Seven Stories to Start Your Day


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Bitcoin’s Shifting Footprint

Posted: 29 Nov 2019 12:23 AM PST

Bitcoin’s Shifting Footprint

Clamours of circuits
compete to complete
composite puzzles
that compound
their complexity.
Assuring the security
of their concealed
networks as they
pan for digital gold;
virtual pickaxes
and crypto sluices
slice through
implicit permutations,
impervious to the
rust and dust of
distant placer mining.
Straining against the
intricacy of their
imagined interpretations,
giant fans wick
corporeal sweat
from digital brow;
caught in a goldrush
of simulated exchange.
Steaming from the excesses
of their exertions,
unseen miners shift
to cooler climes;
their footsteps
gently muffled
by the efficacy
of their implements.
Bitcoin – a form of cryptocurrency or digital currency.
This poem is inspired by recent research, which has estimated the past and future environmental impacts of Bitcoin mining, finding it to be lower than previously thought.
Bitcoin, often described as a cryptocurrency or a

Nearly 40% of Plant Species are Very Rare and Vulnerable to Climate Change

Posted: 28 Nov 2019 10:30 AM PST

Nearly 40% of Plant Species are Very Rare and Vulnerable to Climate Change

Almost 40% of global land plant species are categorized as very rare, and these species are most at risk for extinction as the climate continues to change, according to new research published today in Science Advances.

The findings are published in a special issue of Science Advances that coincides with the 2019 United Nations Climate Change Conference, also known as COP25, in Madrid. The COP25 is convening nations to act on climate change. The international meeting runs from Dec. 2 through Dec. 13.

“When talking about global biodiversity, we had a good approximation of the total number of land plant species, but we didn’t have a real handle on how many there really are,” says lead author Brian Enquist, of the University of Arizona.

Thirty-five researchers from institutions around the world, including University of Connecticut researcher Cory Merow, worked for 10 years to compile nearly 35 million observational records of the world’s land plants.

“We have complied the largest botanical database in the world to try to quantitatively assess the number of species impacted by climate change. There are papers saying the outlook is not good, but there was nothing yet quantifying how many plants would be impacted beyond ‘a lot’,” says Merow.

The researchers hope this information can help reduce loss of global biodiversity by informing strategic conservation action that includes consideration of the effects of climate change.

They found that there are about 435,000 unique land plant species on Earth.

“So that’s an important number to have, but it’s also just bookkeeping. What we really wanted to understand is the nature of that diversity and what will happen to this diversity in the future,” Enquist says. “Some species are found everywhere – they’re like the Starbucks of plant species. But others are very rare – think a small standalone café.”

The team revealed that 36.5% of all land plant species are “exceedingly rare,” meaning they have only been observed and recorded less than five times ever.

“According to ecological and evolutionary theory, we’d expect many species to be rare, but the actual observed number we found was actually pretty startling,” he says. “There are many more rare species than we expected.”

Moreover, the researchers found that rare species tend to cluster in a handful of hotspots, such as the Northern Andes in South America, Costa Rica, South Africa, Madagascar and Southeast Asia. These regions, they found, remained climatologically stable as the world emerged from the last ice age, allowing such rare species to persist.

But just because these species enjoyed a relatively stable climate in the past doesn’t mean they’ll enjoy a stable future. The research also revealed that these very rare-species hotspots are projected to experience a disproportionally high rate of future climatic changes and human disruption, Enquist says.

And it’s these rare species that science knows very little about.

By focusing on identifying rare species, “this work is better able to highlight the dual threats of climate change and human impact on the regions that harbor much of the world’s rare plant species and emphasizes the need for strategic conservation to protect these cradles of biodiversity,” says Patrick Roehrdanz, a co-author on the paper and managing scientist at Conservation International.

This work was done in collaboration with the SPARC project (Spatial Planning for Area Conservation in Response to Climate Change), which was funded by the Global Environment Facility and made possible by Conservation International and a National Science Foundation grant to the University of Arizona.

