Systems Biology Helps to Understand Hematopoiesis

1-After blood loss, large amounts of the hormone Epo flood the hematopoietic system in the bone marrow. Scientists of the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) in Heidelberg and the University of Freiburg have now published an article in Science uncovering how a rapid turnover of Epo receptor molecules on hematopoietic cells ensures that these remain ready to react. Thus, our body can respond even to extreme increases of Epo levels with an adequate supply of red blood cells.

2-Our body reacts to blood loss by stimulating the production of red blood cells (erythrocytes). The cells of the hematopoietic (blood-forming) system in the bone marrow do so upon receipt of a signal by a hormone called erythropoietin, or Epo for short. This hormone is produced mainly by the kidney that increases the Epo level by up to a thousand-fold as a response to falling oxygen saturation of the blood.

3-The hematopoietic cells receive the Epo signal through Epo receptors on their surface. How do the blood progenitor cells that carry only few receptor molecules manage to react adequately to a high rise in the Epo level and to always provide the required amount of red blood cells? "If too much of the hormone floods too few receptor molecules, we would expect the saturation point to be reached soon. This would mean that the hematopoietic cell can no longer respond to a further increase in the hormone level," says Dr. Ursula Klingmüller of DKFZ.

4-Researchers in her department, who participate in the Helmholtz Alliance for Systems Biology and the MedSys Network LungSys funded by the Federal Ministry of Education and Research (BMBF), collaborated with colleagues of a working group headed by Professor Jens Timmer at Freiburg University to find out how hematopoietic cells can react in a linear way if Epo levels increase by several orders of magnitude. To do so, the researchers combined experimental data with mathematical models in a systems biology approach.

5-The research team was able to show that after binding of Epo to its receptor both molecules are rapidly taken up into the interior of the hematopoietic cells where they are broken down. During the process, the cell surface is continuously equipped with newly synthesized receptor molecules that are supplied from intracellular storage places. "This turnover of receptor molecules is a very rapid process," Jens Timmer explains who is a member of the Freiburg Institute for Advances Studies (FRIAS) as well as the excellence cluster BIOSS. "Thus, the cell keeps being able to recognize further hormone molecules in its environment and to react accordingly."

6-Genetically engineered Epo is an important medication for treating anemia, for example in dialysis patients who often suffer from low counts of red blood cells because these are destroyed during dialysis and, in addition, the failure of renal function leads to a lack of natural Epo. The results of the Heidelberg and Freiburg scientists may contribute to developing Epo variants with enhanced binding properties and thus increase the effectiveness of anemia treatment.

7-Verena Becker, Marcel Schilling, Julie Bachmann, Ute Baumann, Andreas Raue, Thomas Maiwald, Jens Timmer, Ursula Klingmüller: Covering a Broad Dynamic Range: Information Processing at the Erythropoietin Receptor. Science 2010, DOI: 10.1126/science.1184913

From- German Cancer Research Center Press release.

Burning brown fat

1-A team of German researchers has identified a cyclooxygenase-2–mediated pathway in mice that increases levels of lipid-burning brown fat and could thus trigger weight loss to treat obesity.¹ 

2-The next challenge is developing compounds that boost the pathway in adipose tissue without increasing cyclooxygenase-2–related inflammation.

3-Mammals have two types of adipose tissue—white and brown. White adipose tissue (WAT) is specialized for lipid storage and can give rise to obesity when energy intake exceeds energy expenditure. In contrast, brown adipose tissue (BAT) is specialized for thermogenesis, the burning of lipids to generate heat during exposure to cold. In humans, newborns have substantial amounts of BAT, whereas adults have much lower but still measurable quantities.^2, 3, 4

4-The presence of BAT in adults has caused speculation that boosting its activity or increasing overall BAT levels could be strategies for enhancing energy expenditure and promoting weight loss. The difficulty has been identifying druggable pathways associated with BAT homeostasis.

5-In the new work, researchers led by Stephan Herzig, head of molecular metabolic control at the German Cancer Research Center, built on previous work by others that had shown that inhibiting cyclooxygenase-2 (COX-2), a key enzyme in prostaglandin synthesis, could lead to decreased energy expenditure and increased fat accumulation in mice.^5, 6 More generally, COX-2 has been shown to be one of several factors that contribute to inflammation associated with adiposity.⁷

6-The researchers thus hypothesized that COX-2 activity might be important for the development of thermogenic BAT and that increasing levels of the enzyme in adipose tissue could generate more BAT and trigger weight loss.

To confirm the importance of COX-2 in adipose tissue, the researchers first measured Cox-2 expression in adipose tissue from a variety of mouse models of impaired energy homeostasis.

7-In mice with genetic or diet-induced obesity and in wasting tumor-bearing mice, Cox-2 mRNA levels in adipose tissue were unchanged compared with those in tissue from wild-type controls. However, a significant increase in Cox-2expression occurred in mice exposed to four weeks of cold (p<0.05). 

8-Moreover, uncoupling protein 1 mitochondrial proton carrier (UCP1), a key mediator of BAT thermogenesis, was also upregulated following exposure to cold.

