Biotecnika newspaper 13 february 2018

February 13th, 2018.

Vol. 02 NO 7

NEWS - PAGE 3

NEWS - PAGE 4 INDIAN FARMS DOSING CHICKENS WITH “LAST RESORT ANTIBIOTIC” IS FOSTERING GLOBAL SUPERBUGS

A DNA TEST THAT SCREENS NEWBORNS FOR 193 GENETIC DISORDERS

NEWS - PAGE 7

NEWS - PAGE 9

BACTERIUM PROTECTS PLANTS FROM DISEASE IN ATTEMPT TO GAIN DOMINANCE

BUDGET SPECIAL

SCIENTISTS DEVISE INTERACTIVE MICROSCOPE, UNVEIL PHYSICAL PRINCIPLES OF CELL ORGANIZATION

NEW FDA APPROVAL | First Gram-Negative Antibiotic Allergan plc’s supplemental New Drug Application (sNDA) has now been approved by the USFDA to expand the approved use of Avycaz (ceftazidime and avibactam).

By Disha Padmanabha

FDA Approves First Gram-Negative Antibiotic in over 15 years for Over HospitalAcquired Pneumonia It is to include the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/ VABP) caused by the following susceptible Gram-negative microorganisms: Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Serratia marcescens, Proteus mirabilis, Pseudomonas aeruginosa, and Haemophilus influenzae in patients 18 years of age or older.

Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are serious bacterial infections that occur in hospitalized patients, which are associated with critically ill and vulnerable populations. The economic burden associated with HABP/VABP is significant. These infections are associated with increased healthcare costs, high morbidity and

mortality, and lengthened hospital stays.

The Dublin-based drugmaker said that this expanded use is based on positive results from a pivotal Phase 3 study evaluating the efficacy and safety of AVYCAZ for the treatment of adult patients with HABP/VABP. In Trial 1, known as RECAPTURE, AVYCAZ was non-inferior to doripenem with regard to both primary endpoints. In Trial 2, known as REPRISE, AVYCAZ demonstrated a higher combined clinical and microbiological cure rate vs. best available therapy (BAT), including meropenem , imipenem , doripenem , and colistin . Additionally, both trials included a subset of patients with infections caused by pathogens producing certain ESBL groups and AmpC beta-lactamases in which the clinical and microbiological cure rates were similar to the overall results.

Certain types of Gram-negative bacteria have become increasingly resistant to available antibiotics, resulting in increased illness and death as well as contributing to escalating healthcare costs. New strategies to fight these challenging infections have been long-awaited by the medical community.

Georgia/Augusta University, Augusta, GA.

David Nicholson, Chief Research and Development Officer, Allergan, said: “Healthcare providers in the U.S. have not had access to a new treatment option for patients with HABP/VABP due to Gram-negative bacteria in over 15 years. Gram-negative pathogens are some of the most pressing antibiotic resistance threats and cause more than 40,000 resistant infections in the U.S. annually. Today’s action by the FDA is further evidence of Allergan’s commitment to improving outcomes and meeting critical needs in patients with life-threatening infectious diseases.”

“Clinical efficacy along with patient safety are critical priorities to clinicians managing serious Gram-negative bacterial infections.

We are thrilled to have a new option available to treat HABP/VABP, some of the most challenging Gram-negative infections in the hospital setting,” said Jose Vazquez, M.D., FIDSA, Division Chief and Professor of Medicine Infectious Diseases, Medical College of

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Vol. 02 NO 7

February 13th, 2018.

RAINING VIRUSES? STUDY QUANTIFIES MICROBES CIRCLING THE PLANET

By Disha Padmanabha

Microbes are found even in the most mundane of places, such as on our hands, in the air and in soil. They grow and reproduce in habitats where no other organisms can survive. They can be found in hot springs and deep underground veins of water, in volcanic rock beneath the ocean floor, in extremely salty water in the Great Salt Lake and the Dead Sea, and below the ice of Antarctica.

Aerosolization of soil-dust and organic aggregates in sea spray facilitates the longrange transport of these bacteria, and likely viruses across the free atmosphere. In one such example, the team of researchers have now, for the first time, quantified the viruses being swept up from the Earth’s surface into the free troposphere, that layer of atmosphere beyond Earth’s weather systems but below the stratosphere where jet airplanes fly. The viruses can be carried thousands of kilometres there before being deposited back onto the Earth’s surface.

“Every day, more than 800 million viruses are deposited per square metre above the planetary boundary layer—that’s 25 viruses for each person in Canada,” said University of British Columbia virologist Curtis Suttle, one of the senior authors of the paper.

Their study, the first on the topic, found that once the viruses are in the troposphere they can travel thousands of kilometers before falling back to earth. The troposphere is the layer of the atmosphere past earth’s weather systems yet below the stratosphere, which is where jet planes travel. The phenomenon might clarify why genetically similar viruses are sometimes present in very completely different environments worldwide.

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“Roughly 20 years ago we began finding genetically similar viruses occurring in very different environments around the globe,” says Suttle. “This preponderance of long-residence viruses travelling the atmosphere likely explains why—it’s quite conceivable to have a virus swept up into the atmosphere on one continent and deposited on another.”

The viruses and micro organism get carried into the ambiance by hitching a trip on tiny soil mud particles or sea spray. The team, in order to determine how much of this material is carried up above the atmospheric boundary layer above 2,500 to 3,000 metres, travelled to heights above 2,500 metres, the minimal altitude at which particles are vulnerable to being carried lengthy distances, in Spain’s Sierra Nevada mountains and recorded knowledge at numerous factors.

They found billions of viruses and tens of millions of bacteria are being deposited per square metre per day. The deposition rates for viruses were nine to 461 times greater than the rates for bacteria.

“Bacteria and viruses are typically deposited back to Earth via rain events and Saharan dust intrusions. However, the rain was less efficient removing viruses from the atmosphere,” said author and microbial ecologist Isabel Reche from the University of Granada.

The researchers also found the majority of the viruses carried signatures indicating they had been swept up into the air from sea spray.

The viruses tend to hitch rides on smaller, lighter, organic particles suspended in air and gas, meaning they can stay aloft in the atmosphere longer.

Vol. 02 NO 7

February 13th, 2018.

A DNA Test That Screens Newborns for 193 Genetic Disorders In the United States, newborns are typically screened at the hospital for 34 health conditions on the Recommended Uniform Screening Panel (RUSP), but the selected conditions vary by state and represent only a fraction of the genetic diseases that can manifest in a child’s first decade of life. But now, a newly launched DNA screening test has made it possible to detect more than five times the number of genetic diseases than a state’s standard hospital test.

For all conditions covered by the test – including atypical epilepsy, spinal muscular atrophy, and childhood cancers, among many others – there are validated medical interventions that may positively influence a baby’s future wellbeing when introduced early enough.

The test uses saliva procured from a baby’s cheek to screen for problematic genetic alterations, as well as potential reactions to a range of medications usually given to young children. All the conditions the Sema4 test looks for—it uses DNA sequencing to examine a subset of genes, rather than the whole genome—have some kind of treatment already available. The test also analyzes how a baby is likely to respond to 38 medications commonly prescribed in early childhood.

“If you can, at birth, canvass some of the most common disorders, you get a better understanding of the health of your child,” says

Eric Schadt, the CEO of Sema4. “We think parents want the best for their children and are going to do whatever they can so that their child can have the healthiest life possible.”

“Until now, families have been likely to be caught off-guard by these early-onset diseases, and prognosis is often poor by the time symptoms have manifested. Thanks to breakthroughs in science and medicine, we can now identify babies at risk for these broader set of diseases and deliver interventions – sometimes as simple as vitamin supplements – in time to make a real difference. We believe Sema4 Natalis will give parents the advantage of early insight in support of the care of their children.”

