Daft about data
Apparently taking a break from their lab duties, a group of UC San Diego neuroscience students have put together a video paean to their tireless (but tiring) pursuit of data – usually while the rest of us are asleep.
The video, intended as a sort of invite to a Monday night social during next week’s Society for Neuroscience conference in San Diego, went viral, even appearing on Scientific American’s website. The UC San Diego video is inspired by Daft Punk’s song, “Get Lucky.”
Judging from YouTube hits (more than 10,000 in just over a day for a video about doing things like gel electrophoresis), the neuroscience students got more than lucky. They’ve got a hit.
$100 Million Gift Launches Sanford Stem Cell Clinical Center
UC San Diego-based effort will speed discoveries to new drugs and treatments for patients
In a bold and singular step toward delivering the therapeutic promise of human stem cells, businessman and philanthropist T. Denny Sanford has committed $100 million to the creation of the Sanford Stem Cell Clinical Center at the University of California, San Diego.
The Sanford Center will accelerate development of drugs and cell therapies inspired by and derived from current human stem cell research; establishing, promoting and disseminating clinical trials and patient therapies that will help more quickly transform promise into reality.
“This gift and the creation of the Sanford Stem Cell Clinical Center will further UC San Diego’s leadership in stem cell science and therapeutics, and advance our region’s reputation as an international, collaborative hub for stem cell research,” said Pradeep K. Khosla, chancellor of UC San Diego. “This Center will support the goals and vision of our strategic planning process by translating discoveries into therapies that will improve and save lives.”
The Sanford Center will integrate operations at four locations: the UC San Diego Jacobs Medical Center and a nearby proposed clinical space, both scheduled to open in 2016; the UC San Diego Center for Advanced Laboratory Medicine (CALM); and the Sanford Consortium for Regenerative Medicine (SCRM). It will provide essential physical and human resources needed to leverage stem cell research currently being conducted at the Sanford Consortium – an innovative “collaboratory” of San Diego scientists from UC San Diego, the Sanford-Burnham Medical Research Institute, the Salk Institute for Biological Studies, The Scripps Research Institute and the La Jolla Institute for Allergy & Immunology – and other institutions on and around the Torrey Pines mesa, such as the J. Craig Venter Institute.
“Every day, scientists learn more about the regenerative powers of stem cells, which tantalize with their potential to treat, cure, even prevent, myriad afflictions, including cancer, Lou Gehrig’s disease and spinal cord injury. I see it in the amazing collaborative advances by researchers and doctors in the Consortium and across the La Jolla mesa,” said Sanford. “I believe we’re on the cusp of turning years of hard-earned knowledge into actual treatments for real people in need. I want this gift to push that reality faster and farther.”
The image above depicts 12 functional regions of the brain clustered by genetic influence, either in terms of cortical thickness or by cortical surface area. The numbers identify specific regions. For cortical thickness: 1. Motor-premotor-supplementary area; 2. Superior parietal cortex; 3. Inferior parietal cortex; 4. Perisylvian region; 5. Occipital cortex; 6. Ventromedial occipital cortex; 7. Ventral frontal cortex; 8. Temporal pole; 9. Medial temporal cortex; 10. Middle temporal cortex; 11. Dorsolateral prefrontal cortex and 12. Medial prefrontal cortex. For surface area: 1. Motor-premotor cortex; 2. Dorsolateral prefrontal cortex; 3. Dorsomedial frontal cortex; 4. Orbitofrontal cortex; 5. Pars opercularis and subcentral region; 6. Superior temporal cortex; 7. Posterolateral temporal cortex; 8. Anteromedial temporal cortex; 9. Inferior parietal cortex; 10. Superior parietal cortex; 11. Precuneus; and 12. Occipital cortex.
Delving deeper into brain-building
Given its incredible structural complexity – 100 billion chattering neurons connected by a network of perhaps a quadrillion synaptic connections – it can hardly be surprising that the actual construction of a human brain is equally complex and marvelous.
A new paper by researchers at UC San Diego School of Medicine and VA San Diego Healthcare System underscores that point by plotting for the first time how genes influence the development and thickness of the cerebral cortex – the thin, outermost sheet of neural tissue, often dubbed “gray matter,” that plays a key role in high-level mental functions like memory, attention, perceptual awareness, thought, language and consciousness.
