'Sugar-coated' microcapsule eliminates toxic punch of experimental anti-cancer drug

3BrPA (red) is illustrated encased in a sugar-based microshell. Credit: Jean-Francois Geschwind, Johns Hopkins

Johns Hopkins researchers have developed a sugar-based molecular microcapsule that eliminates the toxicity of an anticancer agent developed a decade ago at Johns Hopkins, called 3-bromopyruvate, or 3BrPA, in studies of mice with implants of human pancreatic cancer tissue. The encapsulated drug packed a potent anticancer punch, stopping the progression of tumors in the mice, but without the usual toxic effects.

"We developed 3BrPA to target a hallmark of cancer cells, namely their increased dependency on glucose compared with normal cells. But the nonencapsulated drug is toxic to healthy tissues and inactivated as it navigates through the blood, so finding a way to encapsulate the drug and protect normal tissues extends its promise in many cancers as it homes in on tumor cells," says Jean-Francois Geschwind, M.D., chief of the Division of Interventional Radiology at Johns Hopkins Medicine.

The Johns Hopkins team used a microshell made of a sugar-based polymer called cyclodextrin to protect the 3BrPA drug molecules from disintegrating early and to guard healthy tissue from the drug's toxic effects, such as weight loss, hypothermia and lethal hypoglycemic shock.

Geschwind, a professor in the Russell H. Morgan Department of Radiology and Radiological Science at the Johns Hopkins University School of Medicine and its Kimmel Cancer Center, and others at Johns Hopkins have been studying the experimental drug as a cancer treatment for over a decade because of its ability to block a key metabolic pathway of cancer cells.

Most cancer cells, he explains, rely on the use of glucose to thrive, a process known as the Warburg effect, for Otto Heinrich Warburg, who was awarded the Nobel Prize in Physiology for the discovery in 1931. By using the same cellular channels that funnel glucose into a cancer cell, 3BrPA can travel inside the cancer cell and block its glucose metabolic pathway, Geschwind says.

However, animal studies have shown that in its free, nonencapsulated state, the drug is very toxic, says Geschwind.

The toxicity associated with the free-form version of the drug, he says, has prevented physicians from using the drug as a systemic treatment in people, one that can travel throughout the whole body.

In a report about their study published online Oct. 17 in Clinical Cancer Research, the researchers described minimal or zero tumor progression in mice treated with the microencapsulated 3BrPA. By contrast, a signal of tumor activity increased sixty-fold in mice treated with the widely used chemotherapy drug gemcitabine. Activity increased 140-fold in mice who received the drug without encapsulation.

Specifically, daily injections of nonencapsulated 3BrPA were highly toxic to the animals, as only 28 percent of the animals survived the 28-day treatment. All of the mice who received the encapsulated drug survived to the end of the study.

Geschwind says the "extremely promising results" of the study make the encapsulated drug a good candidate for clinical trials, particularly for patients with pancreatic ductal adenocarcinoma. These cancers rank as the fourth most common cause of cancer-related deaths in the world, with a five-year survival rate of less than 5 percent. In the mouse studies, the encapsulated medication also reduced the metastatic spread of pancreatic cancer cells.

Source: Johns Hopkins Medicine

'Darwinian' test uncovers an antidepressant's hidden toxicity

A University of Utah test detects hidden toxic effects by subjecting mice to competition for resources. Biology professor Wayne K. Potts and biologist Shannon M. Gaukler, who recently completed a doctoral degree at the U, stand in front of the test enclosure, illuminated in red light that mice perceive as nightfall. Credit: Andy Brimhall / University of Utah

Because of undetected toxicity problems, about a third of prescription drugs approved in the U.S. are withdrawn from the market or require added warning labels limiting their use. An exceptionally sensitive toxicity test invented at the University of Utah could make it possible to uncover more of these dangerous side effects early in pharmaceutical development so that fewer patients are given unsafe drugs.

