Scientists discover new gene for devastating form of epilepsy

Using whole genome sequencing, a large group of scientists has identified a new genetic cause of progressive myoclonus epilepsy, one of the most devastating forms of epilepsy that emerges in early childhood and can result in early death

The team found that a previously unknown mutation in a potassium ion channel gene - called KCNC1 - was present in 13% of the PME patients and 7% of patients in a secondary cohort.

 The international team - including members from the University of Helsinki in Finland and the Universities of Melbourne and South Australia - report their findings in the journal Nature Genetics.

 

Progressive myoclonus epilepsies (PME) are severe, rare forms of epilepsy and frequently arise from hereditary metabolic disorders. Their core symptoms include epileptic seizures and debilitating involuntary muscle twitching. Muscle rigidity, unsteadiness and mental deterioration are often also present.

 

For the study, the international team recruited 84 patients with PME of unknown cause and used DNA sequencing to identify potential genetic causes of the disorder.

 

Modern DNA sequencing techniques have revolutionized genetic research of rare, severe diseases. In this case, the team used the technology to sequence the protein-coding elements of the human genome.

 

They managed to identify genetic causes in nearly a third of the PME patients (26 patients, 31%).

13% of PME cases had previously unknown mutation of potassium ion channel gene

Remarkably, the team found that a previously unknown mutation in a potassium ion channel gene - called KCNC1 - was present in 11 (13%) of the 84 patients and another two (7%) patients in a secondary cohort.

 

The authors note that the mutation was a "de novo" mutation - meaning it was not inherited from the patients' biological parents.

 

"De novo" or new mutations are errors that occur in cell division or in the copying of genetic material. They emerge in a germ cell of one of the parents, or in the fertilized egg. Every person has dozens of these new mutations, but they rarely cause disease.

 

The researchers estimate that this mutation occurs in about 1 in every 5.7 million conceptions, indicating that globally, at least hundreds of PME patients could have this mutation.

 

Mutations (lightning bolts) in 13 unrelated cases hit the same DNA
nucleotide in KCNC1 gene and disrupt the function of a potassium
ion channel, which causes a severe form of epilepsy.
Image credit: Lehesjoki Lab

Corresponding author and principal investigator Professor Anna-Elina Lehesjoki, from the University of Helsinki and the Folkhälsan Institute of Genetics in Helsinki, says:

 

"The mutation site is an example of a 'mutation hotspot' of the genome - a DNA nucleotide which is more prone for alterations."

 

The KCNC1 mutation that the team identified stops a potassium ion channel in brain cells working properly. The channel - called KV3.1 - plays an important part in signal transmission in the brain.

 

Ion channels are how cells, including brain cells and muscle cells, translate their chemical messages into electrical signals.

 

The cell builds up a concentration of ions inside itself - different to the concentration in the cell's environment - and this creates a voltage difference. Then, when the time is right to send a signal, the cell opens an ion channel, and because of the voltage difference, ions travel out of the cell, embodying an electrical version of a chemical message.

 

The researchers suggest the effect of the mutation is to reduce inhibitory signals - making patients susceptible to epileptic seizures and myoclonus starting in childhood. The mutation also leads to degeneration of the cerebellum - a region of the brain that plays an important role in movement control - and subtle cognitive decline in some cases.

Drugs that restore function in this ion channel may already exist

Professor Lehesjoki says because the mutation occurs in a well-known ion channel, there is hope of developing therapy that can target this.

 

"There are anti-epileptic drugs in the market that target other similar ion channels and follow-up research aims to discover a way to rescue the function of the channel in PME patients," she adds.

 

In October 2014, Medical News Today learned how a team from Johns Hopkins University in Baltimore, MD, has discovered new clues about conditions that stem from faulty ion channels, such as cardiac arrhythmias, epilepsy and Parkinson's disease. The discovery relates to a common protein that the team says plays a different role than previously thought in the opening and closing of channels that let ions in and out of cells.

 

Written by Catharine Paddock PhD

 

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Controversial Cholesterol Drug Reduces Risk of Heart Disease

The ability of ezetimibe to combat heart disease previously was in dispute.

