Archive for March 2010

Surgeons Transplant New Trachea Into Child Using His Own Stem Cells to Rebuild Airway

Posted on Friday, March 26, 2010 by sai kiran reddy

Surgeons Transplant New Trachea Into Child Using His Own Stem Cells to Rebuild Airway

Sai kiran (Mar. 26, 2010) — UCL scientists and surgeons have led a revolutionary operation to transplant a new trachea into a child, using the child's own stem cells to rebuild the airway in the body.

Still image from a video showing a visualization of the transplantation operation using the new trachea. (Credit: Paolo Macchiarini)

The boy, who has not been named, is recovering from surgery but his condition is stable and he is breathing unaided.
He was born with a rare condition called Long Segment Tracheal Stenosis -- a tiny windpipe that does not grow and restricts breathing.
Shortly after birth, he underwent a conventional trachea transplant at Great Ormond Street Hospital for Children (GOSH), but his condition deteriorated last November when a metal stent implanted in that operation began to erode into the aorta, a key artery, causing severe bleeding.
Scientists and surgeons at UCL, GOSH, the Royal Free Hampstead NHS Trust, and the Careggi University Hospital in Florence, Italy, developed a new technique to treat the life-threatening condition.
They stripped cells from a donated trachea, used it to replace the entire length of the damaged airway, and then used the child's own bone marrow stem cells to seal the airway in the body.
Dr Mark Lowdell, Director of Cellular Therapy at Royal Free Hospital and a senior lecturer at UCL Medical School, received the donor trachea from Italy and some bone marrow from the patient at the beginning of surgery.
He and his colleagues prepared two different types of stem cells from the bone marrow together with some growth signalling chemicals and returned them to GOSH with the donor trachea.
Professor Paolo Macchiarini, from Careggi University Hospital, who is an Honorary Consultant at GOSH and Honorary Professor at UCL, applied the cells and the growth factors to the trachea in the operating theatre.
Martin Elliot, Professor of Cardiothoracic Surgery at UCL and Director of the Tracheal Service at GOSH, led the operation to repair the damaged aorta and implant the new trachea.
The application of this technology -- which has never been used on a child before -- should reduce greatly the risk of rejection of the new trachea, as the child's stem cells will not generate any immune response.
Professor Martin Birchall, UCL lead for translational regenerative medicine, who is also a head and neck surgeon specialising in airways and voice, led on ethics and regulatory approvals.
Professor Birchall and Professor Macchiarini achieved the world's first stem cell-based organ transplant on an adult patient in 2008.
Since moving to a Chair at the UCL Ear Institute in 2009, Professor Birchall has developed a research programme with Professor Elliott which includes, for example, the absorbable stent (supporting tube) used in this 10-year-old patient.
When the patient presented to Professor Elliott, Professor Birchall pulled together the various team members into a functional unit capable of delivering a stem cell implant as quickly as possible.
He said: "Professor Macchiarini's seminal work, together with the UCL team, has now saved the life of two adults and one child. We have shown that stem cell-based treatments can save lives and can be used in the creation of living structures which draw upon the body's own natural healing mechanisms for their support.
"The step-wise progression in technique from first patient to the present has delivered a highly streamlined, rapid process. This means that such treatments potentially can be moved out of the hands of a tiny number of specialist centres into many hospitals around the world, including those in developing countries."

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Plant Breeding Breakthrough: Offspring With Genes from Only One Parent

Posted on Thursday, March 25, 2010 by sai kiran reddy


Plant Breeding Breakthrough: Offspring With Genes from Only One Parent


Sai kiran (Mar. 25, 2010) — A reliable method for producing plants that carry genetic material from only one of their parents has been discovered by plant biologists at UC Davis. The technique, to be published March 25 in the journal Nature, could dramatically speed up the breeding of crop plants for desirable traits.
Researchers have developed a new method for producing plants that carry genetic material from only one of their parents. (Credit: iStockphoto)