Proton radiotherapy better for pediatric brain cancer patients

Posted: 28 Nov 2019 10:28 AM PST

Proton radiotherapy better for pediatric brain cancer patients

Radiotherapy is essential for treating pediatric brain tumors, but the treatment comes with the risk of cognitive impairment. Researchers at Baylor College of Medicine, Texas Children’s Hospital and the Hospital for Sick Children (SickKids) in Toronto examined children treated with two different kinds of radiotherapy—proton radiotherapy and photon radiotherapy—and found those treated with proton radiotherapy had less intellectual decline. Their results are published today in the Journal of Clinical Oncology.

The study focused on patients with pediatric medulloblastoma. A group at Texas Children’s Cancer Center was treated with proton radiotherapy, and a group of patients at SickKids was treated with photon radiotherapy. The dose of radiation to healthy tissue is lower with proton radiotherapy than with photon radiotherapy.

Researchers examined changes in patients’ intelligence scores over time. The proton radiotherapy group had stable Global IQ and working memory scores while the photon radiotherapy group showed a decline in both domains. Proton radiotherapy patients also showed higher perceptual reasoning scores compared to photon radiotherapy patients. Patients in both treatment groups showed declines in processing speed over time. Researchers also noted that while proton radiotherapy scores were higher, newer photon radiotherapy techniques also yielded higher scores than older techniques.

“Our findings provide a message of hope. The outcomes for both groups are superior to outcomes reported for children treated several decades ago, thanks to refinement of radiotherapy techniques,” said Dr. Lisa Kahalley, co-principal investigator, first author of the study and associate professor of pediatrics – psychology at Baylor College of Medicine. “Still, our findings show a clear cognitive benefit with proton radiotherapy.”

Despite the promise of proton radiotherapy, the treatment is not widely available, according to Kahalley, director of psychology research at Texas Children’s Hospital and member of the Dan L Duncan Comprehensive Cancer Center at Baylor. Proton radiotherapy is more costly than photon radiotherapy and oftentimes is not covered by insurance.

“If studies continue to demonstrate that proton radiotherapy offers medical and quality of life benefits that are superior to photon radiotherapy, we will need to address barriers to access for pediatric brain tumor patients,” Kahalley said.

“While progress has been made in treating children with brain tumors, this often comes with a host of costs including chronic health conditions and learning challenges,” said Dr. Donald Mabbott, co-principal investigator and psychologist, senior scientist and head of the Neurosciences and Mental Health Program at SickKids. “We are working to find ways to mitigate these challenges for cancer survivors.”

Other contributors to this work include Drs. Rachel Peterson, M. Douglas Ris, Laura Janzen, M. Fatih Okcu, David R. Grosshans, Vijay Ramaswamy, Arnold C. Paulino, David Hodgson, Anita Mahajan, Derek S. Tsang, Normand Laperriere, William E. Whitehead, Robert C. Dauser, Michael D. Taylor, Heather M. Conklin, Murali Chintagumpala, and Eric Bouffet. The authors are affiliated with the following institutions: Baylor College of Medicine, the Hospital for Sick Children (SickKids), the University of Texas MD Anderson Cancer Center, the University of Toronto, Princess Margaret Cancer Centre, the Mayo Clinic and St. Jude’s Research Hospital.

This work was supported by the National Institutes of Health/National Cancer Institute (grants R01CA187202 to LSK and K07CA157923 to LSK) and the Canadian Institute of Health Research (MOP-123537 to DJM) and SickKids Foundation.

A New Theory for How Black Holes and Neutron Stars Shine Bright

Posted: 28 Nov 2019 10:27 AM PST

A New Theory for How Black Holes and Neutron Stars Shine Bright

For decades, scientists have speculated about the origin of the electromagnetic radiation emitted from celestial regions that host black holes and neutron stars—the most mysterious objects in the universe.

Astrophysicists believe that this high-energy radiation, which makes neutron stars and black holes shine bright, is generated by electrons that move at nearly the speed of light, but the process that accelerates these particles has remained a mystery.

Now, researchers at Columbia University have presented a new explanation for the physics underlying the acceleration of these energetic particles.

