NASA VIDEO: SCIENCECASTS: SUBTRACTING GRAVITY FROM ALZHEIMER'S

THE GENETICS OF ALZHEIMER'S

FROM:  THE NATIONAL SCIENCE FOUNDATION 
Uncovering Alzheimer's complex genetic networks
Researchers from the Mayo Clinic use NSF-supported Blue Waters supercomputer to understand gene expression in the brain
February 3, 2015

The release of the film, "Still Alice," in September 2014 shone a much-needed light on Alzheimer's disease, a debilitating neurological disease that affects a growing number of Americans each year.

More than 5.2 million people in the U.S. are currently living with Alzheimer's. One out of nine Americans over 65 has Alzheimer's, and one out of three over 85 has the disease. For those over 65, it is the fifth leading cause of death.

There are several drugs on the market that can provide relief from Alzheimer's symptoms, but none stop the development of disease, in part because the root causes of Alzheimer's are still unclear.

"We re interested in studying the genetics of Alzheimer's disease," said Mariet Allen, a post-doctoral fellow at the Mayo Clinic in Florida. "Can we identify genetic risk factors and improve our understanding of the biological pathways and cellular mechanisms that can play a role in the disease process?"

Allen is part of a team of researchers from the Mayo Clinic who are using Blue Waters, one of the most powerful supercomputers in the world, to decode the complicated language of genetic pathways in the brain. In doing so, they hope to provide insights into what genes and proteins are malfunctioning in the brain, causing amyloid beta plaques, tau protein tangles and brain atrophy due to neuronal cell loss--the telltale signs of the disease--and how these genes can be detected and addressed.

In the case of late onset Alzheimer's disease (LOAD), it is estimated that as much as 80 percent of risk is due to genetic factors. In recent years, researchers discovered 20 common genetic loci, in addition to the well-known APOE gene, that are found to increase or decrease risk for the disease. (Loci are specific locations of a gene, DNA sequence, or position on a chromosome.) These loci do not necessarily have a causal connection to the disease, but they provide useful information about high-risk patients.

Despite all that doctors have learned in recent years about the genetic basis of Alzheimer's, according to Allen, a substantial knowledge gap still exists. It has been estimated that likely less than 40 percent of genetic risk for LOAD can be explained by known loci. Furthermore, it is not always clear which are the affected genes at these known loci.

In other words, scientists have a long way to go to get a full picture of which genes are involved in processes related to the disease and how they interact.

The Mayo team and their colleagues had been very successful in the past in finding genetic risk factors using a method that matched individual differences in the DNA code--single-nucleotide polymorphisms or SNPs, to phenotypes--the outward appearances of the disease. In particular, the Mayo team focused on identifying SNPs that influence expression of genes in the brain. However, they now hypothesize that the single SNP method may be too simplistic to find all genetic factors, and is likely not an accurate reflection of the complex biological interactions that take place in an organism.

For that reason, the Mayo researchers have recently turned their attention to investigating the brain using genetic interaction (epistasis) studies. Such studies allow researchers to understand the effects of pairs of gene changes on a given phenotype and can uncover additional genetic variants that influence gene expression and disease.

The process involves the analysis of billions of DNA base pairs (the familiar C, G, A and T) to find statistically significant correlations. Importantly, the search is not to discover simple one-to-one connections, since these have largely been found, but to study the interaction effects of pairs of DNA sequence variations.

Solving a problem of this size and complexity requires a huge amount of computational processing time, so the researchers turned to the Blue Waters supercomputer at the National Center for Supercomputing Applications (NCSA).

Supported by the National Science Foundation and the University of Illinois at Urbana-Champaign, Blue Waters allows scientists and engineers across the country to tackle a wide range of challenging problems using massive computing and data processing power. From predicting the behavior of complex biological systems to simulating the evolution of the cosmos, Blue Waters assists researchers whose computing problems are at a scale or complexity that cannot be reasonably approached using any other method.