To prove the point, the U researchers ran their test on Paxil, an antidepressant that thousands of pregnant women used in the years before it was linked to an increased risk of birth defects. The U.S. Food and Drug Administration now requires a warning about use in the first trimester of pregnancy. In the U study, mice exposed during development experienced multiple problems: males weighed less, had fewer offspring, dominated fewer territories and died at a higher rate. Females took longer to produce their first litters, had fewer pups and pups that were underweight. The drug doses were relatively close to those prescribed for people. In the conventional animal safety testing reported by the drug's manufacturer, no reproductive side effects emerged until rodents took doses multiple times higher than those given to treat depression.

"We are seeing effects at a dose that is close to human levels. And we are doing it exactly the way we need to determine if it presents a risk of harm to a developing fetus," says University of Utah biologist Shannon M. Gaukler, the study's lead author who recently completed a doctoral degree at the U. The study will be published in the January-February issue of Neurotoxicology and Teratology, which has posted a preprint online.

University of Utah biology professor Wayne K. Potts, the study's senior author, says that detecting toxicity problems early in preclinical testing would not only protect patients from exposure to unsafe drugs, but also help pharmaceutical companies avoid wasting billions of dollars bringing drugs to market only to have them fail.

"If we can find these health problems early on in preclinical testing, it has the potential of saving them a lot of money," Potts says.

Survival-of-the-fittest test

The key to the test's sensitivity is the way it uses untamed house mice -- rather than docile, inbred laboratory strains -- and subjects them to a relentless, Darwinian competition for food, shelter and mates much like they would face in the wild. Mice jostle and race for a place in a roughly 300-square-foot pen divided into six territories by wire fencing that individuals must climb to invade or flee neighboring turf. Four of the territories are prime real estate with multiple hidden nesting sites and direct access to feeders. Two territories are poor, offering only open nesting sites and indirect feeder access. The test is called the organismal performance assay, or OPA.

Potts first came up with the idea as a way to explore the impact of inbreeding. Those studies revealed harmful effects of cousin-level inbreeding that had gone unnoticed for decades of research on mouse genetics. Laboratory mice that are only slightly less healthy may not appear so when given ample food and living space. But if there is a defect in any physiological system, it is likely to stand out during intense competition.

"When they really have to compete directly, males are constantly testing each other and fighting over territories," Potts says. "If they don't win a territory, females won't consider them when it comes time to choose a mate."

In a study published last year, the performance assay revealed that doses of sugar that people regularly consume -- and deemed safe by regulators -- may in fact be toxic. When mice ate a diet of 25 percent extra sugar (the mouse equivalent of drinking three cans of soda daily) females died at twice the normal rate and males were a quarter less likely to hold territory and reproduce.

Testing Paxil

In the Paxil study, the researchers gave food laced with the antidepressant to 20 breeding pairs of mice for several weeks, until all had produced up to four litters. Doses were equivalent to about 1.8 times the level typically prescribed for people. The offspring also ate Paxil-laced chow until they reached breeding age. The researchers then released the exposed offspring into the competitive arena with the offspring of a control group of mice never exposed to Paxil. Groups consisted of eight males and 14 to 16 females, creating population densities comparable to those seen in the wild. The researchers started five such populations and kept them going for six months.

Males exposed to Paxil were about half as likely to control a territory. They also lagged behind control males in body weight throughout the weeks of competition and were more likely to die. Exposed males produced 44 percent fewer offspring. Exposed females showed no significant weight or mortality differences, but they produced half as many offspring as control females at the initial assessment. Their fecundity rebounded at later time points.

Danger signals

The test can provide an early warning of possible toxic effects, but it does not identify causal pathways. In the case of Paxil, the test might have alerted the drug's developers to the risk of birth defects when taken during pregnancy at prescribed doses, not just at the high levels used in conventional safety testing. Other selective serotonin reuptake inhibitors, or SSRIs, don't appear to pose the same level of risk as Paxil, but their safety for use during pregnancy remains unclear.

"It's unknown how Paxil causes birth defects and why Paxil has a stronger correlation with birth defects than other SSRIs," Gaukler says. "We think most of our results are driven by endocrine disruption."

Previous studies have shown that Paxil can lower the level of several reproductive hormones in female rats. In male rats, doses comparable to those prescribed for people can lower testosterone and boost estradiol. Other animal studies have shown that Paxil can lower sperm count and degrade sperm quality.

