VATIS Update Biotechnology . May-Jun 2011

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Biotechnology May-Jun 2011

ISSN: 0971-5622

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

Co-publisher: Biotech Consortium India Ltd
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India to publicize details of patented drugs

The Indian government plans to provide details of every medicine patented in the country to the public to ensure transparency. This move will also help Indian drug-makers to challenge patent holders and sell low-cost versions of high-priced patented drugs. Currently, it is difficult to get such information on patented medicines. However, once the system is in place, drug details can be easily accessed by using the patent number of the product. As of March 2010, around 34,000 patents were in force in India, but only “about 12-13 per cent of the patents were working,” said Mr. P.H. Kurien, Controller General of Patents, Designs and Trademarks. The information to be disclosed would include: whether the patent is working (used); the quantum of products sold, imported or locally made; total sales; and whether the firm is adequately able to supply to meet requirements of local patients. These are mandatory information that a patent holder needs to submit to the government.

Synthetic biology institute to advance bioengineering research

In the United States, an alliance of top scientists at the University of California-Berkeley (UC Berkeley) has formed the UC Berkeley Synthetic Biology Institute (SBI), advancing efforts to engineer cells and biological systems in ways that promise to transform technology in health and medicine, new materials, energy, environment and several other critical areas. The new institute – aiming to create “an industrial revolution in biological engineering” – is launching a collaborative effort with its first industry member Agilent Technologies Inc. Agilent is helping to initiate SBI research with a multi-year, multi-million dollar commitment, including early access to Agilent technologies and active participation of its researchers and engineers.

SBI will be an important link in a constellation of research centres focused on synthetic biology at UC Berkeley and Lawrence Berkeley National Laboratory (LBNL), both of which have made the field a research priority. SBI is unique in its planned collaborations with leading companies, designed to translate leading research on biological systems and organisms efficiently into processes, products and technologies to meet real-world demands. SBI is broadly interdisciplinary, with 33 faculty and scientists from eight academic departments at Berkeley and four divisions at LBNL, spanning engineering, chemical sciences and biology. “SBI seeks to bridge the gap between the small-scale, biological engineering of the present and industrial-level production by developing design tools and other infrastructure to produce synthetic biological systems reliably on a large scale,” says Mr. Matthew Tirrell, Chair of Berkeley’s Department of Bioengineering and SBI’s Founding Director.

Kenya to plant biotech crops

The Kenyan government plans to publish biotechnology guidelines, setting the country on course to join developing countries planting genetically modified (GM) crops. President Mr. Mwai Kibaki signed the Biosafety Act in February 2009 but the law needed guidelines to facilitate implementation. Without them, the government can approve applications for biotechnology products only for research trials. “We are working with the State Law Office because we need to prescribe packaging that will be acceptable because even globally, labelling of genetically modified products remains contentious. We will borrow from Kenya Bureau of Standards because it already has standards of packaging and labelling of biotechnology products,” said Dr. Roy Mugiira, Acting Chief Executive of the National Biosafety Authority.

Dr. Mugiira said the Authority has not authorized importation of any GM material for release into the environment. Africa cannot continue to ignore biotechnology, he pointed out. The Kenya Agricultural Research Institute (KARI) is at the forefront of biotechnology, and is developing bio-fortified sorghum with more nutrients. It is modifying the cereal to reduce production of a chemical that makes it to have bitter taste. Dr. Mugiira said KARI at the forefront of developing technologies that, in the next 5-10 years, may become commercial products. “Therefore we need to see ourselves as originators of these technologies not only as recipients,” he said.

South-South biotech collaborations flourish

Developing countries are turning to each other for affordable and targeted solutions to national health problems, according to a study of South-South biotechnology collaborations. ‘Brother-sister’ trade relationships between developing countries allow cheaper drugs and vaccines to reach more poor people than do ‘parent-child’ relationships with the developed world, according to the study published in Nature Biotechnology. The study was a collaboration between researchers from Canada and five developing countries who interviewed 300 biotech company staff from 13 nations. The researchers state that the study was prompted by the lack of information about such collaborations.

Ms. Halla Thorsteinsdottir, lead author, from the McLaughlin-Rotman Centre for Global Health at the University of Toronto, Canada, expressed that developing countries were establishing mutually beneficial relationships to address health issues they share. “India and South Africa, for instance, are working together on issues like HIV/AIDS and malaria,” Ms. Thorsteinsdottir said. Meanwhile, Egypt turned to China when it desperately needed insulin, establishing a bilateral trade relationship that continues to benefit both countries. Brazil, China, Cuba, Nigeria, Russia, Thailand and Ukraine have networked to promote research and development of diagnostics kits, drugs and vaccines for HIV/AIDS. The collaborations occur against a backdrop of about 12.5 per cent annual increase in the rate of South-South trade, with emerging economies like China and India experiencing unprecedented growth. About 27 per cent of the developing world biotechnology firms surveyed for the study confirmed they were involved in South-South partnerships. But South-North collaborations still dominate, with 53 per cent of firms reporting such relationships.

Australia-Saudi Arabia collaboration in biotechnology

Rose oil for the Saudi perfume industry and barley breeding are the first collaborative research projects between State Agricultural Biotechnology Centre (SABC) and Murdoch University, both in Australia, and Taif University of Saudi Arabia. Researchers for the projects will be based at Murdoch, as well as at Taif’s campus where a new biotechnology centre is being established. A Memorandum of Understanding (MoU) signed by Prof. Jim Reynoldson, Murdoch’s Deputy Vice Chancellor (Research), and Prof. Fareed Felemban, Vice President of Academic Affairs at Taif, will form the basis of a long-term relationship that begins with the setting up of Taif’s Biotechnology Centre and involving a range of disciplines, from crop and animal biotechnology to biomedical sciences. The MoU is based on international recognition of Murdoch University’s research strengths, particularly in crop and veterinary sciences. “The first two collaborative projects have been funded and involve barley breeding and improvement, and analysing the production, composition and metabolism of rose oils for our perfume industry,” said Prof. Talal al Maliki, Dean of Medicine and Founding Director of the Biotechnology Centre at Taif University.

