VATIS Update Biotechnology . Jan-Feb 2008

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Biotechnology Jan-Feb 2008

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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Latin America and Europe to collaborate on biotechnology

The Latin American trade pact Mercosur and the European Union have agreed to develop a programme to fund agricultural biotechnology projects in Latin America. BIOTECSUR was unveiled in December 2007 at Argentina’s Ministry of Science, Technology and Productive Innovation. The European Union has pledged US$10.4 million to the programme, with Mercosur members Argentina, Brazil and Uruguay investing US$1.4 million. The initiative, to be coordinated by Argentina, will fund four regional projects in four areas of interest: forestry, oilseeds, ovine (sheep) and avian (bird).

“We are going to create a regional platform for biotechnology, which gathers policy, science and the private sector,” said Mr. Igueda Menvielle, director of BIOTECSUR and national director of international relationships at Argentina’s Ministry of Science. He said the programme would focus on agricultural biotechnology because this sector has a high impact on innovation and development, which in turn will have a positive impact on the region’s economy.


New biochip technology may eliminate animal testing

In the United States, researchers have developed a new biochip technology, which could soon help avoid the use of animals for testing in the chemical and cosmetics industries. The research was carried out at Rensselaer Polytechnic Institute (RPI), the University of California at Berkeley, and Solidus Biosciences Inc. The researchers developed two biochips, DataChip and MetaChip, that combine to reveal the potential toxicity of chemicals and drug candidates on various organs in the human body, and whether those compounds will become toxic when metabolized in the body, all in one experiment without the use of live animals.

Traditional toxicity test involves the use of animals to predict whether a chemical or drug candidate is toxic. However, with the large number of compounds being generated in the pharmaceutical industry, and new legislation requiring chemicals to undergo toxicity analysis, there is a rapidly emerging need for high-throughput toxicity testing. When the biochips are used together the result is a promising and affordable alternative to animal-based toxicology screening and a direct route to developing safe, effective drugs, said Prof. Jonathan S. Dordick, RPI professor and co-founder of Solidus Biosciences Inc., and co-lead author for the study.

Currently, detailed toxicity screening does not come into the drug discovery process until later in the development, when a company has invested significant time and money in a compound. Further, animal testing does not always provide information that translates to predicting the toxicity of a compound or its metabolites in a human, said Prof. Dordick. The DataChip is a biochip comprising up to 1,080 three-dimensional human cell cultures. The three-dimensional structure is more closely in line with how the cells would be arranged in human organs. The MetaChip is a biochip that mimics the metabolic reactions of the human liver, which processes chemicals.


Environmental impacts of biofuels highlighted

In a new study, researchers at the Smithsonian Tropical Research Institute, the United States, highlighted the factors in environmental costs of biofuel production. Corn, soybean and sugar cane come up short. Dr. Jörn Scharlemann and Dr. William Laurance have urged governments to be far more selective about which biofuels they support, as not all are more environmentally friendly than fossil fuels. Biofuels may not be superior if their production results in environmental destruction, pollution and damage to human health.

A study by Zah et al. commissioned by the Swiss government, calculates the relative merits of 26 biofuels based on relative reduction of greenhouse gas emissions and an environmental impact index, which includes damages to human health and ecosystems and natural resource depletion. The study identifies striking differences in the environmental costs of different biofuels, pointing out that biofuels made from United States corn, Brazilian soybean and Malaysian palm oil may be worse overall than fossil fuels. The best alternatives include biofuels from residual products, such as recycled cooking oil and ethanol from grass or wood. The study, however, falls short in that it fails to consider the secondary consequences of biofuels, such as rising food costs.


All-flu vaccine getting ready

A vaccine to protect against every strains of influenza – the virus behind bird flu, winter flu and pandemics – could be available before 2011. Two preliminary trials of a universal vaccine have been reported by Acambis, the United Kingdom, saying it could be ready within three years if development was accelerated to deal with a pandemic.

Current flu vaccines work only against specific strains, and as these mutate frequently there are concerns about whether a vaccine could be prepared in time to combat a pandemic strain of the kind that killed up to 50 million people in 1918. The new vaccine focuses on parts of the virus that do not mutate. Tests on ferrets, which model human disease accurately, suggest that the vaccine named Acam-Flu-A can protect against deadly influenza strains including the avian strain H5N1.

Dr. Michael Watson, executive vice-president at Acambis, said: “Acam-Flu-A can potentially overcome many of the drawbacks of existing influenza vaccines. It can be manufactured at any time of the year and could be stockpiled in advance of a pandemic or potentially used routinely to ensure population protection against future pandemics.” All three 20th century pandemics were caused by viruses related to avian influenza.


Funding GM rice crops with carbon credits

Money paid by green consumers to offset their flights and by companies that go carbon-neutral will be used to fund the planting of genetically modified (GM) crops under plans drawn up by Arcadia Biosciences, a biotechnology company in the United States. The company is working with the Chinese government to reward farmers in China that grow the firm’s GM rice, with carbon credits that they can sell for cash. The project is in Ningxia, a tiny mountainous province in the north of the country, where fertilizer use is among the highest in the country.

According to Arcadia, its GM rice requires less nitrogen fertilizer, and so farmers that grow it will lower their emissions of nitrous oxide (NO) – a greenhouse gas some 300 times more potent than carbon dioxide (CO2). Using the GM version, it says, would save the equivalent of 50 million tonnes of CO2 each year, and generate 750 million in carbon credits for farmers. Arcadia aims to have the Chinese scheme running by 2012, in time to take advantage of new carbon markets expected to be created by a successor treaty to Kyoto.

The widespread use of nitrogen fertilizer is taken to account for about one-third of all agricultural emissions. Less than half the nitrogen is typically absorbed by crops, with the rest leaking into the soil and water supplies, or released to the air as NO. Arcadia is working to apply the reduced-nitrogen technology to GM wheat, rape seed oil, sugar beet, maize, sugar cane, cotton and turf grass. Its technology inserts a gene to improve the nitrogen uptake, which means less fertilizer is needed to produce a given yield of crop.