As noted in its recent comments to the Centers for Medicare and Medicaid Services, the National Organization for Rare Disorders (NORD) finds that “on average, individuals with a rare disease wait seven to 10 years to obtain an accurate diagnosis, leaving many individuals with chronic conditions still waiting for a diagnosis. There are millions of patients in the U.S. who are still undiagnosed, and [next-generation sequencing] may be their only hope.”

By Disha Padmanabha

Ants Could Help Us Develop Novel, Potent Antibiotics You probably don’t think about them much.

They’re small and there’s probably a ton of them in your front yard right now. But with ants there is so much more than meets the eye.

Now, in an addition to this list of all the wondrous things about these little critters, a new study has identified some ant species that make use of powerful antimicrobial agents – but found that 40 percent of ant species tested didn’t appear to produce antibiotics. The study has applications regarding the search for new antibiotics that can be used in humans.

“These findings suggest that ants could be a future source of new antibiotics to help fight human diseases,” says Clint Penick, an assistant research professor at Arizona State University and former postdoctoral researcher at North Carolina State University who is lead author of the study.

“One species we looked at, the thief ant (Solenopsis molesta), had the most powerful antibiotic effect of any species we tested – and until now, no one had even shown that they made use of antimicrobials,” says Adrian Smith, co-author of the paper, an assistant research professor of biological sciences at NC State and head of the NC Museum of Natural Sciences’ Evolutionary Biology & Behavior

Research Lab. Pathogens and parasites exert strong selective pressures on social animals due to the dense living conditions of social animals and the high genetic relatedness among group members. In response, social species have evolved numerous strategies to combat pathogen spread.

In addition to individual immune responses, social species employ public health strategies to stop the spread of pathogens before they become prevalent. In social insects such as ants, these strategies represent a form of external immunity that includes grooming behaviours and the secretion of antimicrobial compounds whose function is akin to our antibiotics. Because of the production of these antimicrobial compounds, the identification of these social insects as promising sources of new and diverse antibiotics comes with little surprise.

In the course of this study, researchers tested the antimicrobial properties associated with 20 ant species; using a solvent to remove all of the substances on the surface of each ant’s body. The resulting solution was then introduced to a bacterial slurry. The growth of the bacteria in the slurry was then compared to the growth of bacteria in a control group. If bacteria in slurry that contained ant solution grew less than the control group,

By Disha Padmanabha

which meant that an antimicrobial agent was at work. For example, the slurry containing thief ant compounds showed no bacterial growth at all.

The team found that 12 of the 20 ant species had some sort of antimicrobial agent on their exoskeletons – including some species, like the thief ant, that hadn’t previously been shown to do so. But eight of the ant species seemed not to make use of antibiotics at all.

“Finding a species that carries a powerful antimicrobial agent is good news for those interested in finding new antibiotic agents that can help humans,” Smith says. “But the fact that so many ant species appear to have little or no chemical defense against microbial pathogens is also important.”

“We thought every ant species would produce at least some type of antimicrobial,” Penick says. “Instead, it seems like many species have found alternative ways to prevent infection that do not rely on antimicrobial chemicals.”

search for species that actually do hold promise for biomedical research,” Smith says.

“For example, the thief ant is closely related to the red imported fire ant (Solenopsis invicta), which is well known for the antimicrobial properties of its venom. But in our study, we found that the thief ant was even more effective against bacteria than the fire ant. There may be other species in the same genus that are worth studying for their antimicrobial potency.”

The researchers caution that this study is a first step, and that this study does have limitations. For example, the researchers used only one bacterial agent in their tests, meaning it is not clear how each species would fare against other bacteria. “Next steps include testing ant species against other bacteria; determining what substances are producing the antibiotic effects – and whether ants produce them or obtain them elsewhere; and exploring what alternative strategies ants use to defend against bacterial pathogens,” Smith says.

“The fact that not all ants use antimicrobials highlights the importance of refining our

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Vol. 02 NO 7

February 13th, 2018.

Trees Tolerate Extreme Heatwaves by “Sweating”: Study Heatwaves are a regular climate component in many areas of the world, consisting of several consecutive days of extreme temperatures and a dry atmosphere, often combined with dry surface soils.

Extreme heatwaves generally tend to have devastating effects on the ecosystem. The response of trees to extreme heatwaves is uncertain but important for ecosystem function.

Some ecological processes are more sensitive to changes in extremes than to changes in mean values. For example, extreme temperatures combined with prolonged drought have been implicated as drivers of forest mortality.

High temperatures during extreme heatwaves may exceed plant thermal thresholds, leading to direct thermal damage or mortality unless plants can quickly adjust to these extreme conditions. It is not clear, however, whether rapid physiological adjustments in thermal tolerance occur in response to heatwaves in the field, or whether this is an effective protectant during the extreme heatwaves that are predicted to occur in the future.

Now, researchers at the Western Sydney University have uncovered the novel strategies Australian eucalypt trees use to survive extreme heatwaves. Of their findings, one remarkable process involves the tree evaporating large volumes of water through its leaves in a process similar to sweating.

In a year-long experiment, it was demonstrated how trees continue to release water through their leaves as an evaporative cooling system during periods of extreme heat, despite the carbon-fixing process of photosynthesis grinding to a halt.

The study lead, Prof Mark Tjoelker from the University of Western Sydney’s Hawkesbury Institute for the Environment said the findings had significant implications for climate change because they showed that trees

stopped capturing carbon during extreme heatwaves, which are predicted to become more frequent and severe in the future.

“If heatwaves occur over a large surface area … clearly the trees and native forests in that area would take up less carbon,” he said. “And if there is an increased frequency of heatwaves that obviously impacts their ability to serve as carbon sinks.”

The Earth has a mechanism in place to help reduce the massive amount of carbon that humans have been emitting into the atmosphere since the pre-industrial era. Oceans, grasslands and trees serve as “carbon sinks” that sucks carbon from the atmosphere. Now, in an ironic twist- the study suggests trees may actually lose their ability to capture carbon during heat waves.

The researchers, based within the Hawkesbury Institute for the Environment, used the unique Whole Tree Chambers located at the University’s Hawkesbury campus to impose a year of warming and then a four-day, high-intensity heatwave on trees local to the Sydney region.

The Whole Tree Chambers are unique in their ability to grow nearly full-height trees (29.5 ft) in a fully controlled environment and to be able to precisely and accurately measure the trees’ rates of photosynthesis and water use. Within the chambers, researchers imposed an additional 3 degrees Celsius on Parramatta Gums (Eucalyptus parramattensis) to simulate the impacts of higher average temperatures in the Sydney region. After 12 months – in which time the trees grew to more than 6 metres – researchers then imposed four days of heat at 43 degrees Celsius.

The observation was that the trees employed different strategies in order to cope

Indian Farms Dosing Chickens with “Last Resort Antibiotic” is Fostering Global Superbugs In 1941, penicillin was first used to save human life. But now, bacteria has emerged resistant to every known antibiotic, and scientists have begun to fear that the era of the wonder drugs is near to its end.

And now in addition to this growing problem for which we can, frighteningly, do literally nothing about, we have been presented with a new report that has found evidence of considerable use of the antibiotic colistin, in Indian poultry farms so as to promote growth and feed efficiently.

For those who are ignorant enough to not understand the gravity of this situationColistin is considered the antibiotic of last resort for use against Enterobacteriaceae, a

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family of bacteria that contain organisms that we interact with every day; many of which have become superbugs.

But then, in India, this weapon of last resort is being fed to birds to make them gain weight faster so more can be grown each year at greater profit. When the antibiotic should be used as a last resort to save human lives, it is instead (tons of it) is being used on chickens. And what happens is our antibiotic of last resort will be decoded by the bacteria encountered in the animals, and then inactivated.

