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  • richardmitnick 3:50 pm on September 22, 2014 Permalink | Reply
    Tags: , , Biology, ,   

    From Caltech: “Variability Keeps The Body In Balance” 

    Caltech Logo
    Caltech

    09/22/2014
    Jessica Stoller-Conrad

    Although the heart beats out a very familiar “lub-dub” pattern that speeds up or slows down as our activity increases or decreases, the pattern itself isn’t as regular as you might think. In fact, the amount of time between heartbeats can vary even at a “constant” heart rate—and that variability, doctors have found, is a good thing.

    runner

    Reduced heart rate variability (HRV) has been found to be predictive of a number of illnesses, such as congestive heart failure and inflammation. For athletes, a drop in HRV has also been linked to fatigue and overtraining. However, the underlying physiological mechanisms that control HRV—and exactly why this variation is important for good health—are still a bit of a mystery.

    By combining heart rate data from real athletes with a branch of mathematics called control theory, a collaborative team of physicians and Caltech researchers from the Division of Engineering and Applied Sciences have now devised a way to better understand the relationship between HRV and health—a step that could soon inform better monitoring technologies for athletes and medical professionals.

    The work was published in the August 19 print issue of the Proceedings of the National Academy of Sciences.

    To run smoothly, complex systems, such as computer networks, cars, and even the human body, rely upon give-and-take connections and relationships among a large number of variables; if one variable must remain stable to maintain a healthy system, another variable must be able to flex to maintain that stability. Because it would be too difficult to map each individual variable, the mathematics and software tools used in control theory allow engineers to summarize the ups and downs in a system and pinpoint the source of a possible problem.

    Researchers who study control theory are increasingly discovering that these concepts can also be extremely useful in studies of the human body. In order for a body to work optimally, it must operate in an environment of stability called homeostasis. When the body experiences stress—for example, from exercise or extreme temperatures—it can maintain a stable blood pressure and constant body temperature in part by dialing the heart rate up or down. And HRV plays an important role in maintaining this balance, says study author John Doyle, the Jean-Lou Chameau Professor of Control and Dynamical Systems, Electrical Engineering, and Bioengineering.

    “A familiar related problem is in driving,” Doyle says. “To get to a destination despite varying weather and traffic conditions, any driver—even a robotic one—will change factors such as acceleration, braking, steering, and wipers. If these factors suddenly became frozen and unchangeable while the car was still moving, it would be a nearly certain predictor that a crash was imminent. Similarly, loss of heart rate variability predicts some kind of malfunction or ‘crash,’ often before there are any other indications,” he says.

    To study how HRV helps maintain this version of “cruise control” in the human body, Doyle and his colleagues measured the heart rate, respiration rate, oxygen consumption, and carbon dioxide generation of five healthy young athletes as they completed experimental exercise routines on stationary bicycles.

    By combining the data from these experiments with standard models of the physiological control mechanisms in the human body, the researchers were able to determine the essential tradeoffs that are necessary for athletes to produce enough power to maintain an exercise workload while also maintaining the internal homeostasis of their vital signs.

    Because monitors in hospitals can already provide HRV levels and dozens of other signals and readings, the integration of such mathematical analyses of control theory into HRV monitors could, in the future, provide a way to link a drop in HRV to a more specific and treatable diagnosis. In fact, one of Doyle’s students has used an HRV application of control theory to better interpret traditional EKG signals.

    Control theory could also be incorporated into the HRV monitors used by athletes to prevent fatigue and injury from overtraining, he says.

    “Physicians who work in very data-intensive settings like the operating room or ICU are in urgent need of ways to rapidly and acutely interpret the data deluge,” says Marie Csete, MD (PhD, ’00), chief scientific officer at the Huntington Medical Research Institutes and a coauthor on the paper. “We hope this work is a first step in a larger research program that helps physicians make better use of data to care for patients.”

    “For example, the heart, lungs, and circulation must deliver sufficient oxygenated blood to the muscles and other organs while not raising blood pressure so much as to damage the brain,” Doyle says. “This is done in concert with control of blood vessel dilation in the muscles and brain, and control of breathing. As the physical demands of the exercise change, the muscles must produce fluctuating power outputs, and the heart, blood vessels, and lungs must then respond to keep blood pressure and oxygenation within narrow ranges.”

    Once these trade-offs were defined, the researchers then used control theory to analyze the exercise data and found that a healthy heart must maintain certain patterns of variability during exercise to keep this complicated system in balance. Loss of this variability is a precursor of fatigue, the stress induced by exercise. Today, some HRV monitors in the clinic can let a doctor know when variability is high or low, but they provide little in the way of an actionable diagnosis.

    Because monitors in hospitals can already provide HRV levels and dozens of other signals and readings, the integration of such mathematical analyses of control theory into HRV monitors could, in the future, provide a way to link a drop in HRV to a more specific and treatable diagnosis. In fact, one of Doyle’s students has used an HRV application of control theory to better interpret traditional EKG signals.

    See the full article here.

    The California Institute of Technology (commonly referred to as Caltech) is a private research university located in Pasadena, California, United States. Caltech has six academic divisions with strong emphases on science and engineering. Its 124-acre (50 ha) primary campus is located approximately 11 mi (18 km) northeast of downtown Los Angeles. “The mission of the California Institute of Technology is to expand human knowledge and benefit society through research integrated with education. We investigate the most challenging, fundamental problems in science and technology in a singularly collegial, interdisciplinary atmosphere, while educating outstanding students to become creative members of society.”
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  • richardmitnick 9:39 am on September 17, 2014 Permalink | Reply
    Tags: , Biology, , Stem Cell Research   

    From New Scientist: “Stem cells used in landmark therapy for failing sight” 

    NewScientist

    New Scientist

    17 September 2014
    Andy Coghlan

    A woman in Japan has received the first medical treatment based on induced pluripotent stem cells, eight years after they were discovered.

    The iPS cells were made by reprogramming skin cells from the woman’s arm, then transformed into specialised eye cells to treat age-related macular degeneration (AMD) ´ a condition that affects millions of elderly people worldwide, and often results in blindness. Last week, the woman, who is in her 70s, had a patch of the cells measuring 1.3 by 3 millimetres grafted into her eye in a two-hour operation.

    eye
    Grafts derived from stem cells could keep the retina in good working order (Image: Science Source/Science Photo Library)

    She is the first of six people lined up for the landmark treatment, developed by Masayo Takahashi and her colleagues at the RIKEN Center for Developmental Biology in Kobe, Japan. In a pilot study to test the safety of putting iPS-derived cells into humans, the six are all receiving a graft of new retinal pigment epithelial (RPE) cells, which serve to maintain the eye’s light-sensing cells.

    No embryos needed

    Since iPS cells can be made from adult tissue samples, the technique does not require the destruction of embryos, unlike stem-cell-based AMD treatments that are also being worked on – one such treatment is being trialled in the US and UK.

    “It’s an exciting development, and we await the outcome over the next year to see how well these cells integrate, and if there are any potential adverse reactions,” says Mike Cheetham of the Institute of Ophthalmology at University College London, one site which is also researching a human embryonic stem-cell treatment for AMD. “If it goes well, it could be the start of a new era in personalised medicine,” he says.