9-Those findings strongly suggested that Cox-2 was indeed important for the development and/or recruitment of BAT. The next question was whether increasing Cox-2 levels in adipose tissue would lead to weight loss.

10-To help answer that question, the researchers looked at mice that were engineered to overexpress Cox-2 in adipose tissue. On a normal diet, those animals developed clusters of BAT-like cells within WAT and had a 20% reduction in body weight without loss of muscle mass or a reduction in bone length compared with wild-type controls.

Finally, following 16 weeks on a high-fat diet, the Cox-2-overexpressing mice showed no significant weight gain, whereas wild-type mice gained weight throughout the feeding period.

The Cox-2-overexpressing mice were also better protected against hyperglycemia, hyperinsulinemia and glucose intolerance.

11-Corresponding author Herzig told SciBX that his group now wants to better understand the mechanistic details of how COX-2 and prostaglandin trigger cells in WAT to develop into BAT.

12-That work will be important to help “identify the most selective agonists for this pathway,” said Patrick Seale, assistant professor of cell and developmental biology in the Institute for Diabetes, Obesity and Metabolism at the University of Pennsylvania School of Medicine.

13-Simply increasing COX-2 activity in adipose tissue may not be the ideal approach, because that could lead to side effects, especially increased inflammation, Seale told SciBX.

14-COX-2 is the target of a class of NSAIDs that includes Celebrex celecoxib from Pfizer Inc. Another COX-2 inhibitor, Vioxx rofecoxib from Merck & Co. Inc., was withdrawn from the market in 2004 because of concerns over increased risk of cardiovascular events associated with long-term use.

As possible alternatives to directly boosting COX-2 levels, Seale suggested “systemic delivery of a highly specific prostaglandin or a synthetic analog” that would induce less of an inflammatory response.

15-Once the mechanism is better worked out, Herzig said, he would like to generate BAT ex vivo and use the tissue for transplantation studies, first in obese mice and eventually perhaps in obese patients.

16-The animal models used in the Science paper are patented, according to Herzig. He did not disclose the licensing status of the patents.

From- Nature SciBx

Mouse project to find each gene's role

International Mouse Phenotyping Consortium launches with a massive funding commitment.

1-An ambitious effort to identify the function of every gene in the mouse genome looks set to provide scientists with the ultimate mouse model of human disease.

2-The International Mouse Phenotyping Consortium (IMPC) has yet to find all of the US$900 million it needs to complete its task over the next decade. But at a meeting on mouse models of human diseases in London, where the project was unveiled last week, scientists announced a commitment of $110 million from the US National Institutes of Health (NIH) in Bethesda, Maryland over the next five years.

3-The IMPC aims to take mice of identical genetic background and to create viable strains in which one of the 20,000 or so genes in the mouse genome is knocked out, or deactivated. The knockout strains will then be put through rigorous, systematic phenotypic screens, which will check for physical and behavioural differences. The information will be stored in a purpose-built, open-access database.

4-Scientists would, for example, be able to turn to the database to learn more about an unfamiliar gene signalled in a genome-wide association study in humans as being possibly relevant to a particular disease. Making the mutant animal and phenotyping it in a lab could take three years.

5-But the launch of the visionary programme comes at a time of global financial crisis and may have trouble finding additional funders. Some scientists had looked to the European Commission, which sponsored the meeting and has spent close to €250 million (US$305 million) over the past ten years to pioneer systematic phenotyping of mice, and to generate mutant mice. But Leszek Borysiewicz, chief executive of the UK Medical Research Council (MRC) in London, warned at the meeting that the commission's politicians would need a lot of con vincing that mouse genomics was more deserving of funds than other scientific projects.

6-The mouse genome was the first to be sequenced after the human because of its importance as a laboratory model. "But it soon became clear that it is impossible to predict function directly from sequence," says Paul Schofield, a geneticist at the University of Cambridge, UK, who helped to organize the meeting. "Also, there are black holes in the genomes where we simply don't know what the genes do — the mouse phenotype database would give us traction."

7-Mouse 'clinics' have sprung up around the world to screen mutant mice for crude phenotypes — such as heart defects — and to perform secondary screens to investigate the changes in more detail. But it is already clear that even this is not enough. Gene expression, and the resultant phenotype, are profoundly influenced by environment, and many of these mice are raised in a stressed environment for the purposes of experiments — for example, being fed high-fat diets or subjected to infection. Much more will be learnt by comparing phenotype screens carried out on mutant mice raised in a normal environment, say project scientists.

8-"The IMPC sounds expensive but it is not compared with other genomic resources," adds Moore. "The database only needs to help industry to develop a handful of multibillion-dollar blockbuster drugs and it will have paid for itself."