In a study published in the December issue of The Astrophysical Journal, astrophysicists Luca Comisso and Lorenzo Sironi employed massive super-computer simulations to calculate the mechanisms that accelerate these particles. They concluded that their energization is a result of the interaction between chaotic motion and reconnection of super-strong magnetic fields.

“Turbulence and magnetic reconnection—a process in which magnetic field lines tear and rapidly reconnect—conspire together to accelerate particles, boosting them to velocities that approach the speed of light,” said Comisso, a postdoctoral research scientist at Columbia and first author on the study.

“The region that hosts black holes and neutron stars is permeated by an extremely hot gas of charged particles, and the magnetic field lines dragged by the chaotic motions of the gas, drive vigorous magnetic reconnection,” he added. “It is thanks to the electric field induced by reconnection and turbulence that particles are accelerated to the most extreme energies, much higher than in the most powerful accelerators on Earth, like the Large Hadron Collider at CERN.”

When studying turbulent gas, scientists cannot predict chaotic motion precisely. Dealing with the mathematics of turbulence is difficult, and it constitutes one of the seven “Millennium Prize” mathematical problems. To tackle this challenge from an astrophysical point of view, Comisso and Sironi designed extensive super-computer simulations—among the world’s largest ever done in this research area—to solve the equations that describe the turbulence in a gas of charged particles.

“We used the most precise technique—the particle-in-cell method—for calculating the trajectories of hundreds of billions of charged particles that self-consistently dictate the electromagnetic fields. And it is this electromagnetic field that tells them how to move,” said Sironi, assistant professor of astronomy at Columbia and the study’s principal investigator.

Sironi said that the crucial point of the study was to identify role magnetic reconnection plays within the turbulent environment The simulations showed that reconnection is the key mechanism that selects the particles that will be subsequently accelerated by the turbulent magnetic fields. They s also revealed that particles gained most of their energy by bouncing randomly at an extremely high speed. When the magnetic field is strong, this acceleration mechanism is very rapid. But the strong fields also force the particles to travel in a curved path, and by doing so, they emit electromagnetic radiation.

“This is indeed the radiation emitted around black holes and neutron stars that make them shine, a phenomenon we can observe on Earth,” Sironi said.

The ultimate goal, the researchers said, is to get to know what is really going on in the extreme environment surrounding black holes and neutron stars, which could shed additional light on fundamental physics and improve our understanding of how our universe works.

They plan to connect their work even more firmly by comparing their predictions with the electromagnetic spectrum emitted from the Crab Nebula, the most intensely studied bright remnant of a supernova (a star that violently exploded in the year 1054).

“We figured out an important connection between turbulence and magnetic reconnection for accelerating particles, but there is still so much work to be done,” Comisso said. “Advances in this field of research are rarely the contribution of a handful of scientists, but they are the result of a large collaborative effort.”

Other researchers, such as the Plasma Astrophysics group at the University of Colorado Boulder, are making important contributions in this direction, Comisso said.

Researchers get ‘glimpse into a human mind’ as it makes choices in groups, social media

Posted: 28 Nov 2019 10:25 AM PST

Researchers get ‘glimpse into a human mind’ as it makes choices in groups, social media

A method with roots in AI uncovers how humans make choices in groups and social media

The choices we make in large group settings — such as in online forums and social media — might seem fairly automatic to us. But our decision-making process is more complicated than we know. So, researchers have been working to understand what’s behind that seemingly intuitive process.

Now, new University of Washington research has discovered that in large groups of essentially anonymous members, people make choices based on a model of the “mind of the group” and an evolving simulation of how a choice will affect that theorized mind.

Using a mathematical framework with roots in artificial intelligence and robotics, UW researchers were able to uncover the process for how a person makes choices in groups. And, they also found they were able to predict a person’s choice more often than more traditional descriptive methods. The results were published Wednesday, Nov. 27, in Science Advances.

“Our results are particularly interesting in light of the increasing role of social media in dictating how humans behave as members of particular groups,” said senior author Rajesh Rao, the CJ and Elizabeth Hwang professor in the UW’s Paul G. Allen School of Computer Science & Engineering and co-director of the Center for Neurotechnology.

