VATIS Update Biotechnology . Jan-Feb 2009

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Biotechnology Jan-Feb 2009

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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Indias GM cotton plantation seen rising

Indian farmers will grow genetically modified (GM) cotton on 90 per cent of the area under cotton cultivation in two years, a group that advocates the use of such crops said recently. Indian farmers have overwhelmingly adopted genetically modified cotton as better yields pushed output substantially and drastically cut pesticide use, said Mr. Clive James, chairman of the International Service for the Acquisition of Agri-biotech Applications. The organization advocates large-scale use and application of GM crops.

It is noteworthy that for the seven-year period 2002-2008, there was a 150-fold increase in Bt cotton in India, Mr. James said. Indian farmers grow cotton on about 9 million hectares. He said India planted genetically altered fibre on 7.6 million hectares in 2008, up from 6.2 million hectares a year earlier.

Cotton output in India, the worlds second-biggest producer, is expected fall to 29 million bales (1 bale = 170 kg) in the crop year to September 2009 from 31.5 million bales a year ago as late sowing would cut production, according to official estimates.

India allowed commercial cultivation of Bt cotton in 2002, sparking protests from activists who say genetically altered crops are a health hazard, spoil soil texture and harm the environment. Increasing cotton output, however, has encouraged government officials to back the technology, which is seen as a viable step to support the countrys more than one billion population when farmland is shrinking rapidly due to industrialization and urban spread.


Babies genomes to be mapped at birth by 2019

Dr. Jay T. Flatley, CEO of the biotech company Illumina, the United States, has predicted that every baby will have its entire genome decoded at birth by the year 2019. Speaking to The Times newspaper recently, Dr. Flatley estimated that his company would be offering the service for as little as US$1,000 within the decade, one hundredth of the current price.

A babys genome will be computerized, from start to finish, via an innocuous heel-prick blood test. The idea behind this is to recognize risks of developing well-studied genetic conditions, like breast cancer or cystic fibrosis, as often these are manifest as small changes in our DNA. Beginning life with such information could be of great benefit, claims Dr. Flatley. It would enable tailor-made drug regimens, when drugs are prescribed to suit an individuals metabolism. Prophylactic treatment might become routine. Dietary advice could also be given, for instance, where a newborn shows the signs of a cardiovascular disease.

Besides social acceptability, disproportionate costs have been cited as the limiting factor for the idea. However, as the costs of sequencing technologies are now plummeting, Dr. Flatleys forecast of the price makes it once again feasible. Dr. Flatley, however, concedes that acceptability will always be an issue: The limitations are sociological; when and where people think it can be applied, the concerns people have about misinformation and the background ethics questions, he said.


First super cancer centre

Birmingham will become the first link in a unique chain of Cancer Research UK Centres to be set up across the United Kingdom. These cancer centres will draw together world class research and areas of medical expertise to achieve the best possible results for cancer patients nationwide.

As the first Cancer Research UK Centre, Birmingham will set the pace for national and international progress for genetics, gene therapy and the link between viruses and some cancers, as well as focusing on cancers of the prostate and bladder, and leukaemia. It will also become a leading centre for clinical trials.

Collaboration is the key to the success of the Centre, which will also concentrate on large-scale population studies, cell biology and tumour immunology. Professor Lawrence Young, head of the University of Birminghams College of Medical & Dental Sciences, said: We are at the forefront of a cancer revolution, translating our research into new treatments. Partnering the University of Birmingham, the Centre also aims to attract and train the highest quality clinical and non-clinical cancer research students, to develop infrastructure for tissue banking and data collection, to strengthen collaboration between scientists and clinicians, and to improve international communication.


Kenya approves GM crops

Kenya has become the fourth African country to allow the production and use of genetically modified (GM) crops after President Mr. Mwai Kibaki signed on the Parliaments approval of new biosafety legislation in February. The Biosafety Bill 2008 sees the East African nation join Burkina Faso, Egypt and South Africa as African nations that permit GM farming, following years of fine-tuning to the proposed regulations and mechanisms to monitor and regulate GM technology, and protect farmers and consumers.

A National Biosafety Authority will now be created, under the National Council for Science and Technology, to implement the legislation and to follow priorities as stated in the National Biotechnology Development Policy passed in 2006, said Ms. Margaret Karembu, Director of the Kenya-based African centre of the International Service for the Acquisition of Agri-biotech Applications (ISAAA). She added that the new legislation would fast-track the Water Efficient Maize for Africa project to develop drought-resistant maize, which had stalled due to the lack of a legislative framework.

Mr. Charles Watoro, Director of Kenya Agricultural Research Institute (KARI), says that the new law will allow open field trials in several locations, removing previous restrictions and speeding up agricultural improvements. Mr. Watoro says KARI researchers are working on cotton, maize, cassava, sweet potatoes and sorghum GM to resist common pests.

Meanwhile, an international survey of 13 years of GM agriculture up until 2008, released in Nairobi in February by ISAAA, says there is substantial evidence that crops genetically modified to withstand drought, pests and diseases are safe for human consumption.


The United States allows test of human stem cell therapy

The United States Food and Drug Administration has cleared the way for the first trial to see if human embryonic stem cells can treat people safely. The biotechnology company Geron Corporation said it plans a clinical trial to try to use the stem cells to regrow nerve tissue in patients with crushed, but not severed, spinal cords.

Human embryonic stem cell research has been a political issue, with anti-abortion forces arguing that the technique involves the destruction of human embryos, and the advocates of the technique saying it could transform medicine. This approach is one that reaches beyond pills and scalpels to achieve a new level of healing, said Geron Chief Executive Dr. Thomas Okarma. Geron will recruit 8-10 recently injured patients and inject them with small numbers of human embryonic stem cells manipulated to become the oligodendrocyte cells that insulate nerves and produce compounds to stimulate the growth of nerve cells.

Dr. Okarma said the treatment should eventually become cheap and easy to mass produce because the cells can be grown in vats. The cells, he believes, may be useful for treating other diseases such as multiple sclerosis, in which nerve cells are stripped of their insulating sheaths, and perhaps stroke.

