VATIS Update Biotechnology . Sep-Oct 2005

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Biotechnology Sep-Oct 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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International collaborations produce science milestone

The three members of the International Nucleotide Sequence Database Collaboration GenBank (Bethesda, the United States), European Molecular Biology Laboratorys European Bioinformatics Institute (Hinxton, England) and the DNA Data Bank (Mishima, Japan), the worlds three leading repositories for DNA and RNA sequence have reached a milestone: collecting and disseminating 100 gigabases of sequence data.

For nearly 20 years, the repositories have collaborated to provide access to the ever-increasing amount of genetic data produced by institutions around the world. The 100 billion bases, or letters of the genetic code, represented both individual genes and partial and complete genomes of more than 165,000 organisms, including humans, elephants, earthworms, fruit flies, apple trees and bacteria.

The free access to this information allows scientists almost anywhere in the world to study and compare the same data. It also makes possible collaborative research that would lead ultimately to cures for diseases and improved health.


GM maize receives seal of approval in the United Kingdom

Following a series of trials, the government of the United Kingdom has given the go-ahead for the first commercial planting in Britain of one variety of genetically modified (GM) maize crop for animal feed, but rejected the growing of GM beet or oil-seed rape.

The Environment Secretary Mrs. Margaret Beckett told the House of Commons that there would be strict conditions to ensure there was no damage to the environment, while further scientific analysis takes place.

Mrs. Beckett stated that the government would oppose the growing anywhere in the European Union of the two other GM crops, beet and oilseed rape, involved in the recent tests. The GM maize licences would expire in October 2006, and anyone wishing to renew them would have to carry out scientific analysis during cultivation. Further, there was no scientific case for a blanket approval for all uses of GM, but neither was there a scientific case for a blanket ban on the use of GM, said Mrs. Beckett.


Biotech boom in India

In 2003-04, Indian biotechnology companies together had a revenue of more than US$700 million. This year, they have already surpassed US$1 billion. The biotechnology sector is witnessing an impressive 40 per cent annual growth, says Dr. Kiran Mazumdar-Shaw, chief executive of Biocon, Bangalore. The profile of Indian biotech companies is undergoing a change and they are becoming international. Biocon, the most profitable biotechnology company in India, this year posted revenues of US$150 million, a 30 per cent increase over the previous year.

Dr. Mazumdar-Shaw and several other company chiefs are fast becoming household names in India. Five of them won this years Padma awards, the nation's highest honour for civilians. Never in the history of these coveted awards has a small section of the industry grabbed the entire limelight, says Mr. N. Suresh, editor of BioSpectrum magazine, published in Bangalore.

The biggest boost to the biotechnology industry has come from the government itself. Biotech is the governments priority area, says Mr. Kapil Sibal, Minister of Science and Technology. Less than a year after Mr. Sibal took office, the Department of Biotechnology (DBT) drew an ambitious plan to create a biotechnology industry that would generate US$5 billion in revenues per year and create one million jobs by 2010. As part of its strategy, DBT is planning to make it easier for foreign-owned companies to set up shop in India. Foreign investors have in the past had to knock on the doors of several different government agencies. But DBT's new plan is to set up a single independent authority to replace the committees at different ministries.

DBT has also subsidized the construction of three biotechnology parks, including the Genome Valley and aims to help finance at least ten such parks by 2010. Together with the Ministry of Information Technology, DBT plans to build the countrys first biotech/IT park. This is expected to attract bioinformatics contracts from around the world and foster innovative companies. We not only want to build on the existing platform but expand the base to create global leadership in biotechnology, says Mr. Maharaj K. Bhan, DBT secretary. This will require larger investments. The Ministry of Science and Technology has already announced a 50 per cent increase in its budget over the past year for drug-discovery research and called for proposals from the industry.

One reason for this increased investment is that from 1 January 2005, a new patent law, which brings India in line with World Trade Organization (WTO) rules, came into effect. Indian companies will have to honour international patents and stop producing unlicensed generic drugs, a major fount of their revenue over the past three decades. The pharmaceutical industry's R&D spending has shot up from Rs 2 billion in 2000 to Rs 8 billion in 2004, says Mr. D.G. Shah, secretary-general of the Indian Pharmaceutical Alliance.

Nature 436, 28 July 2005

Sorghum to be the second cereal crop sequenced

The National Sorghum Producers (NSP), Texas, the United States, announced that sorghum would be the second cereal crop genome to be sequenced. Dr. Daniel Rokhsar of the Department of Energys Joint Genome Institute (JGI) Computation Genomics Program stated that sorghum has been targeted for sequencing in 2006. According to Dr. Jeff Dahlberg, NSP Research Director, the project would engage an international consortium led by Dr. Andrew Paterson from the University of Georgia, the United States.

Sequencing sorghum is a critical step in building knowledge base on how plants function and, like the use of hybrids, would allow to make significant advancements in crop improvement for the next 50 years. This project would be valuable, as research moves from fundamental studies of genome organization and gene discovery to applied efforts in sorghum. Rice was the first cereal grain to be sequenced and sorghum is an important bridge to closely related large-genome crops in its own tribe such as maize and sugarcane.

Analysis of the levels and patterns of genomic diversity within and between sorghum, sugarcane, rice and maize promises to advance the understanding of the biology and evolution of Poaceae grain and biomass crops, and create new opportunities for their improvement. Sorghum is one of the world's leading grain crops, and it is an important model for tropical grasses worldwide.


Bangladesh to soon have a national biotechnology policy

On the occasion of a conference titled Biotechnology in Agriculture: Myths and Realities, Dr. Abdul Moyeen Khan, Science and ICT Minister of Bangladesh, told that the government would soon formulate a national biotechnology policy to give a boost to the countrys farm output and thus ensure food security.

Setting up of the National Biotechnology Institute was nearing completion at a cost of US$5 million. The entire project has been funded by government resources, which reflected the governments priority to the technology.

