Bioinformatics Institute of India

Parkinson’s treatment using Stem Cell Therapies

noreply@blogger.com (BII Admin) — Tue, 7 Apr 2015 10:46:00 +0530

Parkinson's, which affect as many 10 million people in the world, is caused by a depletion of dopamine-producing neurons in the brain. Current treatments include medications and electrical implants in the brain which causes severe adverse effects over time and fail to prevent disease progression. Several studies have indicated that the transplantation of embryonic stem cells improves motor functions in animal models. However, until now, the procedure has shown to be unsafe, because of the risk of tumors upon transplantation.

To address this issue, the researchers tested for the first time to pre-treat undifferentiated mouse embryonic stem cells with mitomycin C, a drug already prescribed to treat cancer. The substance blocks the DNA replication and prevents the cells to multiply out of control.

The researchers used mice modeled for Parkinson's. The animals were separated in three groups. The first one, the control group, did not receive the stem cell implant. The second one, received the implant of stem cells which were not treated with mitomycin C and the third one received the mitomycin C treated cells.

Figure: Parkinson’s Disease

After the injection of 50,000 untreated stem cells, the animals of the second group showed improvement in motor functions but all of them died between 3 and 7 weeks later. These animals also developed intracerebral tumors. In contrast, animals receiving the treated stem cells showed improvement of Parkinson's symptoms and survived until the end of the observation period of 12 weeks post-transplant with no tumors detected. Four of these mice were monitored for as long as 15 months with no signs of pathology.

Furthermore, the scientists have also shown that treating the stem cells with mitomycin C induced a four-fold increase in the release of dopamine after in vitro differentiation.

"This simple strategy of shortly exposing pluripotent stem cells to an anti-cancer drug turned the transplant safer, by eliminating the risk of tumor formation," says the leader of the study Stevens Rehen, Professor at UFRJ and researcher at IDOR.

The discovery, reported on April in the journal Frontiers in Cellular Neuroscience, could pave the way for researchers and physicians to propose a clinical trial using pluripotent stem cells treated with mitomycin C prior to transplant to treat Parkinson's patients and also other neurodegenerative conditions.

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Bioinformatics Department

BII Noida

Random Mutations Plays Predominant Role in Cancer

noreply@blogger.com (BII Admin) — Tue, 6 Jan 2015 15:49:00 +0530

A statistical model has been created that measures the proportion of cancer incidence, across many tissue types, caused mainly by random mutations that occur when stem cells divide. By this measure, two-thirds of adult cancer incidence across tissues can be explained primarily by “bad luck,” when these random mutations occur in genes that can drive cancer growth, while the remaining third are due to environmental factors and inherited genes.

Scientists from the Johns Hopkins Kimmel Cancer Center have created a statistical model that measures the proportion of cancer incidence, across many tissue types, caused mainly by random mutations that occur when stem cells divide. By their measure, two-thirds of adult cancer incidence across tissues can be explained primarily by "bad luck," when these random mutations occur in genes that can drive cancer growth, while the remaining third are due to environmental factors and inherited genes.

"All cancers are caused by a combination of bad luck, the environment and heredity, and we've created a model that may help quantify how much of these three factors contribute to cancer development.

"Cancer-free longevity in people exposed to cancer-causing agents, such as tobacco, is often attributed to their 'good genes,' but the truth is that most of them simply had good luck," adds Vogelstein, who cautions that poor lifestyles can add to the bad luck factor in the development of cancer.

Figure 1: 3D DNA model

Figure 2: Random DNA Mutation

Researchers claim 65% of cancer cases are a result of random DNA mutations, while the remaining 35% can be explained by a combination of these mutations and environmental and hereditary factors. The implications of their model range from altering public perception about cancer risk factors to the funding of cancer research, they say. "If two-thirds of cancer incidence across tissues is explained by random DNA mutations that occur when stem cells divide, then changing our lifestyle and habits will be a huge help in preventing certain cancers, but this may not be as effective for a variety of others," says bio-mathematician Cristian Tomasetti, Ph.D., an assistant professor of oncology at the Johns Hopkins University School of Medicine and Bloomberg School of Public Health. "We should focus more resources on finding ways to detect such cancers at early, curable stages," he adds.

To sort out the role of such random mutations in cancer risk, the Johns Hopkins scientists charted the number of stem cell divisions in 31 tissues and compared these rates with the lifetime risks of cancer in the same tissues among Americans. From this so-called data scatterplot, Tomasetti and Vogelstein determined the correlation between the total number of stem cell divisions and cancer risk to be 0.804. Mathematically, the closer this value is to one, the more stem cell divisions and cancer risk are correlated.

"Our study shows, in general, that a change in the number of stem cell divisions in a tissue type is highly correlated with a change in the incidence of cancer in that same tissue," says Vogelstein. One example, he says, is in colon tissue, which undergoes four times more stem cell divisions than small intestine tissue in humans. Likewise, colon cancer is much more prevalent than small intestinal cancer.

"You could argue that the colon is exposed to more environmental factors than the small intestine, which increases the potential rate of acquired mutations," says Tomasetti. However, the scientists saw the opposite finding in mouse colons, which had a lower number of stem cell divisions than in their small intestines, and, in mice, cancer incidence is lower in the colon than in the small intestine. They say this supports the key role of the total number of stem cell divisions in the development of cancer. Using statistical theory, the pair calculated how much of the variation in cancer risk can be explained by the number of stem cell divisions, which is 0.804 squared, or, in percentage form, approximately 65 percent.

Finally, the research duo classified the types of cancers they studied into two groups. They statistically calculated which cancer types had an incidence predicted by the number of stem cell divisions and which had higher incidence. They found that 22 cancer types could be largely explained by the "bad luck" factor of random DNA mutations during cell division. The other nine cancer types had incidents higher than predicted by "bad luck" and were presumably due to a combination of bad luck plus environmental or inherited factors.

"We found that the types of cancer that had higher risk than predicted by the number of stem cell divisions were precisely the ones you'd expect, including lung cancer, which is linked to smoking, skin cancer, linked to sun exposure, and forms of cancers associated with hereditary syndromes," says Vogelstein.

"This study shows that you can add to your risk of getting cancers by smoking or other poor lifestyle factors. However, many forms of cancer are due largely to the bad luck of acquiring a mutation in a cancer driver gene regardless of lifestyle and heredity factors. The best way to eradicate these cancers will be through early detection, when they are still curable by surgery," adds Vogelstein.

GenoCAD: Computer Assisted Design Application for Synthetic Biology

noreply@blogger.com (BII Admin) — Sat, 27 Dec 2014 14:24:00 +0530

A computer-aided design tool was created for genetic languages to guide the design of biological systems known as GenoCAD, the open-source software was developed by researchers at the Virginia Bioinformatics Institute at Virginia Tech to help synthetic biologists capture biological rules to engineer organisms that produce useful products or health-care solutions from inexpensive, renewable materials.

GenoCAD helps researchers in the design of protein expression vectors, artificial gene networks, and other genetic constructs, essentially combining engineering approaches with biology.

Synthetic biologists have an increasingly large library of naturally derived and synthetic parts at their disposal to design and build living systems. These parts are the words of a DNA language and the "grammar" a set of design rules governing the language.

GenoCAD is an open-source computer-assisted-design (CAD) application for synthetic biology. The foundation of GenoCAD is to consider DNA as a language to program synthetic biological systems. GenoCAD includes a large database of annotated genetic parts which are the words of the language. GenoCAD also includes design rules describing how parts should be combined in genetic constructs. These rules are used to build a wizard that guides users through the process of designing complex genetic constructs and artificial gene networks. The same rules are used by the GenoCAD compiler to maintain the integrity of existing constructs. GenoCAD provides users with data import and export capabilities using standard formats (FASTA, GenBank, and tab-delimited text) so that users' personal workspaces can be customized to meet their specific needs. It has to be expressive enough to allow scientists to generate a broad range of constructs, but it has to be focused enough to limit the possibilities of designing faulty constructs.

