Genetically encoded cells allow tracking once inside body

Scientists' inability to follow the whereabouts of cells injected into the human body has long been a major drawback in developing effective medical therapies. Now, researchers at Johns Hopkins have developed a promising new technique for noninvasively tracking where living cells go after they are p...

Scientists' inability to follow the whereabouts of cells injected into the human body has long been a major drawback in developing effective medical therapies. Now, researchers at Johns Hopkins have developed a promising new technique for noninvasively tracking where living cells go after they are put into the body. The new technique, which uses genetically encoded cells producing a natural contrast that can be viewed using magnetic resonance imaging (MRI), appears much more effective than present methods used to detect injected biomaterials.

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Described in the February edition of Nature Biotechnology, the method was developed by a team of researchers from Johns Hopkins' Russell H. Morgan Department of Radiology and Radiological Science, the Hopkins Institute for Cell Engineering, and the F.M. Kirby Research Center for Functional Brain Imaging at the Kennedy Krieger Institute in Baltimore.

In their study, the researchers used a synthetic gene, called a reporter gene, which was engineered to have a high proportion of the amino acid lysine, which is especially rich in accessible hydrogen atoms. Because MRI detects energy-produced shifts in hydrogen atoms, when the "new" gene was introduced into animal cells and then "pelted" with radiofrequency waves from the MRI, it became readily visible. Using the technique as a proof of principle, the researchers were able to detect transplanted tumor cells in animal brains.

"This prototype paves the way for constructing a family of reporter genes, each with proteins tailored to have a specific radiofrequency response," says MRI researcher Assaf Gilad, Ph.D., lead author of the study.

"The specific frequencies can be processed to show up as colors in the MRI image," adds collaborator Mike McMahon, Ph.D., an assistant professor of radiology at the Johns Hopkins School of Medicine "In a way, it's the MRI equivalent of the green and red fluorescent proteins found in nature and used by labs everywhere in the world for multiple labeling of cells."

The problem with using fluorescent proteins, however, is that tissue must be removed from the body for examination under a microscope, which means that the method isn't suitable for use in patients. "In contrast," says Hopkins radiology professor Jeff Bulte, Ph.D., "MRI is noninvasive, allowing serial imaging of cells and cellular therapies with a high resolution unmatched by any other clinical whole-body imaging technique."

Current MRI contrast agents also have several disadvantages. "Their concentration becomes lower every time cells divide," says Peter van Zijl, Ph.D., founding director of the Kirby Research Center for Functional Brain Imaging, "so our ability to see them diminishes.. Also, using magnetic metal allows us to detect only one type of labeled cell at a time." The new approach is not hampered by these limitations.

Source: Johns Hopkins Medical Institutions

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Computer-simulations help zero in on causes of Parkinson’s disease, Alzheimer’s disease, rheumatoid arthritis and other diseases

Using the massive computer-simulation power of the San Diego Supercomputer Center (SDSC) at UC San Diego, researchers are zeroing in on the causes of Parkinsons disease, Alzheimers disease, rheumatoid arthritis and other diseases.A study published in this weeks Federation of European Biochemical Soc...

Using the massive computer-simulation power of the San Diego Supercomputer Center (SDSC) at UC San Diego, researchers are zeroing in on the causes of Parkinson%26#8217;s disease, Alzheimer%26#8217;s disease, rheumatoid arthritis and other diseases.

A study published in this week%26#8217;s Federation of European Biochemical Societies (FEBS) Journal offers %26#8211; for the first time %26#8211; a model for the complex process of aggregation of a protein known as alpha-synuclein, which in turn leads to harmful ring-like or pore-like structures in human membranes, the kind of damage found in Parkinson%26#8217;s and Alzheimer%26#8217;s patients.

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The researchers at SDSC and UC San Diego also found that the destructive properties of alpha-synuclein can be blocked by beta-synuclein %26#8211; a finding that could lead to treatments for many debilitating diseases.

The current journal%26#8217;s cover features an image from the research that helps illustrate the scientists%26#8217; work.

%26#8220;This is one of the first studies to use supercomputers to model how alpha-synuclein complexes damage the cells, and how that could be blocked,%26#8221; said Eliezer Masliah, professor of neurosciences and pathology at UC San Diego. %26#8220;We believe that these ring- or pore-like structures might be deleterious to the cells, and we have a unique opportunity to better understand how alpha-synuclein is involved in the pathogenesis of Parkinson%26#8217;s disease, and how to reverse this process.%26#8221;

Igor Tsigelny, project scientist in chemistry and biochemistry at UC San Diego and a researcher at SDSC, said that the team%26#8217;s research helped confirm what researchers had suspected. %26#8220;The present study %26#8211; using molecular modeling and molecular dynamics simulations in combination with biochemical and ultrastructural analysis %26#8211; shows that alpha-synuclein can lead to the formation of pore-like structures on membranes.%26#8221;

In contrast, he said, %26#8220;beta-synuclein appears to block the propagation of alpha-synucleins into harmful structures.%26#8221;

The complex calculations for the study were performed on Blue Gene supercomputers at SDSC and the Argonne National Labs.

Source: University of California, San Diego

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Novel gene mutation causes X-linked mental retardation

Researchers have identified a novel gene mutation that causes X-linked mental retardation for which there was no previously known molecular diagnosis, according to an article to be published electronically on Tuesday, March 20, 2007 in The American Journal of Human Genetics.Investigators F. Lucy Ray...

Researchers have identified a novel gene mutation that causes X-linked mental retardation for which there was no previously known molecular diagnosis, according to an article to be published electronically on Tuesday, March 20, 2007 in The American Journal of Human Genetics.

Investigators F. Lucy Raymond (Cambridge Institute of Medical Research, University of Cambridge, Cambridge, UK) and Patrick S. Tarpey (Wellcome Trust Sanger Institute, Hixton, UK) describe the ZDHHC9 gene found in those with severe retardation as being mutated to the point of entirely losing function.

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"ZDHHC9 is a novel gene," explains Dr. Raymond. "This gene would not have been predicted to play a role in mental retardation based on the previous genetics work. It was found only because we were systematically looking at all the genes on the X chromosome irrespective of what they do."

X-linked mental retardation is severe. Some patients require total care and may not have language ability. The condition runs in families and only affects the male offspring. So far only a few of these genes have been identified.

Working through a large, international collaboration, the researchers collected genetic samples from 250 families in which at least two boys have mental retardation to help identify novel genes that cause X-linked mental retardation. The investigators systematically analyzed the X chromosome for gene mutations.

Dr. Raymond says that the families are receiving information from the study and using it to make decisions in their lives. "We cannot currently make their children better, but knowing that we found a genetic abnormality gives them an explanation for what has happened," she explains. "We had one family that said this knowledge was the best news they had ever been given."

"We have identified the cause of problems in certain families and are able to tell whether or not women are carriers of the condition," Dr. Raymond comments. "Consequently, the families that had previously chosen to forego having children because there was no method of testing can now be tested. We have been able to test a substantial number of people to identify whether are not they are carriers, and we can offer prenatal testing to the carriers who want it."