The Phase I trial will be designed to show that the approach does not develop tumours in patients or damage their nervous systems. It will also indicate whether the stem cells might repair the damaged spinal cords. While the patients will get low doses of immune-suppressing drugs for the first two months, Dr. Okarma is confident the cells will escape immune system recognition, and patients will not have to endure the treatments that organ and tissue transplant recipients usually do. Treatment on the first patient should begin this summer.



Indo-Malaysian initiatives in biotechnology

Malaysian Biotechnology Corporation (BiotechCorp), the lead development agency for the biotechnology industry in Malaysia, kicked off their first business development engagement for 2009 in Hyderabad and Chennai, India. BiotechCorp was established in 2005 to play the leading role in building the biotechnology business in Malaysia by creating a conducive environment as well as to actively promote foreign direct investments in Malaysian biotechnology.

Biotechnology has been identified as one of the key drivers for growth by the Malaysian government and will continue to be supported as one of the new sources of growth not only for the nations economy, but as an enabler to move conventional sectors up the value chain. The government announced a US$3 billion allocation this year to enhance healthcare, which included increasing the supply of medicine, intensifying research and enforcement activities, and further strengthening the growth of healthcare biotechnology.

Malaysia and India continue to collaborate in the field of biotechnology and life sciences with strategic partnerships forged between companies in the two countries. BiotechCorp and the Manipal Education and Medical Group (Manipal Group) of India entered into a partnership in May 2007. Later, Manipal Group set up Stempeutics Research Ltd., which became the first international company in stem cells research and therapeutics to be granted the privileged BioNexus status in Malaysia. Stempeutics Research recently launched a US$5 million first-of-its-kind stem cell research facility in Malaysia to strengthen its leadership position in such research.

Malladi Drugs & Pharmaceuticals Ltd. (Malladi Drugs), an API manufacturer based in Chennai, is committed to invest up to US$300 million in the next 3-5 years with aims to expand into other areas of service offering as a contract research organization in Malaysia. This includes oncology and steroids and beta-lactums. Malladis activities will turn Malaysia into an outsourcing centre for pharmaceutical companies from the United States and Europe.


Bangladesh inducts new vaccine

Bangladesh has introduced a new combination vaccine that will protect its children against five killer diseases in one injection, including, for the first time, the bacterium Haemophilus influenzae type b (Hib) that causes some severe forms of pneumonia and meningitis. The vaccine can prevent about one-third of life-threatening cases of bacterial pneumonia, the leading infectious cause of death in children worldwide.

Each year, Hib is estimated to cause millions of serious illnesses and 400,000 deaths globally, the majority of them among children under five years of age. Even with treatment, thousands of children die of Hib disease every year, while survivors are often permanently disabled paralysed, brain-damaged or deafened.

The vaccine will be provided under the routine immunization programme to nearly four million children born in Bangladesh every year. It is estimated that Hib vaccine can save about 20,000 childrens lives annually in the country. Where used routinely, it (Hib vaccine) has virtually eliminated Hib disease, stated Dr. Rana Hajjeh, Director of the Hib Initiative at Johns Hopkins University.

The new combination vaccine will protect children against Hib, diphtheria, tetanus, pertussis and hepatitis B. Instead of three different injections, the children will now need only one injection at three different times during their first year of life. This will make it easier for health workers who will need less time and less logistics to immunize all children. It will also increase the uptake of vaccine, as each child will get all five vaccines at once. Introduction of the 5-in-1 vaccine in the country is carried out with financial and technical support from the GAVI Alliance, UNICEF, WHO and the Hib Initiative. The Government of Bangladesh is participating in the project by co-financing the vaciine purchase.



Biotage joins MultiSynTech for peptide synthesis

Biotage AB, Sweden, has announced that the company will enter the peptide synthesis business, through two new agreements with the German company MultiSynTech GmbH. The agreements concern both the distribution rights for MultiSynTechs systems and the establishment of a joint development project.

The agreements with MultiSynTech will grant Biotage distribution rights for all the current peptide synthesis systems of MultiSynTech. The companies have also agreed on a joint development project to design and market a new microwave-aided peptide synthesis system that will increase yield and speed in peptide synthesis.


Novartis and Gen-Probe agree to expand collaboration

In the United States, Chiron, a Novartis business unit, has agreed to extend and expand its blood screening collaboration with Gen-Probe until 2025. The companies will continue to work together to develop and commercialize molecular technologies that safeguard donated blood supply.

The collaboration between Novartis and Gen-Probe was established in 1998. It was previously scheduled to expire in 2013. Under the original terms of the agreement, the companies shared revenue from the sale of blood screening assays. Gen-Probe was responsible for manufacturing costs, while Novartis was responsible for commercial expenses. The companies shared research and development (R&D) costs.

Under the revised agreement, Gen-Probe will continue to be primarily responsible for R&D and manufacturing. Novartis will remain responsible for sales and marketing of the products, but will collaborate more closely with Gen-Probe on sales, marketing and distribution strategies. In addition to sharing R&D costs, the companies will share manufacturing expenses. Gen-Probe also will receive a percentage of end-user revenue.

As part of the expanded agreement, Novartis has agreed to help fund development of Gen-Probes PANTHER instrument, a fully automated molecular testing platform for blood screening units. The companies also have agreed to evaluate, using Gen-Probes technologies, the development of companion diagnostics for current or future medicines from Novartis.


Honda plans to build bio-ethanol research plant

Honda Motor Company, Japan, has announced its plans to build a new research facility for bio-ethanol production technology from non-edible cellulosic material, such as the stems and leaves of plants. The facility will be built in Kazusa Akademia Park in Japan. The new facility of Honda R&D will be a single building (1,050 sq. m), with construction scheduled to begin in April 2009. The companys goal is to begin operations in November 2009.

Honda has been collaborating on research into bio-ethanol production technology since 2006 with the Research Institute of Innovative Technology for the Earth (RITE) and has been conducting research on a bio-ethanol conversion process in an experimental plant since April 2007. The new building will allow for research using a large-scale experimental facility, enabling more accurate evaluations.