India and Germany to work together in biomedical research

The Indian Council of Medical Research (ICMR) and Helmholtz Association (HGF), Germany, have signed a Memorandum of Understanding (MoU) on translational efforts in biomedical research for a period of five years. The MoU was signed on 1 June 2011 at New Delhi, India, in the presence of the Prime Minister of India, Dr. Manmohan Singh, and the German Chancellor, Dr. Angela Merkel. The MoU will provide for translational efforts in biomedical research, particularly in infectious diseases, and will offer long-term capacity building for researchers and scientists. Both the countries will benefit in areas pertaining to the biomedicine and public health in terms of joint collaborative research efforts and projects. The other areas identified under the MoU are oncology and biomedical research related to health. The ICMR-HGF collaboration has been running in after an MoU signed in April 2006 at Hannover, Germany, during a visit by the Prime Minister of India. That collaboration led to the development of four ongoing research projects between researchers of the two countries in the areas of genetic susceptibility, vaccines, anti-infectives and viral diseases.


Piramal aims to develop its OTC business

Piramal Healthcare, India, is looking to develop its over-the-counter (OTC) business over five-fold in the next three years. The company’s OTC business could touch US$224 million during 2014-2015 from the current US$35.8 million. “The consumer spending on OTC is increasing. On the other hand, there is under-penetration of OTC. We feel there is tremendous scope for rapid growth,” said Ms. Nandini Piramal, Executive Director of Piramal Healthcare. The growth will be achieved through organic and inorganic routes. Piramal’s OTC products include emergency contraceptive I-pill, skin cream Lactocalamine and pain-reliever Saridon. According to various industry estimates, India’s OTC segment is pegged at about US$1.9 billion, growing at 12-15 per cent annually. In a bid to increase presence, especially in rural and semi-urban areas, pharma majors such as Ranbaxy, Sanofi Aventis and Novartis have launched branded and patented products and increased the sales network to cover more physicians. However, Piramal currently has no plans of launching specific initiatives to tap different regions.

Half billion cancer deal for Human Genome Sciences

In the United States, Human Genome Sciences (HGS) is paying US $50 million up front and up to US$445 million in milestones to gain development rights for the lead cancer candidate of Five Prime Therapeutics. Five Prime’s FP-1039 is a fibroblast growth factor (FGF) ligand trap, a genetically engineered protein drug that prevents blood vessels from feeding tumours. The drug is in early stage trials for a variety of cancers, and Five Prime is gearing up to start mid-stage trials of the drug for endometrial cancer. HGS gets exclusive rights to develop and commercialize FP-1039 for all indications in the United States, Canada and the European Union. Five Prime has an option to co-promote FP-1039 and any next-generation products in the United States. It also has full development as well as commercialization rights in all regions not covered by HGS, and will earn royalty payments on net sales.

FDA approves Johnson & Johnson’s prostate cancer drug

In 2009, Johnson & Johnson, the multinational pharmaceutical and medical devices company based in the United States, inked a US$1 billion deal for Cougar Biotech, also from the United States. The small company was developing breast cancer and multiple myeloma drugs in addition to its treatment for prostate cancer. The United States Food and Drug Administration (FDA) has now approved the company’s Zytiga (abiraterone acetate) in combination with prednisone for those diagnosed with late-stage, castration-resistant prostate cancer who have previously received chemotherapy. In clinical trials, the patients who received Zytiga and prednisone had a median overall survival of 14.8 months compared with 10.9 months for patients receiving the placebo and prednisone.

Zytiga, an oral drug, targets a protein called cytochrome P450 17A1 (CYP17A1). The protein plays a key role in the production of testosterone, which in turn stimulates cancer cell growth. Currently, physicians use surgery or drugs to block testosterone. Patients who resist such approaches can now have Zytiga as a last defence. The drug will cost US$5,000 for a month’s supply – US $40,000 for an eight-month course of treatment.

Eli Lilly and Medtronic join hands on Parkinson’s treatment

In the United States, Eli Lilly has entered into a collaboration deal with Medtronic to explore “a new approach to treating Parkinson’s disease” that involves a new drug delivery system for the brain. The partners will adopt an approach that “combines the strengths of Lilly’s biologic, a modified form of glial cell derived neurotrophic factor (GDNF), with Medtronic’s implantable drug infusion system technology,” according to the firms. Eli Lilly plans to use Medtronic’s drug delivery system to pump its GDNF directly into targeted regions in the brain of Parkinson’s disease patients. According to Mr. Michael L. Hutton, Chief Scientific Officer of the neurodegeneration team at Eli Lilly, “We believe we have biosynthetically engineered this GDNF variant to overcome technical hurdles of previous research in this area... By collaborating with Medtronic from the earliest phase of research, we are maximizing the potential for this therapy’s efficient and effective development.”

Seattle Genetics strikes US$208 million deal with Abbott

In the United States, Seattle Genetics has signed another collaboration pact involving its closely watched antibody-drug conjugate (ADC) technology. The ADC company is pocketing US$8 million from Abbott Laboratories, and has been promised up to US$200 million more as it focuses on a single cancer target. “This is the second ADC collaboration with a multinational pharmaceutical company that we have announced this year, further illustrating the important role that our ADC technology is poised to play in the treatment of many types of cancer,” stated Mr. Eric Dobmeier, Chief Business Officer of Seattle Genetics. Abbott is responsible for research, product development, manufacturing and commercialization of any ADC products under the collaboration. Seattle Genetics has 11 active ADC collaborations.

European firms launch a bio-information project

Seventeen European research groups funded by the European Union with 12 million euros are aiming to integrate genotype and phenotype information to create a huge new resource on genetic variation in man. The Gen2Phen project will internationally orchestrate the electronic collection and use of data that show how DNA sequences contribute to inter-individual differences in disease, drug response, and other characteristics such as phenotypes. The project will build a set of database components, tools and technologies that will be helpful to interpreting all research results concerning genome variation and disease to be integrated and available for analysis via the Internet. Gen2Phen will also unify and integrate locus-specific data, genomics data, phenotype data, and genetic testing data. It will develop its own data model and data format, data access and analysis tools.

Fortis to set up stem cell clinical trial centres

In India, Fortis Healthcare, the country’s second biggest private healthcare chain, has joined hands with technology solutions provider TotipotentRX Cell Therapy Pvt. Ltd. to set up centres of excellence offering cellular therapies and stem cell clinical trials, in select Fortis hospitals. TotipotentRX is a leading technology provider to stem cell banks, hospitals, research institutions and diagnostic centres that handle such therapies and clinical trials.