Fluorescent Chinese pig passes on trait to offspring

A pig genetically modified in China to make it glow has given birth to fluorescent piglets, proving such changes can be inherited. The sow was one of three pigs who had fluorescent green protein injected into their embryos when they were bred in December 2006 by scientists. The pigs glow green when placed under an ultraviolet light. After mating the sow with an ordinary pig, two of the resulting 11 piglets inherited the feature, said Prof. Liu Zhonghua at Northeast Agricultural University in the city of Harbin. “The mouths, trotters and tongues of the two piglets glow green under ultraviolet light, which indicates the technology to breed transgenic pigs via cell nuclear transfer is mature,” said Prof. Liu. His team used somatic cell nuclear transfer technology previously used in the cloning of animals. This technology promises to breed even raise special pigs to provide organs for human transplant operations in the future.



Expanded labelling for MabCampath in Europe

The European Commission has authorized the marketing of MabCampath® (alemtuzumab) for the treatment of patients with B-cell chronic lymphocytic leukemia (B-CLL) for whom fludarabine combination chemotherapy is not appropriate. MabCampath works in an entirely different way than chemotherapy, and is the first and only monoclonal antibody approved in Europe for B-CLL treatment, the leading form of adult leukaemia in the Western hemisphere. MabCampath is jointly developed by Bayer Schering Pharma AG, Germany, and Genzyme, the United States.

“The data supporting this marketing authorization showed that MabCampath produced a higher response rate than that seen in patients with chronic lymphocytic leukaemia for any single agent in previous front-line trials,” said Dr. Peter Hillmen of the Leeds General Infirmary, United Kingdom, who was the lead investigator of the pivotal study supporting the application for first-line B-CLL. The European Commission’s decision to grant extended marketing authorization to MabCampath is based on data from the study, an international open-label Phase III randomized trial comparing MabCampath with chlorambucil in previously untreated B-CLL patients. The study met its primary endpoint by demonstrating superior progression free survival in patients treated with MabCampath versus chlorambucil, with MabCampath reducing the risk of disease progression or death by 42 per cent.


ImmunoGen to develop anti-cancer compound

The United States-based ImmunoGen Inc., a biopharmaceutical company that develops targeted anticancer therapeutics using its Tumour-Activated Prodrug (TAP) technology, has obtained exclusive right to develop and commercialize a TAP compound to a novel target using an antibody created by Centocor. Under the terms of the agreement, ImmunoGen gains the exclusive right to develop and commercialize IMGN388, a TAP compound, which consists of an integrin-targeting antibody developed by Centocor and ImmunoGen’s maytansinoid TAP technology.

Centocor has the right to opt-in on IMGN388 at an agreed-upon stage in early clinical testing. Should Centocor exercise this right, ImmunoGen would receive an opt-in fee and be released from its obligation to pay Centocor any milestone payments or royalties on sales. Both companies would contribute to the costs of developing the compound. The two companies would also share equally any profits on the sales of the compound in the USA, and ImmunoGen would receive royalties on any international sales.

Should Centocor not exercise this right, ImmunoGen has the right, with certain restrictions, to find a new partner for IMGN388. Centocor would be entitled to receive milestone payments potentially totalling US$30 million, with the first payment due upon the completion of a successful Phase III trial, and also royalties on IMGN388 sales, if any.


Global pharma companies prefer emerging drug makers

Multinational drug manufacturers such as Pfizer and DSM are increasingly getting into contract manufacturing alliances with emerging bulk drug makers in India, bypassing established players such as Ranbaxy and Dr Reddy’s. The global manufacturing outsourcing opportunity is estimated at US$20 billion and is expected to reach US$31 billion by 2010. It is estimated that about 40 per cent of outsourcing demand is for active pharmaceutical ingredients (APIs).

Hikal, an upcoming Indian drug manufacturer, has recently entered into a long-term agreement for the supply of (API) for lifestyle drugs to Pfizer, the largest pharma company. Earlier, DSM Anti Infectives (DAI), a part of the Netherlands-based DSM Group, signed a strategic partnership with India’s Arch Pharmalabs to manufacture generic APIs. Arch is also in talks with some global drug companies for drug supply.

Sagent Pharmaceutical, the United States, has an agreement with Strides Arcolab of Bangalore to jointly develop, supply and market about 25 injectable products for the United States market. In another agreement, Amneal Pharmaceuticals, the United States, has contracted Indoco Remedies for the supply of ten ophthalmic products for the American market.

In one way or the other, all pharmaceutical majors have an India plan in the emerging global pharmaceutical scenario. India has nearly a hundred facilities approved by the United States Food and Drug Administration (FDA). This is a major reason for global pharma firms to look at India, says Mr. Shailesh Gadre, managing director, ORG-IMS. Most of these FDA-approved facilities belong to upcoming companies that specialize in specific therapeutic categories.


Genzyme buys into Isis Pharma

In the United States, Genzyme had signed a partnership with Isis Pharmaceuticals to develop the promising cardiovascular drug mipomersen, the flagship product of Isis. Genzyme is paying US$ 175 million in upfront fee and will buy five per cent of the company. Potential milestone payments can make the deal worth more than US$1.9 billion. According to Isis, Genzyme won a bidding war that involved 10 companies interested in the drug.

Mipomersen blocks a gene that opens the gate to cholesterol in the blood. It is now about to enter Phase III trials after posting some impressive data for lowering bad cholesterol. Isis can now budget a maximum of US$75 million in new discovery costs for the programme with Genzyme shouldering the rest of the load. Genzyme, which has emerged as an aggressive biotech powerhouse, also gets “preferred access” to other Isis therapies in the future.


ICGEB forms collaboration to develop vaccines

The International Centre for Genetic Engineering and Biotechnology (ICGEB) based in New Delhi, India, has joined hands with Emory Vaccine Centre (EVC), the United States, to develop vaccines for infectious diseases like tuberculosis, dengue and HIV. The Joint ICGEB-Emory Vaccine Centre will work to control infectious diseases through collaborative research on and development of safe and effective vaccines for global use, ICGEB Director Dr. V.S. Chauhan said.

