http://mitworld.mit.edu/ MIT World media in category 'Medicine'. en-us Tue, 24 Nov 2009 20:20:38 GMT Thu, 12 Nov 2009 00:00:00 -0500 http://mitworld.mit.edu/video/721 http://mitworld.mit.edu/video/721 An exemplar of the purpose-driven life in medical science, Ed Scolnick details research milestones from a remarkably varied career, revealing how scientific insight and collaborative effort translate into life-saving solutions for millions.

This physician turned biochemist has held distinguished positions at the National Institutes of Health, Merck, and now at MIT, but common themes unite his pursuits: “I’m always excited by the inherent beauty of molecular and biochemical insights into how biology works. Making scientific discoveries for me is tremendously emotionally satisfying and in fact addicting.”

In his talk, Scolnick touches on such research breakthroughs as identifying virus oncogenes, and developing treatments for cardiovascular disease, Hepatitis B, and osteoporosis, among others. He emphasizes that teasing out the biochemistry of diseases is “the key to success in drug discovery.” In Marfan syndrome, for example, investigators learned that a mutant gene leads to a malfunctioning aorta. Finding a cure flowed from understanding the underlying pathological processes. Scolnick proudly describes research on a gene involved with cholesterol buildup and an elevated risk for cardiovascular disease. This led to the development of statins, which has helped dramatically reduce the death rate in people with heart disease.

Scolnick offers a dramatic chronology of his pioneering work at Merck starting in 1981 to find an effective AIDS treatment, an effort leading to the protease inhibitor Crixivan. His timeline covers more than a decade of scientific collaboration to block the mechanism of HIV, and involves false starts, the death of a key scientist in the Lockerbie bombing, pressure from AIDS activists and corporate overseers, a “miracle” AIDS patient, breakthroughs in measuring viral protein, and more than one “twist of fate.”

In 2004, Scolnick turned in a new direction: toward mental illness, a field stalled for decades due to ignorance “about the underlying biochemistry and physiology of the disease.” Today, with the help of genomics and computative technologies, researchers are beginning to reveal the basic genetic architecture of schizophrenia and bipolar illness, says Scolnick. The “outline of their biochemistry” is starting to come clear for the first time, leading to the real possibility of novel therapeutics. While the challenges are formidable, he believes, consolidating MIT’s “first rate neuroscience, human genetics, chemistry (creates) a unique opportunity to do something in a field that desperately needs the kind of approach and change we were able to bring to the AIDS field.”

NOTE: Audio levels for Kastner and Horvitz are very low, but improve when Scolnick begins his talk. We apologize for the inferior audio capture in the field. ]]> Mon, 19 Oct 2009 00:00:00 -0400 http://mitworld.mit.edu/video/715 http://mitworld.mit.edu/video/715 John M. Barry brings unsettling news from the frontlines of H1N1 research: this novel influenza virus is very hard to pin down. In spite of international scientific scrutiny, H1N1 continues to baffle and elude, worrying health officials defending against the pandemic, and challenging some ideas about influenza in general. Says Barry, “A lot of things we thought we knew, the virus demonstrates we knew wrong.”

Barry examines the current pandemic in both historic and scientific context. Most influenza viruses share certain features: They can jump to other species by way of mutation, or by mixing genetic components with another virus that happens to be infecting the same cell at the same time. Influenza pandemics go “as far back in history as we can look,” with 10 occurring in just the last 300 years. Four of the most recent pandemics appear to have rolled out in waves of varying lethality, infecting at peak times some 30% of the human population.

Before last year, the latest pandemic threat seemed to be H5N1, an avian flu jumping to humans. But, says Barry, “while we were all looking at H5N1, this H1N1 virus snuck up on us…and we have no idea yet how serious it will be.” The problem for researchers is that H1N1 simply won’t behave in predictable ways. When ordinary influenza viruses are transmissible between humans, novel molecular markers are present. The current H1N1 doesn’t bear these markers, yet is transmissible. There are conflicting reports on whether this flu is more infectious than the seasonal flu. There’s evidence that some people over 60 are resistant, perhaps because they carry antibodies to previous influenzas. And although H1N1 doesn’t exhibit conventional molecular tags for virulence, it is virulent. Unlike seasonal flu, when H1N1 kills, it targets younger people, and it does so through viral pneumonia, as opposed to complicating bacterial infections. “Depending on how you ask the question, it’s either extraordinarily mild, more mild than seasonal flu, or more than 100 times as virulent as seasonal influenza.”

While H1N1 seems stable for the moment, and to some, unthreatening, its path can’t yet be plotted. Some of the most infamous flu epidemics take two years to travel around the world, moving from sporadic activity to “blanketing the entire globe and causing enormous morbidity numbers.” If this flu takes off, history tells us, short of a “retreat on a Vermont mountain with shotguns,” there will be nowhere to hide, says Barry. “This virus is going to find me.” ]]> Sat, 10 Oct 2009 00:00:00 -0400 http://mitworld.mit.edu/video/712 http://mitworld.mit.edu/video/712 How does someone move from recreational drug use to addiction? Barry Everitt’s group at the University of Cambridge has been trying to break down the stages and neural circuitry of addiction with great precision.

Everitt’s research attempts to operationalize a progression in animals from the voluntary taking of drugs, to the acquired habit of drug-taking, to the stage of compulsive drug-seeking and consumption, “where individuals have really lost control.” This progression seems rooted in the sequential activation of different learning systems in the brain, which are particularly sensitive to the neurotransmitter dopamine.

Research suggests that drug-taking is initially dependent on the nucleus accumbens (part of the ventral striatum), but its establishment involves the dorsal striatum. Studies show that dopamine in the dorsal striatum is causally involved in establishing drug-seeking behavior in rats. As the animal gets accustomed to taking the cocaine, there’s a “shift in the balance of associative encoding from ventral to dorsal striatum.” Cocaine craving and self-administration seem to change the functioning of the dorsal striatum in monkeys and humans as well.

While this shift from ventral to dorsal striatum depends to some degree on “pharmacology” (cocaine’s impact on dopaminergic systems), Everitt has hypothesized that it may also involve “spiraling circuitry” connecting the ventral striatum, the midbrain -- the brain’s motivational and motor mechanisms -- and the dorsal striatum. Everitt speculates that the compulsive nature of drug seeking may be rooted in part in the prefrontal cortex, home to “top-down executive control mechanisms.” He describes research that attempted to model this type of compulsion. Animals with short-term access to cocaine and most animals with long-term access to cocaine suppressed their drug-seeking responses when punished. But a subgroup of 20% “persisted in seeking cocaine in the face of punishment.” This result has been replicated many times now, and turns out to have a parallel among humans. This, says Everitt, “brings up the issue of vulnerability to drug addiction.”

Additional research suggests that impulsivity is a “behavioral characteristic that predicts the transition from initial drug intake to loss of control … to compulsive seeking and taking” of drugs. Highly impulsive animals denied cocaine become more impulsive and drug seeking over time, leading to relapses. Everitt and others are tracing the neural basis of compulsivity to impairment in the prefrontal cortex, which involves “a loss of control over maladaptive habits” established after long-term drug taking. ]]> Sat, 03 Oct 2009 00:00:00 -0400 http://mitworld.mit.edu/video/708 http://mitworld.mit.edu/video/708 Researchers have known for some time that the neurotransmitter dopamine is centrally involved in learning and working memory, Roshan Cools tells us, and that dopamine-responsive circuits connect these parts of the human brain to other structures like the striatum, which also helps orchestrate motor control. Cools has been investigating in detail how dopamine acts within these cortico-striatal circuits to influence different types of cognitive processing.

Specifically, Cools examined the effects of dopaminergic drugs (compounds that modulate the quantity of dopamine available to neurons, or the neurons’ responsiveness to dopamine) on human subjects as they performed a variety of performance tasks. She notes that there’s a “huge variability within and across individuals” to such drugs. The same chemical within the same subject may improve performance in one task, and impair it in another. The drug effect depends on an individual’s baseline levels of dopamine: If someone starts with suboptimal levels, a dopamine-enhancing drug can restore someone to baseline, whereas someone starting with optimal levels of dopamine might be overdosed by the same drug.

