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  • richardmitnick 7:45 am on September 9, 2014 Permalink | Reply
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    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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  • richardmitnick 1:46 pm on September 5, 2014 Permalink | Reply
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    From PBS NOVA: “New Drug Clears Cancer Cells Through Immune System Judo” 

    PBS NOVA

    NOVA

    Fri, 05 Sep 2014
    Tim De Chant

    For years, scientists have been probing various immune response proteins in the hopes of finding a new way to target and destroy cancer cells. Yesterday, two months ahead of schedule, the FDA approved a drug that does just that, targeting the protein “programmed cell death 1,” or PD-1. While not the first drug to use the immune system to fight cancer, it may be the most promising to date.

    Pembrolizumab is currently approved for advanced melanoma patients who have no other treatment options left. In clinical trials, tumors shrank in 24% of patients, and in one particular trial, 69% of patients were alive after one year of pembrolizumab treatment, a number that shocked the doctors in charge.

    melanoma
    Melanoma cell

    Pembrolizumab works by suppressing the expression of PD-1. In a healthy cell, PD-1 is active and present on the surface of a cell. But when a cell is nearing the end of it’s life, PD-1 expression tapers off. Immune cells recognize this signal and come in to clear away the dead or dying cell. Researchers have discovered that, in many tumors, PD-1 continues to be expressed. By preventing PD-1 from appearing on the surface of a cell, they predicted that cancer cells would be eliminated by the body’s own defenses.

    Doctors are hopeful that therapies which target PD-1 will give patients new options with fewer side effects than traditional chemotherapy. Andrew Pollack, reporting for the New York Times:

    “This is really opening up a whole new avenue of effective therapies previously not available,” said Dr. Louis M. Weiner, director of the Georgetown Lombardi Comprehensive Cancer Center in Washington and a spokesman for the American Association for Cancer Research. “It allows us to see a time when we can treat many dreaded cancers without resorting to cytotoxic chemotherapy.”

    Pembrolizumab is being marketed as Keytruda by Merck, the drug’s developer. Priced at $12,500 per month or $150,000 per year, the drug is apparently more expensive than other cancer drugs. Pollack reports that some cancer doctors have expressed concern that the high price tag will be too dear for some patients.

    Pembrolizumab is an antibody that specifically targets PD-1, so side effects tend to be less severe than with more general chemotherapy. Patients still run the risk of a potentially harmful inflammatory response—a sign of a runaway immune system, though most tolerated the drug well.

    For now, pembrolizumab is limited to patients with advanced melanoma that doesn’t respond to other treatments, but Merck has seen promising results with lung and kidney cancers. Other pharmaceutical companies are racing to get their PD-1 drugs approved, too. As more drugs come on the market, and new ones are calibrated for different cancers, the next few years could be the beginning of a new era in clinical cancer treatments.

    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 4:15 pm on September 4, 2014 Permalink | Reply
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    From PBS NOVA: “Quantum Physicists Catch a Pilot Wave” 

    PBS NOVA

    NOVA

    Wed, 03 Sep 2014
    Jennifer Ouellette

    In October 1927, some of the greatest minds in physics gathered for the Fifth Solvay International Conference to debate the troubling implications of the then-nascent theory of quantum mechanics. A particularly contentious topic was the perplexing “wave-particle duality,” in which objects we typically think of as particles—like photons and electrons—exhibit wave-like properties as well, and things we think of as waves, like light, sometimes behave like particles.

    The French physicist Louis de Broglie proposed a means by which a photon or electron could behave like both a particle and a wave, complementary aspects of the same phenomenon. He reasoned that the particles could be carried along by what he dubbed “pilot waves”—fluid-like ripples in space and time—much like a buoys bobbing along with the tide.

    droplet

    De Broglie won the Nobel Prize in Physics just two years later, but it wasn’t for pilot waves. His contemporaries largely dismissed his explanation for the dual nature of subatomic particles. Now, more than 80 years later, a series of experiments on the behavior of oil droplets bouncing along a vibrating liquid surface have provided a macroscale analog of de Broglie’s pilot waves, replicating some of the stranger properties of quantum mechanics.