The centres of excellence will undertake stem cell clinical research relating to diabetes, cancer, cardiovascular disease and neurological ischemia. TotipotentRX will also set up current good manufacturing practice (cGMP) laboratories in select hospitals for processing stem cells before transplantation to patients. The clinical trials will focus on new regenerative therapies, using promising adult stem cell sources like cord blood, bone marrow and adipose tissue. A stem cell medical board will be set up to supervise the medical research programme, ensure timely execution and monitor the progress following international and Indian ethical guidelines. The board will also impart training and create awareness around the benefits of stem cell therapy across India.

Biocon to invest US$44.8 million

Biocon Ltd., India, has lined up a capital expenditure of US$33.6-US$44.8 million for setting up a research and development (R&D) facility and for manufacturing. The company would set up a US $22.4 million integrated R&D facility at Bangalore. It will hire 500-600 scientists for the R&D facility and invest US$100 million to develop its insulin drug in the next 3-4 years. The recent move of the National Pharmaceutical Pricing Authority (NPA) allowing price increase of 62 drugs that are mainly based on indigenously manufactured insulin is expected to benefit Biocon.


Cows genetically modified to produce ‚Äúhuman‚ÄĚ milk

In a bid to make cows’ milk more nutritious, scientists in China have created genetically modified (GM) cattle that produce “human” milk. The scientists introduced human genes into 300 dairy cows to produce milk with the same properties as human breast milk. Human milk contains high quantities of key nutrients that can help boost the immune system of babies and reduce the risk of infections.

The researchers led by Prof. Ning Li, Director of the State Key Laboratories for AgroBiotechnology at the China Agricultural University, used cloning technology to introduce human genes into the DNA of Holstein dairy cows before the GM embryos were implanted into surrogate cows. They were able to create cows that produced milk containing a human protein called lysozyme, an antimicrobial protein naturally found in large quantities in human breast milk and helps protect infants from bacterial infections during their early days of life. The researchers also created cows that produce another human milk protein called lactoferrin, which helps to boost the numbers of immune cells in babies. A third human milk protein called alpha-lactalbumin was also produced by the cows. The scientists revealed that they have boosted milk fat content by around 20 per cent and also changed the levels of milk solids, making it closer to the composition of human milk, besides having the same immune-boosting properties. They also state that antimicrobial proteins help reduce infections on udders of the animals.

Full multiple myeloma genome reveals unexpected insights

Scientists in the United States have unveiled the most comprehensive picture to date of the full genetic blueprint of multiple myeloma, a form of blood cancer. A study of the genomes from 38 cancer samples has yielded new and unexpected insights into the events that lead to this cancer and could influence the direction of research on multiple myeloma. The cause of the disease is as yet not known – it can develop in people with no known risk factors and in many cases, no family history of multiple myeloma.

With the whole cancer genome in view, one of the most challenging aspects of multiple myeloma research is now separating the driving events – the important mistakes that drive cells towards becoming cancerous – from passenger mutations – genetic alterations that are merely along for the ride. The researchers found sets of mutations affecting many genes in the same pathways, including the NF-kB pathway. If this pathway is turned on at the wrong time, it can activate genes that allow a cancer cell to grow and divide unchecked. While the researchers had suspected that this pathway was involved in the cancer’s development, it was unclear exactly what events were turning this pathway on. The latest study has uncovered 11 different genes involved in this pathway that were altered in at least one multiple myeloma sample. The study has also brought to light new mutations affecting genes that had never previously been tied to cancer.

One finding with immediate clinical importance is the discovery of BRAF mutations in a few of the multiple myeloma patients. BRAF mutations have “never been a part of the multiple myeloma lexicon before”, said the study’s co-author Dr. Todd Golub from the Dana-Farber Cancer Institute, Boston, Massachusetts, and an investigator at Howard Hughes Medical Institute, but have been previously seen in other forms of cancer, such as melanoma and colon cancer. They found BRAF mutations in four per cent of cases from samples of more than 150 patients with multiple myeloma.

New hope in fight against deadly pulmonary fibrosis

Researchers at the National Jewish Health, the United States, have discovered a new genetic variation that increases the risk of developing pulmonary fibrosis by 7 to 22 times. They report that nearly two-thirds of patients with idiopathic pulmonary fibrosis (IPF) or familial interstitial pneumonia (FIP) carry the genetic variation. It is associated with the MUC5B gene that codes for a mucus-forming protein.

Research into pulmonary fibrosis has been quite difficult. Little is understood about the biological roots of the diseases, and recent clinical trials of several experimental medications have failed to effectively treat them. Previous research has focused mainly on the scarring and inflammatory processes evident in the disease. The new-found genetic variation exists in 19 per cent of healthy controls, 59 per cent of FIP patients and 67 per cent of IPF patients. Carrying one copy of the gene increases the risk of developing FPF by 6.8 times and IPF by 9.0 times. Carrying two copies of the variation increases risk 20.8 times and 21.8 times, respectively. The researchers discovered that the genetic variant increases production of MUC5B more than thirty-fold in unaffected patients. They also found that MUC5B production is elevated in pulmonary fibrosis patients both with and without the gene.

Roundworm may offer clues to tumour genome development

A study of DNA rearrangements in roundworm chromosomes may offer new insights into large-scale genome duplications that occur in developing tumours. The study undertaken in the United States focused on telomeres, a region of repetitive DNA sequence that protects and shields the ends of chromosomes. In humans and many other organisms, chromosome ends are capped by simple repetitive sequences that are replenished by addition of new telomere repeats by the enzyme telomerase. Since most human cells do not produce enough telomerase, they are unable to maintain the repeat DNA sequences that cap their chromosome ends. “Once telomere repeat sequences erode completely, a chromosome end will ‘uncap’ and fuse with another uncapped chromosome end,” explained senior study author Mr. Shawn Ahmed from University of North Carolina’s Lineberger Comprehensive Cancer Centre. The chromosome aberrations that the researchers isolated from telomerase mutants in the common roundworm Caenorhabditis elegans were end-to-end chromosome fusions.

