News Article | April 25, 2017
ROVIDENCE, R.I. [Brown University] -- Researchers intent on understanding how too little sleep can undermine health have long suspected a relationship between short sleep duration and the actions of specific genes, but finding the genes involved has proven difficult. Now, a team of scientists based at Brown University has identified genes carrying "epigenetic" tags that are likely associated with shorter sleep in young adults. "Before this study, specific genes with epigenetic tags hadn't been linked to how much sleep people get," said Anne Hart, a professor of neuroscience and co-corresponding author of the study online in the journal Sleep. "This is the first time we've found genes important in sleep that might be tagged this way. It's exciting to open up a new area in the sleep field. In the long run, this work should help us understand why getting too little sleep causes so many problems for people and should lead to better treatments for those who have trouble sleeping." Epigenetic tags in genes are chemical alterations of the DNA that accrue based on life experiences, such as stress or exposure to environmental substances. This study focused on a specific epigenetic tag, called DNA methylation, which can affect how genes are expressed and therefore change behaviors like sleep. Previous research showed that methylation might change at the whole genome level with inadequate sleep. But in the new study, the researchers went much deeper and looked for specific genes with different amounts of DNA methylation tags in people who got a normal amount of sleep every night and comparable people who slept considerably less. For this study, the team selected 16 students from the hundreds who participated in a larger sleep study led by co-corresponding author Mary Carskadon, a professor of psychiatry and human behavior at the Warren Alpert Medical School and director of the Sleep for Science lab at the Bradley Hospital. "Our carefully selected sample of college students gave us the possibility to pursue this burning question at a molecular level," Carskadon said. Eight of the students had roughly the amount of sleep recommended for young adults, getting 8.1 hours on average. The other eight students selected for the study were short sleepers, getting only 6.6 hours on average a night. Because sleep and mood are intimately connected, all of the students selected had relatively depressed moods, which allowed the researchers to focus their analysis only on sleep. From donated blood samples, the researchers were able to analyze nearly 500,000 sites for possible methylation differences between the groups. They found 87, corresponding to 52 candidate genes. But how could they know whether any of the 52 genes really had anything to do with sleep? For the answer, they turned to worms. Worm and human sleep is remarkably similar; the same basic genetic and molecular biology mechanisms are important. That makes worms convenient models to study the basic biology of sleep. "If you have a lot of things you want to test, worms are fast and easy to do science in," Hart said. For each of the genes identified in people, the research team asked the question of what difference it might make to sleep to knock out the analogous gene in worms. Six of the genes they knocked out -- including five that had never before been identified as sleep-relevant -- affected sleep in worms. Although knock-out of a gene probably has a bigger impact than methylation, the experiments showed that these genes are likely important in sleep, for worms. The last phase of the research was for the researchers to go back to humans to see if they could replicate the finding of methylation tags of the five new worm-proven genes. They assembled a new cohort of 10 more students, all different from the last group. This time all 10 had better mood scores, meaning they were not depressed at all (thereby controlling for mood). As before, one group had the recommended amount of sleep (an average of about 8 hours) and the other group had short sleep (average of 6.3 hours). One gene, called ZFYVE28, still had significantly different methylation tagging when the normal sleepers and the short sleepers were compared. It's not clear why the other four didn't replicate, Hart said, but maybe those four are only important for sleep in people with depressed moods (which was intentionally different between the first group of students and the second). Intriguingly ZFYVE28 has connections to two molecular pathways already known to be relevant in sleep, Hart said: "Notch" and "EGF." But, she acknowledged, despite the worm knock-out results, there is not yet enough evidence yet to determine whether the methylation differences in ZFYVE28 in humans cause short sleep or accrue because of short sleep. There is at least one test Hart said she can imagine doing to help find an answer: Recruit some normal sleepers. Test their ZFYVE28 methylation. Subject them to a few weeks of restricted sleep. Test the methylation again. If it's substantially different, then maybe short sleep causes the methylation. If not, the possibility would remain open that the changes cause short sleep. Indeed, the research team has proposed a grant for just such a project. For now, ZFYVE28 serves as a test case to show that the method of mixing worm and human experiments to discover the sleep-relevance of epigenetic changes is a productive avenue for sleep research, Hart said. "This is the first good evidence that there will be differences in methylation associated with sleep, which opens up a whole new mechanism for regulating sleep," she said. "Now we can get to the mechanisms of what's going on and what's important." The paper's lead author is Huiyan Huang of Brown. In addition to Hart and Carskadon, the paper's other authors are Melissa Eliot of Brown; Valerie Knopik of Brown and Rhode Island Hospital (RIH); Jon McGeary of Brown, RIH and the Providence Veterans Affairs Medical Center; and Yong Zhu of Yale University. The National Institutes of Health, the Brown Institute for Brain Science, the Norman Prince Neurosciences Institute, the Periodic Breathing Foundation and the Sleep Research Society Foundation supported the research.