One of Cools’ studies looked at the impact of dopaminergic drugs in Parkinson’s disease (PD) patients, where “the primary pathology is dopamine depletion in the striatum.” This depletion is not uniform, though, in the early and late stages of the disease, and impacts different sites in the striatum. Early stage PD patients suffer more from motor deficiencies than from higher level cortical deficiencies. Through performance tests and fMRI scans,Cools confirmed her hypothesis that in mild PD, dopamine-enhancing medication impaired performance on probabilistic reversal learning (a higher level cognitive task), “presumably by overdosing relatively intact levels of dopamine” in one part of the striatum. Yet these same drugs improved performance on other tasks associated with a part of the striatum concerned with motor systems.

Cools has recently been testing healthy U.C. Berkeley undergrads with dopaminergic drugs, fMRI and PET scans, to see how levels of dopamine impact their performance on different learning tasks. Says Cools, “Dopaminergic medication improves reward- but impairs punishment-based learning in low-dopamine subjects and PD patients. Conversely, it improves punishment- but impairs reward-based reversal learning in high-dopamine subjects. This shift in the balance between reward- and punishment-based reversal likely reflects modulation by dopamine of striatal processing.” ]]> Sat, 03 Oct 2009 00:00:00 -0400 http://mitworld.mit.edu/video/709 http://mitworld.mit.edu/video/709 In the process of learning, we “sometimes make more deliberative choices, and sometimes make more visceral ones,” says Paul Phillips. These are “semantic terms we intuitively know,” and scientists have become well-versed in creating tasks for animals and humans that demonstrate how these different kinds of learning (analytical- reflective vs. impulsive -reflexive) play out. Phillips has been trying to track dopamine release (a neurotransmitter linked to learning) in such divergent learning processes.

The model-based learning system pairs a stimulus with a reward, and after training, a subject creates a “model representation of the world” that allows it to predict the appearance of the reward after the stimulus. In contrast, the model-free system of learning “uses a one dimensional value that gets updated” as the subject accumulates experience and begins to weigh the difference between expectation and the reward that’s actually delivered.

One of Phillips’ studies involved implanting electrodes for measuring dopamine release in the striatum of rats participating in different types of learning tasks. Phillips work shows time-dependent changes in the release of dopamine during classic conditioning tasks. At first the dopamine spikes only after the reward, but over time, the animal learns it will receive the reward after the stimulus (a light cue), and soon, the cue alone elicits the dopamine response. Phillips has also found that two distinct parts of the striatum register increased dopamine at different points in the training. “This is quite interesting in terms of thinking about what these brain regions have been implicated in, and specifically the idea of habits in the dorsal striatum.”

The results of some research suggest that during these learning processes, all the dopamine neurons should be firing. But Phillips says this doesn’t explain why “we’re getting signals in (one) part of the brain but not in the other.” Phillips speculates that dopamine’s “arch nemesis acetylcholine” might be inhibiting dopamine release in certain parts of the striatum during specific phases of reinforcement learning.

Phillips has also been working with selectively bred lines of rats, which seem to exhibit behaviors, and dopamine release patterns, suggestive of two distinct learning strategies. He concludes that “associations between stimuli and rewards can be learned through multiple strategies with different computational demands,” and he doesn’t believe that animals “are locked into one strategy or another.” ]]> Tue, 29 Sep 2009 00:00:00 -0400 http://mitworld.mit.edu/video/707 http://mitworld.mit.edu/video/707 As a mathematical engineer, Kenji Doya approaches the goal of describing the most intricate brain mechanisms from a computational perspective. He constructs models of reinforcement learning involving the networked structures of the basal ganglia. His efforts are captured and expressed quantitatively as probabilities, regressions, and algorithms.

In this presentation, Doya covers basic concepts of reinforcement learning, then surveys the last decade of inquiry into the components of the basal ganglia circuit governing voluntary motion. Among the topics: action values, action candidates, and reward prediction involving the neurotransmitter dopamine; model-free versus model-based learning strategies; and the essential role of serotonin as modulator in the complex information loop.

Doya’s recent research is carried out via robots he calls “cyber rodents.” His dream as an undergraduate was to “build a robot that learns the variety of behaviors on its own.” That is, the computer, not the human engineer, teaches the robot to move. He accomplished this in designing a machine-creature exhibiting emotion-like attributes characterized as “depression,” “impulsivity,” “greed,” and “patience.”

Doya believes the “metaparameters” of reinforcement learning must be “tuned appropriately…Otherwise the performance of your learning is very, very poor.” The iterative process involves three terms -- the reward itself, the expected reward for a new state based on choice of action, and memory of the reward gained in the previous state. In the comparison, any differential greater than zero can be exploited for learning. The tradeoff: “No pain, no gain.”

As research advanced to increasing levels of structural specificity, Doya posited that “there seems to be spatial segregation in the function” of basal ganglia components. Specialization in aspects of reinforcement learning is now seen, for instance, in ventral versus dorsal areas of the striatum.

Differentiation is also found in the cortico-basal ganglia information network: not a simple closed loop, but parallel electrical pathways conducting distinct neural operations. Further, the neuromodulators each have their respective missions. Dopamine encodes the temporal difference error -- the reward learning signal. Acetylcholine affects learning rate through memory updates of actions and rewards. Noradrenaline controls width or randomness of exploration. Serotonin is implicated in “temporal discounting,” evaluating if a given action is worth the expected reward. Doya reminds us that clinically “it is well known that the serotonin function is impaired in the depression patient.”

The system of basal ganglia components and neuromodulators requires dynamic balancing. A delicate interplay determines outcomes for learning, actions, and affective states. Doya’s synthetic models are proxies for human behavior, and his computational framework describing the moving parts ultimately has therapeutic implications for psychiatric and neurological disorders. ]]> Thu, 24 Sep 2009 00:00:00 -0400 http://mitworld.mit.edu/video/704 http://mitworld.mit.edu/video/704 Like tuning in a station on the FM band of a radio, neuroscientists can detect the particular frequencies of our brains in action. And just as on the radio, a little noise and static is to be expected. In Parkinson’s Disease (PD), as Peter Brown and colleagues are finding, too much of a certain type of frequency is a bad thing. Neurons in the basal ganglia produce a kind of overly synchronized beta frequency (in the 20 Hz range) that seems deeply implicated in some of the telltale symptoms of Parkinson’s.

Brown’s talk outlines efforts to record this “oscillatory synchrony” in PD, to figure out the physiological mechanisms behind it, and to connect beta synchrony directly to such key symptoms in PD patients as rigidity and bradykinesia (slowness in executing movements). Scientists can detect clusters of neurons in the subthalamic nucleus (a key component of the basal ganglia) “beating” at 20 Hz. Brown says the “exaggerated synchrony” of these neurons seems to have something to do with a chronic loss of the neurotransmitter dopamine. Ordinary subjects have a “fair amount of healthy beta activity,” notes Brown, and when these subjects engage in voluntary movements, such as extending a forefinger, the beta activity is suppressed. But in PD patients, says Brown, uncontrolled beta activity seems to promote postural contraction “at the expense of voluntary movement.”

Brown and others have recorded activity in the brains of PD patients undergoing two key treatments, Deep Brain Stimulation (where electrodes implanted in the brain try to break the pattern of normal neuronal firing), and dopaminergic therapy. Both methods relieve the symptoms of slow movement and rigidity. Excessive beta oscillations are suppressed during these two treatments. This is “correlative evidence,” says Brown, that beta activity is behind the symptoms. Scientists are trying to connect the dots, and find a causal link: After stimulating the neurons of the subthalamic nucleus to beat at 20 Hz, they observe a 20% slowing of movement. Brown is conducting additional studies that provide evidence in PD of a looping brain pathway involving not just the basal ganglia, but parts of the cortex, which has an “innate tendency for activity at 20 Hz,” causing bradykinesia and rigidity, and which can be damped by the input of dopamine. In closing, Brown acknowledges he must bring “the beta story …down to reality,” since it doesn’t seem to connect to other PD symptoms such as tremor, and “I’ve been a beta chauvinist here, and ignored other frequencies.” ]]> Thu, 17 Sep 2009 00:00:00 -0400 http://mitworld.mit.edu/video/703 http://mitworld.mit.edu/video/703 New tools are enabling neuroscientists to break therapeutic ground against daunting disorders like Parkinson’s Disease (PD). Andres Lozano is one “of a small group of heroes,” in Ann Graybiel’s estimate, whose work is yielding astonishing advances on a variety of fronts.