It was essential to adopt biotechnology in agriculture of the country along with other developing nations to ensure food security against the backdrop of its increasing population and decreasing farmlands. If biotechnology could be widely used in the country, productivity of crops may rise by 20 per cent.



Bharat Biotech launches rEGF for diabetics

Bharat Biotech International Limited, Hyderabad, India, has launched REGEN-D, Indias first Recombinant Epidermal Growth Factor (rEGF) for diabetic foot care, burn injuries and skin grafts. According to Dr. N.K. Ganguly, Director General of Indian Council of Medical Research, REGEN-D is the result of unique public-private technology collaboration between Bharat Biotech and the Institute of Genomics and Integrated Biology based in New Delhi. REGEN-D is being launched in two strengths, REGEN-150 for diabetic foot ulcers and REGEN-60 for burn and skin grafts.

The World Health Organization (WHO) predicts that diabetes would become one of the worlds main disablers and killers within the next 25 years. WHOs latest estimate for diabetic patients worldwide in 2000 was 177 million. In India alone, close to 40,000 amputations are carried out every year owing to diabetic foot ulcer. According to Dr. K.M. Ella, Bharat Biotechs Chairman and Managing Director, REGEN-D-150 would have tremendous impact on the lives of a vast patients population affected with diabetic foot ulcers.

Chronicle Pharmabiz, 18 August 2005

Dow wins patent for GM crops

In September 2005, the Dow Chemical Co., the United States, won rights to a broad and enabling technology for creating genetically modified crops, such as those sold by Monsanto Co. Concluding a dispute between the two companies that has run for more than a decade, the United States Patent and Trademark Office awarded a patent to Dow AgroSciences LLC, an Indianapolis-based subsidiary of the chemical giant.

The patent applies to a method of transferring genes from the bacterium Bacillus thuringiensis to plants. The bacterium, known as Bt, kills certain pests. The patent allows Dow to seek royalties from competitors, which use Bt technology to make corn and cotton plants resistant to certain destructive pests. Besides Monsanto, Bt crops are sold by Pioneer Hi-Bred International through a partnership with Dow AgroSciences. Syngenta AG is also developing the technology. Dow would use the patent as leverage to settle outstanding intellectual property lawsuits, or to formulate cross-licensing deals for its competitors technology.


AstraZeneca setting up PR&D lab

A new state-of-the-art process research and development (PR&D) laboratory of Bangalore-based AstraZeneca India Pvt. Ltd. is nearing completion. Set up at an investment of US$11.9 million, the facility will be ready for commission by November 2006. The lab is coming up in 8,000 m2 built-up area, next to its present facility in Bangalore.

Dr. Ulf Kruger, Associate Director, Engineering & Facilities, AstraZeneca Plc, says that the PR&D lab in Bangalore is being set up by the parent company to support the initial process development of candidate drugs discovered in Bangalore, as a low cost alternative to outsourcing and to support the companys increased commercial bulk drug activities in Asia.

The two-storied facility would have bench-scale labs, process safety labs, process engineering labs, analytical testing labs and a large-scale lab with utilities, storage and infrastructure. It would focus mainly on Phase I trial in drug development programme and the research work would include the TB drug candidate from AstraZeneca India, besides research into other critical and infectious disease segments pursued by its parent company at other sites.

Chronicle Pharmabiz, 11 August 2005

Serum launches vaccine for DTP and Hepatitis B

Serum Institute of India Limited has launched its combination vaccine Q-Vac for diphtheria, tetanus, pertussis (DTP) and hepatitis B. According to Dr. Cyrus Poonawalla, Chairman of the Pune-based facility, Q-Vac is offered at 75 per cent less than MNC prices to ensure the vaccine is within the reach of the common man. Q-Vac is priced at approximately US$1.2 per dose, which is one-fourth the cost of the available vaccines in the Indian market, and the number of shots would be reduced to only three instead of the usual six.

Chronicle Pharmabiz, 18 August 2005

Sartorius moves international service centre to India

Sartorius, the German biotech engineering and bio-processing company, has relocated its international service centre from Germany to India. Sartorius India, the Indian arm of the company, recently commissioned the new state-of-the-art centre in Bangalore.

The new facility is located adjacent to the existing unit of Sartorius India. The cGMP-complaint validation centre was set up at an investment of US$ 230,000 on 930 m2 area. The centre would cater to the entire Asia-Pacific and United States markets, and would validate equipment and processes for global and domestic customers of Sartorius, besides offering technical support for biotech-pharma production and lab centres. Its centre for sterility testing was a first-of-its-kind in the country at a manufacturing site.

Chronicle Pharmabiz, 18 August 2005

Mexican genomic medicine institute goes in for collaboration

Mexico's Instituto Nacional de Genomica (INMEGEN) is collaborating with Applied Biosystems Group of California, the United State, to establish an Applied Biosystems Sequencing and Geotyping Unit at INMEGEN and conduct collaborative research studies focused on health issues important to the Mexican population. The Mexican population includes a mixture of more than 60 Meso-American native groups and Spaniards. Analysing and characterizing genetic variation in unique population was the only way to costeffectively develop strategies for the prevention, diagnosis and treatment of common diseases in Mexico, such as diabeties, asthama and hypertension, said Dr. Gerardo Jimenez Sanchez, Director General of INMEGEN.

The collaboration represents the largest genotyping study to be undertaken in Latin America. Genotyping would be conducted using Applied Bosystems TaqMan Drug Metabolism Genotyping Assays. A pilot project will be started immediately to determine patterns of sequence variation for genes of pharmaco-genetic interest in the Mexican population. Medical sequencing/resequencing would be performed on a select subset of genes, and a set of specific pharmacogenetic assays developed for INMEGEN and other Mexican National Institutes of Health.


NIH to out-license technologies

The National Institutes of Health, the United States, has released a listing of technologies it has made available for licensing, including one for removing affinity tags from fusion proteins and one related to fluorescence detection.