News Article | February 21, 2017
For all the improvements in computer technology over the years, we still struggle to recreate the low-energy, elegant processing of the human brain. Now, researchers at Stanford University and Sandia National Laboratories have made an advance that could help computers mimic one piece of the brain's efficient design - an artificial version of the space over which neurons communicate, called a synapse. "It works like a real synapse but it's an organic electronic device that can be engineered," said Alberto Salleo, associate professor of materials science and engineering at Stanford and senior author of the paper. "It's an entirely new family of devices because this type of architecture has not been shown before. For many key metrics, it also performs better than anything that's been done before with inorganics." The new artificial synapse, reported in the Feb. 20 issue of Nature Materials, mimics the way synapses in the brain learn through the signals that cross them. This is a significant energy savings over traditional computing, which involves separately processing information and then storing it into memory. Here, the processing creates the memory. This synapse may one day be part of a more brain-like computer, which could be especially beneficial for computing that works with visual and auditory signals. Examples of this are seen in voice-controlled interfaces and driverless cars. Past efforts in this field have produced high-performance neural networks supported by artificially intelligent algorithms but these are still distant imitators of the brain that depend on energy-consuming traditional computer hardware. When we learn, electrical signals are sent between neurons in our brain. The most energy is needed the first time a synapse is traversed. Every time afterward, the connection requires less energy. This is how synapses efficiently facilitate both learning something new and remembering what we've learned. The artificial synapse, unlike most other versions of brain-like computing, also fulfills these two tasks simultaneously, and does so with substantial energy savings. "Deep learning algorithms are very powerful but they rely on processors to calculate and simulate the electrical states and store them somewhere else, which is inefficient in terms of energy and time," said Yoeri van de Burgt, former postdoctoral scholar in the Salleo lab and lead author of the paper. "Instead of simulating a neural network, our work is trying to make a neural network." The artificial synapse is based off a battery design. It consists of two thin, flexible films with three terminals, connected by an electrolyte of salty water. The device works as a transistor, with one of the terminals controlling the flow of electricity between the other two. Like a neural path in a brain being reinforced through learning, the researchers program the artificial synapse by discharging and recharging it repeatedly. Through this training, they have been able to predict within 1 percent of uncertainly what voltage will be required to get the synapse to a specific electrical state and, once there, it remains at that state. In other words, unlike a common computer, where you save your work to the hard drive before you turn it off, the artificial synapse can recall its programming without any additional actions or parts. Only one artificial synapse has been produced but researchers at Sandia used 15,000 measurements from experiments on that synapse to simulate how an array of them would work in a neural network. They tested the simulated network's ability to recognize handwriting of digits 0 through 9. Tested on three datasets, the simulated array was able to identify the handwritten digits with an accuracy between 93 to 97 percent. Although this task would be relatively simple for a person, traditional computers have a difficult time interpreting visual and auditory signals. "More and more, the kinds of tasks that we expect our computing devices to do require computing that mimics the brain because using traditional computing to perform these tasks is becoming really power hungry," said A. Alec Talin, distinguished member of technical staff at Sandia National Laboratories in Livermore, California, and senior author of the paper. "We've demonstrated a device that's ideal for running these type of algorithms and that consumes a lot less power." This device is extremely well suited for the kind of signal identification and classification that traditional computers struggle to perform. Whereas digital transistors can be in only two states, such as 0 and 1, the researchers successfully programmed 500 states in the artificial synapse, which is useful for neuron-type computation models. In switching from one state to another they used about one-tenth as much energy as a state-of-the-art computing system needs in order to move data from the processing unit to the memory. This, however, means they are still using about 10,000 times as much energy as the minimum a biological synapse needs in order to fire. The researchers are hopeful that they can attain neuron-level energy efficiency once they test the artificial synapse in smaller devices. Every part of the device is made of inexpensive organic materials. These aren't found in nature but they are largely composed of hydrogen and carbon and are compatible with the brain's chemistry. Cells have been grown on these materials and they have even been used to make artificial pumps for neural transmitters. The voltages applied to train the artificial synapse are also the same as those that move through human neurons. All this means it's possible that the artificial synapse could communicate with live neurons, leading to improved brain-machine interfaces. The softness and flexibility of the device also lends itself to being used in biological environments. Before any applications to biology, however, the team plans to build an actual array of artificial synapses for further research and testing. Additional Stanford co-authors of this work include co-lead author Ewout Lubberman, also of the University of Groningen in the Netherlands, Scott T. Keene and Grégorio C. Faria, also of Universidade de São Paulo, in Brazil. Sandia National Laboratories co-authors include Elliot J. Fuller and Sapan Agarwal in Livermore and Matthew J. Marinella in Albuquerque, New Mexico. Salleo is an affiliate of the Stanford Precourt Institute for Energy and the Stanford Neurosciences Institute. Van de Burgt is now an assistant professor in microsystems and an affiliate of the Institute for Complex Molecular Studies (ICMS) at Eindhoven University of Technology in the Netherlands. This research was funded by the National Science Foundation, the Keck Faculty Scholar Funds, the Neurofab at Stanford, the Stanford Graduate Fellowship, Sandia's Laboratory-Directed Research and Development Program, the U.S. Department of Energy, the Holland Scholarship, the University of Groningen Scholarship for Excellent Students, the Hendrik Muller National Fund, the Schuurman Schimmel-van Outeren Foundation, the Foundation of Renswoude (The Hague and Delft), the Marco Polo Fund, the Instituto Nacional de Ciência e Tecnologia/Instituto Nacional de Eletrônica Orgânica in Brazil, the Fundação de Amparo à Pesquisa do Estado de São Paulo and the Brazilian National Council.
