VATIS Update Biotechnology . Jan-Feb 2005

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Biotechnology Jan-Feb 2007

ISSN: 0971-5622

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

Co-publisher: Biotech Consortium India Ltd
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World's first Bio-IT park

Software Technology Parks of India (STPI), under the Indian governments Department of Information Technology, intends to establish the worlds first Biotechnology-Information Technology (Bio-IT) park. The central government has invited proposals from interested state governments. States that can offer land at subsidized rates and extend best support would be chosen for setting up the Bio-IT park. Scheduled to come up on a 100 acre plot, the park will house a cluster of IT and life sciences industries, research institutions as well as science-technology academia to address IT related needs of the global life sciences industry.

The basic infrastructure facilities would include 90,000 ft2 of modern modular wet labs, independent plots for Bio-IT units, virtual networking with leading research institutions/universities/R&D laboratories through a grid network and high performance computational facilities. Scheduled to be developed as a public-private initiative, both the central and state governments would partner with the short-listed private developer to develop the park. The private partner will be the lead developer and would be responsible for planning, designing, construction, financing, marketing and operating the proposed park.

Chronicle Pharmabiz, 2 December 2004

Scientists overcome major hurdle in gene therapy

In India, scientists led by Prof. A.N. Maitra from the Department of Chemistry at Delhi University have created particles that can deliver desired DNA to the site in animals body where it is needed. This could prove to be a more effective delivery system than viruses in treating diseases. The new technology involves making nanoparticles and loading them with the gene of interest. The technology has been transferred to American BioScience Inc., a biotechnology company based in the United States.

It is known that gene therapy involves treating diseases by correcting defective genes, as in cancer, or killing invading virus, as in HIV. However, this method has not passed the experimental stage owing to the absence of an effective gene delivery mechanism. Though viruses have been used as gene carriers in experiments, the viruses envelope comprises proteins that elicit strong immunogenic reaction. The new technology utilizes small particles made up of calcium phosphate as gene carriers, which dissolve inside the cell to form pores in the nucleus wall and thus facilitate entry of foreign DNA into the cell.

The team investigated the potential of the new gene delivery system to treat cancer in animals. Increased efficiency nearly 1,000 times was observed in terms of production of ribonucleic acid (RNA) from gene than when other non-virus gene delivery mechanisms like liposome is used, with less gene being translated into the product. The new technology could be useful in developing therapies for diseases like AIDS as it has already been demonstrated that a kind of DNA can kill the virus. Only a suitable mechanism is required to introduce this DNA into cells.

Chemical Weekly, 28 December 2004

Brazil senate allows GMOs

In Brazil, a decree that permits planting of biotech seeds and sale of genetically modified crops in the current crop year has been approved by the nations Senate. Brazil deals with GMOs on an annual basis since permanent legislation is held up in the Brazilian Congress. Brazil is the only major agriculture exporting country in the world which does not have a permanent legislation regulating biotechnology.

While the new legislation is generally satisfactory for seed companies, there are a few provisions that may not go down well. According to one provision, farmers can only plant biotech seeds that have been saved from previous plantings on their own farm. This rule, in effect, prevents companies from collecting technology fees and actually rewards growers who had planted black market GMOs in previous years.


Clue to HIV origin in humans

In the United Kingdom, a team of scientists led by Dr. Jonathan Stoye of the National Institute for Medical Research has uncovered an important clue to help understand the origins of the AIDS epidemic. They have identified crucial differences in a gene present in rhesus monkeys that can prevent HIV infection while its human counterpart cannot. Only a single change to the human gene is needed to enable it to block HIV infection.

According to scientists, their work indicates that HIV would not have become established in the human population if mankind carried the same version of the gene found in rhesus monkeys. Dr. Stoye opines that this discovery has significant implications for the development of effective gene therapy to combat AIDS and it should be possible to take cells from an HIV-infected individual, make them resistant to HIV infection with the modified gene and reintroduce them into the patient. The altered cells could then block progression to AIDS. Alternatively, researchers could seek drugs that activate the human gene against HIV. However, scientists caution that any therapeutic benefits that may arise from their research are unlikely to be felt for many years since this type of gene therapy would involve removing white blood cells from patients, cloning them and modifying their genetic make-up before reintroducing them into the patient on an individual-by-individual basis. Although it is theoretically possible, this approach is unlikely to be practical or cost-effective with present technologies.


New research facilities slated for launch

The Centre for Cellular and Molecular Biology (CCMB), India, is setting up a 600 MHz biomedical magnetic resonance micro-imaging and spectroscopy facility along with a medical biotechnology centre at a total investment of about US$12-18 million. The two facilities are in addition to the new Laboratory for Conservation of Endangered Species, which is under construction. All the three facilities are expected to be commissioned in 2005. According to Dr. Lalji Singh, Director of CCMB, the new research centres would help in conducting investigations in biological systems in non-invasive methods, finding cures for diseases such as tuberculosis, AIDS and hepatitis and conserve endangered lions, tigers, cheetahs, leopards and bird species, respectively.

Micro-imaging and spectroscopy facilitate non-invasive monitoring of disease progression while high-resolution magnetic resonance spectroscopy would make it possible to study drug target interactions as well as monitor the drug response at metabolic, physiological and cellular levels. Such a facility would help reduce the number of animals used in preclinical trials.

Chronicle Pharmabiz, 9 December 2004

National stem cell initiative

India is drawing up plans for a national stem cell initiative to increase clinical applications of stem cell research and build links between scientists and medical doctors while prioritizing areas for research funding. Drafted by the Indian Council of Medical Research and the Department of Biotechnology, the plans include creation of a fund to boost stem cell research.

According to Prof. Dorairajan Balasubramaniam, former Director of the Centre for Cellular and Molecular Biology (CCMB) and the present Director of research at L.V. Prasad Eye Institute, India is especially interested in clinical applications of stem cells in ophthalmology, cardiology and spinal cord repair. India could take a lead in stem cell research, as it is among the few countries with clearly defined ethical guidelines and has initiated the so-called city clusters. A crucial objective of the national initiative is to promote stem cell city clusters, which would link all publicly and privately funded research groups within a city, thus enabling them to share facilities as well as research and business opportunities, and promoting interactions between researchers and clinicians.