 

Ezetimibe reduces cholesterol absorption by

inhibiting the activity of a protein called NPC1L1,

which transports free cholesterol into cells.
Credit: National Library of Medicine

A popular but controversial cholesterol drug reduces the risk of cardiovascular events such as heart attacks and stroke, researchers say. The drug, called ezetimibe, had been shower to lower cholesterol levels, but its ability to combat heart disease was in dispute.

 

But now ezetimibe, made by Merck of Whitehouse Station, New Jersey, has been found to lower the number of cardiovascular events by 6.4% when given with another cholesterol drug. The effect is significant but small; still, some scientists say that the results affirm the ‘lower is better’ hypothesis: that reducing levels of low-density lipoprotein (LDL) cholesterol (often called ‘bad’ cholesterol) lowers the risk of cardiovascular events.

 

“The question that everyone had was, ‘Would this added lowering of LDL cholesterol translate into a real clinical benefit?’” says cardiologist Christopher Cannon of the Brigham and Women’s Hospital in Boston, Massachusetts. “The answer was yes.”

 

That finding, which Cannon presented on November 17 at the American Heart Association meeting in Chicago, Illinois, may come as a relief not only to Merck, but to other pharmaceutical companies — particularly those developing cholesterol drugs (see ‘A gene of rare effect’).

 

It is much faster and cheaper to win drug approval on the basis of lowering cholesterol than of reducing cardiovascular events. Cholesterol levels change rapidly in response to medication, and they are easy to measure. Cardiovascular events, in contrast, are relatively rare. Trials to study them must enrol thousands of people to achieve statistically significant numbers of events.

 

The trial that Cannon presented today, code-named IMPROVE-IT, enrolled more than 18,000 patients and took 9 years to complete.

 

But Harlan Krumholz, a cardiologist at Yale University in New Haven, Connecticut, warns against the assumption that lower is always better when it comes to LDL cholesterol. “I don’t think you can extrapolate from this to say that any drug that lowers cholesterol is better,” he says. “We have lots of examples where that doesn’t happen.”

 

Uncertain significance

 Ezetimibe reduces cholesterol absorption by inhibiting the activity of a protein called NPC1L1, which transports free cholesterol into cells. When combined with a statin, another cholesterol-lowering drug, ezetimibe lowers cholesterol by an extra 20% compared to the statin alone.

 

This seemed to bode well for the drug’s impact on heart health when the US Food and Drug Administration approved ezetimibe in 2002. But in 2008, researchers found that the drug had no impact on the thickness of artery walls in the neck and thigh — a measure of fatty plaque build-up. This plaque build-up is thought to contribute to heart disease by restricting blood flow.

 

The results cast doubt on the usefulness of ezetimibe and of the importance lowering cholesterol in general. Statins had been shown to reduce the risk of heart disease, but that was not true for other medications that lower LDL cholesterol — including niacin and drugs called fibrates.

 

Hopes for ezetimibe were bolstered last week when a genetic analysis of 7,364 people with heart disease and 14,728 controls found that people who had a rare mutation that inactivates the NPC1L1 protein had lower LDL cholesterol levels and a lower risk of coronary heart disease.

 

Cannon tackled the controversy by presenting data from his clinical trial, which compared about 9,000 patients receiving a statin called simvastatin to another 9,000 receiving the statin and ezetimibe. (Neither the patients nor the researchres knew which patients had been assigned which drugs.) The rate of cardiovascular events was 34.7% in patients receiving only the statin, and 32.7% in patients receiving both drugs.

 

“The study affirms the central role of intensive LDL reduction in the prevention of recurrent cardiovascular events,” says Neil Stone, a cardiologist at Northwestern University in Chicago, who was not involved with the study.

 

But Stone warns that the trial was carried out in high-risk patients, a common practice used to boost the likelihood of cardiovascular events. “The data don’t speak to the use of ezetimibe in patients with low risk,” he adds. 

 

For Krumholz, the concern is that people will become overly confident in other drugs that lower cholesterol, in the absence of data on cardiovascular events. “The problem is that drugs can have multiple effects,” he says. “You can’t know for sure what the net effect is on people without formally testing it.”

 

November 18, 2014 |By Heidi Ledford and Nature magazine | Véalo en español

 

 

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Culturing Drug-Resistant Tumors

Improved methods to grow patients’ tumor cells in a dish offer opportunities to find durable therapies.