Wockhardt launches new insulin in India

Wockhardt, Indian pharmaceutical and biotechnology major, has launched Glaritus, a novel recombinant long-acting human insulin analogue. With this, Wockhardt has become the first company in the world after the innovator to launch Glaritus that works slowly for over 24 hours. The new insulin has been successfully clinically tested on 300 diabetic patients for safety and efficacy parameters, and is approved by the Drug Controller General of India, the news release says.

The launch of Glaritus is a significant landmark for India, which has one of the highest diabetes affected populations in the world. The advantage of the new insulin is that it is a once daily dose that provides basal glucose control for 24 hours. Glaritus can hence be easily combined with other oral medications of diabetes for effective blood glucose control. Glaritus is a meal-independent, peakless insulin, which reduces incidences of hypoglycaemia significantly. All these translate into more compliance to insulin therapy, improved blood glucose control and therefore slower progression of diabetes-related complications.

Glaritus is available to the patients as reusable and disposable pen delivery devices. Wockhardt is one of the few select companies in the world to patent the technology of pen-based insulin delivery devices, which is one of the most preferred modes of insulin injection across the globe today. Wockhardt insulin pen devices are ISO 11608 approved and have won awards for excellence in packaging technology.



PC Biotech and Agennix in merger mode

The two oncology-focused biotechnology companies GPC Biotech AG, Germany, and Agennix Inc., the United States, have signed a Business Combination Agreement under which GPC Biotech is to be merged onto a new German company, which will hold all of the shares of Agennix and a 15 million cash contribution by dievini Hopp BioTech holding GmbH & Co KG.

The merger combines the oncology pipelines of both companies, with the clinical development and financial resources of GPC Biotech and dievini Hopp BioTech holding. The Boards of both GPC Biotech and Agennix have voted unanimously to support the proposed merger, which is subject to the approval of the shareholders. The merger is expected to be completed by the end of 2009. The new company will focus on the development of new anti-cancer therapies. The lead compound will be Agennixs Talactoferrin, a novel oral agent being developed for lung, kidney and other cancers, as well as for severe sepsis. Talactoferrin has entered Phase 3 clinical testing for non-small cell lung cancer. The new company will also focus on the clinical development of topical Talactoferrin for treating diabetic foot ulcers, and RGB-286638 from GPC Biotech, a multi-targeted kinase inhibitor for advanced solid tumours.




Genetic information can improve administration of anti-coagulant

Each year, millions of patients are put on warfarin, an anti-coagulant drug that is notoriously hard to administer. If the warfarin dose is too high, patients are at risk of hemorrhage, and if it is too low, they risk blood clots that can lead to stroke, heart attack or even death, says Dr. Brian Gage, Associate Professor of medicine at the Washington University School of Medicine (WUSM) and Director of the outpatient Anti-coagulation Service at Barnes-Jewish Hospital, the United States.

Now a study from the International Warfarin Pharmacogenetics Consortium (IWPC), which includes WUSM researchers, confirms that using a patients genetic information can make it easier to get the warfarin dose right. At WUSM, Dr. Gage, Dr. Charles Eby, Associate Professor of pathology and immunology, and colleagues recently developed improved dosing formulas for warfarin. They calculated the warfarin dose by taking into account the effect of two genes involved in warfarin sensitivity and metabolism. Their research showed that gene-based dosing could more quickly and accurately estimate the appropriate warfarin dose.

The new study gave gene-based dosing a rigorous test in an international collaboration that included more than 5,000 patients who had achieved a stable effective dose of warfarin. The researchers calculated a warfarin dose for each of the patients with the gene-based dosing algorithm and with a formula based only on clinical data. Both formulas incorporate data such as age, body size, medications and race to estimate appropriate warfarin dose, but only the gene-based formula includes genetic information. Using both formulas, the IWPC researchers checked how closely the calculated dose matched the dose actually used for each patient. In 60 per cent of the patients, the gene-based formula got closer to the actual dose than did the clinical formula.

The researchers showed that the gene-based formula was better than the clinical formula at identifying the patients at the low and high ends of the dosing spectrum. It also lays important groundwork for a new clinical trial, the Clarification of Optimal Anticoagulation through Genetics trial. The trial will compare gene-based warfarin dosing to the traditional dosing approach in a prospective, randomized trial involving 1,200 participants of diverse backgrounds and ethnicities at 12 clinical sites in the United States.


Worm gene offers clues to nerve cell repair

Researchers believe that they have found a way to regenerate nerves by stimulating a gene and said their work in worms might some day help people with spinal cord injuries. The gene is part of a network, or pathway, of four genes that appear to be essential for nerve repair, they wrote in the journal Science. We found a pathway that not only regenerates nerves in the worm, but also exists in humans, and we think it serves the same purpose, said Dr. Michael Bastiani of the University of Utah, the United States. The gene could serve as a target for a future drug that could vastly improve the ability of a neuron to regenerate after injury, he added.

In humans, nerve fibres in the arms and legs can regenerate, but not in the brain and spinal cord. Many teams are working to understand why. Dr. Bastianis team looked to nematode worms for clues. Using RNA interference, the team systematically blocked the action of 5,000 worm genes to isolate those important for nerve repair. They found that a gene called dlk-1 was essential to the process at every stage of the worms life. When they blocked this gene network, the worms were unable to repair nerve damage. But when they stimulated the gene, worms with damaged nerves recovered much more quickly.

Curiously, this network of genes is not used by the nervous system during normal development in the embryo, but it is essential for nerve repair after birth. Most of us believed that virtually everything we found in regeneration also would be involved in development, Dr. Bastiani said. His team noted that to be effective, the dlk-1 gene must be stimulated soon after injury to make a protein that activates repair, suggesting that there might be a time window for activating this pathway.


Key gene linked to high blood pressure identified

A gene that affects how the kidneys process salt may help determine a persons risk of high blood pressure, a discovery that could lead to better ways to treat the condition, said researchers from University of Maryland School of Medicine, the United States. They identified the role of the gene a common variant of the gene STK39 in high blood pressure susceptibility by analysing the genes of 542 people in the insular Old Order Amish community in Lancaster County, Pennsylvania. The researchers confirmed the findings by looking at the genes of another group of Amish people, as well as four other groups of white people in the United States and Europe.