Potts says the performance assay may be even more important for identifying the toxic effects of agricultural chemicals, industrial pollutants, and other manufactured chemicals released into the environment.

"We don't really have a sensitive, broad toxicity assessment system," Potts says. "That's why these things slip through the cracks and we often don't discover harmful effects until after 10 or 20 years of epidemiology studies using the public as the experimental guinea pigs."

Source:  University of Utah

Multiple allergic reactions traced to single protein

This is a mast cell. Credit: Priyanka Pundir/University of Alberta

Johns Hopkins and University of Alberta researchers have identified a single protein as the root of painful and dangerous allergic reactions to a range of medications and other substances. If a new drug can be found that targets the problematic protein, they say, it could help smooth treatment for patients with conditions ranging from prostate cancer to diabetes to HIV. Their results appear in the journal Nature on Dec. 17.

Previous studies traced reactions such as pain, itching and rashes at the injection sites of many drugs to part of the immune system known as mast cells. When specialized receptors on the outside of mast cells detect warning signals known as antibodies, they spring into action, releasing histamine and other substances that spark inflammation and draw other immune cells into the area. Those antibodies are produced by other immune cells in response to bacteria, viruses or other perceived threats. However, "although many of these injection site reactions look like an allergic response, the strange thing about them is that no antibodies are produced," says Xinzhong Dong, Ph.D., an associate professor of neuroscience in the Institute for Basic Biomedical Sciences at the Johns Hopkins University School of Medicine.

To zero in on the cause of the reactions, Benjamin McNeil, Ph.D., a postdoctoral fellow in Dong's laboratory, first set out to find which mast cell receptor -- or receptors -- responded to the drugs in mice. Previous studies had identified a human receptor likely to be at fault in the allergic reactions; McNeil found a receptor in mice that, like the human receptor, is found only in mast cells. He then tested that receptor by putting it into lab-grown cells and found that they did react to medications that provoke mast cell response. He found similar results for the human receptor that previous studies had indicated was a likely culprit.

"It's fortunate that all of the drugs turn out to trigger a single receptor -- it makes that receptor an attractive drug target," McNeil says.

To find out whether eliminating the receptor really would eliminate the allergic reactions, the research team also disabled the gene for the suspect receptor in mice. These "knockout" mice did not have any of the drug allergy symptoms that their genetically normal counterparts displayed.

The researchers are now working to find compounds that could safely block the culprit receptor in humans, known as MRGPRX2. Such a drug would not prevent true allergic reactions, which produce antibodies, but only the pseudoallergic reactions triggered by MRGPRX2. Still, it could improve the lives of many patients, says McNeil, by lessening the drug side effects they currently endure. Medications that trigger MRGPRX2 include cancer drugs cetrorelix, leuprolide and octreotide; HIV drug sermorelin; fluoroquinolone antibiotics; and neuromuscular blocking drugs used to paralyze muscles during surgeries.

Dong's research group is also looking into the possibility that MRGPRX2 could be behind immune conditions such as rosacea and psoriasis that don't stem from medication use.

Source: Johns Hopkins Medicine

Special delivery: Hitchhiking microparticles deliver drugs directly

Disc-shaped microparticles use monocytes to get to their destination. Credit: Peter Allen illustration

Inflammation is a normal and often beneficial response to injury or infection. The swelling, heat and even pain are the body's attempts to protect its soft tissue, remove offending objects, substances or microbes and initiate healing. However, persistent inflammation is often indicative of more serious conditions and can lead to problems of its own, including impaired healing, loss of function or even tissue death.

"Many diseases result in inflammation," said Samir Mitragotri, professor of chemical engineering at UC Santa Barbara and director of the campus's Center for Bioengineering. Whether inflammation is a byproduct of the disease or the inflammation is the disease, it is a common indicator of a problem with the system. "If we could target the common denominator, whether the inflammation is coming from cancer or arthritis, we could deliver the drug there," said Mitragotri, who specializes in targeted drug delivery.

By taking advantage of natural body processes, researchers at UC Santa Barbara and MIT have developed a method of targeting inflamed tissues, creating a way to treat both the inflammation and its underlying cause.

"It's a cell-mediated approach to targeted drug delivery," said UCSB grad student researcher Aaron Anselmo, lead author of a study in the current issue of the Journal of Controlled Release.