In India, several major institutes are engaged in stem cell research, focusing on using stem cells to regenerate nerve, heart and adult muscle cells as well as repairing damaged bone tissue. For example, L. V. Prasad Eye Institute in Hyderabad has treated blindness using stem cells derived from the eye. In another instance, Vellore-based Christian Medical College plans to use stem cells derived from bone marrow to treat chronic liver failure and for regenerating tissues to treat heart diseases, traumatic brain injury and Crohns disease, a form of inflammatory bowel disease whose incidence is rising worldwide. Other centres for stem cell research include the National Centre for Cell Sciences (Pune) and National Brain Research Centre near Delhi.



Saket Bio to out-license NDDS of rh-insulin, hepatitis B vaccine

Saket Biotechnologies, India, will license out its NDDS technology for the oral delivery of proteins and peptides. This technology involves a unique carrier system that utilizes nano-particulate encapsulation of the drug using biopolymer linkers and vitamin B12 analogues. Developed together with the Indian Institute of Chemical Technologies (IICT), the technology has a United States patent to deliver insulin and hepatitis B vaccine through the oral route and is expected to be granted patents in the Patent Cooperation Treaty countries shortly.

Saket jointly owns the IPR and patent rights with the Council for Scientific and Industrial Research (CSIR) and has an agreement with CSIR, which gives it exclusive, perpetual and global marketing, sales, licensing and production rights over the NDDS and all associated intellectual property. The company has already completed animal safety, toxicity and bio-efficacy studies on the human recombinant insulin. Phase-I human trials are scheduled to be completed during the first quarter of 2005. Saket has mandated Frost and Sullivan, and APITCO to out-license the technology to a major pharma company.

Chronicle Pharmabiz, 13 January 2005

Shantha to launch DPT-hepatitis B vaccine

In India, Shantha Biotechnics will launch Diphtheria, Pertusis and Tetanus (DPT) + hepatitis B vaccine in addition to the DPT vaccine by March 2005. Shantha also plans to roll out hepatitis B + DPT + Haemophilus Influenzae Type b (Hib) vaccines by the fourth quarter of 2005. Dr. Varaprasad Reddy, Managing Director of Shantha Biotechnics, stated that the firms tetravalent and pentavalent vaccines would provide relief to children who are being administered with various vaccines separately. Combo vaccines will also be convenient to doctors who administer them. Shantha plans to export 75 per cent of these vaccines, with a majority going to UNICEF, to Africa, Far-East Asia, Russia and East European nations.

Shantha has established a state-of-the-art GMP compliant manufacturing facility near Hyderabad. This 80,000 ft2 facility commenced operation in September 2004 and has three production suites with an installed capacity of 300 million doses of each vaccine. Initially, the plant will produce only DTP vaccines. These antigens will be conjugated with the hepatitis B vaccine to make a combo DTP-hepatitis B vaccine. Formulation of the combo vaccine has been completed and production would start shortly.

Chronicle Pharmabiz, 23 December 2004

Pilot therapeutic protein manufacturing plant

Reliance Life Sciences (RLS), India, has set up a pilot facility to manufacture therapeutic proteins. The 50 l capacity plant will produce therapeutic proteins like streptokinase, interferon, erythropoietin and G-CSF till the cGMP manufacturing facility at its Rabale complex is commissioned by 2007. The Rabale facility will manufacture recombinant drugs/monoclonal antibodies and is being built as per the United States FDA (USFDA) requirements. The plant will also undertake contract manufacturing and research activities for overseas clients.

Additionally, RLS plans to introduce 30 high-end biotech drugs in the future, most of which would become generic over the next 5-6 years. The company will apply for USFDA certification for the recombinant drugs unit and target countries in Western Europe and the United States. RLS has already initiated research in the cell biology area, where dedicated groups are working on assisted reproduction, haematopoietic stem cells, embryonic stem cells, skin cells, tissue engineering, genetics and molecular diagnostics.

Chronicle Pharmabiz, 13 January 2005

Shantha introduces DNA recombinant product

Shantha Biotechnics, India, has launched its fourth DNA recombinant product Shanpoietin, an erythropoietin (EPO) product for anaemia treatment. According to Dr. Varaprasad Reddy, Managing Director of Shantha Biotechnics, Shanpoietin was developed indigenously and is based on serum-free culture technology. The gene for erythropoietin has been cloned in Chinese hamster ovary expression vector and expressed extracellularly. Shanpoietin will be marketed in pre-filled syringes.

Each year India has over 150,000 new cases of chronic renal failure. Half of these patients require dialysis or kidney transplantation, which is a huge financial burden. Anaemia is a major problem due to EPO deficiency; EPO is the mainstay for treating anaemia. According to Mr. Khalil Ahmed, Executive Director of Shantha Biotechnics, the market size for EPO in India is estimated at US$15 million per year. Studies indicate that 70 per cent of the EPO requirement is currently imported and Shanpoietin would help reduce Indias imports of EPO.

Express Pharma Pulse, 27 January 2005

Biotech incubation centre

Indias first biotech incubation centre coming up at Shapoorji Pallonji Biotech Park, in the state of Andhra Pradesh, is expected to be fully operational by March 2007. Initiated by the Department of Biotechnology (DBT), Department of Industries and Commerce, and the Council of Scientific and Industrial Research (CSIR), this project is being executed by the Indian Institute of Chemical Technology (IICT) with an investment of over US$4 million. The incubation centre will help in setting up pilot facilities to test biotech processes and develop them at bench-scale/pilot-scale level in addition to establishing technology. The processes could be based either on mammalian cell culture or microbial basis (rDNA and/or non-recombinant).

About twelve labs are planned to enable scientists/entrepreneurs create potential ideas with minimum investment. Micro level planning has already been carried out and by May 2005, orders for process equipment would be placed and procured within another six months from then. The lab facility will be ready by February/March 2006 and scientists/entrepreneurs could use the space and equipment from that period. Pilot plant facilities would be physically ready by July 2006 and for another nine months from then, IICT will evaluate the efficiency of these facilities and procure additional equipment as required. The pilot plant scale-ups would be such that processes can be tested at any give time. Scientists interested in conducting research may even be linked with venture capital funding firms. Talks with prospective venture capitalists are on.

