3D Chemistry Leads to Potential Malaria Breakthrough

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 A new drug has the potential to prevent malaria transmission and stem resistance—all in a single, low dose.
 

 The promising drug is the first to target an essential protein that the parasite uses in all stages of its life cycle. Attacking every stage could be the key to eliminating malaria in a single dose.
 

 So far, it has been tested in mice, where it eliminates infections of
 
 Plasmodium falciparum
 
 , the most lethal malaria species in humans, according to a recent
 <a href="http://www.nature.com/nature/journal/vaap/ncurrent/full/nature19804.html">

 Nature
 
 article
 </a>
 . It was developed by scientists at the Broad Institute in Cambridge, Massachusetts.
 
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 “With new chemistry, we discovered an antimalarial with a mechanism of action that no one has ever seen before,” said Eamon Comer, the lead chemist of the study. The study screened a 100,000 compound library inspired by molecules found in nature but not typically represented in pharmaceutical screenings.
 

 Traditional pharmaceutical libraries are cheap to make, but the compounds are often flat, like sheets of paper. The compounds created by Comer and his team were more three dimensional and thus more likely to be successful drugs. “We can access compounds that nature can’t access,” Comer said. “There are certain reactions available to us that are not available in a living cell.”
 

 While the techniques used to create the library were newly developed, sorting through the candidate compounds relied on an established method, the phenotypic screen. Phenotypic screens compare the drug potential of compounds by assessing the health—or ideally death—of the whole parasite when it’s raised with each compound.
 

 The return of phenotypic screening is recent. At the dawn of the genome era, scientists turned toward a target-based approach, a method that first chooses a protein of interest and then systematically flips through compounds to find one that would inhibit that specific protein. Nobutaka Kato, the lead biologist of the study, said that antibiotic drug discovery projects using target-based screening don’t have a good track record.
 

 Unlike target-based screening, phenotypic screens initially leave more to chance by not starting with a specific target in mind. “At the time, we don’t know what the target is, so it’s almost shooting in the dark,” Kato said. Researchers instead start by finding a compound that kills the parasite and then investigate how it works.
 

 Once Kato found an effective compound, he added it to parasite cultures over months, eventually breeding resistant in the parasites. He then compared their genomes to an untreated parasite genome. In the resistant parasites, Kato found several single base-pair mutations in the gene that corresponds to a tRNA-synthetase protein, which is essential for replacing old, degraded proteins in all parts of the cell and for making new proteins when the parasite is dividing. The new compound is effective against blood-stage, transmission-stage, and liver-stage parasites.
 

 The group made variations of the compound—a bicyclic azetidine—to make it more water soluble, a key quality of orally administered drugs. The variants were then tested in mouse models of human malaria. All mice treated with a single oral dose remained parasite-free for the 30-day monitoring period.
 

 Comer and Kato are optimistic about the compound’s potential. “Some targets gain resistance faster, so there are some on the market that get resistance very quickly,” Comer said. “As for this target, we will have to see when it becomes a therapeutic.”
 

 Drug resistance often arises when an infection goes on and off the drug. This can happen when people don’t finish a course of antimalarial pills, but it can also be a result of the complex lifecycle of malaria, which travels from mosquitos into human livers, to blood, then reproduction in blood, then back to mosquitos. Even if a patient takes their medication regularly, the parasite might not be exposed to the drug for enough time. Dormant parasites in the liver are often the cause of relapse and contribute to creating drug-resistant malaria.
 

 “I think it’s reasonable that [the new compound] would be better for clearing the parasite and making it less likely to develop drug resistance, but it’s hard to know until you actually test it,” said Alexis Kaushanksy, assistant professor at the Center for Infectious Disease Control. Kaushansky studies factors in humans that the malarial parasite needs for survival, an approach that will ultimately combat resistance by eradicating liver-stage parasites.
 

 Despite promising results, in an interview on The Naked Scientists podcast, Comer said it would be about 12 years until a drug from this screen would be on the market.
 
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 Image credit: CDC/Dr. Mae Melvin

New Bio-Based Plastic Leaches Less, Keeps Food Fresher

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 Traditional “green” plastics have their share of problems, whether it be a compostable food container with sides too flexible to a secure lid or a biodegradable bag that rips on its way to the compost bin. But a new and improved biodegradable polypropylene carbonate film—PPC—may have solve those problems.
 

 By blending the biodegradable carbon polymer with starch, the resulting film is more durable and less leaky compared with other bioplastics or even traditional petrochemical-based plastics, said Fariba Dehghani, a professor at the University of Sydney who helped develop the material.
 