ICGEB specializes in research on vaccines for control of HIV, hepatitis B and E, SARS, dengue, tuberculosis and malaria prevalent in the sub-continent. EVC facilities include 26 laboratories where its 39 faculty researchers and nearly 200 post-graduate students are working to develop vaccines for HIV/AIDS, hepatitis C, malaria, influenza and other infectious and chronic disease threats.


ARTES and Minapharm sign long-term strategic pact

ARTES Biotechnology GmbH, Germany, and Rhein Minapharm Biogenetics, a subsidiary of Minapharm SAE based in Egypt, have announced the start of a strategic collaboration to develop three therapeutic proteins. ARTES will apply its proprietary Hansenula technology platform and know-how to the generation of production cell lines, analytical assay development, and lab-scale fermentation. ARTES has also granted Minapharm a commercial licence option to apply its proprietary technologies to the manufacturing and marketing of these therapeutic proteins. In addition, ARTES will be responsible for the production of a Minapharm protein based on an existing process using E. coli. Minapharm will carry out the pertinent process research and development, production and commercialization of the therapeutic proteins.

The yeast strain Hansenula polymorpha is often an alternative to E. coli for producing therapeutic proteins or technical enzymes inexpensively. A number of products derived from Hansenula – such as hepatitis B vaccine, interferon alpha 2a, insulin, and feed and food enzymes – are already marketed worldwide. Several others are in clinical trials.


Prolong Pharmaceuticals join Zydus Cadila for drug discovery

Zydus Cadila, an innovative global pharmaceutical company, and Prolong Pharmaceuticals Inc., a venture-backed drug delivery R&D company in the United States, have announced a collaboration for developing a next generation therapeutic protein, PEG-EPO, for the treatment of severe anaemia. PEG-EPO promises to be a third generation drug for severe anemia, a condition where the haemoglobin level or number of circulating red blood cells is significantly reduced. This is common in chronic renal failure (CRF), cancer patients undergoing chemotherapy, some chronic inflammatory diseases, heart failure, surgical settings and critically ill patients.

The Zydus-Prolong pact seeks to increase productivity in the drug development of PEG-EPO protein by leveraging the combined strengths of both companies. According to the agreement, both companies will use the differentiated PEGylation technology of Prolong to make PEG-EPO. This joint development will help in developing an optimized drug candidate with improved therapeutic properties. Both partners will also be equitably share risk and reward for this collaborative venture.

Zydus Cadila will leverage its expertise in carrying out a focused drug development programme, starting from the pre-clinical candidate selection, filing of the Investigational New Drug, undertaking pre-clinical studies and human clinical trials and marketing it in mutually agreed upon territories globally. The collaborative programme will bring an edge to Zydus global biologics strategy with the introduction of an improved biologic product.


GSK extends GeneGo’s licence and adds new products

GlaxoSmithKline (GSK) has extended its licensing agreement with GeneGo Inc., a leading systems biology tools company in the United States, and added additional capability. This will provide GSK researchers in bioinformatics, R&D and clinical studies with global access to MetaCoreTM, MapEditorTM and MetaBaseTM.

A functional analysis platform for biological OMICs data, MetaCore is used for target identification, validation, biomarker discovery and knowledge mining. GSK will also use MetaCore as a repository of all types of experimental data and resulting analyses. MetaBase provides direct access to the manually curated database of pathways, networks, ontologies, medicinal chemistry and diseases of human, mouse and rat. MapEditor helps create interactive customized maps, which amalgamate MetaBase knowledge content with proprietary information and data.



Key immune response regulatory genes

Researchers at Weill Cornell Medical College in the United States have identified two genes that may be crucial to the production of the immune system cytokine interleukin-10 (IL-10). The discovery fills in an important “missing link” in a biochemical pathway that is long been tied to disorders ranging from lupus and Type 1 diabetes, to cancer and AIDS, according to the scientists. Previous studies had shown that CD36, a protein receptor lying on the surface of macrophages, helped trigger IL-10 production whenever apoptotic cells were present. But the Weill Cornell researchers, led by Dr. Xiaoging Ma, went a step further to find the signals that lead to IL-10 production from CD36 present at the cell surface.


Nanotechnology for gene detection in a single cell

In the United States, scientists at Arizona State University’s Biodesign Institute have developed the world’s first gene detection platform made up entirely from self-assembled DNA nanostructures. The results could have broad implications for gene chip technology and may also revolutionize the way in which gene expression is analysed in a single cell.

According to Dr. Hao Yan, a member of the team, they start with DNA and apply it as a nanoscale building material. They developed a water soluble nanoarray that can take advantage of the DNA self-assembling process and also have benefits that the macroscopic DNA microchip arrays do not have. “The arrays themselves are reagents, instead of solid surface chips,” Dr. Hao explains.

To make the DNA origami RNA probes, the scientists took advantage of the basic DNA pairing rules in the DNA chemical alphabet – “A” can only form a zipper-like chemical bond with “T” and “G” only pair with “C”. By controlling the exact position and location of the chemical bases within a synthetic replica of DNA, Dr. Hao programmed a single-stranded DNA – M13 – into nanotiles to contain the probes for specific gene expression targets. He refers to the self-assembled DNA nanoarrays as nucleic acid probe tiles, which look like a nanosized postage stamp. In a single step, the M13 scaffold system can churn out as many as 100 trillion of the tiles with close to 100 per cent yield. The team designed three different DNA probe tiles to detect three different RNA genes along with a bar code index to tell the tiles apart from each other.

On the surface of each DNA probe tile is a single-stranded piece of DNA that can bind to the RNA target of interest. Each probe contains two half probes. When the target RNA comes in, it will hybridize to the half probes and turn the single-stranded dangling probes into a stiff structure. On stiffening, it will be sensed by the atomic force microscope cantilever. The result is a mechanical, label-free detection, says Dr. Hao. The technology is able to detect even minute quantities of RNA: in principle, a single molecule could hybridize to the probe tile.