Chronicle Pharmabiz, 27 January 2005


Super microbe's life code cracked

An international team of scientists has deciphered the complete DNA sequence of one of the most infectious germs known to humans. The bacterium Francisella tularensis is a candidate bioterror weapon, as it takes just 10 microbes to seriously infect humans. The bacterium causes a disease called tularaemia, or rabbit fever, in humans and animals and is high on the watch-list of biological agents experts. Humans can catch the disease either from tick, fly and mosquito bites or by inhaling airborne particles (aerosols). The World Health Organization estimates that airborne dispersal of 50 kg of F. tularensis over an urban area with five million inhabitants would kill 19,000 people and incapacitate a further 250,000.

The team reports to have already picked out protein targets useful for creating a vaccine. Also, an unusual cluster of genes thought to be involved in causing illness has been uncovered. These genes have never been seen in another living organism and scientists do not yet know how F. tularensis acquired them or how they work. Prof. Richard Titball of the Defence Science and Technology Laboratory (DSTL), the United Kingdom, opines that the presence of the unusual cluster of genes may suggest that the microbe has hitherto unknown ways of causing disease. It is hoped the sequencing work, which took five years to complete, will kick-start a worldwide bio-defence programme for F. tularensis, ultimately leading to the development of new vaccines and diagnostic tools.


Chromosome 16 sequenced

In the United States, the Department of Energys (DOE) Joint Genome Institute (JGI) has published the DNA sequence and analysis of chromosome 16. JGI is the first of five primary Human Genome Project sequencing sites, known as the G5, to publish scientific articles describing each of the human chromosomes that they originally agreed to sequence. Chromosome 16 comprises 78.8 million bases and is home to 880 genes, including those implicated in the development of breast and prostate cancer, Crohns disease and adult polycystic kidney disease.

JGI researchers characterized the many regions on chromosome 16 that have been copied to other places within the chromosome and even to the other chromosomes, a phenomenon known as segmental duplication. These were then compared with regions conserved over time in other vertebrate genomes, including chimpanzee, dog, rat, mice, chicken and puffer fish to reveal changes that have occurred since the last common ancestor, ranging from 5 to 400 million years ago. The effort to sequence chromosome 16 involved more than 100 researchers led by Mr. Joel Martin and Mr. Len Pennacchio. DOEs commitment entailed chromosomes 5, 16 and 19, all sequenced by JGI, representing 11 per cent of the human genome.


New gene in colon cancer discovered

In the United States, a team of researchers has found a Celebrex-like gene that suppresses the growth of colon cancer. Named 15-PGDH, the gene is found in normal cells but is virtually undetectable in colon cancer cells. It was observed that 15-PGDH acts as an antagonist to control an enzyme called COX-2. An increase in COX-2 is a major early event in the genesis of human colon tumours. When researchers restored the gene in tumour cells and injected them back into immune-deficient mice, the subjects exhibited little or no tumour development. The team included researchers from the Ireland Cancer Centre at University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Howard Hughes Medical Institute, University of Kentucky and Protein Design Laboratories.

Previous studies have shown that patients who take non-steroidal anti-inflammatory drugs, which are COX-2 inhibitors, have a lower incidence of colon cancer. COX-2 inhibitors have been shown to shrink the size of tumours in mice. Celebrex is a popular arthritis drug, which is also a COX-2 inhibitor. 15-PGDH has been likened to a naturally occurring COX-2 inhibitor. In the absence of 15-PGDH, uncontrolled COX-2 goes on to cause abnormal changes on the cellular level, which may lead to tumour development. Scientists found that 15-PGDH is directly controlled and activated by another gene called TGF-beta. Normally, TGF-beta sends a signal that allows the colon to shed cells weekly as a way of helping to block development of colon cancers. If there is no TGF-beta signal, there is no 15-PGDH. This implies that the opponent to COX-2 is gone and COX-2 oncogene activity is unopposed. This interaction between TGF-beta and 15-PGDH points to the importance of TGF-beta system in suppressing colon cancer. These genes could be targets for the development of new drugs or gene therapies that may help treat or prevent colon cancer.


Key brain genes mapped

In the United States, researchers led by Dr. Quifu Ma at Dana-Farber Cancer Institute have charted a key network of gene switches in the brain which could aid neurological investigations. These gene regulators monitor the development of various parts of the brain. Created using mouse brains to pinpoint the genes, the map also applies to human brains. This effort is expected to help analyse conditions like brain tumours, linked to mutations in these genes. Tumours and other neurological diseases occur because of mutations in these key genes, called transcription factors (TFs). This leads to a chain reaction, with other genes that they control going awry and causing abnormalities in the development/function of nerves and related structures. TFs direct the formation of neurons and supporting cells called glia from early stage progenitor cells.

Researchers isolated all mouse genes that appeared to be TFs: more than a thousand were expressed in the brains of developing mice. Genetic probes used to investigate thin sections of mouse brains revealed that only 349 of the TF genes were expressed in specific regions, rather than throughout the brain, like the rest. The team concluded that these genes controlled the development of particular areas or structures in which they were uniquely expressed. The TF map will help establish which TF genes regulate the development of which particular brain region and therefore which of them to investigate as possible causes of brain tumours and other diseases. The team is already examining TF genes that regulate nerves involved in pain sensation, specific brain tumours and speech problems caused by abnormally developing motor neurons that control muscles of the tongue.


HIV gene improves AIDS vaccine

Researchers in the United States report that an artificial HIV-1 gene may help develop better AIDS vaccines. Created by scientists at Duke University Medical Centre, the artificial gene is engineered to be similar to many genetic sub-types of the worlds most common strains of HIV-1. According to Dr. Feng Gao, one of the researchers, variations among HIV-1 sub-types make vaccine development very difficult. Centralized genes, designed using computers, may be useful in developing vaccines for areas where different HIV-1 sub-types are circulating. However, since centralized genes are artificially made, there has been great concern that these genes might not be able to perform the biological functions of native genes.