The first technology is an enzymatic reagent for removing C-terminal polyhistidine tags from recombinant proteins. The enzyme, MeCPA, is a carboxypeptidase that could remove histidines and other amino acids from the C-terminus of proteins and could be used to remove affinity tags. Because MeCPA would only digest disordered/ unstructured residues, it could also be used to remove native amino acids from the C-terminus of proteins to facilitate crystallization.

The second technology is a spatially selective fixed-optics multicolour fluorescence detection system specifically for micro-fluidic devices. This sensitive technology performs spectrally resolved laser-induced fluorescence detection from multiple micro-fluidic channels. The scheme of detection could be applied to fluorescence detection for any microchip-based analysis in a transparent substrate.


Pfizer acquires antibody discovery and optimization company

In the United States, Pfizer Inc. and Bioren Inc. have announced the completion of a transaction in which Pfizer purchased all outstanding stock of Bioren for an undisclosed amount. Bioren is the company that developed technologies such as Walk-Through Mutagenesis (WTM) and Look-Through Mutagenesis (LTM) to improve drug development of antibodies. According to Dr. Nick Saccomano, Pfizers senior vice president, acquisition of Bioren strengthens Pfizers commitment to the antibody space. The ability to use and develop these technologies would help the company to identify new antibody leads as well as improve current antibodies in development.



Gene linked to brain cancer

A research team led by Prof. M.R.S. Rao at the Department of Biochemistry, Indian Institute of Science (IISc), Bangalore, India, has spotted a particular gene to identify an expression pattern, which could be used as a differential marker for various stages of development of brain tumours (glioma). The team has completed the first phase of research for identifying 24 different genes expressed in brain cancer or glioma.

The finding would be validated using real-time PCR on many glioma samples under the second phase of the research. A number of genes were identified using microarray to show an up regulation or down regulation, depending on the stages of cancer. The findings would be developed into a diagnostic kit. The programme involved another leading science research institute in the country, Centre for Cellular and Molecular Biology (CCMB) located in Hyderabad, and was supported by four clinical hospitals.

While IISc utilized its expertise in microarray, CCMB used proteomics to identify proteins, which were diagnostic for glioma. Efforts are now on to build up the clinical phase through large-scale validation and also recruit patients undergoing treatment to correlate the gene expression and help establish a technique in faster diagnosis, which could help bring down cost of diagnostics.

Chronicle Pharmabiz, 18 August 2005

Advances in breast cancer research

Cancer specialists led by Dr. Sarah Porter and Prof. Dylan Edwards at the University of East Anglia (UEA), Norwich, the United States, have discovered that, compared with normal breast tissue, several ADAMTS genes are turned off in breast cancer while others are switched on. The ADAMTS genes are recent additions to a large family known as the metalloproteinases, many of which can break down tissues and are therefore linked with tumour metastasis through the body. However, the ADAMTS group had not previously been linked to the development of breast cancer.

Dr. Porter and Prof. Edwards had earlier shown that 11 of the 19 ADAMTS genes in humans are significantly altered as breast cancer develops. Their latest research focused on two of the genes, ADAMTS8 and ADAMTS15, and showed that they can help predict disease outcome in breast cancer patients. These new findings showed that differing levels of activity of these genes meant that patients could be grouped into one of four categories. These categories could be used to predict the likelihood of breast cancer recurrence. Those in the highest risk category are three times more likely to have a recurrence of breast cancer, and over five times more likely to die from the disease, than patients in the lowest risk category. These genes could be targets for the development of smart drugs tailored to treat individual patients tumours.


MicroRNA plays an important role in regulating oogenesis

In the United States, scientists from Northwestern University, Illinois, and Carnegie Mellon University, Pitterburgh, have found that microRNAs (miRNAs) play an important role in regulating oogenesis, the process by which females make eggs. It is the first evidence on the involvement of miRNAs in oogenesis and adds an extra layer of complexity that needs to be explored to understand how development is regulated, said Dr. Jonathan Minden of Biological Sciences at Carnegie Mellon University.

Researchers were initially surprised to find that miRNAs affected only a small fraction of expressed genes within a maturing egg. Closer inspection revealed that the gene affected by miRNAs shared common role as regulators of protein manufacture. These results suggest that miRNAs tightly control the abundance of proteins throughout the process of oogenesis and fertilization.

Using a proteomics tool developed at Carnegie Mellon, the scientists compared maturing fruit fly eggs. One group of eggs was missing a gene essential for producing miRNAs, whereas another group of eggs had normal miRNA production. As all plants and animals have DICER, the gene that produce miRNAs, the researchers used a genetic trick to generate DICER-less eggs. On comparing overall protein production of these two groups, the researchers discovered that miRNAs stopped the manufacturing of a small group of key proteins, including the ones that produce ribosomes. They also found that miRNAs appear to attenuate protein turnover and speculate that this function may allow a developing egg to accumulate large amounts of specific proteins necessary to drive the amazing structural changes seen in embryogenesis.

Express Pharma Pulse, 18 August 2005

Gene discovery sheds light on causes of rare disease

A team of researchers led by Dr. Weidong Wang of National Institute on Aging, Baltimore, the United States, has discovered a gene, FANCM, which sheds light on an important pathway involved in the repair of damaged DNA. Mutation in this gene is responsible for one of the forms of Fanconi anemia (FA), a rare genetic disorder that mainly affects children and appears to be the result of a breakdown in vital DNA repair mechanisms. FA leads to bone marrow failure (aplastic anemia) and is associated with birth defects such as missing or extra thumbs and skeletal abnormalities of the hips, spine or ribs.

Discovery of FANCM and its protein provides a potential target for the development of drugs that could prevent or alleviate FA and a variety of cancers. According to Dr. Wang, FANCM may be a potent cog in the DNA repair machinery and like most genes, contains information for making a specific protein. The FANCM proteinis the only protein within the molecular machine, called the FA core complex, that affects DNA by enzyme activity.