“We can almost get a glimpse into a human mind and analyze its underlying computational mechanism for making collective decisions.”

“In online forums and social media groups, the combined actions of anonymous group members can influence your next action, and conversely, your own action can change the future behavior of the entire group,” Rao said.

The researchers wanted to find out what mechanisms are at play in settings like these.

In the paper, they explain that human behavior relies on predictions of future states of the environment — a best guess at what might happen — and the degree of uncertainty about that environment increases “drastically” in social settings. To predict what might happen when another human is involved, a person makes a model of the other’s mind, called a theory of mind, and then uses that model to simulate how one’s own actions will affect that other “mind.”

While this act functions well for one-on-one interactions, the ability to model individual minds in a large group is much harder. The new research suggests that humans create an average model of a “mind” representative of the group even when the identities of the others are not known.

To investigate the complexities that arise in group decision-making, the researchers focused on the “volunteer’s dilemma task,” wherein a few individuals endure some costs to benefit the whole group. Examples of the task include guarding duty, blood donation and stepping forward to stop an act of violence in a public place, they explain in the paper.

To mimic this situation and study both behavioral and brain responses, the researchers put subjects in an MRI, one by one, and had them play a game. In the game, called a public goods game, the subject’s contribution to a communal pot of money influences others and determines what everyone in the group gets back. A subject can decide to contribute a dollar or decide to “free-ride” — that is, not contribute to get the reward in the hopes that others will contribute to the pot.

If the total contributions exceed a predetermined amount, everyone gets two dollars back. The subjects played dozens of rounds with others they never met. Unbeknownst to the subject, the others were actually simulated by a computer mimicking previous human players.

“We can almost get a glimpse into a human mind and analyze its underlying computational mechanism for making collective decisions,” said lead author Koosha Khalvati, a doctoral student in the Allen School. “When interacting with a large number of people, we found that humans try to predict future group interactions based on a model of an average group member’s intention. Importantly, they also know that their own actions can influence the group. For example, they are aware that even though they are anonymous to others, their selfish behavior would decrease collaboration in the group in future interactions and possibly bring undesired outcomes.”

In their study, the researchers were able to assign mathematical variables to these actions and create their own computer models for predicting what decisions the person might make during play. They found that their model predicts human behavior significantly better than reinforcement learning models — that is, when a player learns to contribute based on how the previous round did or didn’t pay out regardless of other players — and more traditional descriptive approaches.

Given that the model provides a quantitative explanation for human behavior, Rao wondered if it may be useful when building machines that interact with humans.

“In scenarios where a machine or software is interacting with large groups of people, our results may hold some lessons for AI,” he said. “A machine that simulates the ‘mind of a group’ and simulates how its actions affect the group may lead to a more human-friendly AI whose behavior is better aligned with the values of humans.”

Co-authors include Seongmin A. Park, Center for Mind and Brain at UC Davis and Institut des Sciences Cognitives Marc Jeannerod, France; Saghar Mirbagheri, Department of Psychology, New York University; Remi Philippe, Mariateresa Sestito and Jean-Claude Dreher at the Institut des Sciences Cognitives Marc Jeannerod. This research was funded by the National Institute of Mental Health, National Science Foundation, and the Templeton World Charity Foundation.

Will a Treatment for Alzheimer’s Ever Be Found?

Posted: 28 Nov 2019 10:23 AM PST

Will a Treatment for Alzheimer’s Ever Be Found?

In the 90s, Alzheimer’s researchers were full of optimism. New genetic studies all pointed to one culprit—hard clumps of protein, called amyloid, that litter the brains of people with the disease.

With the emergence of the first tangible target, pharmaceutical companies jumped in to develop drugs to clear amyloid from the brain. In animals, the drugs appeared to improve memory. But the results of human clinical trials that followed were disheartening: One after one, these drugs—all designed to target amyloid—have failed to slow the disease.

The onslaught of news about these failures has left the public wondering whether amyloid has anything to do with Alzheimer’s—and whether a new approach is needed.

The field has already begun to redirect its focus, says Scott Small, MD, director of Columbia’s Alzheimer’s Disease Research Center and the Boris and Rose Katz Professor of Neurology at Columbia University Vagelos College of Physicians and Surgeons.