In the broader picture, this research is not only benefiting families with X-linked mental retardation, but it is also defining the genes involved in intellectual development. "If you find genes that are abnormal, it is a reasonable assumption that the identified genes are involved in the formation of normal intellectual processing as well," concludes Dr. Raymond.

Now that a posttranslational modification enzyme has been found to be mutated in X-linked mental retardation, the researchers expect to find similar genes related to other mental retardation syndromes.

Source: University of Chicago

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Brain scans of smokers studied

Within the mind of every smoker trying to quit rages a battle between the higher-order functions of the brain wanting to break the habit and the lower-order functions screaming for another cigarette, say researchers at Duke University Medical Center. More often than not, that cigarette gets lit.
[Mo...

Within the mind of every smoker trying to quit rages a battle between the higher-order functions of the brain wanting to break the habit and the lower-order functions screaming for another cigarette, say researchers at Duke University Medical Center. More often than not, that cigarette gets lit.

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Brain scans of smokers studied by the researchers revealed three specific regions deep within the brain that appear to control dependence on nicotine and craving for cigarettes. These regions play important roles in some of the key motivations for smoking: to calm down when stressed, to achieve pleasure and to help concentration.

"If you can't calm down, can't derive pleasure and can't control yourself or concentrate, then it will be extremely difficult for you to break the habit," said lead study investigator Jed E. Rose, Ph.D., director of the Duke Center for Nicotine and Smoking Cessation Research. "These brain regions may explain why most people try to quit several times before they are successful."

Understanding how the brain responds to cigarette cravings can help doctors change nicotine cessation treatments to address all three of these components of withdrawal, Rose said. Drugs or therapies that target these regions may help smokers stave off the cravings that often spoil their attempts to quit.

The team's findings are now online in the journal Neuropsychopharmacology. The research was funded by Phillip Morris USA.

Approximately one in five Americans smokes. Even though 70 percent of smokers report that they would like to quit, only 5 percent do so successfully.

In this study, the researchers manipulated the levels of nicotine dependence and cigarette craving among 15 smokers and then scanned their brains using positron emission tomography, or PET scans, to see which areas of the brain were most active.

Three specific regions of the brain demonstrated changes in activity when the smokers craved cigarettes versus when they did not.

One region that lights up, called the thalamus, is considered to be the key relay point for sensory information flowing into the brain. Some of the symptoms of withdrawal among people trying to quit stem from the inability to focus thoughts and the feeling of being overwhelmed, and could thus be explained by changes in this region, according to the researchers. The researchers found that changes in this region were most dramatic among those who said they smoked to calm down when under stress.

Another region that lights up is a part of the pleasure system of the brain. Changes in this region, called the striatum, were most notable in people who smoked to satisfy craving and for pleasurable relaxation, the researchers said.

A third region that lights up, called the anterior cingulate cortex, is vital to cognitive functions such as conflict, self regulation, decision making and emotion. People whose brain scans showed the most differences in this region also reported that they smoked to manage their weight.

"This knowledge gives us new clues about brain mechanisms underlying addiction to cigarettes and could allow us design better methods to help smokers quit," Rose said.

Rose and his colleagues are now planning to perform brain scans on smokers undergoing nicotine replacement therapy, such as the nicotine patch, to determine how these treatments affect the same regions of the brain.

Source: Duke University Medical Center

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New gene that may put individuals at higher risk of developing cardiovascular disease

Geneticists have discovered a new gene that may put individuals at higher risk of developing cardiovascular disease.The identification of the gene, called kalirin, implicates a biological mechanism never before linked to cardiovascular disease, according to the Duke researchers who led the study. Fu...

Geneticists have discovered a new gene that may put individuals at higher risk of developing cardiovascular disease.

The identification of the gene, called kalirin, implicates a biological mechanism never before linked to cardiovascular disease, according to the Duke researchers who led the study. Further study of this new clue could lead to novel ways to treat or even prevent the disease, the researchers said.

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"The ultimate goal is to determine who will develop cardiovascular disease," said lead study investigator Liyong Wang, Ph.D., a research associate at the Duke Center for Human Genetics. "Our discovery could lead to a clinical tool for assessing a person's risk of coronary artery disease, so that physicians can try to prevent the disease from progressing."

The team, which includes researchers from several universities in the United States and the United Kingdom, reports its findings in the April 2007 issue of American Journal of Human Genetics. The research was sponsored by the National Institutes of Health.

Coronary artery disease affects more than 13 million Americans and is one of the nation's leading causes of death. The disease occurs when the arteries supplying blood to the heart become narrowed or clogged by plaque deposits. Left untreated, the disease can completely block the blood flow to the heart, leading to a heart attack.

While risk factors such as smoking, high blood pressure and high cholesterol are known to contribute to coronary artery disease, little is known about genes that render an individual susceptible to developing the disease, said study co-investigator Elizabeth R. Hauser, Ph.D., an associate professor of medicine at the Duke Center for Human Genetics.

In a previous study, the researchers had scanned the entire genome -- the body's genetic blueprint -- of a group of families in which at least two siblings had early onset coronary artery disease, looking for regions of "linkage" where DNA variations appeared to be inherited along with the disease. They found just such a region: a small section of the long arm of chromosome 3 where just a handful of genes were located. Chromosome 3 is one of the 23 pairs of chromosomes that comprise the human genome.

In the current study, the researchers focused on specific gene variants, called single nucleotide polymorphisms (SNPs), that occur when a single nucleotide building block in the long strand of DNA is altered. The researchers sought SNPs that occurred more or less often in individuals with coronary artery disease than in individuals without it, as such a link would indicate that these gene variants were associated with the disease.

The researchers first obtained DNA from 500 patients who had volunteered to be studied while being examined at the cardiac catheterization laboratories at Duke University Hospital. Using these DNA samples, the researchers scanned the same small section of chromosome 3 for SNPs that differed in sequence between individuals with and without coronary heart disease.

One SNP, in the kalirin gene, varied between individuals with heart disease and those without. The researchers repeated the same experiment in four additional patient populations, scanning the DNA of a total of 4,000 individuals, and turned up the same result.

"This finding opens up a whole new area of study for looking at risks of cardiovascular disease," said senior study investigator Jeffrey M. Vance, M.D., Ph.D., director of the Center for Molecular Genetics and Genomic Medicine, Miami Institute for Human Genomics at the Miller School of Medicine.

The researchers are now studying kalirin in the blood vessels to see how variations in the gene contribute to cardiovascular disease.

So far, they have found that this particular SNP is significantly correlated with the degree of atherosclerosis in human aortas, the large blood vessel that brings blood from the heart to all parts of the body.

Kalirin contains the hereditary information for the production of a protein that is involved in the migration of cells from one spot to another within smooth muscle. According to the researchers, the newly identified SNP may change the level of this protein in blood vessels, causing cells to congregate in one spot and form a plaque in the vessels to the heart.