Key to this technology is the utilization of monocytes, the type of white blood cell known for its ability to penetrate into deep sections of tissue. Under normal circumstances, the job of these monocytes is to circulate in the blood and respond to biochemical signals that indicate inflammation -- a sign of injury or infection. Once at the site, these monocytes transform into macrophages, cells that reside in the affected tissues to engulf and digest foreign material.

Working with the expertise of chemical engineering and materials science researchers at MIT, including graduate researcher Jonathan Gilbert and professors Robert Cohen and Michael Rubner, the UCSB researchers developed an approach based on "cellular backpacks" -- flat, disc-shaped polymeric particles that could, in the near future, hold therapeutic agents that can be released at the site of the inflammation. These polymeric discs are coated on one side with a single layer of an antibody that can bind to receptors on the monocyte's surface.

To prevent the cellular backpack from being engulfed and devoured by the very cell that is transporting it, the researchers chose a flexible particle that is nonspherical in shape, which, according to the study, has proved to be more durable and resistant to phagocytosis than a rigid spherical particle. The shape and flexibility gives the backpack the ability to bind strongly while resisting phagocytosis to hitchhike onto monocytes and reach the inflamed tissue.

In-vitro and in-vivo tests have proved that cellular backpacks are successful in attaching to and being transported by monocytes to target areas without impairing the monocytes' natural functions, said Anselmo. Further studies will include research into how much drug can be loaded into the cellular backpacks. Ideally, Anselmo said, the cellular backpacks loaded with drugs would be injected into the bloodstream, whereupon they would attach to these traveling monocytes and hitchhike to the target region. At the inflamed site, the particles would simultaneously degrade and release their drugs.

The development of effective cellular backpacks has broad potential, say the researchers.
"Basically the main benefit is that you can deliver the drug in a more effective dose," Mitragotri said. Take for example the case of chemotherapy, which often has a narrow therapeutic range: Too little and the treatment is not effective, too much and it can be lethal. 
Because chemo travels through the bloodstream and affects all the tissues it comes in contact with, dosages are restricted at least in part based on the deleterious effect it has on other, unafflicted organs and their functions. Not only can targeted therapy ensure other body systems remain unaffected, Mitragotri explained, but it could allow for higher doses of drug to the site, which could decrease treatment time.

Source: University of California - Santa Barbara

Novel microneedle patch for faster, effective delivery of painkiller, collagen

Dr Kang Lifeng of the Department of Pharmacy at NUS holding a microneedle patch in his left hand, and a photomask in his right hand. Credit: National University of Singapore

Individuals who are squeamish about injections or are looking for a way to let collagen penetrate deeper into the skin may soon have a solution that is faster, more effective and painless. The key lies in a small adhesive patch topped with minuscule needles that is pioneered by researchers from the National University of Singapore (NUS).

The research team, led by Dr Kang Lifeng of the Department of Pharmacy at the NUS Faculty of Science, has successfully developed a simple technique to encapsulate lidocaine, a common painkiller, or collagen in the tiny needles attached to an adhesive patch. When applied to the skin, the microneedles deliver the drug or collagen rapidly into the skin without any discomfort to the user.

This innovation could be used clinically to administer painkiller non-invasively to patients, or in home care settings for patients suffering from conditions such as diabetes and cancer. In addition, the novel transdermal delivery system could also be used for cosmetic and skincare purposes to deliver collagen to inner skin layers.

Non-invasive delivery of drugs for effective pain relief

Faster delivery of painkillers is key to effective management of acute and chronic pain conditions. Currently, such drugs are mainly administered through invasive injections, or through the use of conventional transdermal patches, which may have limited efficiency due to variability of drug absorption among individuals.

To address the clinical gap, Dr Kang, together with Dr Jaspreet Singh Kochhar, who had recently graduated from NUS with a doctorate degree in Pharmacy, and their team members, used a photolithography based process to fabricate a novel transdermal patch with polymeric microneedles. The tiny needles are encapsulated with lidocaine, a common painkiller known for its pain-relief property.