Mr. Ahmed points out that during development of many forms of cancer, chromosome ends erode and ‘uncap’ and many end-to-end chromosome fusions occur. These fusions create genome rearrangements that may contribute to tumour development. The new findings tested predictions of a long-standing model developed in the 1940s by geneticist Ms. Barbara McClintock, 1983 Nobel Laureate in Physiology or Medicine. This model, named the breakage-fusion-bridge cycle, suggested that DNA duplications at fused chromosome ends would be perfect inverted duplications that are created by fusion and then breakage of a fused chromosome during the process of cell division (mitosis).

“Surprisingly, many of the duplications that we studied were ‘interrupted’ by deletions as well as single copy, three copy and four copy segments of DNA. In addition, some duplications were created by events that copy DNA by hopping backwards and forwards along a chromosome,” Mr. Ahmed said. Similar interrupted duplications have been observed with human genome segments that spontaneously duplicate to cause inherited diseases. “So, the duplications that we observe at fused chromosome ends may be created by a ‘general’ duplication mechanism. Our study provides a blueprint for solving structures of analogous chromosome rearrangements that may occur frequently in tumour genomes, many of which are currently being sequenced,” added Mr. Ahmed.

Four new genes identified for Alzheimer’s disease

Researchers from Mount Sinai School of Medicine, the United States, are part of a consortium that has identified four new genes, the presence of which increases the risk of a person developing Alzheimer’s disease. Follow-up studies could help scientists understand how the genes contribute to Alzheimer’s disease, said lead Mount Sinai scientist Mr. Joseph Buxbaum, Professor of Psychiatry, Neuroscience, and Genetics and Genomic Sciences.

The researchers had two main goals for the study. First was the identification of new Alzheimer’s disease genes to provide major clues as to its underlying cause. The second goal was for the gene discovery of the type to ultimately contribute to predicting who will develop Alzheimer’s disease. Knowing these risk genes will help identify the first disease-initiating steps that begin in the brain long before any symptoms of memory loss or intellectual decline are apparent. This knowledge will help researchers understand the events that lead to the destruction of large parts of the brain and eventually the complete loss of cognitive abilities.

Genes causing antimalarial drug resistance identified

Using a pair of powerful genome-search techniques, researchers from the United States have identified several genes that may be implicated in the malaria parasite’s notorious ability to rapidly evade drug treatments. Further testing by scientists from Harvard School of Public Health (HSPH), Harvard University, and the Broad Institute showed that one of the genes, when inserted into drug-sensitive parasites, rendered them less vulnerable to three antimalarial drugs. The successful experiments suggest that the genomic methods are useful tools for probing the genetic mechanisms underlying drug resistance in the malaria parasite Plasmodium falciparum and potentially other types of disease-causing parasites as well.

The scientists examined diversity of the parasite to identify 20 rapidly evolving loci in the genome, and then carried out a genome-wide association study (GWAS) to identify genetic variants that correlated with or are associated with the drug-resistance trait. These variants are necessarily enriched in the drug-resistant (though not drug-sensitive) parasites, allowing the researchers to home in on the candidate genes that are involved in modulating drug responses. Ms. Daria Van Tyne of HSPH pursued one of the novel genes, PF10_0355, for follow-up functional testing. She used an experimental technique that introduced extra copies of the gene from a resistant parasite into a drug-sensitive one, and discovered that the formerly sensitive parasite was rendered more resistant to three standard antimalarial agents. “This demonstration suggests that the gene is involved in modifying parasite drug response,” stated Ms. Van Tyne, adding that they are working to understand how those genes work. Knowing how the parasite is changing before clinical drug resistance is apparent could help scientists extend the useful life of available drugs and identify new effective antimalarials.


Protein extracted from bones of 600,000-year-old mammoth

Researchers from the Universities of Manchester and York in the United Kingdom have successfully extracted protein from the bones of a 600,000-year-old mammoth, paving the way for the identification of ancient fossils. Using an ultra-high-resolution mass spectrometer, bio-archaeologists were able to produce a near complete collagen sequence for a Steppe Mammoth skeleton, called the West Runton Elephant, discovered in 1990 in Norfolk cliffs. The 85 per cent complete skeleton is the most complete example of its species ever found in the world.

The collagen sequencing was carried out at the Centre for Excellence in Mass Spectrometry at the University of York and is arguably the oldest protein ever sequenced. The research formed part of a study into the sequencing of mammoths and mastodons. The West Runton Elephant was compared with other mammoths, modern elephants and mastodons. Despite the age of the fossil, sufficient peptides were obtained to identify the West Runton skeleton as elephantid, and there was sufficient sequence variation to discriminate elephantid and mammutid collagen.

Inter-protein relationship may help develop cancer therapies

By identifying a surprising association between two intracellular proteins, researchers at the University of Iowa, the United States, have laid the groundwork for the development of new therapies to treat B cell lymphomas and autoimmune disease. The researchers studied mouse B cells expressing the viral Latent Membrane Protein 1 (LMP1), which has been implicated in several types of cancer due to its role in the proliferation and survival of Epstein-Barr virus-infected B cells. The scientists discovered that LMP1 needs the cellular protein Tumour Necrosis Factor Receptor-Associated Factor 6 (TRAF6) to promote its B cell activation signalling pathways. The study also shows that LMP1 and CD40 – a normal activating receptor of B cells – both use TRAF6 as a key signalling protein, but in different ways. LMP1 mimics CD40 in delivering activation signals to B cells, but LMP1’s signals are amplified and sustained, resulting in B cell hyper-activation.

B cells normally mature into plasma cells that produce proteins called antibodies necessary to fight off infections. During the process, mutations can occur and accumulation of such mutations can render B cells cancerous, which is why B cell malignancies are relatively common. “We found that TRAF6 is essential for LMP1 functions, and that it interacts with LMP1 in a way that is distinct from the way in which TRAF6 interacts with CD40,” said lead researcher Ms. Kelly Arcipowski, a Ph.D. candidate in the Molecular and Cellular Biology Interdisciplinary Graduate Programme. “Thus, it might be possible to target LMP1 signalling without disrupting normal immune function. This information is valuable to the development of new therapies to target LMP1-mediated pathogenesis, including B cell lymphomas and autoimmune disease,” she added. LMP1 is produced by a normally latent gene that is expressed when Epstein-Barr virus, a herpes virus, becomes reactivated from its inactive state, causing flares of autoimmune diseases. Epstein-Barr virus can become activated in cases of late-stage Acquired Immuno-Deficiency Syndrome (AIDS) or in organ and bone marrow transplant recipients who are immuno-suppressed to prevent rejection of the transplant.