Gene discovery could explain a third of bowel cancers

Two genetic variants that may triple a person’s lifetime bowel cancer risk have been identified in a study in the United Kingdom by researchers at the London Research Institute of Cancer Research UK. The researchers hope that the discoveries will one day lead to new tests that might flag up those at highest risk from bowel cancer.

Although the risk of bowel cancer associated with each of the two gene variants is small, this risk is amplified significantly if either are combined with two other genes that have previously been linked to cancer. People who have all four genes in combination are two or three times more likely than normal to develop bowel cancer. Looking for genes linked with a bowel cancer called hereditary mixed polyposis syndrome, which mostly affects people of Ashkenazi Jewish descent, the scientists scanned the genomes of 15,000 volunteers, 8,000 of which had bowel cancer. Instead of the gene they were looking for, however, they found other gene variants near the region they were studying, which were linked to cancer in the general population.


Glow-in-the-dark cat could help cut disease

A team of scientists led by Dr. Kong Il-keun at the Gyeongsang National University, Republic of Korea, has genetically modified three kittens incorporating fluorescence so that they glow under ultraviolet light. The team cloned Turkish Angora cats after manipulating a gene to change their skin colour. The procedure might help develop treatments for human genetic diseases and also help clone endangered animals.

To clone the cats the team used skin cells of the mother cat and modified its genes to make them fluorescent by using a virus, which was transplanted into the ova. The ova were then implanted into the womb of the donor cat. Of the three kittens born, two grew to become adults. Dr. Kong said that cloning cats with the same diseases as humans could speed up efforts to find treatment and drugs by allowing scientists to study animals and conduct experiments that are not possible with human patients.


Studying abnormalities linked with childhood cancer

Children with cancer have a higher prevalence of body abnormalities – such as differing length in limbs, broad hands or feet, prominent ears, and curvature of the spine – suggesting that the genetic defect responsible for the abnormality may play a role in the development of cancer, according to a recent study led by Dr. Johannes Merks of Emma Children’s Hospital, Academic Medical Centre, the Netherlands.

Several studies have shown that developmental genes, which play a role in body plan formation during embryogenesis, are also involved in the development of cancer, particularly in children. The study assessed morphological (body structure) abnormalities in 898 long-term survivors of childhood cancer and 175 paediatric patients newly diagnosed with cancer. Compared with the control group, both major abnormalities and minor anomalies were found to be significantly more prevalent in the paediatric cancer group – 268 major abnormalities per 1,000 (155 abnormalities for controls). One or more major abnormalities were present in 26.8 per cent of patients (15.5 per cent in controls), two or more abnormalities in 5.1 per cent of patients (1.6 per cent in controls), and three or more abnormalities were found in 0.9 per cent compared with none in controls. Minor abnormalities too were higher in the patients than in the controls.

An established clinical genetic syndrome was diagnosed in 3.9 per cent patients. Analysis showed 14 age-independent morphological abnormalities that were independently and significantly associated with childhood cancer. For two of these (eyelid abnormalities and asymmetric lower limbs), the researchers identified statistically significant patterns of co-occurring morphological abnormalities suggestive of new tumour predisposition syndromes. The researchers concluded that constitutional genetic defects play “a more important role in paediatric oncogenesis than is currently estimated”.


Genomic screen nets human proteins used by HIV

The human immunodeficiency virus (HIV) contains just nine genes encoding 15 proteins, which wreak havoc on the human immune system. But this bare bones approach can have a fatal flaw. Lacking in robust machinery, HIV hijacks human proteins to propagate, and these might represent powerful therapeutic targets. Using RNA interference to screen thousands of genes, a team of researchers from Harvard Medical School, the United States, has identified 273 human proteins required for HIV propagation. The vast majority had not been connected to the virus by previous studies.

Drugs currently used to treat the viral infection interact directly with the virus itself. A cocktail of HIV inhibitors is used because the virus is less likely to evolve resistance to multiple drugs at the same time. However, some HIV strains have still managed to evade particular drugs. These could eventually develop resistance to several drugs, especially among patients who don’t adhere to their regimens. The new study takes a different approach centred on the human proteins exploited by the virus, says Professor Stephen Elledge, the senior author of the study. “The virus would not be able to mutate to overcome drugs that interact with these proteins,” he explains.

The new study essentially quadruples the list of host factors to include proteins involved with a surprising array of cellular functions ranging from protein trafficking to autophagy. “Scientists can look at the list, predict why HIV needs a particular protein, and then test their hypothesis,” says Prof. Elledge. Of the 273 proteins the research team identified, just 36 had been previously implicated in the HIV life cycle. Immune cells – the very cells HIV attacks – contain high concentrations of many of the 273 host factors.


New gene implicated in cerebral venous thrombosis

Researchers in Germany have identified a new gene linked to cerebral venous thrombosis (CVT), a condition that causes blood clots in the veins of the brain that can lead to stroke. The condition is more common in young and middle-aged women. The study compared 78 people with cerebral venous thrombosis to 201 healthy people. The researchers, led by Dr. Christoph Lichy of the University of Heidelberg, found that a variant of the gene called ‘Factor XII C46T’ is more common in people with CVT than in healthy people. A total of 16.7 per cent of those with CVT had the gene variant, compared with 5.5 per cent of those without the condition.

Other genetic variants have also been linked to CVT, a rare condition that is the cause of less than one per cent of strokes and other cerebrovascular disorders, but it results in death about 10 per cent of the time. In addition to genetic factors, other factors that can cause cerebral venous thrombosis include head injury, infection, and certain drugs.


Genetic variation predicts statin response

Celera Group-Applera Corp., the United States, has identified a genetic variation that not only increases risk of heart attack, but also the chances that statins would prevent it. Dubbed KIF6, the variation is present in nearly 60 per cent of the population. The carriers risk heart attack, stroke or death from heart disease as much as 55 per cent higher than those who don’t have it. Celera plans to roll out a genetic test for the variation.

Celera’s research has to be verified before statin therapy is linked with it. But in studies it analysed, the differences in response between carriers and non-carriers is very clear. Carriers treated with Pravachol had 37 per cent fewer heart attacks compared with placebo-takers, while non-carriers had 14 per cent fewer attacks than did those on placebo. In a finding that could fuel debate over the direct link between lowering LDL and preventing heart attacks, the prevention benefits weren’t related to how much a statin lowered cholesterol.