FLICKR, ANNE WESTON, LRI, CROK. WELLCOME IMAGES

Cancers can become resistant to drugs that once seemed like they could cure a person of the disease. In the unstopping march toward personalized medicine, researchers managed to culture drug-resistant lung tumor cells to screen them for sensitivity to various therapies, finding new and sometimes surprising drug candidates.

 

“It’s a substantial step,” Jeffrey Engelman of Massachusetts General Hospital Cancer Center told Time. “Because before we just had the genetic information but we wouldn’t have the cells alive so that we could test what types of therapies might work.”

 

Engelman and his colleagues published their study in Science last week (November 13). They succeeded in growing cells taken from 20 patients’ tumors. Nature News pointed out that, in many cases, the drug screens turned up unexpected candidates. In half of the tumors, for example, a drug that inhibits a protein called SRC managed to shrink tumor growth in vitro. “There were no genetic results that would have pointed to that combination,” Engelman told Nature News.

 

Engelman’s method has yet to face a clinical challenge; patients’ therapies were not altered based on the screen. “This is really setting up the criteria for what we have to look at next,” Richard Schlegel, director of the Center for Cell Reprogramming at Georgetown University School of Medicine, told the Boston Globe. “Someone has to figure out if we grow up these cells, how many times is this going to be an adequate predictor of patient response?”

Tags

tumor, screening, drug resistance, culture and cancer

 

The Scientist » The Nutshell

By Kerry Grens | November 17, 2014

 

 

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What Is Gluten?

Is gluten bad for You?

Eating gluten, the naturally occurring proteins in wheat, barley and rye can be

life-threatening to people with celiac disease.

Credit: Viktorfischer | Dreamstime

Gluten refers to the proteins found in wheat endosperm (a type of tissue produced in seeds that's ground to make flour). Gluten both nourishes plant embryos during germination and later affects the elasticity of dough, which in turn affects the chewiness of baked wheat products.

 

Gluten is actually composed of two different proteins: gliadin (a prolamin protein) and glutenin (a glutelin protein).

 

Though "true gluten" is sometimes defined as being specific to wheat, gluten is often said to be part of other cereal grains — including rye, barley and various crossbreeds — because these grains also contain protein composites made from prolamins and glutelins.

 

Why is gluten bad?

 

Gluten isn't necessarily bad, but some people are gluten-intolerant, meaning their bodies produce an abnormal immune response when it breaks down gluten from wheat and related grains during digestion.

 

The most well-known form of gluten intolerance is celiac disease, which affects one in every 141 people in the United States, according to the National Institutes of Health. When someone with celiac disease consumes gluten, it triggers an immune response that damages their intestines, preventing them from absorbing vital nutrients. 

 

Wheat allergy is a rare type of gluten intolerance — it's a classic food allergy marked by skin, respiratory or gastrointestinal reactions to wheat allergens.

 

Recently, scientists have become aware of another potential form of intolerance called nonceliac gluten sensitivity. After consuming gluten, patients with gluten sensitivity may experience many celiac disease symptoms, such as diarrhea, fatigue and joint pain, but don't appear to have damaged intestines.

 

In cases of gluten intolerance, doctors typically recommend a gluten-free diet. Patients must avoid eating any foods and ingredients that contains gluten, including bread, beer, french fries, pasta, salad dressing, soy sauce and even some soups (unless otherwise marked as "gluten-free").

 

In recent years, many people without gluten intolerance have taken up gluten-free diets. Experts worry, however, that going on these diets without explicitly needing to could be detrimental to a person's health, as gluten-free foods are often nutrient-deficient.

 

By Joseph Castro, LiveScience Contributor   |   September 17, 2013 05:27pm ET

Follow Joseph Castro on Twitter. Follow us @livescience, Facebook & Google+.

 



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Genetics Explains Why You Drink So Much Coffee

Genes & Health

For those of you attempting to kickstart your Monday: Researchers identified eight gene variants that could explain why some people drink coffee heavily, while others abstain from the drink.

If your favorite order at Starbucks is the “red-eye,” you can thank genetics for your ability to slog down all that caffeine without the shakes.

 

In a new study, scientists identified eight genetic variants that could partly explain why some people drink coffee by the pot, while others avoid the stimulating beverage altogether. By outlining the genetic foundation for coffee consumption, scientists believe they can find firmer evidence to support the positive — and negative — health effects of the popular beverage.

