Biotechwiz

News,Views & Insights on Biotechnology

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

Dear Readers,

I am thrilled to say that I will be writing on my blog once again after a rather long interval. I have missed writing and the excitement of sharing new break-throughs in the field of Biotech. Having said that, I would like to thank all my readers for continuing to read my articles. I am pleased to announce that Biotechwiz has received a Google Page Rank Of 1. I now hope to increase my ranking and of course continue to provide high quality content to my readers. With this in mind I will be introducing a new category which will consist of the Latest news in the various branches of biotechnology. Biotechwiz has been granted access to some of the news releases which will be printed here after giving due credit to the writers. One of the sites that has granted us access is the prestigious AlphaGalileo. Apart from these, the usual analytical articles and interviews with scientists will continue. Thank you once again for your support. Please stay with me.

The draft sequence of the Wheat Genome (Chinese Spring Wheat) has been released and researchers are eagerly looking forward to the possibilities of developing drought resistant, salinity resistant and pest resistant varieties of this important crop plant. Biotechwiz spoke to eminent Wheat Physiologist Dr. Matthew Reynolds from the CIMMYT (International Maize and Wheat Improvement Center) about this momentous development. Dr. Reynolds has been associated with Dr. Norman Borlaug, Nobel prize winner and agronomist whom most readers would know as ” the father of the Green Revolution” Dr. Borlaug was head of the Wheat Program at the CIMMYT.

The Interview with Dr. Reynolds is the first of two parts. The second part will be devoted exclusively to his role in the CIMMYT and the yeoman service this organization has carried out in taking the world closer to food security.

Biotechwiz presents excerpts from an exclusive interview with Dr. Matthew Reynolds, who has been intimately connected with improvement of Wheat strains, on the release of the draft sequence of the reference strain of the Chinese Spring Wheat:

Dr. Mathew Reynolds

Dr Matthew Reynolds: CIMMYT

Biotechwiz: You are described as a wheat physiologist. Can you elaborate on the nature of your work?

Dr. Matthew Reynolds:  As wheat physiologist at CIMMYT the main task is to uncover ways to improve the ability of wheat to be more productive in a range of the environments from those with high yield -such as the Punjab- to those with heat and drought stress, with a special focus on developing countries. Activities encompass the following broad objectives: Through wide consultation define factors that limit current productivity; Develop breeding technologies through collaborative research encompassing novel and conventional approaches; Coordinate multidisciplinary elements of projects over different target countries thereby facilitating relevance and delivery of products; Lead a team of scientists and technicians in Mexico to address specific research objectives as well as human capacity development.


BW: The draft sequence of the genome of the Chinese Spring wheat has just been released. What, according to you, will be the most immediate benefit of this work?

Dr. Reynolds: There will be no immediate benefit as the job of sequencing must be completed thoroughly, however, the long term benefits will be that we can use genetic information to more precisely move useful physiological traits into good agronomic cultivars.

BW: You have spoken in earlier articles of the need to develop crops that will be more resistant to climate change. Do you think that the draft sequence will reveal sufficient data in order to be able to develop such plants or will we need to wait for the finished sequence?

Dr. Reynolds: It will most likely need to wait for the finished sequence.


BW: Breeders have reacted to the news saying they will be able to select for specific traits such as drought or salinity resistance using ‘Macro- assisted selection’. Can you tell us how they would carry out such selection and what does macro-assisted selection actually mean?

Dr. Reynolds: I have not heard of macro-assisted selection before. I assume it refers to whole genome selection, which is a way of taking into account the diversity of the whole genome as opposed to focusing on a few loci. Certainly complex traits like drought adaptation will benefit from considering the whole genome as their genetic basis is complex.

BW: Could you tell us a bit about the CIMMYT and the role you play in the organisation? Also will your organisation be working on developing newer strains of wheat using the sequence data that has become available?

Dr. Reynolds: CIMMYT -a member of the Consultative Group on International Agricultural Research (CGIAR)- partners with hundreds of breeders worldwide and delivers new crop genotypes to developing countries on a large scale as freely available global public goods. The impact of this work on the livelihoods of resource-poor farmers in less developed countries is well documented. The value of the international wheat breeding effort coordinated by CIMMYT is estimated at several billion dollars of extra revenue annually, spread among millions of farmers. While the impact of the so called Green Revolution cultivars were initially in relatively favourable environments, subsequent breeding and dissemination effort has resulted in economic benefits in more marginal environments, including those affected by drought and heat stress. This breeding-evaluation-delivery pipeline encompasses the following elements: (i) free exchange of germplasm with national agricultural research services worldwide, (ii) a centralized breeding effort that focuses on generic needs –i.e. yield potential, yield stability, genetic resistance to range of biotic and abiotic stresses, consumer-oriented quality traits-, (iii) distribution of international nurseries targeted to a number of major wheat agro-ecosystems via national wheat programs in over 120 countries, (iv) analysis of international yield trials and global disease monitoring to ensure relevance of current local, regional and global breeding activities, (v) capacity building and training of research partners, (Reynolds and Borlaug, 2006; attached).

BW: Finally, would you like to speculate on the time-frame it is likely to take for the benefits of the sequence data to become obvious?

Dr. Reynolds: I was told it will take around 5 years to complete the project, then their will be a research phase, followed by application and breeding. Could be around 20 years before benefits are felt by farmers.