Treatments for PD, a progressive, degenerative brain disorder, have until recently dealt primarily with the loss of dopamine-releasing neurons, leading to the classic movement disorders associated with PD: tremor, rigidity, akinesia. But Lozano says that by the time these physical problems are diagnosed, “the reality is that the disease started 10-15 years earlier,” and has involved other brain areas. Lozano determined to focus on three such non-motor symptoms of the disease -- gait and posture, depression (in PD and other patients), and cognitive disorders -- and if possible, “reach these circuits, intervene and help patients.”

PD patients have serious problems controlling balance and posture, and animal studies helped pinpoint an area in the brainstem responsible for these functions. Lozano got permission to plant electrodes in humans in this area, and mapped out the sensitivities of neurons to voluntary movements such as flexing an ankle or walking. In six PD patients, Lozano sent a mild electric current into these neurons. He shows videos demonstrating the remarkable improvement in control (a patient pushed no longer falls) with deep brain stimulation (DBS). A serendipitous offshoot of this therapy is that it improves REM sleep, in which PD patients are deficient.

Lozano has been working as well on mapping and targeting areas of the brain involved in depression, which he has found to be hyperactive. He labeled neurons that responded exclusively to sad and disturbing images, and using DBS, he was able to “turn down the hyperactivity,” successfully reversing severe depression in 60% of his 36 subjects.

His final accomplishment emerged by accident: While attempting to treat a patient’s morbid obesity through DBS, Lozano was startled to find when stimulating the man’s thalamus the patient experienced a vivid sense of déjà vu. (He recalled being in a field 30 years earlier with a girlfriend.) The stronger the current, the more details emerged. When the stimulus ended, the memory ceased. Lozano hopes, via DBS, to help patients with memory disorders. Another intriguing discovery: stimulation in the hippocampus, deeply involved in memory, seems to lead to a burst of new neuron development. These DBS studies suggest, says Lozano, that brain circuits for mood, motor control and cognition can be modulated, and we now “need to determine whether they are safe and beneficial to patients.” ]]> Tue, 11 Aug 2009 00:00:00 -0400 http://mitworld.mit.edu/video/697 http://mitworld.mit.edu/video/697 These panelists use the lens of systems engineering to focus sharply on some signature global challenges in finance, healthcare, energy and IT.

The system failure that undid the small but influential financial services industry was a few decades in the making, says John Reed. In the ‘80s, a sea change swept over firms trading hundreds of billions of dollars each day. The new mantra was “shareholder value.” Firms ditched time-honored rules of capitalizing trades and guaranteeing risk in order to build investor profits. The crystallization of this philosophy was the mortgage-backed security. Trillions of dollars went into “off-balance-sheet investment vehicles.” When the nation’s mortgage portfolio deteriorated, not just one node in the system collapsed, but all of them. To fix the financial sector, says Reed, “A systems view will be essential, including behavioral considerations, not just economics.”

There’s no point in saying U.S.healthcare is broken unless you can offer a vision. For Denis Cortese, this means designing a “learning organization.” Cortese maps out this organization’s goals: simple value, with “better outcomes, better safety, and better service at a lower cost over time.” His proposed system would focus on the patient’s needs in order to “raise the health of the entire population.”

Cortese doesn’t see a role for the government in his ideal organization. But there must be better metrics for determining value, coordination among large and small healthcare organizations, and “common principles in the payer domain.” Ultimately, we’ll need to define quality healthcare and set outcomes: “It won’t be perfect, but it will be better than where we are today.”

Nine billion people will inhabit the planet by 2100, and many of them will either be acquiring energy for the first time, or wanting more. This has “unpleasant if not catastrophic” implications for greenhouse gas emissions, says Steven Koonin. Powering up while securing affordable energy and minimizing emissions involves better modeling of the physical and biological climate system; overcoming the inertia of our current transportation and building industries; and improving the “patchwork” of our current energy grid. Koonin sees immediate opportunities to cut energy use in half in cities, but we “must bring policy up to speed” to make this happen.

Tackling global problems won’t be possible without an improvement in complex organizational systems, says Irving Wladawsky-Berger, which in contrast to physically engineered systems, haven’t progressed in the past century or so. Change is creeping in, though, as organizations manage increasing amounts of data with more integrated instrumentation and swelling computer capacity. Wladawsky-Berger sees new tools emerging such as cloud computing and networked data centers, leading to the standardization and customization of services for producers and consumers. He believes that the “merging of the digital infrastructure with the physical infrastructure” will lead to new ways of life, including smarter cities with smart traffic systems that reduce congestion and pollution. ]]> Fri, 31 Jul 2009 00:00:00 -0400 http://mitworld.mit.edu/video/694 http://mitworld.mit.edu/video/694 It’s rare to find research that simultaneously advances basic science and brings good into people’s lives, but Pawan Sinha’s Project Prakash does precisely that. An investigator of human visual processing, Sinha is interested in how these brain mechanisms develop. For his work, Sinha realized the ideal subjects would be individuals who developed sight after blindness. Since he could not ethically create such an experimental population, he had to “rely on natural experiments” -- children born blind, but who recovered their vision.

Sinha found these subjects in his native India, which has the world’s highest number of blind children -- more than one million. They are victims of Vitamin A deficiency, congenital cataracts, and absent or atrocious medical care. But salient to Sinha’s research, many of these blind children could be treated. He glimpsed a humanitarian and scientific opportunity, and Project Prakash (Sanskrit for light) was born.

Starting a few years ago, Sinha and his team began screening blind children in a few villages to identify cases of treatable blindness, and remedy their disorders. More recently, he’s gained support from hospitals and schools for the blind, reaching many more children. He began to establish a test population. Research on this unique group has yielded many original insights into the development of vision, and shaken some major scientific dogmas. Sinha found that after years without visual stimuli, the brains of these children could process new information flooding in -- challenging the notion of early critical periods in brain development. He discovered that patients who once learned about objects simply via touch could, once they gained sight, identify the same objects simply by looking at them.

Sinha has also delved into the mechanisms of visual integration -- how our brains make sense of visual cues containing diverse colors, illumination, and patterns. He’s learned that newly sighted patients have difficulty parsing overlapping images (such as triangles, squares, circles), but moving these images around magically sparks recognition. Research results are consistent across all ages, and show that early stages of sight acquisition involve seeing the world in a fragmented way, compromising recognition, and that motion cues are critical for putting pictures together meaningfully, serving “a critical bootstrapping function for visual learning.”

The kinds of integrative difficulties experienced by Project Prakesh children bring to mind similar difficulties in autistic children, for whom motion processing also seems to be deficient, and Sinha is now seeking a possible “causal chain in autism” that leads to the disorder’s devastating social impairments -- a research path that might someday yield new therapies. ]]> Thu, 09 Jul 2009 00:00:00 -0400 http://mitworld.mit.edu/video/687 http://mitworld.mit.edu/video/687 In contrast to cardiovascular disease, few breakthrough remedies for psychiatric illness have emerged in the past half century. Edward Scolnick lays blame for this dismal situation on barriers to understanding the genetic basis behind such illnesses. But the research drought may be over, as the current revolution in human genetics opens wide a door into the molecular biology and brain physiology behind diseases like schizophrenia and bipolar disorder.

These common, chronic and disabling mental illnesses are complex, involving abnormal behaviors that vary in expression. They have also lacked the kind of quantitative tests that enable precise diagnosis. While science has demonstrated that the single biggest risk factor for both schizophrenia and bipolar disorder is genetic, it has not been able to design tools for exploring how the genetics relates to the evolution of the disease in people. But just in the last two years, with the sequencing of the human genome and maps of human genetic variation, ignorance has given way to major findings.

In schizophrenia and bipolar disease, researchers have discovered that gene deletions and duplications (called copy number variants) cause significant brain circuit mischief. They’ve also learned there are gene variants common to both diseases, as well as clusters of genes that malfunction. Scolnick describes diverse research at MIT, proceeding at a “breakneck pace,” that uses this genetic information “to delve into the malfunctioning of brain circuits.”

Scientists have applied functional magnetic resonance imaging to compare the brains of ordinary people and schizophrenia patients, and discovered that the schizophrenic’s brain in a resting state is hyperactive. Other researchers found that schizophrenics generate the gamma brainwaves involved with higher mental activities in a different manner than control subjects.