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<figcaption>Plastic works well to preserve foods, but some leach more air and water than others, leading to degradation.
 
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 “Oxygen and humidity are critical,” she said. “If you prevent these two from diffusing into the packaging, you can prevent bacterial growth and increase the shelf life of the food and decrease the spoilage of the food.” Bread packaged in a PPC-coated bag, for example, would take longer to go stale.
 

 Packaging accounted for nearly 40% of the roughly 275,000 million tons of petrochemical-based plastic consumed globally in 2010. Bio-based packaging, or packaging made from primarily renewable resources such as sugar cane, sugar beets, or tapioca, was a small fraction of that at 165,000 tons, according to Gordon Robertson, a professor at the School of Agriculture and Food Sciences at the University of Queensland.
 

 The PPC-starch blend proposed by Dehghani is a petrochemical-based polymer that degrades quickly, making it biodegradable, but with 25% starch, is becomes partially bio-based, too.
 

 While public concern has focused on creating and using biodegradable plastics because they seem “natural” and promise to decompose quickly, freeing space in landfills, he said, the more immediately sustainable solution might be bio-based products, which use less petrochemicals. In order for biodegradable plastics to live up to their promise, they need to be disposed of in municipal composting sites—and few cities have the necessary facilities or the ability to collect biodegradable waste as a separate stream.
 

 Even existing composting facilities vary vastly in their ability to dispense with biodegradable polymers. Mexico, for example, has only two industrial composting sites, and it is unlikely that either could process the current PPC products. “[The polymer] degrades partially, but it doesn’t reach the quality required for fertilizer. In this kind of facility, those compostable plastics won’t fully degrade by the end of the process,” said AlethiaVazquez-Morillas, a professor at the Autonomous Metropolitan University in Mexico City who was not involved with Dehghani’s project. At the end of an incomplete degradation cycle, the remaining plastic solids are sifted out and put into a landfill.
 

 While the results of the study are promising, PPC still has a long way to go before being certified as biodegradable by ASTM International.
 

 Previously, PPC had been restricted to use as an alternative plastic in films, coatings, and adhesives because of the high metal content left over from its manufacturing process. But a new production method washes the polymer with carbon dioxide-laden water to extract residual zinc, making the polymer safe for use with food, Dehghani and her colleagues reported in
 
 Green Chemistry
 
 earlier this year.
 

 To ensure the safety of the new material, Dehghani mimicked conditions that PPC would encounter as a consumer product—oil, acid to simulate fruit juice, base to simulate a detergent, and alcohol—to see how PPC compared to Ecoflex and other commercially available biodegradable polymers. She found that after six months of incubating in food conditions, PPC had not lost much mass.
 

 “You don’t need to worry that you will contaminate your food with the degradation of this polymer,” Dehghani said.
 
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 Photo credit:
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Satellite Tool Might Be Able to Predict Fracking-Related Earthquakes

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 Miniscule changes in the Earth’s surface could indicate an impending earthquake—and now they can be sensed by a satellite in space.
 

 Regions in eastern Texas have experienced an exponential increase in earthquake activity in recent years following the injection of wastewater from energy operations, such as fracking, into wells in the ground. When and how this makes a fault line fail and cause an earthquake is still poorly understood. By combining an improved mathematical model and disposal records with satellite tracking, scientists are developing a tool that might help predict future earthquakes.
 
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<figcaption>Crews raise a fracking derrick into place.
 
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 Using remotely sensed radar data from the ALOS satellite, scientists at the University of Arizona reported being able to track changes in the Earth’s surface as small as 3 mm per year—one tenth of an inch—around wastewater injection sites. ALOS works by beaming down microwaves, which hit the ground and are scattered back to the satellite. By comparing these data over three years, it was possible to detect vertical movement of the Earth’s surface towards the satellite—surface uplift—which can be a sign of changing pressure underground. The study, published recently in
 
 Science
 
 , is the first to demonstrate surface uplift as a result of wastewater disposal.
 

 “We knew that injection could cause surface deformation or uplift, but we were never able to prove it [before now],” said Manoochehr Shirzaei, the lead author of the study. “The satellite is about 800 km above the surface, and we are measuring 3 mm—that’s crazy.”
 

 The study focused on a set of injection sites linked to a 4.8-magnitude earthquake that shook Timpson, Texas, in 2012. The earthquake hazard of a region is linked to the region’s background seismicity—the more earthquakes, the greater the chance of a bigger earthquake following them.
 