Allen and her colleagues used Blue Waters to rapidly advance their Alzheimer's epistasis study through NCSA's Private Sector Program, which lets teams outside of academia access the system.

Instead of requiring as much as a year or more of processing on a single workstation or university cluster, the research team was able to do each analysis on Blue Waters in less than two days.

The researchers conducted three sets of analysis to investigate brain gene expression levels in a group of individuals without Alzheimer's, a group of individuals with Alzheimer's and then a combined analysis of both groups together. To date, these analyses have been completed for the almost 14,000 genes expressed in the majority of the brain samples studied.

Through their work with collaborators at NCSA and the University of Illinois at Urbana-Champaign (including Victor Jongeneel and Liudmila Mainzer), the Mayo team overcame many of the challenges that a project of this scope presented.

"The analysis of epistatic effects in large studies, such as ours, requires powerful computational resources and would not be possible without the unique computing capabilities of Blue Waters," wrote project lead Nilufer Ertekin-Taner from the Mayo Clinic.

"The Mayo Clinic project is emblematic of the type of problem that is beginning to emerge in computational medicine," said Irene Qualters, division director of Advanced Computing Infrastructure at NSF. "Through engagement with the Blue Waters project, researchers at Mayo have demonstrated the potential of new analytic approaches in addressing the challenges of a daunting medical frontier."

The team reported on their progress at the Blue Waters Symposium in May 2014. Allen and her colleagues are currently processing and filtering the results so they can be analyzed.

"Recent studies by our collaborators and others have shown that both the risk for late onset Alzheimer's disease and gene expression are likely influenced by epistasis. However little is known about the effect of genetic interactions on brain gene expression specifically and how this might influence risk for neurological diseases such as LOAD," said Allen. "The goal of our study is to address this knowledge gap; something we have been uniquely positioned to do using our existing data and the resources available on Blue Waters."

-- Aaron Dubrow, NSF

NASA VIDEO: SPACE STATION LIVE: UNTANGLING ALZHEIMER'S PROTEINS ON ORBIT

NSF ON THE BRAIN AT REST

FROM:  NATIONAL SCIENCE FOUNDATION 

What happens to your brain when your mind is at rest?

Kavli Prize winner recognized as pioneer in research in the development and use of brain imaging techniques

For many years, the focus of brain mapping was to examine changes in the brain that occur when people are attentively engaged in an activity. No one spent much time thinking about what happens to the brain when people are doing very little.

But Marcus Raichle, a professor of radiology, neurology, neurobiology and biomedical engineering at Washington University in St. Louis, has done just that. In the 1990s, he and his colleagues made a pivotal discovery by revealing how a specific area of the brain responds to down time.

"A great deal of meaningful activity is occurring in the brain when a person is sitting back and doing nothing at all," says Raichle, who has been funded by the National Science Foundation (NSF) Division of Behavioral and Cognitive Sciences in the Directorate for Social, Behavioral and Economic Sciences. "It turns out that when your mind is at rest, dispersed brain areas are chattering away to one another."

The results of these discoveries now are integral to studies of brain function in health and disease worldwide. In fact, Raichle and his colleagues have found that these areas of rest in the brain--the ones that ultimately became the focus of their work--often are among the first affected by Alzheimer's disease, a finding that ultimately could help in early detection of this disorder and a much greater understanding of the nature of the disease itself.

For his pioneering research, Raichle this year was among those chosen to receive the prestigious Kavli Prize, awarded by The Norwegian Academy of Science and Letters. It consists of a cash award of $1 million, which he will share with two other Kavli recipients in the field of neuroscience.

His discovery was a near accident, actually what he calls "pure serendipity." Raichle, like others in the field at the time, was involved in brain imaging, looking for increases in brain activity associated with different tasks, for example language response.

In order to conduct such tests, scientists first needed to establish a baseline for comparison purposes which typically complements the task under study by including all aspects of the task, other than just the one of interest.

"For example, a control task for reading words aloud might be simply viewing them passively," he says.