Protein’s role in embryo and disease development unravelled

Researchers from Thomas Jefferson University, the United States, have determined that a single protein called FADD controls multiple cell death pathways, a discovery that could lead to better, more targeted autoimmune disease and cancer drugs. Internationally known immunologist Mr. Jinake Zhang and researchers have shown that this protein regulates not one but two types of cell deaths pivotal for embryo and disease development. It is now known that FADD causes the healthy cell death called apoptosis, while preventing the toxic necrosis. An understanding of this pathway is instrumental in developing drugs with selectivity and fewer side effects, said Mr. Zhang from the Kimmel Cancer Centre at Jefferson. The research suggests that with the absence or variation in expression of this one protein, an embryo may not develop properly or a person may develop disease later in life. Researchers found that mice that did not express FADD contained raised levels of Receptor-Interacting Protein 1 (RIP1), an important protein that mediates necrosis and the apoptotic processes, and their embryonic development failed due to massive necrosis.

When the FADD-mediated death process is deregulated, it will produce white bloods cells that will attack one’s own tissue, which causes auto-immune diseases such as arthritis and lupus, said Mr. Zhang. Without necessary cell deaths that are required for tumour surveillance, cancer could develop.

Protein study helps shape understanding of body forms

Scientists have shed light on why some people are apple-shaped and others are pear-shaped. Researchers at the University of Edinburgh, the United Kingdom, have pinpointed a protein that plays a part in how fat is stored in the body. The findings give greater understanding of how the protein works, which could help development of medicines to treat obesity. Levels of the protein known as 11BetaHSD1 tend to be higher in the presence of an unhealthy type of body fat that gets stored around the torso – typical of “apple-shaped”. Healthier fat, linked to lower levels of the protein, tends to be stored around the hips and is used more safely by the body as a source of energy – typical of people who are “pear-shaped”.

The study found that mice with the 11BetaHSD1 protein in their bodies were more likely to have unhealthy fat tissue after four weeks on a high fat diet, compared with mice without the protein. Dr. Nik Morton, University of Edinburgh’s Centre for Cardiovascular Science, states, “Inflammation in the unhealthy fat leads to reactions that can cause harm locally to tissues and affect the whole organism, promoting diabetes. Limiting the presence of this protein could help combat this.” As well as being more likely to be stored around vital organs in the torso, fat with higher 11BetaHSD1 levels is considered unhealthy as it is associated with an over-reaction in the immune system. Cells normally become inflamed in order to kill off an infection, but as there is no infection in the fat tissue the inflammation instead causes damage to healthy cells.

Common ‚Äėchaperone‚Äô protein found to work in surprising way

The Scripps Research Institute, the United States, report that a common “chaperone” protein in cells thought to help other proteins fold has been shown instead to loosen them. The new study offers the first structural insights into the shape of a “client” protein in the presence of a helper or “chaperone” protein. It examined the client protein p53 tumour suppressor and its interactions with chaperone heat shock protein 90 (Hsp90). “It was a real surprise to find that, when bound to Hsp90, p53 is loosened and becomes less ordered, forming a molten globule-like state,” said lead researcher Prof. H. Jane Dyson, a molecular biologist. This contradicts the commonly accepted function of chaperone proteins – to help other proteins fold into a well-defined three-dimensional structure.

The findings add to scientists’ new understanding of proteins, now thought not only to constantly change shape to perform different functions but also to be active when unfolded. One way these intrinsically disordered proteins act is by folding when they bind to other molecules and performing functions such as potentiating cellular signalling or turning on the transcription of a gene. The disordered protein might then dissociate from this partner, unfold and perhaps bind to a different molecule in a new shape. Thus, these proteins can constantly move between unstructured and ordered states, interacting with many different partners as part of the “proteostasis”. Both Hsp90 and p53 are crucial to cell functioning. About one per cent of proteins in a typical cell are Hsp90 chaperone molecules, and they are known to perform a number of functions, including acting as “holding” proteins for hormone receptors. The tumour suppressor p53 is a crucial cell cycle regulator; most mutations seen in cancers occur in the DNA-binding domain of p53, which is also the site of its interaction with Hsp90. The scientists used protein nuclear magnetic resonance (NMR) spectroscopy to learn that Hsp90 acted to unfold p53.

Two proteins may hold the key to artificial chromosome

In the United States, Whitehead Institute scientists report that two proteins, once thought to have only supporting roles, are the true “stars” of the kinetochore assembly process in human cells. The kinetochore is vital to proper DNA distribution during cell division. This finding suggests that scientists may be able to stimulate kinetochore assembly in a process that could lead to new genetic research tools, such as efficient creation of artificial human chromosomes.

At the beginning of cell division, the kinetochore comprises a few proteins associated with a chromosome’s centromere, which is the section where the arms of an X-shaped chromosome join. As cell division progresses, more kinetochore proteins attach at the centromere, ultimately forming a complete kinetochore complex consisting of about 100 proteins. At this point, one kinetochore is partially integrated into each lengthwise half of the chromosome, called a sister chromatid; a chromosome’s sister chromatids are identical copies of the same piece of DNA. To distribute the sister chromatids between the two future cells, long protein filaments from opposite sides of the cell reach out, latch onto the chromatids’ kinetochores, and begin pulling on them until the sister chromatids split apart. Then, the chromatids are dragged to opposite sides of the cell, ensuring that the future cells will each have a DNA copy.

To identify the proteins necessary for a kinetochore to self-assemble, Ms. Karen Gascoigne, a post-doctoral researcher, positioned three of them away from their normal positions and isolated the effects of each protein from potential interactions with the centromere and determined the capabilities attributable only to that protein. The first protein called CENP-A is vital for identifying the kinetochore’s location. The proteins CENP-C and CENP-T were found to be essential and sufficient to build the kinetochore. This ability to form a kinetochore anywhere on DNA may be useful for creating artificial human chromosomes. At present, scientists insert genes by infecting cells with a virus that haphazardly inserts the DNA into the cells’ genomes, a process that can corrupt essential genes and possibly kill cells.