From- Nature News

A Hole in the Genome

A small chunck of DNA linked to schizophrenia, mental retardation, and autism may change the way we think about disease.
1-Go about 145,000,000 bases down the long arm of chromosome 1 and you will come to 1q21.1 the genetic address of a small but important piece of DNA that is particularly prone to mistakes. When chromosome 1 is duplicated during normal cell division, short repetitive bits of DNA within this stretch are all too likely to mistakenly pair up, raising the chance that the new cells will have extra or missing copies of specific pieces of DNA.
2-Several studies in the last year have found that missing or extra pieces of DNA in the 1q21.1 region put the bearer at risk for a surprisingly broad range of psychiatric and neurological disorders, including autism, schizophrenia and mental retardation.
3- The discovery that one piece of DNA can lead to such diverse outcomes is opening new avenues in the study of disease. Rather than focusing solely on finding a common genetic flaw in everyone with a particular disease, researchers have begun to examine the various consequences that the same genetic flaw may have in different people.
4-These studies suggest that even patients with different diagnoses may share common biological problems. "It's been eye-opening," says Mark Daly, a geneticist at the Broad Institute in Cambridge, MA, "because it's made us realize that in searching for the molecular basis of diseases, it may be profitable to search for connections between seemingly unrelated phenotypes."
5- Last year, Daly and his colleagues identified a section of  DNA on chromosome 16 that also raises the risk of several different brain disorders, suggesting that this pattern may be common in the genetics of disease.
6-Over the last few years, new kinds of microarrays- small slides dotted with specific sequence of DNA- have begun allowing scientists to efficiently search the genome for architectural flaws too small to be visible with a microscope. These errors, called copy number variations, are distinct from the single letter changes that until recently have been the focus of most research into genetic variation. Ranging in size from one thousand to more than one million base pairs, they can encompass part of a gene or one or more entire genes.
7-Heather Mefford, a pediatric geneticst at the University of Washington in Seattle, compiled data on variations in 1q21.1 from clinical genetics labs around the world. She found that 25 patients in a sample of more than 5,000 people with autism, mental retardation or other congenital abnormalities were missing the same chunk within the region.
8-Different studies linking 1q21.1 to mental retardation, autism and schizophrenia all identified deletions or duplications in approximately the same region. That's because this particular stretch is flanked by repetitive sequence prone to rearrangement. It contains at least eight known genes, the functions of which are mostlyy unknown. "This region of the genome must clearly have one or more genes that are important for normal cognitive development," says Mefford, whose research was published in the New England Journal of Medicine in October.

From:- MIT Technology Review

Zebrafish larvae are a surprisingly compatible stand-in for humans as researchers test the next generation of insomnia drugs.

1-Researchers at Harvard University have developed a screening tool that tests the effects of thousands of compounds on zebrafish behavior in an effort to discover new pathways that govern sleep. The research, may result in new drugs to treat insomnia and other sleep-related disorders.

2-Alexander Schier and his colleagues at Harvard developed an automated system to assess 60,000 distinct sleep related behaviors in zebrafish. After Screening 5,600 small molecules on the larvae, the team discovered 463 significant sleep altering compounds, many of which have been known to have similar effects in humans.

3- "This was a proof of principle that many of the pathways found in humans are conserved in fish." It's still unclear what molecular mechanisms control sleep and wakefulness. Sleep drugs generate $7 billion in annual profits in the US. However the drug development process is tedious and expensive. Schier believes that testing drug candidates in Zebrafish could be a cheap and straightforward alternative to conventional drug screeing.

4-"The advantage of Zebrafish is that you can keep large numbers of animals in very small space and raise many animals relatively cheaply" says Schier. Unlike files and worms, which are often used in the early stages of pharmaceutical research, fish are vertebrates. " Much can be found in zebrafish that is relevant to mammals, " he says.

5-To screen the drugs, researchers pipetted single Zebrafish larvae into a tiny well of a 96 well tray. Each well was injected with a drug, with one drug tested on 10 different larvae. They placed the tray in a recording chamber  with infrared and white LED lights and a camera connected to computer software. After lining the tray up with a corresponding grid on the computer screen, researchers programmed the timing of light to simulate day and night. The camera recorded each fish's activity over two days and video tracking software plotted out each fish's movements per seconds.

From:- MIT Technology Review

Pigs Offer Cystic Fibrosis Clues

Genetically modified pigs offer clues to the disease's early development.


1-Researchers at the University of Iowa and the University of Missouri have developed a better animal model of cystic fibrosis. Newborn pigs that have been bred with a genetic mutation for the disease are the first animals to exhibit clinical symptoms similar to those in humans with the condition. The results point to a more effective way of studying cystic fibrosis and finding drugs to treat it.


2-Cystic fibrosis is one of the most common life-shortening hereditary diseases. It affects 30,000 people in the United States and 70,000 worldwide. For years, scientists have tried to track the disease in mice engineered with the genetic mutation for cystic fibrosis, but the mice have not developed the trademark symptoms, including chronic lung disease. 


3-The pigs, whose organs are a closer match with humans, developed lung disease several months after birth. The researchers have published the results in the current issue of Science Translational Medicine.

Part of the motivation for the research is that, while the genetic root cystic fibrosis has long been known, it's still unclear how this leads to lung disease.

4-The team found that newborn pigs with the disease had elevated levels of bacteria in their lungs. This finding may help resolve a long-standing debate --whether people with the disease are born with a hypersensitive inflammatory response that leads to lung disease, or whether inflammation occurs only when bacteria are present.