"Just like software engineers need different languages like HTML, SQL, or Java to develop different kinds of software applications, synthetic biologists need languages for different biological applications," said Jean Peccoud, investigator of the GenoCAD project. "From its inception, we envisioned GenoCAD as a framework allowing users to capture their expertise of a particular domain in languages that they could use themselves or share with others."

The researchers said encapsulating current knowledge by defining standards will become increasingly important as the number and complexity of components engineered by synthetic biologists increases.

They propose that grammars are a first step toward the standardization of a broad range of synthetic genetic parts that could be combined to develop innovative products.

"Developing a grammar in GenoCAD is a little like writing a review paper," Purcell said. "You start with the headings and you progressively dig deeper in the details. At the end of the process, you have a much better appreciation for what you know and what you don't know about a particular domain."

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Bioinformatics Department

New way to turn genes on discovered: Technique allows rapid, large-scale studies of gene function (CRISPR)

noreply@blogger.com (BII Admin) — Sat, 13 Dec 2014 15:45:00 +0530

Using a gene-editing system originally developed to delete specific genes, researchers have now shown that they can reliably turn on any gene of their choosing in living cells. The findings are expected to help researchers refine and further engineer the tool to accelerate genomic research and bring the technology closer to use in the treatment of human genetic disease. Using a gene-editing system originally developed to delete specific genes, MIT researchers have now shown that they can reliably turn on any gene of their choosing in living cells.

This new application for the CRISPR/Cas9 gene-editing system should allow scientists to more easily determine the function of individual genes. This approach also enables rapid functional screens of the entire genome, allowing scientists to identify genes involved in particular diseases.

A new function for CRISPR

The CRISPR system relies on cellular machinery that bacteria use to defend themselves from viral infection. Researchers have previously harnessed this cellular system to create gene-editing complexes that include a DNA-cutting enzyme called Cas9 bound to a short RNA guide strand that is programmed to bind to a specific genome sequence, telling Cas9 where to make its cut.

Scientists have tried to do this before using proteins that are individually engineered to target DNA at specific sites. However, these proteins are difficult to work with. There have also been attempts to use CRISPR to turn on genes by inactivating the part of the Cas9 enzyme that cuts DNA and linking Cas9 to pieces of proteins called activation domains. These domains recruit the cellular machinery necessary to begin reading copying RNA from DNA, a process known as transcription.

However, these efforts have been unable to consistently turn on gene transcription. In previous efforts, scientists had tried to attach the activation domains to either end of the Cas9 protein, with limited success. From their structural studies, the MIT team realized that two small loops of the RNA guide poke out from the Cas9 complex and could be better points of attachment because they allow the activation domains to have more flexibility in recruiting transcription machinery.

Using their revamped system, the researchers activated about a dozen genes that had proven difficult or impossible to turn on using the previous generation of Cas9 activators. Each gene showed at least a twofold boost in transcription, and for many genes, the researchers found multiple orders of magnitude increase in activation.

In new research, scientists have shown that they can reliably turn on any gene of their choosing in living cells.

Genome-scale activation screening

Once the researchers had shown that the system was effective at activating genes, they created a library of 70,290 guide RNAs targeting all of the more than 20,000 genes in the human genome.

They screened this library to identify genes that confer resistance to a melanoma drug called PLX-4720. This drug works Drugs of this type work well in patients whose melanoma cells have a mutation in the BRAF gene, but cancer cells that survive the treatment can grow into new tumors, allowing the cancer to recur.

To discover the genes that help cells become resistant, the researchers delivered CRISPR components to a large population of melanoma cells grown in the lab, with each cell receiving a different guide RNA targeting a different gene. After treating the cells with PLX-4720, they identified several genes that helped the cells to survive -- some previously known to be involved in drug resistance, as well as several novel targets.

Studies like this could help researchers discover new cancer drugs that prevent tumors from becoming resistant.

Scientists have tried to do large-scale screens like this by delivering single genes carried by viruses, but that does not work with all genes.

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Biotechnology Department

Computational Tools Will Help Identify Microbes in Complex Environmental Samples

noreply@blogger.com (BII Admin) — Mon, 8 Dec 2014 12:24:00 +0530

A new National Science Foundation-supported project will provide computational tools designed to help identify and characterize the gene diversity of the residents of these microbial communities. The project, being done by researchers at the Georgia Institute of Technology and Michigan State University, will allow clinicians and scientists to compare the genomic information of organisms they encounter against the growing volumes of data provided by the world's scientific community.

The tools will be hosted on a web server designed to be used by researchers who may not have training in the latest bioinformatics techniques. A prototype system containing a limited number of computational tools is already available at http://enve-omics.ce.gatech.edu and is attracting more than 500 users each month.

"Across many areas of science, we are dealing with communities of microorganisms, and one challenge we've had is to identify them because we haven't had good tools to tell apart individual microbes from the mixtures," said Kostas Konstantinidis, an associate professor in the School of Civil and Environmental Engineering at Georgia Tech and the project's principal investigator. "Our tools will be designed to deal with the genomes of whole communities of organisms."

Current techniques identify individual microbes by examining their small subunit ribosomal RNA (SSU rRNA) genes, but the new tools will allow scientists to analyze entire genomes and meta-genomes.

"With the dawn of the genomic era, we can now get the whole genome of these organisms to see not only the ribosomal RNA, but also all the genes in the genome to get a better understanding of what the each organism's potential might be," said Konstantinidis. "There will be many advantages for looking at all the genes instead of just one, the SSU rRNA, such as to identify which organisms encode toxins or the enzymes for breaking down pollutants."

The ability to identify and enumerate the organisms in complex communities using culture-independent, genomic technologies and associated bioinformatics algorithms is becoming more important as scientists study organisms that can't be grown in the lab. The majority of the world's organisms resist traditional lab culture, meaning they have to be studied in the field and identified through genetic information.

Konstantinidis and his research group are studying such communities in the water of lakes in Chattahoochee River system in Georgia and elsewhere. They are examining how these communities respond to perturbations, such as oil or pesticide spills, and the role that different members of the community play in breaking down pollutants.

"These tools actually come from our research practice," said Konstantinidis. "We came to the point where we couldn't process the data to answer the questions we wanted to ask. That led us to this new project to develop the tools we and others need to interrogate the data and get the information we are looking for."

A single liter of lake water may contain as many as 500 different species, and together, their genomic information can total tens of billions of gene-coding letters. From Lake Lanier alone, the team has generated 200 gigabytes of genomic data.

Among the challenges ahead is building an infrastructure able to handle the growing amounts of genomic information produced worldwide.

"We will have to develop some computational solutions for the problems of keeping up with all the new data becoming available," said Konstantinidis. "We need to make tools that have high throughput to keep up with data volumes that are increasing geometrically."

POSTED BY:-

Bioinformatics Department

Genomes of malaria-carrying mosquitoes sequenced

noreply@blogger.com (BII Admin) — Mon, 1 Dec 2014 15:03:00 +0530

Anopheles mosquitoes are responsible for transmitting human malaria parasites that cause an estimated 200 million cases and more than 600 thousand deaths each year. However, of the almost 500 different Anopheles species, only a few dozen can carry the parasite and only a handful of species are responsible for the vast majority of transmissions. Besansky and her fellow researchers investigated the genetic differences between the deadly parasite-transmitting species and their harmless (but still annoying) cousins.