Another MIT lab has begun to manipulate specific brain circuits using optical technology -- shining different wavelengths of light at special interneurons that regulate the firing of other neurons, and which are postulated to have a critical role in the malfunctioning of schizophrenics’ brains. Two other MIT labs are examining the biochemical disruptions due to altered genes, and developing “safe, specific chemical inhibitors” that might yield potential treatments for schizophrenia and bipolar illnesses. In Japan, researchers are growing stem cells into brain cells, which may lead to precise experiments that relate genetic problems to malfunctions in brain wiring. Indeed, adding up this research, a central biochemical pathway central to the pathogenesis of psychogenic illness seems to be emerging, knowledge that “can be exploited to understand illness and to find drug treatments.” ]]> Fri, 12 Jun 2009 00:00:00 -0400 http://mitworld.mit.edu/video/679 http://mitworld.mit.edu/video/679 Measured in human suffering, and by statistics, Alzheimer’s Disease (AD) presents a formidable specter: with incidence approaching 30 million worldwide and growing rapidly, it is now the sixth leading cause of death in the US. As life expectancy lengthens, AD is anticipated to triple in prevalence over the next few decades. The disease is found in nearly 50% of people age 85 and older. Triply higher medical costs are incurred by seniors with AD. These daunting facts give urgency and weight to molecular neuroscientist Li-Huei Tsai’s research.

Tsai begins her presentation with an historical perspective of Alzheimer’s, first documented in 1901 in Germany as “strange behavioral symptoms and loss of short-term memory.” Post-mortem examination of a patient’s brain showed “the hallmark pathological lesions: amyloid plaques and neurofibrillary tangles.” Telltale manifestations include “forgetfulness, …confusion, disorganized thinking, impaired judgment,” difficulty expressing oneself, spatial and temporal disorientation, and incapacity in daily activities. Family members must often quit jobs to provide round-the-clock care. In the advanced disease, becoming bedridden engenders chronic infections, secondary conditions, and eventual demise.

Definitive clinical diagnosis can be elusive. Imaging techniques with radioactive tracers, using a compound that selectively binds with amyloid plaques, help to identify AD. Tsai describes several cognitive tests developed by fellow MIT researchers to aid in confirming the disease. One method assesses retention of verbal facts and geometric figures. Another diagnostic tool is functional MRI, pinpointing brain areas activated upon exposure to new versus repeated scenes, a challenge for memory. Both approaches reveal notable distinctions between AD patients and control subjects.

“Currently there is no treatment that can prevent, delay or reverse Alzheimer’s Disease,” says Tsai. FDA approved drugs that act upon neurotransmitters postpone cognitive deterioration by only a few months.

Using a transgenic mouse model, Tsai’s pioneering research seeks to target compounds that can preferentially manipulate proteins to assume a desired structure. Resulting cellular differentiation into neurons could help correct deficits of AD by augmenting brain volume in specific regions, thereby enhancing learning and memory.

Just as experimental mouse subjects perform better with “environmental enrichment…by keeping them very physically engaged,” Tsai recounts that “people with higher education, more active lifestyles” benefit cognitively as they age. As to the respective contributions of genetic and environmental factors, she believes “it’s really a combination.” Though treatment for Alzheimer’s will not be solely pharmaceutical, Tsai hopes to identify chemical compounds to ameliorate the characteristic brain atrophy that robs one of vitality and dignity. ]]> Tue, 09 Jun 2009 00:00:00 -0400 http://mitworld.mit.edu/video/677 http://mitworld.mit.edu/video/677 In their symposium introduction, Susan Hockfield and Mriganka Sur place MIT at the forefront of a revolution in neuroscience. Hockfield, a neuroscientist by training, recaps the evolution of the discipline at MIT, from its 1964 start in the Department of Psychology to the more recent establishment of the Department of Brain and Cognitive Sciences. These changes mirror the transformation of a field in which, says Hockfield, “at first you could do little more than make qualitative observations about behavior and only speculate about causes, to one that can examine brain function at the level of molecules and cell circuits; that can conduct quantitative experiments with genetically targeted model systems and can directly observe the living human brain in action.”

We are now poised “for the first time in human history to deliver scientifically designed, rational therapies for some crippling disorders of the brain.” Hockfield credits MIT’s progress to “meta-experiments,” specifically collaborations among scientists and engineers, and the generosity of patrons.

Mriganka Sur and his colleagues believe “the vast majority of brain disorders have their roots in brain wiring gone awry,” so a solution to such disorders lies in understanding the wiring, and its associated functions. MIT gets at these questions from many angles of research, including the genetic underpinnings of brain development, the architecture of synaptic pathways and networks, and the brain’s response to environmental stimuli. MIT addresses research problems through a “unique interdisciplinary effort” comprising molecular biology, neuron and cognitive science, and computation. What’s more, researchers have united behind a singular mission -- a “wish to make a difference in the world” -- which involves a specific focus on addressing such brain disorders and diseases as dyslexia, Alzheimer’s, schizophrenia, and autism. “There is not one other entity like this anywhere else,” says Sur, who believes MIT’s potential for future impact is “virtually limitless.” ]]> Tue, 09 Jun 2009 00:00:00 -0400 http://mitworld.mit.edu/video/678 http://mitworld.mit.edu/video/678 This self-described “basic neuroscientist” confesses he never thought he’d give a talk on autism, but as Mark Bear recounts, decades of research in the basics are now paying off with important insights into the etiology and treatment of brain disorders, including autism.

Bear provides a primer on this developmental disorder, noting that its roots are biological, it is highly heritable, and astonishingly prevalent: one in 150 people express some of the symptoms of autism. These fall on a spectrum, from severely reduced social behavior, abnormal language, repetitive movements, seizures and mental retardation, to the milder Asperger’s Syndrome, where individuals are often academically successful, but socially awkward. Particularly significant to Bear: Autism’s underlying genetic changes manifest themselves in problematic communication between neurons.

To unravel autism, researchers are examining its clinical heterogeneity, “genetic risk architecture,” and how it alters brain connections and function. One of the difficulties in approaching autism is that a variety of genetic mutations can result in autistic behaviors, and only a few of these mutations have been identified. Bear himself has been probing the single gene disorder, Fragile X syndrome (responsible for about 5% of the cases “of full-blown autism.”) In Fragile X, the FMR1 gene is silenced, leading to a missing protein that serves as a key regulator of brain proteins involved in neuron communication. Without FMR1, “the brakes are missing,” and there’s excessive protein synthesis leading to altered brain function.

Bear hypothesized that it might be possible to correct Fragile X by bringing the system back in balance. He created mice models of the disease, and found that by reducing the number of neurotransmitter receptors that respond to the excessive brain proteins, he could ameliorate or correct Fragile X defects. These receptors are “druggable targets,” and, says Bear, “if the treatment works in fly, fish or mouse, it better work in humans or Darwin was wrong.”

Based on this work, drug companies are devising compounds to test in human clinical trials of Fragile X syndrome. In addition, Bear notes, colleagues have discovered that other mutations connected with autism also involve protein regulation problems. “This gets us excited, because it looks like a common pathway that causes synaptic dysfunction in different diseases that may ultimately manifest as autism. If that’s the case, then treatment for the disorder may be efficacious in multiple disorders.” ]]> Sun, 07 Dec 2008 00:00:00 -0500 http://mitworld.mit.edu/video/623 http://mitworld.mit.edu/video/623 In an energetic talk delivered prior to the U.S. presidential election, Jonathan Gruber provides a useful breakdown of the two candidates’ remedies for the nation’s troubled health care system. His detailed analysis of the key issues around health care may prove invaluable as the next president assumes office.

After decades of discussing health reform and watching national health costs balloon uncontrollably, says Gruber, we may finally be watching a consensus emerge to fix what’s broken: a crisis where more than 47 million Americans lack health insurance, and “are a car accident away from being bankrupted.” Gruber describes key areas that reform must tackle: pooling of health care markets, affordable plans, and mandates. The left and right differ on how to guarantee that sick, poor, young and old pay a fair price for medical care, the degree to which government must subsidize the poorest Americans, and whether the nation should or can achieve universal coverage. One side favors a single payer system, and the other tax credits, and both sides contain fatal flaws, says Gruber.

A new way is coalescing called incremental universalism, says Gruber, and its basic outlines emerge from Massachusetts’ 2006 health care system. There’s heavily subsidized insurance for folks below the poverty line, as well as insurance that works for those above poverty cutoffs. Every employer in the state with 10 or more employees must offer health insurance. There’s also an individual mandate (a source of contentious debate, as Gruber attests), so no one can skirt the issue of holding health insurance and hoping for the best. Gruber says after two years, the plan “is doing fantastically,” with a huge pickup (440 thousand) of previously uninsured people onto the health care rolls. The cost of people getting free care at hospitals fell almost by half in the first quarter of 2008.