About 20 per cent of the people studied had either one or two copies of this particular variant, the researchers said. The gene produces a protein involved in regulating the way the kidneys process salt in the body a key factor in determining blood pressure, the researchers said. Dr. Yen-Pei Christy Chang, who led the study, said the findings could lead to the development of new high blood pressure drugs targeting the activity of STK39.

While STK39 may play a pivotal role in some people, Dr. Chang said numerous other genes also may be involved. Many factors such as being overweight, lack of exercise, smoking and too much salt in the diet are involved in hypertension. She said the researchers want to find out how people with different versions of this gene respond to the various drugs diuretics, beta blockers, ACE inhibitors and calcium channel blockers used in treating hypertension and to lifestyle interventions such as cutting the amount of salt in the diet.


Two gene mutations linked to most common brain cancers

In the United States, scientists at the Johns Hopkins Kimmel Cancer Centre and Duke University Medical Centre have associated mutations in two genes, IDH1 and IDH2, to nearly three-quarters of several of the most common types of brain cancers known as gliomas. Reporting in the New England Journal of Medicine, the scientists say they looked for IDH1 and IDH2 gene alterations in material obtained from 500 brain tumours and 500 non-central nervous system cancers. They located changes in the IDH1 gene in more than 70 per cent of three common types of gliomas: low-grade astrocytomas, oligodendrogliomas and secondary glioblastomas. The changes occurred within a single spot along a string of thousands of genetic coding letters. Some of the brain cancers that did not have IDH1 alterations had equivalent mutations in IDH2, another closely related gene.

Further analysis of their data showed that glioblastoma and anaplastic astrocytoma patients carrying the mutations survived longer than those who did not. The median survival was 31 months for the glioblastoma patients with mutations versus 15 months for those who lacked mutations. Anaplastic astrocytoma patients with mutations were found to have a median survival of 65 months as compared with 20 months for those who did not. The mutations appear to occur very early in the progression of these cancers, perhaps at the stem cell level, observes Prof. Bert Vogelstein, Co-Director of the Ludwig Centre at Johns Hopkins.


Genes linked to virulence of the 1918 flu identified

In the United States, scientists led by Dr. Yoshihiro Kawaoka, professor of pathobiological sciences in the University of Wisconsin-Madison School of Veterinary Medicine, have identified a set of three genes that enhanced the virulence of the 1918 Spanish flu virus. While conventional flu viruses replicate only in the upper respiratory tract, these genes gave the virus the capacity to reproduce in lung tissue as well.

To find the gene or genes that enabled the virus to invade the lungs, the scientists blended genetic elements from the 1918 flu virus with those of a currently circulating avian influenza virus and tested the variants on ferrets. Substituting single genes from the 1918 virus onto the template of a much more benign contemporary virus called K173 yielded, for the most part, agents that could only replicate in the upper respiratory tract. One exception, however, included a complex of three genes that, acting in concert with another key gene, allowed the virus to efficiently colonize lung cells and make RNA polymerase. Without the protein, the virus is unable to make new virus particles and spread infection to nearby cells.

Using relic genes recovered earlier from the 1918 virus, Dr. Kawaokas group was able to generate viruses that carry different combinations of the 1918 virus and modern seasonal influenza virus. When tested, most of the hybrid viruses only infected the nasal passages of ferrets and didnt cause pneumonia. But one did infect the lungs and it carried the RNA polymerase genes from the 1918 virus that allowed the virus to synthesize its proteins.

In 2004, Dr. Kawaoka and his team identified another key gene from the 1918 virus that enhanced the pathogens virulence in mice. That gene makes hemagglutinin, a protein found on the surface of the virus that confers on viral particles the ability to attach to host cells. This could be another mechanism, Dr. Kawaoka says. The RNA polymerase is used to make copies of the virus once it has entered a host cell. The role of hemagglutinin is to help the virus gain access to cells.


New anti-tumour gene identified

Researchers from Virginia Commonwealth University (VCU), the United States, have identified a new anti-tumour gene called SARI that can interact with and suppress a key protein that is over-expressed in 90 per cent of human cancers. According to Dr. Paul Fisher, Professor and Chair of the Department of Human & Molecular Genetics and Director of the VCU Institute of Molecular Medicine, and lead investigator of the study, this novel gene highlights a previously unrecognized molecular pathway underlying the anti-tumour action of a potent immune system modulator called interferon (IFN).

In the study, published in the Proceedings of the National Academy of Sciences, the researchers report the discovery of a new gene named SARI, which was uncovered by subtraction hybridization, a powerful technique pioneered in the laboratory of Dr. Fisher. SARI, which is induced by IFN, was found to suppress growth and survival of tumour cells by interfering with the action of cancer cell molecules that drive cell division and promote survival.

The researchers delivered SARI to cancer cells using a virus and the infected cancer cells subsequently stopped dividing and died. Since 90 per cent of all cancer types rely on a similar mechanism to proliferate and evade destruction, Dr. Fisher noted that SARI could be an effective anti-cancer treatment for many tumours. Additionally, IFNs are powerful immune modulating agents that contribute to the immune response to cancer and they are effective inhibitors of new blood vessel formation, the process of angiogenesis, which is obligatory for the growth of both primary and metastatic cancers, he said.

IFNs are relevant in the clinical treatment of a number of solid tumours and hematological malignancies, either as a monotherapy or as an adjuvant to chemotherapy of radiotherapy. The SARI gene may provide novel and selective gene therapy applications for cancer. It could also prove amenable for inhibiting proliferative disorders that depend on AP-1 activity, Dr. Fisher said. AP-1 plays a key role in regulating cancer cell proliferation and transformation.



Fruit fly gene responsible for healthy stem cells

Scientists at the Carnegie Institution for Science, the United States, have identified a fruit fly gene, named scrawny, that appears to be a key factor in keeping a variety of stem cells in their undifferentiated state. While the scrawny gene has so far only been identified in fruit flies, very similar genes that may carry out the same function are known to be present in all multi-cellular organisms including humans, say the researchers.

