#Engineered yeast turns sugar into painkiller Scientists have reprogrammed the genetic machinery of baker yeast so that the fast-growing cells can convert sugar into hydrocodone in just three to five days.
and potentially cheaper way to make other types of plant-based medicine. Hydrocodone and its chemical relatives such as morphine and oxycodone are opioids,
It can take more than a year to produce a batch of medicine, starting from the farms in Australia, Europe,
processed, and shipped to pharmaceutical factories in the United states, where the active drug molecules are extracted
and refined into medicines. hen we started work a decade ago, many experts thought it would be impossible to engineer yeast to replace the entire farm-to-factory process,
says senior author Christina Smolke, an associate professor of bioengineering at Stanford university. Now, though the output is smallt would take 4,
400 gallons of bioengineered yeast to produce a single dose of pain reliefhe experiment proves that bioengineered yeast can make complex plant-based medicines. his is only the beginning,
Smolke says. he techniques we developed and demonstrate for opioid pain relievers can be adapted to produce many plant-derived compounds to fight cancers,
infectious diseases and chronic conditions such as high blood pressure and arthritis. any medicines are derived from plants, which our ancestors chewed
or brewed into teas, or later refined into pills using chemical processes to extract and concentrate their active ingredients.
to reprogram the cells into custom chemical assembly lines to produce medicinal compounds. An important predecessor to the new work has been the use of genetically engineered yeast to produce the antimalarial drug artemisinin.
Traditionally artemisinin has been sourced from the sweet wormwood tree in similar fashion to how opiates are refined from poppy.
about one third of the world supply has shifted to bioreactors. The artemisinin experiments proved that yeast biosynthesis was involved possible,
but adding only six genes. The Stanford team had to engineer 23 genes into yeast to create their cellular assembly line for hydrocodone. his is complicated the most chemical synthesis ever engineered in yeast,
a Phd student in chemistry and a member of Smolke team. heye the action heroes of biology. o get the yeast assembly line going,
the Stanford team had to fill in a missing link in the basic science of plant-based medicines.
Many plants, including opium poppies, produce (S)- reticuline, a molecule that is a precursor to active ingredients with medicinal properties.
which enzyme reconfigures reticuline but even after the bioengineers added this enzyme into their microbial factory,
Smolke says. e need options to help ensure that the bio-based production of medicinal compounds is developed in the most responsible way. molke says that in the United states,
where opioid medicines are already widely available, the focus is on potential misuse. But the World health organization estimates that 5. 5 billion people have little
with proper controls against abuse, allow bioreactors to be located where they are needed, she says. In addition to bioengineering yeast to convert sugar into hydrocodone,
Bio-produced thebaine would still need to be refined through sophisticated processes in pharmaceutical factories, but it would eliminate the time delay of growing poppies. he molecules we produced
and the techniques we developed show that it is possible to make important medicines from scratch using only yeast,
and fairly provide medicines to all who need. tanford has patents on the technology and Smolke and researchers on her team have formed a company o
#Scientists Identify Molecular Mechanism that Leads to Maturation of Heart Cells A multi-university team of researchers has identified a molecular switch that seems to be essential for embryonic heart cells to grow into more mature, adult-like
and regenerative medicine researchers as it may lead to laboratory methods to create heart cells that function more like those found in adult hearts.
"said Hannele Ruohola-Baker, Ph d.,University of Washington professor of biochemistry and senior author of the paper."
"We believe we've now found the master switch that drives the maturation process.""In the months before and after birth, an infant's heart cells undergo dramatic changes.
and switch from a metabolism that depends on glucose for most of its energy to a metabolism that derives most of its energy from fats.
which plays a key role in controlling gene expression and, thereby helps regulate the cell's development, growth and function."
and easily repeatable test for pancreatic cancer, scientists at Barts Cancer Institute, Queen Mary University, have developed a three-protein biomarker panel that can screen urine samples to identify pancreatic cancer
The panel, the scientists say, has demonstrated already better than 90%accuracy. Moreover, it readily distinguishes between pancreatic cancer and chronic pancreatitis,
conditions that are mistaken easily for each other. The scientists settled on just three proteins after conducting proteomic analyses of 488 urine samples92 from patients with pancreatic ductal adenocarcinoma (PDAC
92 from patients with chronic pancreatitis, 87 from healthy volunteers, and 117 samples from patients with other benign and malignant liver and gall bladder conditions.
The urine samples were subjected to assays using Gelc-MS/MS (in-gel tryptic digestion followed by liquid chromatography-tandem mass spectrometry) and ELISA.