    Shinya Yamanaka and his colleagues at Kyoto University in Japan discovered iPS cells in 2006. In 2012, Yamanaka was awarded the Nobel prize for the work.

    See the full article here.

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  • richardmitnick 2:12 pm on September 15, 2014 Permalink | Reply
    Tags: , Biology, Harvard University,   

    From NOVA: “‘Biospleen Device’ Uses Magnetic Nanoparticles to Filter Pathogens from Blood” 

    PBS NOVA

    NOVA

    Mon, 15 Sep 2014
    Tim De Chant

    When a patient succumbs to an infection, it’s not the mere presence of the pathogen that kills them, but rather the sheer quantity of it. With many deadly diseases, the immune system simply can’t keep up. So bioengineers figured that outsourcing some of those duties could help keep patients alive.

    A team of bioengineers led by Donald Ingber at Harvard’s Wyss Institute devised a device to filter pathogens from a patient’s blood. Inspired by the spleen, an organ which filters antibody-coated pathogens from the bloodstream, the “biospleen” works by first injecting specially treated, magnetic nanoparticles into the blood flowing through it. The nanoparticles have a protein attached to their surfaces which adheres to bacteria, viruses, and fungi; the protein-coated nanoparticles work like antibodies, which glom onto foreign objects. The biospleen then uses a magnet to pull out the nanoparticles and the pathogens they’re attached to.

    bio
    The filtering section of the biospleen

    The biospleen is similar in concept to dialysis, which mimics the function of the kidneys, but works on pathogens instead of typical bodily waste.

    Sara Reardon, reporting for Nature News, has more details:

    To test the device, Ingber and his team infected rats with either E. coli or Staphylococcus aureus and filtered blood from some of the animals through the biospleen. Five hours after infection, 89% of the rats whose blood had been filtered were still alive, compared with only 14% of those that were infected but not treated. The researchers found that the device had removed more than 90% of the bacteria from the rats’ blood. The rats whose blood had been filtered also had less inflammation in their lungs and other organs, suggesting they would be less prone to sepsis.

    Ingber and his team also tested the device using human volumes of blood, and they found that it took about five hours to filter most pathogens from five liters of blood.

    If the device makes it into trials, which could happen in just a few years, it could give doctors the upper hand in a number of intractable infections, including HIV and Ebola. The biospleen could reduce the pathogen load in a patient’s blood, leaving the drugs that normally treat the infection to clear the virus or bacteria from the patient’s organs. In acute infections, like Ebola, it would also buy doctors valuable time in their efforts to eliminate the virus before the patient succumbs.

    See the full article here.

    NOVA is the highest rated science series on television and the most watched documentary series on public television. It is also one of television’s most acclaimed series, having won every major television award, most of them many times over.

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  • richardmitnick 8:15 pm on September 14, 2014 Permalink | Reply
    Tags: , Biology,   

    From Caltech: “Slimy Fish and the Origins of Brain Development” 

    Caltech Logo
    Caltech

    09/14/2014
    Jessica Stoller-Conrad

    Lamprey—slimy, eel-like parasitic fish with tooth-riddled, jawless sucking mouths—are rather disgusting to look at, but thanks to their important position on the vertebrate family tree, they can offer important insights about the evolutionary history of our own brain development, a recent study suggests.

    eel
    A sea lamprey held by postdoctoral scholar Stephen Green in the Caltech Zebrafish/Xenopus/Lamprey Facility. Credit: Lance Hayashida/Caltech Marketing and Communications

    The work appears in a paper in the September 14 advance online issue of the journal Nature.

    “Lamprey are one of the most primitive vertebrates alive on Earth today, and by closely studying their genes and developmental characteristics, researchers can learn more about the evolutionary origins of modern vertebrates—like jawed fishes, frogs, and even humans,” says paper coauthor Marianne Bronner, the Albert Billings Ruddock Professor of Biology and director of Caltech’s unique Zebrafish/Xenopus/Lamprey facility, where the study was done.

    mb
    Marianne Bronner, the Albert Billings Ruddock Professor of Biology, with the tanks where the sea lamprey are kept during their time at Caltech.
    Credit: Lance Hayashida/Caltech Marketing and Communications

    The facility is one of the few places in the world where lampreys can be studied in captivity. Although the parasitic lamprey are an invasive pest in the Great Lakes, they are difficult to study under controlled conditions; their lifecycle takes up to 10 years and they only spawn for a few short weeks in the summer before they die.

    Each summer, Bronner and her colleagues receive shipments of wild lamprey from Michigan just before the prime of breeding season. When the lamprey arrive, they are placed in tanks where the temperature of the water is adjusted to extend the breeding season from around three weeks to up to two months. In those extra weeks, the lamprey produce tens of thousands of additional eggs and sperm, which, via in vitro fertilization, generate tens of thousands of additional embryos for study. During this time, scientists from all over the world come to Caltech to perform experiments with the developing lamprey embryos.

    tank
    Lamprey embryos are sorted for observation at a microscope in the Caltech Zebrafish/Xenopus/Lamprey facility.
    Credit: Lance Hayashida/Caltech Marketing and Communications

    In the current study, Bronner and her collaborators—who traveled to Caltech from Stower’s Institute for Medical Research in Kansas City, Missouri—studied the origins of the vertebrate hindbrain.

    The hindbrain is a part of the central nervous system common to chordates—or organisms that have a nerve cord like our spinal cord. During the development of vertebrates—a subtype of chordates that have backbones—the hindbrain is compartmentalized into eight segments, each of which becomes uniquely patterned to establish networks of neuronal circuits. These segments eventually give rise to adult brain regions like the cerebellum, which is important for motor control, and the medulla oblongata, which is necessary for breathing and other involuntary functions.

    br
    A lamprey embryo expressing the Hox gene Hoxb3 (green). In the study, Bronner and her colleagues found that Hox genes are important for hindbrain segmentation during lamprey development.
    Credit: Hugo Parker

    However, this segmentation is not present in so-called “invertebrate chordates”—a grouping of chordates that lack a backbone, such as sea squirts and lancelets.

    “The interesting thing about lampreys is that they occupy an intermediate evolutionary position between the invertebrate chordates and the jawed vertebrates,” says Hugo Parker, a postdoc at Stower’s Institute and first author on the study. “By investigating aspects of lamprey embryology, we can get a picture of how vertebrate traits might have evolved.”

    hp
    Hugo Parker, a postdoctoral scholar from the Stowers Institute for Medical Research, works with lamprey embryos at a microscope in the Caltech Zebrafish/Xenopus/Lamprey facility.
    Credit: Lance Hayashida/Caltech Marketing and Communications

    In the vertebrates, segmental patterning genes called Hox genes help to determine the animal’s head-to-tail body plan—and those same Hox genes also control the segmentation of the hindbrain. Although invertebrate chordates also have Hox genes, these animals don’t have segmented hindbrains. Because lampreys are centered between these two types of organisms on the evolutionary tree, the researchers wanted to know whether or not Hox genes are involved in patterning of the lamprey hindbrain.