Java Genes

Researchers from the Harvard School of Public Health and Brigham and Women’s Hospital investigated the genomes of 120,000 European and African American coffee drinkers along with data on how many cups a day they consumed, using findings from dozens of previous studies. Their statistical analysis revealed six new gene variants that governed coffee consumption, and reaffirmed the presence of two others previously discovered by the same group of researchers.

 

The team identified variants in or near genes that play roles in learning, caffeine metabolism, blood pressure regulation and addiction. Two newly discovered variants, near the genes BDNF and SLC6A4, reinforce the positive effects of coffee’s molecular properties. For example, BDNF is involved in the release of pleasure-inducing neurotransmitters like serotonin and dopamine.

Researchers published their findings Tuesday in the journal Molecular Psychiatry.

Heavy Drinkers

Participants in the study that inherited five or six of the gene variations were more likely to be heavy coffee drinkers — four or more cups a day — than those who inherited just one or two, the Boston Globe reports. People with more coffee gene variants may drink more because they metabolize it quickly; thus, they enjoy coffee’s stimulating effects for a shorter period of time.

 

Some of the same gene variations seen in heavy coffee drinkers are risk factors for smoking initiation and obesity. Both obesity and smoking may be fueled by addiction, which could explain why some people can’t stop at just one cup. Researchers plan to dig deeper into the genetics of coffee drinking to see how variants may be positively and negatively affecting coffee fanatics’ health.

 

In the debate about whether coffee is good or bad for your health, genetics could cut through the noise and someday offer more definitive answers.

 

By Carl Engelking | October 7, 2014 1:19 pm

Photo credit: RobinE/Shutterstock

CATEGORIZED UNDER: Living World, top posts

 

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Sealed With a Kiss

A single intimate smooch can transfer upwards of 80 million bacteria.


WIKIMEDIA, ROBERT & MIHAELA VICOL

Locking lips spreads more than just love. A healthy dose of microbes are also swapped between kissing couples, according to a study published today (November 17) in Microbe. Researchers in Amsterdam swabbed the mouths and collected saliva from 21 couples visiting a zoo in the city both before and after they shared 10-second kiss. They found that the couples tended to have similar microbes inhabiting their mouths, likely because they share kisses, food, and space on a regular basis. “Apparently, being with somebody for an extended amount of time and having a relationship leads to a similar collection of bacteria on the tongue,” Remco Kort, lead author and biologist at the Netherlands Organization for Applied Scientific Research, told Time.

 

But when the researchers had one partner sip a probiotic yogurt drink, which contains bacteria not normally present in the mouth, prior to kissing their mate again, they found that an average of 80 million bacteria were swapped between kissers. “French kissing is a great example of exposure to a gigantic number of bacteria in a short time,” Kort told BBC News. “But only some bacteria transferred from a kiss seemed to take hold on the tongue. Further research should look at the properties of the bacteria and the tongue that contribute to this sticking power.”

Tags

probiotic, mouth microbiome, microbiome, microbiology and kissing

The Scientist » The Nutshell

By Bob Grant | November 17, 2014

 

 

http://www.the-scientist.com/?articles.view/articleNo/41450/title/Sealed-With-a-Kiss/

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The science behind total recall: New player in brain function and memory

Artist's abstraction (stock illustration).

Credit: © agsandrew / Fotolia

Is it possible to change the amount of information the brain can store? Maybe, according to a new international study led by the Research Institute of the McGill University Health Centre (RI-MUHC). Their research has identified a molecule that puts a brake on brain processing and when removed, brain function and memory recall is improved. Published in the latest issue of Cell Reports, the study has implications for neurodevelopmental and neurodegenerative diseases, such as autism spectral disorders and Alzheimer's disease.

 

"Previous research has shown that production of new molecules is necessary for storing memories in the brain; if you block the production of these molecules, new memory formation does not take place," says RI-MUHC neuroscientist, Dr. Keith Murai, the study's senior author and Associate Professor in the Department of Neurology and Neurosurgery at McGill University. "Our findings show that the brain has a key protein that limits the production of molecules necessary for memory formation. When this brake-protein is suppressed, the brain is able to store more information."