In addition to identifying the genetic variations in the kalirin gene, the researchers also identified two genes that are involved in the same biological pathway, known as the Rho-GTPase signal transduction pathway.

Source: Duke University Medical Center

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Process simplifies production of medicine based on natural products

Chemists are currently able to synthetically produce almost any compound, but they must typically resort to expensive, complex processes that can require dozens of individual steps. Such natural product syntheses have traditionally relied on the ubiquitous use of protecting groups, which are extra c...

Chemists are currently able to synthetically produce almost any compound, but they must typically resort to expensive, complex processes that can require dozens of individual steps. Such natural product syntheses have traditionally relied on the ubiquitous use of %26#8220;protecting groups,%26#8221; which are extra compounds chemists use to shield reactive portions of a molecule during specific stages of a synthesis scheme. The protecting groups are eventually cleaved chemically to expose the reactive portion during later chemical reactions to complete a product's synthesis. Each protecting group used adds at least two steps to a synthesis, and the groups themselves have reactivity of their own that must be controlled to prevent adverse reactions.

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%26#8220;Protecting groups are almost always a direct result of an inability to address selectivity in synthesis,%26#8221; says project leader Phil Baran, a chemist with The Scripps Research Institute. %26#8220;It is ironic that they often add an additional layer of problems on top of the preexisting ones.%26#8221;

Organic chemistry textbooks have long declared that the use of protecting groups was essential in natural product synthesis. %26#8220;Textbooks have pointed out that avoiding protecting groups is like %26#8216;avoiding death and taxes,%26#8217;%26#8221; says Baran, who, along with Scripps Research Kellogg School of Science and Technology graduate students Thomas Maimone and Jeremy Richter, has now disproved the belief.

To avoid the need for protecting groups, the Baran group took an unorthodox approach. Rather than assume that reactive portions of a molecule had to be shielded during various syntheses, the researchers calculated ways to use such reactivity in an overall scheme to produce the desired final product. Baran says the reason such an approach had not been successfully developed before was likely a by-product of education. %26#8220;From the beginning, we were always taught that the way to solve these types of problems is to protect functionality rather than to try to embrace it,%26#8221; he says.

In the Nature paper, the group showed that, without using a single protecting group, they could produce the representative members of a whole family of over 60 different marine natural products produced by the Stigonemataceae family of cyanobacteria. This family of products has a wide range of bioactivities including anticancer and antibacterial, and some may eventually be developed as commercial pharmaceutical products. The compound family was only used as an example, however, as the demonstrated concepts and principles should be applicable to the synthesis of a wide range of marine and terrestrial natural products.

To synthesize the products, the team designed a variety of chemical reactions that maximize the bonding of carbon atoms between different molecules. In many cases, the products were synthesized in gram quantities in less than 10 steps, as compared to traditional syntheses using protecting groups that have taken as many as 30 steps to produce milligrams of product.

Use of the techniques the group has developed could therefore lead to substantially reduced production costs for natural products. This is a critical concern, as identification of a reasonably economic means of production for marine and other natural products is typically one of the most challenging hurdles in a potential drug's commercial development. An overly complex and expensive synthesis can even slow or halt the development of an otherwise promising drug candidate.

Beyond economic ramifications, Baran hopes the research will offer additional benefits to the drug discovery field. Many pharmaceutical companies' potential drug pipelines are drying up, leading some to suggest that interest in natural products should be renewed. A range of drugs from aspirin to the widely used cancer treatment Taxol has been discovered in nature, but the complexity of producing natural products has made some companies reluctant to focus on them.

%26#8220;There is this far-ranging and damaging perception that natural products are too complex to be used in a drug discovery setting despite their overwhelming track record in medicine,%26#8221; says Baran. %26#8220;I think if our work has helped in even a small way to revive the use of natural products, then we've served our purpose.%26#8221;

The Baran team has focused its work to date on marine natural products, because these chemical compounds from sponges, algae, and other organisms have proven a rich source of bioactivity with pharmaceutical potential, but have also been challenging to work with. Marine natural products are ideal targets for simplified synthesis techniques because they tend to be exceptionally complex, and because they are typically difficult to collect. Researchers often struggle to amass marine organism samples in quantities great enough to yield the volume of a given compound needed for research and clinical trials, much less commercial production, making better and cheaper production means all the more critical.

For the production of some products, both natural and man-made, the use of protecting groups will still be the most efficient route, says Baran. %26#8220;We are not advocating that one should blindly throw away the protecting groups book just for the fun of throwing it away,%26#8221; he says. %26#8220;It's something that should be strategically applied.%26#8221;

Baran, Maimone, and Richter were all authors on the study, %26#8220;Total Synthesis of Marine Natural Products Without Using Protecting Groups.%26#8221;

Source: Scripps Research Institute

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New gene appears to increase risk of developing schizophrenia

Psychiatric researchers at The Zucker Hillside Hospital campus of The Feinstein Institute for Medical Research have uncovered evidence of a new gene that appears to increase the risk of developing schizophrenia, a disorder characterized by distorted thinking, hallucinations and a reduced ability to ...

Psychiatric researchers at The Zucker Hillside Hospital campus of The Feinstein Institute for Medical Research have uncovered evidence of a new gene that appears to increase the risk of developing schizophrenia, a disorder characterized by distorted thinking, hallucinations and a reduced ability to feel normal emotions.

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Working in conjunction with researchers at the Harvard Medical School Partners Center for Genetics and Genomics in Boston, MA, the Zucker Hillside team utilized a cutting-edge technology called whole genome association (WGA) to search the entire human genome in 178 patients with schizophrenia and 144 healthy individuals. WGA technology was used to examine over 500,000 genetic markers in each individual, the largest number of such markers examined to date, and the first published study to utilize WGA technology in a psychiatric illness. Previous studies have been much more limited in scope, often incorporating less than 10 markers.

The study results are scheduled to be published online Tuesday in Molecular Psychiatry, which can be accessed at http://www.nature.com/mp/journal/vaop/ncurrent/index.html.

Of the 500,000 genetic markers, the researchers found that the most significant link with schizophrenia came from a marker located in a chromosomal region called the pseudoautosomal region 1 (PAR1), which is on both the X and Y chromosomes. The marker was located adjacent to two genes, CSF2RA and IL3RA, which previously were thought to play a role in inflammation and autoimmune disorders. Those two genes produce receptors for two cytokines, GM-CSF and interleukin-3. Cytokines are involved in the body%26#8217;s response to infection, and may play a role in the brain%26#8217;s response to injury.

By then examining the DNA sequence of those genes in a separate group of patients with schizophrenia and healthy individuals, the research team %26#8211; working in conjunction with PGx Health in New Haven, CT -- observed multiple gene abnormalities in patients with schizophrenia that were not found, or were found much less commonly, in healthy individuals.