The World Health Organisation has called for the use of such antibiotics, which it calls “critically important to human medicine”, to

By Disha Padmanabha These chambers allow researchers a better understanding of how plants adjust to altered climate conditions (Credit: Western Sydney University – Hawkesbury Institute for the Environment)

with the heat, rather to avoid the damaged due to the heat.

The trees stopped their leaves from reaching critically high temperatures by evaporating large quantities of water, in a process called transpiration that is akin to sweating.

Under dry conditions, plants would normally stop transpiring in order to conserve water. In heatwaves, in contrast, trees must keep using water to avoid leaf damage from burning.

To maintain the high rates of transpiration, the trees sourced water from throughout the soil profile, to depths of 1.5 metres and below, demonstrating the efficiency with which eucalypts find and extract water.

Further, the trees even rapidly increased their high-temperature tolerance. Within 24 hours of the start of the heatwave, the threshold temperature at which leaves start to become damaged had increased by 2 degrees Celsius.

“Under these extreme temperatures, this relationship changes completely – the trees can no longer photosynthesise, but they continue to use a lot of water to keep their leaves from reaching damagingly high temperatures. In addition, the ability to increase the high-temperature tolerance of their leaves helps to explain how eucalypts cope with heatwaves that would burn the leaves of other species.”

“What normally happens is that a tree’s use of water and its rate of photosynthesis are closely related and this process is the basis of how scientists predict what the effects of a warmer Australia on trees and forests will be,” explains Professor Mark Tjoelker.

“This indicates that eucalypts can tolerate elevated temperatures and significant heatwave events as long as they have access to water. If heat and drought combine, then we may see more damage occurring and the potential for tree mortality”, he says.

Dr John Drake, formerly of the Hawkesbury Institute for the Environment and now a researcher at the College of Environmental Science and Forestry in the United States, explains that there is a limit to all plants’ ability to adjust to heat even if some species adapt better than others.

“We were surprised how well these eucalypts acclimated to the heatwaves and maintained their function,” says Dr Drake.

By Disha Padmanabha

be restricted in animals and banned as growth promoters. Their continued use in farming increases the chance bacteria will develop resistance to them, leaving them useless when treating patients.

A report by the Bureau of Investigative Journalism found 2,800 tonnes of the drug were shipped to developing countries including India, Vietnam, Russia, Mexico, Colombia and Bolivia for use on animals in 2016.

India, which is regarded as one of the worst offenders for antibiotic misuse, received hundreds of tonnes of colistin for routine use in animals, particularly chickens.

The south Asian nation is expected to see the highest growth in drug use in animals of

any country over the next decade, with estimates suggesting as much as 4,800 tonnes of antibiotics will be used in feed by 2030 – an 80 per cent increase on current levels.

Although, the World Health Organisation calls this drug “critically important to human medicine”, it also restricts its use in animals and bans it as a growth promoter. In India itself, there are at least five pharmaceutical companies that openly advertise products with Colistin as growth promoter.

Next Page>>>>

Vol. 02 NO 7 One of these companies, Venky’s, is also a major poultry producer. Apart from selling animal medicines and creating its own chicken meals, it also supplies meat directly and indirectly to fast food chains in India such as KFC, McDonald’s, Pizza Hut and Dominos.

The study quotes Professor Timothy Walsh, an adviser to the UN on antimicrobial resistance, who says, “Colistin should only be used on very sick patients. Under any other circumstances it should be thought of and

February 13th, 2018. treated as an environmental toxin. It should be labelled as such. It should not be exported all over the world to be used in chicken feed.”

Professor Walsh, who is professor of medical microbiology at Cardiff University, discovered a colistin-resistant gene in Chinese pigs in 2015. The gene, mcr-1, could be transferred within and between species of bacteria. That meant that microbes did not have to develop resistance themselves – they

could become resistant just by acquiring the mcr-1 gene.

“Colistin-resistant bacteria will spread on the chicken farms, in the air surrounding them, contaminate the meat, spread to the farm workers, and through their faeces flies will spread it over large distances,” Prof Walsh further added.

Probably, a bigger issue here is- there is nothing to prevent Indian farmers, which in-

clude some of the world’s biggest food producers, from exporting their chickens and other related products overseas.

The finding is alarming given the use of such powerful drugs can lead to an increasing resistance among farm animals around the world. Colistin, being regarded one of the last lines of defence against serious diseases could lead to breakouts and diseases commonly treatable previously, becoming deadly once again in its absence.

Scientists Design Novel Technology Platform to Reboot Bacteriophages The unique host specificity and antimicrobial activity of bacterial viruses have inspired many diagnostic and antibacterial applications in industry, agriculture, and medicine.

Because of the rise in antibiotic-resistant infections, phage therapy is a reemerging field of interest.

Specially, the engineered strains of bacteriophages provide powerful tools for biotechnology, diagnostics, pathogen control, and therapy. However, current techniques for phage editing are experimentally challenging and limited to few phages and host organisms.

In this direction, scientists at ETH Zurich, led by Martin Loessner, Professor of Food Microbiology, have now developed a technology platform that allows them to systematically modify and customise bacteriophages. The platform technology enables rapid, accurate, and selection-free construction of synthetic, tailor-made phages that infect Gram-positive bacteria.

The new phage workbench allows such viruses to be created very quickly and the

“toolbox” is extremely modular: it allows the scientists to create almost any bacteriophages for different purposes, with a great variety of functions.

“Previously it was almost impossible to modify the genome of a bacteriophage,” Loessner says. On top of that, the methods were very inefficient. For example, a gene was only integrated into an existing genome in a tiny fraction of the phages. Isolating the modified phage was therefore often like searching for a needle in a haystack.

“In the past we had to screen millions of phages and select those with the desired characteristics. Now we are able to create these viruses from scratch, test them within a reasonable period and if necessary modify them again,” Loessner stresses.

In the course of the study, the team used synthetic biology methods to plan the genome of a bacteriophage on the drawing board and assemble it in a test tube from DNA fragments.

By Disha Padmanabha

At the same time new, additional functions were incorporated in the phage genome, such as enzymes to dissolve the bacterial cell wall.

They were additionally able to remove genes that give a phage unwanted properties, such as the integration into the bacterial genome or the production of cytotoxins.

In order to reactivate a phage from synthetic DNA, the genome was introduced into spherical, cell wall-deficient but viable forms of the Listeria bacterium (L-form Listeria).

Based on the genetic blueprint, these bacterial cells then produce all the components of the desired phage and ensure that the virus particles are assembled correctly.

The team, with this project, has undoubtedly made a giant stride towards applying synthetic bacteriophages for use in therapy, diagnostics or the food industry. The scientists are thus managing to overcome constraints associated with the use of naturally occurring phages. “Our toolbox could help to exploit the potential of phages,” Loessner says.

The researchers have applied for a patent for their technology. They next hope to find licensees to produce the phages for therapy and diagnostics.

Bacteria ‘Fight Club’: Guardians of the Gut Fight it Out Fight! Fight! Fight!

A tale of survival in the Microbial Jungle proceeds.

There’s a war going on that you’re completely oblivious to, even though it’s all happening right under your nose- well, actually inside of you. Rival Strains of Escherichia coli compete for precious real estate within the damp linings of your gut.

You cannot really ever guess how much bacteria like a good fight until you’ve seen this video, scientists at the University of Oxford have made. They literally stab, shove and poison each other in pursuit of the best territory.

For the first time, scientists have observed in real-time the ability of bacteria within a colony to collectively predict and respond to an incoming attack by another colony. This discovery has important implications for understanding both the healthy bacteria that live in the human body and the bacteria responsible for spreading disease.