The discovery came out of a chance observation in the lab that could easily have been written off as an error.
"We were doing completely 'blue skies' research, and we discovered something that is immediately useful," said Simon Chan, assistant professor of plant biology at UC Davis and co-author on the paper.
Like most organisms that reproduce through sex, plants have paired chromosomes, with each parent contributing one chromosome to each pair. Plants and animals with paired chromosomes are called diploid. Their eggs and sperm are haploid, containing only one chromosome from each pair.
Plant breeders want to produce plants that are homozygous -- that carry the same trait on both chromosomes. When such plants are bred, they will pass the trait, such as pest resistance, fruit flavor or drought tolerance, to all of their offspring. But to achieve this, plants usually have to be inbred for several generations to make a plant that will "breed true."
The idea of making a haploid plant with chromosomes from only one parent has been around for decades, Chan said. Haploid plants are immediately homozygous, because they contain only one version of every gene. This produces true-breeding lines instantly, cutting out generations of inbreeding.
Existing techniques to make haploid plants are complicated, require expensive tissue culture and finicky growing conditions for different varieties, and only work with some crop species or varieties. The new method discovered by Chan and postdoctoral scholar Ravi Maruthachalam should work in any plant and does not require tissue culture.
Ravi and Chan were studying a protein called CENH3 in the laboratory plant Arabidopsis thaliana. CENH3 belongs to a group of proteins called histones, which package DNA into chromosomes. Among the histones, CENH3 is found only in the centromere, the part of the chromosome that controls how it is passed to the next generation.
When cells divide, microscopic fibers spread from each end of the cell and attach at the centromeres, then pull the chromosomes apart into new cells. That makes CENH3 essential for life.
Ravi had prepared a modified version of CENH3 tagged with a fluorescent protein, and was trying to breed the genetically modified plants with regular Arabidopsis. According to theory, the cross should have produced offspring containing one mutant gene (from the mother) and one normal gene (from the father). Instead, he got only plants with the normal gene.
"At first we threw them away," Chan said. Then it happened again.
Ravi, who has a master's degree in plant breeding, looked at the plants again and realized that the offspring had only five chromosomes instead of 10, and all from the same parent.
The plants appear to have gone through a process called genome elimination, Chan said. When plants from two different but related species are bred, chromosomes from one of the parents are sometimes eliminated.
Genome elimination is already used to make haploid plants in a few species such as maize and barley. But the new method should be much more widely applicable, Ravi said, because unlike the process for maize and barley, its molecular basis is firmly understood.
"We should be able to create haploid-inducing lines in any crop plant," Ravi said. Once the haploid-inducing lines are created, the technique is easy to use and requires no tissue culture -- breeders could start with seeds. The method would also be useful for scientists trying to study genes in plants, by making it faster to breed genetically pure lines.
After eliminating half the chromosomes, Chan and Ravi had to stimulate the plants to double their remaining chromosomes so that they would have the correct diploid number. Plants with the haploid number of chromosomes are sterile.
The research also casts some interesting light on how species form in plants. CENH3 plays the same crucial role in cell division in all plants and animals. Usually, such important genes are highly conserved -- their DNA is very similar from yeast to whales. But instead, CENH3 is among the fastest-evolving sequences in the genome.
"It may be that centromere differences create barriers to breeding between species," Chan said. Ravi and Chan plan to test this idea by crossing closely-related species.
The work was supported by a grant from the Hellman Family Foundation.

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Mouse Work: New Insights on a Fundamental DNA Repair Mechanism

Posted on Wednesday, March 24, 2010 by sai kiran reddy


Mouse Work: New Insights on a Fundamental DNA Repair Mechanism


Sai kiran (Mar. 24, 2010) — Adding a new link to our understanding of the complex chain of chemistry that keeps living cells alive, a team of researchers from the University of Vermont (UVM), the University of Utah, Vanderbilt University and the National Institute of Standards and Technology (NIST) has demonstrated for the first time the specific activity of the protein NEIL3, one of a group responsible for maintaining the integrity of DNA in humans and other mammals.
New research on a house mouse enzyme, Mus musculus NEIL3, sheds new light on a fundamental DNA repair mechanism. (Credit: iStockphoto/Emily Goodwin)

Their work, published in theProceedings of the National Academy of Sciences, sheds new light on a potentially important source of harmful DNA mutations.
Since it first was identified about eight years ago, NEIL3 has been believed to be a basic DNA-maintenance enzyme of a type called a glycosylase. These proteins patrol the long, twisted strands of DNA looking for lesions -- places where one of the four DNA bases has been damaged by radiation or chemical activity. They cut the damaged bases free from the DNA backbone, kicking off follow-on mechanisms that link in the proper undamaged base. The process is critical to cell health, says NIST biochemist and Senior Research Fellow Miral Dizdaroglu, "DNA is damaged all the time. About one to two percent of oxygen in the body becomes toxic in cells, for example, creating free radicals that damage DNA. Without these DNA repair mechanisms there wouldn't be any life on this planet, really."
The glycosylases seem to be highly specific; each responds to only a few unique cases of the many potential DNA base lesions. Figuring out exactly which ones can be challenging. NEIL3 and its kin NEIL1 and NEIL2 are mammalian versions of an enzyme found in the bacterium E. coli, which first was identified in work at UVM. The lesion targets of NEIL1 and NEIL2 have been known for some time, but NEIL3, a much more complicated protein twice the size of the others, had resisted several attempts to purify it and determine just what it does. In a significant advance, a research team at UVM managed to clone the house mouse version of NEIL3 (99 percent identical to the human variant), and then prepare a truncated version of it that was small enough to dissolve in solution for analysis but large enough to retain the portion of the protein that recognizes and excises DNA lesions.
Using a technique they developed for rapidly analyzing such enzymes, NIST researchers Dizdaroglu and Pawel Jaruga mixed the modified protein with sample DNA that had been irradiated to produce large numbers of random base lesions. Because glycosylases work by snipping off damaged bases, a highly sensitive analysis of the solution after the DNA has been removed can reveal just which lesions are attacked by the enzyme, and with what efficiency. The NIST results closely matched independent tests by others in the team that match the enzyme against short lengths of DNA-like strands with a single specific target lesion.
In addition to finally confirming the glycosylase nature of NEIL3, says UVM team leader Susan Wallace, tests of the enzyme in a living organism -- a tailored form of E. coli designed to have a very high mutation rate -- had an unexpected bonus. Measurements at NIST showed that NEIL3 is extremely effective at snipping out a particular type of lesion called FapyGua (2,6-diamino-4-hydroxy-5-formamidopyrimidine) and seems to dramatically reduce mutations in the bacterium, a result that points both to the effectiveness of NEIL3 and the potentially important role of FapyGua in causing dangerous mutations in DNA.