 “We had less than one earthquake per year [in this region], and now we’ve had more than 1,500 since 2009. If you wanted to translate this to seismic hazard, we would give this a red flag,” Shirzaei said. “It’s a cascade of events. Over time, the size of earthquakes and the number of earthquakes will be upgraded. This is alarming.”
 

 The majority of wastewater in this region is injected into limestone carbonate rocks above the basement layer, and hydraulic pressure propagates down into the basement. “Most of the earthquakes we see in east Texas and Oklahoma are occurring in this basement layer,” said Jake Walter, an earthquake seismologist at the University of Texas at Austin who was not involved in the study. “That’s the big jump right now. If we are injecting everything in these units above the basement, how are all these faults getting triggered? This study shows how it might be [that it’s the cause].”
 

 While it’s possible to detect tiny surface changes, Walter said it will take time before its clear how useful these data will be for understanding the influence of wastewater injection on earthquakes.
 

 Timpson is located between four injection wells—the two west wells are deep and allow water to percolate down to a fault, while the two east wells are shallower and are sealed from both the top and the bottom by an impermeable rock layer. Art McGarr, a research geophysicist at the U.S. Geological Survey, said that these differences in depth and permeability are likely why surface uplift was almost exclusively detected near the east wells, though the west wells were actually responsible for the Timpson earthquake, a conclusion that several previous studies have reached.
 

 But because the east wells were not associated with the earthquake, McGarr said that “it’s premature to make any guesses as to whether [satellite monitoring] is going to become a useful procedure, at least in the foreseeable future.”
 

 Though fracking has slowed in recent years, it shows no sign of stopping. And active disposal doesn’t immediately produce earthquakes—the wells in question were closed and sealed five years before the Timpson earthquake, suggesting that monitoring might be useful in other closed sites.
 

 Shirzaei said that current practices can be modified, for example, by injecting at a slower rate to reduce earthquakes. Satellite sensing may also illuminate where pressure is moving to avoid further injection in those areas. “The best example is that you have a glass, and you can only fill it with a certain amount of water. If you keep filling it, it will spill,” Shirzaei said.
 
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CRISPR and Stem Cells Could Speed Studies of Rare Diseases

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 Alicia Burns is afraid to close her eyes, and more afraid for her children to sleep. Sometimes she’s scared to move, or breathe. The fear comes, she said, when “I have a big meal with family and start feeling ill and light-headed. I’m gardening and the sun is beating down on me and I feel faint.”
 

 “Cardiac arrest can happen at any moment.”
 

 Burns, 38, is a mother of six and describes herself as a happily married housewife. But the internet knows her as “Brugada Girl.”
 

 Though she was hospitalized once in her 20s for heart attack-like symptoms, it wasn’t until her young, healthy father died in his sleep that Burns followed up. After a parade of electrocardiograms (EKG) and appointments where her faintness was dismissed by doctors, Burns was diagnosed with Brugada Syndrome, and began writing a blog.
 

 Brugada is a rare disease, and its genetic underpinnings aren’t clearly understood. While most patients experience sudden cardiac arrest when uncoordinated electrical impulses in their heart’s ventricles disrupt blood flow, researchers are finding that each patient has a unique set of genetic mutations that cause the syndrome. And now, there might be a platform for noninvasively studying an individual’s genetic makeup.
 
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<figcaption>Determining the mutations behind diseases can be challenging, but a new platform could help change that.
 
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 The Brugada brothers, Josep and Pedro, identified Brugada syndrome in 1992. Their younger brother, Ramon, established the genetic underpinnings in 1998. They soon realized that Brugada causes sudden unexpected nocturnal death syndrome and is endemic to regions of Southeast Asia, a phenomenon recorded by the CDC since the 1980s. Brugada also explains some cases of sudden infant death syndrome (SIDS). Currently, the NIH estimates that about five in 10,000 people are affected in the United States, and four times that in Southeast Asia. Brugada is responsible for 12% of sudden cardiac deaths.
 

 People are clinically diagnosed with Brugada because of EKG irregularities—but EKG readings can be unreliable and cannot predict someone’s likelihood of developing Brugada later in life. With the rise of genetic sequencing, researchers identified SCN5A, a sodium channel gene, as causative. But the number of responsible genes has quickly swelled to 23, by some counts. The mutations in SCN5A alone number more than 300.
 

 Channel proteins act as gates into the cell membrane, and allow specific ions, usually sodium, potassium, and calcium, to flow in or out. These ion tides are what create the electrical impulses that trigger muscle movement. The heart relies on channel proteins to communicate the complex electrical signals it needs to contract.
 

