4, KDD5 and KDD30 contained the largest amount of dextran, ranging from 1.0 mg to 1.7 mg g-1 FW. In the KDD series, dextran was found in 9 out of 30 tubers (29 per cent). (ISB News Report, December 2005)


Modelling in Medicine and Biology VI

This book features papers presented at the 6th International Conference on Modelling in Medicine and Biology. It covers a broad spectrum of topics, including simulation of physiological processes, cardiovascular system, biomechanics, neural systems, computational fluid mechanics in biomedicine, orthopaedics and bone mechanics, simulations in surgery, advanced technology in dentistry, data acquisition and analysis, and image processing. It will be of interest to both medical and physical scientists and engineers as well as professionals working in medical enterprises actively involved in this field.

Contact: Witt Press, Ashurst Lodge, Ashurst, Southampton, SO40 7AA, United Kingdom. Tel: +44 (238) 029 3223; Fax: +44 (238) 029 2853


Recombinant Gene Expression: Reviews and Protocols

This second edition presents a collection of cutting-edge protocols for gene expression in bacteria, fungi, plants and animals. Review articles survey new directions in recombinant gene expression research, technique and application, and point the way to using recombinant gene expression for metabolic engineering and the production of non-protein molecules. The readily reproducible protocols provide new host-vector systems like Antarctic and moderately halophytic bacteria, vectors for chromosomal editing and metabolic engineering, and information to aid in problem solving, strategy planning and the promotion of protein folding. The book offers investigators an overview of this critically important field the understanding and tools needed to begin producing non-protein products, etc.

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


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