The scientists found that scrawny modifies a chromosomal protein histone H2B that is used by cells to package DNA into chromosomes. By controlling the proteins that package the genes, scrawny can silence genes that would otherwise cause a generalized cell to differentiate into a specific type of cell. The scientists report that they observed the effects of scrawny on every major type of stem cell found in fruit flies. In the experiments, mutant flies without functional copies of the scrawny prematurely lost their stem cells in reproductive tissue, skin and intestinal tissue.



Protein that links stress and depression

If stress goes on too long, it can lead to debilitating psychological problems. Part of the reason, according to scientists at the Rockefeller University, the United States, may have to do with a little-known family of proteins called kainate receptors that has recently been implicated in major depression. New research in rats may help explain one mechanism by which stress reshapes the brain: by ramping up production of a particular part of these proteins.

We have recently seen large human studies that suggest kainate receptors are targets for response to certain anti-depressants and are also involved in major depression and the susceptibility to suicidal thoughts, states Dr. Richard Hunter, a post-doctoral fellow in the Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology at Rockefeller. Dr. Hunter and his colleagues homed in on one of five subunits of the kainate receptor called KA1. Exploring the impact of stress and steroids on rats, they found that stress, simulated by restraining the rats for six hours a day for three weeks, caused the genes to send instructions messenger RNA to increase production of KA1 subunits in particular parts of the hippocampus, a highly plastic brain structure involved in learning and memory. Stress and depression are known to cause a reversible retraction of dendrites in certain brain cells, particularly in the hippocampus.

The lab produced a similar result by injecting unstressed rats with corticosteroids, suggesting that an increase in these hormones is largely responsible for the stress response in rats. But the researchers also found that the dose is critical. While a moderate amount of corticosteroids increased KA1 messenger RNA, a high dose of the steroids did not. The body seeks to maintain ideal levels, whether it is salts in the blood or any number of other things like KA1, remarks Dr. Hunter. Deviations to either side of these levels can cause pathologies or changes. The body adapts to changing circumstances to keep the levels healthy.

Earlier, Dr. Sidney Strickland, head of the Laboratory of Neurobiology and Genetics at Rockefeller, had shown that KA1 production explodes in the hippocampus during simulated stroke in mice, driving a cell-death cascade that begins when part of the brain is deprived of blood. Combined, the two works suggest that the relatively understudied KA1 subunit plays an important role in a key area of the brain in both causing damage in an uncontrolled trauma such as a stroke and in protecting the brain from damage under the more controlled circumstances of chronic stress.


Alzheimers disease abetted by proteins working in tandem

Evidence found by researchers from the University of Rochester Medical Centre (URMC), the United States, links two proteins working in the brains blood vessels to Alzheimers disease. They have found that the proteins, serum response factor (SRF) and myocardin, reduce the rate of amyloid beta (A-beta) removal in the brain. The proteins work together to turn on a molecule known as sterol-responsive element-binding protein 2 (SREBP2), which then inhibits low-density lipoprotein-related protein 1 (LRP-1) that helps the body remove A-beta under normal conditions. This results in the accumulation of toxic levels of A-beta, aiding the progression of Alzheimers disease.

Although the scientists were surprised to find the two proteins, known for their role in the cardiovascular system, linked to the development of Alzheimers disease, a senior author of the study, Dr. Berislav Zlokovic from URMCs Centre for Neurodegenerative and Vascular Brain Disorders, said, ...both of these processes are mediated by the smooth muscle cells along blood vessel walls, and we know that those are seriously compromised in patients with Alzheimers disease. Dr. Joseph Miano, from URMCs Aab Cardiovascular Research Institute and senior co-author of the study added, There is a great deal of evidence to suggest that Alzheimers disease is a problem having much to do with the vascular plumbing.

The team studied brain cells taken from people who had Alzheimers and compared them to cells from healthy elderly people. Compared with the smooth muscle cells from healthy adults, the cells from patients with Alzheimers disease had about five times as much myocardin, about five times as much SREBP2, four times as much SRF, and about 60 per cent less LRP-1. That translates into a reduced ability to remove A-beta. Cells of patients with the disease had only about 30 per cent of the ability of their healthy counterparts to remove the substance.

When the team lowered levels of SRF to the same level that exists in healthy cells, the cells from Alzheimers patients improved in their ability to remove A-beta, doing it just as well as the cells from healthy individuals. Conversely, when the team boosted levels of SRF and myocardin in the healthy cells, the changes lowered by 65 per cent those cells ability to remove A-beta.


A key protein that may cause cancer cell death

Scientists at A*STARs Institute of Molecular and Cell Biology (IMCB), Singapore, have become the first to discover and characterize a human protein called Bax-beta, which can potentially cause the death of cancer cells and lead to new approaches in cancer treatment. Said Dr. Victor Yu, principal investigator of the IMCB research team, Our research findings reveal that Bax-beta protein levels are normally kept at essentially undetectable levels in healthy cells by the protein degradation machine in cells known as proteasomes. Proteasomes are protein-digesting machines that regulate cellular levels of proteins including that of the lethal Bax-beta, by breaking them into smaller components within the cell.

Dr. Yu postulates that if the degradation of Bax-beta mediated by proteasome could be inhibited in cancer cells, it could cause the harmful cancer cells to self-destruct (apoptosis). While earlier evidence had suggested that more than one protein was encoded by the Bax gene, only a single protein called Bax-alpha had been extensively studied in cells. Dr. Yus team also found that Bax-beta is able to associate with, and promote Bax-alpha activation, and that Bax-beta, in its native form, is 100 times more potent than Bax-alpha in triggering a key step in apoptosis. The future development of novel compounds that can selectively elevate levels of Bax-beta or stimulate its interaction with Bax-alpha could lead to new drug approaches to cancer treatment.