    Quantum mechanics seeks to describe nature at the level of individual atoms and the particles that comprise them. But when physicists began delving into this strange new realm at the dawn of the 20th century, they discovered that the old, deterministic laws of classical physics no longer apply at that scale. Instead, uncertainty reigns supreme. It is a world governed by probabilities, and many physicists found this disquieting, to say the least. Hence Albert Einstein’s famous declaration at the Solvay conference that God does not play dice with the universe, prompting Niels Bohr to counter, “Einstein, stop telling God what to do.”

    At the heart of the discomfort is the question of uncertainty. Flip a coin, and it will land either heads or tails; in principle, with complete information about the coin, the hand doing the flipping, and the movement of air molecules around the flip, it is possible to predict the outcome. In the quantum world, things hover in a fuzzy, nebulous cloud of probability called a wave function that encompasses all potential states, with no prospect of gaining further information. Flip a quantum coin, and it is both heads and tails until we look. Things become definite only when an observation forces them to settle on a specific outcome.

    To Einstein, the notion of observation dictating the outcome of an experiment was ridiculous, since it denied the existence of a solid underlying reality. Even [Erwin]Schrödinger, inventor of the wave function, was deeply disturbed by the implications of what he’d helped create, memorably declaring, “I don’t like it, and I’m sorry I ever had anything to do with it.”

    De Broglie’s alternative pilot wave theory was an attempt to restore that underlying solid reality. Instead of the wave function, de Broglie’s pilot wave theory employs two equations, one describing an actual wave and the other describing the path of an actual particle and how it interacts with, and is guided by, the wave equation. It is deterministic, like a classical coin flip. In principle, at least, we can glean sufficient information to plot a particle’s path, something that is not allowed in Bohr’s interpretation of quantum mechanics.

    While the idea of pilot wave theory never really caught on, it stubbornly refused to die. A physicist named David Bohm proposed a modified version in the 1950s that also failed to gain much traction. But perhaps the pilot wave’s time has come at last.

    The latest resurgence of interest began in Paris about ten years ago, when Yves Couder and Emmanuel Fort of Diderot University started experimenting with oil droplets bounced off a vat of vibrating liquid. The droplet’s impact causes waves to ripple outward, like tossing a pebble in a pond. If the liquid in the vat vibrates at just the right frequency, usually quite close to the droplet’s natural resonant frequency, the droplet interacts with the ripples it creates as it bounces along, which in turn can affect its path. That’s eerily similar to de Broglie’s notion of a pilot wave. Such a system turns out to be a fantastic means for simulating weird quantum effects like the dual nature of light and matter.

    The 19th century physicist Thomas Young demonstrated this with his famous double-slit experiment. In the double slit experiment, a series of photons or electrons strike a screen with two slits in it before landing on a detector behind the screen. If you consider photons and electrons to be particles, you would expect the detector light up along the path through the slits and nowhere else. But that’s not what Young found. Instead, Young discovered an interference pattern of alternating light and dark bands, suggesting that the would-be particles were acting like water waves passing through a barrier wall with two openings. But if one places detectors near the slits to “see” which slit each particle went through, then the interference pattern disappears—the waves start acting like particles. It is the essence of quantum weirdness.

    Couder and Fort replicated Young’s experiment by steering their bouncing droplets toward such a screen with a slit, helped along by the pilot waves created by the vibrating liquid. While they appear to scatter randomly as they pass through the slit, over time, wavy interference patterns emerge. “Guided” by the pilot waves, the droplets appear to be drawn to those regions where the wavefronts add together, and steer clear of those regions where the wavefronts cancel each other out. Disturbing the pilot wave destroys the interference pattern, much like measuring the path of particles as they hit the screen does.

