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Belgian scientists of the Institute of Tropical Medicine (ITM) in Antwerp, Belgium made a breakthrough in bridging high tech molecular biology research on microbial pathogens and the needs of the poorest of the poor. After sequencing the complete genome of Leishmania donovani (a parasite causing one of the most important tropical diseases after malaria) in hundreds of clinical isolates, they identified a series of mutations specific of ‘superparasites’ and developed a simple assay that should allow tracking them anywhere. This EU-funded research was done in collaboration with the Wellcome Trust Sanger Institute in UK and clinical partners of the Banaras Hindu University (India) and the BP Koirala Institute of Health Sciences (Nepal); it is published in the last issue of the Journal of Infectious Diseases.

Leishmania is a unicellular parasite that is transmitted through the bite of sandflies and occurs mainly in Latin-America, East-Africa, Asia and countries around the Mediterranean Sea.  The parasite causes a disease called leishmaniasis which can range from self-healing cutaneous to deadly visceral disease, depending on the infecting species. Recently, the World Health Organisation estimated up to 1,6 million of new cases of leishmaniasis every year, affecting essentially the poorest of the poor. In comparison to these figures, the hundreds of imported cases reported among travelers appear a drop of water in the ocean. Some of these parasites are more dangerous than others, among them those causing visceral leishmaniasis, a clinical form which is lethal in the absence of treatment.

Recently, the same group of scientists reported among these (already) dangerous microbes, the existence of  ‘superparasites’ in the Indian sub-continent, which are drug resistant and at the same time also better equipped to cope with our immune system. To our knowledge, it is the first time such a doubly armed organism is found in nature. These superparasites could jeopardize current efforts to control this devastating disease.

The European Commission currently supports a series of research projects to develop new drugs against this type of parasites or to protect the few existing ones against the development of resistance (See http://www.leishrisk.net/leishrisk/). In the context of the Kaladrug project, the Belgian scientists of ITM, together with British colleagues of the Wellcome Trust Sanger Institute and Indian and Nepalese clinical colleagues, unraveled the DNA code of Leishmania using state-of-the-art genomic technologies while aiming to discover features allowing to track superparasites.  The scientists found a series of mutations that were specific for these drug resistant and more virulent microbes and developed an easy-to-apply assay that would allow to detect them rapidly. “Thanks to the discovery of these mutations, made possible through funding by the European Commission, the spread and emergence of these drug resistant parasites can be more efficiently monitored, contributing to a better and more adequate control of the parasite and the disease it causes.” says Dr Manu Vanaerschot (ITM), first author of the paper. “We hope that this finding will ultimately pave the way to a field applicable drug resistance detection device not only for pentavalent antimonials but for all antileishmanial drugs. This is an important breakthrough which will help immensely in the control of the menace of leishmaniasis”, says Shyam Sundar, from the Banaras Hindu University, a world authority in clinical research.

Technological revolutions during the last years have allowed a huge effort of sequencing the genome of hundreds of microbes. This type of research provides an unprecedented potential for new solutions to fight these pathogens by revealing their Achilles heal, so to say. These technologies can reveal the microbes true identity, offering new targets for drugs or vaccines and allowing scientists to track them.  “Through the application of the latest technologies on precious clinical material to identify easy-to-use markers we strengthen our position among the world top in the field of translational research for infectious diseases and at the same time benefit those, often poor, patients that are usually most neglected in the society”, says Prof Dujardin (ITM), coordinator of the Kaladrug project. “This project also clearly highlights the inestimable value of involving local clinical partners in the affected regions. Here, the European Commission plays an important role by funding fundamental research that at the same time provides solutions for clinical or epidemiological challenges.”

This article is reprinted from alphagalileo.org

The plague, bacterial dysentery, and cholera have one thing in common: These dangerous diseases are caused by bacteria which infect their host using a sophisticated injection apparatus. Through needle-like structures, they release molecular agents into their host cell, thereby evading the immune response. Researchers at the Max Planck Institute for Biophysical Chemistry in Göttingen in cooperation with colleagues at the Max Planck Institute for Infection Biology in Berlin and the University of Washington in Seattle (USA) have now elucidated the structure of such a needle at atomic resolution. Their findings might contribute to drug tailoring and the development of strategies which specifically prevent the infection process.