    To their surprise, the researchers discovered that the lamprey hindbrain was not only segmented during development but the process also involved Hox genes—just like in its jawed vertebrate cousins.

    “When we started, we thought that the situation was different, and the Hox genes were not really integrated into the process of segmentation as they are in jawed vertebrates,” Parker says. “But in actually doing this project, we discovered the way that lamprey Hox genes are expressed and regulated is very similar to what we see in jawed vertebrates.” This means that hindbrain segmentation—and the role of Hox genes in this segmentation—happened earlier on in evolution than was once thought, he says.

    Parker, who has been spending his summers at Caltech studying lampreys since 2008, is next hoping to pinpoint other aspects of the lamprey hindbrain that may be conserved in modern vertebrate information that will help contribute to a fundamental understanding of vertebrate development. And although those investigations will probably mean following the lamprey for a few more summers at Caltech, Parker says his time in the lamprey facility continually offers a one-of-a-kind experience.

    “The lamprey system here is unique in the world—and it’s not just the water tanks and how we’ve learned to maintain the animals. It’s the small nucleus of people who have particular skills, people who come in from all over the world to work together, share protocols, and develop the field together,” he says. “That’s one of the things I’ve liked ever since I first came here. I really felt like I was a part of something very special.

    These results were published in a paper titled A Hox regulatory network of hindbrain segmentation is conserved to the base of vertebrates. Robb Krumlauf, a scientific director at the Stower’s Institute and professor at the Kansas University Medical Center, was also a coauthor on the study. The Zebrafish/Xenopus/Lamprey facility at Caltech is a Beckman Institute facility.

    See the full article here.

    The California Institute of Technology (commonly referred to as Caltech) is a private research university located in Pasadena, California, United States. Caltech has six academic divisions with strong emphases on science and engineering. Its 124-acre (50 ha) primary campus is located approximately 11 mi (18 km) northeast of downtown Los Angeles. “The mission of the California Institute of Technology is to expand human knowledge and benefit society through research integrated with education. We investigate the most challenging, fundamental problems in science and technology in a singularly collegial, interdisciplinary atmosphere, while educating outstanding students to become creative members of society.”
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  • richardmitnick 10:10 am on September 14, 2014 Permalink | Reply
    Tags: , Biology, , , New Technology,   

    From Rutgers- “Novel Local Morphologic Scale: Applications in Disease Diagnosis and Prognosis” 

    Rutgers University
    Rutgers University

    Rutgers Technology

    Invention Summary

    Timely and accurate diagnosis of disease pathologies is critical to providing effective treatment to patients. Rutgers scientists have developed a novel local morphologic scale (LMS) to rapidly and automatically select, quantify and classify tissue/specimen topologies using parallelized computations. This unique tool has the ability to define features for every special image location and generate subsequent scene segmentation and classification for each location. Further this technology is free from shape constraints and generates output based on local structure attributes of complex histological images. This innovation has been successfully utilized in discriminating tumor versus stromal regions by classifying oncogenic tumor infiltrating lymphocytes (biomarker) in ovarian cancer tissue microarrays. Additionally, this technology has been applied across 3 other domains (prostate, breast) under two different stains illustrating its robustness to domain selection. This technology can be immensely useful to identify regions of interest, model heterogeneity of the underlying topology and generate digital signatures. It can also be used to train supervised classifiers to identify similar structural signatures in an image and therefore reduce or eliminate and observer variability.

    Market Application

    Disease Diagnosis, Digital Pathology, Histopathology, Computer Aided Diagnosis (CAD), Tissue Classification, Disease Monitoring and Prognosis, Lymphocyte Infiltration, Cancer.

    Advantages

    Signatures derived from cancerous versus non-cancerous tissues differ greatly. This tool can be highly instrumental in classifying cancerous versus non-cancerous tissue, can reliably and accurately account for cell shape and phenotypes, and provide accurate tissue classification, enabling pathologists to visually discern the two regions.

    Intellectual Property & Development Status
    Patent pending.

    Select Publication
    Janowczyk, A, Chandran S, Feldman MD, Madabhushi A. (2011). Local morphologic scale: Application to segmenting tumor infiltrating lymphocytes in ovarian cancer TMAs. SPIE http://lcib.rutgers.edu/publications/ Andrew/SPIE2011.pdf

    See the full articled here.

    Rutgers, The State University of New Jersey, is a leading national research university and the state’s preeminent, comprehensive public institution of higher education. Rutgers is dedicated to teaching that meets the highest standards of excellence; to conducting research that breaks new ground; and to providing services, solutions, and clinical care that help individuals and the local, national, and global communities where they live.

    Founded in 1766, Rutgers teaches across the full educational spectrum: preschool to precollege; undergraduate to graduate; postdoctoral fellowships to residencies; and continuing education for professional and personal advancement.

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  • richardmitnick 9:43 am on September 14, 2014 Permalink | Reply
    Tags: , , Biology, , ,   

    From M.I.T Tech Review: “Gene-Silencing Drugs Finally Show Promise” 

    MIT Technology Review
    M.I.T Technology Review

    September 14, 2014
    Kevin Bullis

    After more than a decade of disappointment, a startup leads the development of a powerful new class of drugs based on a Nobel-winning idea.

    The disease starts with a feeling of increased clumsiness. Spilling a cup of coffee. Stumbling on the stairs. Having accidents that are easy to dismiss—everyone trips now and then.

    But it inevitably gets worse. Known as familial amyloid polyneuropathy, or FAP, it can go misdiagnosed for years as patients lose the ability to walk or perform delicate tasks with their hands. Most patients die within 10 to 15 years of the first symptoms.

    There is no cure. The disease is caused by malformed proteins produced in the liver, so one treatment is a liver transplant. But few patients can get one—and it only slows the disease down.

    Now, after years of false starts and disappointment, it looks like an audacious idea for helping these patients finally could work.

    In 1998, researchers at the Carnegie Institution and the University of Massachusetts made a surprising discovery about how cells regulate which proteins they produce. They found that certain kinds of RNA—which is what DNA makes to create proteins—can turn off specific genes. The finding, called RNA interference (RNAi), was exciting because it suggested a way to shut down the production of any protein in the body, including those connected with diseases that couldn’t be touched with ordinary drugs. It was so promising that its discoverers won the Nobel Prize just eight years later.

    Inspired by the discovery, another group of researchers—including the former thesis supervisor of one of the Nobel laureates—founded Alnylam in Cambridge, Massachusetts, in 2002. Their goal: fight diseases like FAP by using RNAi to eliminate bad proteins (see “The Prize of RNAi” and “Prescription RNA”). Never mind that no one knew how to make a drug that could trigger RNAi. In fact, that challenge would bedevil the researchers for the better part of a decade. Along the way, the company lost the support of major drug companies that had signed on in a first wave of enthusiasm. At one point the idea of RNAi therapy was on the verge of being discredited.

    But now Alnylam is testing a drug to treat FAP in advanced human trials. It’s the last hurdle before the company will seek regulatory approval to put the drug on the market. Although it’s too early to tell how well the drug will alleviate symptoms, it’s doing what the researchers hoped it would: it can decrease the production of the protein that causes FAP by more than 80 percent.