Initially, around 1, 500 proteins were identified, with approximately half being common to both male and female volunteers.
Patients suffering from chronic pancreatitis had significantly lower levels than cancer patients. Combining the three proteins
the scientists discovered, yielded a robust panel. The panel performance was described August 3 in the journal Clinical Cancer Research, in an article entitled, dentification of a Three-Biomarker Panel in Urine for Early Detection of Pancreatic Adenocarcinoma. hen comparing
PDAC with healthy urine specimens, the resulting areas under the receiver-operating characteristic curves (AUC) of the panel were 0. 89 in the training (70%of the data)
and 0. 92 in the validation (30%of the data) datasets, wrote the authors. hen comparing PDAC stage II with healthy urine specimens,
the panel achieved AUCS of 0. 90 and 0. 93 in the training and validation datasets,
respectively. At present, noninvasive biomarkers for early detection of PDAC are not available. The biomarker panel established by the Barts Cancer Institute scientists,
however, shows promise. e've always been keen to develop a diagnostic test in urine as it has several advantages over using blood.
It's an inert and far less complex fluid than blood and can be repeatedly
while to secure proof of principle funding in 2008 to look at biomarkers in urine, but it's been worth the wait for these results.
This is a biomarker panel with good specificity and sensitivity and we're hopeful that a simple,
if the three-biomarker signature is present during the latency periodhe time between the genetic changes that will cause the cancer to develop and the clinical presentation.
With few specific symptoms even at a later stage of the disease, more than 80%of people with pancreatic cancer are diagnosed
when the cancer has already spread. This means they are not eligible for surgery to remove the tumorurrently the only potentially curative treatment.
Patients are diagnosed usually when the cancer is already at a terminal stage, but if diagnosed at stage II,
the survival rate is 20, %and at stage I, the survival rate for patients with very small tumors can increase up to 60%.
%It is hoped that with early detection, the survival rate for pancreatic cancer will improve. At present, only about 3%of patients found to have pancreatic cancer survive more than five years c
#Genetic Variance Found as Cause for Cerebral palsy Cerebral palsy (CP) is the most common form of physical disability in children, with an incidence rate of approximately two cases for every 1, 000 live births.
Historically, CP has been attributed to an array of factors such as asphyxia, stroke, and infections in the developing brains.
However, researchers from The Hospital for Sick Children (Sickkids) and the Research Institute of the Mcgill University Health Centre (RI-MUHC) have uncovered evidence for genetic causes of CP that may precipitate a change in the clinical
diagnostics for children and expecting mothers.""Our research suggests that there is a much stronger genetic component to cerebral palsy than previously suspected,
"explained lead author Maryam Oskoui, M d.,pediatric neurologist at The Montreal Children's Hospital (MCH) of the MUHC and co-director of the Canadian Cerebral palsy Registry."
"How these genetic factors interplay with other established risk factors remains to be understood fully. For example, two newborns exposed to the same environmental stressors will often have very different outcomes.
Our research suggests that our genes impart resilience or conversely a susceptibility to injury.""The findings from this study were published recently in Nature Communications through an article entitled linically relevant copy number variations detected in cerebral palsy.
The investigators performed genetic tests on 115 children with CP, many of whom had been identified previously with other risk factors as a cause for their disease.
DNA tests were performed also on the children parents, in order to paint a more comprehensive picture of the genetic background for CP.
"When I showed the results to our clinical geneticists, initially they were floored, "said Stephen Scherer, Ph d.,principal investigator on the current study and Director of The Centre for Applied Genomics (TCAG) at Sickkids."
"In light of the findings, we suggest that genomic analyses be integrated into the standard of practice for diagnostic assessment of cerebral palsy."
"CNVS are structural alterations to an individual genome that lead to deletion, additions, or some reorganization of gene sequences that produces aberrant genetic products.
as they are associated with and array of genetic disease states.""It's a lot like autism, in that many different CNVS affecting different genes are involved
which could possibly explain why the clinical presentations of both these conditions are noted so diverse
or new, CNVS identified in these patients with cerebral palsy is even more significant than some of the major CNV autism research from the last 10 years.
We've opened many doors for new research into cerebral palsy.""While the researchers were excited by their findings,
as they noted that their CNV data would have impacted the diagnosis or classification in almost 10%of the patients they studied."
"Finding an underlying cause for a child's disability is an important undertaking in management,
"stated co-author Michael Shevell, M d. co-director of the Canadian Cerebral palsy Registry and chair of the Department of Pediatrics at the MCH-MUHC."