    Last year, pilot wave theory received another boost when MIT physicists Daniel Harris and John Bush used a similar fluid system to mimic a “quantum corral,” in which electrons are trapped within a ring of ions. Harris and Bush made a shallow tray with a circle-shaped trough in the center to serve as the walls of the “corral.” They filled the tray with silicon oil and mounted it on a vibrating stand tuned to a frequency just shy of that required to produce pilot waves spontaneously, without the droplet, according to Bush. Above that threshold, the roiling sea of waves will interfere with the droplet’s walk. Below it, the surface remains smooth except for the waves produced by the bouncing droplet. The closer one tunes the vibrations to that threshold, the more robust and long-lived the generated pilot waves will be.

    When the bouncing droplet produced waves, those waves bounced off the walls and interfered with each other, producing pretty interference patterns. They also affected the trajectory of the droplet. At first it looked like it was bouncing along randomly, but over time (around 20 minutes), the droplet was far more likely to drift towards the center of the circle, and increasingly less likely to be found in the rippling rings spreading out from that center. That probability distribution for the single droplet proved very similar to that of an electron trapped in a quantum corral.

    The droplet experiments provide an intriguing analogue or “toy model” for de Broglie’s pilot waves, but there is still no direct evidence of pilot waves at the quantum scale. “Time will tell whether the quantum-like behavior of the walking dropets is mere coincidence,” Bush told me via email. Also, the theory is currently limited to describing the simplest interactions between particles and electromagnetic fields. “It is not by itself capable of representing very much physics,” Oxford University physics philosopher David Wallace told Quanta earlier this year. “In my own view, this is the most severe problem for the theory, though, to be fair, it remains an active research area.”

    Nobody is claiming that quantum mechanics is wrong; there is too much experimental evidence that the equations do make accurate predictions about how things work at the subatomic scale. But the implications of the standard interpretations remain troubling. The pioneers of quantum mechanics came up with the most plausible theory they could, given the resources they had, and they transformed modern physics in the process. Contemplating the possibility of pilot wave theory might lead to a fresh interpretation of quantum weirdness, one that prompts physicists to rethink their longstanding assumptions about the true nature of the quantum world. Another transformation could be lurking in the wings.

    See the full article, with video, 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 4:12 pm on August 13, 2014 Permalink | Reply
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    From PBS NOVA: “Teaching the Nervous System to Forget Chronic Pain” 

    PBS NOVA

    NOVA

    13 Aug 2014
    Eleanor Nelsen

    “It was an emergency situation,” she says. The horse Sally was riding was barreling straight towards another, younger horse, and the only way to stop him was to pull back on one rein, hard. She felt a pop in her wrist. Heat shot up her arm, excruciating pain fast on its heels.

    That was four years ago. No one knows quite what happened to her wrist that day, but whatever it was has left her with constant pain that stretches from her fingertips to her neck, and sometimes creeps into her ribs. On the really bad days, even a hug is unbearably painful.

    Sally is my youngest sister, and she is one of an unlucky fraction of people for whom an injury catapults their nervous system into a state of chronic pain. The injury itself heals, but like an insidious memory, the pain lingers. We don’t know why. “The whole issue of the transition from acute pain to chronic pain—why some individuals develop that chronic pain and many don’t—is a major, major question,” says Allan Basbaum, a professor at the University of California, San Francisco. Genetics may play a role. So can the severity of the original injury.

    pills
    Today’s painkillers are based on well-known compounds like morphine and are often highly addictive.

    But what we do know is that once that pain has gotten a foothold, doctors and patients don’t have very many choices. “The irony is that morphine, the 2,000-year-old drug, still remains the number-one weapon against pain,” says Yves De Koninck, a professor of neuroscience at Université Laval in Canada.