Discovery paves way for drugs that prevent lung destruction

Scientists from the Infectious Diseases and Immunity Department at Imperial College London, the United Kingdom have identified a key enzyme responsible for destroying lung tissue in tuberculosis (TB). As drugs that inhibit this enzyme are available, the finding could lead quickly to new treatments. Infection by Mycobacterium tuberculosis destroys patients’ lung tissue, causing them to cough up the bacteria, which then spread through the air to others. The mechanism behind this lung damage is poorly understood, and no treatments currently used prevent it. Patients require at least six months of antibiotic treatment. However, drug-resistant strains of the bacterium are becoming increasingly common.

The new research shows that in the lungs of TB patients, there is an increase in the levels of an enzyme called MMP-1. When the researchers infected human immune cells with TB in the lab, they found that the cells greatly increased production of this enzyme. It was also found that a drug proven to be safe in humans was effective at suppressing MMP-1 activity driven by TB infection in human cells. The findings suggest that similar drugs might prevent lung damage in TB patients and help limit the spread of the disease.

Antibiotics cure anthrax in animal models

Respiratory anthrax is fatal in the absence of early antibiotic treatment. But a multi-agent prophylaxis initiated within 24 hours post-infection prevents development of fatality in anthrax infection, and treatment combining antibiotics with immunization with a protective antigen-based vaccine gives long-term protective immunity against recurrence of the disease. This study is the first to characterize the severity of respiratory anthrax that can be cured. The researchers, from the Israel Institute for Biological Research in Ness-Ziona, tested the efficiency of different therapeutic approaches in preventing the disease from developing in infected animals, and their ability to cure animals in which the disease had developed into a systemic, septic phase. Rescue remains possible with appropriate agents even if initiated two days after infection.

Treatment initiated 24 hours after infection with any of the four antibiotics protected the animals during treatment, but many of the animals died of anthrax after treatment was stopped. The antibiotics conferred degrees of protection ranging from 10 to 90 per cent. Combining this treatment with a protective antigen vaccine left all animals fully protected even after the end of treatment. Animals whose treatment was delayed beyond 24 hours post-infection developed varying degrees of bacteremia and toxemia. Treatment with doxycycline cured both sick guinea pigs and rabbits, exhibiting low to moderate bacteremia; adding protective antigen vaccine to the mix boosted the level of bacteremia that was curable ten-fold in the guinea pigs and twenty-fold in the rabbits. But ciprofloxacin plus a monoclonal anti-protective antigen antibody was still more effective. In all cases, the surviving animals developed immunity against anthrax through subcutaneous challenge.

Nanoscale vaults to encapsulate ‚Äėnanodisks‚Äô for drug delivery

A new study by University of California-Los Angeles (UCLA) broadens the potential therapeutic applications of “vaults”. In recent years, researchers have grappled with the challenge of administering therapeutics in a way that boosts their effectiveness by targeting specific cells in the body while minimizing their potential damage to healthy tissue. Researchers at UCLA have developed a new and potentially very effective means of targeted drug delivery using nanotechnology. They demonstrated the ability to package drug-loaded “nanodisks” into vault nanoparticles, naturally occurring nanoscale capsules that have been engineered for therapeutic drug delivery. The study represents the first example of using vaults towards this goal.

Vault nanoparticles are found in the cytoplasm of all mammalian cells and are one of the largest known ribonucleoprotein complexes in the sub-100 nm range. A vault is essentially a barrel-shaped nanocapsule with a large, hollow interior – properties that make vaults ripe for engineering into a drug-delivery vehicle. The ability to encapsulate small-molecule therapeutic compounds into vaults is critical to their development for drug delivery. Recombinant vaults are non-immunogenic and have undergone much engineering, including cell-surface receptor targeting and the encapsulation of a wide variety of proteins. The internal cavity of the recombinant vault nanoparticle is large enough to hold hundreds of drugs, and because vaults are the size of small microbes, a vault particle containing drugs can easily be taken up into targeted cells. With the goal of creating a vault capable of encapsulating therapeutic compounds for delivery, UCLA doctoral student Mr. Daniel Buhler designed a strategy to package another nanoparticle, or nanodisk, into the vault’s inner cavity, or lumen. Mr. Buehler theorizes that given the large vault interior, multiple nanodisks could be packaged, considerably increasing the localized drug concentration.

Pig corneal cells replaced with human stem cells

Researchers at the University of Granada, Spain, have made progress towards bio-artificial organs by extracting pig corneal cells and replacing them with human stem cells. This method, known as decellularization and recellulation, allows scientists to maintain the basic structure of the cornea and replace its cellular components. The scientists belong to the research group that made an artificial cornea with biomaterials designed at the Tissue Engineering Laboratory of the University of Granada. That cornea is currently on the preparatory stage to begin a clinical trial.

Safer treatment for trypanosome parasite infection

A safer and more effective treatment for people who suffer from infections caused by trypanosome parasites could become a reality. Scientists at the School of Biological and Chemical Sciences, Queen Mary, University of London, the United Kingdom, have found out the mechanisms behind a drug used to treat African sleeping sickness and Chagas disease, often fatal infections that trypanosomes cause. They investigated how the drug nifurtimox works to kill trypanosomes. According to Dr. Shane Wilkinson, “ enzyme within the parasites carries out a process nifurtimox needs to be converted to a toxic form. This produces a breakdown product that kills the parasite. This mechanism overturns the long-held belief that nifurtimox worked against the parasites by inducing oxidative stress in cells.”

The backbone of nifurtimox contains a nitro group linked to a ring structure called a furan. When the parasite enzyme reacts with nifurtimox, it converts the nitro group to a derivative called hydroxylamine. The change causes the electrons within the compound’s chemical backbone to be redistributed, which helps break a specific chemical bond in furan ring, resulting in the formation of a toxic product called an unsaturated open chain nitrile. Understanding how nifurtimox kills trypanosomes could help produce safer compounds that enter the bioreductive activity of this parasitic enzyme.

Pig stem cell transplants: the key to future retina treatment

Scientists from the United States and China led by Dr. Douglas Dean of the University of Louisville, the United States, have found that pigs represent an effective proxy species to study stem cells-based treatments for the repair of damaged retina tissue in humans. The study demonstrates how stem cells can be isolated and transplanted between pigs, overcoming a key research barrier. Unlike lower vertebrates, the human retina lacks a regenerative pathway. Research has therefore focused on cell transplantation.