Laboratory experiments showed that the novel microneedles patch can deliver lidocaine within five minutes of application while a commercial lidocaine patch takes 45 minutes for the drug to penetrate into the skin. The shorter time for drug delivery is made possible as the miniature needles on the patch create micrometre-sized porous channels in the skin to deliver the drug rapidly. As the needle shafts are about 600 micro-meters in length, they do not cause any perceivable pain on the skin.

The patch also comprises a reservoir system to act as channels for drugs to be encapsulated in backing layers, circumventing the premature closure of miniaturised pores created by the microneedles. This facilitates continued drug permeation. In addition, the size of patch could be easily adjusted to encapsulate different drug dosages.

By delivering painkillers faster into the body through the skin, patients could potentially experience faster pain relief. In addition, enabling a larger amount of lidocaine to permeate through the skin could potentially reduce the time needed to apply the patch and this reduces the likelihood of patients developing skin irritation.

This novel technique was first reported in the scientific journal Molecular Pharmaceutics.

Enabling deeper penetration of collagen into the skin

To expand their research on potential applications of the microneedles patch, the NUS team 
conducted a study to explore its effectiveness in delivering collagen into skin.

The researchers encapsulated collagen in the microneedles and tested the transdermal delivery of collagen using the novel technique. They found that collagen can be delivered up to the dermis layer of the skin, while current skincare products can only deliver to the outermost layer of skin.

The findings of this study were first published earlier this year in the scientific journal Pharmaceutical Research.

Further research to expand application of novel microneedles patch

As their novel technique for drug delivery is non-invasive and easy to use, the NUS team envisioned that the microneedles patch has great potential for applications in clinical and home care settings for the management of perioperative pain and chronic pain in patients suffering from conditions like diabetes and cancer.

The innovative patch could also have pediatric applications. Dr Kang explained, "One prospective application is during vaccination for babies. The patch can be applied on the baby's arm five minutes before the jab, for the painkiller to set in. In this way, vaccination can potentially be painless for babies."

The research team intends to conduct clinical testing of the painkiller patch to further ascertain its effectiveness for clinical applications. They will also be conducting clinical studies to examine the efficacy of delivering collagen for cosmetic and skincare purposes.
Recognizing that their novel transdermal delivery system is easy to fabricate and commercially scalable, the research team is also keen to work with industry partners to commercialize their work.

Source: National University of Singapore

Simple textiles can be used with catalysts to enable complex chemical reactions

To attach the "chemical tools" to the nylon fibers the chemist simply irradiate the soaked textile with UV light.

In future, it will be much easier to produce some active pharmaceutical substances and chemical compounds than was the case to date. An international team working with chemists from the Max-Planck-Institut für Kohlenforschung in Mülheim an der Ruhr have immobilised various catalysts on nylon in a very simple way. Catalysts mediate between the reagents in a chemical reaction and control the process leading to the desired end product. When textile material is used as a support for the chemical auxiliaries, the reaction can proceed on a large surface thereby increasing its efficiency.

One of the catalysts that the researchers used in this way plays an important role in the synthesis of a pharmaceutical agent which could only be used previously in dissolved form, making the production process very complicated and expensive. Immobilising this catalyst on fabric simplifies production considerably. This process may be expected to yield similar advantages for other chemical processes.

Functional textiles are usually understood as the textiles used to make windproof jackets, breathable footwear and particularly effective thermal underwear. However, the term could soon refer to something else -- textiles which are "functionalised" with the help of organic catalysts. Working in collaboration with scientists from the Deutsches 

Textilforschungszentrum in Krefeld and Sungkyunkwan University in Suwon, Korea, researchers at the Max-Planck-Institut für Kohlenforschung in Mülheim an der Ruhr have developed a process for immobilising different organic catalysts on textiles with the help of ultraviolet light. The fabric thereby acts as a support for the substances on which a chemical reaction occurs.

Up to now, science has focused more on the macroscopic functionality of textiles, for example clothing, explains Dr. Ji-Woong Lee, who recently completed his doctorate at the Max-Planck-Institut für Kohlenforschung under the supervision of Professor Benjamin List, head of the Institute's Homogenous Catalysis Group. "As opposed to this, our method can give simple textiles microscopic functionalities," explains the Korean scientist. Together with his colleagues, Dr. Lee armed pieces of nylon with catalysts. The latter can be imagined as chemical tools which fulfil various tasks during chemical reactions.