The team found that the artificial gene produces a protein that works just like the natural HIV-1 proteins, binding to surface molecules on the human immune system cells which are the primary portals by which HIV-1 enters and infects cells. It was also observed that antibodies in blood from humans infected with different HIV-1 sub-types reacted with the protein better than wild type proteins. Additionally, in guinea pigs the protein induced neutralizing antibodies against some HIV-1 strains, although the level was weak, while in mice, vaccines made with the gene induced an anti-HIV-1 response in T cells. It has thus been shown that both cellular and humoral immune responses could be induced using an artificial HIV-1 gene.


RNA molecules more influential than previously thought

Mr. David Bartel and colleagues at the Whitehead Institute for Biomedical Research in the United States report that more than a third of human genes may be controlled by minuscule molecules called microRNAs. The team built a computer algorithm, which scours messenger RNAs from human genes for characteristic genetic sequences, ones that show they are likely targets of microRNAs. This suggests that the molecules, which were first discovered in 2000, could play a role in almost every process from cell birth to cell death, and may even be useful in treating human diseases. The discovery also supports the idea that when microRNAs go awry they may trigger anomalies such as the uncontrollable cell division that is typical of cancer.

MicroRNAs are similar to DNA fragments and comprise around 22 chemical letters, which act as controls by effectively blocking a gene from doing its normal job in a cell. When a gene is switched on, its sequence is transformed into messenger RNA, which carries the information to make a protein. MicroRNAs recognize and bind to particular messenger RNAs and stop them from making proteins.


Gene found to defend against environmental pollutants

In the United States, researchers led by Dr. Shyam Biswal at Bloomberg School of Public Healths Department of Environmental Health Sciences, have identified a master gene in mice that controls the action of 50 other genes whose products protect the lungs against environmental pollutants. Named Nrf2, the master gene is activated in response to environmental pollutants, e.g. cigarette smoke, and then turns to numerous antioxidant and pollutant-detoxifying genes to protect the lungs from developing emphysema. The Nrf2 gene has now been identified as the key player in protection even in the case of chronic exposure to pollutants.

Earlier Dr. Biswal and colleagues had demonstrated the activation of Nrf2 in response to an anti-cancer agent Sulphoraphane, but little was know about Nrf2 regulated genes and the role they play in lung inflammatory diseases brought on by chronic exposure to environmental agents. The researchers were able to pinpoint the gene that controlled the natural defence mechanism by exposing mice to cigarette smoke. Through gene chip analysis, they identified 50 Nrf2-dependent antioxidant and cytoprotective pulmonary genes that work together to protect lungs from cigarette smoke-induced emphysema, which is a dominant manifestation of chronic obstructive pulmonary disease (COPD). The discovery of the Nrf2 gene could help identify people who are genetically predisposed to developing lung diseases.

Chemical Weekly, 21 December 2004


Malaria parasite modified to prevent future infection

A research team led by Dr. Ann-Kristin Mueller of the Heidelberg University School of Medicine, Germany, has in principle proved that deletion of a single gene could be enough to create a form of malaria parasite that is unable to affect human health. By modifying the genes of a form of the parasite that causes malaria in rodents, the team was able to prevent it from moving from the rats liver to their blood stream. Once in the blood stream, the parasite normally enters red blood cells, causing symptoms of the disease. The parasite was trapped in the liver by knocking out one of the parasites genes that earlier research had suggested was important at the infective stage of the parasites life cycle.

The weakened parasite may be used as a vaccine, thereby giving the immune system a window of opportunity to develop the ability to recognize and repel future infections of normal malaria parasites before they could pose threats to health. To confirm the potential of this line of approach, researchers infected rats with normal malaria parasites after first injecting them with the genetically modified (GM) version. It was observed that the rats stayed healthy even when infected with 50,000 parasites two months after receiving the third of three doses of the GM parasites. According to Dr. Mueller, the next step would be to target the same gene in a human form of malaria, and study how the human immune system deals with the modified parasite. Understanding the role of the deleted gene could also be equally relevant.


Stem cell switch lurking within leukaemias unearthed

In the United States, specific cancer-causing genes that can transform mature white blood cells into leukaemic cells with all the properties of stem cells have been discovered. The research team, led by Dr. Gray Gilliland at Howard Hughes Medical Institute, included investigators from Brigham and Womens Hospital and Harvard Medical School. The team unveiled that certain leukaemia oncogenes could commandeer and switch on genetic programmes that govern self-renewal, a unique characteristic of stem cells. The findings may also help explain why the cancer drug Gleevec, which targets the BCR-ABL enzyme, does not cure the disease but only puts it into remission. Previous studies had established that leukaemia and some other cancers are not made up of a homogeneous population of cells. Dr. Gilliland and his team investigated the differences between two abnormal chromosomal rearrangements deemed capable of imparting the ability to self-renew.

The cancer genes cause leukaemia in white blood cell progenitors that have already been committed to become a particular type of blood cell, and are therefore no longer self-renewing stem cells. The team studied BCR-ABL, the most common genetic mix-up in chronic myeloid leukaemia, and MOZ-TIF2, an abnormal genetic rearrangement that causes acute myeloid leukaemia (AML). These abnormal genes were introduced into normal progenitor cells and the ability of the resulting cells to self-renew was tested. It was observed that only MOZ-TIF2 could cause normal progenitor cells to assume the properties of leukaemic stem cells, most importantly, the ability to self-renew. MOZ-TIF2 could cause AML in any progenitor cell type, in both cell cultures and mice. In contrast, BCR-ABL was unable to trigger such proliferation by itself.

Express Pharma Pulse, 30 December 2004

Vaccine enables recovery of immune system in AIDS patients

A team led by Dr. Rivka Abulafia-Lapid of Hadassah University Medical Centre, Israel, has developed a vaccine that significantly strengthens the bodys immune system against the autoimmune after-effects of HIV infection. Researchers found that although treatment with the widely used AIDS cocktail of medications kills HIV, the immune system continues to kill healthy cells. This effort focused on developing a vaccine to arrest the autoimmune destructive process. The study involved seven patients and was conducted during 1998-2002, with an additional two-year monitoring period.