Animals have evolved a wide diversity of aggressive behavior often based upon the careful monitoring of other individuals. Bac-

teria are also capable of aggression, with many species using toxins to kill or inhibit their competitors. Like animals, bacteria also have systems to monitor others during antagonistic encounters, but how this translates into behavior remains poorly understood.

However, now the researchers have observed such behaviour through warring microbes. They used two strains of Escherichia coli, pitting them against each other. Both strains were engineered to have either fluorescent green or red colors so the Oxford scientists could “follow their combat in real time.” They saw that each strain produced their own toxin as a weapon against the other strain, but the bacteria were not negatively affected by their own toxin.

The findings revealed that not all strains of bacteria fight the same way. In addition to these basic differences in aggression, the research also shows that some strains can not only detect an attack from an incoming toxin, but they can also respond quickly to warn the rest of the colony.

Cells on the edge of the colony will detect the incoming attack, and share this infor-

By Disha Padmanabha

mation with the cells behind the battlefront, allowing them to respond as a collective, in a coordinated and surprisingly sophisticated fashion.

Professor Kevin Foster, senior author on the work and Professor of Evolutionary Biology in the Department of Zoology at the University of Oxford, said: “Our research shows that what appear to be simple organisms can function in a very sophisticated manner. Their behaviour is more complex than we have previously given them credit for.

Much like social insects, such as honey bees and wasps and social animals like birds and mammals who use alarm calls, when under predation, they are capable of generating a coordinated attack.”

Given how the human body is home to vast

numbers of bacteria, particularly our gut microbiome, this effectively means that there is a bacterial war going on inside us. Understanding bacterial competition can help us to understand how bacteria spread, where and why. Professor Foster explains: “We know from other studies that toxins are important for whether or not a particular strain will establish in a community. But understanding how bacteria release toxins and outcompete others is very important for understanding the spread of infection.”

Witness the two epic colonies (of bacteria) engaging in battle, Game of Thrones style, here: https://youtu.be/pg6WUDn16Us

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Vol. 02 NO 7

February 13th, 2018.

Artificial Superconducting Synapses Could Enable More Efficient- And More Human AI Systems For those working in the field of advanced artificial intelligence, getting a computer to simulate brain activity is a gargantuan task, but it may be easier to manage if the hardware is designed more like brain hardware to start with.

Artificial intelligence software has increasingly begun to imitate the brain. Algorithms such as Google’s automatic image-classification and language-learning programs use networks of artificial neurons to perform complex tasks. But because conventional computer hardware was not designed to run brain-like algorithms, these machine-learning tasks require orders of magnitude more computing power than the human brain does.

And now researchers at the National Institute of Standards and Technology may have overcome this significant hurdle by designing a chip with artificial synapses.

The researchers have built a superconducting switch that “learns” like a biological system and could connect processors and store memories in future computers operating like the human brain.

In the brain, neurons “talk” to one another

by sending electrochemical impulses across tiny gates or switches called synapses. When a synapse receives a strong enough incoming signal from one neuron, it triggers an electrochemical reaction that produces an outgoing spike in a second neuron.

“The NIST synapse has lower energy needs than the human synapse, and we don’t know of any other artificial synapse that uses less energy,” NIST physicist Mike Schneider said in a statement.

Even better than the real thing, the NIST synapse can fire much faster than the human brain—1 billion times per second, compared to a brain cell’s 50 times per second—using just a whiff of energy, about one ten-thousandth as much as a human synapse.

The NIST synapse is a type of Josephson Junction, a sandwich of two superconductors around an insulating layer. What makes this unique is the fact that these synapses special is that the insulating layer is packed with special magnetic clusters that allow the researchers to control how much energy is required

By Disha Padmanabha

to throw the switch, known as the critical current.

As Schnieder noted, these junctions include 20,000 manganese and silicon nanoclusters per square micrometer. They gave the researchers the control they needed.

“These are customized Josephson junctions,” he noted. “We can control the number of nanoclusters pointing in the same direction, which affects the superconducting properties of the junction.”

Ultimately, these synapses could play critical roles in making processing data simultaneously a reality. Neuromorphic computers could be the new wave of reality given the increasing need for faster computing at lower energy costs.

Moreover, the team adds, the synapses can

be ‘stacked’ in a three-dimensional arrangement to form a larger system linking devices acting as neurons, which the term says can be made by conventional electronic component construction methodology.

Steven Furber, a computer engineer at University of Manchester, UK, who studies neuromorphic computing, stresses that practical applications are far in the future. “The device technologies are potentially very interesting, but we don’t yet understand enough about the key properties of the [biological] synapse to know how to use them effectively,” he says.

“We’re optimistic that we can start to scale these devices somewhat aggressively,” said Schneider, who puts the figure at between five and 10 years.

Compromised “Gatekeeper” Cells Could be Precursors of Alzheimer’s A new potential for alzheimer’s has been identified by researchers- the protective “gatekeeper” cells of tiny blood vessels.

Normally, the blood vessels in the brain form a tight barrier, preventing toxins and large molecules from flooding the brain, while allowing oxygen and nutrients in. But as people age, the researchers found, this blood-brain barrier starts to break down. The process was found to accelerate in those in the earliest stages of Alzheimer’s disease.

“This is a significant step in understanding how the vascular system affects the health of our brains,” said the senior author of the study, Dr. Berislav Zlokovic, director of the Zilkha Neurogenetic Institute at USC. “To prevent dementias, including Alzheimer’s, we may need to come up with ways to reseal the blood-brain barrier and prevent the brain from being flooded with toxic chemicals in the blood.”

The catastrophe causes a communications failure called small vessel disease. Many people with that disease also have white matter disease, the wearing away of fatty myelin that allows neurons to transfer messages

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within the brain network.

“Many scientists have focused their Alzheimer’s disease research on the buildup of toxic amyloid and tau proteins in the brain, but this study and others from my lab show that the problem starts earlier — with leaky blood vessels in the brain,” said Berislav Zlokovic.

“The collapse of pericytes — gatekeeper cells that surround the brain’s smallest blood vessels — reduces myelin and white matter structure in the brain. Vascular dysfunctions, including blood flow reduction and bloodbrain barrier breakdown, kick off white matter disease.”

The brain has a dense network of blood vessels, which if stretched end-to-end would cover more than 5,000 football pitches. However, unlike the blood vessels in other parts of the body, these vessels restrict which things can enter the brain from the blood stream. It does that by forming a physical overlap of cells, such as pericytes and endothelial cells, that make up the blood vessel wall and forms tight junctions that control the entry and re-

By Disha Padmanabha

Diffusion MRI maps show disrupted white matter connectivity and loss of white matter fiber tracts in 1 year-old pericyte-deficient mice. (Image/Berislav Zlokovic Lab) moval of substances into and out of the brain.

Pericytes play a critical role in white matter health and disease via fibrinogen, a protein that circulates in blood. Fibrinogen develops blood clots so wounds can heal. When gatekeeper cells are compromised, an unhealthy amount of fibrinogen slinks into the brain and causes white matter and brain structures, including axons (nerve fibers) and oligodendrocytes (cells that produces myelin), to die.

Therefore, the team of researchers at the USC proceeded to bioengineer mice to have 25 percent fewer of pericytes. They then prodded the hind legs of the young specimens with an electric stimulus.

The pericyte-lacking mice showed an approximately 30 percent reduction in blood flow in the brain versus normal mice, because their capillaries took about 6.5 seconds longer to open up in the face of the stimulus.

Further, as the specimens aged, it was ob-

served that the cerebral blood-flow response got even worse, dipping to 58 percent lower than their unaffected brethren at six to eight months of age.