Hundreds of tiny hollow needles sticking out of the bacterial membrane – it is a treacherous tool that makes pathogens causing plague or cholera so dangerous. Together with a base, embedded in the membrane, these miniature syringes constitute the so-called type III secretion system – an injection apparatus through which the pathogens introduce molecular agents into their host cell. There, these substances manipulate essential metabolic processes and disable the immune defines of the infected cells. The consequences are fatal as the pathogens can now spread within the organism without hindrance. To date, traditional antibiotics are prescribed to fight the infection. However, as some bacterial strains succeed in developing resistances, researchers worldwide seek to discover more specific drugs.

The exact structure of the 60 to 80 nanometre (60 to 80 millionths of a millimetre) long and about eight nanometre wide needles has so far been unknown. Classical methods such as X-ray crystallography or electron microscopy failed or yielded wrong model structures. Not crystallisable and insoluble, the needle resisted all attempts to decode its atomic structure. Therefore Adam Lange and Stefan Becker at the Max Planck Institute for Biophysical Chemistry together with a team of physicists, biologists and chemists chose a completely novel approach. In cooperation with David Baker at the University of Washington, and Michael Kolbe at the Max Planck Institute for Infection Biology, the scientists successfully combined the production of the needle in the laboratory with solid-state NMR spectroscopy, electron microscopy, and computer modelling. The researchers deciphered the structure of the needle atom by atom and visualised its molecular architecture for the first time in the angstrom range, a resolution of less than a tenth of a millionth of a millimetre.

This required progresses in several fields. “We have made big steps forward concerning sample production as well as solid-state NMR spectroscopy,” says Adam Lange. “Finally, we were also able to use one of the presently most powerful solid-state NMR spectrometers in Christian Griesinger’s NMR-based Structural Biology Department at our Institute.” With 20 tesla, the magnetic field of this 850 megahertz spectrometer is about 400,000 times as strong as that of the earth.

“We were surprised to see how the needles are constructed,” says Lange. As expected, the needles of pathogens causing diseases as diverse as food poisoning, bacterial dysentery, or the plague show striking similarities. However, in contrast to prevailing assumptions, the similarities are found in the inner part of the needles whereas the surface is astonishingly variable. According to the scientist, this variability might be a strategy of the bacteria to evade immune recognition by the host. Changes on the surface of the needle make it difficult for the host’s immune system to recognize the pathogen.

The scientists Lange, Kolbe, Becker, and their Max Planck colleagues Christian Griesinger und Arturo Zychlinsky, have focused on the bacterial injection apparatus for several years. Together with the Federal Institute for Materials Research and Testing they already showed in 2010 how bacteria assemble their miniature syringes. The discovery of their structure in atomic detail not only enables researchers to  gain new insights into how these pathogens outwit their host cells, it also offers the prospect to block the syringe assembly and the delivery of the bacterial factors using tailored molecules. Such substances, referred to as antiinfectives, could act more specifically and much earlier during infection than traditional antibiotics. “Thanks to our new technique, we can produce large amounts of needles in the lab. Our aim is now to develop a high-throughput method. This will allow us to search for new agents that prevent the formation of the needle,” explains Stefan Becker.

This Article has been reprinted from alphagalileo.org

Original Publication :

Antoine Loquet, Nikolaos G. Sgourakis, Rashmi Gupta, Karin Giller, Dietmar Riedel, Christian Goosmann, Christian Griesinger, Michael Kolbe, David Baker, Stefan Becker, and Adam Lange

Atomic Model of the Type III Secretion System Needle.

Nature advance online publication 20 May 2012. doi:10.1038/nature11079

Scientists at Liverpool, University of Bristol and the John Innes centre have released the draft sequence of the entire wheat genome. They were working in collaboration with the International Wheat Genome Consortium. This research has been funded by the Biotechnology and Biological Sciences Research Council. The work was carried out at the University’s Centre for Genomic Research, which is home to 5 next generation analyzers that can read sequences 100 times faster than those used to sequence the human genome!