    And it’s not a weapon that anyone enjoys using. Opioids like morphine and oxycodone are famously addictive, and the numbers of people who abuse them are climbing. Painkiller overdoses now kill more people than cocaine and heroin combined. And while opioids are invaluable for acute pain, they’re less effective for persistent, chronic pain. In fact—in a particularly cruel irony—long-term opioid treatment can actually make pain worse. Non-opioid pain medications exist, but they don’t work for the majority of patients, and even then they are only partly effective.
    Chronic pain is like “a maladaptive memory.”

    Opioids work so well for acute pain because they bind to the receptors the body has designed for its own painkillers—molecules like endorphins and dynorphins that blunt the pain response. Finding good alternatives to opioids for treating chronic pain will mean finding different neurological mechanisms to target—mechanisms that explain not just why people hurt, but why some people hurt for so long.

    De Koninck has found such a mechanism. One of the keys to understanding chronic pain, he believes, is to pay attention to the similarities between long-lasting pain and another, very familiar, neurological process that makes some connections stick around longer than others: memory.

    Chronic pain is like “a maladaptive memory,” Basbaum explains. Both constitute patterns etched in your brain and nervous system that quicken the connections between “snake” and “poison” or between “bump” and “ouch.” Evidence has been piling up that chronic pain and memory share some of the same cellular mechanisms—and now, De Koninck’s work has shown that a neurochemical trick used to erase memory may be able to turn off chronic pain, too.

    An Unmet Need

    The number of people struggling with chronic pain has been hotly debated, and the fact that chronic pain is broadly defined and difficult to quantify doesn’t help. But even conservative estimates suggest that about 20% of the population have had at least one episode of serious, chronic pain. In the United States alone, that’s more than 60 million people. “It’s a major unmet need,” De Koninck says.

    Pain is physically and psychologically debilitating in way that few other conditions are. “In fact, it’s often the most debilitating component of many diseases,” De Koninck notes. And it sharply circumscribes the lives of people who suffer from it. People can find a way to live with the other challenges of painful conditions like arthritis, cancer, even paralysis, he says, but “if you actually ask the patient, their number-one concern, and the one thing that they want us to cure, is the pain.”
    When pain pathways are functioning properly, they play a protective role.

    When chronic pain gets severe, many patients withdraw, sometimes even from their families. Sally says that she’s constantly nervous, afraid to accept invitations or do things that she loves—like riding horses—in case it makes her arm even worse. The ride that day, Sally says, “changed my life.” For some patients, chronic pain can lead to serious mental health problems—it’s strongly correlated with depression and suicide risk.

    When pain pathways are functioning properly, they play a protective role. They are a relay of chemical and electrical signals that move from nerve endings to our brains. Pain teaches us to avoid things that are sharp, prickly, or hot. It’s the way our nervous system has adapted to living in a hazardous world. People who can’t feel any pain typically don’t live very long.

    Our skin is packed with millions of specialized nerve endings, programmed to detect dangerous conditions like heat or pressure. When one of these pathways is activated, the neuron sends an electrical current shooting up its long, thin axon towards the spinal cord. When it reaches the end of the neuron, that electrical signal prompts the release of chemicals called neurotransmitters into the synapse, or the gap between the first neuron and the next. The neurotransmitters dock in receptors on the next neuron, triggering pores to open in the cell’s membrane. Charged particles rush in through these open pores, creating a new electrical current that carries the signal farther up the nervous system.

    nerves
    Nerve cells, like these seen here from a mouse’s spinal cord, send impulses along their axons and connect over synapses.

    The first handoff occurs in a region of the spinal cord known as the dorsal horn, a column of grey matter that looks, in cross-section, like a butterfly. From this first relay point, the signal travels to the thalamus, one of the brain’s switchboards, and eventually to the cerebral cortex, where the signal is processed and decoded.