“We now understand the function of blood vessel gatekeeper cells is to ensure adequate oxygen and energy supply to brain cells,” said Amy Nelson, co-first author and a postdoctoral scholar at the Zilkha Neurogenetic Institute. “Prior to our study, scientists knew patients with Alzheimer’s disease, ALS and other neurodegenerative disorders experience changes to the blood flow and oxygen being supplied to the brain and that pericytes die. Our study adds a new piece of information: Loss of these gatekeeper cells leads to impaired blood flow and insufficient oxygen delivery to the brain. The big mystery now is: What kills pericytes in Alzheimer’s disease?“

Vol. 02 NO 7

February 13th, 2018.

New Form of Botox Isolated from Bacterial Source Clostridium botulinum toxin which can cause a severe flaccid paralytic disease in human and other animals, had the ability to jump into gram-positive bacteria called Enterococcus faecium, through plasmids in the bacteria, a tiny, double-stranded circular DNA molecule that is distinct from a cell’s chromosomal DNA, according to a new study.

Over the past 20 years, there has also been a growing number of therapeutic applications for botulinum toxin type A, known as Botox, including treatment for migraines, leaky bladders, excessive sweating, and cardiac conditions.

“This is the first time that an active botulinum toxin has been identified outside of Clostridium botulinum and its relatives, which are often found in soil and untreated water,” said Andrew Doxey, one of the study’s

two corresponding authors and a bioinformatics professor at the University of Waterloo. “Its discovery has implications in several fields, from monitoring the emergence of new pathogens to the development of new protein therapeutics—it’s a game changer.”

The study was originally designed to investigate the origins of antibiotic resistance in E. faecium bacteria, later, the researchers were able to sequence the genome of the E. faecium bacteria drawn from cow feces.

The genome was then run through computer programs in Doxey’s lab, which found the gene for botulinum toxin in the bacterial strain.

The researchers concluded that the botulinum toxin was likely transferred from C. botulinum bacteria in the environment into the E. faecium bacteria in the cow’s gut, showing that the toxin can be transferred between very

By Disha Padmanabha

different species.

“The botulinum toxin is a powerful and versatile protein therapeutic” says Michael Mansfield, a Biology doctoral candidate in

the Doxey Lab and one of the study’s lead authors. “By finding more versions of the toxin in nature, we can potentially expand and optimize its therapeutic applications even further.”

Bacterium Protects Plants from Disease in Attempt to Gain Dominance Most natural environments harbor a stunningly diverse collection of microbial species. Within these communities, bacteria compete with their neighbors for space and resources.

Members of the rare biosphere that are amplified under favorable conditions to which they are pre-adapted can give rise to discrete, abundant populations. The potential pool of microbial competitors is therefore vast, and a wide range of mechanisms can be responsible for the emergence and radiation of dominant microbial populations. Nutritional resources are a focal point of microbial competition.

Now, in this regard, another warring bacterium has been found by the scientists at McMaster University. They have also been able to identify a toxin the soil-dwelling bacterium employs to get rid of its enemies which in turn has been found to offer protection to the plant against its pathogens.

The bacterium Pseudomonas protegens hold the ability to kill soil-dwelling plant pathogens, including fungi and bacteria that attack the roots of important crops such as cotton by

the means of the toxic, T6SS injection. “[The T6SS] is this molecular nanomachine that injects toxic protein into other species of bacteria and kills them,” lead researcher, John Whitney said. “Plant protective bacteria that have [T6SS] can protect plants from pathogens better relative to [bacteria] that don’t have it.”

Pseudomonas protegens releases diverse antimicrobial compounds into the soil, but the study focused specifically on those compounds that it was injecting directly into other bacteria through the type VI secretion system, or T6SS. Understanding the diversity of bacterial weapons is an active area of study among agricultural researchers who would like to develop better ways to fight plant diseases.

Through the course of the study, the team found that the toxic protein used by P. protegens against other bacteria acts on a molecule found in nearly all living cells: nicotinamide adenine dinucleotide, or NAD+. It

By Disha Padmanabha

is a cofactor, or “helper” molecule, in many biochemical reactions. By injecting a protein that destroys NAD+, P. protegens is able to kill other bacteria.

Delving deeper, the team next analysed the genome of several other bacteria to determine how widespread the strategy of targeting NAD+ is in microbial warfare. They found that many bacteria with secretion systems carry genes similar to the one encoding the NAD-targeting toxin.

“We started to see that this isn’t just a way

of killing that is enacted by plant-protective bacteria,” Whitney said. “If you look at the distribution of this (protein) among all sequenced bacteria, it appears that many different bacteria in many different environmental niches use this mode of action to outcompete other bacteria.”

“The identification and characterization of antibacterial toxins produced by plant-protective bacteria may one day allow us to engineer these bacteria to have enhanced ability to suppress pathogens,” Whitney said.

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Vol. 02 NO 7

February 13th, 2018.

Dye Wipes Out Malaria Parasite at Unprecedented Rate

The malarial parasite along with its now resistant form has rendered our best weapons against it moot and our medications on the brink of defeat.

The World Health Organization (WHO) estimated 800,000 malaria deaths and 225 million cases worldwide in 2010. According WHO, malaria is chargeable for roughly 445,000 deaths once a year. Geographically, malaria overlaps with other infectious maladies including HIV, which often complicate the illness as well as treatment options.

Worryingly, first-line treatment for malaria currently relies on a single drug class called artemisinins, and the existing drug armamentarium is insufficient to answer the call for malaria eradication.

Under the circumstances, scientists are exploring many approaches, targeting different stages of the parasite life cycle, to find agents that will prevent, cure, or eliminate malaria.

But now, a new research has found that the dye methylene blue is a safe antimalarial that kills malaria parasites at an unparalleled rate.

Methylene blue has had a fascinating career. Its history goes back to the 19th century, when it was the first synthetic dyestuff on the market and began to put pressure on its predecessors, plant-based dyes. Now, in the study carried out by scientists at Radboud University Medical Center, the University of California (UCSF), and the Malaria Research and Training Center (MRTC), at Mali, they were able to ascertain the fact that the dye

in combination with artemisinin-based combination therapy (a fairly standard treatment) was able to get rid of malaria in a short period of time.

“Methylene blue is very promising, because it can prevent the spread of malaria within such a short time following treatment,” said Teun Bousema, researcher from Radboud University in the Netherlands.

“There are also indications that methylene blue also works well in species that are resistant to certain medicines,” Bousema added.

As the malaria parasites remain in the blood for a long time, with the chance that other mosquitos are infected if they feed on the patient, our current medications are pretty useless. The parasites split in the patient’s red blood cells, forming male and female sex cells (gametocytes). If another mosquito bites the patient, it sucks up the sex cells and these are fertilized in the mosquito’s stomach. The offspring then find their way to the mosquito’s salivary glands, where the cycle starts again.

In the new study, adding the dye to the antimalaria medicine ensured that patients no longer infected other mosquitos, within as little as 48 hours. Patients who were not given methylene blue were able to infect other mosquitos for at least a week.

By Disha Padmanabha

Researcher Teun Bousema (Radboudumc) coordinated the study which was conducted together with the University of California (UCSF) and the Malaria Research and Training Center (MRTC). Bousema: “We noted that the male parasites disappeared from the bloodstream more quickly than the female parasites.”

Encouraged by the promising results of laboratory experiments, Bousema’s team has investigated for the first time the effect of methylene blue on the spread of malaria amongst

humans. Bousema: “Methylene blue is very promising, because it can prevent the spread of malaria within such a short time following treatment. There are also indications that methylene blue also works well in species that are resistant to certain medicines.” The dye is safe and was tolerated well by patients.

There is however just one awkward side effect: “I have used it myself, and it turns your urine bright blue. This is something that we need to solve, because it could stop people from using it.”

Active Genetics Paves Way for a New Era of Advances in Synthetic Biology We are all very well aware of Mendelism.

Though he was not aware of the concept of genes at the time was his experiments, Mendel essentially worked out that pea plants had two copies of each gene, and that each copy had a 50% chance of being passed on to any one offspring. Yet not all genes actually follow this pattern of inheritance.