    This could be just the beginning for RNAi. Alnylam has more than 11 drugs, including ones for hemophilia, hepatitis B, and even high cholesterol, in its development pipeline, and has three in human trials —progress that led the pharmaceutical company Sanofi to make a $700 million investment in the company last winter. Last month, the pharmaceutical giant Roche, an early Alnylam supporter that had given up on RNAi, reversed its opinion of the technology as well, announcing a $450 million deal to acquire the RNAi startup Santaris. All told, there are about 15 RNAi-based drugs in clinical trials from several research groups and companies.

    “The world went from believing RNAi would change everything to thinking it wouldn’t work, to now thinking it will,” says Robert Langer, a professor at MIT, and one of Alnylam’s advisors.

    Delivering Drugs

    Alnylam started with high hopes. Its founders, among them the Nobel laureate and MIT biologist Philip Sharp, had solved one of the biggest challenges facing the idea of RNAi therapies. When RNAi was discovered, the process was triggered by introducing a type of RNA, called double stranded RNA, into cells. This worked well in worms and fruit flies. But the immune system in mammals reacted violently to the RNA, causing cells to die and making the approach useless except as a research tool. The Alnylam founders figured out that shorter strands, called siRNA, could slip into mammalian cells without triggering an immune reaction, suggesting a way around this problem.

    Yet another huge problem remained. RNA interference depends upon delivering RNA to cells, tricking the cells into allowing it through the protective cell membrane, and then getting the cells to incorporate it into molecular machinery that regulates proteins. Scientists could do this in petri dishes but not in animals.

    Alnylam looked everywhere for solutions, scouring the scientific literature, collaborating with other companies, considering novel approaches of its own. It focused on two options. One was encasing RNA in bubbles of fat-like nanoparticles of lipids. They are made with the same materials that make up cell membranes—the thought was that the cell would respond well to the familiar substance. The other approach was attaching a molecule to the RNA that cells like to ingest, tricking the cell into eating it.

    And both approaches worked, sort of. Researchers were able to block protein production in lab animals. But getting the delivery system right wasn’t easy. The early mechanisms were too toxic at the doses required to be used as drugs.

    As a result, delivering RNA through the bloodstream like a conventional drug seemed a far-off prospect. The company tried a shortcut of injecting chemically modified RNA directly into diseased tissue —for example, into the retina to treat eye diseases. That approach even got to clinical trials. But it was shelved because it didn’t perform as well as up-and-coming drugs from other companies.

    By 2010, some of the major drug companies that were working with and investing in Alnylam lost patience. Novartis decided not to extend a partnership with Alnylam; Roche gave up on RNAi altogether. Alnylam laid off about a quarter of its workers, and by mid-2011, its stock price had plunged by 80 percent from its peak.

    But Alnylam and partner companies, notably the Canadian startup Tekmira, were making steady progress in the lab. Researchers identified one part of the lipid nanoparticles that was keeping them from delivering its cargo of RNA to the right part of a cell. That was “the real eureka moment,” says Rachel Meyers, Alnylam’s vice president of research. Better nanoparticles improved the potency of a drug a hundredfold and its safety by about five times, clearing the way for clinical trials for FAP—a crucial event that kept the company alive.

    Even with that progress, Alnylam needed more. The nanoparticle delivery mechanism is costly to make and requires frequent visits to the hospital for hour-long IV infusions—something patients desperate to stay alive will put up with, but likely not millions of people with high cholesterol.

    So Alnylam turned to its second delivery approach—attaching molecules to RNA to trick cells into ingesting it. Researchers found just the right inducement—attaching a type of sugar molecule. This approach allows for the drug to be administered with a simple injection that patients could give themselves at home.

    In addition to being easier to administer, the new sugar-based drugs are potentially cheaper to make. The combination of low cost and ease-of-use is allowing Alnylam to go after more common diseases—not just the rare ones that patients will go to great lengths to treat. “Because we’ve made incredible improvements in the delivery strategy,” Meyers says, “we can now go after big diseases where we can treat millions of patients potentially.”

    The Next Frontier

    In a sixth-floor lab on the MIT campus, postdoctoral researcher James Dahlman takes down boxes from a high shelf. They contain hundreds of vials, each containing a unique type of nanoparticle that Dahlman synthesized painstakingly, one at a time. “It turns out we have a robot in the lab that can do that,” he says. “But I didn’t know about it at the time.”

    Dahlman doesn’t work for Alnylam; he had been searching for the next great delivery mechanism, one that could greatly expand the diseases that can be treated by RNAi. Some of the materials look like clear liquids. Some are waxy, some like salt crystals. He points to a gap in the rows of vials, where a vial is conspicuously missing. “That’s the one that worked. That’s the miracle material,” he says.

    For all of their benefits, the drug delivery mechanisms Alnylam uses have one flaw—they’re effective only for delivering drugs to liver cells. For a number of reasons, the liver is a relatively easy target—that’s where all kinds of nanoparticles tend to end up. Alnylam sees the potential for billions of dollars in revenue from liver-related diseases. Yet most diseases involve other tissues in the body.

    Dahlman and his colleagues at MIT are some of the leaders in the next generation of RNAi delivery—targeting delivery to places throughout the body. Last month, in two separate articles, they published the results of studies showing that Dahlman’s new nanoparticles are a powerful way to deliver RNAi to blood vessel cells, which are associated with a wide variety of diseases. The studies showed that the method could be used to reduce tumor growth in lung cancer, for example.

    Treating cancer is one area where RNAi’s particular advantages are expected to shine. Conventional chemotherapy affects more than just the target cancer cells—it also hurts healthy tissue, which is why it makes people feel miserable. But RNAi can be extremely precise, potentially shutting down only proteins found in cancer cells. And Dahlman’s latest delivery system makes it possible to simultaneously target up to 10 proteins at once, which could make cancer treatments far more effective. Lab work like this is far from fruition, but if it maintains its momentum, the drugs currently in clinical trials could represent just a small portion of the benefits of the discovery of RNAi.

    See the full article here.

    The mission of MIT Technology Review is to equip its audiences with the intelligence to understand a world shaped by technology.

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  • richardmitnick 3:43 pm on September 12, 2014 Permalink | Reply
    Tags: , Biology, , ,   

    From DESY: “Researchers X-Ray Living Cancer Cells” 

    DESY
    DESY

    27.02.2014

    Nanodiffraction opens up new insights into the physics of life

    Göttingen-based scientists working at DESY’s PETRA III research light source have carried out the first studies of living biological cells using high-energy X-rays. The new method shows clear differences in the internal cellular structure between living and dead, chemically fixed cells that are often analysed. “The new method for the first time enables us to investigate the internal structures of living cells in their natural environment using hard X-rays,” emphasises the leader of the working group, Prof. Sarah Köster from the Institute for X-Ray Physics of the University of Göttingen. The researchers present their work in the scientific journal Physical Review Letters.
    Zoom (17 KB)

    c ells
    X-ray scan of chemically fixed cells. Each pixel represents a full diffraction image. The colours indicate how strong the X-rays are scattered at each individual point. Credit: Britta Weinhausen/University of Göttingen

    Thanks to analytical methods with ever-higher resolution, scientists today can study biological cells at the level of individual molecules. The cells are frequently chemically fixed before they are studied with the help of optical, X-ray or electron microscopes. The process of chemical fixation involves immersing the cells in a type of chemical preservative which fixes all of the cell’s organelles and even the proteins in place. “Minor changes to the internal structure of the cells are unavoidable in this process,” emphasises Köster. “In our studies, we were able to show these changes in direct comparison for the first time.”