5-"One question looming in the field is this chicken or egg concept of whether infection comes first, or whether inflammation precedes," says David Stoltz, assistant professor of pulmonary, critical care and occupational medicine at the University of Iowa, who was involved in the project. "It's important to answer that question because if you now know the sequence of events of lung disease in cystic fibrosis, that could dictate how you treat it."

6-Currently, physicians may choose to aggressively treat both infection and inflammation to slow the progression of lung disease. However, if researchers identify which of the two comes first in the disease, doctors could focus therapies to treat it much earlier, potentially extending lung function.

In order to identify the early effects of cystic fibrosis, Stoltz and his colleagues observed the genetically engineered pigs from birth. Within months, the pigs developed signs of lung disease, including airway inflammation, mucous accumulation, and bacterial infection. 

7-The researchers took lung tissue cultures from both modified and normal piglets, and performed multiple tests to look for early signs of lung inflammation, including elevated white blood cell counts. They also did gene expression profiles related to inflammation. The group found no major differences between the disease and control groups before the disease group began showing symptoms, suggesting that people born with cystic fibrosis are not necessarily born with a hypersensitive immune response.

Going a step further, the team tested the newborns' ability to fight off infection by introducing Staphylococcus aureus into their lungs, a bacteria commonly found in infants and children with cystic fibrosis. After four hours, researchers found the bacteria lingered in the lungs of the modified pigs, whereas their healthy counterparts were able to completely get rid of it.

"This study says that it seems to be the bacteria triggering the immune response," saysWilliam Guggino, director of the Cystic Fibrosis Research Development Program at Johns Hopkins University. "To have an animal model where you could apply drugs and see if they work to correct this bacterial infection is a pretty big advance."

Alice Prince, professor of pediatrics in pharmacology at Columbia University, who was not involved in the study, says studying cystic fibrosis in pigs makes sense physiologically. "I think it's a very promising model," he says. "The immunology of pigs is more like people, and the airway cells in the pig lung are more like a human than in a mouse, so you could try a lot more therapies than you can with mice."

While the pigs reproduce clear clinical trademarks of the human disease, the researchers found that, like humans with cystic fibrosis, the piglets are born with a bowel obstruction that, without surgery, is 100 percent fatal. "These are incredibly expensive animals," says Craig Gerard, chief of the division for respiratory services at Children's Hospital in Boston.

Stoltz and his team plan to test a variety of drugs in the modified pigs, including compounds that counteract the effects of the relevant gene mutation. In cystic fibrosis, the mutated gene, CFTR, alters the activity of a key ion channel in the membranes of organs like the lungs and pancreas, causing thick mucus to build up, which exacerbates lung function. Scientists have recently identified drug compounds that improve the activity of the ion channel, which could potentially restore ion transport and lung function.

Brain Waves Predict Suicide Risk

A new technique might help doctors foresee suicidal thoughts before a patient even has them.


1-Over the past five years, an increasing number of studies have pointed to the rare but serious risk of suicidal thoughts that can accompany new antidepressant treatments. Close monitoring is currently the only clinical option, but a new technique--one that measures and analyzes electrical activity of the brain--could one day predict which people might be most susceptible to antidepressant-induced suicide.

2-While uncommon, the gravity of suicide risk was enough to prompt the U.S. Food and Drug Administration to place a "black box" warning on multiple antidepressant labels. So in order to tease out those individuals at highest risk, researchers at the University of California at Los Angeles's Laboratory of Brain, Behavior, and Pharmacology are using an approach called quantitative EEG (QEEG).

3-Electroencephalography (EEG) uses a cap of electrodes placed at multiple locations across the scalp, each of which measures electrical activity coming from the brain at that particular spot. Neurologists frequently use EEG readouts to diagnose conditions such as epilepsy or brain injury. But instead of using the raw data--a set of jerky, squiggly lines, with each line corresponding to a single electrode--UCLA researchers employ an algorithm that mathematically analyzes data from all of the electrodes to transform the results into a map of brain activity.

4-The lab is using this quantitative EEG to determine how different individuals' brains respond to different antidepressants, trying to find early markers that indicate whether a new therapy will be effective. But in addition to efficacy, research psychologist Aimee Hunter is also interested in side effects, since those often appear long before any improvement in mood. "And with all the increased press about antidepressants causing suicidal ideation, I began looking for brain changes that might specifically be related to that," says Hunter, who is the lead author of a paper about the research, which was published in the April issue of Acta Psychiatrica Scandinavica.

5-An earlier study by Hunter and her colleagues, in which healthy volunteers were placed on either placebo or antidepressants, pinpointed the midline-and-right-frontal (MRF) portion of the brain as a region of interest. Those on medication showed moderately decreased activity in this area after just a week, while placebo-takers exhibited a slight increase. Focusing on the MRF region, Hunter then examined QEEGs from 72 adult patients who had been randomly assigned to take either medication or placebo for eight weeks. At multiple time points--48 hours, one week, two weeks, four weeks, and eight weeks after starting their therapy--the patients returned for QEEG measurements and a mood-assessment questionnaire.

6-When Hunter examined the results, she found a striking effect: Those patients on antidepressants who indicated any increase in suicidal thoughts also showed a drastic decrease in activity in their MRF region just 48 hours after starting their meds--six times the decrease shown in subjects with no change in suicidal thoughts. But after one week, the two groups were nearly identical again. 