Genes that tweak body mass

Researchers from the Monell Centre, the United States, have for the first time attempted to count the number of genes that contribute to obesity and body weight. The findings suggest that over 6,000 genes – about 25 per cent of the genome – help determine an individual’s body weight. To obtain an estimate of how many genes contribute to body weight, the Monell researchers surveyed the Jackson Laboratory Mouse Genome Database for information on body weights of knockout mouse strains. By studying how the knockout mice differ from normal mice, researchers obtain information about that gene’s function and how it might contribute to disease. The Monell survey revealed that body weight was altered in over a third of the viable knockout stains; 31 per cent weighed less than controls (indicating that the missing genes contribute to heavier body weight), while another 3 per cent weighed more (contributing to lighter weight).

Extrapolating from the total number of genes in the mouse genome, this implies that over 6,000 genes could potentially contribute to the body weight of a mouse. “Our results suggest that each newly discovered gene is just one of the many thousands that influence body weight, so a quick fix to the obesity problem is unlikely,” says Monell behavioural geneticist Dr. Michael G. Tordoff. “It is interesting that there are 10 times more genes that increase body weight than decrease it, which might help explain why it is easier to gain weight than lose it,” he comments. Because body weight plays a role in many diseases, including diabetes, hypertension and heart disease, the implications of the findings extend beyond studies of obesity and body weight.



Structural study of anthrax yields new antibiotic target

Researchers studying anthrax knew they were onto something when they discovered an opponent the bacterium couldn’t outwit. Probing a bit deeper, they discovered this was because the attacker was interacting with something anthrax requires to survive: a carbohydrate in its cell wall. Now, in a study that has implications for the development of a new class of antibiotics, scientists from Rockefeller University, the United States, report that they have determined the structure of an enzyme involved in the pathway responsible for building this essential carbohydrate.

The scientists – structural biologist Dr. C. Erec Stebbins and bacteriologist Dr. Vincent Fischetti – not only describe the crystal structure of an enzyme involved in this vulnerable cell-wall pathway, but also use that structure to determine how the enzyme is regulated. As the mammalian form of this enzyme is a bit different from the anthrax form, the researchers propose that it should be possible to inhibit its activity in bacteria without causing collateral damage to mammalian cells.

Dr. Stebbins found that by creating a crystal structure of the enzyme with its substrate attached, the enzyme’s activity is regulated by the very molecules it acts upon. “So if we could bind a small molecule to the binding site in such a way that it doesn’t productively activate it, we could inhibit the activity of the molecule without inhibiting the same active site of mammalian enzymes,” he says. This, he hopes, would result in bacteria that are unable to build their cell walls and therefore would be unable to survive.

The anthrax bacterium has two copies of the gene responsible for producing this enzyme. To examine its potential as a target for drugs, Dr. Fischetti’s laboratory created a new version of the bacterium with one of these genes knocked out. The resulting mutants grew much, much more slowly, Dr. Stebbins says, which tells them that if they could come up with an inhibitor, “it would probably hit these things hard.”


A better drug to suppress hepatitis B virus

Two international studies of telbivudine, a new drug, have produced potentially good news for hepatitis B patients, showing that it suppresses the virus that damages the liver faster and better than other treatments. Reducing the amount of hepatitis B virus in the blood is critical to limiting the adverse effects of chronic hepatitis B, which affects at least 360 million people and is the 10th leading cause of death worldwide. About 25-40 per cent of people suffering from chronic infection eventually die of liver cancer or cirrhosis, said Professor C.L. Lai, chair of hepatology at the University of Hong Kong medical school, China.

One study, involving 1,367 hepatitis B patients from 20 countries, compared a group treated with telbivudine to another treated with the drug lamivudine. It showed that telbivudine reduced the virus more quickly and after 52 weeks, those taking telbivudine achieved 10 times more reduction of the virus per millilitre of blood than those using lamivudine. In addition, a higher percentage of patients in the telbivudine group achieved non-detectable hepatitis B DNA level in blood serum than the group taking lamivudine. Another study compared 135 hepatitis B patients from eight countries taking telbivudine or adefovir, another drug commonly prescribed for hepatitis B, or both. Again, the telbivudine group showed more reduction in mean serum hepatitis B DNA virus than that of the adefovir group in early, middle and late stages of the test. Telbivudine was also found to effectively reduce the virus in patients who switched.


Key trigger found for a cancer-fighting marine product

An unexpected discovery at University of California San Diego (UCSD) has led to new, important information about the fundamental biological processes inside a marine organism that creates a natural product currently being tested to treat cancer in humans. Researchers led by Prof. Bradley Moore at UCSD’s Scripps Oceanography Centre for Marine Biotechnology and Biomedicine, with colleagues from Skaggs School of Pharmacy and Pharmaceutical Sciences, and The Salk Institute for Biological Studies, discovered an enzyme called SalL inside Salinispora tropica, a promising marine bacterium identified in 1991 by Scripps researchers.

The researchers also identified a totally unexpected pathway, for the way the marine bacterium incorporates a chlorine atom, the key ingredient for triggering its potent cancer-fighting natural product. Previously known methods for activating chlorine were processed through oxygen-based approaches. The new method, on the other hand, employs a substitution strategy that uses non-oxidized chlorine as it is found in nature.

The Salinispora derivative “salinosporamide A” is currently in phase I human clinical trials for the treatment of multiple myeloma and other cancers. Knowing the pathway of how the natural product is made biologically may give biotechnology and pharmaceutical scientists the ability to manipulate key molecules to engineer new versions of Salinispora-derived drugs. “It is possible that drug companies could manufacture this type of drug in greater quantities now that we know how nature makes it,” said Prof. Moore. At this point, it is not clear how pervasively SalL and its biological activation pathway exist in the ocean environment. Chlorine is a major component of seawater, and, according to Prof. Moore, a fundamental component of Salinispora’s disease-inhibiting abilities. For instance, salinosporamide A is 500 times more potent than its chlorine-free analogue salinosporamide B.