In the Raichle laboratory, they routinely required subjects to look at a blank screen. When comparing this simple baseline to the task state, Raichle noticed something.

"We didn't specify that you clear your mind, we just asked subjects to rest quietly and don't fall asleep," he recalls. "I don't remember the day I bothered to look at what was happening in the brain when subjects moved from this simple resting state to engagement in an attention demanding task that might be more involved than simply increases in brain activity associated with the task.

"When I did so, I observed that while brain activity in some parts of the brain increased as expected, there were other areas that actually decreased their activity as if they had been more active in the 'resting state,"' he adds. "Because these decreases in brain activity were so dramatic and unexpected, I got into the habit of looking for them in all of our experiments. Their consistency both in terms of where they occurred and the frequency of their occurrence--that is, almost always--really got my attention. I wasn't sure what was going on at first but it was just too consistent to not be real."

These observations ultimately produced ground-breaking work that led to the concept of a default mode of brain function, including the discovery of a unique fronto-parietal network in the brain. It has come to be known as the default mode network, whose regions are more active when the brain is not actively engaged in a novel, attention-demanding task.

"Basically we described a core system of the brain never seen before," he says. "This core system within the brain's two great hemispheres increasingly appears to be playing a central role in how the brain organizes its ongoing activities"

The discovery of the brain's default mode caused Raichle and his colleagues to reconsider the idea that the brain uses more energy when engaged in an attention-demanding task. Measurements of brain metabolism with PET (positron emission tomography) and data culled from the literature led them to conclude that the brain is a very expensive organ, accounting for about 20 percent of the body's energy consumption in an adult human, yet accounting for only 2 percent of the body weight.

"The changes in activity associated with the performance of virtually any type of task add little to the overall cost of brain function," he continues. "This has initiated a paradigm shift in brain research that has moved increasingly to studies of the brain's intrinsic activity, that is, its default mode of functioning."

Raichle, whose work on the role of this intrinsic brain activity on facets of consciousness was supported by NSF, is also known for his research in developing and using imaging techniques, such as positron emission tomography, to identify specific areas of the brain involved in seeing, hearing, reading, memory and emotion.

In addition, his team studied chemical receptors in the brain, the physiology of major depression and anxiety, and has evaluated patients at risk for stroke. Currently, he is completing research studying what happens to the brain under anesthesia.

"The brain is capable of so many things, even when you are not conscious," Raichle says. "If you are unconscious, the organization of the brain is maintained, but it is not the same as being awake."

-- Marlene Cimons, National Science Foundation
Investigators
Marcus Raichle
Related Institutions/Organizations
Washington University School of Medicine

NSF VIDEO: ALZHEIMER'S PATIENTS: A SURPRISE FINDING IN EXECUTIVE FUNCTION

10 FINDINGS ABOUT THE BRAIN

FROM:  NATIONAL SCIENCE FOUNDATION 

From dino brains to thought control--10 fascinating brain findings
Summaries of 10 findings about the brain that involve NSF-funded researchers

February 11, 2014

The human brain is the most complex and least understood biological structure in the known universe.

To advance brain science, President Obama in April 2012 announced the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, which is co-led by the National Science Foundation (NSF).

Even before BRAIN, NSF invested in fundamental brain research that produced amazing discoveries related to humans and animals. Here are 10 recent findings from NSF-funded brain research, running the gamut from insights about the brains of dinosaurs and octopuses to discoveries involving Alzheimer's, brain-controlled machines and more.

1. Surprise! Some types of wrinkles are good

Our human brain is relatively large for our body size and more wrinkled than the brains of other animals. Brain size and wrinkle numbers correlate with intelligence across species.

The outer layer of the human brain is covered by wrinkles, and the more of them the better. Why? Because these wrinkles increase the surface area available for neurons (the functional units of information processing) without increasing head size--good for women during childbirth. Human brain wrinkles are thought to be almost as hereditary as human height.