“There’s now reason to be cautiously optimismistic,” he says, “because we have uncovered new pathways that lead to the disease, and we know that they truly make a difference.”

The CUIMC Newsroom spoke with Small about the current state of research into Alzheimer’s treatments and prevention.

Why have all drugs tested in the past several years failed?In retrospect, the idea that reducing amyloid in the brain—which all the failed drugs do—is based on an incomplete picture of the disease. To treat a disease, we need to treat what’s broken. But it’s very difficult to find what’s broken in these slowly progressive brain disorders. One way to find what’s broken is through genetics, but the first wave of genetic studies in the 80s and 90s only had the technical capabilities to investigate Alzheimer’s cases that run in families, those caused by a single gene. The results of these studies all seemed to converge on one biological process: amyloid. But these single-gene forms of Alzheimer’s are rare—and account for maybe 2% to 3% of cases. Most cases of Alzheimer’s are caused by a complex interplay of many genes and the environment. The field made the assumption that amyloid is the primary culprit in all forms of Alzheimer’s. It made perfect sense, because we see amyloid in all patients with Alzheimer’s, whether their disease is caused by a single gene or not. The amyloid finding was extremely exciting, and there was a sense that we were on the cusp of curing this devastating, horrible disease.

Does that mean the amyloid hypothesis is completely wrong?The amyloid hypothesis is that amyloid is the trigger of everything in Alzheimer’s. That seems now to be wrong. New studies from the past decade tell us that amyloid is part of the story of Alzheimer’s disease, but it’s the smoke, not the fire. We’ve learned that the single-gene and more common, complex forms of Alzheimer’s are not identical, though they do overlap. There’s been a lot of backlash against the amyloid hypothesis lately, but in the 90s, it was the right idea. The pharmaceutical industry was right to jump on the amyloid bandwagon. And they’re now right to give it up, I think.

If drugs against amyloid aren’t the answer, what is?
Back in the 80s and 90s, genetic tools weren’t quite developed enough to address the real question we had: What genes are involved in most cases of Alzheimer’s disease? Techniques have advanced and we can now answer this question. New studies—many led by Richard Mayeux, MD [chair of neurology at Columbia]—have been pointing to other processes in the brain. We also have better biological tools that can reveal the basic problem inside neurons. Based on this research, the new consensus in the field is that there are two other pathways that cause the disease. One involves “protein trafficking,” which is how proteins are shipped to different sites within a single cell. The health of neurons, more so than other cells, depends on protein trafficking in and out of one particular site: the endosome.

In Alzheimer’s, the flow of proteins out of the endosome is blocked, and we think that causes the other problems we see in the disease: the amyloid, the tau tangles also common in the Alzheimer’s brain, and the neurodegeneration. Essentially it’s a plumbing problem. Our research here at Columbia provided some early evidence for an endosomal trafficking problem in Alzheimer’s. And genetic studies—including those led by Dr. Mayeux—have now found that some endosomal genes are linked to Alzheimer’s, which provides more support. The second pathway involves microglia, which are cells in the brain that help maintain the health of neurons and help keep the spaces between neurons clear of pathogens, protein aggregates, and other cellular debris. Recently discovered genes—by Phil De Jager, MD, PhD, in our center and others—point us to these cells. But what exactly is wrong with the microglia is still hotly debated. We don’t know if they’re working too well or not well enough, but we do know they’re not working properly.

What makes you so optimistic that we will find a treatment that slows or stops the disease?We now, I believe, have evidence to help us understand why the first hypothesis was wrong. Scientifically, we have very good justification to argue why our new hypotheses are correct. We’re now seeing that companies are getting back into drug development because these new pathways are so compelling. In the coming years, our biggest focus at the Alzheimer’s Disease Research Center at Columbia will be accelerating drug discovery. One of the most important goals is to develop new biomarkers—for the new Alzheimer’s pathways. These biomarkers are crucial for developing the new generation of therapeutic agents. These biomarkers will be useful for enrolling patients into new anticipated clinical trials, following the logic of precision medicine. Also, just as biomarkers of amyloid were important for testing assumptions about the primacy of amyloid in the disease, these biomarkers are important for testing—or potentially refuting—the new pathways.