Excellent yields, little wear and tear

For their tests, the Mühlheim-based researchers used three organic catalysts: a base (dimethylaminopyridine, DMAP), a sulfonic acid and a catalyst which functions as both an acid and a base. The latter is used in the pharmaceuticals industry to steer a reaction to one of two products, which are chemically completely identical. The two forms have mirror-image structures, like a left and right hand, but only one variant has the desired medical effect. Up to now, the catalyst that generates this variant could only be used in dissolved form and then had to be separated again. The complicated separation process could be avoided using a catalyst immobilised on fabric.

To attach the catalysts to the nylon fibres, the chemists irradiated the textile to which a catalyst was applied with UV light for five minutes -- but no longer, as this would impede the activity of the catalyst and its immobilisation on the nylon. A comparable process did not exist up to now.

The catalysts, which were practically interwoven with the fabric, displayed all of the characteristics that the chemists expect from such a system: the result of the chemical reactions which the scientists undertook with the catalyst-loaded nylon strips is impressive. 

All three catalysts converted around 90 percent of the source materials to the desired products. And the catalyst which is used in the pharmaceutical industry and only generates one out of two mirror-image molecules, achieved a success rate of over 95 percent without showing any major signs of wear and tear. Ji-Woong Lee carried out several hundred test-runs and observed that the catalysts relinquished little of their functionality.

A large surface makes chemical reactions more efficient

Compared with other ways of immobilising catalysts, "organotextile catalysis" has several advantages: in particular, it provides the reagents with a larger surface than other supports, for example plastic spheres or foils -- the larger the surface, the more efficiently a reaction proceeds. Moreover, nylon is flexible and very inexpensive. Dry textiles loaded with catalysts are easy to transport, which means that it is simpler to meet the requirements for some chemical processes where it is practically impossible to set up sophisticated chemical systems. For example, organotextile catalysis could help in the treatment of water in locations where people are cut off from the water supply.

"Our method enables the low-cost production of long-term functionalised textiles without causing any pollution," says Ji-Woong Lee. He is entirely convinced that the process can be applied in several scientific areas -- and industrial processes. "In addition to chemistry, these could include biology, the materials science and pharmaceutics."

Source: Max-Planck-Institut für Kohlenforschung

Volunteers can now help scientists seek Ebola cure in their (computer's) spare time

The Scripps Research Institute’s Professor Erica Ollmann Saphire is leading the new effort against Ebola. Credit: Photo courtesy of The Scripps Research Institute.

Although some medical therapies show promise as treatments for Ebola, scientists are still looking urgently for a definitive cure.

For the first time, anyone with access to a computer or Android-based mobile device can help scientists perform this critical research -- no financial contribution, passport or PhD necessary. In fact, volunteers can be asleep, traveling or on a coffee break when they help researchers search for an Ebola cure.

Beginning today, anyone can download a safe and free app that will put their devices to work when the machines would otherwise be idle. With their collective processing power, the computers will form a virtual supercomputer to help The Scripps Research Institute (TSRI) screen millions of chemical compounds to identify new drug leads for treating Ebola. 

Meanwhile, the devices will remain fully available for normal use by their owners.

This citizen science effort is possible through a partnership with IBM's (NYSE: IBM) World Community Grid, which has been making similar data-driven health and sustainability initiatives possible for 10 years as a free, philanthropic service to the science community. 

The "Outsmart Ebola Together" volunteer computing project announced today is being run by the Ollmann Saphire laboratory at TSRI, which has mapped the structures and vulnerabilities of the proteins comprising the Ebola virus.

The best candidate compounds that emerge from this crowdsourced effort will be physically tested in the lab to pinpoint their effectiveness against real virus infection. The most promising compounds will then be modified to perform even better, at lower concentrations, and with fewer side effects. Subsequent drug trials could ultimately lead to an approved medicine.