 

FXR1P: a controller of certain forms of memory

 

Dr. Murai and his colleagues used a mouse model to study how changes in brain cell connections produce new memories. They demonstrated that a protein, FXR1P (Fragile X Related Protein 1), was responsible for suppressing the production of molecules required for building new memories. When FXR1P was selectively removed from certain parts of the brain, these new molecules were produced that strengthened connections between brain cells and this correlated with improved memory and recall in the mice.

 

Disease link

 

"The role of FXR1P was a surprising result," says Dr. Murai. "Previous to our work, no-one had identified a role for this regulator in the brain. Our findings have provided fundamental knowledge about how the brain processes information. We've identified a new pathway that directly regulates how information is handled and this could have relevance for understanding and treating brain diseases."

 

"Future research in this area could be very interesting," he adds. "If we can identify compounds that control the braking potential of FXR1P, we may be able to alter the amount of brain activity or plasticity. For example, in autism, one may want to decrease certain brain activity and in Alzheimer's disease, we may want to enhance the activity. By manipulating FXR1P, we may eventually be able to adjust memory formation and retrieval, thus improving the quality of life of people suffering from brain diseases."

 

Date:November 13, 2014

Source:McGill University Health Centre

 

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Controlling genes with your thoughts

Researchers have constructed the first gene network that can be controlled by our thoughts. Scientists have developed a novel gene regulation method that enables thought-specific brainwaves to control the conversion of genes into proteins (gene expression). The inspiration was a game that picks up brainwaves in order to guide a ball through an obstacle course.

 

It sounds like something from the scene in Star Wars where Master Yoda instructs the young Luke Skywalker to use the force to release his stricken X-Wing from the swamp: Marc Folcher and other researchers from the group led by Martin Fussenegger, Professor of Biotechnology and Bioengineering at the Department of Biosystems (D-BSSE) in Basel, have developed a novel gene regulation method that enables thought-specific brainwaves to control the conversion of genes into proteins -- called gene expression in technical terms.

Thoughts control a near-infrared LED, which starts the production of a molecule in a reaction chamber.

Credit: Martin Fussenegger et al., Copyright ETH Zurich

"For the first time, we have been able to tap into human brainwaves, transfer them wirelessly to a gene network and regulate the expression of a gene depending on the type of thought. Being able to control gene expression via the power of thought is a dream that we've been chasing for over a decade," says Fussenegger.

 

A source of inspiration for the new thought-controlled gene regulation system was the game Mindflex, where the player wears a special headset with a sensor on the forehead that records brainwaves. The registered electroencephalogram (EEG) is then transferred into the playing environment. The EEG controls a fan that enables a small ball to be thought-guided through an obstacle course.

 

Wireless Transmission to Implant

 

The system, which the Basel-based bioengineers recently presented in the journal Nature Communications, also makes use of an EEG headset. The recorded brainwaves are analysed and wirelessly transmitted via Bluetooth to a controller, which in turn controls a field generator that generates an electromagnetic field; this supplies an implant with an induction current.

 

A light then literally goes on in the implant: an integrated LED lamp that emits light in the near-infrared range turns on and illuminates a culture chamber containing genetically modified cells. When the near-infrared light illuminates the cells, they start to produce the desired protein.

 

Thoughts Control Protein Quantity

 

The implant was initially tested in cell cultures and mice, and controlled by the thoughts of various test subjects. The researchers used SEAP for the tests, an easy-to-detect human model protein which diffuses from the culture chamber of the implant into the mouse's bloodstream.

 

To regulate the quantity of released protein, the test subjects were categorised according to three states of mind: bio-feedback, meditation and concentration. Test subjects who played Minecraft on the computer, i.e. who were concentrating, induced average SEAP values in the bloodstream of the mice. When completely relaxed (meditation), the researchers recorded very high SEAP values in the test animals. For bio-feedback, the test subjects observed the LED light of the implant in the body of the mouse and were able to consciously switch the LED light on or off via the visual feedback. This in turn was reflected by the varying amounts of SEAP in the bloodstream of the mice.

 

New Light-sensitive Gene Construct

 

"Controlling genes in this way is completely new and is unique in its simplicity," explains Fussenegger. The light-sensitive optogenetic module that reacts to near-infrared light is a particular advancement. The light shines on a modified light-sensitive protein within the gene-modified cells and triggers an artificial signal cascade, resulting in the production of SEAP. Near-infrared light was used because it is generally not harmful to human cells, can penetrate deep into the tissue and enables the function of the implant to be visually tracked.