%26#8220;WGA technology allowed us to shine a light across virtually the entire genome, rather than looking at just one gene at a time,%26#8221; said Todd Lencz, PhD, the first author of the study, and an investigator at Zucker Hillside and The Feinstein Institute. %26#8220;Using WGA, we found genes that had not been previously considered in studies of schizophrenia.%26#8221; Dr. Lencz added that %26#8220;the critical next step is confirming these results in independent datasets.%26#8221;

Source: The Feinstein Institute for Medical Research

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Cells use biochemical "noise" to transform from one state to another

Electrical noise, like the crackle heard on AM radio when lightning strikes nearby, is a nuisance that wreaks havoc on electronic devices. But within cells, a similar kind of biochemical "noise" is beneficial, helping cells transform from one state to another, according to a new study led by a UT So...

Electrical noise, like the crackle heard on AM radio when lightning strikes nearby, is a nuisance that wreaks havoc on electronic devices. But within cells, a similar kind of biochemical "noise" is beneficial, helping cells transform from one state to another, according to a new study led by a UT Southwestern Medical Center researcher.

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Dr. G%26#252;rol S%26#252;el, assistant professor of pharmacology, said his research and that of his colleagues published today in the journal Science represents "a new paradigm," suggesting that rather than being bad for biology, cellular noise might have an important function, such as prompting stem cells to transform into a specific tissue type.

Electronic noise is an unwanted signal characteristic of all electrical circuits, typically caused by random fluctuations in the electric current passing through the components of a circuit. Similarly, within each living cell there are myriad "genetic circuits," each composed of a distinct set of biochemical reactions that contribute to some biological process. Randomness in those reactions contributes to biological noise, technically referred to as stochastic fluctuations.

"Noise in biological systems is a fact of life," said Dr. S%26#252;el, a member of the systems biology division of the Cecil H. and Ida Green Comprehensive Center for Molecular, Computational and Systems Biology at UT Southwestern. "Even though each cell may have the same set of genes turned on %26#8211; the same hard-wired genetic circuit %26#8211; there will still be slight variations in the amount of the various proteins those genes produce, some fluctuation in the amount of each circuit component. No two cells are alike in terms of their chemical composition."

Conventional scientific thinking has been that the random nature of such fluctuations within cells interferes with the reliable operation of biological systems. However, Dr. S%26#252;el's research team hypothesized that noise in one particular genetic circuit might be beneficial, linked to a process that controls cell fate.

To determine the biological role for noise, the researchers analyzed a genetic circuit that controls the transformation of bacteria cells from one state to another. This process, called differentiation, is akin to that used by human stem cells to change into a specific tissue type.

In a series of theoretical calculations and actual experiments, the researchers found that the particular circuit they investigated appears to have evolved in this bacterium to amplify cellular noise. Dr. S%26#252;el and his colleagues determined that by dampening the noise level within the bacterial cells, they could prevent the cells' transformation between states, essentially "tuning" cellular behavior.

"The amplitude of cellular noise correlates with the probability of triggering differentiation," Dr. S%26#252;el said. "This is experimental evidence that a genetic circuit utilizes noise to drive a biological process."

Typically, scientists examine genes and proteins individually to try to determine their functions within a cell. However, Dr. S%26#252;el said that's like examining each capacitor or switch in an electrical circuit in an attempt to understand the function of the electrical device in which the circuit is housed.

"Our research provides a systems-level view of how gene circuits work as a whole," he said.

Dr. S%26#252;el said the next step in his research would be to uncover the theoretical design principles of genetic circuits and what role interactions between distinct circuits play in regulating complex biological processes, such the differentiation of multipotent stem cells.

Source: UT Southwestern Medical Center

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Computers simulating populations of hundreds of thousands of people search for genetic causes of cancer, other diseases

More powerful computers are allowing scientists and engineers to conduct simulations that grow more realistic each year. While companies are using these tools to slash the costs of producing everything from airliners to antibiotics, researchers in Houston are using them to refine their search for th...

More powerful computers are allowing scientists and engineers to conduct simulations that grow more realistic each year. While companies are using these tools to slash the costs of producing everything from airliners to antibiotics, researchers in Houston are using them to refine their search for the genetic causes of disease.

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In a new study published today in the journal PLoS Genetics, statisticians and genetic epidemiologists from Rice University and The University of Texas M. D. Anderson Cancer Center used computer simulations to trace genetic changes over thousands of generations in a simulated population of hundreds of thousands of people. The goal: find out whether the tools that statistical geneticists use to pinpoint disease genes are up to the task of identifying multiple genes that cause complex diseases like cancer.

"In a real population, you never have the complete genetic picture, particularly for complex diseases where more than one gene is implicated and where environmental factors play a role," said lead author Bo Peng of M. D. Anderson. "If we only see the people who get sick, we can never be sure how many people with the disease variant of the gene avoided getting sick. And there's always the question about how many people got the disease even though they didn't carry the variant."

In order to simulate the evolution of complex human diseases, Peng developed a computer program called simuPOP that generates genetic profiles for large multi-generation populations. The program, which Peng developed during his doctoral studies at Rice, allows researchers to sample individuals from a simulated population and test whether statistical methods are up to the task of accurately identifying genes that interact to cause complex diseases.

"Though they have much in common, the disciplines of statistical genetics, population genetics, molecular genetics and genetic epidemiology have traditionally used their own tools and techniques," said co-author Marek Kimmel, professor in the Statistics Department at Rice. "simuPOP is one of the first examples of a new paradigm where the tools of the various disciplines are being used in concert to create a clearer picture of genetic health effects."

"Complex diseases like hypertension and cancer are usually caused by multiple disease-susceptibility genes, environmental factors and interactions between environmental and genetic factors," said co-author Christopher Amos, professor of epidemiology at M. D. Anderson. "In the current study, we show that our method of simulating populations as they move forward in time, over multiple generations, is a practical and useful approach for simulating complex diseases."

Peng said the latest findings are preliminary but they confirm that known statistical genetic methods are limited in their ability to accurately identify the genetic interactions implicated in complex diseases. Peng said the findings are useful because they identify which methods work best with particular types of populations. He said simuPOP could be useful in developing and testing new methods for gene mapping, and he's already gotten interest from more than 20 research groups that are interested in using the program.

Source: M. D. Anderson Cancer Center

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NeuroRobotic system helps stroke patients restore motor function

At age 32, Maggie Fermental suffered a stroke that left her right side paralyzed. After a year and a half of conventional therapy with minimal results, she tried a new kind of robotic therapy developed by MIT engineers. A study to appear in the April 2007 issue of the American Journal of Physical Me...

At age 32, Maggie Fermental suffered a stroke that left her right side paralyzed. After a year and a half of conventional therapy with minimal results, she tried a new kind of robotic therapy developed by MIT engineers. A study to appear in the April 2007 issue of the American Journal of Physical Medicine %26amp; Rehabilitation shows that the device, which helped Fermental, also had positive results for five other severe stroke patients in a pilot clinical trial.

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Fermental, a former surgical nurse, used the rehabilitation device 18 times over nine weeks. After 16 sessions, Fermental, now a stroke education nurse at Beth Israel Hospital, was able to fully bend and straighten her elbow on her own for the first time since the stroke. "It was incredible to be able to move my arm again on command," she said. "Cooking, dressing, shopping, turning on light switches, opening cabinets--it's easier now that I have two arms again."