Embryonic stem cells accrue genetic changes

Scientists led by Dr. Aravinda Chakravarti at the Institute of Genetic Medicine at Johns Hopkins, the United States, have discovered that human embryonic stem cell lines far more genetically stable than other stem cells accumulate changes in their genetic material over time. The scientists in the United States, Singapore, Canada and Sweden compared early and late batches of each of nine federally approved human embryonic stem cell lines. Most of the late batches of stem cells displayed gross changes in the number of copies or parts of chromosomes, in the marks that control whether a gene is used by the cell or in the DNA sequence found in the cells mitochondria. The analysis revealed that five of the nine cell lines had extra or fewer copies of at least one section of their genetic material in the late batch compared with the same cell lines early batch. Two of the lines had changes in their mitochondrial DNA over time.

The researchers also examined whether genetic material had shifts in epigenetic marks, which sit on genes and are passed from cell to cell during cell division. These marks, methyl groups on the promoter region in this case, help decide whether a gene is used by a cell to make proteins. Three of the genes did show different methylation patterns in late batches compared with early batches. All nine stem cell lines exhibited some shift in methylation of at least one of three genes. One of these genes, called RASSF1A, was also methylated in many cancers.


Key genetic mutations in brain tumour identified

In the United States, a team of scientists headed by Dr. Robert L. Strausberg, from J. Craig Venter Institute, Ludwig Institute for Cancer Research, and The Johns Hopkins University School of Medicine used high throughput sequencing and bioinformatics to identify three novel mutations in two receptor tyrosine kinases in glioblastoma, an aggressive form of brain cancer. Studies identified receptor tyrosine kinases to be the cell regulators responsible for rapid cell growth in cancers.

The researchers used genes from 19 glioblastoma tumours from eight females and 11 males in the age range of 7-77 years and analysed them against healthy DNA samples. The bi-directional dideoxy sequencing of 20 receptor kinase domains and their adjacent regions revealed novel somatic mutations in fibroblast growth receptor 1 (FGFR1) and frame-shift mutations in growth factor receptor alpha (PDFGRA). Identification of these mutations in key cancer causing genes would hopefully enable the development of small molecules and antibodies to regulate their abnormal function and thus inhibit the growth of cancerous cells.



Key regulator of blood glucose levels discovered

Researchers led by Prof. Marc Montminy at The Salk Institute for Biological Studies in California, the United States, have discovered a key cellular switch that controls glucose production in liver cells, particularly in patients with type II diabetes. The switch, a protein named TORC2, turns on the expression of genes necessary for glucose production in liver cells.

The body switches from glucose to fat burning mainly in response to two key hormones insulin and glucagon that are produced by the pancreas. During feeding, the pancreas releases insulin, which promotes the burning of glucose. At sleep, the pancreas releases glucagon into the bloodstream, which signals the body to fire up the fat burner. However, as the brain needs a constant supply of glucose even during sleep or fasting to function properly, the liver actually manufactures glucose through gluconeogenesis process.

As glucose levels run low during fasting, the pancreas through the hormone glucagon instructs the liver to produce glucose. This increase in glucagon turns on the TORC2 switch and allows the liver to make more glucose. Mice that were genetically modified to make more or less TORC2 produced more or less glucose depending on the amount of available TORC2 (transducer of regulated CREB activity). Most of the time, TORC2 sits in the cellular compartment that surrounds the nucleus, where all the genes are located. When a glucagon signal arrives, the TORC2 switch crosses the nuclear membrane, teams up with the transcriptional activator CREB and turns on all the genes necessary for gluconeogenesis. The researchers also discovered that a chemical modification on TORC2 itself sequesters the protein in the cytoplasm.


Human gene prevents blindness in mice

Dr. William Hauswirth and his colleagues at the Genetic Institute, University of Florida, the United States, have used a healthy human gene to prevent blindness in mice with a form of an incurable eye disease that strike boys. They successfully used gene therapy in mice to treat retinoschisis, a large genetic disorder that is passed from mother, who retains her sight, to son. In a healthy eye, retinal cells secrete a protein called retinoschisin (RSI), which acts like glue to connect the layers of the retina. Without it, the layer separate and tiny cysts form, devastating the vision and often causing blindness in about 1 of every 5,000 boys.

The researchers injected a healthy version of the human RSI gene to the sub-retinal space of the right eye of 15-day-old male mice, which, like boys with the disease, did not have the healthy gene to maintain the retina. After six months, researchers found cyst formation in untreated eyes, but the treated eyes appeared healthy. The eyes photoreceptor cells were spared from the disease and the connections between the layers of the retinas were intact. In addition, the protein appeared capable of moving within the retina to its target sites with long-lasting beneficial changes.

The treatment has implications for other genetic eye diseases that involve the eyes ability to process light including retinitis pigmentosa, one of the most common inherited causes of blindness in people between the ages of 20 and 60. According to Dr. Hauswirth, replication of the successful treatment in humans might take 2 to 5 years.

Express Pharma Pulse, 11 August 2005

Foetal skin cells heal burns

A research team led by Dr. Patrick Hohlfeld at the University Hospital in Lausanne, Switzerland, has reported the application of a small number of foetal cells that could heal the wounds of young burn victims. The new procedure could produce a speedier and more complete recovery than traditional skin grafts, used to treat deep second- and third-degree burns, in which a patch of skin is removed from one area of the body and transplanted to cover the wound.

Eight burn victims, ranging in age from 14 months to 9 years, underwent the new treatment. Dr. Hohlfelds team placed tiny swatches of foetal cells onto the burn wounds and covered the area with gauze. The team obtained the cells from a woman whose pregnancy was terminated at 14 weeks. The cells were allowed to divide in the laboratory, seeded onto a bed of collagen an important protein for skin elasticity and incubated for two days.