This work has been received with great excitement and is expected to help wheat breeders to be able to select for strains of Wheat having desired characteristics. The reference variety used for the sequencing is the Chinese Spring Wheat (Triticum aestivum L. cv Chinese Spring) Strain. The availability of this sequence is expected to highlight natural Genetic variants between wheat types to help breeding programs. Wheat breeders have had precious little genetic information in the past to be able to make a choice as to the variety of wheat to be selected.

 

Wheat: One of the most important Food Crops in the World

Wheat: One of the most important Food Crops in the World

 

The sheer size of the wheat genome has been daunting in terms of whole genome sequencing. The Wheat genome is about five times the size of the human genome and hence was considered close to impossible to sequence. In Comparison to other important crop plants such as Soyabean and Rice, the difficulty of working with such a large genome has left wheat lagging behind in the race of genome sequencing. However, using advanced sequencing techniques employed by Roche’s 454 sequencers, the effort has managed to cover about 95% of the known wheat genes. The results of the study are now available for public use via Genbank, EMBL and CerealsDB. Nevertheless, there are those who warn that the gene map is far from complete and that the first high quality complete map data will be available only within five years. The full sequenced genome requires further read-throughs, assembly of the data into chromosomes and significant work to fully annotate the sequence data.

According to Dr. Neil Hall of the University of Bristol, within the next 40 years the food production should be increased by at 50 % of the current value. This can only be achieved if we are able to produce wheat strains resistant to drought conditions, pesticides and salinity. Traditional methods require time consuming crosses and painstaking selection of desired characteristics sometimes after several generations. The use of genetic techniques would hopefully reduce the time frame and enable the breeder to efficiently select desired traits. These traits may include disease resistance, the ability to grow under extremes of whether and soil characteristics, & producing increased yields with minimum inputs in terms of fertilizers and other growth factors.

Wheat is one of the most important food crops around the world (though most of the wheat produces is what is known as red wheat and not the one that has been used for the study) with an estimated annual production close to 550 million tonnes. Mike Bevan of the John Innes institute has placed emphasis on the importance of the study in the light of a sharp spike in the international prices of wheat following a ban on wheat exports by Russia (due to droughts and wildfires) and the overall decrease in wheat production by countries such as Pakistan and China due to heavy rains and floods.

The wheat genome holds secrets aplenty waiting to be unlocked. We are racing against time as far as food security is concerned and any step forward is all for the best. We are waiting eagerly for the promise to be fulfilled and for the time when wheat breeders can easily and quickly select varieties that will pave the way for the next revolution. Countries like India that are struggling to meet the demands of burgeoning populations and where cultivable land is at a premium are sure to benefit from this research.

 

A lot of research depends upon making comparisons between healthy and sick individuals. And the results of these comparisons have been used to develop newer and better diagnostics, prophylactics and treatments. The current study is also pretty much based on comparison between ducks that are infected with the Bird Flu virus and those that were completely healthy. The only difference here being that the comparison involved the smell of the feaces of the two groups of ducks in question, and the ‘detectors’ of these olfactory differences were lab-trained mice!

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The debate on the modified Brinjal seemed to have ended when Indian Union Minister for Environment and Forests, Jairam Ramesh abruptly calling off the battle and settling for a 2 year moratorium on the commercial release of the Bt-Brinjal in India. However, he made it clear that this decision was for Brinjal alone and as of now did not apply to all the other modified foods in the pipeline. So, we must prepare ourselves for the inevitable controversies that might arise once these other modified veggies are forced into the limelight. Of course the Government is now seriously looking at a National Biotechnology Regulatory Authority (not approval, mind you, but regulatory) for assessing the safety and putative efficacy of these crops. The idea, while supported in principle by most sections, nevertheless has incurred some negative comments. Many scientists and activists regard the move with suspicion as it has been mooted by the Department of Biotechnology, which has a vested interest in promoting transgenic Crops in India.

