Visscher Lab Makes News
Computing challenges are found across the UAB campus, from physics and neurology to genetics and the microbiome. Alabama’s most advanced supercomputer is now at UAB, making it possible to solve these challenges.
Kristina Visscher is using fMRI images from several hundred brains to learn how the brain adapts after long-term changes in vision.What do the human brain, the 3 billion base-pair human genome and a tiny cube of 216 atoms have in common?
All of them, from the tiny cube to the 3-pound human brain, create incredibly complex computing challenges for University of Alabama at Birmingham researchers, and aggressive investments in UAB’s IT infrastructure have opened new possibilities in innovation, discovery and patient care.
For example, Kristina Visscher, Ph.D., assistant professor of neurobiology, UAB School of Medicine, uses fMRI images from several hundred human brains to learn how the brain adapts after long-term changes in visual input, such as macular degeneration. Frank Skidmore, M.D., an assistant professor of neurology in the School of Medicine, studies hundreds of brain MRI images to see if they can predict Parkinson’s disease.
David Crossman, Ph.D., bioinformatics director in UAB’s Heflin Center for Genomic Science, deciphers the sequences of human genomes for patients seeking a diagnosis in UAB’s Undiagnosed Diseases Program, and he processes DNA sequencing for UAB researchers who need last-minute data for their research grant applications.
Ryoichi Kawai, Ph.D., an associate professor of physics in the UAB College of Arts and Sciences, is laying the groundwork for a better infrared laser by calculating the electronic structure for a cube made up of just 216 atoms of zinc sulfide doped with chromium or iron.
Each researcher faces a mountain range of computational challenges. Those mountains are now easier to scale with UAB’s new supercomputer — the most advanced in Alabama for speed and memory.
The tiny cubeThe 216-atom electronic structure problem “is the largest calculation on campus, by far,” Kawai said. “If you give me 2,000 cores, I can use them. If you give me 10,000 cores, I can use them all without losing efficiency.” (UAB's new supercomputer has 2,304 cores.)
| Learn more about UAB’s new supercomputer in this story
BrainsIn their research, both Skidmore and Visscher have to compare brains with other brains. Because each brain differs somewhat in size, shape and surface folds, every brain has to be mapped onto a template to allow comparisons.
Physicist Kawai describes his computations as the most intensive on campus.“We want to capture information in an image, such as information on an individual’s brain condition,” Skidmore said. “The information we are trying capture, however, can often be difficult to see in the sea of data we collect. One brain may contain millions of bits of data in the form of ‘voxels,’ which are a bit like the pixels on your TV but in three dimensions.”
“When we map to a template,” Skidmore said, “we quadruple the data. When we ask, ‘How does this compare to a healthy brain?’ we double the data again. Then if we look across one brain or across multiple kinds of brain images, the amount of data truly explodes.”
Physicist Ryoichi Kawai's complex calculations of the electronic structure of a cube of atoms are laying the groundwork for better lasers.“This is made even more complex by the fact that a given image can include more than three dimensions of information,” he said. “One type of image we use generates 5-dimensional brain maps. Since we can’t see in five dimensions, we ask the computer to work in these higher-dimensional spaces to help us pull the information out of the data.”
To look at the adult brain’s plasticity — the ability to change function and structure through new synaptic connections — Visscher studies visual processing.
“Because we look at spatial and temporal data, the number of pieces of information is huge — gigabytes per subject,” she said. “We need to do correlations on all the data points at the same time. To get faster, we optimize the data analysis with a lot of feedback. Then we run what we learned from one brain on a hundred brains.”
UAB customersCrossman deciphers the sequences of human genomes for patients seeking a diagnosis, and he processes DNA sequencing for UAB researchers. Providing excellent customer service to his clients is vital, Crossman says, and it takes computer power to crunch genome sequencing data for those researchers, physicians and patients.
Managing traffic on the new UAB computer clusterSize:
The data floodgates of genomics burst open about a dozen years ago with the arrival of next-generation, high-throughput sequencing, says Elliot Lefkowitz, Ph.D., director of Informatics for the UAB Center for Clinical and Translational Science. Lefkowitz has been serving the bioinformatics needs of the UAB Center for AIDS Research for 25 years, and now also handles bioinformatics for the UAB Microbiome Facility. His team has grown to five bioinformaticians and several programmers.
“We deal with billions of sequences when we do a run through the DNA sequencing machine,” Lefkowitz said. “We need to compare every one of the billion ‘reads’ (the 50- to 300-base sequence of a short piece of DNA) to every other one. With high-performance computing and thousands of nodes, each one does part of the job.”
“In not too many years,” Lefkowitz speculated, “we will be sequencing every patient coming into University Hospital.”
Changes like that mean ever-increasing computer demands.
“Biomedical research,” Crossman said, “now is big data.”