 

The system functions efficiently and effectively in the human-cell culture and human-mouse system. Fussenegger hopes that a thought-controlled implant could one day help to combat neurological diseases, such as chronic headaches, back pain and epilepsy, by detecting specific brainwaves at an early stage and triggering and controlling the creation of certain agents in the implant at exactly the right time.

 

Date: November 11, 2014

Source: ETH Zurich

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Bio-inspired bleeding control: Synthesized platelet-like nanoparticles created

Stanching the free flow of blood from an injury remains a holy grail of clinical medicine. Controlling blood flow is a primary concern and first line of defense for patients and medical staff in many situations, from traumatic injury to illness to surgery. If control is not established within the first few minutes of a hemorrhage, further treatment and healing are impossible.

 

Artist's rendering of synthetic platelets.

Credit: Peter Allen illustration

At UC Santa Barbara, researchers in the Department of Chemical Engineering and at Center for Bioengineering (CBE) have turned to the human body's own mechanisms for inspiration in dealing with the necessary and complicated process of coagulation. By creating nanoparticles that mimic the shape, flexibility and surface biology of the body's own platelets, they are able to accelerate natural healing processes while opening the door to therapies and treatments that can be customized to specific patient needs.Taking a cue from the human body’s own coagulation processes, researchers have synthesized platelet-like nanoparticles that can do more than clot blood.

 

"This is a significant milestone in the development of synthetic platelets, as well as in targeted drug delivery," said Samir Mitragotri, CBE director, who specializes in targeted therapy technologies. Results of the researchers' findings appear in the current issue of the journal ACS Nano.

The process of coagulation is familiar to anyone who has suffered even the most minor of injuries, such as a scrape or paper cut. Blood rushes to the site of the injury, and within minutes the flow stops as a plug forms at the site. The tissue beneath and around the plug works to knit itself back together and eventually the plug disappears.

 

But what we don't see is the coagulation cascade, the series of signals and other factors that promote the clotting of blood and enable the transition between a free-flowing fluid at the site and a viscous substance that brings healing factors to the injury. Coagulation is actually a choreography of various substances, among the most important of which are platelets, the blood component that accumulates at the site of the wound to form the initial plug.

 

"While these platelets flow in our blood, they're relatively inert," said graduate student researcher Aaron Anselmo, lead author of the paper. As soon as an injury occurs, however, the platelets, because of the physics of their shape and their response to chemical stimuli, move from the main flow to the side of the blood vessel wall and congregate, binding to the site of the injury and to each other. As they do so, the platelets release chemicals that "call" other platelets to the site, eventually plugging the wound.

 

But what happens when the injury is too severe, or the patient is on anti-coagulation medication, or is otherwise impaired in his or her ability to form a clot, even for a modest or minor injury?

That's where platelet-like nanoparticles (PLNs) come in. These tiny, platelet-shaped particles that behave just like their human counterparts can be added to the blood flow to supply or augment the patient's own natural platelet supply, stemming the flow of blood and initiating the healing process, while allowing physicians and other caregivers to begin or continue the necessary treatment. Emergency situations can be brought under control faster, injuries can heal more quickly and patients can recover with fewer complications.

 

"We were actually able to render a 65 percent decrease in bleeding time compared to no treatment," said Anselmo.

 

According to Mitragotri, the key lies in the PLNs' mimicry of the real thing. By imitating the shape and flexibility of natural platelets, PLNs can also flow to the injury site and congregate there. With surfaces functionalized with the same biochemical motifs found in their human counterparts, these PLNs also can summon other platelets to the site and bind to them, increasing the chances of forming that essential plug. In addition, and very importantly, these platelets are engineered to dissolve into the blood after their usefulness has run out. This minimizes complications that can arise from emergency hemostatic procedures.

 

"The thing about hemostatic agents is that you have to intervene to the right extent," said Mitragotri. "If you do too much, you cause problems. If you do too little, you cause problems."

 

These synthetic platelets also let the researchers improve on nature. According to Anselmo's investigations, for the same surface properties and shape, nanoscale particles can perform even better than micron-size platelets. Additionally, this technology allows for customization of the particles with other therapeutic substances -- medications, therapies and such -- that patients with specific conditions might need.