    After an injury, it’s normal for the damage sensors near the trauma site to be touchy for a little while. During that time, your nervous system is encouraging you to protect the damaged tissue while it’s healing. But sometimes that extra sensitivity, called “hyperalgesia,” sticks around long after it’s useful. Hyperalgesia is often a major component of chronic pain, and it means that people with chronic pain have to be unceasingly alert. For example, Sally says, before she hurt her arm, hot coffee sloshing onto her hand might have hurt for a few seconds. Now, a careless moment like that means days of burning pain.

    Symptoms like this suggest that changes in the nervous system have migrated to the spinal cord. De Koninck believes that a major factor is the number of receptors on the signal-receiving neurons in the dorsal horn. If those neurons synthesize too many receptors, they’ll pick up too many neurotransmitter molecules. Then the neurons’ pores will flutter open to let charged particles in more often than they should, sending electrical signals shooting up to the brain at too high a frequency. The result is a pain signal that’s much stronger than it should be. De Koninck’s work gives us a new window into how it happens, and how to stop it.

    Recall, Then Erase

    The key lies in a study about memory that was published nearly 15 years ago. Long-term memories seem to depend on the synthesis of extra receptors, too, and scientists knew that blocking the synthesis of those receptors during a memorable event could keep memories from forming.

    But what a group of researchers at New York University discovered was that there is a brief period when interrupting receptor synthesis can actually erase old memories. Memories are reinforced when they’re retrieved, but, paradoxically, during that process, even well-established memories have a brief window of vulnerability—like jewelry in a safe deposit box, memories are useless when they’re stored but accessible to thieves when they’re being used. A chemical called anisomycin blocks the production of receptors that neurons need to form memories. When the researchers injected anisomycin into rats’ brains right after triggering a particular memory, that memory didn’t just fail to get reinforced—it was erased altogether.

    The right chemical injected at just the right place at just the right time could erase the physiological “memory” of pain.

    Accumulating evidence that pain and memory use similar mechanisms led De Koninck to wonder if this same neurochemical trick could erase chronic hyperalgesia. De Koninck and his colleagues made mice hypersensitive to pain by injecting their paws with capsaicin, the chemical responsible for chili peppers’ fiery bite. Capsaicin activates the same pain sensors that respond to extreme heat and can turn on hyperalgesia without the tissue damage that an actual burn would cause. After their capsaicin injection, the mice’s paws were more sensitive to pressure for hours afterward.

    Before that sensitivity had had a chance to wear off, the team gave the mice a second capsaicin injection—and this time, they added an injection of anisomycin. What happened after this second injection is “like magic,” De Koninck says. When the second injection initiated the same flurry of neurotransmitters and electrical signals that encoded the hyperalgesia the first time—the pain analogue of recalling a memory—anisomycin shut down the pain-amplifying mechanism by keeping the spinal cord neurons from making extra receptors. “It’s in the process of reorganizing itself,” De Koninck explains, “and there there’s that window of opportunity to actually shut it back down.” The mice lost seventy percent of their hypersensitivity to pain.

    The theory that overdeveloped connections other than memories could be attenuated by retriggering them “is not a new idea,” Basbaum says, “but the fact is, there really has been very little evidence that it’s doable.” De Koninck’s results suggest that the right chemical injected at just the right place at just the right time, can erase the physiological “memory” of pain. Ted Price, a professor at the University of Texas-Dallas, says that this “ paves the road to disease modification instead of just palliatively treating people with these terrible drugs like opioids, which everybody, everybody in the field wants to get away from.”
    New Options

    For now, there are a few other types of treatment doctors can turn to besides opioids. Antidepressants help some people, as do certain antiseizure medications. A controversial technique called “transcutaneous electrical nerve stimulation” may work by making sure that there are plenty of receptors in the dorsal horn for the body’s natural opioid chemicals; a wearable device using this technology was just approved for over-the-counter sale by the FDA.