News Article | December 1, 2016
When we are in a deep slumber our brain's activity ebbs and flows in big, obvious waves, like watching a tide of human bodies rise up and sit down around a sports stadium. It's hard to miss. Now, Stanford researchers have found, those same cycles exist in wake as in sleep, but with only small sections sitting and standing in unison rather than the entire stadium. It's as if tiny portions of the brain are independently falling asleep and waking back up all the time. What's more, it appears that when the neurons have cycled into the more active, or "on," state they are better at responding to the world. The neurons also spend more time in the on state when paying attention to a task. This finding suggests processes that regulate brain activity in sleep might also play a role in attention. "Selective attention is similar to making small parts of your brain a little bit more awake," said Tatiana Engel, a postdoctoral fellow and co-lead author on the research, which is scheduled to publish Dec. 1 in Science. Former graduate student Nicholas Steinmetz was the other co-lead author, who carried out the neurophysiology experiments in the lab of Tirin Moore, a professor of neurobiology and one of the senior authors. Understanding these newly discovered cycles requires knowing a bit about how the brain is organized. If you were to poke a pin directly into the brain, all the brain cells you'd hit would respond to the same types of things. In one column they might all be responding to objects in a particular part of the visual field - the upper right, for example. The team used what amounts to sets of very sensitive pins that can record activity from a column of neurons in the brain. In the past, people had known that individual neurons go through phases of being more or less active, but with this probe they saw for the first time that all the neurons in a given column cycled together between firing very rapidly then firing at a much slower rate, similar to coordinated cycles in sleep. "During an on state the neurons all start firing rapidly," said Kwabena Boahen, a professor of bioengineering and electrical engineering at Stanford and a senior author on the paper. "Then all of a sudden they just switch to a low firing rate. This on and off switching is happening all the time, as if the neurons are flipping a coin to decide if they are going to be on or off." Those cycles, which occur on the order of seconds or fractions of seconds, weren't as visible when awake because the wave doesn't propagate much beyond that column, unlike in sleep when the wave spreads across almost the entire brain and is easy to detect. The team found that the higher and lower activity states relate to the ability to respond to the world. The group had their probe in a region of the brain in monkeys that specifically detects one part of the visual world. The monkeys had been trained to pay attention to a cue indicating that something in a particular part of the visual field - the upper right, say, or the lower left - was about to change slightly. The monkeys then got a treat if they correctly identified that they'd seen that change. When the team gave a cue to where a change might occur, the neurons within the column that senses that part of the world all began spending more time in the active state. In essence, they all continued flipping between states in unison, but they spent more time in the active state if they were paying attention. If the stimulus change came when the cells were in a more active state, the monkey was also more likely to correctly identify the change. "The monkey is very good at detecting stimulus changes when neurons in that column are in the on state but not in the off state," Engel said. Even when the monkey knew to pay attention to a particular area, if the neurons cycled to a lower activity state the monkey frequently missed stimulus change. Engel said this finding is something that might be familiar to many people. Sometimes you think you are paying attention, she pointed out, but you will still miss things. The scientists said the findings also relate to previous work, which found that more alert animals and humans tend to have pupils that are more dilated. In the current work, when the brain cells were spending more time in an active state the monkey's pupils were also more dilated. The findings demonstrate an interaction between synchronous oscillations in the brain, attention to a task and external signs of alertness. "It seems that the mechanisms underlying attention and arousal are quite interdependent," Moore said. A question that comes out of this work is why the neurons cycle into a lower activity state when we're awake. Why not just stay in the more active state all the time in case that's when the saber tooth tiger attacks? One answer could relate to energy. "There is a metabolic cost associated with neurons firing all the time," Boahen said. The brain uses a lot of energy and maybe giving the cells a chance to do the energetic equivalent of sitting down allows the brain to save energy. Also, when neurons are very active they generate cellular byproducts that can damage the cells. Engel pointed out that the low-activity states could allow time to clear out this neuronal waste. "This paper suggests places to look for these answers," Engel said. Additional co-authors include colleagues from Newcastle University. Kwabena Boahen is also a member of Stanford Bio-X and the Stanford Neurosciences Institute. Tirin Moore is also an HHMI investigator as well as a member of Stanford Bio-X, the Stanford Neurosciences Institute and the Child Health Research Institute. The work was funded by the NIH, Stanford NeuroVentures, the HHMI, the MRC and the Wellcome Trust.
News Article | December 3, 2016
SAN DIEGO--(BUSINESS WIRE)--Celgene Corporation (NASDAQ:CELG), Dana-Farber Cancer Institute and the University of Arkansas for Medical Sciences today announced the creation of the Myeloma Genome Project, a collaborative initiative aimed at compiling the largest dataset of high-quality genomic and clinical data to identify distinct molecular disease segments within multiple myeloma to advance diagnosis, prognosis and treatment of multiple myeloma patients. The initiative seeks to develop clinically relevant tests. Details of the project and initial characterization and preliminary analyses of newly diagnosed myeloma patient data were presented today by Brian Walker, Ph.D., of the University of Arkansas for Medical Sciences at the 58th American Society of Hematology Annual Meeting in San Diego, Calif. “The Myeloma Genome Project is a really exciting initiative that may change the way we manage myeloma patients,” said Gareth Morgan, M.D., Ph.D., Director of the Myeloma Institute at the University of Arkansas for Medical Sciences. Current technologies have discovered five major translocation groups within myeloma patients and these mutations have demonstrated varying effects on prognosis. The Myeloma Genome Project is also looking at minor translocation and mutational groups that are often poorly described due to small sample numbers in limited data sets. The group has established a set of 2,161 patients for which whole exome sequencing (WES; n=1,436), whole genome sequencing (WGS; n=708), targeted panel sequencing (n=993) and expression data from RNA-sequencing and gene expression arrays (n=1,497) were available. The data were collected from the Myeloma XI trial (UK), Intergroupe Francophone du Myeloma/Dana-Farber Cancer Institute, Myeloma Institute at the University of Arkansas for Medical Sciences and the Multiple Myeloma Research Foundation. “Understanding the various subgroups within multiple myeloma that exhibit distinct pathogenesis and clinical behavior is critical