Novel anti-cancer strategy moves from laboratory to clinic

Scientists at Emory University, the United States, have developed a novel anti-tumour compound that represents a distinct strategy: targeting one of the most important “intercept points” for cancer cells. The idea behind the intercept point strategy is to shut down the transmission of a large number of growth signals in cancer cells at once, says Dr. Donald L. Durden, professor of paediatrics at Emory University School of Medicine and the Emory Winship Cancer Institute. He and his colleagues targeted a class of enzymes called PI-3 kinases, which represent an intercept point and occupy important space in almost every cell in the body. Genes that encode the PI-3 kinases are mutated in a large number of tumour types, putting them in overdrive. In addition, PTEN phosphatase, a single enzyme that opposes PI-3 kinases, is inactivated in 20-50 per cent of human prostate, brain, endometrial and breast cancers.

The researchers showed that a chemical inhibitor of all PI-3 kinases, modified with a tag that directs the compound to the blood vessels needed by growing tumours, stops the growth of seven types of tumours in mice. The compound, called SF1126, is active against prostate, breast, renal, multiple myeloma, neuroblastoma, glioblastoma and rhabdomyosarcoma. It went into phase I clinical trial at the end of 2007 in people with solid tumours. A phase I trial for multiple myeloma patients will begin in 2008. It is anticipated that SF1126 will enter paediatric cancer trials within a year.


Insight into the cause of Parkinson’s disease

A glitch in the mechanism by which cells recycle damaged components may trigger Parkinson’s disease, according to a study by scientists in the United States. All cells depend on a surveillance system known as autophagy to digest and recycle the damaged molecules that arise as cells age. In autophagy, defective proteins and other molecules are transported to membrane-bound sacs called lysosomes. After attaching to the lysosomal membrane, the molecules enter the lysosome, where they are digested by enzymes. This clean-up process may be particularly important for nerve cells, which generate defective molecules more rapidly than most other types of cells. When autophagy is impaired, toxic compounds can accumulate and cause cell death.

“It is widely suspected that accumulation of a particular protein, known as alpha-synuclein, within affected nerve cells of Parkinson’s disease patients contributes to the death of these cells,” says Dr. Ana Maria Cuervo from Albert Einstein College of Medicine of Yeshiva University. She had previously shown that mutant forms of alpha-synuclein – found in the 5-10 per cent of patients who have familial Parkinson’s disease – are poorly digested via autophagy and also block the breakdown of other substances. While these alpha-synuclein mutations are rare, other modifications of alpha-synuclein – phosphorylated and oxidized forms, for example – can be found in the brains of all Parkinson’s disease patients.

The study – with participation from Columbia University, University of Pennsylvania and Harvard Medical School – looked at how several different modified forms of alpha-synuclein affected autophagy in vitro and in tissue culture. One particular modification – the compound created by the interaction of alpha-synuclein with dopamine, the main neurotransmitter produced by the nerve cells damaged in Parkinson’s disease – was found to interfere with autophagy. The molecules of the compound were not effectively transported into the lysosome, and therefore were poorly digested and interfered with autophagic digestion of other compounds as well. The study has proposed that inhibition of autophagy caused by dopamine’s alteration of alpha-synuclein could explain the selective death of dopamine-producing nerve cells in Parkinson’s disease.


Ethical creation of human embryonic stem cell lines

Advanced Cell Technology Inc. (ACT), the United States, has announced the development of five human embryonic stem cell (hESC) lines without the destruction of embryos – a result that has the potential to end the ethical debate surrounding the use of embryos to derive stem cells. The peer-reviewed technique was initially carried out by ACT scientists under the direction of Dr. Robert Lanza, and then independently replicated by scientists from University of California San Francisco and StemLifeLine.

Single cells were removed from the embryos using a technique similar to pre-implantation genetic diagnosis; the biopsied embryos continued to develop normally. The cells that were removed were cultured utilizing a proprietary method that recreates an optimal developmental environment. This greatly improved the efficiency of deriving stem cells to rates comparable to using the traditional approach of deriving stem cells from the inner cell mass of a blastocyst stage embryo. The stem cells differentiated into cell types of all three germ layers of the body, including blood cells, neurons, heart cells, cartilage, and other cell types of potentially therapeutic significance.

“This is a working technology that exists here and now,” said Dr. Lanza. The work addresses some other key issues. The stem cells were derived without culturing multiple cells from each embryo together, and at efficiency levels similar to that of conventional stem cell derivation techniques. The method addresses ethical objections that the derivation system needs co-culture with hESCs from other embryos that are destroyed. The current study demonstrates that hESC co-culture is not an essential part of the derivation procedure. The hESC lines generated appear to have the same characteristics as other hESC lines, such as expression of the same pluripotency markers, self-renewing capacity, genetic stability and ability to differentiate into derivatives of all three germ layers.


New vaccine against deadliest strain of avian flu

A vaccine against H5N1, the most common and deadliest strain of avian flu, has been engineered and tested by scientists at the Centre for Vaccine Research, University of Pittsburgh, and Novavax Inc., the United States. The vaccine produced a strong immune response in mice and protected them from death following infection with the H5N1 virus. It is being tested in humans in an early-phase clinical trial.

Unlike other avian flu vaccines that are partially developed from live viruses, the new vaccine uses a virus-like particle (VLP) that is recognized by the immune system as a real virus but lacks genetic information to reproduce, making it a potentially safer alternative for a human vaccine. Given the evolving nature of H5N1, the vaccine was engineered to encode genes for three influenza viral proteins, offering enhanced protection against possible new strains of the virus.

To test the vaccine, researchers administered it to mice in one-dose and two-dose regimens. Mice immunized twice with the vaccine developed antibodies against H5N1 and were protected from disease when directly exposed to the virus. The researchers also compared modes of vaccine administration by delivering the vaccine to the muscle or the nose. Both methods of vaccine administration were equally effective.