The device--which sensed Fermental's electrical muscle activity and provided power assistance to facilitate her movements--also altered her brain.

Following a stroke, the destruction of brain cells leads to loss of motor function. With painstakingly repetitive exercise therapy, other neurons can take over some of the lost function. Devices such as the MIT-developed robotic brace can help people exploit their neural plasticity--the increasingly recognized ability of the brain to rewire itself in response to experience and training.

The robotic therapy device, which is awaiting FDA approval, was tested on stroke patients at MIT's Clinical Research Center and at Spaulding Rehabilitation Hospital in Boston. According to the researchers, the results show that "the ability of the device to provide a 'power assist' to %26#8230; muscle groups may help close the feedback loop of brain intention and actual limb movement that is believed to be a key component of cerebral plasticity in motor recovery."

The study showed that the severely impaired patients' arm function improved, on average, 23 percent after using the brace, and the arm muscle tightness typical of stroke victims was significantly reduced.

Cost-effective rehabilitation

In the United States, there are 5.7 million stroke survivors and 700,000 new cases per year. Stroke is the single leading cause of disability in the United States. Many of the medical devices aimed at treating patients afflicted with neurological disorders have not fundamentally changed in decades, or require costly, high-risk brain implants.

The robotic therapy device was one of the first recipients of a grant from MIT's Deshpande Center for Technological Innovation. The center funds novel early-stage research and connects MIT's innovators with the resources needed to increase their commercial viability. The robotic therapy device received Deshpande grants in 2002 and 2003.

"We saw this as a novel technology with the potential to have a significant impact on the quality of life for people," said Charles Cooney, faculty director of the Deshpande Center and a professor in the Department of Chemical Engineering. "This study proves we were right."

The wearable, portable, lightweight robotic brace slides onto the arm. By sensing the patient's electrical muscle activity through electromyography (EMG)--which detects muscle cells' electrical activity when they contract--and sending that data to a motor, it allows stroke patients to control their affected limbs.

When used under the supervision of an occupational or physical therapist, the device can be used to help patients progress from basic motor training, such as lifting boxes or reaching for a light switch, to more complex tasks such as carrying a laundry basket or flipping a light on and off while holding an object with the unaffected limb.

According to the study researchers--Dr. Joel Stein, Kathryn Krebs and Richard Hughes of Harvard Medical School and Spaulding Rehabilitation Hospital and MIT graduates Kailas Narendran and John McBean--even people who have experienced a stroke years ago may be able to use the device to regain mobility.

"This brace will allow people who have suffered from neurological trauma to rebuild strength, rehabilitate and gain independence," said Woodie Flowers, Pappalardo Professor of Mechanical Engineering at MIT, who led the original research team that developed the device. "The joint brace is easily controlled by the user and appears to be cost-effective. It could afford self-driven therapy for a large patient population."

Relearning how to move

In 2002 and 2003, Flowers, along with then-students Narendran and McBean, developed a working prototype of the active joint brace. The first prototype system enabled paralyzed victims with certain kinds of spinal cord injuries to move their arms. In 2004, Narendran and McBean won the MIT $50K business plan competition and shortly afterward started the Boston-based company Myomo (an acronym for "my own motion") to develop a new class of medical technology they call NeuroRobotics.

"NeuroRobotics noninvasively helps people suffering from neurological trauma regain mobility by facilitating their ability to relearn how to control affected muscles and neurological pathways," Narendran said.

"Unlike other systems that stimulate or move the muscle for a patient, NeuroRobotics is embedded in lightweight wearable devices that actually adjust to a person's body and use the person's own electrical muscle activity signal to initiate and control movement," McBean said.

"Without the device, many of the individuals we tested were simply unable to complete the movement, and thus had no practical way to improve their performance through practice," Stein said. "By allowing the user to complete an intended movement through its 'power assist' function, the device helps the user improve his or her performance through practice. Thus the device acts as a facilitator of the innate capability of the human brain to improve function through practice."

Source: MIT

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Biologists solve vitamin B12 puzzle

Solving a mystery that has puzzled scientists for decades, MIT and Harvard researchers have discovered the final piece of the synthesis pathway of vitamin B12--the only vitamin synthesized exclusively by microorganisms.B12, the most chemically complex of all vitamins, is essential for human health. ...

Solving a mystery that has puzzled scientists for decades, MIT and Harvard researchers have discovered the final piece of the synthesis pathway of vitamin B12--the only vitamin synthesized exclusively by microorganisms.

B12, the most chemically complex of all vitamins, is essential for human health. Four Nobel Prizes have been awarded for research related to B12, but one fragment of the molecule remained an enigma--until now.

The researchers report that a single enzyme synthesizes the fragment, and they outline a novel reaction mechanism that requires cannibalization of another vitamin.

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The work, which has roots in an MIT undergraduate teaching laboratory, "completes a piece of our understanding of a process very fundamental to life," said Graham Walker, MIT professor of biology and senior author of a paper on the work that will appear in the March 22 online edition of Nature.

Vitamin B12 is produced by soil microbes that live in symbiotic relationships with plant roots. During the 1980s, an undergraduate research course taught by Walker resulted in a novel method for identifying mutant strains of a soil microbe that could not form a symbiotic relationship with a plant.

Walker's team has now found that one such mutant has a defective form of an enzyme known as BluB that leaves it unable to synthesize B12.

BluB catalyzes the formation of the B12 fragment known as DMB, which joins with another fragment, produced by a separate pathway, to form the vitamin. One of several possible reasons why it took so long to identify BluB is that some bacteria lacking the enzyme can form DMB through an alternate pathway, Walker said.

One of the most unusual aspects of BluB-catalyzed synthesis is its cannibalization of a cofactor derived from another vitamin, B2. During the reaction, the B2 cofactor is split into more than two fragments, one of which becomes DMB.

Normally, the B2-derived cofactor would assist in a reaction by temporarily holding electrons and then giving them away. Such cofactors are not consumed in the reaction.

Cannibalization of a cofactor has very rarely been observed before in vitamin synthesis or any type of biosynthetic pathway, says Michiko Taga, an MIT postdoctoral fellow in Walker's lab and lead co-author of the Nature paper.

"There are almost no other examples where the cofactor is used as a substrate," she said.

One early clue to BluB's function was that a gene related to it is located near several other genes involved in B12 synthesis in a different bacterium. Still, the researchers were not convinced that one enzyme could perform all of the complicated chemistry needed to produce DMB.

"It looked like a number of things had to happen in order to make the DMB," said Walker. "We originally thought that BluB might be just one of several enzymes involved in DMB synthesis."

Therefore, it came as a surprise when Taga isolated the BluB protein and showed that it could make DMB all by itself.

Nicholas Larsen, lead co-author and a former college classmate of Taga's now at Harvard Medical School, did a crystallographic analysis of the protein after Taga told him about her research over coffee one day. The protein structure he developed clearly shows the "pocket" of BluB where the DMB synthesis reaction takes place.