We’re also testing gene therapies and other ways to restore endosomal trafficking to see if that prevents neurodegeneration in animal models. Frank Provenzano and Adam Brickman are developing new techniques, with imaging and cognitive testing, to detect patients with endosomal defects as early as possible. We think the sooner we can treat people, the better. Sabrina Simoes, one of our newest members, is developing new ways to use spinal fluid and blood to remotely monitor endosomal trafficking. That’s a critical step in measuring a drug’s effectiveness when the drug moves to clinical testing. In science, though, you never can be sure. The only way we’ll know we’re right is by developing drugs and testing the hypothesis in clinical trials in patients, like we did with the amyloid hypothesis.

Is there anything people can do now to prevent the disease, or at least delay it for several years?In my practice, I encounter many people who have family members with Alzheimer’s and they’re worried about their genes. But in most cases, just because your mother has it doesn’t mean you’re going to get it.
In a complex disease, each gene and each environmental factor is like putting a pebble on a scale. None of them by themselves can prevent or cause Alzheimer’s. So if your parent has Alzheimer’s, that puts one pebble on the scale. But if you went to college, if you exercise, those are pebbles on the other side of the scale. Many of the things that we thought historically cause Alzheimer’s have been debunked—for example, the idea that it was caused by various heavy metals. But we do know that maintaining cardiac health is good: Exercise is good; smoking is bad; developing diabetes or obesity increases the risk. These recommendations, as most people know, are true for any disease. People often ask me this question, hoping I know something that no one else does. I don’t have any other answers at the moment, but everyone in the field is doing their best to find new ways to forestall this disease.

New Images Show How Malaria Parasites Evade Frontline Drugs

Posted: 28 Nov 2019 10:16 AM PST

New Images Show How Malaria Parasites Evade Frontline Drugs

Malaria parasites are rapidly developing resistance to front-line drugs across the world, threatening to undo years of progress in reducing deaths from the disease.

New pictures of a key mediator of drug resistance for the parasite—captured with single-particle cryo-electron microscopy by a team of scientists at Columbia University Vagelos College of Physicians and Surgeon—are now giving researchers clues about how to combat resistance.

The study, published Nov. 27 in the journal Nature, shows that drug resistance in the malaria parasite is linked to a specific protein and illustrates how mutations in the protein allow the parasite to expel the drug. The new discovery may help scientists find ways to restore the drugs’ potency and will allow health officials in other parts of the world to monitor for emerging resistance.

“The fight against malaria is stalling,” says David Fidock, PhD, the C.S. Hamish Young Professor of Microbiology & Immunology, who led the effort with Filippo Mancia, PhD, associate professor of physiology & cellular biophysics, and Matthias Quick, PhD, associate professor of neurobiology (in psychiatry). “Uncovering the molecular underpinnings of resistance is essential to prolonging the effectiveness of current drugs and developing new ones.”

Here are six take-aways from the paper:


Image shows how a frontline malaria drug is losing effectiveness

For nearly 15 years, the drug piperaquine, or PPQ, has been used all over the world to treat people infected with the malaria parasite. The drug, in combination with artemisinin, has helped slash the number of deaths caused by the disease from over 1 million in 2004 to an estimated 435,000 in 2017. The disease strikes more than 220 million individuals each year across the globe, including Africa, Southeast Asia, the Western Pacific, and South America. Almost all fatal infections occur in young African children.

New Images Show How Malaria Parasites Evade Frontline Drugs
Malaria parasites are becoming resistant to frontline antimalarials due to changes in PfCRT proteins (shown above) that line the parasite’s digestive vacuole. Image: Filippo Mancia / Columbia University.

But resistance to PPQ has exploded recently in Southeast Asia. “In some areas, the frontline combination of PPQ with dihydroartemisinin (which also has succumbed to resistance) is now effective in only 13% of patients, making this an essentially useless drug in those regions,” Fidock says.

