School of Medicine retreat focuses on applications in research, patient care and education.

(From left) Joseph DeRisi, Clay Johnston, Sam Hawgood, UC San Francisco

In the world of bioinformatics, the rush is on to extract gold from a data mine.

The amount of data that health care providers and scientists collect from patients and research participants is growing explosively. This information ranges from the genetic to laboratory tests and imaging exams, to medical histories and information about treatment and outcomes — and in some cases to survey data on large populations.

This deluge of data and the bioinformatics capabilities necessary to take advantage of it were the focus of this year’s daylong UC San Francisco School of Medicine leadership retreat on Jan. 20. In his welcome address, Dean Sam Hawgood, M.B.B.S., outlined his goal for the day — to engage campus leaders in the question of how to optimally develop, organize and integrate clinical-outcome data, research data, business intelligence, and population data so that information is accessible and usable to empower research and improve medical practice.

Making greater use of available data to improve care

Some have compared efforts to take advantage of the data to trying to drink from a fire hose. Consider DNA as an example. Our genetic variations contain clues to disease risk, disease prognosis and treatment response. The identification of such clues by scientists and their translation into medical practice is a major enterprise. Soon, expense will no longer be a major limitation to obtaining a readout of an individual’s entire genetic makeup. “A complete human genome assay will be an assay like any other, at least in terms of cost and time,” Hawgood said.

However, as vivid as the water hose analogy may be, it might be more apt to say that in many organizations data of many types dwells in various unconnected dammed reservoirs, with little of it flowing to potential users.

Much of the day’s discussions centered not only on identifying data to collect and on ways to use this data, but also on how best to “unlock the data” that already exists.

In introducing the day’s theme, Hawgood said that in his view, UCSF, despite the depth and range of clinical and research data being collected, must develop ways to make much greater use of available data in the day-to-day workflow to improve research and patient care.

UCSF’s leaders in informatics can learn from what others have already done. “We want to take enough time to make sure that we’re not repeating other people’s mistakes,” Hawgood said.

Already this year UCSF is completing implementation of a new electronic medical records system, called APeX, tailored to UCSF by EPIC Systems Corp. of Madison, Wis. The system features a single, comprehensive record for each patient.

Apart from being a boon to physicians and other care providers, information within the new clinical record can be “de-identified” to protect privacy and then made available to researchers.

The experience gained from the implementation and the system itself may be a good jumping off point for using data to advance research and education. But the true potential of APeX as a platform to support collaborative research is still being investigated. Taking full advantage of UCSF medical records for research — and enabling ways for new research findings to be used to better guide patient care — will require new innovations.

UCSF already has convened a task force, soliciting input from an external team of international leaders in the field, to explore strategies to bolster bioinformatics on campus, including the establishment of new academic programs and infrastructure through which computer sciences faculty and other bioinformatics experts could be recruited, new experts trained, and novel research collaborations launched. In addition, Hawgood noted, thanks to UCSF’s proximity to Silicon Valley, “We are in a spectacular region for partnerships.”

UCSF is exploring how to accomplish its bioinformatics goals within UCSF and its affiliates, as well as ways in which to access and use data in research networks that span institutions. In addition, there is a need to share information with other providers to provide the best care to patients who also obtain health care outside of UCSF, a theme discussed at last year’s School of Medicine retreat as well.

Using hospital systems as living laboratories

In his keynote address at this year’s retreat, “Aligning the Academic Health Care Enterprise for Acceleration of Precision Medicine,” Isaac Kohane, M.D., Ph.D., a renowned bioinformatics expert and a professor of pediatrics and health sciences and technology at Harvard Medical School, said that the expense of working with data from clinical records has historically been much more expensive than working with genetic and molecular laboratory data.

Kohane, who co-directs the Harvard Medical School Center for Biomedical Informatics, has led efforts to develop computer systems to allow cheaper use of clinical records data from multiple hospital data systems in the study of genes and disease, while maintaining privacy.

Kohane talked about the potential for “apps” to capture useful information related to health outside of the hospital or clinic — for instance a tool that tallies nutritional information on purchases from the cash register.