While it was expected that the skin cells would act as a graft, the cells seemed to confer restorative powers to the burnt skin, allowing the damaged tissue to heal itself. It is not known exactly how the skin cells had this effect but the technique could work for adult burns and other wounds. Other forms of treating similar burns frequently take up to six times as long. The remarkable flexibility of the skin mended with the foetal cells gave the patients nearly perfect skin and spared them the trauma of having a graft taken from elsewhere on their body.


Researchers discover an inhibitor to SARS virus

A team of researchers led by Dr. Paul Bates, Department of Microbiology, University of Pennsylvania School of Medicine, the United States, has found that inhibitors of an enzyme called cathepsin L prevent the severe acute respiratory syndrome (SARS) virus from entering target cells. The study demonstrated a new mechanism of how viral proteins were activated within host cells.

To gain entry, a virus binds to receptors on the surface of the host cell and is taken up into a vesicle, or sphere, inside the cell. Unlike most known viruses, however, the SARS coronavirus requires one more step to infect the cell. The proteins within the membrane of SARS need to be cut by special cellular enzymes (cathepsins) in order to replicate within the host cell. The researchers found that several chemical inhibitors of cathepsin activity blocked infection of human cell lines by the SARS virus. In general, these findings have led to better understanding that the cutting of viral protein by cathepsins is necessary for infectivity, and that this is not unique because Ebola virus is also known to use similar mechanism to invade host cells.

This research was carried out jointly with the group led by Dr. Scott Diamond, Director of the Peen Centre for Molecular Discovery. While independently screening for inhibitors, Dr. Diamonds lab found a cathepsin L inhibitor called MDL28170, which Dr. Bates and team tested for efficacy in inhibiting SARS coronavirus infection.

Express Pharma Pulse, 11 August 2005

Omega-6 fatty acids may cause prostate tumour cell growth

A team of researchers led by Dr. Millie Hughes-Fulford, Director of the Laboratory of Cell Growth at San Francisco VA Medical Centre (SFVAMC), the United States, has demonstrated that omega-6 fatty acids promote the growth of prostate tumour cells in culture. The study also identified a potential new molecular target for anti-tumour drugs: an enzyme known as cPLA2, which plays a key role in the chain leading from omega-6 fatty acids to prostate tumour cell growth.

Working with human prostate cancer cells in tissue culture, they have identified for the first time a direct chain of causation. When introduced into prostate tumour cells in culture, omega-6 fatty acids caused the production of cPLA2, which then caused the production of the enzyme COX2. In turn, COX2 stimulated the release of PGE2, a hormone-like molecule that promotes cell growth. Omega-6 fatty acids are found in corn oil and most of the oils used in bakery goods, which means that eating a diet high in omega-6 fatty acids could turn on the cancer cascade, which is a common denominator in the growth of prostate, colorectal and some breast cancers.

Dr. Hughes-Fulfords team also found that flurbiprofen, a non-steroidal anti-inflammatory drug commonly prescribed for arthritis, blocked the production of cPLA2 and broke the chain leading to cell growth. This means, that new drugs might be developed that could specifically target cPLA2 and prevent COX2 from being released. cPLA2 inhibitors would avoid the problems inherent in the class of drugs known as COX2 inhibitors, which are effective against tumour growth but cause increased risk of cardiovascular problems in those who take them regularly. Unlike cPLA2 inhibitors, COX2 inhibitors also inhibit prostacyclins, which are enzymes that are beneficial to the heart.


Linking microRNA to hepatitis C

A surprising new role for a microRNA (miRNA) in the accumulation of hepatitis C virus in the liver has been found by a team of researchers led by Dr. Peter Sarnow at Stanford University School of Medicine, California, the United States. Liver-specific microRNA-122 (miR-122) interacts with the 5' non-coding region of the viral messenger RNA (mRNA) to enhance its replication. This is the first time such a molecule has been found to interact with the 5' region in an animal cell, or to positively regulate gene expression.

To determine if miR-122 was needed to regulate hepatitis C gene expression, the team sequestered miR-122 by transfecting complementary oligonucleotides in Huh7 liver cell lines expressing a hepatitis C RNA replicon. They found that the amount of hepatitis C RNA was reduced by about 80 per cent when miR-122 was inactivated, establishing that miRNA was important for hepatitis C abundance. They found that mutation at 3' end of non-coding region of viral RNA genome had no effect on hepatitis C RNA accumulation. RNA with mutations in the 5' non-coding region binding site failed to accumulate. But when miR-122 was ectopically expressed with the corresponding 5' mutations in these cells, levels of hepatitis C RNA were restored.


Stem-cell technique may spare embryo

Scientists at the George Reproductive Specialists, Atlanta, the United States, have devised a technique in a mouse model to obtain embryonic stem cells without harming or destroying an embryo. This approach, if successful on human embryos, could circumvent some of the moral objections to the research.

Working with mice cells, the team headed by Dr. Eric Scott Sills devised two techniques to harvest stem cells from embryos. The first involved obtaining cells from embryos that were considered unviable and were destined to be discarded. This technique, however, still resulted in destruction of the embryo. In the second method, they did biopsy on an embryo to obtain cells that might have the potential to give rise to embryonic stem cells. The biopsy left the original embryo intact and available for implantation into a uterus. How successful the biopsy technique would prove with human cells remains to be established.


Unerring hormone delivers cancer drug

Many current chemotherapy treatments use medicines that also kill normal cells, with side effects that range from hair loss to infertility. Dr. Tamara Minko and her team in Rutgers University, New Jersey, the United States, may have found a way to better target anti-cancer drugs at tumours: they attach the medicine to hormones.

Many tumour cells are known to contain more receptors for a hormone, known as luteinizing hormone-releasing factor, than normal cells. The team attached a portion of luteinizing hormone-releasing factor to a drug called camptothecin, which kills cells by disrupting the repair and replication of DNA. Twenty times more cells died in mice tumours treated with the drug when it was joined to the hormone, as most of the camptothecin reached the cancerous cells while hardly affecting healthy organs. The result was more targeted than many drug delivery approaches, but the accuracy of the technique still needs to be tested.