This study in Nature shows that the source of PPQ resistance is a protein in the malaria parasite called PfCRT.

PfCRT is the same protein that had mediated resistance to the former first-line drug, chloroquine (CQ).

That coincidence may create new opportunities for treatment, since the new mutations, which are spreading like wildfire across Southeast Asia, often cause parasites to lose their chloroquine resistance. Combining antimalarials could treat drug-resistant and sensitive parasite infections.


Resistant parasites spit out drug

The antimalarial drugs CQ and PPQ work by entering the parasite’s digestive vacuole (a compartment resembling a stomach) and altering it so that the parasite poisons itself on its own toxic waste product, formed from digested hemoglobin.

PfCRT is located in the vacuole’s membrane, and the location of mutations—inside a central cavity of PfCRT—reaffirm the observation that resistant parasites use variant forms of this protein to expel the drug out of the vacuole.

“It looked like the protein spits the drug out of the parasite’s stomach,” says Mancia, “keeping it away from its target.”

Though the images were evocative, biochemical testing of the PfCRT’s transport properties was needed to confirm the researchers’ suspicions. By making other mutations in the protein and testing their drug binding and transport abilities, Quick found that only mutations in the protein’s central cavity give PfCRT the ability to expel the drug from the vacuole.


Scientists can now predict how resistance will arise in other parts of the world

With images of PfCRT in hand—combined with the location and properties of resistance-causing mutations—it is now possible to predict how PPQ resistance will arise in other parts of the world.

“The PfCRT gene is difficult to sequence, so it’s been hard for people to monitor,” Fidock says. “There are hundreds of locations in PfCRT that could be mutated, but now we can say just look at these handful in the central cavity with specific structural and conservation properties. They are the only ones that can drive resistance.”

Based on what’s now known, Fidock says South America could be the next place where PPQ fails. Results presented in this report already show one such mutation in PfCRT that, should it appear and spread in South America, would lead to high-grade resistance and augment the risk of treatment failures.

“Getting ahead of the ‘drug resistance curve’ by knowing where to look in the parasite’s genome will be critical to identifying where resistance arises and having time to move to alternative treatment strategies,” Fidock says.

Fidock and Quick are now testing whether PfCRT mutations identified in Asian malaria parasites will also cause PPQ resistance in African parasites, which are genetically distinct and which cause the vast majority of the global malaria burden. Those experiments may also help officials in Africa who are planning to deploy PPQ more broadly in areas of high transmission and who need to know how to monitor for signs of emerging resistance.


Study suggests ways to restore the potency of antimalarial drugs

Parasites have enlisted PfCRT in their fight against antimalarials, but researchers could also co-opt PfCRT to restore the potency of PPQ and similar drugs.

“We may be able to restore the efficacy of these drugs with an agent that entirely blocks the capacity of this protein to transport anything,” says Fidock, who is working with colleagues to develop parasite-based screens to identify potential candidate compounds.

“That would make PPQ and the earlier first-line drug chloroquine fully functional.”


Limits of Nobel technique pushed to acquire images

New Images Show How Malaria Parasites Evade Frontline Drugs
Thousands of electron microscope images of the malaria protein PfCRT were used to create a 3D model of the protein. Images: Filippo Mancia / Columbia University Vagelos College of Physicians and Surgeons.

The malarial protein (49 kDa) is one of the smallest molecules of its type to be visualized with cryo-electron microscopy (cryo-EM), which is typically limited to proteins of at least 100 kDa in size. PfCRT needed to be bulked up with an antibody fragment before it could be seen under the electron microscope. This fragment, which was found to bind to the PfCRT central cavity, allowed the researchers to see PfCRT from multiple angles, which was necessary to generate a 3D model.

PfCRT’s small stature wasn’t the only problem in obtaining clear images by cryo-EM. PfCRT is normally surrounded by lipids inserted in a biological membrane, so the protein required the use of detergents to be extracted and purified, creating an often destabilizing and non-natural environment to image the protein. The researchers sidestepped this problem by creating nanosized lipid discs to hold PfCRT in a nearly natural state without obscuring important details from view.