The war is not over even as far as the various Ministers and Departments of the Government of India (GOI) are concerned. Agriculture Minister, Sharad Pawar wants the moratorium reversed as he feels the current data provided by the Company (Monsanto –Mahyco) and the tests carried out by them are sufficient to warrant commercialization of the crop. Similarly, though not directly opposing the Moratorium, Minister Prithviraj Chauhan says that he is “satisfied with the tests carried out by the scientists but not opposed to further tests for evaluating safety.” With all this strong posturing and severely divided scientific opinion, the Prime Minister Manmohan Singh has been forced to step in and prevent a full-blown face-off between his ministers. He will meet with the ministers today and try to sort out the differences in opinion that have arisen. He will also try and clear the scene as far as the approval authority is concerned. Considering that the GEAC has come under flack for its controversial decision, the big question is if not the GEAC, who will be the next body that will decide the fate of the crops.

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Well, the world celebrated the Birthday of Charles Darwin on the twelfth of February, a few days back. International Darwin’s Day was observed in many Universities and Colleges of the World where special events and conferences marked our tribute to one of the greatest naturalists and Scientists of our time. This unassuming man defied his fate so to speak and became a scientist instead of a clergyman, much against his father’s wishes.

Battling his intense fear of the sea, he undertook the now legendary voyage aboard the HMS Beagle, and collected and classified a colossal number of specimens, both plant and animal. In fact, he even collected mineral rocks and skeletal remains. So great was his passion for collection and identification, that he began observing details that had earlier been overlooked. From these details emerged a theory and he wrote his seminal work, “On The Origin of Species”.

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In a move that took the nation by surprise, Indian Minister for Environment and Forests, Jairam Ramesh, announced a moratorium on the commercialization of Bt-Brinjal. He did this almost a day ahead of schedule and managed to leave everyone amazed at the speed with which the decision was made. Coming in the wake of heated and emotional debates with farmers, scientists, environmental groups and various other stake-holders, held across India, the decision has come as a huge relief for marginal farmers who would have borne the brunt of this technology to the hilt. Also, I personally consider this to be a victory of activists like Dr.Vandana Shiva, who have been battling the skewed policies of Monsanto for years now. The furore created by the current food-crop has been instrumental in making the government listen to sane voices instead of simply pushing an invalidated and potentially dangerous technology down our throats. So I guess it is a victory for democracy as well. This debate has taught us many important lessons, and I think this is a good opportunity to learn from them and to enable ourselves to build a strong, unbiased and scientifically irrefutable system for regulating the entry of new technology in this country.

Jairam Ramesh

Jairam Ramesh

In a hurried press conference on Tuesday night, Mr. Ramesh, announced the moratorium on Bt-Brinjal, which has been marketed in India by Mahyco-Monsanto. The moratorium will last “till such time independent scientific studies establish, to the satisfaction of both the public and professionals, the safety of the product from the point of view of its long-term impact on human health and environment, including the rich genetic wealth existing in brinjal in our country,” said Ramesh. He further went on to say, “If you need long term toxicity tests, then you must do it, no matter how long it takes… There is no hurry. There is no overriding urgency or food security argument for [release of] Bt brinjal. Our objective is to restore public confidence and trust in the Bt brinjal product. If it cannot be done, so be it.” He made an important point as far as seed security and biodiversity are concerned, saying, “I don’t believe India should be dependent on the private sector seed industry, I believe seeds are as strategic to India as space and nuclear issues.”

Dr M S Swaminathan

Dr M S Swaminathan

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In what is turning into the most awaited event of the year, the countdown to the decision on the fate of our beloved Brinjal has begun. I am sure there are millions like me waiting with bated breath for Union Minister for Environment of the Government of India to pronounce judgment on the commercialization of the controversial Bt-Brinjal crop, the very first food crop to be approved for direct human consumption in the world. The decision is to be made tomorrow, after tumultuous public debates organized by the minister across India with the major stake-holders in the current situation, namely, Farmers, Social activists, Consumers and Scientists. Seldom has any debate been so heated or has any Minister lost his head so many times even going so far as to tell opposing activists “to get your heads examined”. He further went on record last night on national television saying that he did not want to make anyone happy. But, I humbly submit Mr. Ramesh that you seem to be missing the point by a long shot. You are not voted to power to make people happy but to see to it that the constitution of the country is safeguarded and that justice is done to all sections of society in any matter that comes before you.