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Sea Creatures' Sex Protein Provides New Insight Into Diabetes

Posted on Tuesday, March 23, 2010 by sai kiran reddy


Sea Creatures' Sex Protein Provides New Insight Into Diabetes


Sai kiran (Mar. 23, 2010) — A genetic accident in the sea more than 500 million years ago has provided new insight into diabetes, according to research from Queen Mary, University of London.
Sea urchin. (Credit: iStockphoto/Steven Maltby)

Professor Maurice Elphick, from Queen Mary's School of Biological and Chemical Sciences, says his findings could help to explain a rare form of the disease that causes sufferers to urinate more than three litres every day.
As reported in the journal Gene, Professor Elphick has discovered that some marine animals produce 'NG peptides' -- proteins that help the creatures release their eggs and sperm at the same time. Critically, it emerges that NG peptides are made by a gene very similar to the mutant gene that causes diabetes insipidus.
He says: "Genetic tests on patients with diabetes insipidus show their symptoms are caused by an inability to produce the hormone vasopressin, which tells the body how much urine to make.
"I have discovered that marine animals, like sea urchins and acorn worms, produce NG peptides in much the same way to how our brain cells produce vasopressin. This similarity can be traced back to a one-off genetic accident in one of our ancient sea-dwelling ancestors, when a gene for vasopressin-like molecules mutated and became associated with a gene for NG peptides."
Asked about the medical relevance of his discovery, Professor Elphick said: "By researching further into how animals like sea urchins produce NG peptides, we will understand better why the faulty human vasopressin gene can cause this form of diabetes in around 10,000 people in the UK.

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Cracking the Plant-Cell Membrane Code

by sai kiran reddy


Cracking the Plant-Cell Membrane Code


Sai kiran (Mar. 23, 2010) — To engineer better, more productive crops and develop new drugs to combat disease, scientists look at how the sensor-laden membranes surrounding cells control nutrient and water uptake, secrete toxins, and interact with the environment and neighboring cells to affect growth and development. Remarkably little is known about how proteins interact with these protective structures. With National Science Foundation funding, researchers at the Carnegie Institution's Department of Plant Biology are using the first high-throughput screen for any multicellular organism to pinpoint these interactions using the experimental plant Arabidopsis.

Researchers have analyzed some 3.4 million potential protein/membrane interactions and have found 65,000 unique relationships. (Credit: Image courtesy of Carnegie Institution)

They have analyzed some 3.4 million potential protein/membrane interactions and have found 65,000 unique relationships. They made the preliminary data available to the biological community by way of the . Since proteins are similar in all organisms, the work is relevant to fields from farming to medicine.
"This is just the beginning," remarked Wolf Frommer director of Carnegie's Department of Plant Biology. "Arabidopsis shares many of its genes with other organisms including humans. As the library of interacting proteins grows, scientists around the world will be able to study the details of protein interactions to understand how they are affected by forces such as climate change and disease and how they can be harnessed to produce better crops and medicines more effectively."
All of a cell's internal machinery relies on the binding of proteins. Complementary shaped proteins dock with one another to start processes, such as turning on a gene or letting in the proper nutrient. These membrane proteins make up some 20-30% of the proteins in Arabidopsis, a relative of the mustard plant.
The team uses a screen called the mating-based protein complementation assay, or split ubiquitin system. Ubiquitin is a small protein. The scientists fuse candidate proteins onto a version of ubiquitin that is split in half. When the two candidates interact, the two halves of the ubiquitin reassemble, triggering a process that liberates a transcription factor -- a protein that switches a gene on -- which then goes to the nucleus. When genes are turned on in the nucleus, the researchers are alerted to the successful interaction. The ultimate goal is to test the 36 million potential interactions as well as the sensitivity of the interactions to small molecules with a high-throughput robotics system.
The group plans to start a second round of screening at the end of this month to test another 3.4 million interactions.
This work was made possible by grants from NSF 2010 : Towards a comprehensive Arabidopsis protein interactome map: Systems biology of the membrane proteins and signalosomes (grant MCB-0618402) in addition to support from Carnegie. Other participants on the 2010 project include UCSD, Penn State and the University of Maryland. The group previously donated 2010 clones to the Arabidopsis Biological Resource Center (ABRC is at Ohio State University), and more recently another 1010 for other scientists to use to help advance fields from medicine to farming.