Simplicity is crucial to design optimization at nanoscale

Researchers at the Massachusetts Institute of Technology, the United States, have discovered that the particular arrangement of proteins that produces the sturdiest product is not the arrangement with the most built-in redundancy or the most complicated pattern. Instead, the optimal arrangement of proteins in the rope-like structures they studied is a repeated pattern of two stacks of four bundled alpha-helical proteins. This composition of two repeated hierarchies (stacks and bundles) provides great strength, the ability to withstand mechanical pressure without giving way, and great robustness, the ability to perform mechanically.

Dr. Markus Buehler and Dr. Theodor Ackbarow, in a paper published in Nanotechnology, describe a model of the proteins performance, based on molecular dynamics simulations. With their model, they tested the strength and robustness of four different combinations of eight alpha-helical proteins: a single stack of eight proteins, two stacks of four bundled proteins, four stacks of two bundled proteins, and double stacks of two bundled proteins. Their molecular models replicate realistic molecular behaviour, including hydrogen bond formation in the coiled spring-like alpha-helical proteins.


Man-made proteins may beat the real ones

Researchers have constructed a protein out of amino acids not found in natural proteins, discovering that they can form a complex, stable structure that closely resembles a natural protein. The findings could help scientists design drugs that look and act like real proteins but will not be degraded by enzymes or targeted by the immune system, as natural proteins are.

The scientists, led by Prof. Alanna Schepartz of the Howard Hughes Medical Institute, Yale University, the United States, built the short protein, or peptide, from beta-amino acids, which, although they exist in cells, are never found in ribosomally produced proteins. Beta-amino acids differ from the beta-amino acids that compose natural proteins by the addition of a single chemical component a methylene group into the peptide backbone.
The fundamental insight from this study is that beta-peptides can assemble into structures that generally resemble natural proteins in shape and stability, Prof. Schepartz said. Their findings on the structure of the molecule that the scientists synthesized would help construct more elaborate beta-peptide assemblies and ones that possess true biologic function. Such beta-peptides could also be designed as drugs that would be more effective than natural protein drugs, because the enzymes that degrade natural proteins will not affect them.

In their studies, Prof. Schepartz and colleagues synthesized a beta-peptide they called Zwit1-F. They allowed the chain of beta-amino acids to assemble into its own structure and then analysed it with X-ray crystallography. They found that the Zwit1-F peptide folded into a bundle of coiled helices that resembled those in natural proteins. In particular, they noted that both natural proteins and the beta-peptide bundle folded in ways that placed the hydrophobic segments of the molecule in the core of the structure. Other features, too, were remarkably similar to a coiled helix bundle formed of beta-amino acids.

There were major differences too. For instance, when helices of natural peptides nestle against one another, often their side chains extend from the sides of each helix, fitting together like ridges in grooves. The beta-peptide helices, however, are structured so that their side chains alternate like interlocking fingers.




Medicines from genetically engineered animals

The United States government has approved the first drug produced by genetically engineered livestock. ATryn, the drug meant to prevent fatal blood clots in people with a rare condition, is a protein extracted from the milk of goats that have been given a human gene. The drug is the first to have been cleared by the United States Food and Drug Administration (FDA) under guidelines the agency adopted recently to regulate the use of transgenic animals in the nations drug and food supply.

GTC Biotherapeutics produces ATryn from a herd of 200 goats that live under quarantine on a high-security farm in central Massachusetts. The goats were bred to contain a human gene that causes their milk to produce a human blood protein, antithrombin, that can be extracted and processed into the anti-clotting drug. Such animals could become a way of producing biotechnology drugs at lower cost or in greater quantities than with the existing methods.

GTC Biotherapeutics said one of its goats can produce as much antithrombin in a year as can be derived from 90,000 blood donations. To make its protein, GTC took the human gene for antithrombin and linked it to goat DNA that normally controls production of a protein found in milk. That ensured that the protein would be produced only in the milk. The gene was injected into a one-celled goat embryo, which was then implanted into the womb of a surrogate mother. The goat with the gene that produced antithrombin in its milk, the founder animal, was then mated with others through conventional breeding to start a herd.

A Dutch company, Pharming, plans to apply for United States approval of a drug produced in the milk of transgenic rabbits to treat hereditary angio-oedema, a protein deficiency leading to dangerous swelling of tissues. Another company, PharmAthene, working under a United States Defence contract, is developing a treatment for nerve-gas poisoning in the milk of transgenic goats.

Many of the newer protein-based drugs, such as the cancer drugs Avastin and Erbitux and the arthritis drugs Enbrel and Humira, are produced in genetically engineered Chinese hamster ovary cells that are grown in big stainless-steel vats. But a cell culture factory can cost hundreds of millions of dollars to build. Using livestock eliminates all that steel and shrinks the investment to tens of millions of dollars, said Mr. Geoffrey Cox, CEO of GTC.



Functional neurons from engineered stem cells

In a new study at the University of California Los Angeles (UCLA), the United States, researchers were able to generate functionally mature motor neurons from induced pluripotent stem (iPS) cells, which are engineered from adult somatic cells and can differentiate into most other cell types. This study is the first to use human iPS cells to generate electrically active motor neurons, a key hallmark of functional maturation that is essential for any future application of iPS cells.

The UCLA Broad Stem Cell Research Centre research team of Dr. William Lowry, Dr. Bennett Novitch, Dr. Harley Kornblum and Dr. Martina Wiedau-Pazos compared the ability of different human cell lines to generate motor neuron progenitors and fully differentiated motor neurons. When measuring the electrophysical properties of the iPS-derived neurons, the researchers found that the iPS cells followed a normal developmental progression to form mature, electrically active neurons. Dr. Lowrys team used skin fibroblasts and reprogrammed them back into an embryonic state, with the ability to differentiate into any cell type in the human body. They then took those cells and differentiated them into motor neurons.

The study demonstrated the feasibility of using iPS-derived motor neurons and their progenitors to replace damaged or dead motor neurons in patients with certain disorders. It also opened the possibility of studying motor neuron-related diseases in the laboratory to uncover their causes.