Dr. Douglas Dean’s team turned their attention to pigs because, as with humans, the swine eye contains a cone-dominant central visual streak, making it a closer anatomical and physiological match. The team gathered induced pluripotent stem cells (iPSCs) from swine skin fibroblasts and demonstrated that these cells differentiated in culture and could be integrated with the cells of a second pig’s retina. While only a small section of the retina was transplanted for this study, the results could open a new avenue of research into degenerative conditions as researchers have a more effective human proxy species to work with.

New cell type discovery may help eradicate cancer stem cells

Researchers at Whitehead Institute, the United States, have discovered that a differentiated cell type found in breast tissue can spontaneously convert to a stem cell-like state – the first time such behaviour has been observed in mammalian cells. These results refute scientific dogma that differentiation is a one-way path; once cells specialize, they cannot return to the flexible stem cell state on their own. This surprising finding may have implications for the development of cancer therapeutics, particularly those aimed at eradicating cancer stem cells.

“It may be that if one eliminates the cancer stem cells within a tumour through some target agent, some of the surviving non-stem tumour cells will generate new cancer stem cells through spontaneous de-differentiation,” says Mr. Robert Weinberg, a Whitehead Founding Member. Cancer stem cells are capable of reseeding tumours at both primary and distant sites in the body. During differentiation, less-specialized stem cells mature into many different cell types with defined functions. These differentiated cells work together to form tissues and organs. In breast tissue, for example, differentiated basal cells and luminal cells combine to form milk ducts. While analysing cells from human breast tissue, Ms. Christine Chaffer, a post-doctoral researcher, observed a small number of living basal cells floating freely in the tissue culture medium. She conducted further targeted investigations, including injection of the floating basal cells into mice. After 12 weeks, it was found that the injected basal cells gave rise to milk duct-like structures containing both basal and luminal cells – a clear indication that the floating cells had de-differentiated into stem-like cells. Until now, no one has shown that differentiated mammalian cells, like these basal cells, have the ability to spontaneously revert to the stem-like state – a behaviour described as plasticity. Further study revealed that basal cells in breast cancer tumours can serve as a new source of cancer stem cells. Ms. Chaffer is now focusing on what actually prompts these flexible cells to de-differentiate, and in the case of cancer cells, how to stop the cells from converting into cancer stem cells.


New key to plant disease resistance discovered

In the United States, University of Kentucky plant pathologists have discovered a metabolite that plays a critical role early on in the ability of plants, animals, humans and unicellular micro-organisms to fend off a wide range of pathogens at the cellular level, which is known as systemic immunity. This mode of resistance has been known for more than 100 years, but the key events that stimulate that resistance have remained a mystery. Using soybeans and Arabidopsis, a model laboratory plant, scientists identified the metabolite glycerol-3-phosphate as a key mobile regulator of systemic immunity. Glycerol-3-phosphate transforms into an unknown compound and uses a protein, DIR1, to signal systemic immunity.

“The metabolite and protein are dependent on each other to transport immunity from one location in the plant tissue to the other,” states Mr. Pradeep Kachroo. “Metabolite levels increase in plant tissues after the plant has been inoculated by a pathogen.” While the research was conducted on plants, Mr. Kachroo said all organisms have a similar process of triggering systemic immunity. “The metabolite is a highly conserved compound in all species across the board.” In addition, increased levels of this metabolite do not affect plant productivity, as different from other known systemic immunity inducers.

India to grow bio-fortified crop

India will soon be the first country to commercially cultivate bio-fortified pearl millet (bajra). The crop has been bio-fortified to improve its iron and zinc nutrients, and it will be released in 2012 by HarvestPlus, a global alliance of research and implementing agencies. The crop developed by the International Crops Research Institute for the Semi-Arid Tropics (ICRISAT) will be first released in four states. “It targets hidden hunger of undernourished and malnourished people, especially the poor who are not able to meet micronutrient requirements from the food they eat,” said Mr. Howarth E. Bouis, Director, HarvestPlus. However, it is too early to ascertain the usefulness of bio-fortified pearl millet, said Mr. B. Sersikaran, Director of India’s National Institute of Nutrition at Hyderabad. The Institute is undertaking efficacy studies of bio-fortified pearl millet for HarvestPlus. Mr. B. Kodkany of Jawaharalal Nehru Medical College in Karnataka state is carrying out a foundation study to measure the amounts of iron and zinc in bio-fortified pearl millet that are absorbed by children, and compare it with absorption of minerals in normal commercial varieties.

Bio-fortified pearl millet aims to increase the absorption level of iron in people by 5-10 per cent and grain yield by 5-6 per cent, said Mr. Kedar Rai, Director, HarvestPlus India’s bio-fortification programme and a Principal Scientist at ICRISAT. About 35 million people eat pearl millet that costs much less than rice and wheat. According to Mr. Rai, this new crop can be one of the strongest means to fight anaemia. It has 50-65 ppm iron, about twice more iron than modern wheat varieties. Its increased zinc content is crucial for a person’s brain functions, reproductive health and immunity.

The United States and Russia to develop high-tech crop map

AgroAtlas is a new interactive website that shows the geographic distributions of: 100 crops; 640 species of crop diseases, pests and weeds; and 560 wild crop relatives growing in Russia and neighbouring countries. Downloadable maps and geographic information system (GIS) software are also available, allowing layering of data, such as that relating to major wheat production areas to concentrations of Russian wheat aphids. United States Department of Agriculture (USDA) plant geneticist Ms. Stephanie Greene said the impetus behind developing AgroAtlas was to promote world food security. She leads the project together with Mr. Alexandr N. Afonin, a senior scientist with St. Petersburg State University in Russia.

The Internet-based map is the result of a proposal submitted in 2003 for funding under a programme coordinated by the Agricultural Research Service (ARS) Office of International Research Programmes (OIRP) and supported by United States Department of State. Demonstrations of AgroAtlas include showing where in Crimea, a major wine-producing region, United States wine grapes can be successfully grown, as well as the distribution of major wheat diseases in the North Caucasus region according to agroclimatic zones. AgroAtlas, Ms. Greene notes, also has potential to aid in the detection and identification of insect weeds, pests or pathogens that have entered – or could enter – the United States from Russia or neighbouring countries.