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Researchers Discover Two New Ways to Kill TB Bacteria; Findings Could Help Tame Extremely Drug-Resistant Strains

Posted on Monday, March 22, 2010 by sai kiran reddy


Researchers Discover Two New Ways to Kill TB Bacteria; Findings Could Help Tame Extremely Drug-Resistant Strains


Sai kiran (Mar. 22, 2010) — Researchers at Albert Einstein College of Medicine of Yeshiva University have found two novel ways of killing the bacteria that cause tuberculosis (TB), a disease responsible for an estimated two million deaths each year. The findings, published in the March 21 online issue of Nature Chemical Biology, could lead to a potent TB therapy that would also prevent resistant TB strains from developing.
"This approach is totally different from the way any other anti-TB drug works," says William R. Jacobs, Jr., Ph.D., the study's senior author and professor of microbiology & immunology and of genetics at Einstein, as well as a Howard Hughes Medical Institute investigator. "In the past few years, extremely drug resistant strains of TB have arisen that can't be eliminated by any drugs, so new strategies for attacking TB are urgently needed."
Tuberculosis is caused by the bacterial species Mycobacterium tuberculosis. In searching for a new Achilles' heel for M. tuberculosis, Dr. Jacobs and colleagues focused on an enzyme called GlgE. Previous research had suggested that GlgE might be essential for the growth of TB bacteria. GlgE would also be an excellent drug target because there are no enzymes similar to it in humans or in the bacteria of the human gut.
The GlgE research revealed a previously unknown enzymatic pathway by which TB bacteria convert the sugar trehalose (consisting of two glucose molecules) into longer sugar molecules known as alpha glucans -- building blocks that are essential for maintaining bacterial structure and for making new microbes through cell division. GlgE was the third of four enzymes involved in this pathway leading to alpha glucans molecules.
Sure enough, when the researchers inhibited GlgE, the bacteria underwent "suicidal self-poisoning": a sugar called maltose 1-phosphate accumulated to toxic levels that damaged bacterial DNA, causing the death of TB bacteria grown in Petri dishes as well as in infected mice.
"We were amazed when we knocked out GlgE that we saw this DNA damage response," says Dr. Jacobs. "That's usually a very effective way to kill bacteria, when you start damaging the DNA."
The researchers discovered a second way of killing TB after observing a crucial connection between their novel alpha glucan pathway and a second pathway that also synthesizes alpha glucans.
When the researchers knocked out one of the other enzymes in their novel pathway, the pathway's shutdown didn't kill the bacteria; similarly, inactivating an enzyme called Rv3032 in the second alpha glucan pathway failed to kill the microbes. But inactivating both of those enzymes caused what the researchers term synthetic lethality: two inactivations that separately were nonlethal but together cause bacterial death.
"The bacteria that cause TB need to synthesize alpha glucans," notes Dr. Jacobs. "And from the bacterial point of view, you can't knock out both of these alpha glucan pathways simultaneously or you're dead. So if we were to make drugs against GlgE and Rv3032, the combination would be extremely potent. And since TB bacteria need both of those alpha glucan pathways to live, it's very unlikely that this combination therapy would leave behind surviving bacteria that could develop into resistant strains."
Dr. Jacobs adds that findings from this study could also enhance treatment of diseases caused by other species of mycobacteria. Leprosy, for example, which still occurs in the U.S. and other countries, is caused by a mycobacterium related to TB. Treating leprosy now involves using several different drugs, some of which are also used to treat tuberculosis.
The group's paper appears in the March 21 online edition ofNature Chemical Biology. In addition to Dr. Jacobs, other Einstein researchers involved in the study were Rainer Kalscheuer, Ph.D., Brian Weinrick, Ph.D., and Karolin E. Biermann, M.S. Other researchers include Karl Syson and Stephen Bornemann, John Innes Centre; Zhen Liu and James C. Sacchettini, Texas A&M University; and Usha Veeraraghavan and Gurdyal Besra; University of Birmingham in the United Kingdom.
Albert Einstein College of Medicine has filed a patent application on the discoveries described in the paper.



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Wide Variety of Genetic Splicing in Embryonic Stem Cells Identified

Posted on Sunday, March 21, 2010 by sai kiran reddy


Sai kiran (Mar. 21, 2010) — Like tuning in to an elusive radio frequency in a busy city, human embryonic stem cells must sort through a seemingly endless number of options to settle on the specific genetic message, or station, that instructs them to become more-specialized cells in the body (Easy Listening, maybe, for skin cells, and Techno for neurons?). Now researchers at the Stanford University School of Medicine have shown that this tuning process is accomplished in part by restricting the number of messages, called transcripts, produced from each gene.
Michael Snyder's research sheds light on the flexibility exhibited by embryonic stem cells. (Credit: Steve Fisch Photography)