The non-Mendelian transmission of heritable traits or known as Active Genetics, takes place by means of self-propagating genetic elements. It was first conceived and developed at UC San Diego in pioneering work on the fruit fly, Drosophila melanogaster (Gantz and Bier, 2015).

It is an exciting new technology that can also be used to bypass prohibitive constraints imposed by standard genetic methods to permit aggregation of multiple naturally occurring genetic variations in crop strains. It has immense potential in transforming health and agriculture.

Immediate targets of active genetics included gene-drive systems for immunizing mosquitoes against vector borne diseases such as malaria. Bier and Gantz also proposed using active genetics for a variety of other potential human health and agricultural benefits.

A research team now, led by Shannon Xu, together with Gantz and Bier, has employed

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CRISPR/Cas9 in order to edit gene regulatory elements in their native genomic environments, revealing new fundamental mechanisms that control gene activity. Their work also provides experimental validation for using active genetics as an efficient means for targeted gene insertion, or “transgenesis,” and single-step replacement of genetic control elements.

To understand mechanisms controlling gene activity in space and time, the researchers analyzed the genetic control of a gene responsible for coordinating the formation of a simple structure in fruit flies—a wing vein— during its development.

The team used a new active genetic element called a CopyCat element and more traditional genome editing to analyze the control of a gene that coordinates the formation of a simple structure in a fruit fly – a vein in the wing. So-called “CopyCat” cloning vectors offer the potential to be inserted precisely into the genome at any desired location and then get copied with high efficiency from one parental chromosome to another so that all offspring inherit the CopyCat element.

As a result, the researchers found evidence for a new potential form of interaction between chromosomes that contributes to the control of gene activity. These observations

By Disha Padmanabha

UC San Diego Professor Ethan Bier. Credit: Erik Jepsen, UC San Diego Publications raise the intriguing possibility that similar forms of cross-talk between chromosomes may occur in other organisms and might eventually define potential targets for epigenetic intervention.

Additionally, their work demonstrates significant advantages of editing gene regulatory sequences in their native location to uncover new functionalities. This leads to a better understanding of how control switches work to turn genes on and off in the body. Perhaps most importantly, these studies demonstrate the general utility of active genetics as a platform for engineering new organisms with novel traits.

“These advances should encourage other researchers to employ active genetics in a broad range of organisms to enable and accelerate their research,” said Xu.

“This knowledge may eventually lead to biological design based on first principles.

That is, acquiring the knowledge to engineer organisms with specifically designed novel features,” said Bier, professor and recently named holder of the Tata Chancellor’s Endowed Professorship in Cell and Developmental Biology.

“Such genetic engineering manipulations should open new avenues of research and animal and plant engineering that are out of reach using current technologies,” the researchers note. These innovative new areas of biological research are in line with the goals of the Paul G. Allen Frontiers Group, which named professor Bier an Allen Distinguished Investigators in 2016.

Vol. 02 NO 7

February 13th, 2018.

Algae Underside of Arctic Thrive Even at 0.02% Light Microalgae colonizing the underside of sea ice in spring are a key component of the Arctic foodweb as they drive early primary production and transport of carbon from the atmosphere to the ocean interior.

Onset of the spring bloom of ice algae is typically limited by the availability of light, and the current consensus is that a few tens-of-centimeters of snow is enough to prevent sufficient solar radiation to reach underneath the sea ice.

Given the unique conditions, a new study by scientists at the Aarhus University, Denmark comes as a surprise. The team has found that the small ice algae on the underside of the Arctic sea ice live and grow at a light level corresponding to only 0.02% of the light at the surface of the ice.

It is pitch dark all winter in the Arctic. And even when the spring sun appears in the sky, the compact ice and snow layer allows only a tiny amount of light to penetrate into the sea. Here, in this extreme environment where temperatures are below the freezing point and salinity is higher than in the sea water, and where light penetration is extremely low for a large part of the year, the ice algae are found.

On the underside of the sea ice microscopic algae have adapted to the very extreme conditions prevailing here. Among these are diatoms that reside on the underside of the ice and in small channels in the ice – the so-

called brine channels, where heavier saline water flows out of the ice and into the sea.

This light level measuring at 0.02 percent of the light hitting the top of the ice and snow on a sunny day wherein the algae was able to thrive, is the lowest threshold for active photosynthesis ever recorded.

“We worked on the sea ice in April-May, where there was a meter of sea ice and a meter of snow on top of the ice,” Lars Chresten Lund-Hansen, a scientist with Aarhus University’s Arctic Research Center in Denmark, said in a news release. “With special ice corers we drilled holes in the ice so that we could measure the ice algae on the underside of the ice and collect samples.”

“Our measurements showed that the ice algae began to grow at a light intensity below 0.17 μmol photons m-2 s-1. This corresponds to less than 0.02% of the amount of light that reaches the surface of the snow on a sunny day,” says Kasper Hancke, currently working at the Norwegian Institute for Water Research (NIVA) in Oslo, who was responsible for the field work.

The general view has been that ice algae do not obtain sufficient light for growth when they are covered by a more than 30-50 cm deep cover of snow and ice. The new measurements completely change that view and

By Disha Padmanabha

show that ice algae may play an important role much earlier in the spring in the Arctic than hitherto assumed.

“Temperatures are rising in the Arctic.

When the snow on top of the ice gets warmer, the algae residing on the underside of the

ice receive more light,” Lund-Hansen said.

“This may significantly impact the growth of the algae and the extent of the ‘spring bloom.’ This new knowledge must be considered in the puzzle of how the Arctic will respond to a warmer world.”

Scientists Devise Interactive Microscope, Unveil Physical Principles of Cell Organization Cell membranes, in addition to their structural-mechanical functions, regulate diverse cellular functions, and play a significant role in several physiological and pathological processes.

The spatiotemporal organization of cells largely depends on physical processes such as diffusion or cytoplasmic flows, and strategies to perturb physical transport inside cells are not yet available.

Therefore, there is a need for a generic, accessible analytical tool that can combine full-lipidome quantification with simultaneous monitoring of the turnover, the flux, of individual lipids.

Enter focused-light-induced cytoplasmic streaming aka FLUCS. Developed by a collaborative team of scientists at the MaxPlanck Institute for Cell Biology and Genetics (MPI-CBG) and École polytechnique fédérale de Lausanne (EPFL), scientists of the Institute for Pancreatic Islet Research (IPI) of Helmholtz Zentrum München in Dresden.

FLUCS is local, directional, dynamic, probefree, physiological, and is even applicable through rigid egg shells or cell walls.

By making a microscope this interactive, the team has found a way to induce and control

motion within living cells and early embryos- they were able to actively guide central developmental processes in worm embryos.

Matthäus Mittasch, the leading author of the study says: “With FLUCS, microscopy of growing embryos becomes truly interactive“.

And indeed: with the help of realistic computer simulations the researchers even managed to reverse the head-to-tail body axis of worm embryos with FLUCS, leading to inverted development.

Lead investigator Moritz Kreysing, with a dual affiliation to the Center for Systems Biology Dresden, concludes: “The ability to actively move the interior of biological cells will help to understand how these cells change shape, how they move, divide, respond to external signals, and ultimately how entire organisms emerge guided by microscale motion.” On the medical side, FLUCS has the potential to improve our understanding of developmental defects, aid in-vitro fertilization, organism cloning, and the discovery of new drugs.

By Disha Padmanabha

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Vol. 02 NO 7

February 13th, 2018.

Reassessing Discarded Chemicals in Search of New Antibiotics

The growing prevalence of antibiotic resistance in pathogenic bacteria is severely eroding our ability to manage bacterial infection.