    The team used cancer cells from the adrenal cortex for their analyses. They grew the cells on a silicon nitrite substrate, which is almost transparent to X-rays. In order to keep the cells alive in the experimental chamber during the experiment, they were supplied with nutrients, and their metabolic products were pumped away via fine channels just 0.5 millimetres in diameter. “The biological cells are thus located in a sample environment which very closely resembles their natural environment,” explains Dr. Britta Weinhausen from Köster’s group, the paper’s first author.

    The experiments were carried out at the Nanofocus Setup (GINIX) of PETRA III’s experimental station P10. The scientists used the brilliant X-ray beam from PETRA III to scan the cells in order to obtain information about their internal nanostructure. “Each frame was exposed for just 0.05 seconds, in order to avoid damaging the living cells too quickly”, explains co-author Dr. Michael Sprung from DESY. “Even nanometre-scale structures can be measured with the GINIX assembly, thanks to the combination of PETRA III’s high brilliance and the GINIX setup which is matched to the source.”

    The researchers studied living and chemically fixed cells using this so-called nanodiffraction technique and compared the cells’ internal structures on the basis of the X-ray diffraction images. The results showed that the chemical fixation produces noticeable differences in the cellular structure on a scale of 30 to 50 nanometres (millionths of a millimetre).

    “Thanks to the ever-greater resolution of the various investigative techniques, it is increasingly important to know whether the internal structure of the sample changes during sample preparation,” explains Köster. In future, the new technique will make it possible to study unchanged living cells at high resolution. Although other methods have an even higher resolution than X-ray scattering, they require a chemical fixation or complex and invasive preparation of the cells. Lower-energy, so-called soft X-rays have already been used for studies of living cells. However, the study of structures with sizes as small as 12 nanometres first becomes possible through the analysis of diffraction images produced using hard X-rays.

    See the full article here.

    desi

    DESY is one of the world’s leading accelerator centres. Researchers use the large-scale facilities at DESY to explore the microcosm in all its variety – from the interactions of tiny elementary particles and the behaviour of new types of nanomaterials to biomolecular processes that are essential to life. The accelerators and detectors that DESY develops and builds are unique research tools. The facilities generate the world’s most intense X-ray light, accelerate particles to record energies and open completely new windows onto the universe. 
That makes DESY not only a magnet for more than 3000 guest researchers from over 40 countries every year, but also a coveted partner for national and international cooperations. Committed young researchers find an exciting interdisciplinary setting at DESY. The research centre offers specialized training for a large number of professions. DESY cooperates with industry and business to promote new technologies that will benefit society and encourage innovations. This also benefits the metropolitan regions of the two DESY locations, Hamburg and Zeuthen near Berlin.

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  • richardmitnick 2:33 pm on September 12, 2014 Permalink | Reply
    Tags: , Biology, , ,   

    From physicsworld: “Synchrotron X-rays track fluids in the lungs” 

    physicsworld
    physicsworld.com

    Sep 12, 2014
    Ian Randall

    A new method of soft-tissue imaging could allow doctors to monitor respiratory treatments of cystic-fibrosis patients, reports an international research team. The technique – which measures the refraction of a grid pattern of X-rays passing through the lungs – has been successfully demonstrated in live mice, and could eventually find application in visualizing other soft tissues, such as the brain and heart.

    synchro
    Synchrotron source: phase-contrast imaging in the lab

    Cystic fibrosis is a life-threatening genetic disorder that affects the exocrine glands, resulting in unusually thick secretions of mucus. In lungs, mucus is supposed to keep the airways moist, along with forming a conveyor belt, moved by beating cilia, which carries away foreign particles and pathogens. In cystic-fibrosis patients, however, the thicker mucus flows less easily – resulting in a build-up that can cause inflammation, breathing difficulties and increased susceptibility to bacterial infection.

    Respiratory therapies for cystic-fibrosis patients typically focus on increasing hydration of the airways to improve mucus flow. Tracking the progress of these treatments, however, is challenging. “At the moment, we typically need to wait for a cystic-fibrosis treatment to have an effect on lung health, measured by either a lung CT scan or breath measurement, to see how effective it is,” explains lead researcher Kaye Morgan from Monash University in Australia. With successful medications often taking months to have a measurable impact, progress in developing new treatments is correspondingly slow.

    Fast yet sensitive

    The challenge lies in imaging the surface layers of liquid in the airways. These are usually only a few tens of microns across, bear a close resemblance to the underlying tissue and – given the passage of air in and out of lungs – constantly move around. Consequently, any technique for imaging this interface needs to be high-resolution, as well as sufficiently fast and sensitive.

    mouse
    Single-grid-based phase-contrast X-ray imaging reveals a liquid surface layer in the lungs of a live mouse
    Sharper image: X-rays reveal a liquid surface layer

    Morgan and colleagues have developed an imaging method that they call single-grid-based phase-contrast X-ray imaging. Unlike conventional radiography, which measures the absorption of X-rays, the new approach measures the refraction of a grid pattern of radiation as it passes through the soft tissues.

    “A good analogy is the patterns we see on the bottom of swimming pools,” explains Morgan. At the detector, the X-ray grid will appear distorted in accordance with the properties of the tissues that the rays have passed through – much in the same way that tiles in a pool appear distorted when seen through water. “By tracking the distortions in the grid pattern, we can reconstruct the airway structures.”

    Anaesthetized mice

    To test their method, the researchers imaged the airways of eight anaesthetized mice. Using a nebulizer, each mouse was treated first with a saline control solution, and then with a treatment designed to block the dehydrating effect of the cells lining the airway. X-rays from a synchrotron travelled through a 25.4 µm grid to create the desired pattern; this produced images at the detector with 0.18 µm-sized pixels. Images were recorded at three-minute intervals for 15 minutes after each treatment.

    By tracking the distortions in the grid pattern, we can reconstruct the airway structures
    Kaye Morgan, Monash University

    The method successfully imaged the airway, surface liquids and underlying tissues. A noticeable increase in the surface hydration depth was observed after treatment in comparison with the control. “The new imaging method allows us, for the first time, to non-invasively see how the treatment is working, ‘live’ on the airway surface,” Morgan says.