Most genes can yield a variety of transcripts through a process called splicing. Variations in the ways a gene is spliced can change the form and function of the final protein product. Nearly all our genes can be spliced in more than one way. This research is the first time, however, that splicing variety has been linked to the unprecedented developmental flexibility, or pluripotency, exhibited by embryonic stem cells.
"The embryonic stem cells are loaded with many splicing variants for each gene," said Michael Snyder, PhD, chair of Stanford's genetics department. "But as the cells differentiate and become more specialized, the number of types of transcripts decreases."
Snyder and his colleagues studied the changes in RNA transcript levels occurring as the embryonic stem cells were induced in a laboratory dish to differentiate into neural cells. (The creation of RNA transcripts is an intermediate step in the generation of proteins from DNA.) In the process they generated a unique "dictionary" of neural-specific splicing variants, or isoforms.
"We've identified an extremely comprehensive suite of neural-specific transcripts that will be very powerful," said Snyder. "We can begin to study neural differentiation with a degree of precision that's never been dreamed of before."
Snyder is the Stanford W. Ascherman, MD, FACS, Professor in Genetics and a member of Stanford's Cancer Center. He is the senior author of the research, which will be published online March 1 in the Proceedings of the National Academy of Sciences. The study's first author is postdoctoral scholar Jia Qian Wu, PhD.
One way to understand gene splicing is to think of it like this: Genes are made up of several "words" of DNA called exons. These exons are separated from one another on the cell's raw genetic material by intervening bits of unexpressed DNA. By changing the way the exons are joined, or spliced, together in the final RNA transcript, the cell can generate several related, yet distinct, protein products, or "sentences" from each gene. These RNA variants are called RNA isoforms -- and they're important in many biological processes, from generating antibodies to detoxifying drugs.
Snyder and Wu used a method of RNA sequencing Snyder invented while at Yale University called RNA-Seq to track the many RNA isoforms found at varying levels in human embryonic stem cells. The technique can identify a much greater range of RNA transcript levels and is much more sensitive than more traditional methods like DNA microarray analysis. That means it's possible to more reliably detect rare isoforms, and, as a result, more accurately plumb the secret transcriptional life of an embryonic stem cell -- which turns out to be richer than previously imagined.
"The average human gene is known to have four or five transcripts," said Snyder. "But that number will likely go much higher now with this new technology. We are measuring these with a degree of specificity that's never been possible before." Choosing which genes to express, and then how to splice those genes, adds a layer of complexity that allows a cell to fine-tune its final protein profile.
The researchers chose to study neural differentiation in a laboratory dish, rather than in the brain, because it's possible to start with and follow populations of purified cells. They monitored the variety of RNA isoforms found in the human embryonic stem cells and compared them to those found in the cells as they were coaxed through three stages of differentiation into neural cells called glia. At each stage, they found, the variety of isoforms in the cells decreased -- a phenomenon they termed "isoform specialization" -- as they settled into their chosen station.
When the researchers looked more closely, they saw that the isoforms remaining were involved in key neural signaling pathways or cellular receptors. Furthermore, at the earliest stages of their differentiation, the nascent glial cells contain isoforms for receptors found on many other types of neural cells -- suggesting they could be induced down several other developmental pathways.
Finally, the value of the researcher's transcript "dictionary" is hinted at by the finding that the timing of expression of two genes important in neural differentiation -- SOX1 and PAX6 -- in humans is different than that observed in mice.
Snyder and Wu collaborated with researchers from Yale University, Imperial College London and 454 Life Sciences Sequencing Center in Branford, Conn., to conduct the research. The research was supported by the National Institutes of Health, the state of Connecticut and the IOG Trust

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Even Oysters Pay Taxes: 'Metabolic Taxation' Accounts for Part of Difference Between Fast and Slow Growth of Animals

Posted on Saturday, March 20, 2010 by sai kiran reddy


Even Oysters Pay Taxes: 'Metabolic Taxation' Accounts for Part of Difference Between Fast and Slow Growth of Animals