Still to be explored is the question of why soil bacteria synthesize B12 at all, Walker said. Soil microorganisms don't require B12 to survive, and the plants they attach themselves to don't need it either, so he speculates that synthesizing B12 may enable the bacteria to withstand "challenges" made by the plants during the formation of the symbiotic relationship.

More than 30 genes are involved in vitamin B12 synthesis, and "that's a lot to carry around if you don't need to make it," Walker said.

The full implications of the new research will probably not be known for some years, which is often the case with basic research, Walker said. "I've been in many other situations in research where we did something very basic and did not immediately realize the importance of it, and subsequently the implications were found to be much more broad-reaching," he said.

Source: MIT

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Creating tissues that can augment or replace injured, defective, or diseased body parts

Tissue engineering is a relatively new field of basic and clinical science that is concerned, in part, with creating tissues that can augment or replace injured, defective, or diseased body parts. The approach to fabricating the tissues involves adding specific cell types to grow on a polymer scaffo...

Tissue engineering is a relatively new field of basic and clinical science that is concerned, in part, with creating tissues that can augment or replace injured, defective, or diseased body parts. The approach to fabricating the tissues involves adding specific cell types to grow on a polymer scaffold having the shape of the tissue to be restored. The scaffold gradually disappears, while the cells continue developing in the scaffold shape. With the use of non-human animal cells, there has been considerable recent progress made in the engineering of skin, bladder, cartilage, and several other tissues.

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Today, during the 85th General Session of the International Association for Dental Research, scientists are reporting on experiments applying human cells from cartilage (chondrocytes) on a scaffold. If the chondrocytes could be successfully grown in this manner, they were also interested in determining whether their development could be enhanced by a protein (osteogenic protein-1) that was known to increase production by chondrocytes of a major cartilage extracellular matrix component, proteoglycan. This study had not been undertaken previously.

Experiments were conducted as follows: Normal ankle cartilage was obtained from a deceased adult through the Gift of Hope Organ %26amp; Tissue Donor Network in Elmhurst, IL. The chondrocytes from the cartilage were isolated and purified by standard laboratory procedures. They were then applied to small polymer (polyglycolic acid) scaffolds that were disc-shaped. Three such constructs were created for comparison of possible cell growth and proteoglycan production. The first consisted of a scaffold treated with cells only, the second a scaffold with cells to which osteogenic protein-1 (from Stryker Biotech, Hopkinton, MA) was added drop-wise, and the third a scaffold incorporating timed-release capsules of osteogenic protein-1 together with cells. The constructs were maintained for 4 weeks and then analyzed for the presence of chondrocytes and production of proteoglycan. Results showed successful tissue engineering of the chondrocytes on scaffolds and enhancement of proteoglycan production with osteogenic protein-1 delivered to the cells by either droplet addition or timed release.

The studies established that human chondrocytes are able to develop cartilage by the tissue-engineering methods used, and promise further advances toward therapeutic tissue engineering by laboratory means.

Source: International %26amp; American Association for Dental Research

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Oral fluids hold promise as a potential alternative to blood as a diagnostic fluid

Oral fluids hold promise as a potential alternative to blood as a diagnostic fluid. Currently, diseases like HIV, hepatitis, and certain cancers can be detected through the analysis of oral fluids. In the past, it has been difficult to detect meaningful amounts of disease markers in oral fluids, bec...

Oral fluids hold promise as a potential alternative to blood as a diagnostic fluid. Currently, diseases like HIV, hepatitis, and certain cancers can be detected through the analysis of oral fluids. In the past, it has been difficult to detect meaningful amounts of disease markers in oral fluids, because they are not always found in the same abundance as in blood. Proteomics is a relatively new method of studying the amounts and types of protein in cells and body fluids on a much smaller scale than was previously possible. The analysis of oral fluids using proteomics has opened new doors for the study of oral diseases and links between oral and systemic diseases.

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Researchers at the Mayo Clinic in Rochester, MN, reporting today during the 85th General Session of the International Association for Dental Research, are conducting a study using proteomics to analyze two different oral fluids: saliva and gingival crevicular fluid, the fluid which is present in the pocket between the teeth and gum tissue. The purpose of the study is to demonstrate how these fluids contribute unique proteins to oral fluid, and to establish what proteins are found in healthy, "normal" oral fluid. In the future, this information will be compared with that obtained from individuals who have disease, to discover new ways to diagnose and treat disease.

Source: International %26amp; American Association for Dental Research

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Scientists re-grow dental enamel from cultured cells

Dental enamel is the hardest tissue produced by the body. It cannot regenerate itself, because it is formed by a layer of cells that is lost by the time the tooth appears in the mouth. The enamel spends the remainder of its lifetime vulnerable to wear, damage, and decay. For this reason, it is excit...

Dental enamel is the hardest tissue produced by the body. It cannot regenerate itself, because it is formed by a layer of cells that is lost by the time the tooth appears in the mouth. The enamel spends the remainder of its lifetime vulnerable to wear, damage, and decay. For this reason, it is exciting to consider the prospect of artificially growing enamel, or even whole teeth, using culturing and transplantation techniques. In the emergent field of tooth-tissue engineering, several groups have developed their own approaches. Although there has been some success in producing enamel-like and tooth-like tissues, problems remain to be solved before the technology comes close to being tested in humans. One of the issues has been how to produce, in culture, sufficient numbers of enamel-forming cells.

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Today, during the 85thth General Session of the International Association for Dental Research, a team of researchers from the Institute of Medical Science, the University of Tokyo (Japan), reports on a new technique for culturing cells that have the capacity to produce enamel. This group has recently shown that epithelial cells extracted from the developing teeth of 6-month-old pigs continue to proliferate when they are cultured on top of a special feeder layer of cells (the feeder-layer cells are known as the 3T3-J2 cell line). This crucial step boosts the number of dental epithelial cells available for enamel production. In the study being reported today, the researchers seeded the cultured dental epithelial cells onto collagen sponge scaffolds, along with cells from the middle of the tooth (dental mesenchymal cells). The scaffolds were then transferred into the abdominal cavities of rats, where conditions were favorable for the cells in the scaffolds to interact and develop. When removed after 4 weeks, the remnants of the scaffolds were found to contain enamel-like tissue. The key finding of this study was that even after the multiple divisions that occurred during propagation of the cells in culture, the dental epithelial cells retained the ability to produce enamel, as long as they were later provided with an appropriate environment.

The idea for the culturing technique originates from 1975, when Dr. J.G. Rheinwald and Dr. H. Green of Harvard Medical School reported the use of feeder layers for culturing epithelial cells from the skin (the 3T3-J2 cells used in the current study were gifted by Dr. Green). The cell-scaffold approach is based on tissue-engineering technology developed at the Forsyth Institute (MA) and was applied by one of the Tokyo researchers to produce enamel-like tissues in 2002. Now that dental epithelial cells can be propagated in culture, the next step will be to achieve the same success with their partners in tooth formation, the dental mesenchymal cells. Further development of this technique will be aimed toward production of tissue to replace damaged or missing enamel, and ultimately, regeneration of whole teeth.