A remarkable editing system for protein production

Even small mistakes made by cells during protein production can have profound disease effects, but the processes that cells use to correct mistakes have been challenging to decipher. Recent work by scientists at The Scripps Research Institute, the United States, has found two surprising new methods for such editing. The work, led by Professor Paul Schimmel of the Skaggs Institute for Chemical Biology, could help identify underlying causes of a range of diseases.

Messenger RNA within cells acts as the instructions for protein synthesis. Ribosomes read the instructions and follow their directions to bind with bits of transfer RNA carrying the amino acids needed for a given protein chain. In most cases, a single unique form of transfer RNA (tRNA) binds only to a single amino acid, and an enzyme called synthetase is responsible for joining the two. In very rare cases tRNA binds with the wrong amino acid. If this mistranslation is not corrected, that amino acid is gets ultimately incorporated into a protein. As little as one wrong amino acid can have profound consequences for health.

It was believed that the portions of synthetases that bind tRNA and appropriate amino acids are so accurate that little editing is required. What little editing does occur was thought tied to the checkpoints within the synthetases. The current study gives a new perspective, at least for one widely studied synthetase that binds the amino acid alanine. It revealed that a distinct segment of the enzyme acts as a second checkpoint to spot mistranslations and remove any amino acid besides alanine that might attach to the alanine tRNA. This second zone focuses its activity on the very same two nucleotides in the genetic code of the tRNA used by the first checkpoint, a guanine and uracil pair – G3•U70. This editor point efficiently cleaves mistranslated amino acids from the alanine tRNA. When the G3•U70 pair was transferred to a different type of tRNA, the editing unit still removed a non-alanine amino acid, indicating clearly that the pair is the trigger for the activity.


A protein that helps pancreatic cancer cells

A protein that helps prevent a woman’s body from rejecting a foetus may also play an important role in enabling pancreatic cancer cells to evade detection by the immune system, allowing them to spread in the body. Researchers at the Kimmel Cancer Centre of Thomas Jefferson University, the United States, found that the metastatic cancer cells in the lymph nodes of patients with pancreatic cancer produce enough of indolamine 2’3 dioxygenase (IDO), a protein, to essentially wall-off the immune system’s T-cells and recruit cells that suppress the immune response to the tumour.

The Jefferson scientists wanted to know if metastatic pancreatic cancer cells residing in the lymph nodes expressed IDO to avoid being found, and if so, could they target this enzyme with available drugs to prevent the cancer cells from hiding from the immune system. They analysed IDO expression in 14 lymph nodes to which pancreatic cancer cells had spread and compared them with the primary tumours that had not spread in the same patients. In every case, greater expression of the IDO protein was found in the cancerous lymph nodes. They also found little IDO present at three cases of lymph node-negative pancreatic cancers. The data from the study point to the fact that IDO may play a role in helping cancer cells avoid the immune system. “The immune system appears to have a balance that can allow cancer cells to grow but also can detect and destroy them,” explains Dr. Jonathan Brody, assistant professor of Surgery at Jefferson Medical College.


Human hair protein could help regenerate nerves

A protein found in human hair shows promise for promoting the regeneration of nerve tissue and could lead to a new treatment option for cut or crushed nerves. Scientists from Wake Forest University School of Medicine, the United States, reported that in animal studies the protein keratin was able to speed up nerve regeneration and improve nerve function compared with current treatments. “We found that the nerve repair happened more quickly and consistently, and that functional recovery was higher,” said Dr. Mark Van Dyke, assistant professor of Regenerative Medicine.

The scientists used keratin to form gels that were then used to fill the nerve guidance conduit – an empty tube placed between the cut ends so that nerve fibres can grow through it and back into the muscle. The laboratory studies showed that keratin activated Schwann cells, which play a vital role in nerve regeneration, and increased their proliferation and migration. Next, the scientists used a keratin-filled tube to attempt to repair a 4 mm nerve gap in mice – a fairly significant gap considering the size of the animal. The results were compared with animals treated with an empty nerve guidance conduit and with animals treated with a nerve graft. After six weeks, all the animals in the keratin and nerve graft groups showed visible nerve regeneration across the gap, compared with only 50 per cent for those who got the empty conduit. The speed of repair and speed of nerve impulses were best in the keratin group. The amount of signal that got through the nerve was also better in the keratin group than in the empty tube group.


Proteomics accurate in identifying liver cancer

A recent study, led by researchers at Beth Israel Deaconess Medical Centre (BIDMC) in the United States, has demonstrated that a novel form of proteomic profiling based on mass-spectrometry is more accurate than traditional biomarkers in distinguishing liver cancer patients from patients with hepatitis C liver cirrhosis, particularly with regard to identifying patients with small, curable tumours. The surface enhanced laser desorption/ionization time of flight mass spectrometry (SELDI-TOF MS) could help lead to earlier diagnostic methods, and subsequent treatments, for liver cancer.

The best hope for early detection is biomarkers, serum proteins found in altered amounts in blood or other body fluids. Alpha fetoprotein (AFP), the current biomarker for liver cancer in clinical use, has a number of shortcomings, including false positives and false negatives. AFP fails to detect many early tumours and is not a specific indicator for cancer.

The scientists, therefore, decided to evaluate the sensitivity and specificity of SELDI-TOF MS for the detection of liver cancer and to compare its effectiveness with AFP. They examined serum samples of 92 patients – 51 patients with liver cirrhosis and 41 patients with liver cancer, and among the cancer patients, individuals with both large and small tumours – by SELDI-TOF mass spectrometry. They were able to identify an 11-protein signature that accurately discriminated between the cirrhosis and cancer patients. The diagnostic values – 74 per cent sensitivity and 88 per cent specificity – compared favourably with the diagnostic accuracy of AFP (73 per cent sensitivity and 71 per cent specificity) as well as with two other biomarkers currently in clinical development for liver cancer, AFP-L3 and PIVKA-IL. Most importantly, in patients with small tumours (less than 2 cm) too, the 11-protein signature proved far superior to the other biomarkers in early stage identification of the disease, notes Dr. Towia Libermann, director of BIDMC Genomics Centre.