But Gruber admits he’s not sure what to do about cost control. We currently spend 16% of GDP on health care. Obama’s plan, modeled after Massachusetts’ but with no mandate, will likely cost between $60-100 billion. McCain advocates ending the tax exclusion for employer sponsored insurance, and handing out tax credits. Says Gruber: “Obama’s got a terrific plan that needs money and McCain’s got money in need of plan so put them together.” Add a mandate to Obama’s plan, and then get rid of the tax exclusion. “You could have universal coverage in America more generous than in Massachusetts, and have 50 billion a year left over to spend on wars or whatever.” ]]> Mon, 17 Nov 2008 00:00:00 -0500 http://mitworld.mit.edu/video/614 http://mitworld.mit.edu/video/614 In what Dean Dave Schmittlein bills as a master class, Ronald A. Williams discusses how an emphasis on new technology and application of basic values helped turn around the health care giant Aetna.

Williams’ case study begins in 2001, when he arrived to find a corporation bleeding out -- having lost $280 million in the past year. He diagnosed key areas of failure and opportunity in Aetna’s vast enterprise: orchestrating medical, dental and other health and insurance benefits in a network of 843 thousand health care professionals with 37 million members. Williams shaped a path to recovery focusing on a better understanding of Aetna’s current customers, from small employers to the largest corporations, and the best way of expanding into new markets such as retailers, banks and law firms. To do this, Aetna needed to build products and services suited for those groups, and Williams’ strategy involved developing integrated information systems for both employers and consumers, to ensure cost-effective, and high quality health care delivery.

Williams repeatedly made the his case for this new strategy directly with Aetna’s staff. He pressed the issue of values: integrity, employee engagement, excellent service and high quality healthcare, and put in place employee surveys and biannual performance reviews. Employees were invited to answer whether they believed their supervisors held true to Aetna’s values and whether they were proud to be working with the company. Williams has noted a marked improvement in responses over just a few years. External benchmarks reflect positive growth as well: Aetna has reached the number one spot as Fortune Magazine’s most admired health care company, after occupying the rock bottom position.

Williams invested a great deal in technology he believes will “shape the future of health care.” He describes a Care Engine, containing an individual member’s personal health record and up-to–the-minute journal information and health guidelines that are “converted into computer algorithms.” This system can detect and fill gaps in care for patients -- conditions that go undetected, tests that should be administered, medicine that should not be prescribed. Williams has also given consumers the ability to find and compare the costs of tests and doctor visits. He believes we can check the trillions of dollars in health care spending through smart technology. For him, health care reform means we “get and keep everyone covered; maintain the employer-based system… reorient the system toward prevention, value, and quality of care; and use market incentives to improve coverage, drive down costs and make the system more consumer-oriented.” ]]> Sat, 13 Sep 2008 00:00:00 -0400 http://mitworld.mit.edu/video/594 http://mitworld.mit.edu/video/594 Don’t believe everything you learn in business school, cautions Harvard Business School professor Clayton Christensen. “It’s the principles of good management we teach that cause successful companies to fail.” In this meaty lecture, Christensen distills several books’ worth of research describing how business leaders sometimes metamorphose into losers when confronted with market-rocking innovations. He also reveals how we may harness his insights in such socially significant and complex industries as health care.

Christensen distinguishes between the kind of sustained and incremental technological improvements that help a market leader retain its edge, and “disruptive technology,” where a simple and affordable idea takes root in “an undemanding application at the bottom of the market, then improves from that foothold.” Christensen, looking at lots of industries “found almost invariably that an entrant company came in and killed the leaders” by way of a simplifying technology. He offers a case study of apparently marginal mini-steel mills that over a few decades toppled big U.S. steel mills. As the little guys pursued the lowest profit segment of the steel market with their more efficient, lower-cost methods, the big mills fled to where they imagined higher profits lay. Says Christensen, “You’re a little boy and want to win a fight against the giant. The best way to win is to pick a fight where the giant is motivated to flee rather than to fight.”

This has happened in the computer industry (mainframes to PCs), and with autos (Ford to Toyota). Department stores yielded to Walmarts, and JP Morgan to Fidelity, says Christensen. In each case, three enablers come into play: the transformation of a basic technology problem in the industry into “something that’s foolproof and idiot simple;” and the embedding of that solution into a cost-effective business model, which itself falls within a “complete vertical commercial system.”

Christensen spies symptoms of such disruptions bubbling up in the health care industry, such as molecular diagnostics, imaging technologies and high bandwidth telecom, and business model innovations. Integrated health systems like Kaiser Permanente have a leg up in deploying and optimizing these disruptive technologies.

The push for widespread health care reform must come from employers, who in spite of their declared intent to cut health care costs also know “they profit when their employees are healthy and productive.” Affordable health care, he concludes, “doesn’t come by expecting high end, expensive institutions or expensive caregivers to become cheap, but by bringing technology to lower cost providers and venues of care, so they can become more capable.”
]]> Sat, 16 Aug 2008 00:00:00 -0400 http://mitworld.mit.edu/video/587 http://mitworld.mit.edu/video/587 In a neat series of time capsules tagged to his MIT experience, Neil Pappalardo shares his story with MIT graduates in the hope that it will give them “an idea of the possibilities that lie ahead.”

His story begins in 1964, when as a senior majoring in Physics, he decided to pursue a thesis on a medical topic, without, Pappalardo notes, having attended a single course in design or synthesis. He met cardiologists at a Boston hospital searching for a labor-saving way to analyze hours’ worth of EKG data. In a matter of months, he had invented a device to solve the problem, graduated in Electrical Engineering, and set out for a career at Mass. General Hospital. Lesson learned: “An MIT education will awaken creativity and discovery within you.”

Pappalardo recounts his early financial hardships (he had to sell blood for 12 weeks in order to buy a piano for his wife), as well as setbacks in trying to improve the complex and often error-prone workings of the hospital, via the entirely new concept of computer systems. “Everyone knows computers can be used for financial accounting,” Pappalardo recalls people telling him, “but they can never orchestrate clinical processes, treatment or care.” No one believed someone as young as he could tackle the complexities of hospital administration. He was determined, though, and took “every computer science course MIT has to offer -- all two of them.” With some partner programmers, Pappalardo in six months came up with an automated system to reduce errors in clinical laboratory tests at the hospital. Lesson: A rigorous MIT education will ignite passion within you.

In 1968, a 26-year-old Pappalardo, father of three, departed Mass General to start his own company. While venture capital liked his software, they didn’t think his business plan would fly if hospitals had to purchase it on $200 thousand computers. So Pappalardo tweaked the plan with a bold innovation: Run the software on his company’s computer and use a phone line to connect to the hospital. The VCs were impressed, and Meditech was formally born, August 4, 1969, the same day as Pappalardo’s fourth child. Since then, Pappalardo’s company has grown to provide a comprehensive set of medical, administrative, and financial software products, serving 25 million patients in 2,200 hospitals worldwide. And he has become one of MIT’s most generous patrons. Says Pappalardo: “An MIT degree will open doors, and bestow confidence.”

Pappalardo closes: May your own children be proud of you, of your accomplishments … and of your contributions to society. ]]> Mon, 14 Jul 2008 00:00:00 -0400 http://mitworld.mit.edu/video/576 http://mitworld.mit.edu/video/576 Few scientists have charted the grim territory of fear and anxiety with the same doggedness and precision as Michael Davis.

Nearly four decades ago, researchers learned that animals, including humans, startle more when fearful. A sudden noise in a dark, creepy alley provokes a greater reaction than in a well-lit room, for instance. That got Davis and his colleagues wondering what neural mechanisms underlie the startle reflex, and how fear plays a part in the response.

In his talk, Davis describes the meticulous experiments he and others have conducted over many years. Starting with the fear potentiated startle test -- where animals are trained to pair a stimulus such as light, or sound, with a shock -- researchers began to track the pathways that mediate the response in the nervous system. Using chemical tracers that could follow electrical activity in the brain, Davis found a group of cells in the central nucleus of the amygdala that are critical for fear conditioning. “It was a nice day in the laboratory,” he says. When he knocked out this part of the amygdala with drugs or a lesion, it selectively decreased fear potentiated startle.

More studies produced maps showing that outputs of the central nucleus affect other areas of the brain involved in the symptoms of fear and anxiety, such as elevated blood pressure, sweating, clammy skin, panting and pupil dilation. Of particular interest to Davis, though, were the connections between the central nucleus and another part of the amygdale long thought to be interrelated, the bed nucleus of stria terminalis (BNST). When drugs inactivated the BNST, the startle response was completely blocked.