HIV infects a type of white blood cells called CD4, which is an integral part of the bodys immune system. As HIV attacks and destroys CD4 cells, the weakened immune system is less efficient at fighting off infections and diseases. Researchers have identified that CD8 cells are responsible for destroying CD4 cells. At this stage, preparation of the vaccine involved neutralization of CD8 cells and preparation of portions of ten million cells each to be used by injection under the skin in order to trigger a vaccination against the harmful cells. Patients were treated with the new therapeutic vaccine, each receiving 3-4 injections over a six month period. After the treatment, the patients CD4 cell counts were monitored to determine if the number of CD4 cells increased in the peripheral blood, and subsequently, reinforced the strength of the immune system. CD4 cells increased by over 50 per cent in five of the seven patients.


New network of gastro-intestinal immune cells discovered

Researchers, led by Dr. Hans-Christian Reinecker, at the Centre for the Study of Inflammatory Bowel Diseases at Massachusetts General Hospital, the United States, have identified a new network of gastro-intestinal immune cells in mammals. The discovery could help scientists better understand how the immune system identifies and reacts to dangerous bacteria and viruses. This knowledge could lead to the development of new vaccines and treatments for gastro-intestinal diseases.

The team uncovered in mice an extensive system of immune cells throughout the intestinal tract that takes up bacteria and other antigens. It was hitherto believed that there were only a limited number of gastro-intestinal dendritic cells, which were confined to specific areas. Researchers identified populations of dendritic cells throughout the small intestine, in a layer just below the epithelial lining. Dendritic cells are found in tissues skin, lungs and digestive system which come into direct contact with the external environment. A key feature of these cells is that they constantly scan for bacteria and viruses. When dangerous bacteria or viruses are detected, the cells ingest them, break them down and mark the protein fragments for destruction by other immune cells.

According to Dr. Reinecker, this is a new way for the immune system in the gastro-intestinal tract to monitor and interact with the environment. Insights into these mechanisms could lead to a better understanding of conditions like Crohns disease and ulcerative colitis, intestinal infections and food allergy. Researchers hope that by targeting these dendritic cells it may be possible to develop new types of vaccines. Dr. Reinecker states that it is also possible that some of the gastro-intestinal bacteria and viruses, which cause some serious illnesses, may co-opt the activity of these cells to evade some immune defences and enter the body.


Antibiotic-resistant bacterium uses sonar-like strategy to see

In the United States, researchers led by Dr. Michael Gilmore have uncovered that bacteria employ a sonar-like system to identify other cells (either normal body cells or other bacteria) and mark them for destruction. This finding explains how some bacteria know when to produce a toxin that makes infection more severe, which may lead to new toxin inhibitors. By blocking or interfering with a bacteriums detection mechanism, it would be possible to prevent toxin production and limit the severity of infection.

Dr. Gilmore and his team studied Enterococcus faecalis bacterium, one of the leading causes of hospital-acquired infections that are frequently resistant to most, and sometimes all, antibiotics. It has been known since 1934 that especially harmful strains of Enterococcus manufacture a toxin that destroys other cells, including human cells and other types of bacteria. Moreover, the toxin is produced only under some conditions, e.g. whenever another cell type is present in the environment near the bacterium, like a human blood cell. In the laboratory, the team found that Enterococcus releases two substances into the environment. One substance sticks to foreign cells while the other reports back and signals the organism to make the toxin. If no cells are in the area, the first substance sticks to the second, preventing it from reporting back to the Enterococcus strain, and as a result, no toxin is made.

According to Dr. Gilmore, these bacteria actively probe their environment for enemies or food and based on whether or not they see other cells, they make the toxin appropriately. Dr. Gilmore opines that this discovery will help scientists to develop new methods to treat infections that are resistant to antibiotics, making them less severe. Based on an understanding of the mode and action of the toxin system, new toxin inhibitors could be developed.


Embryonic stem cells perform quality control inspections!

Researchers led by Dr. Yang Xu at the University of California, the United States, have found a fundamental mechanism used by embryonic stem cells to assure that genetically damaged stem cells do not divide and pass along the damage to daughter stem cells. This discovery solves the long standing mystery of how embryonic stem cells, which have the potential to divide an unlimited number of times and differentiate to form any cell type in the body, are able to avoid duplicating cells that have sustained genetic damage. DNA damage can occur during normal cellular propagation as well as after exposure to DNA-damaging radiation and chemicals. It is critical for embryonic stem cells to develop stringent mechanisms to ensure the repair of DNA damage and prevent transition of DNA damage to their daughter cells. Unrepaired DNA damage will cause genetic instability and, ultimately, cellular transformation into cancer cells.

Dr. Xus team made this discovery while working with embryonic stem cell lines from mice, which possess the same known traits and capabilities as human embryonic stem cells. The team found that a protein known to play a critical role in the suppression of tumours in both humans and mice, p53, is also used to maintain the genetic stability of embryonic stem cells. The p53 protein, activated by DNA damage in mouse embryonic stem cells, directly suppresses the expression of a gene called Nanog, which is necessary for the self-renewal, or unlimited duplication, of stem cells. Suppression of Nanog promotes embryonic stem cells to differentiate into other cell types. The end result of all these actions is to deprive embryonic stem cells with damaged DNA the ability to self-renew. The p53 protein also contributes to the eventual elimination of DNA damage in embryonic stem cells that have already differentiated into specific cell types, thus preventing the development of cancerous cells. These findings provide a base for future studies involving human embryonic stem cells regarding how these cells maintain genetic stability during self-renewal.



Toxic proteins affect memory

A team led by Dr. William L. Klein, a Professor of neurobiology and physiology at Northwestern University, the United States, has discovered a molecular mechanism that could explain why brain damage in early Alzheimers disease results in memory loss and not other symptoms like loss of balance or tremors. The team found that toxic proteins, called amyloid -derived diffusible ligands (ADDLs), from the brain tissue of individuals with Alzheimers disease specifically attack and disrupt synapses, the nerve cell sites responsible for information processing and memory formation. Dr. Klein and colleagues were the first to discover and report the presence of ADDLs in humans. They found up to 70 times more toxic proteins in the brain tissue of individuals with Alzheimers disease compared with that of normal individuals.