Expression of miRNA differs in cancer and non-cancer tissues

Preliminary research has found an association between certain miRNA expression patterns and poor survival and treatment outcomes for colon cancer, report a research team from National Cancer Institute of Canada, Chinese University of Hong Kong, and Ohio State University Comprehensive Cancer Centre and the University of Texas M. D. Anderson Cancer Centre in the United States. The team evaluated miRNA profiles of colon tumours and paired non-tumourous tissue to study their potential role in tumour formation, diagnosis and therapeutic outcome in colon cancer. The study included 84 patients from Maryland, the United States. Associations were validated in a second, independent group of 113 patients from Hong Kong. Using miRNA microarray analysis in the Maryland test cohort, 37 miRNAs were found to be differentially expressed in tumour tissues. Expression patterns of five tested miRNAs were validated in the Hong Kong cohort. The power of five microRNAs to differentiate between tumour and non-tumourous tissue suggests that changes of microRNA expression patterns may occur during tumourigenesis.



New cranberry line packed with health features

Juice drinks, saucy relishes and dried fruit products may one day boast a new cranberry variety with a readily absorbable dose of healthful antioxidants. In the United States, scientists are using traditional breeding methods to develop a wholesome new cranberry line with just such a genetic trait. Plant pathologist Dr. James J. Polashock, with the Agricultural Research Service’s Genetic Improvement of Fruits and Vegetables Laboratory, and Dr. Nicholi Vorsa, with the Philip E. Marucci Centre for Blueberry and Cranberry Research and Extension at Rutgers University, are collaborating on the project.

The researchers found a cranberry species from Alaska that is genetically similar enough to the American cranberry to produce fertile progeny. The Alaskan species is also attractive because some of the fruit’s many healthful chemical compounds, called anthocyanins, are glucose-linked. In nature, most anthocyanins are bound to sugars. The glucose-linked anthocyanins are relatively high in antioxidant capacity and are well absorbed in the human gut. The researchers found that, compared with the typical American cranberry’s anthocyanins, which are 3-5 per cent glucose-linked, the anthocyanins in hybrids from the first breeding cross were 50 per cent glucose-linked. The progeny of these crosses deliver two benefits: the pro-anthocyanidins long known for inhibiting bacterial E. coli from sticking to the lining of the urinary tract, and higher amounts of the potentially well-absorbed antioxidative anthocyanins.


New high-protein rice strain

Scientists in the United States and India report the development of a high-protein variety of rice, dietary staple for half the world’s population. In the study, Dr. Hari B. Krishnan from the United States’ Agricultural Research Service and colleagues from Tamilnadu Agricultural University in India and University of Missouri, the United States, created a hybrid by crossing a common variety of rice called Oryza sativa with a wild species, Oryza nivara. The product showed a protein content of 12.4 per cent, which is 18 per cent and 28 per cent higher than those of the parents. Screening germplasm collections of cultivated rice has shown that protein content tends to range from 5 to 18 per cent, with an average of 9.5 per cent.

The results demonstrate the potential for wild rice’s relatives for boosting the protein content in rice. The researchers concluded that the hybrid could serve as initial breeding material for new rice genotypes that could combine types with superior cooking quality with those of high protein content.


Genetically modified carrots help absorb calcium

In the United States, researchers at Texas A&M AgriLife’s Vegetable & Fruit Improvement Centre have studied the calcium intake of humans who ate a genetically modified (GM) carrot and found a net increase in calcium absorption. One serving of the GM carrot means absorption of 41 per cent more calcium than from a regular carrot, said Dr. Jay Morris, a post-doctorate researcher at Baylor College of Medicine, which collaborated in the research. The main goal of the research was to increase the calcium in fruit and vegetables to benefit human health and nutrition.

For this study, the researchers fed carrots to a group of 15 men and 15 women. The people were fed either the GM carrots, called sCAX1, or regular carrots in week 1. On a second visit two weeks later, they were fed the other type of carrot. Urine samples collected 24 hours after each feeding were analysed to determine the amount of specially marked calcium absorbed. It was found that both men and women absorbed higher amounts of calcium from the modified carrots.


Grasses’ guardian gene found

The world’s grasses might not have survived long enough to evolve into the crops – wheat, corn, rice, rye, barley, sorghum, etc. – that feed the human race, had it not been for one gene that has protected them against a deadly fungal pathogen for more than 50 million years. Joint research by Dr. Steven Scofield from the Agricultural Research Service Crop Production & Pest Control Research Unit and Dr. Guri Johal and Dr. Michael Zanis from Purdue University has proved that HM1 has been present in all grasses since shortly after their origin and protects them from the fungus Cochliobolus carbonum Race 1 (CCR1).

Dr. Johal isolated HM1 gene from mutants of corn in which the gene was not functional. CCR1 is a devastating pathogen in these mutant corn lines, causing leaf blight, root and stalk rots, and ear mould. Dr. Johal also found that HM1 genes were present in other grass crops, raising the question: does HM1 also protect these other plants from CCR1? Dr. Scofield and colleagues developed a virus-induced gene silencing system that switched off all HM1 genes in barley, causing it to be highly susceptible to CCR1. This proved that HM1 gene provides CCR1 resistance in other grasses as well. Source:

History of the modern potato

Almost all modern potato varieties planted today are the direct descendents of varieties that once grew in Chile. How the Chilean germplasm came to dominate the modern potato, which spread worldwide from Europe, has been debated among scientists for long. Some held that Chilean potatoes were the first to be planted in Europe. For others European potatoes came from the Andes Mountains, and were replaced by Chilean varieties after their wipe-out by the Great Irish Potato Famine, the 19th century late-blight epidemic that decimated potato fields across Europe.

Ms. Mercedes Ames and Dr. David Spooner from the University of Wisconsin-Madison, the United States, say both theories are wrong. Their DNA analysis of historical potato specimens found that both Chilean and Andean potatoes were grown in Europe decades before and after the famine. The Andean potatoes did get to Europe first, but the Chilean potatoes were starting to get popular there 34 years before the late blight epidemic. The results also show that Andean potatoes grew as late as 1892 in Europe, proving they weren’t polished off by the epidemic, and that they grew side by side with Chilean potatoes for many decades before the latter became dominant.



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