Terminator virus destroys tumour growth

Dr. Paul Fisher and his team at Columbia University Medical Centre, the United States, is reported to have developed the next generation of viral-based cancer therapies that use terminator virus to destroy primary tumours. Terminator viruses are therapeutic viruses that allow replication uniquely in cancer cells, and have the potential to become effective treatments for a wide range of both primary and distant tumours (metastases) without harming normal cells or tissues.

The researchers administered the virus to mice with pancreatic cancers at both primary and distant sites. When the virus was injected directly into the primary tumour, the virus destroyed not only the primary tumour, but also distant tumours. While the infection caused by the virus killed the primary tumour, interferon-gamma was used to eliminate the metastases. Dr. Fishers team also described the production of a virus similar to the terminator virus, which selectively replicated and eliminated near and distant tumours on immune-deficient mice.



Research characterize proteome of human cornea

An international research group headed by Dr. Jan J. Enghild of the University of Aarbus, Denmark, has characterized the proteome of human cornea. The group identified 141 distinct proteins, 99 of which had not been previously recognized in mammalian corneas. Among the molecules that the scientists identified were proteins involved in antimicrobial defence, haem and iron transport, tissue protection against UV radiation and oxidative stress. Several others were known anti-angiogenic factors, which prevent the formation of blood vessel.

This research could facilitate future therapeutics for a myriad of corneal disorders. By comparative proteomic studies of diseased and normal corneas it would be possible to identify difference in the expression profiles that suggest avenues for therapeutic interventions. Identification of protein profile of the normal human cornea may also be very useful in the efforts towards generating artificial corneas for transplantation. The team has begun proteomic studies of corneas affected by granula and lattice corneal dystrophies, and is planning on looking at other cornea diseases such as keratoconus and Fuchs dystrophy.

Express Pharma Pulse, 11 August 2005

Structure of protein that powers cell movement solved

At the not-for-profit Boston Biomedical Research Institute in the United States, a team of scientists guided by Dr. Roberto Dominguez has published the three-dimensional structure of myosin V, a key part of the molecular motor protein. The flexing of a muscle, a heartbeat, digestion or transport that within cells are all powered by myosin, or more strictly speaking, by one of the members of the myosin family of molecular motor proteins.

The scientists combined several techniques such as X-ray crystallography, resonance energy transfer and molecular modelling to obtain a three-dimensional, atomic resolution structure of the neck region of myosin V. This form of myosin is responsible for organelle transport inside the cells. The neck region was initially thought to be a mere link within the molecule but has an unexpectedly complex structure, demonstrating that in addition to the previously recognized function as a rigid link, it was also involved in regulation of function of this important protein and possibly mediated its interactions with other proteins. Understanding the function of myosin V could shed light on disease states involving inappropriate cell movement, such as cancer metastasis.


Protein cyclin D1 helps arrest breast cancer

A team of researchers led by Dr. Richard Pestell, Director of Lobradi Comprehensive Cancer Centre at Georgetown University Medical Centre, Washington, the United States, has discovered that a protein called cyclin D1 is grossly overproduced in about half of all cases of breast cancer. Cyclin D1 routinely functions in events that promote cell division. In cancer, cyclin D1 is abundantly overexpressed by a number of factors that promote tumour growth, such as the oncogenes ErB2, src and ras. In more than half of human proteins with breast cancer, tumour cell produce as much as eight times the amount of cyclin D1 than healthy breast cells.

About 5-10 per cent of breast cancers result from the mutation of a specific gene called BRCA1, which in its normal state helps check tumour formation. Cyclin D1 could disrupt BRCA1s normal role as a cancer inhibitor because it binds to the same oestrogen receptor as does BRCA1. When the cell is flooded with cyclin D1, BRCA1 is unable to activate a pathway that stops cancer development. Researchers identified the mechanism by which cyclin D1 nullified one activity of BRCA1. Cyclin D1 is a collaborative oncogene. Besides blocking the functional activity of the BRCA1, it inhibits the activity of ERa, the protein that transduces the growth signal of oestrogen.

Cyclin D1 interferes with BRCA1 function because the two proteins both bind to the same spot on Era, an important protein that governs cell proliferation properties in both healthy and cancerous cells. In healthy cells, BRCA1 binds to ERa to retain and control oestrogen-target genes that promote cell division. In cancer cells, however, cyclin D1 occupies the binding site on the ERa to promote proliferation. The results reaffirm cyclin D1 as a candidate target for molecular therapeutic control of breast tumour development.

Express Pharma Pulse, 18 August 2005

Protein that blocks targeted cancer drug

Researchers in the United States have identified the presence of a protein called EMP-1 in the tumours of patients who fail to respond to treatment with gefitinib, a drug that has had only limited success in the treatment of patients with non-small cell lung cancer (NSCLC) the most common and deadly form of lung cancer. The study was carried out by Dr. David Agus and his team at the Louis Warschaw Prostate Cancer Centre of Samuel Oschin Comprehensive Cancer Institute, Los Angeles, the United States.

EMP-1 protein is a biomarker for resistance to treatment with gefitinib and may enable to identify patients who do not respond to the drug. The drug is taken in pill form and works by blocking the action of a key growth-signalling pathway in a protein called the epidermal growth factor receptor (EGFR). But gefitinib works in only about 11 per cent of patients with NSCLC, and most of these patients eventually develop drug resistance.

To identify the proteins involved in resistance to gefitinib, the researchers first developed a resistant tumour model in the laboratory. This model was generated in such a way that it closely mimicked acquired resistance to gefitinib, and EMP-1 was identified as a surface biomarker whose expression correlated with the development of resistance to gefitinib. This model showed that while the absence of EMP-1 did not completely predict whether a person would cease responding to gefitinib, the presence of EMP-1 at the outset of treatment could help physicians predict which patients would not benefit from the drug. Investigations of tumour samples from patients with adenocarcinoma and squamous cell carcinoma two types of NSCLC that do not respond to gefitinib showed that EMP-1 was expressed in 66 per cent of the squamous cell carcinoma and 40.9 per cent of those with adenocarcinoma, confirming EMP-1s direct link to gefitinib-resistance.