Two papers published in editions of Science Express, an electronic publication of the journal Science in advance of print, describe detailed genomic comparisons of these mosquitoes and the deadliest of them all, Anopheles gambiae. These results offer new insights into how these species are related to each other and how the dynamic evolution of their genomes may contribute to their flexibility to adapt to new environments and to seek out human blood. These newly sequenced genomes represent a substantial contribution to the scientific resources that will advance our understanding of the diverse biological characteristics of mosquitoes, and help to eliminate diseases that have a major impact on global public health.

Picture representing the Anapheles mosquito bite and the life cycle of malaria.

Malaria parasites are transmitted to humans by only a few dozen of the many hundreds of species of Anopheles mosquitoes, and of these, only a handful are highly efficient disease-vectors. Thus, although about half the world's human population is at risk of malaria, most fatalities occur in sub-Saharan Africa, home of the major vector species, Anopheles gambiae. Variation in the ability of different Anopheles species to transmit malaria known as "vectorial capacity" are determined by many factors, including feeding and breeding preferences, as well as their immune responses to infections. The sequencing of the Anopheles gambiae genome in 2002, which was led by Notre Dame researchers and which has since facilitated many large-scale functional studies that have offered numerous insights into how this mosquito became highly specialized in order to live amongst and feed upon humans.

Until now, the lack of such genomic resources for other Anopheles limited comparisons to small-scale studies of individual genes with no genome-wide data to investigate key attributes that impact the mosquito's ability to transmit parasites. DNA sequencing and assembly efforts at the Broad Institute were funded by NHGRI and led by Daniel Neafsey, with samples obtained from mosquito colonies maintained through BEI Resources at the United States Centres for Disease Control and Prevention, and wild-caught or laboratory-reared mosquitoes from scientists in Africa, India, Iran, Melanesia and Southeast Asia.

"Getting enough high-quality DNA samples for all species was a challenging process and they had to design and apply novel strategies to overcome the difficulties associated with high levels of DNA sequence variations, especially from the wild-caught sample,"according to Neafsey.

With genome sequencing complete, scientists from around the world contributed their expertise to examine genes involved in different aspects of mosquito biology including reproductive processes, immune responses, insecticide resistance, and chemosensory mechanisms. These detailed studies involving so many species were facilitated by large-scale computational evolutionary genomic analyses led by Robert Waterhouse from the University of Geneva Medical School and the Swiss Institute of Bioinformatics.

The researchers carried out interspecies gene comparisons with the Anopheles and other insects, to identify equivalent genes in each species and highlight potentially important differences.

Examining gene evolution across the Anopheles revealed high rates of gene gain and loss, about five times higher than in fruit flies. Some genes, such as those involved in reproduction or those that encode proteins secreted into the mosquito saliva, have very high rates of sequence evolution and are only found in subsets of the most closely-related species.

"These dynamic changes may offer clues to understanding the diversification of Anopheles mosquitoes; why some breeds in salty water while others need temporary or permanent pools of fresh water, or why some are attracted to livestock while others will only feed on humans."

This study substantially improves the understanding of the process of gene flow between closely related species a process believed to have occurred from Neanderthals to the ancestors of modern humans and how it may affect the evolution of common and distinct biological characteristics of mosquitoes such as ecological flexibility and vectorial capacity.

These two very different evolutionary timescales spanning all the Anopheles or focusing on the subset of very closely-related species offer distinct insights into the processes that have moulded these mosquito genomes into their present-day forms. Their dynamic evolutionary profiles may represent the genomic signatures of an inherent evolvability that has allowed Anopheles mosquitoes to quickly exploit new human-generated habitats and become the greatest scourge of humankind.

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Biotechnology Department

Flu virus key machine: First complete view of structure revealed

noreply@blogger.com (BII Admin) — Mon, 24 Nov 2014 11:57:00 +0530

The structure, obtained by scientists at the European Molecular Biology Laboratory (EMBL) in Grenoble, France, allows researchers to finally understand how the machine works as a whole. Published in two papers in Nature, the work could prove instrumental in designing new drugs to treat serious flu infections and combat flu pandemics. The machine in question, the influenza virus polymerase, carries out two vital tasks for the virus. It makes copies of the virus' genetic material. The viral RNA to package into new viruses that can infect other cells; and it reads out the instructions in that genetic material to make viral messenger RNA, which directs the infected cell to produce the proteins the virus needs. Scientistsincluding Cusack and collaborators had been able to determine the structure of several parts of the polymerase in the past."The flu polymerase was discovered 40 years ago, so there are hundreds of papers out there trying to fathom how it works. But only now that we have the complete structure can we really begin to understand it," says Stephen Cusack, head of EMBL Grenoble, who led the work.

The complete structure allows researchers to understand how the polymerase uses host cell RNA (red) to kick-start the production of viral messenger RNA.

Using X-ray crystallography, performed at the European Synchrotron Radiation Facility (ESRF) in Grenoble, Cusack and colleagues were able to determine the atomic structure of the whole polymerase from two strains of influenza: influenza B, one of the strains that cause seasonal flu in humans, but which evolves slowly and therefore isn't considered a pandemic threat; and the strain of influenza A. The fast-evolving strain that affects humans, birds and other animals and can cause pandemics that infects bats.

"The high-intensity X-ray beamlines at the ESRF, equipped with state-of-the-art Dectris detectors, were crucial for getting high quality crystallographic data from the weakly diffracting and radiation sensitive crystals of the large polymerase complex," says Cusack.

The structures reveal how the polymerase specifically recognises and binds to the viral RNA, rather than just any available RNA, and how that binding activates the machine. They also show that the three component proteins that make up the polymerase are very intertwined, which explains why it has been very difficult to piece together how this machine works based on structures of individual parts.

Although the structures of both viruses' polymerases were very similar, the scientists found one key difference, which showed that one part of the machine can swivel around to a large degree. That ability to swivel explains exactly how the polymerase uses host cell RNA to kick-start the production of viral proteins. The swivelling component takes the necessary piece of host cell RNA and directs it into a slot leading to

the machine's heart, where it triggers the production of viral messenger RNA.

Now that they know exactly where each atom fits in this key viral machine, researchers aiming to design drugs to stop influenza in its tracks have a much wider range of potential targets at their disposal -- like would-be saboteurs who gain access to the whole production plant instead of just sneaking looks through the windows. And because this is such a fundamental piece of the viral machinery, not only are the versions in the different influenza strains very similar to each other, but they also hold many similarities to their counterparts in related viruses such as lassa, hanta, rabies or ebola.

The EMBL scientists aim to explore the new insights this structure provides for drug design, as well as continuing to try to determine the structure of the human version of influenza A, because although the bat version is close enough that it already provides remarkable insights, ultimately fine-tuning drugs for treating people would benefit from/require knowledge of the version of the virus that infects humans. And, since this viral machine has to be flexible and change shape to carry out its different tasks, Cusack and colleagues also want to get further snapshots of the polymerase in different states.

Rheumatoid arthritis (RA) research shows potential of large-scale genetic studies for drug discovery

noreply@blogger.com (BII Admin) — Mon, 17 Nov 2014 11:48:00 +0530

The results of the largest international study to date into the genetic basis of rheumatoid arthritis shed light on the biology of the disease and provide evidence that large-scale genetic studies can assist in the identification of new drugs for complex disorders such as rheumatoid arthritis.

The study, conducted by Dr. Robert M. Plenge from the Harvard Medical School and the Broad Institute in the USA and Dr. Yukinori Okada from the RIKEN Center for Integrative Medical Sciences in Japan, collaborating with colleagues from 70 institutions worldwide, is published in the journal Nature.