The work adds a new dimension to a 2012 study by the same scientists that rendered the first atlas of the surface of the human brain based on genetic information.
“There are two major dimensions on the cortical ribbon or cortical sheet,” said first author Chi-Hua Chen, PhD. “One is the horizontal dimension for the expansion of surface area and the other is the vertical dimension for the size of cortical thickness. The 2012 work was to study the genetic topography of surface area; this study was to study cortical thickness.”
The researchers found that genetic influences work differently depending upon the direction taken during brain development. On the surface of the cortex, the effects are most striking horizontally, with maximum differences between those at the anterior or front of the brain compared to the posterior or back of the brain. With cortical thickness, the differences were dictated vertically, with maximum deviation measured dorsal (top) to ventral (bottom).
According to Chen, the findings confirm other evidence that cortical construction involves different mechanisms of brain development. “I think the importance and relevance of this study is that human cortical morphology is under genetic control that shows orderly spatial patterns on the cortical ribbon,” she said. Previous animal studies had suggested as much, but the concept of brain development through genetic gradation has not been well-studied in humans.
While there are no immediate clinical applications for the research, Chen and Kremen say the findings will further understanding of how complex genetic influences affect cortical morphology and aid future efforts to identify involved genes and associated neurological disorders.
“The genetic underpinnings of the brain are poorly understood, especially for the human brain,” said Kremen. “New genomic technologies are making it possible to explore this area and answer, from a genetic perspective, how genes affect brain development and how they are involved in neurological disorders like Alzheimer’s disease, mild cognitive impairment, schizophrenia and autism.
A transmission electron micrograph (false color) depicting a neuron from a patient who suffered from Alzheimer’s disease. The cell nucleus is green, the body of the cell yellow and the surrounding tissue blue. Filaments that form neurofibrillary tangles – a hallmark of AD – are colored red. Image courtesy of Thomas Deerinck, NCMIR
Why don’t we all get Alzheimer’s disease?
Alzheimer’s disease afflicts an estimated 5 million Americans, with the number projected to triple by 2050. Currently, no therapy has been shown to slow the progression of the neurodegenerative disease, let alone cure it. The last drug to even temporarily ease symptoms of AD – memantine – was approved a decade ago.
These are worrisome facts that fuel profound questions and concerns, not least among them whether we can afford not to find a remedy.
But the dilemma presents an altogether different question as well: Why don’t we all get Alzheimer’s disease?
The happy reality is that the vast majority of people will never develop the devastating neurological condition. Subhojit Roy, MD, PhD, an associate professor in the departments of Pathology and Neurosciences at the UC San Diego School of Medicine, and colleagues recently proposed an answer in a paper published in the journal Neuron.
As it turns out, every brain cell possesses the ingredients necessary to spark AD, but nature has wisely devised ways to keep the explosive cellular ingredients apart.
“It’s like physically separating gunpowder and match so that the inevitable explosion is avoided,” said Roy, a cell biologist and neuropathologist in the Shiley-Marcos Alzheimer’s Disease Research Center at UC San Diego. “Knowing how the gunpowder and match are separated may give us new insights into possibly stopping the disease.”
The main players are a pair of proteins called APP and BACE-1, both abundant in the brain but largely kept apart from one another. In AD, said Roy, these proteins too often combine with calamitous consequences.
You can read the full news release and watch a video here.
The epigenetics of Parkinson’s disease
Parkinson’s disease (PD) is a neurodegenerative disorder with high incidence in the elderly, caused by a combination of environmental and genetic factors. In addition, epigenetic changes – changes in gene expression that are caused by non-genetic factors – such as DNA methylation have recently been associated with PD.
In the August 1 online edition of the Landes Biosciences journal Epigenetics, researchers from the University of California, San Diego School of Medicine investigated genome-wide methylation in brain and blood samples from PD patients. They observed a distinctive pattern of methylation involving many genes previously associated with the disease, supporting the role of epigenetic alterations as a molecular mechanism in neurodegeneration.
DNA methylation, a biochemical process that is one of the methods used to regulate the expression of genes, represents a highly promising biomarker for neurodegenerative disorders. Emerging techniques allow monitoring DNA methylation from blood – a method that could replace post-mortem brain tissue as a way to detect PD.