Sai kiran (Mar. 20, 2010) — In physical, as in financial growth, it's not what you make but what you keep that counts, USC marine biologists believe.
Their study of genes associated with growth in oysters suggests that slow-growing animals waste energy in two ways: by making too much of some protein building blocks and then by having to dispose of the excess.
Donal Manahan, director of the USC Wrigley Institute for Environmental Studies and the study's senior author, calls the inefficient process "metabolic taxation."
By contrast, fast-growing oysters make just enough and keep most of it, Manahan hypothesized.
The theory of metabolic taxation needs verification, but if proven correct, it would help to answer two basic questions:
  • Why do some animals grow big, while others stay small? Differences in diet account for about half the size variation, according to Manahan. Gene expression related to metabolic taxation could explain part of the rest.
  • What is the biological cost of rapid growth: lower disease resistance, perhaps, or blander flavor? If metabolic taxation is real, rapidly growing animals are simply more efficient at making proteins and do not necessarily need to sacrifice other traits.
Manahan compared metabolic taxation to a vehicle assembly plant with supply chain problems, where too many engines come in one day and not enough transmissions the next.
The vehicle assembly plant in the cell is the ribosome, which makes and assembles protein parts from genetic instructions.
Manahan and co-author Eli Meyer -- his former graduate student at USC and now a postdoctoral fellow at the University of Texas, Austin -- identified 17 oyster genes related to the ribosome.
The expression of those genes was out of balance in slow-growing oysters, Meyer and Manahan observed. They suspect that the underlying problem is a lack of coordination in the production of protein parts.
Proteins are crucial to growth since they make up the bulk of an animal's muscles, organs and tissues.
A fast-growing oyster is simply "well-tuned," Manahan said.
"It's not just about quickness, it's about coordination. And that was a big surprise to me," Manahan said.
Meyer and Manahan also identified 17 more genes related to energy metabolism, feeding activity and other factors related to growth.
The 34 genes represent the most promising subset of 350 growth-related genes identified by Meyer, Manahan, his USC Wrigley Institute colleague Dennis Hedgecock and other researchers in a study published in 2007 in Proceedings of the National Academy of Sciences.
Manahan and Hedgecock's long-term goal is to identify the genes responsible for hybrid vigor: the ability of some children of crossbreeding to outgrow both parents.
Many plants have hybrid vigor. Seed companies exploited this property to increase corn yields many times over from the 1920s to the present. Manahan sees potential for growing more food from the ocean by studying the "seeds" of animal development -- the larval stages.
Most animals do not express hybrid vigor to the same extent. That makes oysters, which do show characteristics of hybrid vigor, unusually strong candidates for aquaculture.
"Their hybrids grow much faster than either of the parents. And this is like corn," Manahan said.
With the latest study, published this month in The Journal of Experimental Biology, "we believe that we have identified some of the genes that are biological markers for hybrid vigor," Manahan said.
With this advance, it should be possible to identify fast-growing oyster families early in larval development by their genetic signature -- potentially a big step forward in oyster farming.
Manahan calls oysters the "corn of the sea" for their potential to help feed the planet as traditional fisheries collapse and land-based farming reaches its limit. Currently, the Pacific oyster is the most farmed aquatic species on the planet.
The "Green Revolution" that multiplied crop yields needs to be followed by a "Blue Revolution" in ocean farming, Manahan has argued.
"We're going to have to make future decisions as a society [on] how to provide enough food for a growing population."
The W. M. Keck Foundation and the National Science Foundation funded the research.

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What Makes You Unique? Not Genes So Much as Surrounding Sequences, Study Finds

Posted on Friday, March 19, 2010 by sai kiran reddy


What Makes You Unique? Not Genes So Much as Surrounding Sequences, Study Finds


Sai kiran (Mar. 19, 2010) — The key to human individuality may lie not in our genes, but in the sequences that surround and control them, according to new research by scientists at the Stanford University School of Medicine and Yale University. The interaction of those sequences with a class of key proteins, called transcription factors, can vary significantly between two people and are likely to affect our appearance, our development and even our predisposition to certain diseases, the study found.

Researchers have found that the unique, specific changes among individuals in the sequence of DNA affect the ability of "control proteins" called transcription factors to bind to the regions that control gene expression. (Credit: iStockphoto/Andrey Prokhorov)

The discovery suggests that researchers focusing exclusively on genes to learn what makes people different from one another have been looking in the wrong place.
"We are rapidly entering a time when nearly anyone can have his or her genome sequenced," said Michael Snyder, PhD, professor and chair of genetics at Stanford. "However, the bulk of the differences among individuals are not found in the genes themselves, but in regions we know relatively little about. Now we see that these differences profoundly impact protein binding and gene expression."
Snyder is the senior author of two papers -- one in Science Expressand one in Nature -- exploring these protein-binding differences in humans, chimpanzees and yeast. Snyder, the Stanford W. Ascherman, MD, FACS, Professor in Genetics, came to Stanford in July 2009 from Yale, where much of the work was conducted.
Genes, which carry the specific instructions necessary to make proteins do the work of the cell, vary by only about 0.025 percent across all humans. Scientists have spent decades trying to understand how these tiny differences affect who we are and what we become. In contrast, non-coding regions of the genome, which account for approximately 98 percent of our DNA, vary in their sequence by about 1 to 4 percent. But until recently, scientists had little, if any, idea what these regions do and how they contribute to the "special sauce" that makes me, me, and you, you.
Now Snyder and his colleagues have found that the unique, specific changes among individuals in the sequence of DNA affect the ability of "control proteins" called transcription factors to bind to the regions that control gene expression. As a result, the subsequent expression of nearby genes can vary significantly.
"People have done a lot of work over the years to characterize differences in gene expression among individuals," said Snyder. "We're the first to look at differences in transcription-factor binding from person to person." What's more, by selectively breeding, or crossing, yeast strains, Snyder and his colleagues found that many, but not all, of these differences in binding and expression levels are heritable.
In the Science Express paper, which will be published online March 18, Snyder and his colleagues compared the binding patterns of two transcription factors in 10 people and one chimpanzee. They identified more than 15,000 binding sites across the genome for the transcription factor called NF-kB and more than 19,000 sites for another factor called RNA PolII. They then looked to see if every site was bound equally strongly by the proteins, or if there were variations among individuals.
They found that about 25 percent of the PolII sites and 7.5 percent of the NF-kB sites exhibited significant binding differences among individuals -- in some cases greater than two orders of magnitude from one person to another. (For comparison, the binding differences between the humans and the chimpanzee were about 32 percent.) Many of these binding differences could be traced to differences in sequences or structure in the protein binding sites, and several were directly correlated to changes in gene expression levels.
"These binding regions, or chunks, vary among individuals," said Snyder, "and they have a profound impact on gene expression." In particular, the researchers found that several of the variable binding regions were near genes involved in such diseases as type-1 diabetes, lupus, leukemia and schizophrenia.
The researchers confirmed and extended their findings in theNature paper, which will be published online March 17. In this study, they used yeast to determine that many of the binding differences and variations in gene expression levels in individuals are passed from parent to progeny, and they identify several control proteins that vary -- a study that would have been impossible to perform in humans.
"We conducted the two studies in parallel," said Snyder, "and found the same thing. Many of the binding sites differed. When we mapped the areas of difference, we found that they were associated with key regulators of variation in the population. Together these two studies tell us a lot about the so-called regulatory code that controls variation among individuals."
The research in the Science Express study was supported by the National Institutes of Health, the European Molecular Biology Laboratory and the Howard Hughes Medical Institute's Medical Fellows Program. The research in the Nature study was supported by the National Institutes of Health. In addition to Snyder, other Stanford researchers involved in the two studies include postdoctoral scholars Fabian Grubert, PhD; Minyi Shi, PhD; and Manoj Hariharan, PhD; and graduate student Konrad Karczewski.