ADDLS are small, soluble aggregated proteins. Clinical data support a recent theory according to which ADDLs accumulate at the beginning of Alzheimers disease and block memory function by a process predicted to be reversible. Although both are a form of amyloid beta, ADDLs and their properties differ significantly from the amyloid fibrils (known as plaques) that are a diagnostic hallmark of Alzheimers. ADDLs found in human brains, mostly 12 or 24 amyloid beta proteins clumped together, are tiny and undetectable in conventional neuropathology; fibrils are much, much larger. While fibrils are immobile toxic waste dumps, ADDLs are soluble and diffuse between brain cells until they find vulnerable synapses.

According to researchers, ADDLs bind to some synapses and not others, which is a very specific attack. At the vulnerable synapses there is a gene, called Arc, linked to memory and is normally expressed. When ADDLs attack the synapses, they disrupt the normal expression of this gene, which results in memory loss. Over-expression of the Arc gene has been linked to dysfunctional learning in previous studies on memory. In this study, researchers used ADDLs obtained from human brain tissues as well as those synthesized in the laboratory. Tests have demonstrated that all the ADDLs, regardless of origin, exhibit the same pattern of binding to synapses on specific neurons. A key feature is that ADDLs disrupt the neurons ability to communicate with each other without killing them. Subtle changes were observed in the Arc gene after just five minutes of exposure to ADDLs, and these changes were sustained for an unexpectedly long time. An understanding of how ADDLs disrupt synapses without actually killing neurons could lead to the development of new therapeutic drugs capable of reversing memory loss in patients, who have been treated earlier, in addition to preventing or delaying the disease.


Malaria secretome uncovered

Two different research groups have identified a general export signal required for the secretion of Plasmodium proteins into host erythrocytes and defined the exported proteome or secretome of Plasmodium falciparum, a major malaria parasite. The life cycle of the malaria parasite involves developmental stages in both the mosquito vector and humans. During the asexual blood stage, P. falciparum propagates in human erythrocytes confined within a membrane-bound vacuole known as the parasitophorous vacuole. To create a suitable niche for its survival and multiplication, the parasite induces extensive remodelling of the erythrocyte membrane and cytoplasm. A variety of malaria proteins has already been identified as secreted proteins. For a sub-set of these, it was known that not only was an amino-terminal signal sequence involved but that an additional targeting sequence downstream of the signal sequence was also important. The groups have independently identified the specific motif essential for the parasite to secrete proteins into erythrocytes.

Researchers in one group aligned sequences of the N-termini of ten known secreted Plasmodium proteins and were able to identify a conserved five-residue motif, RXLXE/Q, which they named Pexel, for Plasmodium export element. The other group used a different bioinformatics approach, multiple expectation maximization for motif elicitation (MEME) analysis, and identified a motif that, at 11 residues, was longer than that identified by the first group, but which contains the Pexel motif at its core. To determine the functionality of Pexel motif, the team created fusion proteins comprising the N-terminal regions of soluble exported proteins and green or yellow fluorescent protein. The team showed that when the Pexel motif is deleted or truncated, the fusion proteins are not exported but accumulate within the parasitophorous vacuole. Similar experiments were also carried out with membrane-bound surface proteins, and the Pexel motif was found to be essential for export.

The research teams have defined the P. falciparum secretome, which is the full complement of proteins that are secreted into host erythrocytes. The number of putative erythrocyte-targeted proteins identified varies between the two groups, from approximately 320-400. The identified proteins comprise many known secreted proteins, including members of the Rifin/Stevor superfamily, but also up to 150 proteins that are yet to be identified. Also, the identified proteins include proteins from other stages of the parasites life cycle, perhaps indicating that the export motif could target proteins into a variety of host cell types. Both groups also found that the export signal was conserved in other Plasmodium species. As yet, the putative translocon remains unidentified. The two separate studies have identified the specific sequence motif that allows the malaria parasite to export a vast array of remodelling and virulence proteins into human erythrocytes, thus facilitating its survival and multiplication. As the motif is conserved across Plasmodium spp., it would be of potential interest as a target for new antimalarial strategies.


Fundamental question of cell death answered

Dr. Chunying Du, Assistant Investigator at Stowers Institute of Medical Research, the United States, has published findings that reveal a previously unknown pathway of Bruce, the gene encoding a protein that inhibits apoptosis or programmed cell death. This discovery answers the fundamental question of apoptosis and has implications for a wide variety of diseases. Bruce has long been recognised as an inhibitor of apoptosis, however, its method of inhibition was not clear.

Dr. Du analysed Bruce mutant mice and found that Bruce regulates p53, a tumour suppressor gene, and the mitochondrial pathway of apoptosis. Bruces primary function resides upstream of the mitochondria. Loss of function of Bruce increases the level of p53, making cells more sensitive to apoptosis. The transcriptional activity of p53 is responsible for the activation of genes including Pidd, Bax and Bak which in turn activate the mitochondria, leading to apoptosis. According to Dr. Du, identification of Bruce as a regulator of p53 raises the possibility that therapeutic inactivation of Bruce activity could keep p53 levels high in order to combat certain tumours. As such, over-expression of Bruce may help maintain cell survival in neurodegenerative diseases like Alzheimers.


Plant protein mimics weight-loss hormone

In the United States, a team of researchers led by Dr. Ray Bressan at Purdue University has found that a common protein which protects plants from fungal infection mimics the activity of a hormone in mammals that is linked to weight loss and believed to play a role in mitigating heart diseases, obesity and diabetes. The protein, called osmotin, belongs to a large, diverse family of proteins that defend plants from fungal pathogens. Dr. Bressans team found that a protein in mammal muscle cells called a receptor, which normally binds to the hormone adiponectin, also binds osmotin. They also found that the plant-derived osmotin activates receptors in mammals in the same manner as adiponectin. Both adiponectin and osmotin jump-start a process called AMP kinase phosphorylation, which increases both sugar and fat use by muscle cells. When bound to its receptor, adiponectin regulates sugar uptake and, in mouse models, prevents the development of diabetes and atherosclerosis. Previous studies have shown that people with diabetes tend to have lower levels of adiponectin in their blood than non-diabetics. In addition, adiponectin levels tend to be lower in obese individuals and patients with heart disease than in healthier individuals.