Davis began disentangling the mechanisms of these two areas, and found that a specific peptide, corticotrophin releasing hormone (CRH) “produces a constellation of behaviors that look very much like fear and anxiety” -- and acts on receptors only in the BNST. He began to test the idea of two systems acting in parallel in the brain: fear, of relatively short duration, orchestrated by the central nucleus; and anxiety, more diffuse and sustained, originating in the BNST.

Davis proposes that cognitive inputs (perhaps bad experiences and memories) help drive the release of CRH and long-term anxiety, including common debilitating phobias (fear of heights, darkness) and post-traumatic stress disorder. Research has shown that to extinguish such fears, new kinds of ‘inhibitory’ learning must take place. Davis recently discovered a compound, D-cycloserine, that has proved extremely promising in psychotherapy aimed at extinguishing phobias. ]]> Mon, 11 Feb 2008 00:00:00 -0500 http://mitworld.mit.edu/video/524 http://mitworld.mit.edu/video/524 Cancer is a conniving enemy. Try to kill it off through surgery or chemotherapy, and it finds a way to sneak back in. Jacqueline Lees tells an engaged Soap Box audience what insights and tools research now offers in the longstanding battle against this relentless disease.

Big gains have come from molecular study of tumors at different stages, Lees says. It often takes many years for a cancerous cell to develop into a dangerous tumor, one that can yield metastases. There might be six phases of development over 15 years in a cancer’s evolution, and scientists have formed a good understanding of what these different lesions look like in various cancers, and how they behave. Lees calls this process “actually a beautiful example of evolution,” since the cell that mutates and begins to divide uncontrollably evolves to become more successful relative to other cells in the tissue.

Other research focuses on the genetic basis of cancers. Two “flavors” of genes appear responsible for provoking cancerous changes in cells: oncogenes and tumor suppressor genes. It may be possible to intervene along the genetic pathways underlying cancer growth, says Lees. Her own work, involving mutant mice and zebrafish, hopes to identify the mechanisms involved in specific kinds of tumors, and to figure out ways of inhibiting cancer cell growth. Understanding the nature of specific cancers might help prevent treating people with chemical agents that don’t work for their kind of cancer, and that actually increase their tumor’s growth.

With the advent of fast and inexpensive genetic screens, it may soon be possible to determine whether each of us carries genes that predispose us toward certain kinds of cancers. But Lees questions the universal adoption of DNA testing, not just because of privacy concerns, but because there may very well be no known cure if a predisposition to disease is found. “If we sequenced every baby, and said you’re highly predisposed to a cancer, and there’s nothing we can do, would that be information people want to have?” Lees wonders. “If we could find a rapid way to sequence small subsets of genome, identify people with high risk and we could treat them if we knew they had those diseases, there’d be an argument for that, much as we do testing for diseases where we know can intervene if find children carrying them,” says Lees. ]]> Wed, 16 Jan 2008 00:00:00 -0500 http://mitworld.mit.edu/video/516 http://mitworld.mit.edu/video/516 Jim Yong Kim and Partners in Health are paradoxically suffering from their own success. They demonstrated over the past decade that it is possible to set up effective HIV and primary care clinics in such developing nations as Haiti, and that it’s possible to cure multiple drug resistant tuberculosis. They even managed to persuade pharmaceutical companies to permit the production of generic, less expensive antiretroviral medicines so they could be affordable to the poorest people. But now, as billions of dollars flow into efforts to attack diseases that needlessly kill and maim the world’s poor, we find ourselves “living in the middle of an implementation bottleneck,” says Kim.

Whether from the Gates or Clinton Foundations, or from international government initiatives, money is flowing into new products like HIV/AIDS vaccines, TB vaccines, microbicides, anti-malarial drugs, and surgical services such as male circumcision. It could all “have a huge impact,” says Kim, helping to forestall 10 million preventable deaths per year, but for the increasingly massive logjam in delivering all the care. Why is it so hard to distribute the expertise, technology, resources, to the people in need? There are all kinds of “just answers” that Kim gets: just align incentives; just make the markets work better; just fund infrastructures adequately; just give workers the management skills.

While he agrees that these are all relevant issues, Kim really wants an integrated response. He’d like to see medical schools like Harvard, where he’s on staff, develop the kind of case studies commonly employed at business and engineering schools to dissect complex strategy problems. For instance, medical students today have no idea how smallpox was eradicated – the story of this immense project combining management and epidemiology has been lost as a teaching tool. Just as Harvard Business School was “teaching the Jet Blue meltdown three weeks after it happened,” so must medical schools capture current problems and approach them both qualitatively and quantitatively.

Kim calls on institutions like MIT Sloan to help devise new analytic frameworks for examining and improving global health delivery. “There’s room for a whole new field, health care delivery science,” says Kim, combining multiple disciplines, and developing leaders to advance evidence based strategies. We can’t alleviate human suffering caused by disease “just being the lab, or by doing clinical research.” It’s now time “to build functioning health care systems everywhere in the world.” ]]> Wed, 09 Jan 2008 00:00:00 -0500 http://mitworld.mit.edu/video/514 http://mitworld.mit.edu/video/514 Don’t foolishly advise Paul Farmer that his bold projects can’t succeed. For the past 20 years, Farmer’s been toppling orthodoxies concerning the delivery of health care to people of developing nations, and to our country’s inner city poor. In a talk full of insights and anecdotes, Farmer brings his audience up to date on his groundbreaking work and methods.

In the early 80s, Farmer was a Harvard medical student studying infectious disease in Haiti. HIV was taking a deadly toll there and in the U.S., but Farmer was struck by the inequity of treatment. “The idea of a different standard of care for people 1 ½ hours from Miami didn’t strike me as a good idea.” Health care, Farmer came to believe, is a basic human right.

In the early 90s, antiretroviral drugs emerged in the U.S. as a powerful treatment for AIDS -- but were priced beyond the reach of developing countries. Farmer and his colleagues began a public battle against such global inequalities. They demanded affordable drugs, and support for community-based health care initiatives, viewed by international funders as unsustainable and cost-ineffective.

With a loan from a commercial bank in Boston, Farmer set out to prove everyone wrong. Starting with one facility, Farmer established community medical clinics across Haiti, run by and for Haitians, securing and disbursing affordable drugs for HIV and TB, and educating the community in preventive medicine. Local workers spread out into neighborhoods, to initiate and follow up on care. Farmer used his AIDS programs “as a battle horse to ride into the fight against poverty, and to talk about education, food security and housing.”

Farmer’s support broadened to include such powerful funders as the Clinton Foundation. This has enabled him to take his program into Africa, first to Rwanda and more recently to Lesotho and Malawi. Farmer’s Partners in Health group rebuilds medical infrastructure weakened by war or years of neglect; takes care of the sick; and then trains hundreds of local citizens. Haitians, whom Farmer describes as his teachers, have been spearheading much of the work in Africa. The costs of scaling up come less from labor, than from basic goods like food, and bumps in the supply chain. But the biggest obstacle of all, says Farmer, is “nay-saying, low expectations, a certain undertow of censorious opinion. As if it weren’t hard enough to do the work, you have to fight a lot of skepticism, not from patients, coworkers or family members, but from your peers.” ]]> Mon, 10 Dec 2007 00:00:00 -0500 http://mitworld.mit.edu/video/504 http://mitworld.mit.edu/video/504 If, as Paul Levy says, “medicine for the most part remains a cottage industry,” then how can you impose system-wide improvements -- especially if you’re presiding over an academic hospital, where the culture rewards brilliant, independent, free-thinking doctors?

This has been Levy’s challenge since 2002, when he took over an ailing Beth Israel Deaconess Medical Center. The result of a merger between two hospitals in the late ‘90s , BIDMC immediately fell into a “downward spiral,” recounts Levy. Doctors and nurses left, and losses grew to nearly $70 million a year. The hospital burned up $200 million of a $500 million endowment.

When he arrived, Levy recognized that the hospital’s problems had less to do with medicine than with management and organization. For instance, it took 100 days for a bill to go out after the actual service was performed, and bills were often inaccurate, based on a doctor’s hand-scribbled note.

Levy set to work enhancing the hospital’s routines, such as providing an electronic billing system with pull-down menus. He met with demoralized nurses to address their concerns, and succeeded in reversing the 15% turnover rate. Then, says Levy, “we started focusing on what really matters: how well we’re taking care of people, how often are we hurting and killing people and what to do to stop.”