This study will provide the impetus to make genetic testing a standard part of the comprehensive assessment of the child with cerebral palsy."
"Cerebral palsy (CP) is the most common form of physical disability in children, with an incidence rate of approximately two cases for every 1, 000 live births.
Historically, CP has been attributed to an array of factors such as asphyxia, stroke, and infections in the developing brains.
However, researchers from The Hospital for Sick Children (Sickkids) and the Research Institute of the Mcgill University Health Centre (RI-MUHC) have uncovered evidence for genetic causes of CP that may precipitate a change in the clinical
diagnostics for children and expecting mothers.""Our research suggests that there is a much stronger genetic component to cerebral palsy than previously suspected,
"explained Dr. Oskoui.""How these genetic factors interplay with other established risk factors remains to be understood fully.
Our research suggests that our genes impart resilience or conversely a susceptibility to injury.""The findings from this study were published recently in Nature Communications through an article entitled linically relevant copy number variations detected in cerebral palsy.
The investigators performed genetic tests on 115 children with CP, many of whom had been identified previously with other risk factors as a cause for their disease.
DNA tests were performed also on the children parents, in order to paint a more comprehensive picture of the genetic background for CP.
"When I showed the results to our clinical geneticists, initially they were floored, "said Dr. Scherer."
"In light of the findings, we suggest that genomic analyses be integrated into the standard of practice for diagnostic assessment of cerebral palsy."
"CNVS are structural alterations to an individual genome that lead to deletion, additions, or some reorganization of gene sequences that produces aberrant genetic products.
as they are associated with and array of genetic disease states.""It's a lot like autism, in that many different CNVS affecting different genes are involved
which could possibly explain why the clinical presentations of both these conditions are noted so diverse
or new, CNVS identified in these patients with cerebral palsy is even more significant than some of the major CNV autism research from the last 10 years.
We've opened many doors for new research into cerebral palsy.""While the researchers were excited by their findings,
as they noted that their CNV data would have impacted the diagnosis or classification in almost 10%of the patients they studied."
"Finding an underlying cause for a child's disability is an important undertaking in management,"stated Dr. Shevell."
This study will provide the impetus to make genetic testing a standard part of the comprehensive assessment of the child with cerebral palsy. e
The researchers say it's important to understand how the toxins work because they are key to enabling bacteria to cause disease.
Toxins typically go after molecules that are either scarce or whose role is to send important metabolic signals.
The OSU study (CD toxinroduced actin oligomers poison formin-controlled actin polymerization which is published in Science,
shows that one toxin linked to cholera and other diseases, which hones in on a popular and plentiful protein target,
"It appears that this toxin followed some of the most sophisticated battlefield strategies long before they were invented by humans:
It recognizes that to win the war, one doesn't need to kill all the soldiers.
All that is needed is to send in a spy to recruit a few soldiers who will betray their own army
and neutralize the officers, "said Dmitri Kudryashov, Ph d.,assistant professor of chemistry and biochemistry at OSU and senior author of the study."
"This finding suggests that with other toxins that appear to act on highly abundant structures, it's likely that we don't actually know how they work."
"In this case, the soldiers are the protein actin, which is produced in abundance by almost all human cells
and is an important player in the body's response to an infectious disease. In particular, actin is a molecular motor that enables immune cells to chase
cholera (Vibrio cholera), septicemia or gastroenteritis from eating infected raw oysters (Vibrio vulnificus) and gastric illnesses that threaten people with weakened immune systems (Aeromonas hydrophila.
That kind of power raised new questions about how ACD works. Actin is present in cells in two different forms:
a monomer, or a single molecule, and a filament, which is a strand of those molecules strung together.
"Therefore, ACD effectively hijacks formin by converting actin molecules into new potent poisons,"said co-corresponding author Elena Kudryashova, Ph d.,a research scientist in chemistry and biochemistry at OSU.
"said first author David Heisler, a graduate student in the Ohio State Biochemistry Program.""This establishes an entirely new toxicity mechanism. e
#Engineering Therapeutic Proteins into Antibodies Scientists at the Scripps Research Institute (TSRI) have devised an improved method for building proteins into larger proteins such as antibodies.
The new technique mimics evolution by generating millions of possible junction segments between the inserted protein
and its antibody host, selecting the rare ones that allow the inserted protein to fold
otherwise, including powerful hormone-based therapies.""Unlike prior approaches to this design problem, ours is based a selection method,
"said senior investigator Richard A. Lerner, Ph d.,the Lita Annenberg Hazen Professor of Immunochemistry at TSRI.