Crowdsourcing this citizen science effort will dramatically accelerate the process of identifying a cure. The speed and scale of a drug search is essential, as this particularly lethal disease continues to spread and mutate. Once believed to be less of a widespread public health risk than other communicable diseases because of its existence in mainly isolated regions, Ebola now carries a higher risk of spreading farther because people are more mobile than ever before.

"Our molecular images of the Ebola virus are like enemy reconnaissance," said Dr. Erica Ollmann Saphire of TSRI, one of the largest private biomedical research institutes in the United States. "These images show us where the virus is vulnerable and the targets we need to hit. In the Outsmart Ebola Together project, we will be able to harness World Community 

Grid's virtual supercomputing power to find the drugs we need to aim at these targets."

IBM's World Community Grid has successfully run other projects that search for drug candidates for both high- and low-profile diseases -- such as AIDS, cancer, malaria, Dengue fever, and influenza. It has enabled multiple breakthroughs, such as helping the Chiba Cancer Center in Japan discover seven new drug candidates to fight childhood neuroblastoma. The IBM-managed program also hosts projects that have led to important scientific advances in renewable energy and water purification technology.

"It is a privilege to partner with The Scripps Research Institute to advance the process of identifying an Ebola cure," said Stanley S. Litow, IBM's vice president of Corporate Citizenship and president of the IBM International Foundation. "It is only fitting that IBM's World Community Grid 10-year anniversary of accomplishments coincide with the launch of perhaps one of the most critical scientific and humanitarian efforts."

Conceived and managed by IBM, and powered by IBM's reliable and secure SoftLayer cloud technology, World Community Grid provides computing power to scientists by harnessing the unused, surplus cycle time of volunteers' computers and mobile devices. The software receives, completes, and returns small computational assignments to scientists. The combined power contributed by hundreds of thousands of volunteers has created one of the fastest virtual supercomputers on the planet, advancing scientific work by hundreds of years.

Nearly three million computers and mobile devices used by more than 680,000 people and 460 institutions from 80 countries have contributed virtual supercomputing power for vitally important projects on World Community Grid over the last 10 years. Since the program's inception, World Community Grid volunteers have powered more than 20 research projects, donating more than one million years of computing time to scientific research, and enabled important scientific advances in health and sustainability. IBM invites researchers to submit research project proposals to receive this free resource, and invites members of the public to donate their unused computing power to these efforts at worldcommunitygrid.org.

TSRI also invites members of the public to support Dr. Saphire's crowdfunding campaign at www.crowdrise.com/CUREEBOLA to secure resources needed to analyze the enormous volume of data generated by Outsmart Ebola Together.

The software used for screenings in the Outsmart Ebola Together project is called AutoDock and AutoDock VINA, developed by the Olson laboratory at TSRI.

World Community Grid is enabled by software developed in 2002 by Berkeley Open Infrastructure for Network Computing (BOINC) at the University of California, Berkeley and with support from the National Science Foundation. The BOINC project choreographs the technical aspects of volunteer computing.

Source: Scripps Research Institute

‘Smart’ drugs won’t make smart people smarter, research concludes

Dr. Ahmed Dahir Mohamed is in the School of Psychology at The University of Nottingham Malaysia Campus. Credit: The University of Nottingham

The study carried out by Dr Ahmed Dahir Mohamed, in the School of Psychology at The University of Nottingham Malaysia Campus, and published in the open access journal PLOS ONE, showed the drug had negative effects in healthy people.

Dr Mohamed said: "We looked at how the drug acted when you are required to respond accurately and in a timely manner. Our findings were completely opposite to the results we expected."

In a randomised double blind study, 'Modafinil increases the latency of response in the Hayling Sentence Completion Test in Healthy Volunteers: A Randomised Controlled Trial', they administered 32 participants with the drug and 32 with a placebo. All the participants were given a famous neuropsychological task known as the Hayling Sentence Completion Test in which they were asked to respond both quickly and accurately. Dr Mohamed found the drug slowed down reaction times, impaired their ability to respond in a timely manner and failed to improve their performance of the task.

Dr Mohamed said: "It has been argued that Modafinil might improve your performance by delaying your ability to respond. It has been suggested this 'delay dependent improvement' might improve cognitive performance by making people less impulsive. We found no evidence to support those claims.