Hospitals, he notes, “are very dangerous places,” with “bugs floating around and mistakes being made.” One common problem at BIDMC, ventilator associated pneumonia, had a 30% mortality rate. The fixes were simple --raising beds, better oral hygiene, hand-washing --but accomplishing them required systemic compliance.

Levy identified doctors who could lead colleagues in the new practices. He attached protractors to beds so nurses could raise them by precisely 45 degrees. “Lots of low-tech solutions must be institutionalized,” says Levy. Mortality due to this pneumonia dropped, and Levy figures the hospital saves 96 lives per year, or $12 million in expenses.

By shadowing nurses and other staff, Levy’s discovered that individuals often find workarounds to problems, but aren’t aware that others might benefit from their solutions. Levy set up a blog to post these solutions and focus the organization as a whole on areas of concern. Supporting good performance, sharing clinical results such as “how many people we hurt and kill” stimulates people in a hospital to do better, he believes. Public exposure goes a long way in helping academic medical staff to understand they must be “held accountable for their actions particularly when it comes to harm.”

]]> Sun, 25 Nov 2007 00:00:00 -0500 http://mitworld.mit.edu/video/499 http://mitworld.mit.edu/video/499 In conversation with Richard Larson and Sanford Weiner, John M. Barry, author of The Great Influenza, discusses current understanding of the dynamics of a flu outbreak, and our general state of preparedness. Based on historical patterns, we can expect three to four pandemics per century, of varying severity. In the last century, the 1918 flu was unrivaled in its ferocity, says Barry. Estimates of deaths worldwide run from 50 to 100 million people. Since the world population then was only a third of today’s, should a similar flu evolve in the 21st century, humanity would stand to lose between 175 to 300 million people.

With the emergence of the current avian flu virus, H5N1, which has a mortality rate in excess of 50%, there is reason to be concerned about another flu scourge. But, says Barry, “there’s no guarantee this will be the next pandemic,” or that the virus in its current form will remain as virulent, he says. It does make sense to prepare for the worst by setting up emergency protocols at all levels of government. Barry believes this will prove useful should other disasters occur, so “you’re not pouring money down a rat hole if there’s no disease.”

In his study of the 1918 flu, which played out during World War 1, Barry learned that when officialdom played down concerns at the start of the outbreak -- denying the existence of this terrible new disease that killed some victims overnight, and left other victims blue in the face for lack of oxygen -- the outcome was inevitably worse for a community. The flu virus spread from person to person explosively, sometimes before symptoms showed up, so prevention was beside the point. In cities that jumped in quickly, “gross, blunt force public health measures” such as serious hand washing, putting masks on sick people, and containment, worked to some degree.

The most powerful barrier to the next outbreak, believes Barry, will be complete transparency of governments on an international and local scale, so scientists worldwide can share accurate data on a new virus, and the public can trust the advice of elected officials; scrupulously observed personal hygiene; and the well-timed use of “social distancing,” such as school closings. With any luck, we’ll get a few months’ advance notice on the next one, and put the lessons of 1918 to use, he concludes.]]> Mon, 24 Sep 2007 00:00:00 -0400 http://mitworld.mit.edu/video/479 http://mitworld.mit.edu/video/479 Imagine a time when technology trumps injury and disease, and the very notion of disability begins to fade. These panelists suggest that we are at the dawn of such an era.

John Hockenberry, who zips around the stage in his flashing light –equipped wheelchair, tells us that “vast, extraordinary and sometimes frightening physical change can instead of being feared … actually be embraced and become an opportunity for people to take authorship of their own lives, using products and tools made by technology to make their life experiences better.” He sees an aging and longer-lived demographic necessitating new and better devices, and the likelihood that such tools may find broader use among a larger, able-bodied population.

Hugh Herr lost both legs below the knee to frostbite while hiking Mt. Washington in 1982. But his drive to climb compelled him to invent replacements that from his perspective far surpass the clumsy, skin-colored prostheses generally available. Herr demonstrates his biomechanical inventions, which provide not only a natural gait but additional energy to each stride – like an airport walkway, he says. Herr believes with some tweaking, his device could help stroke victims walk with better balance, and that the advantage conferred by such a device could make it desirable beyond the disabled population – think physical improvement by way of robotics, rather than steroids. As technology once intended exclusively for disabled people finds wider applications, there will be a transformation, says Herr, which “creates a world where there is not disability, but in fact augmentation. It makes it sexy. It’s the muscle car.”

Dean Kamen performs astonishing pirouettes in his iBOT, a device inspired by his desire to give wheelchair users the same view of the world taken for granted by those able to stand. This machine can give physically challenged people the independence to climb stairs, take a walk in the woods or at the beach.

Kamen also presents, through video clips, breathtaking developments in a robotic artificial arm – the result of U.S. government efforts to fast track (in two years!) a state-of-the-art prosthesis for victims of the conflicts in Iraq and Afghanistan. Nerve and muscle-sensing electrodes enable this arm to pick up small blocks, pieces of paper, and rotate at the wrist. Without government funding, this device would not have been developed, Kamen notes, due to market limitations. Kamen himself subsidizes development of other high tech tools for disabled people (his more lucrative day job involves making insulin pumps and stents). While he’d like these technologies to become “a killer app among people who can pay,” Kamen says, “We will continue to fund them with the naïve notion that it’s the right thing to do, and hope that we will meet our original objective of making the world a better place.” ]]> Mon, 16 Jul 2007 00:00:00 -0400 http://mitworld.mit.edu/video/464 http://mitworld.mit.edu/video/464 A microscopic roundworm has come to play a dominant role in some of the most pivotal medical research of our time. In the labs of Robert Horvitz and his colleagues, C. elegans has helped reveal cell death as a normal part of biological development.

In this talk, Horvitz painstakingly delineates the series of discoveries based on C. elegans that identified the genetics behind programmed cell death (apoptosis), the disorders that emerge if this normal process stalls, and human counterparts to these disorders, which suggest potential targets for therapy.

Because the mature roundworm consists of just 959 cells, it was possible for scientists to track the organism’s entire lineage of cell divisions, and to characterize what genetic accidents created mutant worms.

Scientists figured out genetic pathways that were essential to normal development in the worm, and which, if disrupted, led to harmful mutations. For instance, the immature roundworm contains 131 cells that are not found in the adult, because they are genetically programmed to die. Every animal, Horwitz says, undergoes apoptosis as a “normal aspect of development.” Tadpoles lose their tails to become frogs; lots of animals have webbing “sculpted out by the process of programmed cell death.” Over years, Horvitz and his colleagues determined the precise genes responsible for programmed cell death in C. elegans, as well as the genes that protect cells from dying, and the way these genes interact. Horvitz’s teams also found likely human equivalents to these critical genes and pathways. If these genes go awry, says Horvitz, “then something is going to lead to disease.”

Cancer, autoimmune diseases and viral infections result from too little programmed cell death. That’s because cell division goes unchecked. There are also human diseases that occur because cells die when they should not: neurodegenerative disorders, retinal degeneration, liver disease, and heart attacks. As a result of Horvitz’s work, many new targets have emerged for these diseases, some of which Horvitz himself is pursuing. Horvitz is now aiming his sights at different genetic regulators that tell certain types of cells to live or die, leading to novel therapies for some of our most formidable diseases.

]]> Thu, 07 Jun 2007 00:00:00 -0400 http://mitworld.mit.edu/video/453 http://mitworld.mit.edu/video/453 It’s no wonder there was an outcry when Gilbert Burnham’s group released its report on mortality in Iraq. The numbers of civilian deaths so overwhelmed body counts calculated by other groups that many were stunned or disbelieving, and Burnham earned the enmity of some U.S. and Iraqi government officials.

Burnham’s public health team looked at pre- and post-invasion deaths. The 2004 study showed that the mortality rate among Iraqis before the invasion was 2%, and after, 7.9%. The 2006 survey, which polled more households and covered greater territory, was more devastating: In the three years since the invasion, crude mortality rose to 13.2 per 1000 people per year. The leading cause was gunshot wounds and deaths from car bombs. The majority of victims of violence were men, 15-45 years old, and children also died in great numbers. By the end of the analysis period, crude mortality rates approached 17 deaths per 1000 per year.

The most disturbing statistic is the report’s estimate that there have been 654,000 excess deaths since the invasion of March 2003 -- 600,000 from violent causes. Critics, who are legion, Burnham acknowledges, point fingers at his study’s methodology, accusing his group of inaccurate and inadequate record-keeping, or skewing the numbers for political purposes.