“Since early identification of pathological changes is crucial to enable therapeutic intervention in Parkinson’s disease before major neurologic damage occurs, these findings could prove important in monitoring disease progression and the effectiveness of treatment,” said lead author Paula Desplats, PhD, project scientist with the Department of Neurosciences at UC San Diego School of Medicine.
In this study, Desplats and UC San Diego colleagues Eliezer Masliah, MD, Wilmar Dumaop and Douglas Galasko, MD, report differential methylation for several genes, and identified concordant methylation alterations in a subset of genes in both the brain and blood samples of patients with PD.
Earlier studies by the UC San Diego researchers reported a significant decrease in DNA methylation in the frontal cortex of patients with PD and the related disorder called Dementia with Lewy bodies. Here, they further investigated the extent of epigenetic deregulation by analyzing genome-wide DNA methylation profiles in both postmortem frontal cortex samples and peripheral blood leukocytes (or PBLs) from the same individuals in a cohort of PD patients. They then compared these profiles to those of age-matched, healthy control subjects. Individual methylation profiles obtained from blood distinguished control subjects from those with PD.
“We observed similar overall methylation patterns in the brain and blood, and that the same functional groups were affected – genes involved with cell communication, as well as with cellular and metabolic processes, such as genes related to cell death,” Desplats said.
The scientists’ analyses suggest that a number of methylation changes are shared between brain and blood, positioning 124 genes (which co-varied among blood and brain tissues) as candidates for biomarker discovery.
Since accurate diagnosis of PD cannot currently be achieved until clear motor features have developed (which occurs when half of more of neurons in a particular region of the brain called the substantia nigra), increasing efforts are being dedicated to identifying early, non-motor symptoms. These may include depression and sleep disorders as well as olfactory dysfunction or reduced sense of smell.
Top: Vesicles containing APP (green) and BACE (red) are normally segregated in neurons. Bottom: After neuronal stimulation, known to produce more beta-amyloid, APP and BACE converge in common vesicles, depicted in yellow.
Though one might think the brains of people who develop Alzheimer’s disease (AD) possess building blocks of the disease absent in healthy brains, for most sufferers, this is not true. Every human brain contains the ingredients necessary to spark AD, but while an estimated 5 million Americans have AD – a number projected to triple by 2050 – the vast majority of people do not and will not develop the devastating neurological condition.
For researchers like Subhojit Roy, MD, PhD, associate professor in the Departments of Pathology and Neurosciences at the University of California, San Diego School of Medicine, these facts produce a singular question: Why don’t we all get Alzheimer’s disease?
In a paper published in the August 7 issue of the journal Neuron, Roy and colleagues offer an explanation – a trick of nature that, in most people, maintains critical separation between a protein and an enzyme that, when combined, trigger the progressive cell degeneration and death characteristic of AD.
“It’s like physically separating gunpowder and match so that the inevitable explosion is avoided,” said principal investigator Roy, a cell biologist and neuropathologist in the Shiley-Marcos Alzheimer’s Disease Research Center at UC San Diego. “Knowing how the gunpowder and match are separated may give us new insights into possibly stopping the disease.”
The severity of AD is measured in the loss of functioning neurons. In pathological terms, there are two tell-tale signs of AD: clumps of a protein called beta-amyloid “plaques” that accumulate outside neurons and threads or “tangles” of another protein, called tau, found inside neurons. Most neuroscientists believe AD is caused by the accumulating assemblies of beta-amyloid protein triggering a sequence of events that leads to impaired cell function and death. This so-called “amyloid cascade hypothesis” puts beta-amyloid protein at the center of AD pathology.
Creating beta-amyloid requires the convergence of a protein called amyloid precursor protein (APP) and an enzyme that cleaves APP into smaller toxic fragments called beta-secretase or BACE.
“Both of these proteins are highly expressed in the brain,” said Roy, “and if they were allowed to combine continuously, we would all have AD.”
But that doesn’t happen. Using cultured hippocampal neurons and tissue from human and mouse brains, Roy – along with first author Utpal Das, a postdoctoral fellow in Roy’s lab, and colleagues – discovered that healthy brain cells largely segregate APP and BACE-1 into distinct compartments as soon as they are manufactured, ensuring the two proteins do not have much contact with each other.