Image Credit:

http://blog.cimmyt.org/?s=mathew++reynold


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.

An Interview with Dr. Krishanu Saha from the Whitehead Institute of Biomedical Research: On the invention of a new Synthetic Surface for the Cultivation of Human Stem cells for up to three months.

Scientists at MIT have developed a novel synthetic surface for the cultivation of human stem cells. The research team, led by Professors Robert Langer, Rudolf Jaenisch and Daniel G. Anderson, describes the new material in the Aug. 22 issue of Nature Materials. First authors of the paper are postdoctoral associates Krishanu Saha and Ying Mei. The new material was singled out of almost 500 polymers designed during the course of the study, and was found to be optimal after analysing  several chemical and physical properties of surfaces, including roughness, stiffness, and affinity for water that might play a role in stem cell growth. The new surface not only enabled Stem Cells to be grown for up to three months but also enabled harvesting of cells in the millions. Both of these attributes are very important to researchers as the in vitro culture of human Stem cells is fraught with difficulty. The surface also enables clonal growth of a stem cell allowing for easy selection of a particular cell with attributes of interest. As Researchers laud this important invention, Biotechwiz is proud to present an exclusive interview with Dr. Krishanu Saha, one of the authors of this seminal work. An excerpt of the interview is presented below:

Dr. Krishanu Saha

Dr. Krishanu Saha

Biotechwiz: Why did you feel the need to develop a new material for the growth of stem cells?

Dr. Krishanu Saha: When we started this work, there were only a handful of culturing materials that were used to grow human embryonic stem cells. Most of these materials included components from animal sources. These animal-derived components are problematic for any cell therapy applications envisioned with these cells, because such components utilized during cell culture can increase the risk of immune rejection when such cells are injected into a patient.  We therefore sought to explore whether a library of synthetic polymers coated with human-derived proteins could replace and improve on the conventional methods of growing human embryonic stem cells.

We also wanted to gain more molecular insight into how human embryonic stem cells grow outside of the body. Mouse embryonic stem cells have particular properties of cell growth and genetic manipulation that make them easier to work with in the lab.  We wondered whether we could devise better culture conditions for human embryonic stem cells by systematically exploring stem cell growth on a diverse set of polymeric materials.

BW: Can you elaborate a bit on the nature of this new surface that you have developed and what is the most unique feature of your invention according to you?

Dr. Saha: The new surfaces can be synthesized entirely from standard chemicals.  They utilize a particular chemistry that was not defined before this work to interact with a human protein, Vitronectin.  The most unique feature is that it can support the long-term culture of fully dissociated human embryonic stem cells as well as the recently ‘reprogrammed’ human induced pluripotent stem cells.

BW:  How soon do you think the research you have done will be available as a commercially viable product?

Dr. Saha: This question of technology transfer is a difficult one to predict. There are already a few commercial products based on other work with novel stem cell culture materials that was just published in May. So if we extrapolate from those cases, our work could be translated into products in less than a year.  I believe the MIT technology transfer office is dedicated to ensuring that the materials get widely used.

BW:  What is the trend your future research is likely to take?

Dr. Saha: I am generally interested in combining this work with recent advances in cellular reprogramming. Cellular reprogramming can produce embryonic stem cell-like cells called induced pluripotent stem (iPS) cells from virtually any human cell source, such as a blood sample or biopsy.  I believe there is a key role of materials and engineering to play in developing these iPS cells for disease modelling and regenerative medicine applications.

BW: Can you tell us about any one hurdle that bugged you the most during your work?

Dr. Saha: Finding common patterns in the material characteristics that controlled the growth of the human embryonic stem cells was challenging.  We had hundreds of polymers with lots of data about surface chemistry, stiffness, and roughness that needed to be sorted and globally analyzed. At times, this seemed tedious, but it is part of the research process.

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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For all those who were waiting with bated breath for the first ever Human Embryonic stem cell (HESC) phase I clinical trials to begin, well there’s good news. On the 30th of July 2010, the US based Geron Corporation announced the FDA’s approval to its HESC based clinical trials in humans. The announcement comes after a year-long set-back to the proposed trials, after the company discovered during some of its tests that the rats treated with the stem cell line developed cysts. This set off a spate of further tests to ensure efficacy and safety of the therapy. After a year, the company seems to have effectively allayed fears of tumorigenicity and has obtained a green signal from the US FDA and will be beginning the first human trials of Human Embryonic stem cell therapy in the world.

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The District Court Judge of the Southern District of New York, Judge Robert Sweet will go down in History. Amidst much speculation and debate, the Judge, on March 29th 2010, ruled in the case of Association for

Judge Robert Sweet

Judge Robert Sweet

Molecular Pathology v. U.S. Patent and Trademark Office, that the patents For BRCA1 and BRCA2 held by the company Myriad Genetics, were invalid. The decision was a highly anticipated one since this particular lawsuit has been hailed by many as being a direct attack on the company and the USPTO (The United States Patent and Trademarks Office). The issue of gene patenting has always been a controversial one and there have been heated debates for and against it. However, in recent times, we have seen with increasing unease, the extent to which essential health care testing, diagnostics and even treatments have slowly but steadily passed the truly needy patients by because of prohibitively high costs and monopolistic trade practices by many such companies in the name of millions of dollars sunk into research for the same.

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