 

"This technology could address a plethora of clinical challenges," said Dr. Scott Hammond, director of UCSB's Translational Medicine Research Laboratories. "One of the biggest challenges in clinical medicine right now -- which also costs a lot of money -- is that we're living longer and people are more likely to end up on blood thinners. When an elderly patient presents at a clinic, it's a huge challenge because you have no idea what their history is and you might need an intervention."

With optimizable PLNs, physicians would be able to strike a finer balance between anticoagulant therapy and wound healing in older patients, by using nanoparticles that can target where clots are forming without triggering unwanted bleeding. In other applications, bloodborne pathogens and other infectious agents could be minimized with antibiotic-carrying nanoparticles. Particles could be made to fulfill certain requirements to travel to certain parts of the body -- across the blood-brain barrier, for instance -- for better diagnostics and truly targeted therapies.

 

Additionally, according to the researchers, these synthetic platelets cost relatively less, and have a longer shelf life than do human platelets -- a benefit in times of widespread emergency or disaster, when the need for these blood components is at its highest and the ability to store them onsite is essential.

 

Further research into PLNs will involve investigations to see how well the technology and synthesis can scale up, as well as assessments into the more practical matters involved in translating the technology from the lab to the clinic, such as manufacturing, storage, sterility and stability as well as pre-clinical and clinical testing.

 

Date: November 13, 2014

Source: University of California - Santa Barbara

      

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Diabetes: β cells at last

The race to generate β cells from stem cells has taken another big turn. We can already generate definitive endoderm from human embryonic stem cells and functional insulin-producing cells from transplanted pancreatic progenitors. Now, differentiating glucose-responsive insulin-producing cells in vitro that function like adult human β cells has been achieved.

 

Intensive insulin therapy can considerably reduce the incidence and severity of complications associated with type 1 diabetes mellitus; however, only the replacement of lost β cells (islet transplantation) can restore physiological control of blood levels of glucose and could potentially cure patients with diabetes mellitus.¹ Unfortunately, the scarcity of islet donors has restricted the number of patients who have been able to receive this therapy. In clinical practice, two or three donors are usually required for a transplantation procedure in a single patient. The discovery of human pluripotent stem cells (hPSC) was, therefore, readily adopted as a potential means of providing cell therapy to millions of patients with type 1 diabetes mellitus or advanced type 2 diabetes mellitus, as it was assumed that an unlimited number of β cells could be generated upon their differentiation. This hope, as shown by early studies in the field, did not sufficiently consider the complexity of incorporating features of pancreatic development into a model of pluripotent stem cell differentiation in vitro. Despite the difficulties, the development of a therapy for diabetes mellitus based on stem cells (Figure 1) has now reached another milestone with the publication of a study by Pagliuca and colleagues.² In this study, the researchers demonstrated that functional β cells can be obtained in vitro from hPSC that were sequentially treated with a total of 11 extracellular growth and differentiation factors for 4–5 weeks. These findings are valuable for developing cell-based therapies for diabetes mellitus, and might also provide a platform for disease modelling and for screening thousands of small molecules (with potential effects on human β-cell function, proliferation or survival) for the development of antidiabetic drugs.

 

Figure 1: β-cell differentiation from pluripotent stem cells.

The third most important milestone (differentiating glucose-responsive insulin-producing cells) has just been set in this process. Pagliuca and colleagues achieved in vitro differentiation of functional β cells using a scalable 3D culture system.

As in the majority of previous studies in the field,^{3, 4, 5, 6, 7, 8} the study by Pagliuca and co-workers built on the knowledge gathered from examining pancreatic development in model organisms. Pagliuca et al. also followed the fairly safe strategy of modulating the extracellular microenvironment to induce cell differentiation rather than introducing DNA encoding transcription factors inside the hPSC. They tested 150 different combinations of factors that had to be added sequentially to their cultures to induce proper cell differentiation.