    “This is a novel and interesting biomedical application,” says Mark Anastasio, a biomedical engineer from Washington University in St Louis. With existing solutions unable to reveal such subtle soft-tissue interfaces, he adds, this result “motivates the further development of X-ray phase-contrast imaging technologies”.
    Practical issues

    Ke Li, a medical physicist from the University of Wisconsin-Madison, points out that making measurements on live mice “is a huge step along the course of applying phase-contrast X-ray projection imaging to medical imaging”. However, Li questions the practicality of using a synchrotron X-ray source in a clinical environment, especially given the high radiation dose necessary for such an ultra-fine pixel size.

    Some of these concerns could soon be addressed, with Morgan and colleagues now exploring how their work might translate into a clinical setting. At the same time, the team is investigating other possible medical applications, looking both at lungs and other soft tissues, such as the brain and heart.

    See the full article here.

    PhysicsWorld is a publication of the Institute of Physics. The Institute of Physics is a leading scientific society. We are a charitable organisation with a worldwide membership of more than 50,000, working together to advance physics education, research and application.

    We engage with policymakers and the general public to develop awareness and understanding of the value of physics and, through IOP Publishing, we are world leaders in professional scientific communications.
    IOP Institute of Physics

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  • richardmitnick 2:44 pm on September 9, 2014 Permalink | Reply
    Tags: , , , Biology   

    From Astrobiology: “New Study Revisits Miller-Urey Experiment at the Quantum Level” 

    Astrobiology Magazine

    Astrobiology Magazine

    Sep 9, 2014
    Johnny Bontemps

    New Study Revisits Miller-Urey Experiment at the Quantum Level
    By Johnny Bontemps – Sep 9, 2014

    spark
    The famous spark discharge experiment was designed to mimic lightning and the atmosphere of early Earth.

    For the first time, researchers have reproduced the results of the Miller-Urey experiment in a computer simulation, yielding new insight into the effect of electricity on the formation of life’s building blocks at the quantum level.

    exp
    The experiment

    In 1953, American chemist Stanley Miller had famously electrified a mixture of simple gas and water to simulate lightning and the atmosphere of early Earth. The revolutionary experiment—which yielded a brownish soup of amino acids—offered a simple potential scenario for the origin of life’s building blocks. Miller’s work gave birth to modern research on pre-biotic chemistry and the origins of life.

    For the past 60 years, scientists have investigated other possible energy sources for the formation of life’s building blocks, including ultra violet light, meteorite impacts, and deep sea hydrothermal vents.

    sm
    Stanley Miller, 1999 Credit: James A. Sugar

    In this new study, Antonino Marco Saitta, of the Université Pierre et Marie Curie, Sorbonne, in Paris, France and his colleagues wanted to revisit Miller’s result with electric fields, but from a quantum perspective.

    Saitta and study co-author Franz Saija, two theoretical physicists, had recently applied a new quantum model to study the effects of electric fields on water, which had never been done before. After coming across a documentary on Miller’s work, they wondered whether the quantum approach might work for the famous spark-discharge experiment.

    The method would also allow them to follow individual atoms and molecules through space and time—and perhaps yield new insight into the role of electricity in Miller’s work.

    “The spirit of our work was to show that the electric field is part of it,” Saitta said, “without necessarily involving lightning or a spark.”

    Their results are published this week in the scientific journal Proceedings of the National Academy of Sciences.

    An Alternate Route

    As in the original Miller experiment, Saitta and Saija subjected a mixture of molecules containing carbon, nitrogen, oxygen and hydrogen atoms to an electric field. As expected, the simulation yielded glycine, an amino acid that is one of the simplest building blocks for proteins, and one the most abundant products in the original Miller experiment.

    A typical intermediate in the formation of amino acids is the small molecule formaldehyde.

    form
    Formaldehyde – A typical intermediate in the formation of amino acids.

    But their approach also yielded some unexpected results. In particular, their model suggested that the formation of amino acids in the Miller scenario might have occurred via a more complex chemical pathway than previously thought.

    A typical intermediate in the formation of amino acids is the small molecule formaldehyde. But their simulation showed that when subjected to an electric field, the reaction favored a different intermediate, the molecule formamide.

    It turns out, formamide could have not only played a crucial role in the formation of life’s building blocks on Earth, but also elsewhere.

    “We weren’t looking for it, or expecting it,” Saitta said. “We only learned after the fact, by reviewing the scientific literature, that it’s an important clue in prebiotic chemistry.”

    For instance, formamide has recently been shown to be a key ingredient in making some of the building blocks of RNA, notably guanine, in the presence of ultra violet light.

    Formamide has also recently been observed in space—notably in a comet and in a solar-type proto star. Earlier research has also shown that formamide can form when comets or asteroids impact the Earth.

    Their model suggested that the formation of amino acids in the Miller scenario might have occurred via a more complex chemical pathway than previously thought.

    forma
    Formamide – In their computer model, the reaction favored this more complex intermediate.

    “The possibility of new routes to make amino acids without a formaldehyde intermediate is novel and gaining ground, especially in extraterrestrial contexts,” the authors wrote. “The presence of formamide might be a most telling fingerprint of abiotic terrestrial and extraterrestrial amino acids.”

    However, Jeff Bada, who was a graduate student of Miller’s in the 1960s and spent his career working of the origin of life, remains skeptical about their results and theoretical approach.

    “Their model might not meaningfully represent what happens in a solution,” he says. “We know there’s a lot of formaldehyde made in the spark discharge experiment. I don’t think the formamide reaction would be significant in comparison to the traditional reaction.”

    But Saitta points out that formamide is very unstable, so it may not last long enough to be observed in real Miller experiments. “In our simulation, formamide always formed spontaneously. And it was some sort of crucible—it would either break up into water and hydrogen cyanide, or combine with other molecules and form the amino acid glycine.”

    Life’s Origin–on the Rocks?

    Another key insight from their study is that the formation of some of life’s building blocks may have occurred on mineral surfaces, since most have strong natural electric fields.

    “The electric field of mineral surfaces can be easily 10 or 20 times stronger than the one in our study,” Saitta said. “The problem is that it only acts on a very short range. So to feel the effects, molecules would have to be very close to the surface.”

    “I think that this work is of great significance,” said François Guyot, a geochemist at the French Museum of Natural History.

    “Regarding the mineral surfaces, strong electric fields undoubtedly exist at their immediate proximity. And because of their strong role on the reactivity of organic molecules, they might enhance the formation of more complex molecules by a mechanism distinct from the geometrical concentration of reactive species, a mechanisms often proposed when mineral surfaces are invoked for explaining the formation of the first biomolecules.”

    One of the leading hypotheses in the field of life’s origin suggests that important prebiotic reactions may have occurred on mineral surfaces. But so far scientists don’t fully understand the mechanism behind it.

    “Nobody has really looked at electric fields on mineral surfaces,” Saitta said. “My feeling is that there’s probably something to explore there.”

    See the full article here.

    NASA

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  • richardmitnick 7:45 am on September 9, 2014 Permalink | Reply
    Tags: , , Biology, ,   

    From PBS NOVA: “Why There’s No HIV Cure Yet” 

    PBS NOVA

    NOVA

    Wed, 27 Aug 2014
    Alison Hill

    Over the past two years, the phrase “HIV cure” has flashed repeatedly across newspaper headlines. In March 2013, doctors from Mississippi reported that the disease had vanished in a toddler who was infected at birth. Four months later, researchers in Boston reported a similar finding in two previously HIV-positive men. All three were no longer required to take any drug treatments. The media heralded the breakthrough, and there was anxious optimism among HIV researchers. Millions of dollars of grant funds were earmarked to bring this work to more patients.