when looking to advance new therapies, particularly when considering a targeted approach,” said Rob Hershberg, M.D., Ph.D., Executive Vice President and Chief Scientific Officer at Celgene. “We look forward to the insights that this collaboration will provide for research and for patients.” “The Myeloma Genome Project expects to lead the way towards developing personalized and targeted therapy to improve patient outcomes in myeloma,” said Nikhil Munshi, M.D., Director of Basic and Correlative Science at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute. The Myeloma Genome Project has begun to integrate these diverse, large genomic data sets and is identifying genetic information that may inform clinical targets for therapy. While analyses are not completed, the current efforts clearly demonstrate the feasibility of this approach and the project leaders plan to expand collaboration to include additional investigators and institutions and present updates at future medical and scientific meetings including publications in peer-reviewed journals. Celgene Corporation, headquartered in Summit, New Jersey, is an integrated global biopharmaceutical company engaged primarily in the discovery, development and commercialization of innovative therapies for the treatment of cancer and inflammatory diseases through next-generation solutions in protein homeostasis, immuno-oncology, epigenetics, immunology and neuro-inflammation. For more information, please visit www.celgene.com. Follow Celgene on Social Media: @Celgene, Pinterest, LinkedIn, Facebook and YouTube. From achieving the first remissions in childhood cancer with chemotherapy in 1948, to developing the very latest new therapies, Dana-Farber Cancer Institute is one of the world’s leading centers of cancer research and treatment. It is the only center ranked in the top 4 of U.S. News and World Report’s Best Hospitals for both adult and pediatric cancer care. Dana-Farber sits at the center of a wide range of collaborative efforts to reduce the burden of cancer through scientific inquiry, clinical care, education, community engagement, and advocacy. Dana-Farber/Brigham and Women’s Cancer Center provides the latest in cancer care for adults; Dana-Farber/Boston Children's Cancer and Blood Disorders Center for children. The Dana-Farber/Harvard Cancer Center unites the cancer research efforts of five Harvard academic medical centers and two graduate schools, while Dana-Farber Community Cancer Care provides high quality cancer treatment in communities outside Boston’s Longwood Medical Area. Dana-Farber is dedicated to a unique, 50/50 balance between cancer research and care, and much of the Institute’s work is dedicated to translating the results of its discovery into new treatments for patients locally and around the world. About the University of Arkansas for Medical Sciences The University of Arkansas for Medical Sciences (UAMS) is Arkansas’ only comprehensive academic health center, with colleges of Medicine, Nursing, Pharmacy, Health Professions and Public Health; a graduate school; a hospital; a northwest Arkansas regional campus; a statewide network of regional centers; and seven institutes: the Winthrop P. Rockefeller Cancer Institute, the Jackson T. Stephens Spine & Neurosciences Institute, the Myeloma Institute, the Harvey & Bernice Jones Eye Institute, the Psychiatric Research Institute, the Donald W. Reynolds Institute on Aging and the Translational Research Institute. It is the only adult Level 1 trauma center in Arkansas. UAMS physicians and other professionals provide care to patients at UAMS, Arkansas Children’s Hospital, the VA Medical Center and UAMS regional centers throughout the state. The UAMS Myeloma Institute is the most comprehensive center in the world for research and clinical care related to multiple myeloma and related diseases, such as Castleman Disease and Waldenstrom Macroglobulemia. The institute’s team of scientists and clinicians has pioneered many advances that have become standards of care, leading to improved survival rates. The UAMS Myeloma Institute is known for its “bench to bedside” approach, continually translating advances in the laboratory into breakthrough clinical treatments. Visit www.uams.edu or www.uamshealth.com. Find us on Facebook, Twitter, YouTube or Instagram.
News Article | November 15, 2016
For the first time in Nevada, the cloud-based LIFENET® System is coming online to further reduce time to treatment LAS VEGAS, NV--(Marketwired - November 15, 2016) - Southern Nevada emergency medical services (EMS) personnel respond to nearly 11,000 chest pains calls each year. For the first time, now EMS and hospital care teams will use a secure Internet connection to work together more efficiently to respond to those heart emergencies. That's because Sunrise Health System is launching a new system that provides faster treatment for patients in Las Vegas and the surrounding region who experience the most dangerous type of heart attack. The LIFENET® System from Physio-Control is a cloud-based data network that can help shorten the critical period between the patient's arrival to the hospital and the start of life-saving medical care -- an interval known as door-to-balloon time. The faster patients receive treatment the more likely they are to have a positive outcome. With the LIFENET System, Sunrise Health Systems' member hospitals -- they include MountainView Hospital, Southern Hills Hospital, Sunrise Hospital and Medical Center and Sunrise Children's Hospital -- can help improve patients' chances for survival. "Sunrise Health System is fully committed to making sure a patient with a heart-related emergency can get immediate access to enhanced heart care -- even before he or she reaches our doors," said Daniel Llamas, Sunrise Health Systems' Emergency Medical Services director. "Having this capability helps our community of first responders meet our shared goal which is to save more lives." The most serious form of heart attack poses the biggest threat to the heart muscle and can result in a patient's death or serious disability. The heart attack is stopped with the insertion of a balloon catheter, called angioplasty, or the placement of a stent, a small mesh tube, within the patient's blocked artery. Both procedures are designed to open the artery and restore blood flow. Studies show that minimizing this time is key to improving patients' chances for survival. Sunrise Health is the most technologically advanced hospital network in the Southwest. Committed to providing the finest healthcare, Sunrise Health includes Sunrise Hospital & Medical Center, MountainView Hospital, Southern Hills Hospital and Medical Center and Sunrise Children's Hospital, as well as outpatient diagnostic, imaging and surgical centers. Specialty services include a suite of the latest diagnostic and surgical technologies, advanced cardiovascular services, comprehensive neurological services, a designated Comprehensive Cancer Center, The Nevada Neurosciences Institute, The Breast Center at Sunrise, MountainView Cardiovascular & Thoracic Surgery Associates, the state's most comprehensive Children's Hospital, women's healthcare services and Las Vegas' first network of Certified Stroke Centers and Accredited Chest Pain Centers. For more information on Sunrise Health, visit SunriseHealthInfo.com. LIFENET is a comprehensive, cloud-based platform that provides EMS and hospital care teams with innovative tools for quick, reliable access to critical patient and device data, resulting in improved patient care, ongoing process improvement and greater operational efficiency. Accessing LIFENET through a secure Internet connection, paramedics send a patient's electrocardiogram (ECG) data to hospital care teams, which are then able to