 

Previous studies have indicated that insulin-producing cells derived in vitro from hPSC are polyhormonal, are similar to fetal β cells and do not respond to glucose challenge.^{3, 4, 5, 6} However, the stem-cell-derived β (SCβ) cells described in this new study display the major and specific characteristics of a genuine adult β cell (including calcium flux, glucose-responsiveness and expression of a single hormone—insulin). The SCβ cells also expressed several β-cell differentiation markers (PDX1, NKX6.1 and ZnT8) and had ultrastructural morphological features similar to those of adult human β cells. In addition, in a mouse model of diabetes mellitus, transplantation of SCβ cells quickly restored and maintained normal blood levels of glucose.

“...the importance of this breakthrough will depend on the reproducibility of its findings...”

The thorough characterization of the SCβ cells in the paper by Pagliuca and associates is more comprehensive than that reported for insulin-producing cells derived from hPSC that were glucose responsive upon culture in a 3D matrix during the maturation stage of in vitro differentiation.⁷ Thus, the work by Pagliuca and colleagues is an important technical and biological breakthrough in the field of pancreatic β-cell differentiation from hPSC in vitro. The research has unravelled the minimal conditions required to efficiently turn hPSC-derived pancreatic progenitor cells into endocrine progenitor cells that are amenable to acquiring a phenotype very close to that of genuine islet β cells. These conditions could only be poorly defined in previous in vivo experiments, wherein hPSC-derived pancreatic progenitors required 3–4 months to mature into β cells, which contrasts with the 4–5 weeks required for SCβ to mature in vitro.⁸ The study has also consolidated the central position that a good understanding of tissue and organ developmental biology occupies in the race for generating different cell types of interest from hPSC. However, despite the mention that the protocol works on a total of four cell lines in the authors' laboratory, the importance of this breakthrough will depend on the reproducibility of its findings by other investigators using different hPSC lines.

 

The SCβ cells are phenotypically very close, but not transcriptionally identical, to primary β cells. In addition to the strategies highlighted by the authors to tackle this issue, it will be of interest to examine whether this discrepancy fades with time spent in culture or upon SCβ cell transplantation in vivo, given that the reported protocol is still a big reduction of the 13–15 weeks required for islet development in the human embryo. Nevertheless, the SCβ cells are obtained at a sufficiently high efficiency (33%) in the current system so that any future moves towards clinical implementation would probably not face challenges with mass production. As the SCβ cells could respond to several glucose challenges and their transplantation in mice resulted in detectable levels of human C-peptide and normalization of blood glucose levels within 2 weeks, they might represent an optimal candidate for testing in clinical trials in patients with diabetes mellitus. However, important questions need to be solved before reaching this step.

 

Many laboratories around the world are working toward the goal of using genuine or 'surrogate' insulin-producing cells as a basis for treating patients with type 1 diabetes mellitus and advanced type 2 diabetes mellitus. The current paper is very important in this context; however, it will undoubtedly be some time before these results are translated into treatment for patients with diabetes mellitus. For example, the FDA has just approved the first clinical trial using a product derived from embryonic stem cells that consists of pancreatic progenitor cells delivered in a macro-encapsulation device; however, this cell product was developed on the basis of research that was published 8 years ago.³

 

An advantage of the product developed by Pagliuca and co-workers is that it consists of fairly pure β cells. However, some encapsulation technology to prevent graft rejection will also be needed. Cellular grafts encapsulated in biomaterials often trigger a process that begins with inflammation and ends with the implant being surrounded by macrophages and fibrotic tissue. This reaction to a foreign body is absent in transplantation experiments using immune-deficient animals,² but might severely compromise the survival and function of encapsulated cells in patients.⁹ For this reason (and others, such as the lack of direct vascularization of the encapsulated cells in a graft of sufficient size for use in humans), islet transplantation in combination with encapsulation has not yet been successful in clinical trials. Encapsulation is also needed to prevent the risk of outgrowth of teratoma cells or cells containing potentially oncogenic mutations.¹⁰ The presence of such cells actually needs to be ruled out by more sensitive techniques than those used by Pagliuca et al., even though mice examined 18 weeks after transplantation were declared to be free of tumours. Furthermore, the SCβ cells might function differently in the human microenvironment. Therefore, caution is needed when we talk of a therapeutic breakthrough for diabetes mellitus.

 

Josué K. Mfopou^1, & Luc Bouwens^1,

Nature Reviews Endocrinology | News and Views

Nature Reviews Endocrinology

doi:10.1038/nrendo.2014.200

Published online 11 November 2014

 

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