7-"It was very strange: There was a very large downward spike, and then ... nothing," Hunter says. "But the suicidal worsening isn't happening at 48 hours--it's happening at some later point over the next eight weeks." She was seeing what appeared to be a harbinger of future response.

"They're onto something important," says Barry Lebowitz, a professor of psychiatry at the University of California at San Diego, who was not involved with the research. "This is clearly a first step in trying to personalize antidepressant treatment."

From:- MIT Technology Review

From the Labs: Biomedicine

 Better Cancer Tracking:-Physicians could monitor cancer by screening for tumor DNA


1-Source: "Development of Personalized Tumor Biomarkers Using Massively Parallel Sequencing"Victor Velculescu et al. Science Translational Medicine 2: 20ra14.


2-Results: Researchers from Johns Hopkins University analyzed the DNA of tumors in patients with breast and bowel cancer and found regions of abnormal, re arranged DNA that served as unique biomarkers of each patient's disease. They then measured levels of cancer-specific DNA in one patient before and after treatment. The ratio of cancer DNA to normal DNA in blood samples dropped dramatically after treatment, but the marker was still detectable, suggesting that the patient should be monitored more closely for possible recurrence of the disease.


3-Why it matters: Cancer arises when a number of genetic alterations in cells allow them to grow uncontrollably.Tracking those alterations in a patient's cancer DNA could provide a new way of detecting small tumors or stray cancer cells that linger after treatment. Scientists say the DNA changes detected in the study will prove much more accurate than existing biomarkers such as the prostate-specific antigen (PSA) associated with prostate cancer, which may yield false positives because even healthy cells can produce the protein.

4-Methods: Researchers compared the genome sequence of patients' healthy DNA and DNA isolated from tumor tissue. After isolating unique tumor signatures, they developed a test that uses DNA amplification to measure the amount of tumor DNA and normal DNA in blood.

5-Next steps: To determine how the technology can be most useful in medicine, researchers will use it to analyze different tumor types as well as different stages of tumor progression. They are also working on automating the technique and reducing its cost.

Replacement Neurons:-A simple genetic recipe reveals the surprising flexibility of adult cells

1-Source: "Direct conversion of fibroblasts to functional neurons by defined factors"

Marius Wernig et al.
Nature 463: 1035-1041

2-Results: By making a few simple genetic tweaks, scientists can transform mouse skin cells directly into brain cells, without first returning them to the embryonic state required by previous methods. The resulting cells express neuron-specific genes, have the characteristic branching shape of neurons, and form connections both with each other and with regular neurons collected from the brain.

3-Why it matters: The research could someday offer an effective way to replace damaged neurons. Because brain cells derived from a skin graft would be genetically identical to the patient's own tissue, they wouldn't carry the risk of immune rejection associated with transplants. And scientists say the technique is faster than the existing approach to generating replacement brain cells from an individual patient: reprogramming adult cells to behave like embryonic cells and then prodding them to develop into neurons.

4-Methods: Scientists began by studying the genes for 19 transcription factors--proteins that bind to DNA and regulate expression of other genes. All were known to play a role in neural development and were found only in the brain. When the researchers used viruses to deliver two genes known to be particularly important for neural development into skin cells growing in a dish, they discovered that one of them had the power to convert the cells into what looked like immature neurons. They identified two additional genes that made the process faster and more consistent.

5-Next steps: The researchers are trying to repeat the process with human cells. They also plan to transplant the reprogrammed mouse cells into the brains of engineered mice that have a disease similar to Parkinson's. Those experiments could reveal whether the cells can function properly in the brain and relieve symptoms of the disease.

From:- MIT Technology Review

Artificial Pancreas Tracks Two Hormones

A new system controls diabetics' blood sugar by monitoring both insulin and glucagon.

1-Managing type 1 diabetes is a feat of organization and control. The better a diabetic can keep blood sugar in check, the less likely are long-term health complications. But even with devices like automated insulin pumps, which release a continuous dose of insulin, diabetics still need to remember to add an extra dose of insulin at meals, and many spend a significant amount of time each day with blood-sugar levels either higher or lower than normal.

2-Scientists have been working to develop an "artificial pancreas" system that would monitor blood-sugar levels and normalize them automatically, without any human input. A preliminary clinical trial detailed this month in Science Translational Medicine marks a significant advance in creating a fully automated system. The system was able to control blood sugar in a small group of diabetic patients, even when patients ate high-carbohydrate meals, which is one of the major challenges for artificial-pancreas systems.

3-Most artificial-pancreas systems under development pair a blood-sugar monitor with an insulin pump. The device in this study adds another component that monitors the hormone glucagon, which counteracts insulin. Glucagon helps prevent blood-sugar levels from dropping too low if too much insulin is given. Although diabetics still produce glucagon, it doesn't always function properly.

4-"Our feeling is that glucagon is an important extra measure of safety," says Steven Russell, an endocrinologist at Massachusetts General Hospital, who co-led the research. Russell explains that hypoglycemia can be a major problem for diabetics--paradoxically, the better diabetics control their blood sugar, the more they are at risk. 