Genome-wide association studies are a method employed by scientists to identify the genes contributing to human disease. The current Nature study is the first to demonstrate that integrating the information provided by genome-wide association studies with existing datasets of genomic and biological information, such as drug targets, can assist in the discovery of drugs to cure human disease.

Rheumatoid arthritis is an autoimmune disease leading to inflammation of the joints and affecting 0.5-1% of adults in the developed world. The disease is thought to be caused by a complex combination of genetic and environmental factors and several genes have been shown to be associated with the disease. However, most of the findings were based on single population studies, and no large-scale trans-ethnic study had been carried out to date.

Figure a) Showing RA

Figure b) Showing Bioinformatics Process for Drug Discovery of RA

The international team performed a genome-wide association study meta-analysis on a total of over 100,000 subjects of European and Asian descent -- 29,880 rheumatoid arthritis patients and 73,758 controls -- by analysing around 10 million genetic variants called single nucleotide polymorphism (SNPs). They identified 42 new regions in the genome (loci) that are associated with rheumatoid arthritis, bringing the total number of known rheumatoid arthritis loci to 101.

By conducting bioinformatics studies integrating existing datasets with this new information, the researchers were able to pinpoint 98 genes in these 101 loci that could potentially contribute to the onset of rheumatoid arthritis. By integrating their findings with existing drug databases they demonstrate that these genes indeed possess many overlapping regions with the genes targeted by approved rheumatoid arthritis drugs -- although this wasn't known when the drugs were developed. The team identifies existing drugs used to treat cancer that also target rheumatoid arthritis genes and could potentially be used as therapy for the disease, such as CDK4/6 inhibitors.

The bioinformatics study also reveals that there is significant overlap between the genes involved in rheumatoid arthritis, human primary immunodeficiency disorders and blood cancers.

"This study sheds light on the fundamental genes, pathways and cell types that contribute to the onset of rheumatoid arthritis and provides evidence that the genetics of rheumatoid arthritis can provide important information for drug discovery," conclude the authors.

Bioinformatician helps biologists find key genes

noreply@blogger.com (BII Admin) — Mon, 10 Nov 2014 15:42:00 +0530

It's like looking for a needle in a haystack. Scientists searching for the gene or gene combination that affects even one plant or animal characteristic must sort through massive amounts of data.

"Biologists used to study one gene at time, but now they can look at tens of thousands of genes at once." Xijin Ge said. Just one experiment to analyze gene expression can produce one terabyte of sequence data. "That's a little beyond many biologists' comfort zone."

He leads the bioinformatics research group, which provides the expertise that SDSU plant and animal scientists need to uncover how genes and proteins affect cell functions.

Setting up the experiments

Typically, scientists consult with their colleagues when planning their studies. After examining what they want to investigate, the researchers decide which techniques should be used to obtain data and a plan to analyze the data."It's critical to have the statistician and biologist working together," noted plant science professor Fedora Sutton, who worked with Ge on identifying gene interactions that account for freeze resistance in winter wheat. "He is able to say, based on statistical rules and regulations, this is where this has to be."

Using the same technique on one sample is not enough, Sutton pointed out. Multiple samples must be grown under the same conditions and then analyzed to have biological replicates. Scientist explained that experiments must be designed to gather biological rather than technical replicates. Once the technique to gather data is chosen and a plan of data analyses is created, scientist said, "we can figure out how many replicates are needed."

Analyzing megabytes of data

"Bioinformatics is an important tool to zoom in on the target gene networks," said Xing-You scientist, who collaborated with scientist to identify genes that are associated with seed dormancy in weedy rice. Weeds survive adverse environmental conditions because of strong seed dormancy, scientist explained. "To devise new weed management strategies, we need to understand the molecular genetics mechanisms of seed dormancy."

Scientists used a map-based cloning strategy and then applied bioinformatics tools, such as statistical tests and clustering, to find the candidate genes. This task involved looking at more than 30,000 to 40,000 genes, which can produce three to four million data points, according to the scientist. To determine which genes are responsible, scientist must first eliminate those data points that contain noise and then "focus on the reliable signals because we're looking at so many genes." Sometimes nearly half the data are eliminated.

Visualizing gene expression

Scientists use data-mining algorithms to find patterns of interest to the scientists. Typically, his analysis produces a visual representation of the data that is statistically significant.

One of Sutton's visuals was a heat map depicting gene expressions that were increased or up-regulated in red, those that were shut down or down regulated in green and those unaffected in black. This allowed her to identify six genes as potential markers which will then help breeders develop more lines of freeze-resistant winter wheat.

After identifying the genes, the researchers "want to piece together the jigsaw puzzle and figure out the common characteristics of the affected genes," scientists explained. This will allow us to identify the sub-systems, or pathways, that are regulated.

IMMUNOINFORMATICS: BIOINFORMATICS STRATEGIES FOR BETTER UNDERSTANDING OF IMMUNE FUNCTION

noreply@blogger.com (BII Admin) — Mon, 3 Nov 2014 11:47:00 +0530

Bioinformatics Successfully Predicts Immune Response To One Of The Most Complex Viruses Known

The use of computers to advance human disease research – known as bioinformatics -- has received a major boost from researchers at the La Jolla Institute for Allergy & Immunology (LIAI), who has used it to successfully predict immune response to one of the most complex viruses known to man – the vaccinia virus, which is used in the smallpox vaccine. Immune responses, which are essentially how the body fights a disease-causing agent, are a crucial element of vaccine development.

Bioinformatics holds significant interest in the scientific community because of its potential to move scientific research forward more quickly and at less expense than traditional laboratory testing.

The research was executed with resulted in "A consensus epitope prediction approach identifies the breadth of murine TCD8+-cell responses to vaccinia virus," in the online version of the journal Nature Biotechnology. LIAI scientist Magdalini Moutaftsi was the lead author on the paper.

While bioinformatics – which uses computer databases, algorithms and statistical techniques to analyze biological information -- is already in use as a predictor of immune response, the LIAI research team's findings were significant because they demonstrated an extremely high rate of prediction accuracy (95 percent) in a very complex pathogen – the vaccinia virus. The vaccinia virus is a non-dangerous virus used in the smallpox vaccine because it is related to the variola virus, which is the agent of smallpox. The scientific team was able to prove the accuracy of their computer results through animal testing.

"Before, we knew that the prediction methods we were using were working, but this study proves that they work very well with a high degree of accuracy," Sette said.

The researchers focused their testing on the Major Histocompatibility Complex (MHC), which binds to certain epitopes and is key to triggering the immune system to attack a virus-infected cell. Epitopes are pieces of a virus that the body's immune system focuses on when it begins an immune response. By understanding which epitopes will bind to the MHC molecule and cause an immune attack, scientists can use those epitopes to develop a vaccine to ward off illness – in this case to smallpox.

The scientists were able to find 95 percent of the MHC binding epitopes through the computer modeling. "This is the first time that bioinformatics prediction for epitope MHC binding can account for almost all of the (targeted) epitopes that exist in very complex pathogens like vaccinia," said LIAI researcher Magdalini Moutaftsi. The LIAI scientists theorize that the bioinformatics prediction approach for epitope MHC binding will be applicable to other viruses.

Figure: Showing involvement of antibodies to destroy the pathogens in blood stream

"The beauty of the virus used for this study is that it's one of the most complex, large viruses that exist," said Moutaftsi."If we can predict almost all (targeted) epitopes from such a large virus,then we should be able to do that very easily for less complex viruses like influenza, herpes or even HIV, and eventually apply this methodology to larger microbes such as tuberculosis."