"Our research showed that when a task required instant reactions the drug just increased reaction times with no improvement to cognitive performance."

This backs up the findings of a previous study carried out by Dr Mohamed and published in September 2014 in The Journal of Creative Behaviour. The study: The Effects of Modafinil on Convergent and Divergent Thinking of Creativity: A Randomised Controlled Trial showed that the so called 'smart' drug impaired the participant's ability to respond in a creative way particularly when they were asked to respond laterally -- outside the box.

Does Modafinil benefit anyone?

When Dr Mohamed looked at participant's ability to problem solve in a creative manner he found that those who weren't particularly creative to start with were improved by the drug while those who were creative were impaired by the drug. He said: "Our study backs up previous research that suggests psychostimulants improve people at the lower end of the spectrum in cognition whereas they impair people who are at the optimum level of cognitive function -- healthy people for example. It looks like Modafinil is not helpful for healthy individuals and it might even impair their ability to respond and might stifle their lateral thinking, while people who have some sort of deficiency in creativity are helped by the drug."

What can make us smarter?

Ahmed Mohamed's research was carried out while he was at Cambridge University. He has since moved to The University of Nottingham Malaysia Campus where he will be looking at the effects of non-pharmacological interventions, such as meditation, exercise and diet on the healthy brain. He is also currently using Electroencephalography (EEG) to study how mindfulness can affect the healthy adolescent brain.

Dr Mohamed said: "What I have found in my doctoral studies is that if you are already a healthy person and functioning at an optimum level, it is really difficult to improve your cognition. But the brain of the adolescent is still in development and you might be able to improve cognition at this stage of our development through positive interaction, healthy diet or mindfulness."

Source: University of Nottingham

Poisonous cure: Toxic fungi may hold secrets to tackling deadly diseases

Take two poisonous mushrooms, and call me in the morning, said no doctor ever. Credit: Photo by G.L. Kohuth

Take two poisonous mushrooms, and call me in the morning. While no doctor would ever write this prescription, toxic fungi may hold the secrets to tackling deadly diseases.

A team of Michigan State University scientists has discovered an enzyme that is the key to the lethal potency of poisonous mushrooms. The results, published in the current issue of the journal Chemistry and Biology, reveal the enzyme's ability to create the mushroom's molecules that harbor missile-like proficiency in attacking and annihilating a single vulnerable target in the human liver.

The team revealed how the enzyme contributes to the manufacture of chemical compounds known as cyclic peptides, a favorite type of molecule that pharmaceutical companies use to create new drugs. These findings could lead to single-minded medicines with zero side effects, said Jonathan Walton, professor of plant biology and co-lead author.

"Mushrooms are prolific chemical factories, yet only a few of their peptides are poisonous," he said. "These toxins survive the high temperatures of cooking and the acids of digestion, and yet they're readily absorbed by the bloodstream and go directly to their intended target. These are the exact qualities needed for an effective medicine."

Walton published the paper with fellow MSU scientists Hong Luo, Sung-Yong Hong, R. Michael Sgambelluri and Evan Angelos. Working with the mushroom species Amanita, Walton and his teammates disassembled one of its poisonous peptides, which can be compared to a laser-guided missile with a nuclear warhead.

By removing the molecular equivalent of the deadly warhead, they now have a sturdy, precise delivery system that can supply medicine -- rather than poison -- to a single target. By taking a laser, rather than a shotgun approach, scientists could develop medicines capable of curing disease without the patient suffering any side effects.

The enzyme the team discovered is called POPB, and it converts toxins from their initial linear shape into cyclic peptides, fortress-like molecular circles comprising eight amino acids.

Harnessing the distinct properties of POPB will allow scientist to create billions of variant molecules, which can be tested against many different medical targets such as pathogenic bacteria and cancer.

"We've found some variables that are key," said Walton, an AgBioResearch scientist. "By making more variants, we can add or replace molecules that may or may not work. To date we've created a library of a hundred or so, and we eventually plan to create millions."

The challenge of the next stage of research, though, is testing the variants against diseases such as cancer. The bottleneck lies in the screening process. While Walton's team has discovered a missile capable of carrying a million different potential medicines, as of yet the payload that will be effective remains a mystery.

Source: Michigan State University