quickly identify critical heart attack patients, determine where to route them for care and have staff prepared before the patient arrives -- reducing time to treatment. Hospital teams can also engage with remote clinicians for decision support through a dedicated LIFENET iPhone application. LIFENET is administered by Physio-Control and works quietly in the background, allowing paramedics, physicians and nurses to focus on treatment decisions and patient care. In addition, by speeding communication among members of the care team, LIFENET helps the team save critical time in delivering treatments. Today, LIFENET is making a difference for whole communities as increasing numbers of medical professionals turn to LIFENET to give critical heart patients their best possible outcomes. The most critical form of heart attack is called STEMI (ST-segment elevation myocardial infarction) and affects close to 400,000 people every year in the U.S. alone, according to the American Heart Association. In STEMI heart attacks, coronary arteries experience a total blockage, causing various sections of the heart muscle to die. In contrast, non-STEMI, or NSTEMI, heart attacks are the result of a partial arterial blockage. To determine if a patient is experiencing a STEMI, medical teams look at the results of the patient's ECG reading: if the ST segment of the reading is elevated, the patient has suffered a STEMI heart attack. Studies show that when door-to-balloon time is 90 minutes or less, patients experiencing a STEMI heart attack have significantly better outcomes and shorter hospital stays. LIFENET can play a key role in reducing door-to-balloon time, ensuring that patients get the treatment they need as quickly as possible. Physio-Control, Inc. is part of the medical division of Stryker Corporation and is the world's leading provider of professional emergency medical response solutions that predict or intervene in life-threatening emergencies. The company's products include LIFEPAK® monitor/defibrillators, LIFEPAK® and HeartSine® automated external defibrillators, the LIFENET® System, HealthEMS® electronic patient care reporting (ePCR) software, LUCAS® 2 Chest Compression System, TrueCPR™ coaching device, and more.
News Article | December 9, 2016
Graduate student Paul Gonzalez at Stanford University's Hopkins Marine Station recently became a hunter, breeder and farmer of a rare marine worm, all to fill in a considerable gap in our understanding of how animals develop. He knew that some animals go through a long larval stage, a developmental strategy known as indirect development, and this rare worm was his chance to better understand that process. What Gonzalez and his colleagues found was that the worms go through a prolonged phase with little more than head. This work, published in the Dec. 8 issue of Current Biology, suggests that many animals in the ocean likely share this trunk-less stage, and it may even shed light on the biological development of early animals. "Indirect development is the most prevalent developmental strategy of marine invertebrates and life evolved in the ocean," said Chris Lowe, senior author of the paper and associate professor of biology. "This means the earliest animals probably used these kinds of strategies to develop into adults." Most research animals commonly found in labs, such as mice, zebrafish and the worm C. elegans, are direct developers, species that don't go through a distinct larval stage. To understand how indirect developers differ from these, Gonzalez needed to study an indirect developer that was very closely related to a well-studied direct developer. His best bet was a group of marine invertebrates called Hemichordata because there is already a wealth of molecular developmental work done on direct developers in this group. A flaw in this plan was that the indirect developers in this phylum were uncommon in areas near the station. Undeterred, Gonzalez poured through marine faunal surveys until a 1994 study gave him his big break: Schizocardium californicum, a species of acorn worm and indirect developer in the Hemichordata phylum, was once in Morro Bay, only two hours away. Through contacting the researchers from that decades-old paper, Gonzalez obtained the exact coordinates of the worms. Once there, he pulled on a wet suit, readied his shovel and began his hunt for the odd-looking ocean-dwellers. Direct developers are more often used in research largely for reasons of practicality. "Terrestrial, direct developing species develop fast, their life cycle is simple and they are easy to rear in the lab," said Gonzalez, who was lead author of the paper. By comparison, indirect developers develop slowly, have a long larval stage, and their larvae are difficult to feed and maintain in captivity. The reproductive adults are also challenging to keep in the lab and, as Gonzalez has shown, collecting them can be an arduous process. However, the relative ease of studying direct developers has made for a lack of diversity in what scientists know about evolution and development, Gonzalez said. "By selecting convenient species, we select a non-random sample of animal diversity, running the risk of missing interesting things," he said. "That's what brought me to the Lowe lab. We specialize in asking cool evolutionary questions using developmental biology and molecular genetics, and we're not afraid to start from scratch and work on animals that no one has worked with before." After spending months perfecting the rearing and breeding techniques needed to study these worms, the researchers were eventually able to sequence the RNA from various stages of the worm's development. They did this in order to see where specific genes are turned on or off in an embryo. They found that in the worms, activity of certain genes that would lead to the development of a trunk are delayed. So, during the larval stage, the worms are basically swimming heads. "When you look at a larva, it's like you're looking at an acorn worm that decided to delay development of its trunk, inflate its body to be balloon-shaped and float around in the plankton to feed on delicious algae," said Gonzalez. "Delayed trunk development is probably very important to evolve a body shape that is different from that of a worm, and more suitable for life in the water column." As they continue to grow, the acorn worms eventually undergo a metamorphosis to their adult body plan. At this point, the genes that regulate the development of the trunk activate and the worms begin to develop the long body found in adults, which eventually grows to about 40 cm (15.8 inches) over the span of several years. Even with such a fascinating result, this research is only the beginning of the Lowe lab's examination of indirect developers. These worms will never tell us about human diseases, unlike work with stem cells or mice, but they could reveal the intricacies of how life works for many organisms beyond the model species that we've studied so heavily. They may also show us how life in general came to be what it is today. "Given how pervasive larvae are in the animal world, we understand very little about this critical phase in animal development," said Lowe. "These are not the kind of species you want to pick if you want deep, mechanistic insights into developmental biology. But, if your goal is to understand how animals have evolved, then you cannot avoid using these species." Next, the researchers want to figure out how the acorn worm body development delay happens. They also have begun to sequence the genome of S. californicum. Kevin R. Uhlinger, lab manager in the Lowe lab at Hopkins Marine Station, is also a co-author of this paper. Chris Lowe is also a member of Stanford Bio-X and the Stanford Neurosciences Institute.