As we wait for the announcement to be made, the debate has far from ended. Hot discussions in scientific and social circles still abound and opinion is sharply divided. In this situation, I thought I must make an effort to summarize the implications of the impending decision one way or the other. This is by no means a complete argument or statement of facts however, as the sheer volume of data and papers available on the matter of GM available nationally and internationally is overwhelming. I have just tried to pin down some of the aspects that have repeatedly come up during this fantastic debate.

Brinjal-In the Eye of the Storm

Brinjal-In the Eye of the Storm

If We Say Yes To The Commercialization Of Bt-Brinjal

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Some interesting facts: 3

GM tomatoes: The first and only safety evaluation of a GM crop, the FLAVR SAVRTM tomato, was commissioned by Calgene, as required by the FDA. This GM tomato was produced by inserting kanr genes into a tomato by an ‘antisense’ GM method. The test has not been peer-reviewed or published but is on the internet. The results claim there were no significant alterations in total protein, vitamins and mineral contents and in toxic glycoalkaloids. Therefore, the GM and parent tomatoes were deemed to be “substantially equivalent.”

In acute toxicity studies with male/female rats, which were tube-fed homogenized GM tomatoes, toxic effects were claimed to be absent. However: Some rats died within a few weeks after eating GM tomatoes.

  • The unacceptably wide range of rat starting weights (±18% to ±23%) invalidated these findings.
  • No histology on the intestines was done even though stomach sections showed mild/moderate erosive/necrotic lesions in up to seven out of twenty female rats but none in the controls. However, these were considered to be of no importance, although in humans they could lead to life-endangering hemorrhage, particularly in the elderly who use aspirin to prevent thrombosis.
  • Seven out of forty rats on GM tomatoes died within two weeks for unstated reasons.
  • These studies were poorly designed and therefore the conclusion that FLAVR SAVRTM tomatoes were safe does not rest on good science, questioning the validity of the FDA’s decision that no toxicological testing of other GM foods will in future be required.

GM maize: Two lines of Chardon LL herbicide-resistant GM maize expressing the gene of Phosphinothricin Acetyltransferase Enzyme (PAT-PROTEIN) before and after ensiling showed significant differences in fat and carbohydrate contents compared with non-GM maize and were therefore substantially different. Toxicity tests were only performed with the PAT-PROTEIN even though with this the unpredictable effects of the gene transfer or the vector or gene insertion could not be demonstrated or excluded. The design of these experiments was also flawed because:

Rats’ ability to digest was decreased after eating GM corn.

  • The starting weight of the rats varied by more than ±20% and individual feed intakes were not monitored.
  • Feed conversion efficiency on PAT-PROTEIN was significantly reduced.
  • Urine output increased and several clinical parameters were also different.
  • The weight and histology of the digestive tract (and pancreas) was not measured.

Thus, GM maize expressing PAT-PROTEIN may present unacceptable health risks.

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The New Year has begun and this year, 2010 is to be celebrated as the year of Biodiversity. I am enjoying the delicious irony of this situation, as one of the most hotly debated topics today in India is that of the first- ever genetically modified food to be approved for direct human consumption in the world, namely the Bt-Brinjal. Also known as Aubergine, this humble vegetable is consumed across the length and breadth of India; we are home to about 2500 varieties of this plant.  I can think of no better mascot for Biodiversity than the Brinjal. One of the key aspects that is worrying people in India is the probable loss of indigenously cultivated varieties of this plant because of its GM cousin. The debate over the approval of the Commercialization of Bt-Brinjal by the GEAC in India continues to rage in all circles. Like all great issues, this one has united people in India across all sections of Society.

In October 2009, the GEAC in India cleared the commercialization of the genetically modified Brinjal, the Bt-Brinjal. The vegetable has been modified to contain genes from the Soil Bacterium Bacillus thuringiensis. These genes encode resistance to certain pests of the Lepidoptera family of pests. However, immediately after this decision, there was furious opposition to it by farmers groups, NGOs and Environmental activists such as Dr. Vandana Shiva. The reasons? Well there were many. The failure of a similar non-crop plant, Bt-Cotton to deliver on its promises of pest resistance, the criminal pricing policy of the company involved in the marketing of both the crops in question, namely, the international biotechnology giant Monsanto, the increase in the cases of suicides of small and Marginal farmers in areas where Bt-cotton was being cultivated, to name just a few.

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