Central to an effective response to this problem will be the development of novel antibacterial drugs that display activity against bacteria resistant to existing antibiotics.

In one of such quests, University of Leeds scientists are taking time out to revisit long-forgotten, discarded chemical compounds to find if any of them possess any requisite properties of an antibacterial drug.

By initiating the discovery process with compounds about which something is already known, including the fact that they possess antibacterial activity, this approach offers a potential fast-track through the challenging early stages of discovery, write the scientists.

Dr Alex O’Neill, from the Antimicrobial Research Centre at the University, said: “We’re showing the value of reviewing compounds previously put on the back of the shelf. Amongst the 3,000 or so antibiotics discovered to date, only a handful have been brought into clinical use. There may be a wealth of compounds out there with untapped potential.

A family of compounds, known as the actinorhodins, was originally identified in the 1940s and was pronounced as having weak antibiotic properties, thereby not taken forward for development into a drug.

But Dr O’Neill now claims that this chemical was not fully appreciated at the time attributable to how scientists at the time did not fully differentiate the individual compounds within the family when they examined them, leading to a less than precise picture of their properties. This prompted his team to divide the family and select a specific compound (y-ACT) for further evaluation, using an array of 21st century approaches, to assess its potential and to understand how it works against bacteria.

Dr O’Neill and colleague Professor Chris Rayner believe the compound is worth serious consideration as the basis for a new drug to combat certain types of bacterial infections.

“At the moment, the bugs are outsmarting the scientists, and we can’t allow that to continue. By studying compounds which past research has shown already have antibacterial

Dr O’Neill added: “y-ACT exhibits potent antibacterial activity against two important representatives of the ESKAPE* class of pathogens, which are bacteria that have de-

properties, there is scope for a potential fasttrack through the challenging early stages of drug discovery. This approach could pave the way for life-saving new drugs.”

veloped the ability to ‘escape’ the action of existing drugs.”

“A major challenge in tackling the problem of antibiotic resistance is to discover new drugs – our study shows that potentially useful drug candidates can be ‘discovered’ from amongst the antibiotics we already know about. The weak activity previously published for the ACT family as a whole probably explains why this group was not further evaluated, and it is intriguing to think that other potentially useful antibiotic groups are languishing in obscurity in academic journals just needing expert review using modern processes and equipment.”

Supporting Dr O’Neill’s work, Dr Jonathan Pearce, Head of Infections and Immunity at the Medical Research Council, said: “There is an urgent need to discover new ways to fight AMR and the scientific community is leaving no stone unturned in its search for new antibiotics. This includes revisiting chemical compounds that were once shelved.

“Until recently, no new antibiotics had been discovered for 25 years. Dr O’Neill’s research is important: it’s providing another way of looking for potential antibiotics and could hold the key to uncovering options that were overlooked before but may be incredibly useful now.”

Another research in the university was led

by Dr Michael Webb, whose research focuses on a compound, called pentyl pantothenamide.

First introduced in the 1970s, it was found to be able to stop the growth of E.coli but not completely kill the bacteria, therefore was

deemed useless and was never taken into clinical use. Scientists who first analysed the compound did not understand how it was able to stop the growth, but Dr Webb and his team have proved it is driven by Vitamin B5, which is used to metabolise energy.

Bacteria have to make B5 and a key part of the machinery they use to do so is called the PanDZ complex. Pentyl pantothenamide targets the PanDZ complex, preventing E. coli from making Vitamin B5 and so starving it of the means to grow.

Dr Webb said: “The results of our latest studyopen up the possibility of designing new drugs that use the same means to attack E. coli, but in a more effective way.”

Dr O’Neill concludes: “Our findings underscore the importance of revisiting unexploited antibiotics as a potential source of new antibiotic drug candidates. We now believe a comprehensive re-evaluation of such compounds is worthwhile, potentially offering new ways to protect against infections.”

Each year, the Medical Research Council spends approximately £6.5 million on AMR-related research. With decades of work, MRC researchers have pioneered innovations in AMR research from mapping how infections spread, discovering new resistance mechanisms, and identifying new antibacterial compounds.

The next frontier is to usher in a new class of antibiotics to tame superbugs that have steadily built resistance to our current arsenal of therapies, including last-resort options to fight multi-drug resistant bacteria.

USFDA Issues Second Breakthrough Therapy Designation for GSK’s Meningitis Vaccine GlaxoSmithKline’s meningitis B vaccine Bexsero [Meningococcal group B Vaccine (rDNA, component, adsorbed)] has now received a Breakthrough tag for the prevention of invasive meningococcal disease in children ages 2 -10.

It is currently approved in the U.S. for people aged 10 – 25 for which it had received BTD for development in the prevention of IMD in 2015. Bexsero is the first vaccine in the world to receive the Breakthrough Therapy Designation (BTD) twice.

Invasive meningococcal B disease is the leading cause of life-threatening meningitis in the industrialized world. The disease can develop rapidly in healthy populations and can result in high morbidity and mortality.

The designation will expedite the development and review of drugs and vaccines that are intended to treat or prevent serious conditions and preliminary clinical evidence indicates that the drug or vaccine may demonstrate substantial improvement over available therapy on a clinically significant endpoint(s).

Drugs and vaccines that receive Breakthrough Therapy Designation are eligible for all features of the FDA’s Fast Track designation, including more frequent communication

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with the FDA about the drug’s development plan and eligibility for Accelerated Approval and Priority Review, if relevant criteria are met.

GSK Vaccines Chief Scientist Rino Rappuoli, who spent more than 20 years developing Bexsero, said: “This designation emphasises the importance of tackling big scientific challenges like meningitis B and breaking new ground in disease prevention through approaches like reverse vaccinology. GSK is committed to the pursuit of innovative vaccines that help protect against serious diseases with significant unmet need.”

“Thirty-five percent of all meningitis B cases in the U.S. occur in children under 11 years old. This designation is an important step forward in meningococcal prevention and extending the protection provided by this vaccine to a vulnerable age group in the U.S. We look forward to continuing to work with regulators and public health partners to make this vaccine available for them,” Thomas Breuer, GSK Vaccines chief medical officer said.

By Disha Padmanabha

Vol. 02 NO 7

February 13th, 2018.

Mirror-Image Molecules Clear the Deck for More Durable Drugs Proteins and peptides have a number of properties that make them highly effective as therapeutic agents. These include very precise specificity, high binding affinity, low toxicity, and low risk of drug–drug interactions. Their diversity also provides very broad coverage of disease targets.

Despite this, there are relatively few peptide drugs approved—around 60—compared with around 1,500 small molecule drugs- a major obstacle being- proteins and peptides are easily destroyed by proteases and, thus, typically have prohibitively short half-lives in human gut, plasma, and cells.

For reasons that are not fully understood and which go back to the origin of life, almost all amino acids in the natural world occur in one geometric form. Their atoms are arranged in such a way that makes the entire amino acid molecule appear left-handed, or “L” for short.

As a result, natural peptides are also left-handed. Because peptides produced by microbes, plants and animals can be harmful, the human body has evolved efficient ways to purge them. Wrap your head around this brilliant plan- if we could, let’s say, find a way to rotate/inverse these molecules, not only would they be right-handed amino acids, which are also known as “D” for dextrorotary, they would additionally bind to the same

receptors they did earlier while sliding unnoticed past the body’s defense mechanisms.

And this is exactly what a team the University of Toronto has been able to achieve using a purely computational approach.

The team, led by Philip Kim, a professor of computer science and molecular genetics in the Donnelly Centre for Cellular and Biomolecular Research, has developed a new technology for making mirror-image peptides, which bind and activate receptors on the surface of cells.

“Mirror image peptides are not recognized and degraded by enzymes in the stomach or bloodstream and therefore have a long-lasting effect,” says Kim. The other advantage, he said, is that mirror-image peptides also get overlooked by the immune system, which often mistakes natural peptides for foreign invaders and thus limits drug efficacy.