The study took efforts of three labs at Columbia University

The discoveries in the new study were made possible only with the close collaboration of three laboratories at Columbia University’s Vagelos College of Physicians and Surgeons.

David Fidock’s malaria research lab had uncovered the first evidence for PfCRT’s role in resistance and mutations present in the field. This work began with a seminal report in 2000 in Molecular Cell where he and others first reported PfCRT as the cause of chloroquine resistance in the human malaria parasite Plasmodium falciparum. Drs. Fidock and Mancia started collaborating in 2013 on this project, both interested in shedding a mechanistic light on the process of resistance, but the yields of purified protein were too low for other structural biology techniques, and cryo-EM was not yet within reach to study such a small protein.

In Filippo Mancia’s structural biology lab, Jonathan Kim devised methods to obtain enough protein for the experiments and to prepare pure and homogeneous proteins suitable for imaging, a process that took several years of testing and optimization. Yong Zi Tan contributed his expertise in cryo-EM to solve PfCRT’s structure, utilizing know-how and facilities at the Simons Electron Microscopy Center at the New York Structural Biology Center.

The final confirmation of PfCRT’s role in resistance came from the lab of Matthias Quick, an expert in membrane transport processes, which measured how mutations in PfCRT affected drug binding and transport.

“This study is a first step, but it shows that we have the basic science tools at Columbia to answer important questions about malaria parasites and the spread of drug resistance in the field,” Mancia says.

“Our labs are thousands of miles from the middle of Cambodia where these changes are happening,” adds Fidock, “but our work joins the two directly together. We can now rapidly translate clinical findings about emerging resistance into detailed structural and functional understandings of how resistance works and feed that back to field workers to adjust their treatment strategies. Ultimately, these approaches are vital to ensure that we don’t let resistance gain the upper hand and that we continue to drive down the burden of this devastating infectious disease.”


More Information

The research was published in Nature in a paper titled, “Structure and Drug Resistance of the Plasmodium falciparum Transporter PfCRT.”

Additional authors: Kathryn J. Wicht (Columbia University Irving Medical Center), Satchal K. Erramilli (University of Chicago), Satish K. Dhingra (CUIMC), John Okombo (CUIMC), Jeremie Vendome (Schrödinger, Inc., New York), Laura M. Hagenah (CUIMC), Sabrina I. Giacometti (CUIMC), Audrey L. Warren (CUIMC), Kamil Nosol (University of Chicago), Paul D. Roepe (Georgetown University), Clinton S. Potter (CUIMC and Simons Electron Microscopy Center), Bridget Carragher (CUIMC and Simons Electron Microscopy Center), and Anthony A. Kossiakoff (University of Chicago).

The antibody fragments that were instrumental to determining the structure of PfCRT were produced in the lab of Anthony Kossiakoff, PhD, at the University of Chicago.

At the time the work was performed, Yong Zi Tan, PhD, was a graduate student in the labs of Filippo Mancia in the Department of Physiology and Cellular Biophysics at Columbia University Vagelos College of Physicians and Surgeons and of Bridget Carragher and Clint Potter in the Simons Electron Microscopy Center at the New York Structural Biology Center.

David Fidock, PhD, is also professor of medical sciences in the Department of Medicine at Columbia University Vagelos College of Physicians and Surgeons.

Matthias Quick, PhD, is also a member of the Center for Molecular Recognition at Columbia University Vagelos College of Physicians and Surgeons.

The work was supported by the NIH (R01AI147628 to Filippo Mancia, David Fidock, and Matthias Quick; R35GM132120R01GM111980R37AI50234R01AI124678R01GM119396R01AI056312R01AI111962R01GM117372T32HL120826; the Agency for Science, Technology and Research Singapore; the Simons Foundation (SF349247); and NYSTAR. Some of the work was performed at the Center for Membrane Protein Production and Analysis (COMPPÅ) (supported by NIH grant P41GM116799 to Wayne Hendrickson) and at the National Resource for Automated Molecular Microscopy at the Simons Electron Microscopy Center (supported by P41GM103310), both located at the New York Structural Biology Center.

The authors declare no competing interests.


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