In the current study, researchers looked at how osmotin functioned in yeast and also assessed how osmotin acted in adiponectin receptors in a culture of mouse muscle cells. Researchers determined that activation of the osmotin receptor in yeast killed yeast cells by inducing apoptosis or programmed cell death. Thus, a screen to look for compounds that activate this receptor could simply rely on finding out which compounds kill yeast cells by the same process. Furthermore, by binding to the adiponectin receptor, osmotin, like adiponectin, could control the energy status of muscle cells. Adiponectin could also kill some types of mammalian cells. Other studies have shown a strong correlation between low levels of adiponectin and increased risk of breast cancer. Whether osmotin also has a similar lethal effect on other mammalian cell types remains to be seen. However, osmotin, when bound to its receptor on yeast cells, does kill those cells.


Study pinpoints proteins role in heart failure prevention

A research group headed by Dr. Cam Patterson at North Carolina University, the United States, has shown that a protein in cardiac muscle cells may play a crucial role in preventing heart failure. The muscle-specific RING finger 1 protein (MuRF1), helps regulate cardiac cellular molecules involved in abnormal enlargement of the human heart. This condition, known as cardiac hypertrophy, occurs in 50-60 per cent of people older than 70 years and makes them more prone to developing a potentially fatal type of heart failure. Cardiologists consider cardiac hypertrophy as one of the most potent predictors for heart failure and arrhythmia, or abnormal heart rhythms.

Researchers uncovered that the protein MuRF1 is responsible for signalling other molecules in heart cells to degrade a protein called troponin-1, a critical component of the cardiac contractile machinery that makes heart muscles beat. When heart cells hypertrophy, or become enlarged, troponin-1 and other contractile proteins greatly increase in abundance. It has been known for some time that contractile proteins are degraded but the specific molecules involved were not defined till now. MuRF1 reverses hypertrophy by degrading proteins such as troponin-1. Thus, the action of MuRF1 appears to determine the balance between hypertrophic (enlargement) and anti-hypertrophic signals in heart muscle cells.

The team believes that their findings may lead to new drugs to reverse hypertrophy by targeting the ubiquitin ligase signalling pathways in cardiac cells.

Contact: Dr. Cam Patterson, the United States. Tel: +1 (919) 8436 477;



Key proteins associated with ageing and cancer identified

Researchers led by Dr. Peter D. Adams at Fox Chase Cancer Centre, the United States, have found that the composition and assembly of key chromosomal protein complexes are involved in shutting down reproduction of ageing cells. Most normal cells undergo a limited number of cells divisions but are eventually arrested, either through final differentiation or senescence. Senescence and differentiation both involve reorganization of the chromatin structure. Previous studies have shown that as cells reach senescence, a change in the chromatin structure called senescence-associated heterochromatin foci (SAHF) silences the genes that promote cell growth. SAHF are domains of densely packed chromatin which repress the activity of genes that normally drive cell proliferation.

The team has identified at least three proteins that contribute to the formation of SAHF, namely HIRA, ASF1a and PML. PML, named after acute promyelocytic leukaemia, suppresses the formation of this cancer, but the reason was not known. The new research suggests the possibility that this cancer arises because PML is unable to do its job in forming SAHF. If so, then extrapolating from recent findings in other cancers, inactivation of PML, HIRA, ASF1a and formation of SAHF could also contribute to other human cancers.

Express Pharma Pulse, 13 January 2005


Biofortification of groundnuts

A research programme aimed at enhancing -carotene in groundnuts has been launched by the International Crops Research Institute for the Semi-Arid Tropics (ICRISAT), India. This research is a part of a global challenge programme of the Consultative Group for International Agricultural Research (CGIAR) aimed at biofortification of crops to combat malnutrition due to the deficiency of nutrients like iron, zinc and vitamin A in food crops. ICRISAT is one of 15 international agricultural research institutes affiliated to CGIAR.

According to Dr. K.K. Sharma of ICRISAT, this research would help combat vitamin A deficiency in malnourished people, particularly women and children across the globe. A major portion of the malnourished live in the semi-arid tropics. Tissue culture and transformation methods have been optimized to obtain high frequency (80-90 per cent) shoot regeneration from cotyledon and leaf explants of groundnut. This technology is now being used to produce new transgenic groundnuts with higher levels of -carotenes. Scientists hope that such groundnuts would form an important genetic base for incorporating resistance into other biotic and abiotic constraints to the productivity of this important crop of the semi-arid tropics.

While vitamin A is present only in animal products, its predecessor -carotene or provitamin A is found in several plant species. However, these are not taken up easily from digested food, because they are fat-soluble and their bioavailability depends on the presence of fat or oil in the same meal, failing which they are excreted undigested. Oral delivery of vitamin A is problematic mainly because of the lack of infrastructure, thus necessitating an urgent need for alternatives.


Rice genome decoded

An international team of scientists from ten nations has completed sequencing the rice genome, an accomplishment that should lead to the development of new rice varieties to meet different needs, including resistance to disease. The international team included researchers from the United States, Taiwan, Thailand, China, Republic of Korea, India, France, the United Kingdom, Brazil and Japan. Rice used for the research was a Japanese variety called Nippon Bare. The team found an estimated 40,000 genes in this strain.

Dr. Takuji Sasaki, head of the Japanese team in this international effort, stated that researchers completed mapping some 370 million out of 390 million base pairs, or 95 per cent of the genome, with an accuracy of 99.99 per cent. It is expected that this research will contribute to the identification of useful genetic functions and lead to rapid improvement of crop varieties and an increase in food production. The results could also be used for the production of new varieties of maize and wheat that have features similar to rice in their genetic maps.