In his own research Kohane now combines clinical and genomic data to learn more about cancer and autism, but he also presented research showing that such systems — had they been in place earlier — could have called attention to serious side effects of Vioxx and other drugs much sooner.

Kohane’s described workflows and systems that can better “unlock” clinical data to speed research discovery and its application in medical practice, while lowering the costs of using clinical data.

Imagining UCSF’s future in the Digital Age

Speakers at a morning panel titled “Imagining UCSF’s Future in the Age of Information Technology,” included Opinder Bawa, chief technology officer for the School of Medicine; Michael Blum, M.D., medical director of information technology for the UCSF Medical Center; Catherine Lucey, M.D., vice dean for education; Joe DeRisi, Ph.D., co-chair of the Department of Biochemistry and Biophysics; and moderator Clay Johnston, M.D., Ph.D., director of the Clinical and Translational Science Institute at UCSF and vice chancellor for research.

Not all bioinformatics applications are orchestrated institution-wide from the top down. Panelists and commenters from the audience highlighted a role for applications developed by smaller groups. For instance, as an educational tool, UCSF faculty from the Department of Emergency Medicine have spearheaded implementation of software used by physicians-in-training to respond to simulated clinical scenarios unfolding in real time.

The data collected during these exercises can be used to better understand how long it is likely to take for emergency room physicians to take critical actions — in the management of chest pain or in the ordering of pain medication, for example. In essence, the data can be used to learn more about how we learn, knowledge that can be incorporated into successive generations of teaching tools.

In the coming years, physicians will be trained to become increasingly comfortable using improved, data-driven, decision-making software tools, according to Lucey. “We will be able to teach students how to learn for themselves for 30 to 40 years, and we will free faculty up to teach in person what needs to be taught in person.”

DeRisi described how information on UCSF graduate school applicants is being used to identify factors associated with future success. In addition, he described how extensive data collection is being used to log graduate students’ progress and decision-making throughout their careers —  another way of identifying early career paths that bode well for future success. DeRisi also talked about an information-technology partnership that allows lab notebook entries made on pad devices to be immediately incorporated into a computerized database.

Developing more innovative research, clinical protocols

An afternoon panel — “The Future Is Now” — moderated by Robert Hiatt, M.D., Ph.D., co-chair of the Department of Epidemiology and Biostatistics and deputy director of the UCSF Helen Diller Family Comprehensive Cancer Center, focused on two large-scale collaborative research programs co-led by UCSF researchers in which molecular, clinical and demographic data already are being put to work to develop more innovative research and clinical protocols.

Laura van’t Veer, Ph.D., leader, and Laura Esserman, M.D., co-leader of the cancer center’s breast oncology program, described the ATHENA Breast Health Project, which unites UC academic medical centers in a state-wide collaboration. The project will initially involve 150,000 women throughout California who will be screened for breast cancer and followed for decades.

ATHENA project leaders aim to create common systems to integrate clinical research and care across the UC campuses to advance the science of prevention, screening, diagnosis, and treatment of breast cancer. The collaborators are creating a biospecimen repository that has broad racial and ethnic representation. A major goal is to marshal molecular and clinical data to better personalize breast care, tailoring treatment to the patient and avoiding overtreatment, and to use the information gained to drive innovation in prevention, diagnosis and treatment.

Neil Risch, Ph.D., co-chair of the Department of Epidemiology and Biostatistics at UCSF and director of the UCSF Institute for Human Genetics, along with Catherine Schaefer, Ph.D., director of the Kaiser Permanente Research Program on Genes Environment and Health, described progress to date in building the largest data base of its kind to focus on genetic variation and environmental exposures in an older population.

The average age of the hundreds of thousands of individuals whose genetic information will be genotyped for the project is 65. The project’s foundation is Kaiser’s electronic health record, which for many Kaiser Permanente members has information spanning decades — including information on clinical diagnosis and treatment as well as lab-test results and prescription information. UCSF expertise has allowed extraordinarily fast genotyping, as well as uniquely large-scale analysis of telomeres to quickly grow the molecular component of the data resource.