The big advantage of using bioinformatics to predict immune system targets, explained Sette, is that it overcomes the need to manufacture and test large numbers of peptides in the laboratory to find which ones will initiate an immune response. Peptides are amino acid pieces that potentially can be recognized by the immune system. "There are literally thousands of peptides," explained Sette. "You might have to create and test hundreds or even thousands of them to find the right ones," he said."With bioinformatics, the computer does the screening based on very complex mathematical algorithms. And it can do it in much less time and at much less expense than doing the testing in the lab."

The LIAI scientific team verified the accuracy of their computer findings by comparing the results against laboratory testing of the peptides and whole infectious virus in mice. "We studied the total response directed against infected cells," Sette said. "We compared it to the response against the 50 epitopes that had been predicted by the computer. We were pleased to see that our prediction could account for 95% of the total response directed against the virus."

Posted By:-
Bioinformatics Department

Prevalence and impacts of genetically engineered feedstuffs on livestock populations.

noreply@blogger.com (BII Admin) — Tue, 28 Oct 2014 10:20:00 +0530

A new review study finds there is no evidence in earlier scientific studies indicating that genetically engineered feed crops harmed the health or productivity of livestock and poultry, and that food products from animals consuming such feeds were nutritionally the same as products from animals that ate non-GMO feeds. Globally, food-producing animals consume 70 to 90% of genetically engineered (GE) crop biomass. This review briefly summarizes the scientific literature on performance and health of animals consuming feed containing GE ingredients and composition of products derived from them. It also discusses the field experience of feeding GE feed sources to commercial livestock populations and summarizes the suppliers of GE and non-GE animal feed in global trade. Numerous experimental studies have consistently revealed that the performance and health of GE-fed animals are comparable with those fed isogenic non-GE crop lines. United States animal agriculture produces over 9 billion food-producing animals annually, and more than 95% of these animals consume feed containing GE ingredients.

Green soybean plants, mixed organic and GMO

Data on livestock productivity and health were collated from publicly available sources from 1983, before the introduction of GE crops in 1996, and subsequently through 2011, a period with high levels of predominately GE animal feed. These field data sets, representing over 100 billion animals following the introduction of GE crops, did not reveal unfavorable or perturbed trends in livestock health and productivity. No study has revealed any differences in the nutritional profile of animal products derived from GE-fed animals. Because DNA and protein are normal components of the diet that are digested, there are no detectable or reliably quantifiable traces of GE components in milk, meat, and eggs following consumption of GE feed. Globally, countries that are cultivating GE corn and soy are the major livestock feed exporters. Asynchronous regulatory approvals (i.e., cultivation approvals of GE varieties in exporting countries occurring before food and feed approvals in importing countries) have resulted in trade disruptions. This is likely to be increasingly problematic in the future as there are a large number of "second generation" GE crops with altered output traits for improved livestock feed in the developmental and regulatory pipelines. Additionally, advanced techniques to affect targeted genome modifications are emerging, and it is not clear whether these will be encompassed by the current GE process-based trigger for regulatory oversight. There is a pressing need for international harmonization of both regulatory frameworks for GE crops and governance of advanced breeding techniques to prevent widespread disruptions in international trade of livestock feed stuffs in the future.

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Biotechnology Department

Bioinformatics approach helps Researchers find new use for Old drug

noreply@blogger.com (BII Admin) — Tue, 21 Oct 2014 16:19:00 +0530

Developing and testing a new anti-cancer drug can cost billions of dollars and take many years of research. Finding an effective anti-cancer medication from the pool of drugs already approved for the treatment of other medical conditions could cut a considerable amount of time and money from the process. Now, using a novel bioinformatics approach, a team led by investigators at Beth Israel Deaconess Medical Center (BIDMC) has found that the approved antimicrobial drug pentamidine may help in the treatment of patients with advanced kidney cancer. Described online in the journal Molecular Cancer Therapeutics, the discovery reveals how linking cancer gene expression patterns with drug activity might help advance cancer care.

"The strategy of repurposing drugs that are currently being used for other indications is of significant interest to the medical community as well as the pharmaceutical and biotech industries," says senior author Towia Libermann, PhD, Director of the Genomics, Proteomics, Bioinformatics and Systems Biology Center at BIDMC and Associate Professor of Medicine at Harvard Medical School. "Our results demonstrate that bioinformatics approaches involving the analysis and matching of cancer and drug gene signatures can indeed help us identify new candidate cancer therapeutics."

Renal cell cancer consists of multiple subtypes that are likely caused by different genetic mutations. Over the years, Libermann has been working to identify new disease markers and therapeutic targets through gene expression signatures of renal cell cancer that distinguish these different cancer subtypes from each other, as well as from healthy individuals. In this paper, he and his colleagues were looking for drugs that might be effective against clear cell renal cancer, the most common and highly malignant subtype of kidney cancer. Although patients with early stage disease can often be successfully treated through surgery, up to 30 percent of patients with renal cell cancer present with advanced stages of disease at the time of their diagnosis.

To pursue this search, they made use of the Connectivity Map (C-MAP) database (http://www.broadinstitute.org/cmap), a collection of gene expression data from human cancer cells treated with hundreds of small molecule drugs.

"C-MAP uses pattern-matching algorithms to enable investigators to make connections between drugs, genes and diseases through common, but inverse, changes in gene expression," says Libermann. "It provided us with an exciting opportunity to use our renal cell cancer gene signatures and a new bioinformatics strategy to match kidney cancer gene expression profiles from individual patients with gene expression changes inducted by various commonly used drugs."

After identifying drugs that may reverse the gene expression changes associated with renal cell cancer, the investigators used assays to measure the effect of the selected drugs on cells. This led to the identification of a small number of FDA-approved drugs that induced cell death in multiple kidney cancer cell lines. The investigators then tested three of these drugs in an animal model of renal cell cancer and demonstrated that the antimicrobial agent pentamidine (primarily used for the treatment of pneumonia) reduced tumor growth and enhanced survival. Gene expression experiments using microarrays also identified the genes in renal cell cancer that were counteracted by pentamidine.

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Bioinformatics Department

Human genome was shaped by an evolutionary arms race with itself

noreply@blogger.com (BII Admin) — Tue, 30 Sep 2014 11:25:00 +0530

New findings suggest that an evolutionary arms race between rival elements within the genomes of primates drove the evolution of complex regulatory networks that orchestrate the activity of genes in every cell of our bodies.

The arms race is between mobile DNA sequences known as "retrotransposons" (a.k.a. "jumping genes") and the genes that have evolved to control them. The identified genes in humans that make repressor proteins to shut down specific jumping genes. The researchers also traced the rapid evolution of the repressor genes in the primate lineage.

The primate genomes have undergone repeated episodes in which mutations in jumping genes allowed them to escape repression, which drove the evolution of new repressor genes, and so on. The findings suggest that repressor genes that originally evolved to shut down jumping genes have since come to play other regulatory roles in the genome.

Retrotransposons are thought to be remnants of ancient viruses that infected early animals and inserted their genes into the genome long before humans evolved. Now they can only replicate themselves within the genome. Depending on where a new copy gets inserted into the genome, a jumping event can disrupt normal genes and cause disease. Often the effect is neutral, simply adding to the overall size of the genome. Very rarely the effect might be advantageous, because the added DNA can itself be a source of new regulatory elements that enhance gene expression. But the high probability of deleterious effects means natural selection favors the evolution of mechanisms to prevent jumping events.

The jumping genes or "transposable elements" account for at least 50 percent of the human Genome and retrotransposons are by far the most common types. The expansion of this family of repressor genes occurred in response to waves of retrotransposon activity. Because repression of a jumping gene also affects genes located near it on the chromosome, the researchers suspect that these repressors have been co-opted for other gene-regulatory functions, and that those other functions have persisted and evolved long after the jumping genes the repressors originally turned off have degraded due to the accumulation of random mutations.