Burnham notes that getting actual body counts in Iraq is literally impossible, since there is no working system for keeping accurate track of the dead in hospitals and mortuaries, and “numbers are highly susceptible to manipulation.” The backbone of public health studies are surveys, in which geographic clusters are chosen, households counted and individuals interviewed. As the number of clusters increase, “precision improves and confidence intervals narrow.” This enables measurements “accurate and precise enough to make the right decisions even though we will never have absolute, true numbers to two or three decimal points.”

At great personal peril, Burnham’s on-ground Iraqi surveyors went house to house in neighborhoods all over Iraq, asking for death certificates. The author of the report “hid out at a basement of a hotel, and finally got out on forged U.N. documents.” The 2004 survey reached 7868 people, and the 2006 contacted 12,800 individuals. The sample size was large enough to support the team’s grisly conclusions. Civilians are doing badly in this war, dying in far greater numbers than combatants. Burnham’s hope is to use such data “to protect people wrapped up in conflict,” since this “won’t be the only one in the 21st century.” ]]> Thu, 07 Jun 2007 00:00:00 -0400 http://mitworld.mit.edu/video/454 http://mitworld.mit.edu/video/454 This session goes a long way toward demonstrating the “happy face of the atom,” as moderator David Kaiser puts it, replacing the mushroom cloud image with a multidimensional picture of the uses of nuclear technology.

As a plasma physicist, Ian Hutchinson works on controlled fusion -- a very hot area of nuclear technology in more ways than one. By fusing together isotopes of hydrogen, you can achieve the energy source of stars, says Hutchinson. This promises infinite reserves of clean energy. These reactions are only possible at super high temperatures, and “to bring these down to a human scale,” the gases created must be contained by powerful magnets in machines called tokamaks. MIT and other labs have produced fusion energy and now a major international project to create a large fusion reactor is under way. The big challenge, says Hutchinson, is understanding the “great stirrings and eddies inside the plasma” that cause gas leaks and disruption to the fusion process.

We are now entering a time when “angst seems to be subsiding and we are able to discuss the benefits of nuclear technology in the security arena,” says Dwight Williams. He describes some major upgrades to the detection devices commonly used to prevent people from getting “bad stuff on an airplane or through a port.” Williams explains active system devices, which can induce a radioactive signature in something that was not originally radioactive, and thus signal an item’s “elemental content.” A machine using thermal neutron activation analysis can penetrate all kinds of shielding, to produce gamma rays and a 3D image of the contents of a bag. Since explosives share some of the features of jam, marzipan and chocolate, says Williams, advanced nuclear techniques will help inspectors distinguish between the benign and dangerous.

Medical applications of nuclear technology deploy different types of radiation to kill tumor cells and spare healthy tissue. But, says Jeffrey Coderre, shielding healthy cells to prevent radiation’s side effects turns out to be a tricky proposition. Coderre investigated the nature of radiation damage and determined it was a function of damage to stem cells (rather than damage to blood vessels). He describes how the radioisotopes used in medical radiation, virtually all of which come from Canadian reactors, can be used in a variety of ways: to view areas of rapid bone growth, or tumor sites in bone; to sterilize syringes and drapes used in hospitals; and in a radiation helmet called the gamma knife to get focused radiation into difficult brain tumors.

Alan Jasanoff provides a one-stop tour of medical imaging techniques, differentiating between those scans that use high energy radiation (such as computed tomography and positron emission tomography); and low wavelength radiation, based on radio waves, such as nuclear magnetic resonance imaging. PET scans detect molecular tracers that have been consumed in a sugary drink to find areas where cells are rapidly dividing, for example. New applications for this well established imaging method include locating plaques in the brain that cause Alzheimer’s disease. MRI, unlike CT or PET scans, has minimal destructive impact on tissues, and allows 3D mapping of blood vessels, and more recently, the tracing of microscopic fibers in the brain. Jasanoff’s lab uses calcium-sensitive contrast agents to detect events in the brain. ]]> Mon, 09 Apr 2007 00:00:00 -0400 http://mitworld.mit.edu/video/437 http://mitworld.mit.edu/video/437 The Rx for an ailing healthcare industry lies only partly with new technology, say these panelists, who report on their attempts to realize a streamlined vision of healthcare at their Hudson Valley regional hospital.

Pediatrician and CEO Daniel Aronzon describes a set of organizational challenges his institution faces, including accountability, transparency, safety, capacity, efficiency and cost. Myriad small problems can add up to millions in losses, and an occasional but catastrophic error may drain hospital resources. Aronzon notes that in the U.S., 97 thousand people die in hospitals every year because of such mistakes as giving a chemotherapy drug the wrong way. To get a handle on the safety problem, Aronzon has tried to create “a non-punitive just culture,” where employees who hurt patients by making “an honest mistake” are not punished. The hospital also invested in systems enhancements and prescription bar-coding technology to eliminate or mitigate such errors.

To cut expenses, Aronzon tagged computerized IV pumps with RFID, which prevented hoarding by staff and unnecessary replacement of the pricey machines. He frets about the coming demand on healthcare as boomers age: “Can’t you see it coming,” asks Aronzon, imagining this scene: “What do you mean there’s not enough nurses? I’ll sit on the call bell till they all come!”

After examining his hospital’s business model, Nicholas Christiano says his team decided that the most robust area for change lay with nurses. “They’re continually in motion,” running back and forth dealing with non-clinical issues. The model is “crazy and doesn’t work,” says Christiano.

The closest analogy to hospitals is the airline industry, where “if you make a mistake you have a catastrophic event,” says Christiano. To avoid errors, the airline industry has an infrastructure “that can support and track everything in a real-time environment.” Christiano proposed a wireless communication network for nurses, which he promoted through an internal marketing campaign as a way of easing nurses’ workload and enhancing their interactions with patients.

Despite all the technological advances, Stephen Katz believes healthcare is still informed by a 1950s culture. Medicine “hasn’t had to deal with efficiencies other businesses have had to establish in the same years.” But more so than other industries, “we’re a people business -- people at their very worst and stressed out.” The question, says Katz, is how to improve the lives of staff, with new systems and technology, “to bring them along with us for the betterment of the patients.” ]]> Sat, 03 Mar 2007 00:00:00 -0500 http://mitworld.mit.edu/video/426 http://mitworld.mit.edu/video/426 Anyone who suffers from hearing loss as well as those less familiar with this affliction should attend closely to this lecture. Brian Moore describes different kinds of damage to the cochlea, and he plays tapes that simulate what it’s like to hear with these impairments. Moore also offers the solace that research is leading to improved technology for the hearing impaired.

Moore first takes us on an animated ride into the ear canal, through the ear drum, to look at a part of the cochlea, the basilar membrane, which plays a crucial role as a frequency analyzer. Two classes of hair cells lying on top of the membrane serve distinctive purposes, and damage to them leads to common types of hearing loss.

Injuries to the outer hair cells result in a higher than normal threshold for detecting sounds, and inability to hear high and low sounds at the same time. People have difficulty separating sounds they want to hear from background noise, especially speech. Current hearing aids don’t compensate well for this impairment. Describes Moore, “Imagine sitting there listening to a concert with a friend with normal hearing and suddenly they’re playing quietly and you can see that they’re playing. You can’t hear a damn thing, you turn up the volume control on your hearing aid, they come back to a loud passage and aiyee! That’s why people say ‘Don’t shout’ when they’re wearing hearing aids.”

Inner hair cells on the basilar membrane send signals to the auditory nerve, and if they’re impaired, then the message they send to the brain gets scrambled. “It really screws up the ability to understand speech,” says Moore. There are “dead regions” where large sections of these cells are completely nonfunctioning at different sound frequencies. Scientists are learning how to compensate for these dead regions by moving sounds to other frequencies that will be audible. Moore also discusses damage to auditory processing that affects the ability to hear changes in pitch -- the “dips of normal talkers” in which people with ordinary hearing “grab information.”

Moore and other researchers are trying to tailor hearing aids that compensate for reduced frequency selectivity and for insensitivity to pitch, and which feel more comfortable. In development are open ear canal aids with refined digital feedback algorithms, directional microphones and signal processing. Farther down the road are implantable hearing aids that use mechanical vibration to transmit a wide frequency range without distortion, and beyond that, the possibility of regenerating hair cells: “Don’t bother with aids at all, let’s fix the ear,” says Moore. ]]>