PUMA protein coordinates apoptosis activities

A study by Dr. Jerry E. Chipuk and his team from St. Jude Childrens Research Hospital, Memphis, the United States, has discovered how the protein p53 initiate signals that trigger programmed cell suicide (apoptosis), which in turn offers critical insights for developing new anti-cancer drugs. The study showed that the protein PUMA frees p53 from the grip of a third protein, Bcl-xL, so p53 could activate the series of signals that trigger apoptosis. If the cells genetic material suffers a non-repairable injury, the p53 gene produces the p53 protein, which accumulates in the nucleus and cytoplasm of the damaged cell. The accumulation of p53 in the cytoplasm as well as in the nucleus contribute to apoptosis.

Accoridng to Dr. Chipuk, first p53 inside the nucleus regulates the expression of several genes linked to apoptosis, including PUMA. The PUMA protein is then produced in the cytoplasm, where other p53 proteins are bound to Bcl-xL. Finally, PUMA is bound to the p53/Bcl-xL pair, causing p53 to break free. The liberated p53 triggers a series of signals on the cells mitochondria and the membranes covering mitochondria become punctured, allowing certain molecules to leak out and begin the process of apoptosis. The binding of PUMA to the p53/Bcl-xL pair is the tripartite nexus that orchestrates the complex web of signals leading to apoptosis.


Scientists get a glimpse of how cells repair UV-damaged DNA

A team of scientists led by Dr. Dongping Zhong at the Ohio State University, Columbus, the United States, has for the first time observed how some cells are able to repair DNA damage caused by the suns ultraviolet (UV) radiation. The study revealed how the enzyme photolyase used energy from visible light to repair UV damage. This enzyme is missing in all mammals, including humans, although all other animals and all plants have it. Scientists believe that all placental mammals lost the ability to make this enzyme and this is the reason why all mammals are particularly vulnerable to cancer-causing UV rays from the sun. But the rest of the animal kingdom insects, fish, birds, amphibians, marsupials, and even bacteria, viruses and yeast retained a greater ability to repair such damage.

It has long been suspected that visible light excites the photolyase molecule and boosts the energy of electrons in its atoms, thereby enabling the enzyme to inject an electron into the DNA molecule at the UV damage site temporarily to perform repairs. Water plays a key role in the process, by regulating how long the donated electron stays inside the damage site before returning to the photolyase molecule. Further, scientists have been trying to understand how the DNA in plants and some animals can be damaged by UV light. Scientists proposed a mechanism for photolyase, and tried to understand how it donated an electron to damaged DNA and how it formed a tiny water-filled pocket to host damage site within the cell nucleus. This latest series of experiments explains how water affects the reaction.

The researcher team mixed photolyase with UV-damaged DNA, and hit the mixture with a blue strobe light for less than a trillionth of a second to simulate the energy that it would receive from visible light. They then made a very fast series of measurements to follow how the chemical reaction evolved over time. The measurements were put together like a series of stop-motion photographs to reveal the individual steps of UV repair.

According to Dr. Zhong, when a UV photon strikes a portion of DNA, the atoms in the DNA molecule become excited. Sometimes an accidental bond forms between them, which is called a photo-lesion, and can lead to a kind of molecular injury called a dimer. Dimers prevent DNA from replicating properly, and cause genetic mutations that lead to diseases such as cancer. In cell nuclei that contain photolyase, the enzyme forms a water-filled pocket that can accommodate the dimer for the repair. When a photon of visible light hits the pocket, the enzyme becomes excited, and expels one of its own electrons into the dimer, which forces a rearrangement of the atoms in the DNA. In less than a billionth of a second, the damaged DNA bases recover their original form, as if the UV damage never occurred. When the photolyase enzyme becomes excited, it jostles the water molecules, and that motion within the pocket delays the electrons exit from the dimer until just after the repair is done.


Protein copying technique useful for drug research

Dr. Partho Ghosh and his team at the University of California, San Diego, the United States, have found that a phage can generate a kaleidoscope of variants of a particular protein. This method for generating proteins provides an effective way to produce therapeutic enzymes and other medically important proteins.

The massively variable phage protein tethers the phage to the bacteria they infect. The phages predator protein fits into a prey protein on the bacteria like a three-dimensional puzzle piece. As the bacteria constantly change their surface proteins, the phage generates many different proteins to keep up with these unpredictable changes and have an acceptable fit. The researchers showed how by altering the amino acids at one or more of just 12 sites on the predator protein, the phage generates 10 trillion proteins, each of which can bind to a different prey protein. This variability arises as the DNA is being copied into the RNA blueprint for the protein. The sequence of DNA bases at the 12 sites has unique characteristics that cause frequent mistakes to be made in the copying process. The RNA thus ends up specifying a different amino acid, and a structurally and chemically different protein is created. Because of its stability, the phage protein makes a good model to create protein diversity and it opens up a whole new platform for protein development.



Replacement for bacterial DNA in transgenic crops

Scientists from University of Tennessee, Knoxville, the United States, have developed a potentially less controversial way to bioengineer plants, by replacing a marker gene normally borrowed from the bacterium Escherichia coli with a gene from weeds. This nullifies the possibility that the code for antibiotic resistance could hop, in a process known as horizontal gene transfer, from the bioengineered food.