Source: International %26amp; American Association for Dental Research

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Tai chi chih significantly boosts the immune systems of older adults

Tai chi chih, the Westernized version of the 2,000-year-old Chinese martial art characterized by slow movement and meditation, significantly boosts the immune systems of older adults against the virus that leads to the painful, blistery rash known as shingles, according to a new UCLA study.The 25-we...

Tai chi chih, the Westernized version of the 2,000-year-old Chinese martial art characterized by slow movement and meditation, significantly boosts the immune systems of older adults against the virus that leads to the painful, blistery rash known as shingles, according to a new UCLA study.

The 25-week study, which involved a group of 112 adults ranging in age from 59 to 86, showed that practicing tai chi chih alone boosted immunity to a level comparable to having received the standard vaccine against the shingles-causing varicella zoster virus. When tai chi chih was combined with the vaccine, immunity reached a level normally seen in middle age. The report appears in the April issue of the Journal of the American Geriatrics Society, currently online.

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The results, said lead author Michael Irwin, the Norman Cousins Professor of Psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA, confirm a positive, virus-specific immune response to a behavioral intervention. The findings demonstrate that tai chi chih can produce a clinically relevant boost in shingles immunity and add to the benefit of the shingles vaccine in older adults.

"These are exciting findings, because the positive results of this study also have implications for other infectious diseases, like influenza and pneumonia," said Irwin, who is also director of the UCLA Cousins Center for Psychoneuroimmunology. "Since older adults often show blunted protective responses to vaccines, this study suggests that tai chi is an approach that might complement and augment the efficacy of other vaccines, such as influenza."

The study divided individuals into two groups. Half took tai chi chih classes three times a week for 16 weeks, while the other half attended health education classes %26#8212; including advice on stress management, diet and sleep habits %26#8212; for the same amount of time and did not practice tai chi chih. After 16 weeks, both groups received a dose of the shingles vaccine Varivax. At the end of the 25-week period, the tai chi chih group achieved a level of immunity two times greater than the health education group. The tai chi chih group also showed significant improvements in physical functioning, vitality, mental health and reduction of bodily pain.

The research follows the success of an earlier pilot study that showed a positive immune response from tai chi chih but did not assess its effects when combined with the vaccine.

The varicella zoster virus is the cause of chickenpox in kids. Children who get chickenpox generally recover, but the virus lives on in the body, remaining dormant. As we age, Irwin said, our weakening immune systems may allow the virus to reemerge as shingles. Approximately one-third of adults over 60 will acquire the infection at some point.

"It can be quite painful," Irwin said, "and can result in impairment to a person's quality of life that is comparable to people with congestive heart failure, type II diabetes or major depression."

Tai chi chih is a nonmartial form of tai chi and comprises a standardized series of 20 movements. It combines meditation, relaxation and components of aerobic exercise and is easy to learn.

Source: University of California, Los Angeles

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Biopolymer suture stronger, safer

With the help of a new type of suture based on MIT research, patients who get stitches may never need to have them removed.A biopolymer suture cleared last month by the FDA is made of materials that the human body produces naturally, so they can be safely absorbed once the wound is healed. They are ...

With the help of a new type of suture based on MIT research, patients who get stitches may never need to have them removed.

A biopolymer suture cleared last month by the FDA is made of materials that the human body produces naturally, so they can be safely absorbed once the wound is healed. They are also 30 percent stronger than sutures now used and very flexible, making them easier for surgeons to work with.

The sutures were developed by Tepha, Inc., a Cambridge company that hopes to use the same material to produce an array of absorbable medical devices, including stents, surgical meshes and possibly a heart valve scaffold, says Simon Williams, CEO of Tepha and a former MIT postdoctoral associate.

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Williams said he envisions that the new sutures will be used for abdominal closures, which are prone to re-opening, and to stitch tendons and ligaments.

Developed using a method created at MIT, the absorbable sutures are the first made from material produced by genetically modified bacteria.

About 20 years ago, researchers in the laboratory of MIT biology professor Anthony Sinskey started swapping genes between different bacteria, hoping to achieve industrial production of desirable natural compounds synthesized by those bacteria.

The researchers focused their "biopolymer engineering" efforts on a group of genes that code for enzymes in a pathway that produces polyesters. Those polyesters can be broken down into metabolites naturally produced by humans, so they cause no harm when absorbed.

Once the genes were identified, they could be transferred into a strain of industrial E. coli that can produce large quantities of the strong, flexible polymer.

The FDA cleared the biopolymer sutures on Feb. 8, and Williams said Tepha plans to start marketing them soon, in partnership with another company.

"Not only is it technically and in an engineering sense a tremendous victory, but it's also a victory for society because this leads to new medical devices that can help people in new and novel ways," said Sinskey, who is one of the founders of Tepha and sits on its board of directors.

The new suture is the first of what the researchers hope will be many medical devices made from the natural polyesters.

"What we've found is that this one material seems to be finding a lot of use in different applications," because of its wide range of desirable properties, Williams said.

Tepha is now working on developing other medical devices, such as surgical meshes, multifilament fibers and stents. Ultimately, the researchers hope to develop an artificial scaffold that could be used to grow heart valves after being implanted in a patient, which would spare children with heart valve defects from undergoing repeated surgeries.

Tests of the device in animals have shown promise.

"We've been able to show we can produce a valve scaffold that functions better and can grow with the animal," Williams said. "If the valve can grow with the patient, you don't need the repeated surgeries."

Source: MIT

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Major breakthrough in treatment of Type 1 diabetes

More than 12 million people worldwide are afflicted with Type I diabetes, an autoimmune disease in which insulin-producing pancreatic islets are damaged, thereby impeding the bodys ability to regulate glucose concentrations in the blood. One proposed therapy for this disease involves the transplanta...

More than 12 million people worldwide are afflicted with Type I diabetes, an autoimmune disease in which insulin-producing pancreatic islets are damaged, thereby impeding the body%26#8217;s ability to regulate glucose concentrations in the blood. One proposed therapy for this disease involves the transplantation of pancreatic islets from a donor source. The main problem with this approach is the possibility of rejection by the body%26#8217;s immune system.

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Now, in a major breakthrough, a collaborative team of chemists, physicists, and clinical researchers at the University of Chicag have devised a technique for coating pancreatic islets with a thin polymer shell that allows the transport of glucose and insulin but protects the islets from being attacked by the immune system.

Milan Mrksich, Sidney Nagel, Marc Garfinkel, and their colleagues have developed an encapsulation method based on the flow of water and oil through a thin tube. The islets are pulled from the water%26#8211;oil interface so that they are surrounded by a uniform microscopic layer of water. In the method used by the researchers, a polymeric component present in the aqueous phase is stitched together by shining green light from a laser to start the crosslinking process. A thin and porous polymer shell is thus obtained around the islets.