5-Hypoglycemia, which occurs when blood sugar drops too low, can lead to sweating, trembling, dizziness, and confusion, and in some cases it can be life-threatening.

6-The new study was primarily designed to test an algorithm the team developed to predict the amount of insulin and glucagon needed to keep blood-sugar levels normal. Edward Damiano, a bioengineer at Boston University and co-leader of the study, says that because insulin is absorbed and cleared from the body slowly, the algorithm can't simply respond to the current blood-sugar level but must also anticipate where it is headed. "At each dose, it keeps track of the rising insulin it's given, as well as the decay of previous doses," he says.

7-The system was tested in 11 adults with type 1 diabetes for a period of 27 hours, during which the subjects ate three high-carbohydrate meals. Rather than relying on a glucose monitor under the skin, the researchers took direct blood-sugar readings from the blood every five minutes. Software then calculated the amount of insulin and glucagon needed. Doses were administered by nurses. 

8-In the first trial, the system kept blood-sugar levels normal for six of the subjects, but the other five experienced hypoglycemia that needed to be rescued by drinking fruit juice. The researchers found that these five patients took much longer than anticipated to absorb and clear the insulin they received. So they adjusted the parameters of the system to match a slower insulin absorption rate, and retested the same subjects. The system was then able to keep the blood-sugar levels of all participants under control, although levels were slightly higher in those who had absorbed insulin quickly in the first trial.

9-Bruce Buckingham, a pediatric endocrinologist at Stanford University who was not involved in the work, says that demonstrating that the system works even after subjects have eaten large meals is a key achievement. "Dealing with meals is the real obstacle" in developing any artificial pancreas, he says. A recent study from a group at Cambridge University, U.K., tested a similar system, but only overnight, when patients were not eating. Buckingham says that another challenge for the devices will be handling periods of exercise, which also causes blood sugar to fluctuate.

10-The team behind the new device is planning a further trial using an FDA-approved continuous glucose monitor and an automated system for delivering the two hormones. This trial will compare the dual-hormone system with an insulin-only one, and it will cover two days and include a period of exercise.

11-Aaron Kowalski, director of the Artificial Pancreas Project at the Juvenile Diabetes Research Foundation, which partially funded the study, says that the insulin-glucagon system represents the future of artificial-pancreas technologies. "Our ultimate goal is to try to come as close to a human physiology without diabetes as possible," he says. But bringing such a system to market will be challenging. 

12-Kowalski says that there are no FDA-approved pumps that deliver two different substances, and glucagon is currently used only in emergencies when diabetic patients become dangerously hypoglycemic--it comes in the form of a powder that must be reconstituted.

13-In the more immediate term, Kowalski believes that insulin-only artificial-pancreas devices will become available much sooner. An insulin pump that can shut off automatically when blood sugar drops too low has already been approved in Europe. And the Artificial Pancreas Project is working with Animas Corporation, which makes glucose monitors, on a system that monitors blood sugar but only automatically delivers insulin when blood-sugar levels fall above or below a certain range. Kowalski believes that such a device, while not entirely automating the delivery of insulin, can offer diabetics crucial peace of mind.

From:-MIT Technology Review

Touch-responsive nano-generator films could power touch screens.

Touch-screen computing is all the rage, appearing in countless smart phones, laptops, and tablet computers.

1-Now researchers at Samsung and Sungkyunkwan University in Korea have come up with a way to capture power when a touch screen flexes under a user's touch. 

2-The researchers have integrated flexible, transparent electrodes with an energy-scavenging material to make a film that could provide supplementary power for portable electronics. The film can be printed over large areas using roll-to-roll processes, but are at least five years from the market.

3-The screens take advantage of the piezoelectric effect--the tendency of some materials to generate an electrical potential when they're mechanically stressed. 

4-Materials scientists are developing devices that use nanoscale piezoelectronics to scavenge mechanical energy, such as the vibrations caused by footsteps. But the field is young, and some major challenges remain. The power output of a single piezoelectric nanowire is quite small (around a picowatt), so harvesting significant power requires integrating many wires into a large array; materials scientists are still experimenting with how to engineer these screens to make larger devices.

5-Samsung's experimental device sandwiches piezoelectric nanorods between highly conductive graphene electrodes on top of flexible plastic sheets. The group's aim is to replace the rigid and power-consuming electrodes and sensors used on the front of today's touch-screen displays with a flexible touch-sensor system that powers itself. Ultimately, this setup might generate enough power to help run the display and other parts of the device functions. Rolling up such a screen, for instance, could help recharge its batteries.

6-"The flexibility and rollability of the nano-generators gives us unique application areas such as wireless power sources for future foldable, stretchable, and wearable electronics systems," says Sang-Woo Kim, professor of materials science and engineering at Sungkyunkwan University. Kim led the research with Jae-Young Choi, a researcher at Samsung Advanced Institute of Technology.

7-The same group previously put nano-generators on indium tin oxide electrodes. This transparent, conductive material is used to make the electrodes on today's displays, but it is inflexible.