Friedman, M d.,Ph d.,at Rockefeller University and the TSRI groups of Ian A. Wilson and Patrick R. Griffin, appears in Chemistry and Biology.
In one proof-of-principle demonstration, the team edited the genetic code of a standard human antibody to replace one of its target-grappling elements structure that normally would bind to a virus
First identified by Dr. Friedman in 1994 as a satiety hormone that switches off hunger, leptin initially failed as an obesity therapy,
and also diabetes. Leptin on its own and in an unmodified state isn't ideal as a therapy
because it doesn't last long in the bloodstream.""The kidneys and other organs clear it very rapidly,
a staff scientist in the Lerner laboratory who was first author of the study with Wenwen Zeng of Friedman's lab at Rockefeller."
if it were part of a larger structure such as an antibody.""The major challenge for Dr. Lerner, Peng and their colleagues was to design leptin into an antibody in such a way that it would fold up into a functional structure
despite being bound to its host protein at either end. Designing simple, highly flexible"junction"segments to join leptin to an antibody could work a recent paper (www. ncbi. nlm. nih. gov/pubmed/25605877) by a group including TSRI's Peter Schultz, Ph d,
. Scripps Family Chair Professor of Chemistry, described such a feat. But Dr. Lerner's team reasoned that a selection-based design of these junctions would be a more general approach to making useful protein-in-protein molecules.
Using their established techniques for generating large libraries of variant antibodies the team made nearly 30 million versions of the leptin-in-antibody protein,
each version having a different amino-acid sequence for its junction segments. To find the rare versions that enabled leptin to fold up
and function properly, the researchers used a selection system that they had developed previously for finding therapeutic antibodies in large antibody libraries.
First they employed viral vectors to insert the leptin-in-antibody DNA into test cells that contain leptin receptors.
When one of the resulting leptin-in-antibody proteins successfully activated a leptin receptor in its test cell,
the event was signaled by a highly sensitive set of fluorescent beacons. The cells whose beacon signals rose above a certain threshold were analyzed for the leptin-in-antibody DNA they contained,
and this DNA was inserted then into new test cells and so on, for round after round of selection,
until the process yielded the leptin-in-antibody protein that did best at activating the leptin receptor.
As is often the case for antibodies the leptin-in-antibody protein effectively could not cross from the bloodstream into the brain
and thus could not hit all of leptin's neuronal targetsnd so its effects at reducing eating
But, in principle, antibodies can be modified to enable them to cross the blood-brain barrier more easily, and the team is working on that now.
the researchers also used it to"selection-design"an antibody that incorporates the growth and reproductive hormone FSH,
The resulting FSH-in-antibody protein showed activity against the FSH receptor that was virtually the same as the natural hormones.
The team is now working to improve their FSH-and leptin-in-antibody proteins, and to design entirely new protein-in-antibody molecules l
#Expanding the Super-Resolution Arsenal Technological advances in the field of microscopy and imaging have seen a flurry of activity over the past several years,
. group leader at the Howard hughes medical institute's Janelia Research Campus."This will bring super-resolution to live-cell imaging for real."
a variation of structured illumination microscopy (SIM), can now show the movement and interactions of proteins as cells remodel their structural supports
In traditional SIM, the sample under the lens is observed while it is illuminated by a pattern of light (similar to scanning a barcode).
Computer software then extracts the information from the moiré images and translates it into a three-dimensional, high-resolution reconstruction.
"I fell in love with SIM because of its speed and the fact that it took so much less light than the other methods,"Dr. Betzig noted.
Dr. Betzig and his team were convinced that SIM had the potential to generate significant insights into cellular mechanics,
and he suspected that improving the technique's spatial resolution would go a long way toward increasing its use by biologists.
However, traditional SIM was not suitable for living cells, as the method was designed to generate an image by switching on all of the fluorescent labels in the cell
"Alternatively, the new method, called patterned photoactivation nonlinear SIM, begins by switching on just a subset of fluorescent labels in a sample with a pattern of light."
The combined effect of those patterns led to final images with 62-nanometer resolutionuch better than standard SIM and a threefold improvement over the limits imposed by the wavelength of light."
I have to take the data in a tenth of a second, or else it will smear out."