Japan Times, 14 December 2004

Key gene in the development of maize plants identified

Prof. Robert J. Schmidt and colleagues at the University of California, the United States, have identified a gene that appears to have played a critical role in allowing the earliest plant breeders 7,000 years ago to transform teosinte, a wild grass that grows in the Mexican Sierra Madre, into maize, the worlds third most planted crop after rice and wheat. Researchers reported their discovery of a gene that regulates the development of secondary branching in plants, presumably permitting the highly branched, bushy teosinte plant to be transformed into the stalk-like modern maize.

According to the team, the presence of numerous variants of this gene in teosinte but only one variant of the gene in all inbred varieties of modern maize yields evidence that Mesoamerican crop breeders most likely used this trait in combination with a small number of other traits to selectively transform teosinte to maize. This gene is critical for branching to occur in maize, including branches that give rise to the ears of corn. The team presumed that there was something unusual in the morphology that the early farmers selected from wild teosinte that made it easier for them to plant, grow or harvest their crops. The gene now identified could provide important clues to what genetic traits the crop breeders focused on when they transformed teosinte to maize.

The gene cloned by scientists is called barren stalk1 because when the gene product is absent a relatively barren stalk results, one with leaves but without secondary branches. In maize, these secondary branches include female reproductive parts of the plant, or ears of corn, and the male reproductive organ, or tassel. While teosinte has several tassels and tiny ears in its highly branched architecture, maize has only one tassel and fewer, but larger, ears. This suggests that the limitations to branching imposed by some combination of the barren stalk1 and other genes that were selected by the early plant breeders allowed genetic mutants of teosinte to concentrate more of the plants resources into producing bigger ears.

Dr. John Doebley, a professor of genetics at the University of Wisconsin-Madison and an expert in the evolution of teosinte to maize, found that the barren stalk1 gene was located in one of five regions of the maize genome known to be crucial in the breeding of teosinte to maize. His team uncovered that many variants of the gene existed in teosinte, yet only one was incorporated into modern maize inbreeds. This led them to conclude that targeted selection of this particular barren stalk1 variant was likely an important addition to the traits responsible for the development of modern maize.


Chemicals in cherries may help fight diabetes

In the United States, researchers led by Dr. Muralee Nair, a natural products chemist at Michigan State University, have identified a group of naturally occurring chemicals abundant in cherries that could help lower blood sugar levels in people with diabetes. In early laboratory studies using animal pancreatic cells, chemicals called anthocyanins increased insulin production by 50 per cent. The current study involves tart cherries (also known as sour cherries or pie cherries), a popular variety in the United States, and Cornelian cherry, which is widely consumed in Europe. The cherry anthocyanins show promise for both prevention of type 2 (non-insulin-dependent) diabetes and controlling glucose levels in those who already have diabetes.

Anthocyanins are a class of pigments responsible for the colour of many fruits, including cherries. They also are potent antioxidants, highly active chemicals that have been increasingly associated with a variety of health benefits, including protection against heart disease and cancer. The team developed a unique process, which has been patented by the university, for removing sugar from fruit extracts that contain anthocyanins. This could lead to sugar-free medicinal products for people with diabetes. Dr. Nair and his colleagues are currently feeding anthocyanins to a group of obese, diabetic mice to determine how the chemicals influence insulin levels in live subjects and results of these tests are awaited. According to the team, it is possible that consumption of cherries and other fruits containing anthocyanins could have a significant impact on insulin levels in humans.


Protein-rich potato developed

A genetically engineered protein-enriched potato developed by Dr. Asis Datta at the National Centre for Plant Genome Research of Jawaharlal Nehru University, India, is being readied for commercial field tests. Named protato pro from protein and tato from potato this variety contains up to 35 per cent more protein than the normal type. This is because scientists isolated the gene responsible for protein synthesis in the amaranth plant and introduced it into potato, thereby increasing the tubers protein content.

Potato is a starch-rich tuber containing barely 1 per cent protein while the amaranth plant has nutrition-rich leaves and seeds used for culinary purposes. Dr. R.B. Singh, a member of the National Commission of Farmers, opines that as protato contains proteins similar to those in the amaranth plant, negative effects are not likely. The Review Committee on Genetic Manipulation, Department of Biotechnology, has cleared the product.


Vitamin E in plant seeds could halt prostate and lung cancers

In the United States, scientists from the College of Consumer and Family Sciences, and Childrens Hospital Oakland Research Institute have found that gamma-tocopherol a form of vitamin E that occurs naturally in walnuts, pecans, sesame and corn inhibits the proliferation of lab-cultured human prostate and lung cancer cells. Presence of the vitamin interrupted the synthesis of fatty molecules called sphingolipids, which are important components of cell membranes. However, the gamma-tocopherol left healthy human prostate cells unaffected, which could give it value as an anticancer agent. According to team leader Dr. Qing Jiang, this is the first time that gamma-tocopherol has been shown to induce death in lab-grown human cancer cells while leaving healthy cells alone.

Earlier research by Dr. Jiang and colleagues had revealed that gamma-tocopherol inhibits inflammation, which has already been implicated in cancer development. Theorizing that it might retard the progress of cancer and cardiovascular disease, the team evaluated their hypothesis by exposing cultures of cancerous prostate and lung cells to the vitamin. Normal prostate epithelial cells were used as a control group. It was observed that as the quantity of gamma-tocopherol increased, the growth of cancer cell growth became slower while the growth of normal prostate cells was unaffected. This indicates that the vitamin could be employed to target lung and prostate cancer cells without the damaging side effects of chemotherapy. The study also revealed that gamma-tocopherol caused cell death by interrupting sphingolipid synthesis. However, as most nutritional supplements contain only alpha-tocopherol, a different form of vitamin E that alone does not have these anticancer properties, it may be better to supplement the diet with mixed forms of vitamin E. Dr. Jiang also cautioned that foods rich in gamma-tocopherol are also rich in fats and some products brought other hazards as well.



Molecular Biotechnology: Principles and Applications of Recombinant DNA

Completely revised and updated, this second edition covers the underlying scientific principles as well as the wide-ranging industrial, agricultural, pharmaceutical, and biomedical applications of recombinant DNA technology. Ideally suited as a text, this is also an excellent reference book.

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The Biotech Investor: How to Profit from the Coming Boom in Biotechnology

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