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Discovery may lead to a treatment to slow Parkinson's disease
Researchers have found that an interaction between a mutant gene and alpha synuclein in neurons leads to hallmark pathologies seen in Parkinson’s disease, findings that may lead to new mechanisms and targets for neuroprotection.
Laura A. Volpicelli-DaleyUsing a robust model for Parkinson’s disease, University of Alabama at Birmingham researchers and colleagues have discovered an interaction in neurons that contributes to Parkinson’s disease, and they have shown that drugs now under development may block the process.
The research team has shown that the most common genetic cause of Parkinson’s disease — a mutant LRRK2 kinase enzyme — contributes to the formation of inclusions in neurons, resembling one of the hallmark pathologies seen in Parkinson’s disease. These inclusions are made up of aggregated alpha synuclein protein, which — the research also shows — can be prevented from forming by using two LRRK2 kinase inhibitor drugs now being developed for clinical use.
The interaction between mutant LRRK2 kinase and alpha-synuclein “may uncover new mechanisms and targets for neuroprotection,” the researchers write in a recent Journal of Neuroscience paper. “These results demonstrate that alpha-synuclein inclusion formation in neurons can be blocked and that novel therapeutic compounds targeting this process by inhibiting LRRK2 kinase activity may slow progression of Parkinson’s disease-associated pathology.”
The potential clinical applications for novel neuroprotection strategies in LRRK2-linked Parkinson’s need to be tested in other preclinical models of Parkinson’s disease, say the researchers, led by corresponding author Laura A. Volpicelli-Daley, Ph.D., and senior author Andrew B. West, Ph.D., Center for Neurodegeneration and Experimental Therapeutics, UAB Department of Neurology.
“These data give us hope for the clinical potential of LRRK2 kinase inhibitors as effective therapies for Parkinson’s disease,” Volpicelli-Daley said. “The LRRK2 kinase inhibitors may inhibit the spread of pathologic alpha-synuclein, not only in patients with LRRK2 mutations, but in all Parkinson’s disease patients. Future studies to validate the safety and efficacy of the LRRK2 inhibitors will be necessary before testing the inhibitors in human clinical trials.”
Besides Parkinson’s disease, alpha-synuclein also plays a central role in development of dementia with Lewy bodies and multiple system atrophy, and it is associated with Alzheimer’s disease and other neurodegenerative disorders.
Primary hippocampal neurons from mice expressing G2019S-LRRK2. The neurons were treated with alpha-synuclein fibrils, and 18 days later immunofluorescence was performed. The magenta shows phospho-alpha-synuclein inclusions in the cell bodies and throughout the axons, which are visualized as green.Research detailsThe Parkinson’s disease model developed by Volpicelli-Daley applies very low concentrations of pre-formed fibrils of alpha-synuclein to in vitro or in vivo neurons. This causes formation of modified alpha-synuclein inclusions that share morphology with those found in the Parkinson’s disease brain after death.
They used this model to test the effects of neuron expression of the mutant LRRK2 (“lark two”) kinase, G2019S-LRRK2, on the formation of the inclusion pathology.
They found that:
- G2019S-LRRK2 enhanced alpha-synuclein inclusions in primary hippocampal neurons from the hippocampus region of the brain, 18 days after fibril exposure, as compared with neurons that over-expressed normal LRRK2.
- The effects of G2019S-LRRK2 expression in the fibril-exposed neurons were lessened by very low concentrations of potent and selective preclinical drugs that inhibit LRRK2 kinase. This suggested that the kinase activity of G2019S-LRRK2, which adds a phosphate onto target proteins, underlies the faster formation of pathologic alpha-synuclein inclusions.
- G2019S-LRRK2 expression enhanced alpha-synuclein inclusion formation in dopamine neurons from the region of the brain called the substantia nigra pars compacta. The substantia nigra pars compacta is the area of the brain that dies in Parkinson’s disease, so this experiment further supports a link between the G2019S-LRRK2 mutation and Parkinson’s pathogenesis.
Andrew B. WestIn fluorescence-recovery-after-photobleaching experiments, they found there was a larger pool of mobile alpha-synuclein, as opposed to membrane-bound alpha-synuclein, in neurons that expressed G2019S-LRRK2. Recent work by others has shown that mobile alpha-synuclein is prone to misfolding and aggregation, so the researchers hypothesize that the G2019S-LRRK2 mutation may contribute to Parkinson’s susceptibility by boosting the amounts of mobile alpha-synuclein in neurons.