The afternoon panel provided a useful point of reference for break-out groups that met afterward, charged with identifying institutional priorities, problems and potential solutions in advancing the use of bioinformatics in research, clinical care and education.

For instance, the ATHENA collaborators have standardized protocols used at the different medical centers, including protocols for mammography screening. To make clinical data more useful for research, some breakout session panelists advocated more extensive standardization of clinical imaging and clinical lab protocols and reporting throughout UCSF clinical practices.

The Kaiser-UCSF collaboration highlights ways to combine strengths across organizations. While Kaiser is famous as a health maintenance organization, UCSF is perhaps best known as a tertiary care center. Some breakout session panelists raised the question — also raised at last year’s retreat — of whether or not the focus of UCSF research should more closely reflect the patient population seen at UCSF and its affiliated medical centers. UCSF specialists routinely gather extensive information on large numbers of patients with serious acute and chronic conditions, including many of the most difficult–to-treat cases. This extensive data is a potential gold mine for research aimed at identifying factors related to disease risk, prognosis and treatment outcomes.

Moving toward a new taxonomy of disease

The retreat followed on the heels of a similarly themed report by the National Academy of Sciences (NAS), “Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease” [PDF] by a committee co-led by UCSF Chancellor Susan Desmond-Hellmann, M.D., M.P.H. The NAS committee advocated the creation of a “knowledge network” that could link researchers in collaborations that span the nation and globe.

The NAS panel envisioned a future in which there is much greater use of genomic and other molecular data to improve and refine the classification of diseases, but also recognized an opportunity to improve research by more extensively taking into account information about how patients fare in the clinic or hospital.

Instead of the current state of affairs, through which biological, pre-clinical and clinical research eventually lead to advances in medical practice, the new paradigm will be a virtuous cycle through which — with appropriate privacy protections — patient data also will feed back into research. In patient care increasing amounts of laboratory information will become available and interpretable more quickly to help teams of caregivers make more accurate and effective decisions and choices in diagnosis, prognosis and treatment for each individual patient.

Newly discovered gene mutations associated with Joubert syndrome, a rare form of autism.

Image using an electron microscope shows a cilium growing from a neuron

A team led by researchers at the University of California, San Diego, School of Medicine reports that newly discovered mutations in an evolved assembly of genes cause Joubert syndrome, a form of syndromic autism.

The findings are published in today’s (Jan. 26) online issue of Science Express.

Joubert syndrome is a rare, recessive brain condition characterized by malformation or underdevelopment of the cerebellum and brainstem. The disease is due specifically to alterations in cellular primary cilia — antenna-like structures found on most cells. The consequence is a range of distinct physical and cognitive disabilities, including poor muscle control and mental retardation. Up to 40 percent of Joubert syndrome patients meet clinical criteria for autism, as well as other neurocognitive disorders, so it is considered a syndromic form of autism.

The cause or causes of Joubert syndrome are not well-understood. Researchers looked at mutations in the TMEM216 gene, which had previously been linked to the syndrome. However, only half of the expected Joubert syndrome patients exhibit TMEM216 gene mutations; the other half did not. Using genomic sequencing, the research team, led by Joseph G. Gleeson, M.D., professor of neurosciences and pediatrics at UC San Diego, broadened their inquiry and discovered a second culprit: mutations in a neighboring gene called TMEM138.

“It is extraordinarily rare for two adjacent genes to cause the same human disease,” said Gleeson. “The mystery that emerged from this was whether these two adjacent, non-duplicated genes causing indistinguishable disease have functional connections at the gene or protein level.”

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DNA mutation found to disrupt cellular function in patients with acute myeloid leukemia.

Norbert Reich, UC Santa Barbara

Researchers at UC Santa Barbara have discovered a molecular pathway that may explain how a particularly deadly form of cancer develops. The discovery may lead to new cancer therapies that reprogram cells instead of killing them. The findings are published in a recent paper in the Journal of Biological Chemistry.