News Article | December 8, 2016
Graduate student Paul Gonzalez at Stanford University's Hopkins Marine Station recently became a hunter, breeder and farmer of a rare marine worm, all to fill in a considerable gap in our understanding of how animals develop. He knew that some animals go through a long larval stage, a developmental strategy known as indirect development, and this rare worm was his chance to better understand that process. What Gonzalez and his colleagues found was that the worms go through a prolonged phase with little more than head. This work, published in the Dec. 8 issue of Current Biology, suggests that many animals in the ocean likely share this trunk-less stage, and it may even shed light on the biological development of early animals. "Indirect development is the most prevalent developmental strategy of marine invertebrates and life evolved in the ocean," said Chris Lowe, senior author of the paper and associate professor of biology. "This means the earliest animals probably used these kinds of strategies to develop into adults." Most research animals commonly found in labs, such as mice, zebrafish and the worm C. elegans, are direct developers, species that don't go through a distinct larval stage. To understand how indirect developers differ from these, Gonzalez needed to study an indirect developer that was very closely related to a well-studied direct developer. His best bet was a group of marine invertebrates called Hemichordata because there is already a wealth of molecular developmental work done on direct developers in this group. A flaw in this plan was that the indirect developers in this phylum were uncommon in areas near the station. Undeterred, Gonzalez poured through marine faunal surveys until a 1994 study gave him his big break: Schizocardium californicum, a species of acorn worm and indirect developer in the Hemichordata phylum, was once in Morro Bay, only two hours away. Through contacting the researchers from that decades-old paper, Gonzalez obtained the exact coordinates of the worms. Once there, he pulled on a wet suit, readied his shovel and began his hunt for the odd-looking ocean-dwellers. Direct developers are more often used in research largely for reasons of practicality. "Terrestrial, direct developing species develop fast, their life cycle is simple and they are easy to rear in the lab," said Gonzalez, who was lead author of the paper. By comparison, indirect developers develop slowly, have a long larval stage, and their larvae are difficult to feed and maintain in captivity. The reproductive adults are also challenging to keep in the lab and, as Gonzalez has shown, collecting them can be an arduous process. However, the relative ease of studying direct developers has made for a lack of diversity in what scientists know about evolution and development, Gonzalez said. "By selecting convenient species, we select a non-random sample of animal diversity, running the risk of missing interesting things," he said. "That's what brought me to the Lowe lab. We specialize in asking cool evolutionary questions using developmental biology and molecular genetics, and we're not afraid to start from scratch and work on animals that no one has worked with before." After spending months perfecting the rearing and breeding techniques needed to study these worms, the researchers were eventually able to sequence the RNA from various stages of the worm's development. They did this in order to see where specific genes are turned on or off in an embryo. They found that in the worms, activity of certain genes that would lead to the development of a trunk are delayed. So, during the larval stage, the worms are basically swimming heads. "When you look at a larva, it's like you're looking at an acorn worm that decided to delay development of its trunk, inflate its body to be balloon-shaped and float around in the plankton to feed on delicious algae," said Gonzalez. "Delayed trunk development is probably very important to evolve a body shape that is different from that of a worm, and more suitable for life in the water column." As they continue to grow, the acorn worms eventually undergo a metamorphosis to their adult body plan. At this point, the genes that regulate the development of the trunk activate and the worms begin to develop the long body found in adults, which eventually grows to about 40 cm (15.8 inches) over the span of several years. Even with such a fascinating result, this research is only the beginning of the Lowe lab's examination of indirect developers. These worms will never tell us about human diseases, unlike work with stem cells or mice, but they could reveal the intricacies of how life works for many organisms beyond the model species that we've studied so heavily. They may also show us how life in general came to be what it is today. "Given how pervasive larvae are in the animal world, we understand very little about this critical phase in animal development," said Lowe. "These are not the kind of species you want to pick if you want deep, mechanistic insights into developmental biology. But, if your goal is to understand how animals have evolved, then you cannot avoid using these species." Next, the researchers want to figure out how the acorn worm body development delay happens. They also have begun to sequence the genome of S. californicum. Kevin R. Uhlinger, lab manager in the Lowe lab at Hopkins Marine Station, is also a co-author of this paper. Chris Lowe is also a member of Stanford Bio-X and the Stanford Neurosciences Institute. Funding for this work was provided by Natural Sciences and Engineering Research Council of Canada (NSERC), the Dr. Earl H. Myers and Ethel M. Myers Oceanographic and Marine Biology Trust of Pebble Beach, NASAExobiology and the National Science Foundation (NSF).