“Nature seems to have come up with an interesting trick to separate co-conspirators,” said Roy.
Healthy brains require a balance of two energy sources – ATP and GTP – regulated by the gene AMPD2. A mutation in the gene can result in pontocerebellar hyplasia, a neurodegenerative disease afflicting children. Illustration courtesy of Evgeny Onutchin, Buryat Studio
Researchers at the University of California, San Diego School of Medicine have identified the gene mutation responsible for a particularly severe form of pontocerebellar hypoplasia, a currently incurable neurodegenerative disease affecting children. Based on results in cultured cells, they are hopeful that a nutritional supplement may one day be able to prevent or reverse the condition.
The study, from a team of international collaborators led by Joseph G. Gleeson, MD – Howard Hughes Medical Institute investigator and professor in the UCSD Departments of Neurosciences and Pediatrics and at Rady Children’s Hospital-San Diego, a research affiliate of UC San Diego – will be published in the August 1 issue of the journal Cell.
Pontocerebellar hypoplasia is a group of rare, related genetic neurological disorders characterized by abnormal development of the brain, resulting in disabilities in movement and cognitive function. Most patients do not survive to adulthood.
Gleeson and colleagues identified a specific gene mutation that causes pontocerebellar hypoplasia and linked it to an inability of brain cells to generate a form of energy required to synthesize proteins. Without this ability, neurons die, but the researchers also found that bypassing this block with a nutritional supplement restored neuronal survival.
“The goal is to one day use this supplement to prevent or reverse the course of neurodegeneration in humans, and thus cure this disease,” said Gleeson.
The rates of regional brain loss and cognitive decline caused by aging and the early stages of Alzheimer’s disease (AD) are higher for women and for people with a key genetic risk factor for AD, say researchers at the University of California, San Diego School of Medicine in a study published online July 4 in the American Journal of Neuroradiology.
The linkage between APOE ε4 – which codes for a protein involved in binding lipids or fats in the lymphatic and circulatory systems – was already documented as the strongest known genetic risk factor for sporadic AD, the most common form of the disease. But the connection between the sex of a person and AD has been less-well recognized, according to the UC San Diego scientists.
“APOE ε4 has been known to lower the age of onset and increase the risk of getting the disease,” said the study’s first author Dominic Holland, PhD, a researcher in the Department of Neurosciences at UC San Diego School of Medicine. “Previously we showed that the lower the age, the higher the rates of decline in AD. So it was important to examine the differential effects of age and APOE ε4 on rates of decline, and to do this across the diagnostic spectrum for multiple clinical measures and brain regions, which had not been done before.”
The scientists evaluated 688 men and women over the age of 65 participating in the Alzheimer’s Disease Neuroimaging Initiative, a longitudinal, multi-institution study to track the progression of AD and its effects upon the structures and functions of the brain. They found that women with mild cognitive impairment (a condition precursory to AD diagnosis) experienced higher rates of cognitive decline than men; and that all women, regardless of whether or not they showed signs of dementia, experienced greater regional brain loss over time than did men. The magnitude of the sex effect was as large as that of the APOE ε4 allele.
“Assuming larger population-based samples reflect the higher rates of decline for women than men, the question becomes what is so different about women,” said Holland. Hormonal differences or change seems an obvious place to start, but Holland said this is largely unknown territory – at least regarding AD.
“Another important finding of this study is that men and women did not differ in the level of biomarkers of Alzheimer’s disease pathology,” said co-author Linda McEvoy, PhD, an associate professor in the UCSD Department of Radiology. “This suggests that brain volume loss in women may also be caused by factors other than Alzheimer’s disease, or that in women, these pathologies are more toxic. We clearly need more research on how an individual’s sex affects AD pathogenesis.”
Holland acknowledged that the paper likely raises more questions than it answers. “There are many factors that may affect the sex differences we observed, such as whether the women in this study may have had higher rates of diabetes or insulin resistance than the men. We also do not know how the use of hormone replacement therapy, reproductive history or years since menopause may have affected these differences. All these issues need to be examined. There is no prevailing theory.”
A three-dimensional, reconstructed magnetic resonance image (upper) shows a cavity caused by a spinal injury nearly filled with grafted neural stem cells, colored green. The lower image depicts neuronal outgrowth from transplanted human neurons (green) and development of putative contacts (yellow dots) with host neurons (blue).