%26#8220;The thin coats produced by this technique may allow for more flexibility in choosing a transplantation site%26#8221;, said Garfinkel, proposing that the islets could be transplanted into the portal vein that flows into the liver. The large sizes of encapsulated islets obtained by conventional methods have precluded their transplantation in these sites because of their tendency to obstruct the flow of blood in terminal blood vessels.

By controlling the thickness of the shell and the crosslinking density of the polymer, the researchers are able to exclude the smallest components of the immune system from attacking the islets, while still allowing the rapid diffusion of glucose and insulin. Remarkably, these encapsulated islets are able to match bare islets in producing insulin in response to varying concentrations of glucose.

Nagel pointed out that unlike other encapsulation methods which give a fixed outer diameter of the resulting core%26#8211;shell structures, this approach enables coatings of the same thickness to be formed for islets of varying sizes. This is especially important since the islets can vary in size by a factor of five.

%26#8220;The properties of the microcapsule can be systematically tuned by adding functional molecules to each polymeric layer%26#8221;, added Mrksich, %26#8220;for example, the outer layer can be equipped with vascular growth factors and anti-inflammatory drugs, whereas the inner layer can be modified to enhance insulin secretion%26#8221;. The protection afforded to the islets from the immune system suggests that it may be possible to use islets from animal sources in replacement therapy for Type I diabetes.

Source: Wiley

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Bioengineering heart tissue - Laboratory-grown muscle may replace damaged areas after heart attack

Some day, heart attack survivors might have a patch of laboratory-grown muscle placed in their heart, to replace areas that died during their attack. Children born with defective heart valves might get new ones that can grow in place, rather than being replaced every few years. And people with clogg...

Some day, heart attack survivors might have a patch of laboratory-grown muscle placed in their heart, to replace areas that died during their attack. Children born with defective heart valves might get new ones that can grow in place, rather than being replaced every few years. And people with clogged or weak blood vessels might get a new %26#8220;natural%26#8221; replacement, instead of a factory-made one.

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These possibilities are all within reach, and could transform the way heart care is delivered, say University of Michigan Medical School researchers in the new issue of the journal Regenerative Medicine. Technology has advanced so much in recent years, they write, that scientists are closer than ever to %26#8220;bioengineering%26#8221; entire areas of the heart, as well as heart valves and major blood vessels.

But hurdles still remain before the products of this tissue engineering are ready to be implanted in patients as replacements for diseased or malformed structures, the team notes. Among the hurdles: determining which types of cells hold the most potential, and finding the best way to grow those cells to form viable cardiac tissue that is strong, long-lasting and structured at a cellular level like natural tissue.

The new article reviews the current state of cardiac tissue engineering, both at the U-M Cardiac Surgery Artificial Heart Laboratory and in labs worldwide.

%26#8220;Tissue engineering is a rapidly evolving field, and cardiovascular tissue is one of the most exciting areas but also one of the most challenging,%26#8221; says Ravi Birla, Ph.D., the paper%26#8217;s senior author and director of the U-M Artificial Heart Laboratory. %26#8220;With this paper, we%26#8217;re presenting the current state of the art as it exists in our lab and others, and pointing out both potential applications and hurdles that remain.%26#8221;

The paper presents a model for collaborative research between engineers, clinicians and biologists for successful cardiovascular tissue engineering research.

%26#8220;Although there remain tremendous technological challenges, we are now at a point where we can engineer first-generation prototypes of all cardiovascular structures: heart muscle, tri-leaflet valves, blood vessels, cell-based cardiac pumps and tissue engineered ventricles,%26#8221; says Birla.

Research at the Artificial Heart Laboratory has focused on comparing different platforms to engineer functional heart muscle in the laboratory. Last December, Birla and first author Yen-Chih Huang, PhD, published a paper describing their success in growing pulsing, three-dimensional patches of bioengineered heart muscle, or BEHM. That paper describes the use of an innovative technique, using a fibrin hydrogel, that is faster than others, but still yields tissue with significantly better properties.

The gel was able to support rat cardiac cells temporarily, before the fibrin broke down as the cells multiplied and organized into tissue within a few days. Tests showed that the BEHM was capable of generating pulsating forces and reacting to stimulation more like real muscle than ever before.

Previously, the group described the results of a self organization strategy, showing that it was possible to engineer heart muscle that closely resembles normal heart muscle physiology without any synthetic scaffolding material. The U-M team and others have also shown how polymeric scaffolds can be used to engineer heart muscle of any shape or size to match the area of the damaged heart muscle %26#8211; raising the possibility of engineering customized patches to meet the specific requirements of patients. All of these approaches are described in the recent review article.

The new article, by Birla and lead author Louise Hecker, a graduate student in the U-M Department of Cell %26amp; Developmental Biology, describes the %26#8220;bioreactor%26#8221; that the team uses to grow their BEHM. It also details many other discoveries that have been made by other teams using different cell-growing surfaces and conditions, as well as hurdles that still lie ahead. In all, the authors say, bioengineered cardiac tissue holds immediate promise as a way to study heart disease and its treatment in cell cultures %26#8211; and promise over the longer term as a source of new patient treatments.

As part of the effort to make the leap from the lab to the clinic, U-M is applying for patent protection on the Artificial Heart Laboratory%26#8217;s developments and is actively looking for a corporate partner to help bring the technology to market.

The U-M team%26#8217;s bioreactor was developed Robert Dennis, Ph.D., formerly of the U-M College of Engineering and now at the University of North Carolina. It allows up to 11 specimens of tissue to be grown in the same conditions at the same time, while allowing each specimen to be %26#8220;stretched%26#8221; using a specially made device that can both apply forces and measure the forces generated when the tissue begins contracting and beating on its own. In the new paper, the team reports that it has achieved a doubling of the contracting force in just seven days, by stretching the BEHM at 1 Hertz.

The growing of heart muscle, heart valve and blood vessel tissue in the lab also requires careful control of conditions such as temperature, oxygen and carbon dioxide levels, nutrients and pH level. This can then encourage the cells to begin producing the kinds of molecules needed to signal to and connect with other cells, and to produce the extracellular matrix that supports cells in tissue.

The U-M Artificial Heart Laboratory has teamed up with a commercial partner to develop a novel perfusion system that can deliver controlled nutrient exchange to the tissue engineered heart muscle. The perfusion system is the first of its kind, because it does not rely on a traditional cell culture incubator, giving the researchers the ability to carefully control the culture environment of the cells during heart muscle formation and foster a higher degree of functionality.

Even if cell-growing conditions can be perfected to produce tissue that is strong, durable and shaped like the native tissue it is designed to replace, another major challenge remains: which type of cells to use. Or more clearly, which types of cells to use %26#8211; because heart muscle tissue is made up of several types of cells. Human heart cells are hard to come by, and %26#8220;adult%26#8221; stem cells haven%26#8217;t yet been shown to be changeable into cardiac cells. Embryonic stem cells, while promising, come with political baggage. And other types of muscle cells taken from elsewhere in the body %26#8212; including skeletal muscles %26#8212; have been used in early clinical trials, but results are mixed.

Source: University of Michigan

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