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Synthetic Biology: Engineered Bacteria

Posted on Thursday, March 18, 2010 by sai kiran reddy

Synthetic Biology: Engineered Bacteria

Sai kiran (Mar. 18, 2010) — Researchers have devised a way to attach sugars to proteins using unique biological and chemical methods. This means that large quantities of different glycoproteins can be generated for various medical and biological studies

The E. coli bacterium produces a protein to which a sugar is attached using an engineered glycosylation machinery. Outside the cell, enzymes trim off the monosaccharide. Other chemically synthesized sugars are then attached. (Credit: Diagram: F. Schwarz / ETH Zurich)

The E. coli bacterium produces a protein to which a sugar is attached using an engineered glycosylation machinery. Outside the cell, enzymes trim off the monosaccharide. Other chemically synthesized sugars are then attached. (Diagram: F. Schwarz / ETH Zurich)
When the intestinal bacterium E. coliand the diarrheal pathogenCampylobacter work together, it does not have to result in serious illness. Rather, when biologists and chemists team to use the product of this bacterial collaboration, it opens up a whole new technology with potential pharmaceutical applications. Now, the PhD student Flavio Schwarz from Professor Markus Aebi's group at the Institute of Microbiology of ETH-Zurich and researchers from the University of Maryland have developed a new method for producing glycoproteins.
New tool
E. coli is a well-known biological workhorse that can be used to produce recombinant proteins. The problem is that E. coli is missing many of the functions required to modify proteins with sugar molecules. Markus Aebi's team, however, recently discovered that Campylobacter can do something that only eukaryotes like human cells can: attach sugar molecules to proteins following synthesis to produce glycoproteins.
The researchers recently reported this ground-breaking work in the journal Nature Chemical Biology. In this engineered glycosylation system, some of the genes from theCampylobacter glycosylation machinery are introduced into E. coli, thereby enabling the E. coli to produce glycoproteins. In a second step, unnecessary parts of the sugars are removed outside the bacterial cells and replaced with chemically synthesized sugar molecules of different size and structure, to produce sugar structures resembling human glycans.
Glycoproteins define blood group
This means that different glycoproteins can now efficiently be produced, thus helping researchers to analyze the structure and function of individual glycoproteins in a more precise manner. If you want to study host-pathogen interactions, for instance, you need pure samples of a particular glycoprotein, whereas natural systems can only offer researchers a highly complex blend of such substances.
Glycoproteins play a crucial role in biology. They are found more frequently on the surface of cells than "normal" proteins and they participate in numerous cellular processes, such as cell to cell communication. They are present throughout the human body, also in mucus, and the different glycosylation of blood proteins contribute to define the blood group antigen.
Blossoming concept
The new technology also has great potential for the development of new cancer treatments. These therapeutic glycoproteins can be produced specifically-tailored to remain in the bloodstream longer while targeting cancerous cells.
"For now, we have simply managed to prove that our concept works. It remains to be seen what potential practical applications it might have," says Flavio Schwarz from the Life Science Zurich Graduate School. The new process was actually a "by-product" of his dissertation -- further proof that basic research can also produce application-oriented results. It just needs resourceful people like Flavio Schwarz who recognize this.