"The way this type of repressor works, part of it binds to a specific DNA sequence and part of it binds other proteins to recruit a whole complex of proteins that creates a repressive landscape in the genome. The idea that they are involved in repression of jumping genes is not new, previous studies by other researchers have shown that these proteins silence jumping genes in mouse embryonic stem cells. But until now, no one had been able to demonstrate that the same thing occurs in human cells.

The results demonstrated that two human proteins called ZNF91 and ZNF93 bind and repress two major classes of retrotransposons (known as SVA and L1PA) that are currently or recently active in primates. Analysis of primate genomes, including the reconstruction of ancestral genomes, which showed that ZNF91 underwent structural changes 8 to 12 million years ago that enabled it to repress SVA elements.

Experiments with ZNF 93, which shuts down L1PA retrotransposons, provided a striking illustration of the arms race between jumping genes and repressors. The researchers found that, while it is good at shutting down many L1PA elements, there is one subset of a recently evolved lineage of L1PA that has lost a short section of DNA that includes the ZNF93 binding site. Without the binding site, these jumping genes evade repression by ZNF93. Interestingly, when the researchers put the missing sequence back into one of these genes and put it in a mouse cell without ZNF93, they found that it was better at jumping. So even though the sequence helps with jumping activity, losing it gives the jumping gene an advantage in primates by allowing it to escape repression by ZNF93.

Advancements in Biotechnology

noreply@blogger.com (BII Admin) — Mon, 8 Sep 2014 13:53:00 +0530

Biotechnology as the name indicates is the assemblage of technology in science of biology. Modern Biotechnology initiated with the discovery of double helical structure of the DNA. Subsequent investigation that helped in unraveling the process of inheritance pattern provided impetus to biotechnological research. It plays a key role in various areas, such as functional genomics, structural genomics, and proteomics. It soon becomes evident that by the use of suitable plasmid and bacteriophage vectors that transformation and transduction of foreign genes into heterologous hosts could be achieved. This led to the production of therapeutic proteins, transgenic plants and development of many novel vaccines. There are many applications of Biotechnology such as development of various medicines, vaccines, increase of productivity, conservation and animal breeding, improvement of quality of seeds, insecticides and fertilizers.

Career in biotechnology: Biotechnologist can work in pharmaceutical companies, chemical, agriculture and allied industries, bio-processing industries, research laboratories run by the government as well as the corporate sector. Bioinformatics, an application of biotech and an interdisciplinary field that solves biological problems using computational techniques. When most people think of opportunities for careers in biotechnology, they think of a scientist in a white coat in a laboratory developing drugs to improve the quality of life. However, biotechnology has a wide variety of career opportunities ranging from sales and marketing, to research and development, to manufacturing and quality control and assurance.

The biotechnology industry continues to flourish nationwide. Not only are the total number of biotechnology companies increasing, but employment in the biotechnology field continues to grow as well. The biotechnology industry is constantly growing; during the past 10 years the number of employees has increased by more than 90 percent! If you enjoy science, math, technology, investigating and solving problems, and making useful products, a career in biotechnology may be for you. Various biotechnology careers include forensic DNA analyst, scientist, clinical research associate job, laboratory assistant, microbiologist, greenhouse and field technician, bioinformatics specialist, animal caretaker and many more.

Biotech Department

BII Noida

“Global Bioinformatics Market: Industry Size, Trends and Forecast 2014-2018”

noreply@blogger.com (BII Admin) — Mon, 8 Sep 2014 10:54:00 +0530

Global Industry Analysts Inc. (GIA) announces the release of a comprehensive global report on Bioinformatics markets. The global Bioinformatics market is forecast to reach US$6.8 billion by the year 2017. Principal factors driving market growth include significant development in the field of genomics and its ever-growing application in the research and development processes; breakthrough technologies in drug discovery initiatives; and the entry of new market players along with the growth in size and revenues of existing companies. Going forwards, the penetration of genomics in drug discovery is expected to increase further, which bodes tremendous market prospects for bioinformatics.

Research and Development Extent

Backed by significant developments in the area of genomics, there is increase in the overall volume of distinct biological data, which includes protein and gene sequences. This leaves an arduous task for R&D laboratories of analysis. Data management tools based on bioinformatics have helped companies in easing this task, thereby enhancing their productivity by way of identifying new biomarkers for toxicity and drug efficacy, diagnostic biomarkers as well as new drug targets. Bioinformatics help utilization of this gene and protein data and construct interactive models that aid in identifying disease pathways and effects of compounds. The penetration of genomics in drug discovery is expected to witness further growth, which bodes tremendous market prospects for bioinformatics. It is expected that more and more investments would be made by pharmaceutical companies in research and development initiatives, of which a major chunk would be towards bioinformatics. Concerns associated with patent expiries of several blockbuster drugs, shrinking product pipelines, and increasing drug development costs are driving pharma companies to seek help from biotechnology. Bioinformatics, being helpful at every stage of R&D processes in biotechnology and pharmaceutical sectors, offers increasing potential for future growth.

Market Reports Related to Applications in Bioinformatics

The market of bioinformatics report includes market dynamics and trends in order to give a thorough analysis of the overall competitive scenario in the global bioinformatics market. Thus, market overview section of the report demonstrates market dynamics and trends such as the drivers, restraints, and opportunities that influence the current nature and future status of bioinformatics market globally. Impact factors such as market attractiveness analysis (by geography), market share analysis by key players and Porter’s five forces (bargaining power of suppliers, bargaining power of buyers, threat of substitutes, threat of new entrants and competitive rivalry) analysis have also been explained in the market overview section of the report. Further, this report includes average selling price analysis (in terms of USD) and value chain analysis of bioinformatics market.

The global bioinformatics market is classified on the basis of platforms, tools and services. Platforms segment includes market analysis of sequence manipulation platforms, sequence alignment platforms, sequence analysis platforms and structural analysis platforms. Tools segment includes market analysis of general knowledge management tools and specialized knowledge management tools. Services segment includes market analysis of sequencing services, database and management services, data analysis services and other services. A thorough market analysis and forecast for these segments has been provided in this study, in terms of market revenue (USD million) for the period 2012 to 2020. The report also provides compounded annual growth rate (CAGR %) for each segment type for the forecast period of 2014 to 2020, while market size estimations have been made considering 2013 as the base year.

Further, the global bioinformatics market is classified into application namely, preventive medicine, molecular medicine, gene therapy, drug development and others. The present and future market sizes (in terms of USD million) of the above mentioned application segments have been given in the report for the period of 2012- 2020 along with their compound annual growth rate (CAGR %) for the period 2014 to 2020. The study further provides recommendations which would be useful for the current and future market players to sustain and grow in the global bioinformatics market.

The report further includes market analysis of regional markets namely, North America, Europe, Asia-Pacific, and Rest of the World (RoW). A thorough market analysis and forecast for these regional markets has been provided in this study, in terms of market revenue (USD million) for the period 2012 to 2020. The report also provides the compounded annual growth rate (CAGR %) for each regional market for the forecast period of 2014 to 2020, while market size estimations have been made considering 2013 as the base year.

Bioinformatics Companies Concern

Bioinformatics globally is a fairly concentrated market characterized by few large companies and several small players. About 55% of the companies are based in the US, while 30% are based in Europe. Major players profiled in the report include 3rd Millennium Inc., Accelrys Inc., Affymetrix Inc., Agilent Technologies, Celera Group, Gene Logic, Geneva Bioinformatics S.A, IBM Life Sciences, ID Business Solutions Ltd., Instem Scientific Limited (Formerly BioWisdom, Ltd.), Life Technologies Corp., Kinexus Bioinformatics Corp., Nonlinear Dynamics Ltd., among others.