The UC Santa Barbara research team described how a certain mutation in DNA disrupts cellular function in patients with acute myeloid leukemia (AML). The researchers were prompted to study this process by another research team’s discovery that AML patients have a mutation in a certain enzyme, which was reported in the New England Journal of Medicine. The enzyme is a protein called DNMT3A, which leads to changes in how the DNA of AML patients is methylated, or “tagged.” Norbert Reich, professor in the Department of Chemistry and Biochemistry at UC Santa Barbara, was already studying that particular enzyme with his research group, so they began to study the disease process of AML at the cellular level.

Reich explained that tagging is a way of reading DNA at the cellular level. This falls within an area of study called epigenetics, a process that occurs “on top” of genetics. Each person has approximately 200 types of cells, all with the same DNA, and these must be controlled in different ways. “There is an enzyme — a protein — that tags DNA and controls which of the genes in your cells, your DNA, gets turned on and off,” said Reich. “So you have 20,000 genes, and you have to control them differently in your brain than in your liver.”

Reich explained that there is current interest in this broader field of epigenetics as a direction for the treatment of cancer. “There’s definitely the idea that this may be a new way of developing therapeutics, because you don’t have to kill the cancer cell,” said Reich. “Almost every cancer therapy that’s out there works on the principle that a cancer cell needs to be killed.”

With epigenetics, instead of only having DNA sequence coding for certain genes, there is an epigenetic process, with another layer of information on top of the genetic process. In this case, that information is the tagging by the methyl groups.

“If you really think about it, this is part of the answer as to how your cells can be so different and yet they all have the same DNA,” said Reich. “You have the same genome in every one of your cells, but you do not have the same epigenome, which is basically the methylation pattern, the tagging pattern. That is different in every type of your cells. And the way this relates back to cancer, with leukemia, in those patients, the tagging is messed up. The patterns are not correct. Our big contribution to that is we’ve explained how the mutations in the enzyme could lead to that disruption of the tagging pattern.”

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Study to sequence DNA from 4,000 people with epilepsy.

Daniel Lowenstein, UC San Francisco

To probe the genetic secrets of one of the most common neurological diseases, more than 4,000 people with various forms of epilepsy will have their DNA decoded over the next five years in a study led by researchers at the University of California, San Francisco and several collaborating institutions.

“This is the largest, most sophisticated project that has ever been attempted for identifying the genetic causes of epilepsy, and it has come about as the result of a great spirit of collaboration among scientists, clinicians, patients and their family members from throughout the world,” said Daniel Lowenstein, M.D., vice chair of the Department of Neurology and director of the UCSF Epilepsy Center.

Sorting the patients’ DNA sequences and comparing them to their histories, brain scans and other clinical data will help frame understanding of a disease that strikes tens of millions worldwide, including about 2 million people in the United States. The work may also reveal new ways to treat people with epilepsy.

UCSF has been one of the world’s leading institutions involved in epilepsy research for years and has one of the few medical centers in the world with top-ranking departments in the areas most relevant to this research: biomedical imaging, neurology and neurosurgery.

The new project, funded by a $25 million grant from the National Institute of Neurological Disorders and Stroke, follows on the heels of another study known as the Epilepsy Phenome/Genome Project and led by Lowenstein and colleagues worldwide, which is collecting detailed clinical data and DNA samples from 3,750 people with epilepsy and 1,500 of their relatives without the disease.

In addition to sequencing DNA from a larger number of people, the new project will apply cutting-edge methods for identifying disease-causing variations in the genome known as copy number variants (CNVs), and it will look for genetic clues that might explain why an apparently similar form of epilepsy can be responsive to treatment in one patient and not so in another.

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They hope to better understand its cause, aid in development of therapeutics.

The research team prepares to sign the memorandum of understanding for the achondroplasia genetic analysis.

Los Alamos National Laboratory and the Centre for Chemical Biology at Universiti Sains Malaysia (CCB@USM) have launched a human genome project to study an individual with achondroplasia disorder, the most common form of dwarfism.