8-To make the new nano-generators, the researchers start by growing graphene--a single-atom-thick carbon material that's highly conductive, transparent, and stretchy--on top of a silicon substrate, using chemical vapor deposition. Next, through an etching process developed by the group last year, the graphene is released from the silicon; and the graphene is removed by rolling a sheet of plastic over the surface. The graphene-plastic substrate is then submerged in a chemical bath containing a zinc reactant and heated, causing a dense lawn of zinc-oxide nanorods to grow on its surface. Finally, the device is topped off with another sheet of graphene on plastic.

9-In a paper published this month in the journal Advanced Materials, the Samsung researchers describe several small prototype devices made this way. Pressing the screen induces a local change in electrical potential across the nanowires that can be used to sense the location of, for example, a finger, as in a conventional touch screen. The material can generate about 20 nanowatts per square centimeter. Kim says the group has subsequently made more powerful devices about 200 centimeters squared. These produce about a microwatt per square centimeter. Kim says this is enough for a self-powered touch sensor and "indicates we can realize self-powered flexible portable devices without any help of additional power sources such as batteries in the near future."

10-"It's pretty impressive to integrate all these things in a foldable, macroscale device," saysMichael McAlpine, professor of mechanical engineering at Princeton University. He notes that the potential of zinc oxide nanowires as a piezoelectric sensing material and nanoscale power source was previously demonstrated by Georgia Tech materials scientistZhong Lin Wang. But integrating these materials over a large area with a flexible, transparent electrode opens up new applications, says McAlpine.

The methods used to make the nano-generators are compatible with large-scale manufacturing, according to Kim. His group is working to boost the power output of the films--the main obstacle is the quality of the electrodes. One possible solution is to improve the connection between the nanowires and the electrodes by eliminating flaws in the structure of the graphene. The Korean group is also experimenting with adding small amounts of impurities to the material, a process called doping, to improve its conductivity.

From:- MIT Technology Review

How Personal Genomics Could Change Health Care

1-Several months after deciphering his genetic code last year, Stanford bioengineer Stephen Quake approached a cardiologist colleague. Early analysis of his DNA had flagged a rare genetic variant as potentially linked to heart problems. The variant, in fact, was located in a gene linked to sudden cardiac death in athletes, so physician Euan Ashley suggested Quake visit his office for some follow-up screening. Inspired by that meeting, the scientists spent the next year figuring out how to examine his genome in a way that would be meaningful to both Quake and his doctor.

2-The result--published today in The Lancet--is the most comprehensive clinical analysis of a human genome to date, highlighting both the medical potential of genomics and the hurdles that remain. "We wanted to try to answer the question of what a physician should do when a patient walks into the office with a copy of his genome and says 'treat me,' " says Quake, who was named one of Technology Review's top young innovators in 2002.

3-As the cost of sequencing has plummeted in the last few years--from about $3 billion for the Human Genome Project to less than $5,000 today--the number of complete human genomes has blossomed. Hundreds have now been sequenced, though only about 13 have been made public. 

4-Scientists are moving their focus from the technical hurdles of sequencing itself to what they say that will be a much more difficult task: analyzing the content of genomes to better understand human disease and the health risks of the individual.

5-Quake and 13 other "genome pioneers"--a select group who have had their entire genomes sequenced--described their efforts to use their genomes to better manage their health at a conference in Cambridge, MA, this week. The early adopters included James Watson, co-discoverer of the structure of DNA, Harvard professor Henry Louis Gates, Jr., entrepreneur Ester Dyson, 17-year-old Anne West, and a handful of genomics executives.

6-Despite the complexity and remaining mystery of the human genome--scientists still don't know the function of 90 to 95 percent of human genes--many of the pioneers at the event described using their genomic information to make medical decisions. John West, former CEO of Solexa, a sequencing company that was acquired by genomics giant Illumina, recently had his genome sequenced along with that of his wife and two children. West and his wife discovered they have higher risk of a certain type of glaucoma, which sent them to the ophthalmologist for screening. "Now we know there is something to look for, and the test is easy and relatively inexpensive," he said at the conference. (Daughter Anne presented the results of her analysis of her family's genomes to the illustrious audience.)

7-Seong-Jin Kim, director of the Lee Gilya Cancer and Diabetes Institute at Gachon University of Medicine and Science, in South Korea, discovered after genome sequencing that he has a tenfold increased risk of macular degeneration, the leading cause of blindness in people over age 60. "I am diligently taking preemptive steps in everyday life to prevent it," he said at the conference. He takes high doses of antioxidants, which have been shown to slow progression of the disease, has regular eye exams, and avoids activities that tend to overexert the eyes. (The scientist is also trying to convince his wife to switch to an LED television, because they may be less damaging to the eyes than LCD.)

8-While individual genetic tests could have been performed for each of the medical conditions in these cases, the cost of genome sequencing is dropping so quickly that it will soon be cheaper to sequence the whole genome rather than various parts. Quake, who published his own genome sequence, without interpretation, in 2009, can now go back to his genome anytime a new publication describes the possible implications of one of his variations.

10-In the Lancet paper, Quake and his collaborators undertook a comprehensive analysis of his genome. The researchers focused on variants that had been linked to risk of disease in previous studies, and those thought to play a role in a patient's response to drugs. Beginning with an average risk for a particular disease of someone of Quake's age and background, they added or subtracted risk using the genetic information. "That's the most challenging thing, there is no accepted method for how to do that," says Ashley. "We tried to prioritize what would be the most important thing to discuss with a doctor."