    Treatments based on De Konick’s capsaicin-anisomycin model would constitute an entirely new category of drugs. “When you find a new mechanism,” De Koninck says, “boy, it opens a whole new array of things.” But finding the right combination of chemicals won’t be easy. Capsaicin patches are already sold over the counter at drugstores, but anisomycin is far too indiscriminate for clinical use. Brian Wainger, a physician and researcher at Massachusetts General Hospital, says, “It’s obviously going to be a long time for a discovery like this to work towards a clinical approach, but I think it sort of sets a framework for some options.”

    “Options” is a word that seems to come up a lot among pain specialists. One of the reasons chronic pain is so difficult to treat is because “there’s a lot of different forms of chronic pain,” De Koninck says. “But the arsenal that we have so far to treat it is still quite meager.” And the weapons we do have are woefully inadequate.

    Still, discovering that this retrigger-and-erase phenomenon works for hyperalgesia, as well as for memory, suggests that it may be useful in other parts of the nervous system. If that’s true, these kinds of treatments could help with pain syndromes more complicated than hyperalgesia—conditions that are so severe that even light touches become painful, or in cases where patients experience pain with no stimulus at all.

    One big advantage of De Koninck’s strategy is that it isn’t just an incremental improvement, a way to make a slightly more effective or slightly less addictive analgesic. It’s a totally different angle on the problem. It targets the “chronic” part of chronic pain. “What the field I think really needs is options,” Price says. “And more importantly, patients need options.” For millions of people, and their doctors, a totally different angle is exactly what they’ve been looking for.

    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 9:10 am on August 6, 2014 Permalink | Reply
    Tags: , , , , PBS NOVA   

    From PBS NOVA: “Collapsing 4D Star Could Have Spawned Universe” 

    PBS NOVA

    NOVA

    Mon, 16 Sep 2013
    Allison Eck

    There could be a gaping hole in the Big Bang theory. Or rather, a giant, colossal black-hole caused by the collapse of a four-dimensional star.

    One of the main problems with the Big Bang is that the temperature of the universe is nearly uniform. If a “big bang” event had created the universe, then according to some explanations, there hasn’t been enough time between then and now for it to have reached that temperature equilibrium. Here’s Zeeya Merali writing for Nature News:

    To most cosmologists, the most plausible explanation for that uniformity is that, soon after the beginning of time, some unknown form of energy made the young Universe inflate at a rate that was faster than the speed of light. That way, a small patch with roughly uniform temperature would have stretched into the vast cosmos we see today.

    But the Big Bang, as it’s envisioned, was so chaotic that few people had any idea what or from where that initial homogenous patch could have come from.

    bh

    supermassive-black-hole
    Some astrophysicists propose that the universe was formed by a collapsing 4D star.

    So Canadian astrophysicist Niayesh Afshordi and his colleagues have turned to an idea first proposed 13 years ago. In that model, our 3D universe is merely a membrane—also known as a brane—floating through a 4D “bulk universe:”

    Ashfordi’s team realized that if the bulk universe contained its own four-dimensional (4D) stars, some of them could collapse, forming 4D black holes in the same way that massive stars in our Universe do: they explode as supernovae, violently ejecting their outer layers, while their inner layers collapse into a black hole.

    In our Universe, a black hole is bounded by a spherical surface called an event horizon. Whereas in ordinary three-dimensional space it takes a two-dimensional object (a surface) to create a boundary inside a black hole, in the bulk universe the event horizon of a 4D black hole would be a 3D object — a shape called a hypersphere. When Afshordi’s team modelled the death of a 4D star, they found that the ejected material would form a 3D brane surrounding that 3D event horizon, and slowly expand.

    Afshordi’s team believes that the universe—its stars, nebulae, planets, even us—might be that very membrane, and that its inflation might be triggered by motion through a “higher-dimensional reality.” In other words, we might be living in a brane around the event horizon of a collapsed hyperdimensional star that gave birth to the universe.

    See the full article, with additional material, 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.

    ScienceSprings relies on technology from

    MAINGEAR computers

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