News Article | February 22, 2017
Cells within our bodies divide and change over time, with thousands of chemical reactions occurring within each cell daily. This makes it difficult for scientists to understand what's happening inside. Now, tiny nanostraws developed by Stanford researchers offer a method of sampling cell contents without disrupting its natural processes. A problem with the current method of cell sampling, called lysing, is that it ruptures the cell. Once the cell is destroyed, it can't be sampled from again. This new sampling system relies on tiny tubes 600 times smaller than a strand of hair that allow researchers to sample a single cell at a time. The nanostraws penetrate a cell's outer membrane, without damaging it, and draw out proteins and genetic material from the cell's salty interior. "It's like a blood draw for the cell," said Nicholas Melosh, an associate professor of materials science and engineering and senior author on a paper describing the work published recently in Proceedings of the National Academy of Sciences. The nanostraw sampling technique, according to Melosh, will significantly impact our understanding of cell development and could lead to much safer and effective medical therapies because the technique allows for long term, non-destructive monitoring. "What we hope to do, using this technology, is to watch as these cells change over time and be able to infer how different environmental conditions and 'chemical cocktails' influence their development - to help optimize the therapy process," Melosh said. If researchers can fully understand how a cell works, then they can develop treatments that will address those processes directly. For example, in the case of stem cells, researchers are uncovering ways of growing entire, patient-specific organs. The trick is, scientists don't really know how stem cells develop. "For stem cells, we know that they can turn into many other cell types, but we do not know the evolution - how do they go from stem cells to, say, cardiac cells? There is always a mystery. This sampling technique will give us a clearer idea of how it's done," said Yuhong Cao, a graduate student and first author on the paper. The sampling technique could also inform cancer treatments and answer questions about why some cancer cells are resistant to chemotherapy while others are not. "With chemotherapy, there are always cells that are resistant," said Cao. "If we can follow the intercellular mechanism of the surviving cells, we can know, genetically, its response to the drug." The sampling platform on which the nanostraws are grown is tiny - about the size of a gumball. It's called the Nanostraw Extraction (NEX) sampling system, and it was designed to mimic biology itself. In our bodies, cells are connected by a system of "gates" through which they send each other nutrients and molecules, like rooms in a house connected by doorways. These intercellular gates, called gap junctions, are what inspired Melosh six years ago, when he was trying to determine a non-destructive way of delivering substances, like DNA or medicines, inside cells. The new NEX sampling system is the reverse, observing what's happening within rather than delivering something new. "It's a super exciting time for nanotechnology," Melosh said. "We're really getting to a scale where what we can make controllably is the same size as biological systems." Building the NEX sampling system took years to perfect. Not only did Melosh and his team need to ensure cell sampling with this method was possible, they needed to see that the samples were actually a reliable measure of the cell content, and that samples, when taken over time, remained consistent. When the team compared their cell samples from the NEX with cell samples taken by breaking the cells open, they found that 90 percent of the samples were congruous. Melosh's team also found that when they sampled from a group of cells day after day, certain molecules that should be present at constant levels remained the same, indicating that their sampling accurately reflected the cell's interior. With help from collaborators Sergiu P. Pasca, assistant professor of psychiatry and behavioral sciences, and Joseph Wu, professor of radiology, Melosh and co-workers tested the NEX sampling method not only with generic cell lines, but also with human heart tissue and brain cells grown from stem cells. In each case, the nanostraw sampling reflected the same cellular contents as lysing the cells. The goal of developing this technology, according to Melosh, was to make an impact in medical biology by providing a platform that any lab could build. Only a few labs across the globe, so far, are employing nanostraws in cellular research, but Melosh expects that number to grow dramatically. "We want as many people to use this technology as possible," he said. "We're trying to help advance science and technology to benefit mankind." Melosh is also a professor in the photon science directorate at SLAC National Accelerator Laboratory, a member of Stanford Bio-X, the Child Health Research Institute, the Stanford Neurosciences Institute, Stanford ChEM-H and the Precourt Institute for Energy. Wu is also the Simon H. Stertzer, MD, Professor; he is director of the Stanford Cardiovascular Institute and a member of Stanford Bio-X, the Child Health Research Institute, Stanford ChEM-H and the Stanford Cancer Institute. Pasca is also a member of Stanford Bio-X, the Child Health Research Institute, the Stanford Neurosciences Institute and Stanford ChEM-H. The work was funded by the National Institute of Standards and Technology, the Knut and Alice Wallenberg Foundation, the National Institutes of Health, Stanford Bio-X, the Progenitor Cell Biology Consortium, the National Institute of Mental Health, an MQ Fellow award, the Donald E. and Delia B. Baxter Foundation and the Child Health Research Institute.