Dr. Neal Stewart and Dr. Ayalew Mentewab have eliminated the E. coli gene and used a gene called Atwbc19 from Arabidopsis thaliana that also conferred antibiotic resistance. When this gene was expressed at unusually high levels, it helped to capture and squelch antibiotic compounds. The scientists designed a piece of DNA including this gene and another that coded for blueish pigments, making plants that pick it up easily identifiable. The Atwbc19 gene was three times larger than the antibiotic-resistance gene from E. coli. Both the large size of the gene and its plant origin made it less likely to hop into microbes. To test whether the Atwbc19 gene worked, the scientists incorporated the linked genes into tobacco plants. The modified tobacco seedlings continued to grow when blasted with antibiotics. According to Dr. Stewart, the technique could be adopted in parts of the world that have remained skeptical about bioengineered foods.


GM plant produces non-GM watermelon

A team of Korean biotechnologists, led by Dr. Fernan Lambein of the Institute for Plant Biotechnology for Developing Countries in Belgium, has modified only the rootstock, a kind of underground stem, to which seedlings of commercial watermelon varieties were grafted, instead of genetically modifying an entire watermelon plant. This produced fruit that contained no foreign genes.

This method could be applied to other crops, such as cucumber and melon. Seedlings of commercial watermelon species tend to be grafted to hardier, wild watermelon rootstocks that are better able to resist infection. But even robust rootstock is vulnerable to cucumber green mottle mosaic virus, a virus found in soil. The virus causes the plants leaves to turn yellow and makes the fruit rot.

According to the researchers, genes conferring resistance to the virus do not exist in nature. As traditional plant breeding cannot solve the problem, they inserted a viral gene into watermelon rootstock to create a resistant plant. One in ten of the modified rootstocks were resistant to infection though it is unclear how the inserted viral gene protects the watermelon. Dr. Lambein states that this combination of genetic modification and traditional plant grafting technique is economical for poor farmers in developing countries as they do not have to buy chemical virusides. The technique also used less fertiliser, and produced more and higher-quality fruit.


Plants given an immune system

A group of researchers headed by Dr. Rosella Francon in Rome have evaluated the intracellular performance of antibodies and constructed them in such a way that they can thwart off pathogens or help regulate cellular events.

Researchers have also come up with a way to overcome the limiting factors of antibodies and have developed single-chain antibody fragments (scFv, where the variable domains are joined by a flexible linker peptide), which provide many of the necessary features to still survive and carry out certain tasks within the cell, being able to recognize and attach to their targets appropriately. This use of scFv intrabodies has proven to be a very important technique to thwart pathogens in plants, besides treating human diseases.

The researchers wanted to produce scFv in plants that recognize the cucumber mosaic virus (CMV), thus providing them with one basic component of an immune system. They screened F8 antibody library to obtain scFv structures that best recognized CMV. They then introduced its gene into mini-tomatoes so that the plants expressed the antibodies. Subsequently, the plants were infected with CMV. The results revealed that the antibodies recognized the pathogen and hindered an infection. A breakthrough was that one line of transgenic tomato plants was found to fully protected from CMV infection. Further studies should reveal how the scFv intrabodies precisely mediate protection of plants and whether they interfere with other processes.


Vitamin A-rich mustard for developing nations

A mustard variety rich in beta-carotene is being developed in India to enhance the availability of vitamin A to populations in developing countries. The project, organized under the supervision of Dr. Vibha Dhawan at The Energy and Resources Institute (TERI), uses the technology developed by Monsanto to raise beta-carotene levels in rapeseed. The mustard species is closely related to rapeseed and its oil is more widely used in countries like India. Mustard oil is the second most common cooking oil used in India, with an estimated 25 per cent of the population using it.

After the initial work on genetic transformation on Brassica juncea cv. Pusa Bold and Varuna at the Monsanto Research Centre in Bangalore, T3 transgenic seeds with enhanced beta-carotene content were provided to TERI. The seeds were grown at two places to raise the T3 generation of plants. Selfed seeds harvested from the T3 generation were sown again for bulking up for one more cycle. The developed plants are currently under field test.


Salt tolerant gene found in rice

A team of researchers from the Shanghai Institute for Biological Sciences, China, and the University of California at Berkeley, the United States, has identified a rice gene linked to salt tolerance. This discovery could have tremendous significance for Chinas food security, as about 8 per cent of its rice fields have high levels of salt.

The research group, headed by Dr. Lin Hongxuan, identified a gene named as SKC1, which naturally occurs in a Japanese rice variety called Nona Bokra, that controls the amount of sodium that builds up in rice plants as they grow. Dr. Lins team used genetic engineering methods to insert the gene into a rice variety with low salt tolerance and it had been seen that sodium concentration in the modified plants fell by 25-30 per cent. In addition, the potassium concentration improved by 20 per cent, which was beneficial for rice growth.


Transgenic rice that survives herbicides

Dr. Sakiko Hirose from the Plant Biotechnology Department at the National Institute of Agrobiological Sciences (NIAS) in Ibaraki, Japan, and her co-researchers have developed a transgenic rice that can degrade various classes of herbicides.

From past research, scientists know that cytochrome P450 monoxygenase (P450) degrades herbicides and thus renders plants resistant to some compounds. In mammalian liver, however, eleven P450s are known to be involved in the metabolism of foreign substances. Since they do not specifically degrade a certain range of compounds, they improve the mammals ability to abolish a variety of unknown compounds. One very useful example is human CYP2B6, which is able to decompose various classes of herbicides.

The researchers inserted the human gene CYP2B6 into Oryza sativa cv. Nipponbare. The genetically engineered rice plants showed high tolerance to the herbicides alachlor and metolachlor, which otherwise inhibit the synthesis of very long chain fatty acids in plants. In the CYP2B6 rice variety, the researchers detected very little intact metolachlor. In non-transformed Nipponbare rice, however, they found large amounts of the herbicide and also noticed a byproduct of metolachlor, which signified that the transgenic plants had degraded the metolachlor. Three other herbicides pyributicarb, pendimethalin and trifluralin inhibited root growth or germination of Nipponbare rice, while, CYP2B6 rice varieties produced roots and grew better.



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