    But in December 2013, the optimism evaporated. HIV had returned in both of the Boston men. Then, just this summer, researchers announced the same grim results for the child from Mississippi. The inevitable questions mounted from the baffled public. Will there ever be a cure for this disease? As a scientist researching HIV/AIDS, I can tell you there’s no straightforward answer. HIV is a notoriously tricky virus, one that’s eluded promising treatments before. But perhaps just as problematic is the word “cure” itself.

    Science has its fair share of trigger words. Biologists prickle at the words “vegetable” and “fruit”—culinary terms which are used without a botanical basis—chemists wrinkle their noses at “chemical free,” and physicists dislike calling “centrifugal” a force—it’s not; it only feels like one. If you ask an HIV researcher about a cure for the disease, you’ll almost certainly be chastised. What makes “cure” such a heated word?

    cells
    HIV hijacks the body’s immune system by attacking T cells.

    It all started with a promise. In the early 1980s, doctors and public health officials noticed large clusters of previously healthy people whose immune systems were completely failing. The new condition became known as AIDS, for “acquired immunodeficiency syndrome.” A few years later, in 1984, researchers discovered the cause—the human immunodeficiency virus, now known commonly as HIV. On the day this breakthrough was announced, health officials assured the public that a vaccine to protect against the dreaded infection was only two years away. Yet here we are, 30 years later, and there’s still no vaccine. This turned out to be the first of many overzealous predictions about controlling the HIV epidemic or curing infected patients.

    The progression from HIV infection to AIDS and eventual death occurs in over 99% of untreated cases—making it more deadly than Ebola or the plague. Despite being identified only a few decades ago, AIDS has already killed 25 million people and currently infects another 35 million, and the World Health Organization lists it as the sixth leading cause of death worldwide.

    HIV disrupts the body’s natural disease-fighting mechanisms, which makes it particularly deadly and complicates efforts to develop a vaccine against it. Like all viruses, HIV gets inside individual cells in the body and highjacks their machinery to make thousands of copies of itself. HIV replication is especially hard for the body to control because the white blood cells it infects, and eventually kills, are a critical part of the immune system. Additionally, when HIV copies its genes, it does so sloppily. This causes it to quickly mutate into many different strains. As a result, the virus easily outwits the body’s immune defenses, eventually throwing the immune system into disarray. That gives other obscure or otherwise innocuous infections a chance to flourish in the body—a defining feature of AIDS.
    Early Hope

    In 1987, the FDA approved AZT as the first drug to treat HIV. With only two years between when the drug was identified in the lab and when it was available for doctors to prescribe, it was—and remains—the fastest approval process in the history of the FDA. AZT was widely heralded as a breakthrough. But as the movie The Dallas Buyer’s Club poignantly retells, AZT was not the miracle drug many hoped. Early prescriptions often elicited toxic side-effects and only offered a temporary benefit, as the virus quickly mutated to become resistant to the treatment. (Today, the toxicity problems have been significantly reduced, thanks to lower doses.) AZT remains a shining example of scientific bravura and is still an important tool to slow the infection, but it is far from the cure the world had hoped for.

    In three decades, over 25 highly-potent drugs have been developed and FDA-approved to treat HIV.

    Then, in the mid-1990s, some mathematicians began probing the data. Together with HIV scientists, they suggested that by taking three drugs together, we could avoid the problem of drug resistance. The chance that the virus would have enough mutations to allow it to avoid all drugs at once, they calculated, would simply be too low to worry about. When the first clinical trials of these “drug cocktails” began, both mathematical and laboratory researchers watched the levels of virus drop steadily in patients until they were undetectable. They extrapolated this decline downwards and calculated that, after two to three years of treatment, all traces of the virus should be gone from a patient’s body. When that happened, scientists believed, drugs could be withdrawn, and finally, a cure achieved. But when the time came for the first patients to stop their drugs, the virus again seemed to outwit modern medicine. Within a few weeks of the last pill, virus levels in patients’ blood sprang up to pre-treatment levels—and stayed there.

    In the three decades since, over 25 more highly-potent drugs have been developed and FDA-approved to treat HIV. When two to five of them are combined into a drug cocktail, the mixture can shut down the virus’s replication, prevent the onset of AIDS, and return life expectancy to a normal level. However, patients must continue taking these treatments for their entire lives. Though better than the alternative, drug regimens are still inconvenient and expensive, especially for patients living in the developing world.

    Given modern medicine’s success in curing other diseases, what makes HIV different? By definition, an infection is cured if treatment can be stopped without the risk of it resurfacing. When you take a week-long course of antibiotics for strep throat, for example, you can rest assured that the infection is on track to be cleared out of your body. But not with HIV.

    A Bad Memory

    The secret to why HIV is so hard to cure lies in a quirk of the type of cell it infects. Our immune system is designed to store information about infections we have had in the past; this property is called “immunologic memory.” That’s why you’re unlikely to be infected with chickenpox a second time or catch a disease you were vaccinated against. When an infection grows in the body, the white blood cells that are best able to fight it multiply repeatedly, perfecting their infection-fighting properties with each new generation. After the infection is cleared, most of these cells will die off, since they are no longer needed. However, to speed the counter-attack if the same infection returns, some white blood cells will transition to a hibernation state. They don’t do much in this state but can live for an extremely long time, thereby storing the “memory” of past infections. If provoked by a recurrence, these dormant cells will reactivate quickly.

    This near-immortal, sleep-like state allows HIV to persist in white blood cells in a patient’s body for decades. White blood cells infected with HIV will occasionally transition to the dormant state before the virus kills them. In the process, the virus also goes temporarily inactive. By the time drugs are started, a typical infected person contains millions of these cells with this “latent” HIV in them. Drug cocktails can prevent the virus from replicating, but they do nothing to the latent virus. Every day, some of the dormant white blood cells wake up. If drug treatment is halted, the latent virus particles can restart the infection.
    Latent HIV’s near-immortal, sleep-like state allows it to persist in white blood cells in a patient’s body for decades.

    HIV researchers call this huge pool of latent virus the “barrier to a cure.” Everyone’s looking for ways to get rid of it. It’s a daunting task, because although a million HIV-infected cells may seem like a lot, there are around a million times that many dormant white blood cells in the whole body. Finding the ones that contain HIV is a true needle-in-a-haystack problem. All that remains of a latent virus is its DNA, which is extremely tiny compared to the entire human genome inside every cell (about 0.001% of the size).

    Defining a Cure

    Around a decade ago, scientists began to talk amongst themselves about what a hypothetical cure could look like. They settled on two approaches. The first would involve purging the body of latent virus so that if drugs were stopped, there would be nothing left to restart the infection. This was often called a “sterilizing cure.” It would have to be done in a more targeted and less toxic way than previous attempts of the late 1990s, which, because they attempted to “wake up” all of the body’s dormant white blood cells, pushed the immune system into a self-destructive overdrive. The second approach would instead equip the body with the ability to control the virus on its own. In this case, even if treatment was stopped and latent virus reemerged, it would be unable to produce a self-sustaining, high-level infection. This approach was referred to as a “functional cure.”