The study created mirror-image versions of existing drugs, which last longer in the body because they’re harder to digest. For patients, this would mean less frequent drug injections and more medicines could potentially be made available as pills.

The team was able to create these mirror molecules of two blockbuster drugs, a diabetes medication called glycogen-like-peptide

By Disha Padmanabha

1 (GLP1) and the thyroid drug parathyroid hormone (PTH). And the results when analysed showed how these rotated forms had longer effects on cells than the existing version of these drugs.

In the study, the team started with the largest public database which contains structural information for three million helical peptides. They then created an algorithm to flip these peptides into their D versions. Finally, the team looked in this new virtual library of mirror-image peptides for those that best matched GLP1 and PTH. They computationally generated a D version of every protein in the Protein Data Bank (PDB), creating the D-PDB, and extracted the D-proteins’ α-helices into more than 2.8 million separate database files. They then used known drug-target interactions to screen the helix database for D-helices with binding features positioned similarly to those of natural peptide and protein drugs. To create matches for drugs that bind in complex ways, the researchers made short D-strands by retroinversion and used the strands to link D-helices into three-part D-analogs.

Kim and coworkers used the method to create D-analogs for GLP-1, a diabetes and obesity treatment that targets the GLP-1 receptor,

and parathyroid hormone, an osteoporosis medication that hits the parathyroid receptor.

The D-analogs had about the same efficacy as their natural counterparts in cells, although the GLP-1 replacement required a higher dose. And the D-analogs withstood the cells’ proteases for longer than the natural peptides.

“We are now investigating whether the D-PTH could be orally delivered because it is avoiding breakdown in the stomach”, says Kim. “For frequently dosed medication, this is of great interest, as taking a pill is much easier than having an injection. This could lead to many more peptide drugs being taken as pills.”

Kim is currently working with the U of T patent office to protect his technology as he explores opportunities to partner with the pharmaceutical industry to commercialize the research. He is also developing mirror-image versions of peptides that work against the Dengue and Zika viruses in order to make them more durable in the bloodstream.

“We are testing our approach on as many interesting peptides as we can,” Kim said.

Asparagine Found in Food Linked to Metastasis of Breast Cancer Asparagine, a non-essential amino acid named after the humble asparagus, has now been discovered to drive the spread of breast cancer in a CRUK study investigating whether a change in diet could help patients with breast tumours.

The study “adds to a growing body of evidence that suggests diet can influence the course of the disease,” one of the study’s first authors, Simon Knott, associate director of the Center for Bioinformatics and Functional Genomics at Cedars-Sinai Medical Center in Los Angeles, said in a statement.

Most breast cancer patients do not die from their initial tumour, but from secondary malignant growths (metastases), where cancer cells are able to enter the blood and survive to invade new sites. Researchers have shown how limiting the body’s production of this amino acid – a building block for larger protein molecules in the body – or curbing it with drugs or dietary restrictions, significantly reduced the ability of breast cancers to spread.

The results have yet to be shown in human trial, but after tests on mice, academics said in future an asparagine restrictive diet and treatment could be given after surgery to remove the primary tumour.

“Our work has pinpointed one of the key mechanisms that promotes the ability of breast cancer cells to spread,” said Professor Greg Hannon, lead author of the study based

at the Cancer Research UK Cambridge Institute. “When the availability of asparagine was reduced, we saw little impact on the primary tumour in the breast, but tumour cells had reduced capacity for metastases in other parts of the body. In the future, restricting this amino acid through a controlled diet plan or by other means could be an additional part of treatment for some patients with breast and other cancers.”

The international team of cancer specialists from Britain, the US, and Canada studied mice with an aggressive form of breast cancer. The mice develop secondary tumours in a matter of weeks and tend to die from the disease within months.

In the course of their study, the team looked at the genes that were switched on inside each cell type, and found 192 that were more active in those with a greater ability to spread, called 4T1-T cells. When they then compared gene data with similar information from patient samples, the researchers found the same genes were more active in people with aggressive breast cancer. The researchers then used molecular tools to switch genes off individually in 4T1-T cells and watched how this affected their spread in Petri dishes and mice. In both tests, switching off a gene called asparagine synthetase stopped the cells from spreading. As the name suggests, this gene is responsible for making asparag-

By Disha Padmanabha

ine in the body.

Breast tumours in mice made of the 4T1-T cells were less able to spread when the mice were treated with a leukaemia drug that chops up asparagine. And the same result happened when the researchers simply fed the mice a low asparagine diet.

Professor Charles Swanton, Cancer Research UK’s chief clinician, said: “This is interesting research looking at how cutting off the supply of nutrients essential to cancer’s spread could help restrain tumours.

“The next step in the research would be to understand how this translates from the lab to patients and which patients are most likely to benefit from any potential treatment.”

“This is one case where we can show at a deep biochemical level how a change in diet can impact properties of cells that are relevant to the progression of lethal disease,” said Hannon. “But of course, until human

studies are done, this isn’t a DIY method to prevent cancer.”

Baroness Delyth Morgan, chief executive of Breast Cancer Now, said: “This early discovery could offer a long-awaited new way to help stop breast cancer spreading – but we first need to understand the true role of this nutrient in patients. With nearly 11,500 women still dying from breast cancer each year in the UK, we urgently need to stop the disease spreading around the body, where it becomes incurable.

“On current evidence, we don’t recommend patients totally exclude any specific food group from their diet without speaking to their doctors. We’d also encourage all patients to follow a healthy and varied diet – rich in fruit, vegetables and pulses, and limited in processed meat and high fat or sugar foods – to help give them the best chance of survival.”

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Vol. 02 NO 7

February 13th, 2018.

Altruistic Immunity Could be an Interesting Approach to Tackle Malaria Malaria kills roughly twice as many people worldwide as AIDS, drugs no longer work against some strains, and mosquitoes in diverse parts of the United States now carry the disease.

When the malaria-causing Plasmodium falciparum enters the body through female anopheles mosquito, a subsequent immune response can result in the production of anti-parasitic antibodies. These acquired antibodies could be ingested by other Plasmodium-harboring mosquitoes, inhibiting the survival and transmission of the parasite.

Attributable to this pathway, an estimated 1 in 25 malaria patients are able to stop the spread of malaria, conferring a type of altruistic immunity- says a recent study by scientists led by researcher Teun Bousema at Radboud university medical center. This is observed more prominently among missionaries who had been infected with malaria several times.

“This is the first time that we have been able to produce direct evidence that human antibodies against malaria parasite proteins are able to prevent the spread of malaria” said Bousema.

This study examined blood from more than 600 malaria patients, testing their ability to inhibit mosquito infection and their immune response to over 300 malaria proteins: An-

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tibodies targeting 45 of these proteins were linked with people’s ability to inhibit the spread of malaria, and people with these antibodies were ten times less infectious for mosquitoes.

The results mean better understanding of how people contribute to the spread of malaria. The team is now investigating roles of a number of proteins as to their potential in the transmission blocking malaria vaccine.

Bousema: “We have developed a malaria parasite that expresses a firefly gene, allowing us to see just by looking at the mosquito whether or not it has been infected.”

PhD student Will Stone who has studied people’s immune response to over 300 malaria proteins says, “We saw that our test subjects produced antibodies that are able to slow the spread of malaria in response to 45 of these proteins. People with these antibodies were ten times less likely to infect mosquitos.”

Bousema concludes, “This research enables us to better understand which patients prevent the spread of malaria. We are now looking at whether it is possible to develop a malaria vaccine using some of these proteins.

A vaccine that prevents the spread of malaria would help reduce the disease burden of malaria worldwide.”

By Disha Padmanabha