New technique for cancer screening

Research by Dr. Marija Balic from the Medical University in Graz, Austria, and her colleagues suggests that a new technique to determine tumour methylation status can be used in archived tissue samples. The report is published in the Journal of Molecular Diagnostics.

DNA in tumours is often altered compared with DNA in normal tissues. One common DNA alteration in cancerous tissue is hypermethylation, which results in loss of gene expression. The difference in methylation between normal and cancerous tissues can be used as a biomarker for early cancer diagnosis, risk assessment and response to therapy. Archival tissues, or tissues that are formalin-fixed and paraffin-embedded for long-term storage, are however difficult to screen for cancer biomarkers due to the low quality of their DNA. It is therefore important to develop new techniques to screen for DNA methylation that can be used in archival tissues.

Dr. Balic and colleagues examined the ability of high-resolution melting analysis (HRM) to detect methylation on archival tissues from colorectal cancer patients. They found that HRM provided similar results for both archival and fresh tissues. In addition, they validated the results using the widely used MethyLight assay. Most importantly, the reported method has the potential to make DNA methylation analysis possible on tissues that have undergone formalin fixation and paraffin embedding, the most common means of tissue storage, thus enabling analysis of this vast tissue resource.



Human monoclonal antibodies effective against flu viruses

In the United States, researchers at the Dana-Farber Cancer Institute (Dana-Farber), Burnham Institute for Medical Research (Burnham) and the Centres for Disease Control and Prevention (CDC) report the identification of human monoclonal antibodies (mAb) that neutralize an unprecedented range of influenza A viruses, such as avian influenza (H5N1) virus, previous pandemic influenza viruses, and some seasonal influenza viruses. The antibodies identified bind to the highly conserved stem region of H5 type hemagglutinin (HA), instead of its highly mutable head portion. Binding to the stem prevents a conformational change in the protein that is necessary for viral entry into the host cell, thereby preventing further infection. In the study, the scientists used a human antibody phage display library to identify 10 mAb that bind to the stem of H5 type HA, the influenza protein responsible for viral entry into the host cell. They determined the X-ray crystal structure of the mAb bound to the H5N1 HA, which showed that the heavy chain of the mAb inserts into a highly conserved pocket in the HA stem, inhibiting the conformational change required for membrane fusion and viral entry into the cell. The scientists further showed that an unprecedented number of different types of bird flu and seasonal influenza viruses were inhibited and the mAb protected mice that were exposed to H5N1 virus.


Learning to control islet cell growth to benefit diabetes study

A new study has revealed the molecular mechanism of how a protein determines the fate of the cells that make and release insulin. Dr. Michael Lan Professor of Paediatrics and Genetics at Louisiana State University Health Sciences Centre, the United States, and the senior author of the study and colleagues are studying INSM1, a protein involved in the regulation of endocrine cells. INSM1 plays a critical role in the development of pancreatic beta cells the only cells in the body that secrete insulin. Beta cells are located in islet cell clusters throughout the pancreas.

Diabetes mellitus type 1 results from the destruction or dysfunction of islets and their beta cells. Type 2 diabetes results from the bodys inability to use insulin properly and a gradual decrease in the ability of pancreas to make it. The scientists used pancreatic cancer cells to investigate the effects of INSM1, a transcription factor, on cell cycle function. They developed an inducible system to turn on INSM1 in pancreatic cancer cells and found that it resulted in a significant reduction in the cells growth rate. They showed that the mechanism for this growth inhibition was due to an interaction between INSM1 and cyclin D1, an important cell growth promoting protein. The interaction between these two proteins impaired the growth of the tumour cells. Further, transplantation of INSM1 on pancreatic tumour cells into mice showed the growth rate of these tumour cells was greatly inhibited compared with the control cells.



Biofuel yeasts for commercial cellulosic ethanol

Current technologies for bio-ethanol production from plants can use only the storage sugars, such as glucose, sucrose or starch. These sugars are converted into ethanol in a fermentation process using yeasts, as in beer brewing or in distilleries. However, this technology is in competition with food and feed production.

One of the major problems using other parts of plants, which today are considered as waste, is the inability of the yeasts to ferment some of the sugars of a large part of the plant material says Dr. Eckhard Boles, a professor at the Goethe-University Frankfurt, Germany, and co-founder of the Swiss biofuel company Butalco GmbH. Yeasts readily convert glucose, but leave xylose, or waste sugars, unused. Now, Dr. Boles and his colleagues report in the journal Applied Environmental Microbiology success in genetically modifying yeast, which enable the production of ethanol from waste sugars as well.

The researchers discovered a new enzyme from a bacterial organism and inserted this enzyme into yeast cells taken from a commercial ethanol plant. With just minor effort, we were able to teach the yeast cells how to ferment the waste sugar xylose into ethanol. The new enzyme can convert xylose in a single step, unlike the current cellulosic ethanol technologies. Further, it is not inhibited by other chemical compounds normally present within the yeast cells. This is a breakthrough in the commercial production of cellulosic ethanol, claimed Dr. Bole.


Parasite-resistant maize a hit with Nigerian farmers

Nigerian farmers who tested new maize crops resistant to the widespread Striga plant parasite are so enthusiastic about their increased crop yields that they are selling more seeds than the official distribution channels. The varieties, known as Sammaz 15 and 16 contain genes that diminish the growth of parasitic flowering plants such as Striga, which attaches to the maize root. Both Sammaz varieties tolerate heavy Striga infestations without suffering crop losses.

The crops were developed in the Nigerian laboratories of the International Institute for Agricultural Research (IITA). They dramatically cut maize losses from the root-infecting Striga, or witchweed, during two years of trial cultivation by farmers. Nigerias Institute for Agricultural Research began distributing the new parasite-resistant maize seeds in December 2008.

While a maize variety without Striga resistance can sustain from 60 per cent to 100 per cent grain yield loss in farmers fields that are severely infested, Sammaz 16 loses just 10 per cent of yield in an extreme invasion. Sammaz 16 is a late-maturing variety requiring 110 to 120 days of growth, while Sammaz 15 can often be harvested in 100 days and is more suitable for regions with short growing periods or unpredictable water supplies.