News Article | October 28, 2016
What: PinnacleHealth System is proud to join with the Pennsylvania Departments of Health and Insurance, as well as State Lawmakers, sepsis survivors, health care professionals, and other leaders during an important statewide public awareness event, press conference, and campaign launch. Sepsis is one of the leading causes of death in our nation’s hospitals and a silent killer that claims more than 258,000 lives per year in the United States. Pennsylvanians are being called upon to take an active role in protecting their health and well-being, and in helping to combat the devastating effects of sepsis. During Sepsis Awareness Month, PinnacleHealth System will outline its new life-saving measures in championing this public health campaign recognizing that sepsis is a medical emergency where every minute counts. Health care professionals and community health advocates consider it to be an epidemic. When: Wednesday, September 28, 9:00 a..m. Press Conference and Campaign Launch Who: Pennsylvania Secretary of Health Karen Murphy, RN, PhD, Pennsylvania Insurance Commissioner Teresa Miller, State Representative Mike Regan (R-York/Cumberland), State Representative Patty Kim (D-Dauphin), State Representative Marguerite Quinn (R-Bucks), Dr. Thomas Stoner, physician champion and sepsis expert, PinnacleHealth President and CEO Michael Young, PinnacleHealth Medical Director Dr. Steven Lilie, Franklene Williams, MSN, AGACNP-BC, CRNP, chief nurse practitioner-critical care, PinnacleHealth West Shore Hospital, and medical staff who battle sepsis on the front lines Also participating are sepsis survivors and heroes—Carol Brame, mother of Sean Brame, from Etters, PA, and Duck Donuts CEO Russ DiGilio of Mechanicsburg, PA The Facts: Sepsis is a blood infection and an equal-opportunity invader; it significantly impacts our elderly and children. One person is diagnosed with sepsis every 20 seconds, which leaves 1.6 million people affected annually. More people die from sepsis in the U.S. than breast cancer, prostate cancer, and HIV/AIDS combined. For more information on PinnacleHealth System's #KnockOutSepsis Campaign, or to learn more about signs, symptoms, and treatment, please visit http://www.pinnaclehealth.org/sepsis. As one of Pennsylvania’s largest leading health care providers, PinnacleHealth’s aggressive and steadfast commitment to early sepsis diagnosis, prevention, and treatment has resulted in a major overall reduction in sepsis deaths in the last year. About PinnacleHealth System PinnacleHealth System has been a leading provider of inpatient and outpatient healthcare services in central Pennsylvania since 1873. The 636-bed system has three acute care hospitals (Community General Osteopathic, Harrisburg and West Shore Hospitals) on four campuses (Community, Harrisburg, Polyclinic and West Shore) serving a five-county service area and supporting rural hospitals through affiliations and telehealth services. PinnacleHealth pursues innovative treatment options for the region through cardiac and cancer clinical trials, while offering convenient community services including medical home-certified primary care, urgent care, Magnet-recognized nursing excellence, emergency services, imaging, high-volume maternity care and a level III NICU, and workplace-based wellness services. PinnacleHealth includes a CardioVascular Institute and Cancer Institute, as well as a Bone and Joint Institute, Neurosurgery and Neurosciences Institute, and Spine Care Center that combine a multi-disciplinary approach to comprehensive spine, bone, joint, orthopedic and sports medicine services. PinnacleHealth is recognized for high-quality care with national and regional recognitions for volumes, outcomes and safety. For more information, visit pinnaclehealth.org.
News Article | February 22, 2017
There's an idea out there of what a drug-addled teen is supposed to look like: impulsive, unconscientious, smart, perhaps - but not the most engaged. While personality traits like that could signal danger, not every adolescent who fits that description becomes a problem drug user. So how do you tell who's who? There's no perfect answer, but researchers report February 21 in Nature Communications that they've found a way to improve our predictions - using brain scans that can tell, in a manner of speaking, who's bored by the promise of easy money, even when the kids themselves might not realize it. That conclusion grew out of a collaboration between Brian Knutson, a professor of psychology at Stanford, and Christian Büchel, a professor of medicine at Universitätsklinikum Hamburg Eppendorf. With support from the Stanford Neurosciences Institute's NeuroChoice program, which Knutson co-directs, the pair started sorting through an intriguing dataset covering, among other things, 144 European adolescents who scored high on a test of what's called novelty seeking - roughly, the sorts of personality traits that might indicate a kid is at risk for drug or alcohol abuse. Novelty seeking isn't inherently bad, Knutson said. On a good day, the urge to take a risk on something new can drive innovation. On a bad day, however, it can lead people to drive recklessly, jump off cliffs and ingest whatever someone hands out at a party. And psychologists know that kids who score high on tests of novelty seeking are on average a bit more likely to abuse drugs. The question was, could there be a better test, one both more precise and more individualized, that could tell whether novelty seeking might turn into something more destructive. Knutson and Büchel thought so, and they suspected that a brain-scanning test called the Monetary Incentive Delay Task, or MID, could be the answer. Knutson had developed the task early in his career as a way of targeting a part of the brain now known to play a role in mentally processing rewards like money or the high of a drug. The task works like this. People lie down in an MRI brain scanner to play a simple video game for points, which they can eventually convert to money. More important than the details of the game, however, is this: At the start of each round, each player gets a cue about how many points he stands to win during the round. It's at that point that players start to anticipate future rewards. For most people, that anticipation alone is enough to kick the brain's reward centers into gear. This plays out differently - and a little puzzlingly - in adolescents who use drugs. Kids' brains in general respond less when anticipating rewards, compared with adults' brains. But that effect is even more pronounced when those kids use drugs, which suggests one of two things: Either drugs suppress brain activity, or the suppressed brain activity somehow leads youths to take drugs. If it's the latter, then Knutson's task could predict future drug use. But no one was sure, mainly because no one had measured brain activity in non-drug-using adolescents and compared it to eventual drug use. No one, that is, except Büchel. As part of the IMAGEN consortium, he and colleagues in Europe had already collected data on around 1,000 14-year-olds as they went through Knutson's MID task. They had also followed up with each of them two years later to find out if they'd become problem drug users - for example, if they smoked or drank on a daily basis or ever used harder drugs like heroin. Then, Knutson and Büchel focused their attention on 144 adolescents who hadn't developed drug problems by age 14 but had scored in the top 25 percent on a test of novelty seeking. Analyzing that data, Knutson and Büchel found they could correctly predict whether youngsters would go on to abuse drugs about two-thirds of the time based on how their brains responded to anticipating rewards. This is a substantial improvement over behavioral and personality measures, which correctly distinguished future drug abusers from other novelty-seeking 14-year-olds about 55 percent of the time, only a little better than chance. "This is just a first step toward something more useful," Knutson said. "Ultimately the goal - and maybe this is pie in the sky - is to do clinical diagnosis on individual patients" in the hope that doctors could stop drug abuse before it starts, he said. Knutson said the study first needs to be replicated, and he hopes to follow the kids to see how they do further down the line. Eventually, he said, he may be able not just to predict drug abuse, but also better understand it. "My hope is the signal isn't just predictive, but also informative with respect to interventions." Knutson is also a member Stanford Bio-X. Additional co-authors include the members of the IMAGEN collaboration. The research was funded in part by a grant from the Stanford Neurosciences Institute.