 Parents with Brugada were thought to have a 50% chance of passing SCN5A to their children, and any child who received the gene would be certain of developing the syndrome. Burns had genetic tests ordered for her six kids, and three of them came back with the exact same mutation she has—but none have been diagnosed yet. While part of this is due to their age, there are an increasing number of people who have the SCN5A genotype but no physical manifestation of the Brugada syndrome phenotype and even more people who are clinically diagnosed but have a healthy SCN5A gene.
 

 “It is a big failure in diagnostics compared to other genetic tests, where you have a good correlation between the genotype and the phenotype,” said Julien Barc, a research associate at the Institute for Medical Research in Nantes, and a co-author of several Brugada genetics studies. “We start to question if it really adds value to do diagnostics for Brugada syndrome.”
 

 The availability of genetic testing has only complicated the understanding of the relationship between a patient’s genotype and their likelihood for developing the disease. Only about 20% of Brugada patients have SCN5A mutations. Meanwhile, the general population carries an array of harmless, one-letter changes in their DNA. When these genetic variants were found in patients from Brugada families, researchers were quick to add them to the database of Brugada-causing mutations. As a result, many of the mutations reported may not actually have anything to do with Brugada syndrome, particularly in genes other than SCN5A. “We have been polluted by variants that have been described but are not causal,” Barc said.
 

 Barc and others have shown that the best genetic predictor of Brugada is the combination of several rare variants—DNA changes shared by fewer than 0.5% of the general population. In the past, finding these may have been difficult. But the ability to comprehensively examine a whole genome, instead of only genes that were already implicated in heart conditions, is fast expanding.
 

 This summer, scientists at Stanford demonstrated how a single patient’s unique Brugada syndrome could be modeled in a lab dish. Researchers collected skin cells of two patients with a common SCN5A mutation, which they converted to pluripotent stem cells, cells that have the potential to become virtually any other cell in the body. They then differentiated these into cardiomyocytes, the self-contracting heart muscle cells. By measuring the electrical signals of individual cardiomyocytes, they showed that the cells behaved similarly to cells in a patient’s heart. Next, the group used the gene editing technique CRISPR-Cas9 to restore SCN5A back to its healthy version. With the gene permanently fixed, the cells began sending normal electrical signals.
 

 This approach could be a powerful tool for determining if individual variants are responsible for Brugada syndrome. Based on a patient’s EKG and history, a clinician might not be completely sure of a diagnosis and send a sample for genome sequencing. “So you do the DNA genotype, and it comes back as some kind of variant,” said Joe Wu, professor of cardiovascular medicine and radiology, and the senior author of the study. Cardiomyocytes are made from a patient sample, and if the cells have the disease phenotype, “that will give you more confidence,” he said. If the variant is edited out and the healthy phenotype restored, that gives you additional confidence.
 

 Physicians associate Brugada syndrome with its usual presentation: ventricular arrhythmia, the discoordination between the heart’s two larger, lower chambers. But the model reinforces that genetic mutations effect the whole organ and that Brugada mutations could also impact the upper, atrial chambers’ functioning. “Now we understand that there is a single cell predisposition that carries over to all the cells in the heart,” said Karim Sallam, a cardiovascular medicine fellow working with Wu.
 

 Modeling individual patients—and determining if their variants are responsible for their Brugada syndrome—could aid doctors in diagnosis, assigning risk, and knowing which patients to follow up with, particularly family members. The CRISPR editing-pluripotent stem cell approach is now being used to study other rare diseases, either for those so rare that investigators can’t recruit patients or in cases where investigators want to confirm their data, Wu said. But not everyone is as optimistic about this platform’s performance.
 

 For a model like this to be useful, it needs to accurately represent the disease. The cardiomyocytes created in the dish should have the same “Brugada phenotype” of electric signals and ion currents that show up on a patient EKG. Charles Antzelevitch, the director of research at the Lankenau Heart Institute, believes that the model fails to create the key EKG signatures of the disease and could be more specific to Brugada syndrome. “The reason for that is clear to many of us who have used induced pluripotent stem cells. These cells are very immature,” he said.
 

 Accurately screening family of a person with Brugada syndrome might still be years away. In the meantime, Burns takes her children for frequent EKG’s, hoping that any Brugada sypmtoms will be caught before it is too late.
 
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 Image credit: NIH

Kate Telma

Articles

3D Chemistry Leads to Potential Malaria Breakthrough

New Bio-Based Plastic Leaches Less, Keeps Food Fresher

Satellite Tool Might Be Able to Predict Fracking-Related Earthquakes

CRISPR and Stem Cells Could Speed Studies of Rare Diseases

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