    The functional cure approach acknowledged that latency alone was not the barrier to a cure for HIV. There are other common viruses that have a long-lived latent state, such as the Epstein-Barr virus that causes infectious mononucleosis (“mono”), but they rarely cause full-blown disease when reactivated. HIV is, of course, different because the immune system in most people is unable to control the infection.

    The first hint that a cure for HIV might be more than a pipe-dream came in 2008 in a fortuitous human experiment later known as the “Berlin patient.” The Berlin patient was an HIV-positive man who had also developed leukemia, a blood cancer to which HIV patients are susceptible. His cancer was advanced, so in a last-ditch effort, doctors completely cleared his bone marrow of all cells, cancerous and healthy. They then transplanted new bone marrow cells from a donor.

    Fortunately for the Berlin patient, doctors were able to find a compatible bone marrow donor who carried a unique HIV-resistance mutation in a gene known as CCR5. They completed the transplant with these cells and waited.

    For the last five years, the Berlin patient has remained off treatment without any sign of infection. Doctors still cannot detect any HIV in his body. While the Berlin patient may be cured, this approach cannot be used for most HIV-infected patients. Bone marrow transplants are extremely risky and expensive, and they would never be conducted in someone who wasn’t terminally ill—especially since current anti-HIV drugs are so good at keeping the infection in check.

    Still, the Berlin patient was an important proof-of-principle case. Most of the latent virus was likely cleared out during the transplant, and even if the virus remained, most strains couldn’t replicate efficiently given the new cells with the CCR5 mutation. The Berlin patient case provides evidence that at least one of the two cure methods (sterilizing or functional), or perhaps a combination of them, is effective.

    Researchers have continued to try to find more practical ways to rid patients of the latent virus in safe and targeted ways. In the past five years, they have identified multiple anti-latency drug candidates in the lab. Many have already begun clinical trials. Each time, people grow optimistic that a cure will be found. But so far, the results have been disappointing. None of the drugs have been able to significantly lower levels of latent virus.

    In the meantime, doctors in Boston have attempted to tease out which of the two cure methods was at work in the Berlin patient. They conducted bone marrow transplants on two HIV-infected men with cancer—but this time, since HIV-resistant donor cells were not available, they just used typical cells. Both patients continued their drug cocktails during and after the transplant in the hopes that the new cells would remain HIV-free. After the transplants, no HIV was detectable, but the real test came when these patients volunteered to stop their drug regimens. When they remained HIV-free a few months later, the results were presented at the International AIDS Society meeting in July 2013. News outlets around the world declared that two more individuals had been cured of HIV.

    Latent virus had likely escaped the detection methods available.

    It quickly became clear that everyone had spoken too soon. Six months later, researchers reported that the virus had suddenly and rapidly returned in both individuals. Latent virus had likely escaped the detection methods available—which are not sensitive enough—and persisted at low, but significant levels. Disappointment was widespread. The findings showed that even very small amounts of latent virus could restart an infection. It also meant meant that the anti-latency drugs in development would need to be extremely potent to give any hope of a cure.

    But there was one more hope—the “Mississippi baby.” A baby was born to an HIV-infected mother who had not received any routine prenatal testing or treatment. Tests revealed high levels of HIV in the baby’s blood, so doctors immediately started the infant on a drug cocktail, to be continued for life.

    The mother and child soon lost touch with their health care providers. When they were relocated a few years later, doctors learned that the mother had stopped giving drugs to the child several months prior. The doctors administered all possible tests to look for signs of the virus, both latent and active, but they didn’t find any evidence. They chose not to re-administer drugs, and a year later, when the virus was still nowhere to be found, they presented the findings to the public. It was once again heralded as a cure.

    Again, it was not to be. Just last month, the child’s doctors announced that the virus had sprung back unexpectedly. It seemed that even starting drugs as soon as infection was detected in the newborn could not prevent the infection from returning over two years later.
    Hope Remains

    Despite our grim track record with the disease, HIV is probably not incurable. Although we don’t have a cure yet, we’ve learned many lessons along the way. Most importantly, we should be extremely careful about using the word “cure,” because for now, we’ll never know if a person is cured until they’re not cured.

    Clearing out latent virus may still be a feasible approach to a cure, but the purge will have to be extremely thorough. We need drugs that can carefully reactivate or remove latent HIV, leaving minimal surviving virus while avoiding the problems that befell earlier tests that reactivated the entire immune system. Scientists have proposed multiple, cutting-edge techniques to engineer “smart” drugs for this purpose, but we don’t yet know how to deliver this type of treatment safely or effectively.

    As a result, most investigations focus on traditional types of drugs. Researchers have developed ways to rapidly scan huge repositories of existing medicines for their ability to target latent HIV. These methods have already identified compounds that were previously used to treat alcoholism, cancer, and epilepsy, and researchers are repurposing them to be tested in HIV-infected patients.
    The less latent virus that remains, the less chance there is that the virus will win the game of chance.

    Mathematicians are also helping HIV researchers evaluate new treatments. My colleagues and I use math to take data collected from just a few individuals and fill in the gaps. One question we’re focusing on is exactly how much latent virus must be removed to cure a patient, or at least to let them stop their drug cocktails for a few years. Each cell harboring latent virus is a potential spark that could restart the infection. But we don’t know when the virus will reactivate. Even once a single latent virus awakens, there are still many barriers it must overcome to restart a full-blown infection. The less latent virus that remains, the less chance there is that the virus will win this game of chance. Math allows us to work out these odds very precisely.

    Our calculations show that “apparent cures”—where patients with latent virus levels low enough to escape detection for months or years without treatment—are not a medical anomaly. In fact, math tells us that they are an expected result of these chance dynamics. It can also help researchers determine how good an anti-latency drug should be before it’s worth testing in a clinical trial.

    Many researchers are working to augment the body’s ability to control the infection, providing a functional cure rather than a sterilizing one. Studies are underway to render anyone’s immune cells resistant to HIV, mimicking the CCR5 mutation that gives some people natural resistance. Vaccines that could be given after infection, to boost the immune response or protect the body from the virus’s ill effects, are also in development.

    In the meantime, treating all HIV-infected individuals—which has the added benefit of preventing new transmissions—remains the best way to control the epidemic and reduce mortality. But the promise of “universal treatment” has also not materialized. Currently, even in the U.S., only 25% of HIV-positive people have their viral levels adequately suppressed by treatment. Worldwide, for every two individuals starting treatment, three are newly infected. While there’s no doubt that we’ve made tremendous progress in fighting the virus, we have a long way to go before the word “cure” is not taboo when it comes to HIV/AIDS.

    See the full article here.

    NOVA is the highest rated science series on television and the most watched documentary series on public television. It is also one of television’s most acclaimed series, having won every major television award, most of them many times over.

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