Besides Volpicelli-Daley and West, co-authors of the paper “G2019S-LRRK2 expression augments alpha-synuclein sequestration into inclusions in neurons” are Hisham Abdelmotilib, Zhiyong Liu, Lindsay Stoyka, João Paulo Lima Daher and Kyle Fraser, all of the Center for Neurodegeneration and Experimental Therapeutics, UAB Department of Neurology; Austen J. Milnerwood, Centre for Applied Neurogenetics, University of British Columbia; Vivek K. Unni, Jungers Center for Neurosciences Research and Parkinson Center of Oregon, Oregon Health & Science University; Warren D. Hirst, Pfizer Neuroscience and Pain Research Unit, Cambridge, Massachusetts; Zhenyu Yue, Departments of Neurology and Neuroscience, Icahn School of Medicine at Mount Sinai; Hien T. Zhao, Ionis Pharmaceuticals, Carlsbad, California; and Richard E. Kennedy, Comprehensive Center for Healthy Aging and Division of Gerontology, Geriatrics, and Palliative Care, UAB Department of Medicine.
Grants to fund this work came from the American Parkinson’s Disease Association, the Michael J. Fox Foundation LEAPS Award and the National Institutes of Health NS064934.
Volpicelli-Daley is an assistant professor in the Department of Neurology.
West is co-director of the Center for Neurodegeneration and Experimental Therapeutics, and the John A. and Ruth R. Jurenko Professor of Neurology at UAB.
NEURAL Conference draws new minds to Neuroscience
NEURAL, the cornerstone effort of the UAB Neuroscience Roadmap Scholars Program, is moving to change this reality. NEURAL, which stands for “National Enhancement of Underrepresented Academic Leaders,” is an annual conference targeted toward trainees and graduate students in the neuroscience fields who are members of underrepresented groups. Bringing together students and trainees from inside and outside UAB, the NEURAL 2016 conference offers opportunities to present original research, and to interface with respected neuroscientists from across the country.
The Neuroscience Roadmap Scholar program and its flagship NEURAL conference were conceptualized by Farah Lubin, PhD, and Lori McMahon, PhD, who received funding on an R25 NIH grant in order to launch the program. Although the undergraduate programs which interacted with neuroscience at UAB included a diverse population of students, Lubin and McMahon realized that racial and ethnic minorities and those with physical or mental disabilities were still underrepresented at the graduate level. The UAB Neuroscience Roadmap Scholar program was created as a means to provide both incentive and support for graduate students who are racial or ethnic minorities, and/or who have a physical or mental impairment from a broad range of scientific fields, including chemistry, biology, and bioengineering, to pursue careers in neuroscience. The UAB Neuroscience Roadmap Scholar program is hugely supported by the Neuroscience community and faculty who serve as career coaches for the scholars.
The UAB Neuroscience Roadmap Scholar program held its NEURAL 2016 conference June 22-24 on UAB’s campus with opening ceremonies at the Birmingham Civil Rights Institute. Bringing together roughly 75 UAB students and 50 students from outside UAB, it offered not only insight into neuroscience career paths, but also professional development workshops on personal finance, electronic portfolios, successful paper submissions, and dealing with stereotype threat.
One of the tremendous offerings of the NEURAL conference is its ability to bring in renowned neuroscientists who offer unique perspectives. At the NEURAL conference in 2015, Roger Nicoll, MD, a professor at UCSF’s School of Medicine and recipient of the Gruber Prize in Neuroscience, discussed his struggles with severe dyslexia.
The NEURAL 2016 conference featured Gordon E. Legge, PhD, a professor of psychology from the University of Minnesota who heads the Minnesota Laboratory for Low-Vision Research. Author of more than 400 papers, and the recipient of a wide range of professional honors, including the Charles F. Prentice Medal from the American Academy of Optometry and the Access Achievement Award from the University of Minnesota, Legge himself is visually impaired.
Students and trainees, who participated in a faculty-judged poster session during the conference, were given the opportunity not only to hear from Legge and other distinguished speakers, but to interact with them one-on-one. Yisel Cantres Rosario, PhD, of the University of Puerto Rico Medical School, was one of the trainee participants. In a letter following the conference, she articulated the importance of the opportunities offered by the NEURAL conference. “I would have liked to participate in a small meeting like this when I was a graduate student,” she wrote. “I have participated in a good number of big meetings, but because of the amount of people attending those conferences, we dilute ourselves and are not able to interact with everybody as we did in NEURAL. I personally talked to all the keynote speakers opening new doors of communication, which is a critical component of my career, now that I am beginning as a post-doctoral. I came to Puerto Rico with a lot of ideas for my research and also to help graduate students from our institution, thanks to you. Congratulations to all for such a good meeting for underrepresented students! It means a lot for us and shows how much you care for your students.”
Lubin says that the gears are already turning in preparation for the conference’s third year. Thanks to institutional support, she sees the Neuroscience Roadmap Scholar program and the NEURAL conference flourishing well into the future and serving its critical mission to draw underrepresented graduate students and trainees into neuroscience. “You can’t model what you haven’t seen,” she says. “The more examples we put in front of students, the more we make it clear they have no excuse to not succeed.”