Elizabeth Atkinson of Washington University in St. Louis recently identified chromosome segments and genes that correlate with wrinkle numbers in about 1,000 baboons, which are genetically similar to humans. The next step: Pinpointing exactly where in these genetic regions folding patterns originate, which would provide insights into the evolution of the human brain.

2. Dinosaurs: Not big and dumb, after all--just big?

A new map of a generalized dinosaur brain suggests the possible existence of a cerebrum, a brain part that controls complex cognitive behaviors in mammals. Although scientists don't know what functions dinosaur cerebrums may have controlled, their existence would suggest that dinosaurs may have performed more complex behaviors than previously believed--such as forming social groups and possibly communicating.

The map is based on inferences from the genetics and organization of crocodile and bird brains. Crocodiles pre-date many dinosaurs and are their closest living relatives, while birds post-date dinosaurs.

Because crocodiles, dinosaurs and birds form an evolutionary chain, scientists believe that these animals' brain structures shared important traits, and so key features of dinosaur brains may be deduced from crocodile and bird brains.

The brain map is also based on fossilized dinosaur skull cavities, which yield implications about the shape of dinosaur brains. Such evidence provides the best clues to the dinosaur brain in the absence of any known fossilized brain tissue from dinosaurs. The dinosaur brain map was created by a team led by Erich Jarvis of Duke University.

3. A possible explanation for Einstein's intelligence

Studies of Einstein's brain conducted in the 1980s revealed that Einstein had an unusually large number of brain cells, called glia, in his cerebral cortex, and that one type of his glia was unusually large and complexly shaped. Though lacking statistical significance, these studies helped generate interest in glia.

Glia had long been dismissed as connective tissue that doesn't contribute to learning and memory, as do neurons. This idea had become entrenched because glia don't generate electrical signals--considered to be the core of brain function--as do neurons.

Harder evidence of the glia's influence on intelligence includes a 2013 study involving the injection of human glia into the brains of newborn mice. As adults, the injected mice became faster learners than control subjects.

Also, two recent papers promoted a new consensus among leading brain scientists about the importance of glia--which may even aid learning. How? Brain imaging indicates that when people learn new skills, from juggling to playing computer games, the structure of specific brain regions changes. These changes may be due to the glia's formation of myelin, a fatty insulating substance, around axons (nerve fibers), which speeds the transmission of electrical signals from axons.

4. In mind-computer melds, brains still important

A brain-computer connection is a partnership: A human brain tells a machine what to do and the machine responds accordingly.

When this type of partnership works, a brain and machine may accomplish amazing things together. For example, in experiments, students flew model helicopters using their thoughts via special head caps equipped with sensors that decoded their brain activity. In similar setups, people with physical disabilities used a robotic arm to grab cups of coffee.

But humans often struggle to control their mechanical partners, partly because it takes significant time to learn how to do so. One way to reduce this training time may be to improve mind/body awareness--as indicated by a recent study led by Bin He, director of the Center for Neuroengineering at the University of Minnesota. His results showed that that training in mind/body awareness through practices such as yoga or meditation enabled people to master a brain-computer interface almost five times faster than untrained people did.

Even as brain-computer connections are made more user-friendly, He's results underscore the continuing importance of the human element for these systems.

5. Scientists may be able to predict when you'll be primed for risky business

Recent advances in brain imaging technology may allow researchers to predict whether someone will make a safe or a risky financial decision based on certain types of brain activity prior to deciding.

According to Brian Knutson and Charlene C. Wu of Stanford University, people who expect to win big show increased activity in certain brain regions, including the nucleus accumbens, which is associated with reward and pleasure, whereas those who expect to lose show increased activity in the anterior insula, which is linked to anxiety and disgust.

The more money at stake, the more activity is seen in those regions. But while more activity in the nucleus accumbens encouraged risk-taking, more activity in the anterior insula reduced risk taking.

These findings imply that when people are more excited, they will take bigger risks. In fact, long-shot wins (like potential lottery wins) powerfully increased both excitement and nucleus accumbens activity, encouraging people to take risks, even as they strayed from the choices of a "rational" person.