An international team led by researchers at the University of California, San Diego School of Medicine reports that a single injection of human neural stem cells produced neuronal regeneration and improvement of function and mobility in rats impaired by an acute spinal cord injury (SCI).
The findings are published in the May 28, 2013 online issue of Stem Cell Research & Therapy.
Martin Marsala, MD, professor in the Department of Anesthesiology, with colleagues at UC San Diego and in Slovakia, the Czech Republic and The Netherlands, said grafting neural stem cells derived from a human fetal spinal cord to the rats’ spinal injury site produced an array of therapeutic benefits – from less muscle spasticity to new connections between the injected stem cells and surviving host neurons.
“The primary benefits were improvement in the positioning and control of paws during walking tests and suppression of muscle spasticity,” said Marsala, a specialist in spinal cord trauma and spinal injury-related disorders. Spasticity – exaggerated muscle tone or uncontrolled spasms – is a serious and common complication of traumatic injury to the spinal cord.
The human stem cells, said the scientists, appeared to vigorously take root at the injury site.
“In all cell-grafted animals, there was robust engraftment, and neuronal maturation of grafted human neurons was noted,” Marsala said. “Importantly, cysts or cavities that can form in or around spinal injuries were not present in any cell-treated animal. The injury-caused cavity was completely filled by grafted cells.”
The rats received the pure stem cell grafts three days after injury (no other supporting materials were used) and were given drugs to suppress an immune response to the foreign stem cells. Marsala said grafting at any time after the injury appears likely to work in terms of blocking the formation of spinal injury cavities, but that more work would be required to determine how timing affects functional neurological benefit.
These photomicrographs depict comparative stained sections of a healthy brain (top) and of patient EP, in which significant structures in the medial temporal lobe are heavily damaged or missing. The letters identify specific brain structures, such as EC and PRC for entorhinal cortex and perirhinal cortex, respectively, both important to memory formation and function.
Gone, But Not Forgotten
UC San Diego scientists recall EP, perhaps the world’s second-most famous amnesiac
An international team of neuroscientists has described for the first time in exhaustive detail the underlying neurobiology of an amnesiac who suffered from profound memory loss after damage to key portions of his brain.
Writing in this week’s Online Early Edition of PNAS, principal investigator Larry R. Squire, PhD, professor in the departments of Neurosciences, Psychiatry and Psychology at the University of California, San Diego School of Medicine and Veteran Affairs San Diego Healthcare System (VASDHS) – with colleagues at UC Davis and the University of Castilla-La Mancha in Spain – recount the case of EP, a man who suffered radical memory loss and dysfunction following a bout of viral encephalitis.
EP’s story is strikingly similar to the more famous case of HM, who also suffered permanent, dramatic memory loss after small portions of his medial temporal lobes were removed by doctors in 1953 to relieve severe epileptic seizures. The surgery was successful, but left HM unable to form new memories or recall people, places or events post-operation.
HM (later identified as Henry Gustav Molaison) was the subject of intense scientific scrutiny and study for the remainder of his life. When he died in 2008 at the age of 82, he was popularized as “the world’s most famous amnesiac.” His brain was removed and digitally preserved at The Brain Observatory, a UC San Diego-based lab headed by Jacopo Annese, PhD, an assistant adjunct professor in the Department of Radiology and a co-author of the PNAS paper.
Like Molaison, EP was also something of a scientific celebrity, albeit purposefully anonymous. In 1992, at the age of 70, he was diagnosed with viral encephalitis. He recovered, but the illness resulted in devastating neurological loss, both physiologically and psychologically.
Not only did he also lose the ability to form new memories, EP suffered a modest impairment in his semantic knowledge – the knowledge of things like words and the names of objects. Between 1994, when he moved to San Diego County, and his death 14 years later, EP was a subject of continued study, which included hundreds of different assessments of cognitive function.
“The work was long-term,” said Squire, a Career Research Scientist at the VASDHS. “We probably visited his house 200 times. We knew his family.” In a 2000 paper, Squire and colleagues described EP as a 6-foot-2, 192-pound affable fellow with a fascination for the computers used in his testing. He was always agreeable and pleasant. “He had a sense of humor,” said Squire.