Scientists find genes to protect wheat from rust

Scientists have pinpointed two genes that protect wheat against devastating fungal diseases found worldwide, potentially paving the way to hardier wheat strains, international researchers report. New research published in the journal Science showed how the genes provide resistance to leaf rust, stripe rust and powdery mildew, diseases responsible for millions of hectares of lost wheat yield each year.

Dr. Simon Krattinger of the Institute of Plant Biology, Switzerland, and colleagues isolated a gene called Lr34 using a resistant wheat line, knocking out genes until they found the one that offered protection. They do not know exactly what the gene does but believe it produces a protein that transports molecules in a cell that help fight off diseases. Unlike other resistance genes that only offer short-term protection because of mutations, the Lr34 gene is far more durable, Dr. Krattinger said. The gene has been active for more than 50 years, he said.

In another study, scientists led by Dr. Cristobal Uauy of John Innes Centre, the United Kingdom, identified a gene called Yr36 found in wild wheat but absent in modern pasta and bread varieties. The gene confers resistance to stripe rust. We have recovered a gene that has been lost during domestication, Dr. Uauy said, adding We now have a new tool to combat this disease. The researchers do not know what the gene does but believe it recognizes a lipid from a disease and somehow triggers a resistance response. Like the Lr34 gene, Yr36 appears to offer longer protection and it also seems to fight off more than one strain of stripe rust, Dr. Uauy added.


Insulin grown in plants gets human tests

For the first time, insulin grown in plants has been injected into people. The hope is that plants will provide a cheaper source of insulin for people with diabetes. Sembiosys Genetics, a Canadian company, inserted human insulin genes into safflowers, causing them to make a pro-insulin compound. Enzymes then converted this into a type of insulin called SBS-1000. Previous tests had shown SBS-1000 to be identical to human insulin.

Most insulin products are produced by bacteria in a fermenter. As this is an expensive process, Sembiosys hopes using plants will be cheaper because they do not need this stage. Safflowers are not widely grown in North America, and have no wild relatives there. This should minimize the risk of genes escaping from insulin-producing safflowers grown there, says Mr. Maurice Maloney of Sembiosys.



New waterproof rice varieties

Waterproof versions of popular varieties of rice, which can withstand two weeks of complete submergence, have successfully passed on-field tests. Several of these varieties are now ready for release by seed certification agencies in India and Bangladesh, where farmers suffer crop losses of up to 4 million tonnes of rice per year enough rice to feed 30 million people because of flooding.

The flood-tolerant versions of the high-yielding varieties popular with both farmers and consumers that are grown over huge areas across Asia are effectively identical to their susceptible counterparts, but recover after severe flooding to yield well. Dr. David Mackill, senior rice breeder at the International Rice Research Institute (IRRI), the Philippines, said the project has been a great success in both its results and the international collaboration that made it possible. Besides IRRI, several national organizations, such the Bangladesh Rice Research Institute and Indias Central Rice Research Institute and Narendra Dev University of Agriculture and Technology participated in the research.

The new varieties were made possible following the identification of a single gene that is responsible for most of the submergence tolerance. Thirteen years ago, Dr. Mackill, working at the University of California (UC) at Davis, and Mr. Kenong Xu, his graduate student, pinpointed the gene in a low-yielding Indian rice variety known to withstand flooding. Mr. Xu later worked as a post-doctoral fellow with Dr. Pamela Ronald, a UC Davis professor, and they isolated the specific gene called Sub1A and demonstrated that it confers tolerance to normally intolerant rice plants. Dr. Ronalds team showed that the gene is switched on when the plants are submerged.

Dr. Julia Bailey-Serres, a geneticist at UC Riverside, is leading the work to determine exactly how Sub1A confers flood tolerance. Along with Dr. Takeshi Fukao, a post-doctoral researcher in her lab, she explored the response of plants with and without Sub1A to submergence. Sub1A effectively makes the plant dormant during submergence, allowing it to conserve energy until the floodwaters recede, Dr. Bailey-Serres said.
Typically, rice plants will extend the length of their leaves and stem in an attempt to escape submergence. The Sub1A gene is an evolutionarily new gene in rice found in only a small proportion of the rice varieties originating from eastern India and Sri Lanka. The activation of this gene under submergence counteracts the escape strategy.

Using modern techniques that allow breeders to do much of their work in the lab rather than the field, Dr. Mackill and his team at IRRI were able to precisely transfer Sub1A into high-yielding varieties without affecting the characteristics such as high yield, good grain quality, and pest and disease resistance that made the varieties popular in the first place.




Plant Genetics and Genomics: Crops and Models

Plant Genetics and Genomics: Crops and Models book series provides current overviews and summaries of the state of the art in genetics and genomics for each of the important crop plants and genetic models. Most volumes focus on a single crop, species, or group of close relatives. Potential targets include sorghum, maize, poplar, rice, the Brassicaceae, Medicago and Mimulus. Genomes of nearly all of these have been sequenced or are currently being sequenced and a large number of biologists and biotechnologists are working on them. Other volumes planned will adopt a disciplinary or technological focus, such as plant cytogenetics, comparative genomics, epigenetics, and functional genomics.

Contact: Springer Medizin Verlag, Heidelberger Platz 3, 14197 Berlin, Germany. Tel: +49 (30) 82787-5739; Fax: +49 (30) 82787-5300.


Plant Biotechnology: Current and Future Applications of Genetically Modified Crops

The book covers in detail the development, use and regulation of genetically modified (GM) crops. Part 1 introduces GM crops and describes the GM crops that are used commercially. Part 2 looks at new developments and methodologies in areas including potential applications of GM crops for the production of vaccines, enhanced nutritional value of GM food, and engineering resistance to fungal pathogens. Part 3 concludes by considering the key issues of safety and legislation, including allergenicity, environmental impacts, risk assessment and labelling.

Contact: Customer Service Department, John Wiley & Sons (Asia) Pte. Ltd., 2, Clementi Loop #02-01 LogisHub@Clementi, Singapore 129809. Tel: +65 6463 2400; Fax: +65 6463 4604.



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