Studying people's brains while they consider their risk-taking options reveals insights about why people make certain financial decisions. These findings have implications for individual patterns of risk-taking--such as saving for a 401K--as well as for basic theories that describe group behavior.

6. Cell-based therapy may ultimately help beat back brain cancers

Brain tumors are the second-leading cause of U.S. cancer-related deaths, with 70,000 diagnoses of this invariably deadly disease made annually.

Now, Stefan Bossmann and Deryl Troyer of Kansas State University are working to improve a type of promising cell therapy that has yet to be used successfully. The researchers' therapy would work by collecting a cancer patient's blood; refurbishing selected white blood cells with "cargo holds" or closed cavities that would be filled with anticancer drugs; and then re-injecting the patient's blood to deliver drugs directly to tumors.

Previous efforts to develop this type of cell therapy produced weak, leaky medicinal cavities that killed carrier cells, not tumors. But the researchers are improving these cavities by developing a new type of material for them that forms something akin to a self-assembling artificial bubble--designed to be selectively absorbed by the right type of white blood cells, remain strong enough to hold medicine and naturally self-destruct upon reaching tumors.

Cell therapy delivers significantly more anticancer drugs to tumors than does conventional chemotherapy and nanotherapy, without damaging the body's immune system.

With preliminary experiments in mice competed, the therapy will soon be used to specifically target mice tumors for the first time, with the hope that this therapy will ultimately be able to be successfully used on human brain tumors.

7. The octopus: The eyes have it--literally

The octopus is a successful predator, partly because it has excellent eyesight--the best of any invertebrate--which enables it to visually zero in and focus on its prey.

What's more, each of the octopus's eight agile, boneless arms is equipped with about 44 million nerve cells (almost 10 percent of all of its neurons). These arm neurons are connected to the animal's brain.

When an octopus spots a tasty-looking fish, resulting visual information travels from the animal's eye to its brain. This information then travels through its arm neurons to help these soft-bodied contortionists determine how to snatch the meal.

Conversely, tactile information, such as the feel of a crab's rough shell, travels back through the octopus's arm to its brain's learning and memory centers to help these clever animals improve their hunting skills.

A team led by Clifton Ragsdale of the University of Chicago is the first to use modern molecular techniques to study how the octopus's unique nervous system processes visual information, and if the octopus's processing system significantly differs from that of vertebrates. If such differences are found, they may reveal alternative ways for brains to process visual information and learn. Resulting insights may yield important applications for robotics and image detection devices.

8. Birds' responses to climate change: It's all in their heads

Different bird species use different cues to determine when to migrate and to reproduce. Whether any particular species will be able to adjust its timing of such activities fast enough to keep up with climate change may partly depend on which cues it uses.

To varying degrees, all bird species use day length as a cue. They measure day light and anticipate seasonal changes via light-activated receptors located deep in their brains. The light penetrates their skulls without even necessarily passing through their eyes.

Because day length is unaffected by climate change, some long-distance migrators, such as the pied-flycatcher, whose main migratory cue is day length, have maintained fairly consistent arrival times at their spring breeding grounds. Yet, spring temperatures now tend to increase earlier in the year because of climate change. So such migrators now tend to arrive at their breeding grounds late relative to premature springs--and, therefore, now miss insect population peaks upon which they previously feasted. With less to eat, such migrators are now producing fewer chicks, which may cause population declines.

Some bird species augment day length cues for migrating and/or breeding with other cues, like temperature changes, which are probably also processed in their brains. Changes in the timing of the migratory activities of some temperature-sensitive bird species correlate with climate change-related temperature changes.

But most studies of the processing of day length by birds have addressed only males. Now Nicole Perfito of the University of California, Berkeley is studying how females of two bird species process day length and other cues that influence the timing of egg laying--an important factor in their potential responses to climate change.