Seeing rice with X-rays may improve crop yields

In the laboratory of Dr. Quin Liu in Wuhan at the Britton Chance Centre for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, China, rice plants were the patients in a novel use of computed tomography (CT) scanners as part of an agriculture study to increase rice yield. The non-invasive CT analysed tissues and matched their traits against a computer programme to aid rice breeders in selecting plants with the best rice tillers. Tillers are specialized grain-bearing shoots of the plant that determine grain yield and hence, are crucial to crop success. “In rice breeding, it is imperative that the traits of the tillers that result from hybridization or mutation are monitored and analysed accurately,” Dr. Liu explains. “This is so because with modern crop breeding methods using genetically modified organisms, it is possible to produce hundreds of new varieties daily. We need efficient techniques for screening the best plant material possible. Automating tillering by CT provided higher throughput, higher measurement accuracy and lower cost than other technologies previously used to measure the tillers on rice plants.”

New hybrids of rice to be unveiled soon

In India, Barwale Foundation, a non-profit organization founded by Mr. B.R. Barwale, is working to develop a new variety of rice that can grow without stagnant water. The new rice – aerobic rice – is in nascent stages of research. “Generally, 1 kg of rice requires nearly 5,000 litres of water. We are doing the research where ‘aerobic rice’ can be grown with less water. We have successfully grown some (of aerobic rice) at our centre,” said Ms. Neeru Jain, a scientist at the Foundation. Ms. Jain refused to divulge details of the crop, as it is in the preliminary stage of research. Mr. Barwale is the Chairman of Maharashtra Hybrid Seeds Company Ltd. (Mahyco), which too will introduce three new hybrid seeds this year for rice, wheat and tomato. All these new varieties of seeds will have early maturity, are less prone to pest attacks and offer better yield. Mahyco had earlier successfully launched Bt cotton and other hybrid seeds.

Genetic ‚Äėwiring‚Äô of seeds

Scientists have revealed the genetic ‘wiring’ that helps a seed decide the perfect time to germinate. Plant biologists led by Dr. George Bassel at the United Kingdom’s University of Nottingham have also discovered that the same mechanism that controls germination is responsible for another important decision in the life cycle of plants – when to start flowering. Their discovery throws light on the genetic mechanisms that plants use to detect and respond to vital environmental cues and could be a major step towards the development of new crop species resistant to climate change and would help future food security. The scientists compiled publicly available gene expression data and used a systematic statistical analysis to untangle the complex web of genetic interactions in the plant Arabidopsis thaliana, which is commonly used for studying plant biology. The resulting gene network called SeedNet highlighted what little scientists already know about the regulation of seed germination while being able to predict new regulators of the process with great accuracy.

Breakthrough in understanding how plants fight disease

New research by Ms. Wenbo Ma, a plant pathologist at University of California-Riverside (UCR), the United States, provides insights into how exactly bacterial pathogens cause diseases in plants. Ms. Ma performed research on the soybean plant to enhance the understanding of interactions of plant pathogens. This breakthrough research has shown that the bacterial pathogens target isoflavones, a group of compounds in plant cells that defends the plant from bacterial infection, resulting in a reduction in isoflavone production.

According to Ms. Ma, her results could be extrapolated to understand how plants defend themselves when pathogens attack. She is resuming research first started by UCR’s Mr. Noel Keen, the late plant scientist and a pioneer in molecular plant pathology, who did groundbreaking work on understanding how isoflavones and isoflavone-derived compounds play a role in defending plants when threatened with microbial infection. “We need to fully understand how isoflavones function to protect plants so that we can design specific strategies aimed at better protecting the plant,” Ms. Ma observed.

Improved plant boosts biofuel yield by more than one-third

Bioethanol from new perennial prairie grass lines could become less costly because of plant engineering carried out by the Samuel Roberts Noble Foundation and fermentation research at Oak Ridge National Laboratory in the United States. Researchers describe their transgenic version of switchgrass as one that produces about one-third more ethanol by fermentation than conventional switchgrass. This improved plant feedstock will be able to generate more biofuel per acre.

To achieve their goal, a team led by Mr. Zeng Yu Wang of the Samuel Roberts Noble Foundation chose to “downregulate” – a process that involves decreasing a cellular component – the caffeic acid 3-O-methyltransferase, or COMT, gene in the Alamo variety of switchgrass. This change decreased the plant’s lignin content by about one-eighth. This gene was chosen based on encouraging lignin modification observed in previous research conducted in alfalfa and other plants. What the team from the Noble Foundation ended up with was a switchgrass that is more easily converted to biofuels under milder conditions and with much less costly additions during fermentation. “The transgenic lines require lower temperature pre-processing and only one-quarter to one-third the level of enzymes for equivalent ethanol fermentation compared with the unmodified switchgrass,” observes Mr. Wang. This notably lowers the cost of biofuels and biochemicals from this switchgrass.


Patent Litigation in the Pharmaceutical and Biotechnology Industries

This book looks at the characteristics and strategies typically used in fighting multi-jurisdictional litigation within the pharmaceutical and biotechnology industries. In particular, patentability and the enforceability of biotechnological inventions are examined, as they remain one of the most fluid, commercially important and emotive topics in the patent industry. The publication reviews the current position of these issues in the biotechnology industry and report on likely developments. These include the United States gene patent litigation that brought to block gene patents in principle and also the reference currently pending before the Court of Justice in Europe that will determine the scope of protection provided under Article 9 Biotechnology Directive in relation to DNA-based patent claims. It also provides insight and opinion regarding the future of patent litigation in the European Union.

Contact: Biohealthcare Publishing Ltd., TBAC Business Centre, Avenue 4, Station Lane, Witney, Oxford OX28 4BN, United Kingdom. Tel: +44 (1993) 848 726; Fax: +44 (1865) 884 448; Website:

Stem Cell Engineering Handbook

Stem cell engineering holds great promise for scientists using stem cells for testing the safety and effects of new drugs, for the treatment of disease, as well as for the regeneration of injured tissues. This volume brings researchers from engineering, chemistry, physics and biology to discuss basic and advanced topics in this burgeoning field.

Contact: CRC Press, 6000, Broken Sound Parkway, NW, (Suite 300) Boca Raton, FL 33487, United States of America. E-mail:; Website:


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