Bioinformatics Department

BII Noida

How lizards regenerate their tails: Researchers discover genetic 'recipe

noreply@blogger.com (BII Admin) — Thu, 21 Aug 2014 16:00:00 +0530

By understanding the secret of how lizards regenerate their tails, researchers may be able to develop ways to stimulate the regeneration of limbs in humans. Now, a team of researchers from Arizona State University is one step closer to solving that mystery. The scientists have discovered the genetic "recipe" for lizard tail regeneration, which may come down to using genetic ingredients in just the right mixture and amounts.An interdisciplinary team of scientists used next-generation molecular and computer analysis tools to examine the genes turned on in tail regeneration. The team studied the regenerating tail of the green anole lizard (Anolis carolinensis), which when caught by a predator, can lose its tail and then grow it back.

"Lizards basically share the same toolbox of genes as humans," said lead author Kenro Kusumi, professor in ASU's School of Life Sciences and associate dean in the College of Liberal Arts and Sciences. "Lizards are the most closely-related animals to humans that can regenerate entire appendages. We discovered that they turn on at least 326 genes in specific regions of the regenerating tail, including genes involved in embryonic development, response to hormonal signals and wound healing."

Other animals, such as salamanders, frog tadpoles and fish, can also regenerate their tails, with growth mostly at the tip. During tail regeneration, they all turn on genes in what is called the 'Wnt pathway' -- a process that is required to control stem cells in many organs such as the brain, hair follicles and blood vessels. However, lizards have a unique pattern of tissue growth that is distributed throughout the tail.

"Regeneration is not an instant process," said Elizabeth Hutchins, a graduate student in ASU's molecular and cellular biology program and co-author of the paper. "In fact, it takes lizards more than 60 days to regenerate a functional tail. Lizards form a complex regenerating structure with cells growing into tissues at a number of sites along the tail."

"We have identified one type of cell that is important for tissue regeneration," said Jeanne Wilson-Rawls, co-author and associate professor with ASU's School of Life Sciences. "Just like in mice and humans, lizards have satellite cells that can grow and develop into skeletal muscle and other tissues."

"Using next-generation technologies to sequence all the genes expressed during regeneration, we have unlocked the mystery of what genes are needed to regrow the lizard tail," said Kusumi. "By following the genetic recipe for regeneration that is found in lizards, and then harnessing those same genes in human cells, it may be possible to regrow new cartilage, muscle or even spinal cord in the future."

The researchers hope their findings will help lead to discoveries of new therapeutic approaches to spinal cord injuries, repairing birth defects, and treating diseases such as arthritis.The research team included Kusumi, Hutchins, Wilson-Rawls, Alan Rawls, and Dale DeNardo from ASU School of Life Sciences, Rebecca Fisher from ASU School of Life Sciences and the University of Arizona College of Medicine Phoenix, Matthew Huentelman from the Translational Genomic Research Institute, and Juli Wade from Michigan State University. This research was funded by grants from the National Institutes of Health and Arizona Biomedical Research Commission.

By:-

Keerti Mishra

Faculty Of Biotechnology

When Will We Have a Vaccine for Ebola Virus?

noreply@blogger.com (BII Admin) — Wed, 13 Aug 2014 16:55:00 +0530

The deadly Ebola outbreak in west Africa highlights the urgent need for a vaccine, and researchers say one may be available in a few years

Source: Scientific American

The latest outbreak of Ebola virus in west Africa is the worst ever—as of Monday, it had infected more than 1,200 people and claimed at least 672 victims since this spring. Guinea, Liberia and Sierra Leone all have confirmed cases. An official at Doctors Without Borders has declared the outbreak as “totally out of control,” according to NBC News. Unfortunately, doctors have no effective vaccines or therapies. Health care workers can only attempt to support patients’ immune systems (regulating fluids, oxygen levels, blood pressure and treating other infections) to help the afflicted fight off the virus as best they can.

A vaccine to help battle future Ebola outbreaks may be just a few years away, however. During the past decade researchers have made significant progress, and vaccines have worked in nonhuman primates. But it has been hard to raise money for human safety tests. To learn about the latest advances as well as obstacles, Scientific American spoke to Thomas Geisbert, a virologist in the Department of Microbiology and Immunology at The University of Texas Medical Branch at Galveston. He’s studied the Ebola virus since 1988 and is currently involved in vaccine research and development.

Are there any promising vaccines in development for the Ebola virus?
There are quite a few preventative vaccines in development, with three to five that have been shown to completely protect nonhuman primates against Ebola. Some of these vaccines require three injections or more and some require just a single injection. Most of them are being funded by the U.S. government, so they’re in various stages of development, but none of them are licensed.

The hang-up point with these vaccines is the phase I trials in humans. That’s where scientists get frustrated because we know these vaccines protect animals and we don’t quite understand the regulatory process of why things can’t move faster. I can’t give you an answer as to why it’s taking so long.

Why doesn’t the human immune system fight the virus off?
The Ebola virus is usually transmitted by close contact and the first cells it affects are cells important to your primary immune response—monocytes, macrophages and dendritic cells. These cells are important because they’re the first to recognize that something foreign has entered your body and the first cells to trigger your innate immune system to fight off the infection. This makes it hard to mount an effective immune response against the virus—your body has a tough time fighting the virus off, and the virus multiplies to the point that it takes over major organs in your body.
I’ll give you an example of how a vaccine might work. The vaccine VSV is probably one of the most promising, and it’s based on a viral vector related to the rabies virus. It’s a bullet-shaped particle, and on its surface is a structural protein called a “glycoprotein,” which allows a virus to recognize a host cell, bind to it and take over the host cell’s machinery. With a vaccine, we remove the gene that encodes the glycoprotein of the VSV virus and we replace it with a gene that encodes the glycoprotein of Ebola. You end up with a vaccine that has an Ebola glycoprotein on the surface. Now, it doesn’t behave like Ebola because the rest of its genome is not Ebola, but because it has the Ebola glycoprotein your body is going to recognize it as foreign and build up an immune response against Ebola.

How far along in development is the VSV vaccine?
It’s at the point now where we’re trying to get the funds to do the human studies.

What are the biological challenges of developing a vaccine for Ebola?
There are some vaccines that are “replication defective,” meaning they don’t replicate, and they tend to be safer. Then there are other vaccines that are more efficacious, but they’re “replication competent.” An example of the latter would be the measles vaccine or yellow fever vaccine. They’re usually crippled, so they’re not as dangerous as a wild type virus but certain people could have an adverse event when given a vaccine that’s replication competent.

Replication-competent vaccines may only require a single injection whereas with the replication-defective vaccines you might have to get boosters every year, because they’re not as efficient. So do you go for a vaccine that protects humans in a single injection? In Africa you almost have to, because in an area like that you’re lucky to get someone into a clinic to be vaccinated once. It’s a trade-off—efficacy versus safety. That’s one of the biggest challenges.

Can you give an estimate for when we might have an effective Ebola virus vaccine?
My guess is anywhere from two to six years. I hate to say this, but it really depends on financial support for the small companies that develop these vaccines. Human studies are expensive and require a lot of government dollars.
I would like to see a situation where we tried to advance our lead candidate vaccines as fast as we can to get phase I studies done. I think we should start with the first responders—the health care workers in areas of high risk. This outbreak is so unique because it’s occurring in an area we’ve never seen it before and also because it seems there’s a higher percentage of medical staff infected than we’ve seen before. I’ve seen all of these vaccines work in numerous animals and I’ve never seen an adverse event from them. I appreciate the safety concerns but it would be great if there were some way to fast-track this. People are being exposed to Ebola and there’s a 60 to 90 percent chance they’re going to die—I think we have to look at it in this context.