9. Still wanted: A complete parts list of the human brain

The human brain has about 100 billion neurons. But scientists don't yet have a complete inventory of the many types of brain cells that exist and their functions. They also don't understand how electrical and chemical signals from neurons produce thoughts, behaviors and actions.

Without such knowledge, scientists cannot yet explain how traumatic injuries and neurodegenerative diseases impair brain function or should be treated. By comparison, imagine a mechanic trying to fix a car engine without a complete parts list and/or an understanding of how its engine runs!

Yet, new types of brain cells are often being identified, partly because of new brain imaging techniques that can zoom in on the brain to reveal increasing detail, just as Google Maps can zoom in on neighborhoods.

But without a universal classification system, cell types that have already been discovered may have been named and classified according to inconsistent criteria, such as shape, function or location. Therefore, some newly "discovered" cell types may really be rediscovered, renamed cell types.

To standardize the naming of neurons and create a universally accepted inventory of neuron types, Edward Boyden of MIT and others are working with the Allen Institute for Brain Science to create the first comprehensive database of types of brain cells.

10. Designer antibodies may ultimately help fight Alzheimer's

Antibodies, which are proteins traditionally made by the body's immune system in response to invaders, are already established allies in our fight against the flu virus and other harmful entities. Now, they are being engineered to treat and possibly protect us against disease-linked proteins, such as those associated with Alzheimer's disease.

Such engineering requires designing antibodies that have extreme targeting capabilities so that they can be directed to go where and do exactly what is needed. Antibodies used for therapeutic or experimental reasons are usually taken from immunized animals or enormous antibody libraries. So it's difficult to custom-order them.

Peter Tessier of Rensselaer Polytechnic Institute in Troy, N.Y., is working to engineer antibodies that have precise properties. By placing DNA sequences of the target protein within antibodies, Tessier may design antibodies to bind to select proteins, such as beta-amyloid plaques, a protein linked with Alzheimer's. Further research may lead to the development of antibodies that recognize and remove toxic particles before they do harm.

Editor's Note: This Behind the Scenes article was first provided to LiveScience in partnership with the National Science Foundation.

-- Sarah Bates, National Science Foundation (703) 292-7738 sabates@nsf.gov
-- Lily Whiteman, National Science Foundation (703) 292-8070 lwhitema@nsf.gov
Investigators
Bin He
Uri Eden
Earl Miller
Beth Stevens
Deryl Troyer
Erich Jarvis
Nancy Kopell
Brian Knutson
Claudio Mello
Edward Boyden
Peter Tessier
George Bentley
James Cheverud
Richard Fields
Stefan Bossmann
Clifton Ragsdale
Matti Hamalainen
Elizabeth Atkinson
Related Institutions/Organizations
Duke University
Stanford University
University of Chicago
Kansas State University
Trustees of Boston University
Duke University Medical Center
Children's Hospital Corporation
Rensselaer Polytechnic Institute
University of California-Berkeley
University of Minnesota-Twin Cities
Washington University School of Medicine
Related Awards
#0229351 Alan T. Waterman Award
#1021909 Octopus Neural Systems
#0748915 Anticipatory Affect and Financial Risk Taking
#1042134 Cognitive Rhythms Collaborative: A Discovery Network
#0920753 Neuroendocrine Mechanisms of Reproduction in Songbirds
#1242765 INSPIRE: Neutrophil Delivery of Apoptosis-Inducing Anticancer Drugs
#0933067 Neuroimaging of Motor Imagery for Brain Computer Interface Applications
#1159943 Design of conformation-specific antibodies against unfolded and misfolded proteins
#1258562 Glial Biology of Learning and Cognition, to be held in Arlington, Virginia, February, 2013
#0084357 Multiple Disciplinary Collaborative Research: Evolution of Brain Structures for Vocal Learning in Birds
#1260844 Doctoral Dissertation Improvement: The evolution and genetic basis of primate brain cortical gyrification in a pedigreed Papio population
Total Grants
$6,908,570