11-In addition, researchers found variants in other genes linked to cardiomyopathy, a disease that weakens and enlarges the heart, which may help explain a history of sudden death in the family. "Maybe I could have guessed it based on family history," says Quake. "But it's one thing to know there is a family history and another to know I had the allele. That sent me to a cardiologist."

From:- MIT Technology Review

Extending the Life of Donated Organs

An experimental solution could buy time for transplant patients.


1-The 100,000-plus U.S. patients waiting for organ transplants face a perilous race against time. Most organs can only be preserved outside the body for somewhere between four and 24 hours--a problem that aggravates the chronic shortage of donors. In 2008, 6,684 patients died waiting for organs, according to the National Kidney Foundation.

2-A Harvard scientist is hoping to change those bleak statistics. Hemant Thatte, associate professor of cardiothoracic surgery, has developed a liquid solution that may preserve organs for up to 10 days outside the body. 

3-Thatte's lab devised a recipe of 21 chemical compounds that they believe will slow down the process of cell deterioration. "Our whole goal is to maintain the metabolism of the organ without having to lower the temperature" of the preservation system, Thatte explains. "It's like a state of suspended animation." Thatte dubbed the solution "Somah," which is Sanskrit for "ambrosia of rejuvenation."

4-In October 2009, Thatte and his colleagues published a paper in the journal Circulation comparing Somah to the widely used preservation solution Celsior, made by biotech company Genzyme. 

5-The researchers harvested hearts from female pigs, stored them in one of the two solutions, then biopsied them at several points over the next four hours. They observed the function of the cardiomyocyte and endothelial cells--both of which must be preserved in order for the transplanted heart to survive over the long term. 

6-By measuring key proteins, they determined that the rate of cell death was significantly slower in the Somah-preserved hearts than it was in those stored with Celsior. Their experiments in pigs suggest that Somah keeps hearts and livers viable for at least 10 days. By contrast, solutions such as Celsior can only be counted on to preserve hearts and livers for about four and 12 hours, respectively.

7-Three students who were taking a class at Harvard's business school got wind of Thatte's research from Harvard's Office of Technology Development, and they decided to write up a business plan as an assignment. The team named their startup Hibergenica and set out to find investors in January. 

8-They believe they need $5 million to get Somah to market.The Hibergenica team is pitching investors on the idea that Somah will expand the market for transplanted organs from $30 million a year to as much as $200 million. Some of that growth will arise from an increased supply of viable organs, which could potentially be shipped from faraway places like Hawaii, or even from overseas. Team member Haytham Elhawary, a scientist at Brigham & Women's hospital who was auditing the business-plan class, believes market expansion might also come from premium pricing--Somah could fetch a price that's as much as five times higher than competing solutions, he says.

9-To command that price tag, Hibergenica will have to show that Somah improves the quality of harvested organs, and thus boosts the long-term survival prospects for transplant patients. The solution has the potential to achieve that goal, the entrepreneurs believe, because it is designed to preserve the metabolism of the organs while they are outside the body.

The ingredients work together to transform tissue metabolites into products that protect cells. 

10-In the heart, for example, Somah converts ammonia--a toxic byproduct of tissue metabolism--into a metabolite that augments the nitric-oxide pathway. "That opens up the vasculature of the heart, which helps to preserve its function," says Alison Williams, a scientist at Harvard's School of Public Health, who is serving as Hibergenica's chief scientific officer. Specifically, nitric oxide inhibits vasoconstriction, clotting, and inflammation.

11-Hibergenica's plan is to build on Thatte's initial research by transplanting Somah-preserved organs from pigs into other pigs, so they can measure post-transplant survival rates. If their expectations are met, they'll need about a year of human trials before they can apply for FDA approval. They'll start with kidneys and other abdominal organs, "because that's where the volume is," Elhawary says. If all goes well, they'll test the solution in heart and lung transplants.

12-There haven't been any significant advances in organ preservation in over 20 years, though other companies are certainly trying. In March, Andover, MA-based TransMedics raised $36 million to develop a technology that uses blood perfusion to preserve organs ina system designed to mimic the conditions of the human body.

Proving that Somah reduces organ damage will be critical for convincing transplant surgeons to embrace the solution, says Luca Cicalese, director of the Texas Transplant Center and John Sealy Distinguished Chair in Transplantation Surgery at the University of Texas Medical Branch in Galveston, TX. "Organs get wasted not because of time factors, but because of quality issues," Cicalese says. "If this solution reduces damage to cells, that would be a major help."

13-Other surgeons argue that extending the time window for transplantation could, in fact, offer significant advantages. Michael Marvin, chief of transplant surgery at the University of Louisville, points out that many donated organs have to be flown on chartered airplanes and transplanted in the middle of the night. "Surgeons are working on very little sleep, which may not be optimal," he says. And if organs could be flown on commercial airlines instead of chartered jets, "I imagine there would be a dramatic reduction in costs," he adds.

From:- MIT-Technology Review