Faculty of Bii

Ankita

Merck Serono initiates phase II study of anti-PD-L1 antibody MSB0010718C in metastatic Merkel cell carcinoma

noreply@blogger.com (BII Admin) — Fri, 1 Aug 2014 11:37:00 +0530

Merck Serono, the biopharmaceutical division of Merck, announced the initiation of an international Phase II study designed to assess the efficacy and safety of MSB0010718C, an investigational fully human IgG1 monoclonal antibody that binds to programmed death-ligand 1 (PD-L1). This multicenter, single-arm, open-label study is being conducted in patients with metastatic Merkel cell carcinoma (mMCC), a rare and aggressive type of skin tumor,1,2who have previously received one line of chemotherapy. It is expected to recruit 84 patients across Asia Pacific, Australia, Europe and North America.

The primary endpoint of the study is overall response.

The PD-L1/PD-1 pathway is implicated as a major mechanism by which tumors evade elimination by the immune system.3 The PD-L1 molecule is expressed in many cancer types, including mMCC.3,4 MSB0010718C, which blocks the interaction of PD-L1 with its receptor PD-1, may have the potential to restore effective anti-tumor T-cell responses and thereby to inhibit tumor growth.

Immune mechanisms are implicated in the pathogenesis of MCC, with an increased risk observed in immunosuppressed individuals.5 MCC also is associated with the presence of the Merkel cell polyomavirus, which may have a role in tumor formation.6 Globally, the incidence of MCC is increasing, and outcomes for patients with this disease are poor.1,2 Therefore, new treatment approaches are required to improve the outcome of patients with this type of cancer.

Fig: Cell internal structure during merkel cell carcinoma

"We believe that modulating the immune system by targeting PD-L1 represents a promising new approach in the treatment of this aggressive cancer, especially considering that many of the predisposing factors for mMCC seem to be related to functional disruptions of the immune system," said Helen Sabzevari, Senior Vice President of Immuno-Oncology at Merck Serono. "Our anti-PD-L1 compound may present a potential new approach for the treatment of mMCC patients. The initiation of this Phase II study is an important milestone, as we endeavor to help those suffering from mMCC, a devastating disease with significant unmet need."

In addition to this new study in mMCC, MSB0010718C is currently being explored in a Phase I clinical trial for the treatment of solid tumors. The study aims to recruit 590 patients and has enrolled 422 patients to date. On June 1, 2014, Merck Serono presented initial data from this dose escalation study in solid tumors at the annual American Society of Clinical Oncology (ASCO) meeting in Chicago.7 This study is currently recruiting patients into expansion cohorts in seven cancer types: castrate-resistant prostate cancer, colorectal cancer, gastric/gastroesophageal cancer, melanoma, metastatic breast cancer, non-small cell lung cancer and ovarian cancer.

About MSB0010718C

MSB0010718C is an investigational fully human IgG1 monoclonal antibody that binds to the PD-L1 (programmed death-ligand 1) protein, which is present at high levels in many cancer types. By competitively blocking the interaction with PD-1 receptors, it is believed that MSB0010718C thereby restores anti-tumor T-cell responses.

About Merkel cell carcinoma (MCC)

MCC is a rare and aggressive disease in which cancer cells form in the top layer of the skin, close to nerve endings. MCC, which is also known as neuroendocrine carcinoma of the skin or trabecular cancer, often starts in those areas of skin that are most often exposed to the sun, including the head and neck, arms, legs, and trunk. Risk factors for MCC include sun exposure and having a weak immune system (i.e., solid-organ transplant recipients, people with HIV/AIDS and people with other cancers, such as chronic lymphocytic leukemia, are at higher risk). Caucasian males over age 50 are at increased risk.

MCC tends to metastasize at an early stage, spreading initially to nearby lymph nodes, and then potentially to more distant areas in the body, including other lymph nodes or areas of skin, lungs, brain, bones, or other organs.

Current treatment options for MCC include surgery, radiation and chemotherapy. Treatment for metastatic or Stage IV MCC is generally palliative.

Effects of starvation can be passed to future generations, through small RNAs apparently without DNA involvement

noreply@blogger.com (BII Admin) — Fri, 18 Jul 2014 12:52:00 +0530

Source: Columbia University Medical Center

Evidence from human famines and animal studies suggests that starvation can affect the health of descendants of famished individuals. But how such an acquired trait might be transmitted from one generation to the next has not been clear. A new study, involving roundworms, shows that starvation induces specific changes in so-called small RNAs and that these changes are inherited through at least three consecutive generations, apparently without any DNA involvement. The study, conducted by Columbia University Medical Center (CUMC) researchers, offers intriguing new evidence that the biology of inheritance is more complicated than previously thought. The study was published in the July 10 online edition of the journal Cell.

The idea that acquired traits can be inherited dates back to Jean Baptiste Larmarck (1744-1829), who proposed that species evolve when individuals adapt to their environment and transmit the acquired traits to their offspring. According to Lamarckian inheritance, for example, giraffes developed elongated long necks as they stretched to feed on the leaves of high trees, an acquired advantage that was inherited by subsequent generations. In contrast, Charles Darwin (1809-82) later theorized that random mutations that offer an organism a competitive advantage drive a species' evolution. In the case of the giraffe, individuals that happened to have slightly longer necks had a better chance of securing food and thus were able to have more offspring. The subsequent discovery of hereditary genetics supported Darwin's theory, and Lamarck's ideas faded into obscurity.

"However, events like the Dutch famine of World War II have compelled scientists to take a fresh look at acquired inheritance," said study leader Oliver Hobert, PhD, professor of biochemistry and molecular biophysics and a Howard Hughes Medical Institute Investigator at CUMC. Starving women who gave birth during the famine had children who were unusually susceptible to obesity and other metabolic disorders, as were their grandchildren. Controlled animal experiments have found similar results, including a study in rats demonstrating that chronic high-fat diets in fathers result in obesity in their female offspring.

In a 2011 study, Oded Rechavi, a postdoctoral fellow in Dr. Hobert's laboratory, found that roundworms (C. elegans) that developed resistance to a virus were able to pass along that immunity to their progeny for many consecutive generations. The immunity was transferred in the form of small viral-silencing RNAs working independently of the organism's genome. Other studies have reported similar findings, but none of these addressed whether a biological response induced by natural circumstances, such as famine, could be passed on to subsequent generations.

To address this question, Dr. Hobert's team starved roundworms for six days and then examined their cells for molecular changes. The starved roundworms, but not controls, were found to have generated a specific set of small RNAs. (Small RNAs are involved in various aspects of gene expression but do not code for proteins.) The small RNAs persisted for at least three generations, even though the worms were fed normal diets. The researchers also found that these small RNAs target genes with roles in nutrition.

Since these small RNAs are produced only in response to starvation, they had to have been passed from one generation to another. "We know from other studies that small RNAs can be transported from cell to cell around the body," said Dr. Hobert. "So, it's conceivable that the starvation-induced small RNAs found their way into the worms' germ cells -- that is, their sperm or eggs. When the worms reproduced, the small RNAs could have been transmitted generationally in the cell body of the germ cells, independent of the DNA."

The study also found that the progeny of the starved worms had a longer life span than the progeny of the controls. "We have not shown that the starvation-induced small RNAs were responsible for the increased longevity -- it's just a correlation," said Dr. Hobert. "But it's possible that these small RNAs provided a means for the worms to control the expression of relevant genes in later generations."

The findings have no immediate clinical application. "However, they do suggest that we should be aware of other things -- beyond pure DNA changes -- that may have a long-term impact on the health of an organism," said Dr. Hobert. "In other words, something that happened to one generation, whether famine or some other traumatic event, may be relevant to the health of its descendants for generation.

By:

Ankita Nagpal

Faculty BII