However, he went on to note that"most of the magic is in the software, not the hardware. t
such as the preparation of foods, dietary supplements, therapeutics, and chemical materials. The ability to precisely tune enzymatic reactions with small biomolecules holds enormous potential for industrial manufacturing, analytical science,
and drug therapeutics. Now, researchers at the University of Chicago have developed what they believe is a novel approach to control the activity of enzymes through the use of synthetic,
antibody-like proteins they call monobodies. The investigators were able to change the specificity of an enzyme,
commonly utilized in the food industry, without altering the enzyme itselfstablishing a new direction for enzyme engineering
and demonstrating the versatility of these synthetic proteins.""This is the first time that synthetic accessory molecules have been engineered to change the specificity of an enzyme
in order to achieve a desired end-product, "explained senior author Shohei Koide, Ph d.,professor of biochemistry and molecular biophysics at the Chicago."
"In this paper, we demonstrated their efficacy on sugars, but one can envision applications of this concept with enzymes acting on other types of molecules such as lipids
"The findings from this study were published recently in Nature Chemical Biology through an article entitled onobody-mediated alteration of enzyme specificity."
and used directed evolution techniques to identify molecules that bound near the active site of ß-Gal,
and are already in use as a platform for other applications by biotechnology companies. The University of Chicago team is currently investigating other enzymes that might benefit from monobody technology,
as well as working with an industry partner to develop monobody-modified ß-Gal for commercial use."
Yet now, scientists at the University of Buffalo (UB) Hunter James Kelly Research Institute (HJKRI) have developed a new method for
The cellular interactions that trigger the production of myelin are especially hard to pinpoint since the point of contact is buried essentially between the intertwined myelin layers and neuronal plasma membrane."
"explained senior author M. Laura Feltri, M d.,professor of biochemistry and neurology in the Jacobs School of medicine and Biomedical sciences at UB."
"This work may help to provide much-needed insight into demyelinating diseases such Krabbe Leukodystrophy, MS,
and Charcot-Marie-Tooth disease.""In Krabbe's, for example, the problem is not just that there isn't sufficient myelin,
The new technique described in the current study involves using the neuron as a trigger to attract glial cells.
and look to continue their work with the hope of better understanding this critical connection between neuronal cellsossibly leading to a druggable target for demyelinating diseases."
"This research has profound implications for glial disease like Krabbe's, Charcot-Marie-Tooth, peripheral neuropathies or Multiple sclerosis,
"Similarly, neurodegenerative diseases like Huntington's disease or Lou Gehrig's, that were considered unique diseases of neurons in the past,
are considered now diseases of cellular communications between neurons and glial cells
#Protein Based Sensors Expand Synthetic biology Repertoire Engineering proteins to detect specific DNA, RNA, or peptide sequences may not be a new idea,
but a new approach taken by synthetic biology engineers at the Massachusetts institute of technology (MIT) is as interesting as it is elegant.
The MIT researchers developed a flexible system of proteins that sense particular sequences of DNA,
senior author James Collins, Ph d.,professor of medical engineering and science in MIT's Department of Biological engineering and Institute of Medical Engineering and Science (IMES)."
while treating diseases using this system is likely many years away, it could be used much sooner as a research tool.
whether genetic material has been delivered successfully to cells that they are trying to alter genetically. Cells that did not receive the new gene could be induced to undergo cell death
#At home Molecular Diagnostics could become Reality with New Test Design Does being able to test for allergies, STD,
or even cancer in minutes from the comfort and privacy of your home sound like science fiction?
Well, a newly designed test from researchers at the University of Montreal could make it a reality before the next Star trek movie comes to theaters.
This new design could aid efforts in building point-of-care devices for quick medical evaluations.
This design allows the assay to detect a wide range of protein markers associated with various disease states."
"explained senior author Alexis Vallée-Bélisle, Ph d.,professor in the department of chemistry at the University of Montreal."
and the results sent back to the doctor's office. If we can move testing to the point of care,
which would enhance the effectiveness of medical interventions. The findings from this study were published recently in the Journal of the American Chemical Society through an article entitled highly selective electrochemical DNA-based sensor that employs steric hindrance effects to detect proteins directly in whole blood.
Interestingly a key breakthrough for the realization of the test design came about serendipitously.""While working on the first generation of these DNA-base tests,
(or traffic) at the surface of a sensor, which drastically reduced the signal of our tests,
. postdoctoral scholar at the University of Montreal"Instead of having to fight this basic repulsion effect,
and limits the ability of this DNA to hybridize to its complementary strand located on the surface of a gold electrode.
The resulting current created by the signaling mechanism is sufficient enough to be picked up by simple electronic devices,
allowing us to build inexpensive devices that could detect dozens of disease markers in less than five minutes in the doctor's office or even at home,"concluded Dr. Vallée-Bélisle a
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