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Fungi Can Change Quickly, Pass Along Infectious Ability

by sai kiran reddy


Fungi Can Change Quickly, Pass Along Infectious Ability


Sai kiran (Mar. 18, 2010) — Fungi have significant potential for "horizontal" gene transfer, a new study has shown, similar to the mechanisms that allow bacteria to evolve so quickly, become resistant to antibiotics and cause other serious problems.
This discovery, to be published March 18 in the journal Nature, suggests that fungi have the capacity to rapidly change the make-up of their genomes and become infectious to plants and possibly animals, including humans.
Studies done with this fungus have challenged existing beliefs about how quickly fungi can change their genetic makeup and become infectious. (Credit: Photo courtesy of Oregon State University)

They are not nearly as confined to the more gradual processes of conventional evolution as had been believed, scientists say. And this raises issues not only for crop agriculture but also human health, because fungi are much closer on the "evolutionary tree" to humans than bacteria, and consequently fungal diseases are much more difficult to treat.
The genetic mechanisms fungi use to do this are different than those often used by bacteria, but the end result can be fairly similar. The evolution of virulence in fungal strains that was once believed to be slow has now been shown to occur quickly, and may force a renewed perspective on how fungi can behave, change and transfer infectious abilities.
"Prior to this we've believed that fungi were generally confined to vertical gene transfer or conventional inheritance, a slower type of genetic change based on the interplay of DNA mutation, recombination and the effects of selection," said Michael Freitag, an assistant professor of biochemistry and biophysics at Oregon State University.
"But in this study we found fungi able to transfer an infectious capability to a different strain in a single generation," he said. "We've probably underestimated this phenomenon, and it indicates that fungal strains may become pathogenic faster than we used to think possible."
Researchers from the Center for Genome Research and Biocomputing at OSU collaborated on this study with a large international group of scientists, including principal investigators from The Broad Institute in Massachusetts, the University of Amsterdam, and the USDA Agricultural Research Service at the University of Minnesota.
Bacteria use "horizontal" genetic transfer through chromosomes and DNA plasmids to change quickly, which is one reason that antibiotic resistance can often develop. This capability was believed to be possible, but rare, in fungi. In the new study, based on a genome-wide analysis of three Fusarium species, it was shown experimentally that complete chromosomes were being transferred between different fungal strains, along with the ability to cause infection. Various Fusarium fungi can infect both plants and humans.
In humans, fungal infections are less common than those caused by bacteria, but can be stubborn and difficult to treat -- in part, because fungi are far more closely related to animals, including humans, than are bacteria. That limits the types of medical treatments that can be used against them. Fungal infections are also a serious problem in people with compromised immune systems, including AIDS patients, and can be fatal.
According to Freitag, this new understanding of fungal genetics and evolution is great news.
For one thing, it may help researchers to better understand the types of fungal strains that are most apt to develop resistance to fungicides, and help crop scientists develop approaches to minimize that problem.
Fungal diseases are a major problem in crop agriculture, and billions of dollars are spent around the world every year to combat new and emerging fungal pathogens in plants, animals and humans.
On a more basic level, this study provides evidence that the "tree of life," with one trunk and many branches, is outdated. It should be replaced by a "network of life" in which many horizontal connections occur between different species.

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Molecules in Cell Membranes Move in a Flowing Motion Rather Than Chaotically, New Research Finds

by sai kiran reddy


Molecules in Cell Membranes Move in a Flowing Motion Rather Than Chaotically, New Research Finds


Sai kiran (Mar. 18, 2010) — Researchers Sebastian Busch, Christoph Smuda, Luis Carlos Pardo and Tobias Unruh have published an article in the Journal of the American Chemical Society in which they demonstrate that the molecules in cell membranes move in a flowing motion rather than chaotically, as previously thought.
New research suggests that molecules in cell membranes move in a flowing motion rather than chaotically. (Credit: Image courtesy of Universitat Politècnica de Catalunya)

Researchers Sebastian Busch, Christoph Smuda, Luis Carlos Pardo and Tobias Unruh have discovered using neutron spectroscopy techniques that the molecules of a cell membrane do not move at random as previously believed, but rather in a flowing motion as suggested by various computer simulations. The discovery has a major impact on the regeneration of cell membranes and the biological mechanisms that involve membrane proteins.
The human body is formed by cells whose 'skin' consists of a phospholipid membrane with amphipathic molecules that can repel and absorb water. This property enables them to self-organize into cell walls, in a manner similar to bricks being thrown in water and then moving to form the walls of a house. The membrane also has a surprising ability to regenerate itself. According to Luis Carlos Pardo, a researcher at the Department of Physics and Nuclear Engineering of the UPC, "although the molecules that form the membrane are huge in relative terms, they have the uncanny ability to move and this is precisely what is responsible for the self-healing process. Imagine the bricks of a house being able to rebuild a broken wall.."
The research team of the UPC's Materials Characterization Group has devised a Bayesian analysis method (fitting algorithm for Bayesian analysis of data, FABADA) that has refuted the idea that membrane molecules move chaotically by diffusion. Instead, the team has discovered that they form currents that run through the cell membranes like a river. "This means that their small-scale mobility is greater than previously thought," says Professor Pardo, a member of the team at the UPC's Nanoengineering Research Center.
Phospholipid cell membranes are a very interesting area of research due to their natural abundance (every human body contains several square kilometers) and their pharmaceutical applications.
A fascinating albeit obscure membrane Cell membranes were largely unknown until just over a decade ago, when the development of nanotechniques yielded detailed information on their structure. Nevertheless, their movement dynamics remained a mystery that did not begin to be solved until the discovery of neutron spectroscopy, a technique that uses a beam of neutrons to reveal the properties of certain materials and for which Bertram Brockhouse was awarded the Nobel Prize in Physics in 2004.

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