The project began with the dream of Malaysian graduate student Ling Sze Lee to answer the question “Why am I different?” Using unique methods for high-throughput sequencing of ultra-low quantity chromosomal DNA and advanced sequence analysis, the team and Lee herself hope to identify previously unknown genomic markers for this disease to better understand its cause and to aid in the development of therapeutics and/or methods of prevention. The LANL Genome Science Group has already completed the sequencing of all 23 chromosomes of the study’s volunteer patient, a graduate student at the Universiti Sains Malaysia.

Achondroplasia is the most common cause of short-limbed dwarfism in humans, with the term achondroplasia meaning “without cartilage formation.” In fact, cartilage is formed, but the development of long bones fails to occur completely. This genetic disease has social and medical complications including delayed motor milestones, leg bowing, lower back pain, respiratory complications such as apnea, middle ear disease, speech delay and articulation problems, obesity, and dental crowding. Sequencing the genomes of people with achondroplasia provides clues to diagnosis, treatment, and prevention of this and other genetic diseases.

Prior to this work, a tiny mutation in a growth factor gene (fgfr3), located in chromosome 4, had been identified as the cause of achondroplasia. In an effort to learn more about her own dwarfism, graduate student Lee volunteered to have her genome sequenced.

Lee optimized the isolation of the individual chromosomes from her own blood sample using flow cytometry, and the initial sequence analysis of Lee’s chromosome 4 indicated that the classical diagnostic mutations of achondroplasia and hypochondroplasia were absent.

This result shows that gene fgfr3 is not the only marker for achondroplasia. To identify other possible markers, the remaining 22 chromosomes have been isolated and sequenced. Lee plans to come to Los Alamos in February to spend approximately a month working directly with the Genome Science Group to analyze the genome data. Her hope is that they can identify the alternate cause of her dwarfism — leading to a better understanding of the genetics of the disorder.

Los Alamos National Laboratory and Universiti Sains Malaysia signed a Memorandum of Understanding in September solidifying their joint interest for the application of scientific research and technology development to help tackle this crippling disorder. Funding is from the Malaysia Ministry of Higher Education under an Accelerated Program for Excellence grant.

About Los Alamos National Laboratory

Los Alamos National Laboratory, a multidisciplinary research institution engaged in strategic science on behalf of national security, is operated by Los Alamos National Security, LLC, a team composed of Bechtel National, the University of California, The Babcock & Wilcox Co. and URS for the Department of Energy’s National Nuclear Security Administration.

Los Alamos enhances national security by ensuring the safety and reliability of the U.S. nuclear stockpile, developing technologies to reduce threats from weapons of mass destruction, and solving problems related to energy, environment, infrastructure, health, and global security concerns.

UCLA researchers find genetic link between iron transport and brain structure.

Paul Thompson, UCLA

Iron is a popular topic in health news. Doctors prescribe it for medical reasons, and it’s available over the counter as a dietary supplement. And while it’s known that too little iron can result in cognitive problems, it’s also known that too much promotes neurodegenerative diseases.

Now, researchers at UCLA have found that in addition to causing cognitive problems, a lack of iron early in life can affect the brain’s physical structure as well.

UCLA neurology professor Paul Thompson and his colleagues measured levels of transferrin, a protein that transports iron throughout the body and brain, in adolescents and discovered that these transferrin levels were related to detectable differences in both the brain’s macro-structure and micro-structure when the adolescents reached young adulthood.

The researchers also identified a common set of genes that influences both transferrin levels and brain structure. The discovery may shed light on the neural mechanisms by which iron affects cognition, neurodevelopment and neurodegeneration, they said.

Their findings appear in the current online edition of the journal Proceedings of the National Academy of Sciences.

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In eukaryotes — which include humans — a key to survival is ability of certain proteins to repair genetic errors.

In eukaryotes — the group of organisms that include humans — a key to survival is the ability of certain proteins to quickly and accurately repair genetic errors that occur when DNA is replicated to make new cells.

In a paper published in Friday’s (Dec. 23) issue of the journal Science, researchers at the Ludwig Institute for Cancer Research and the University of California, San Diego, School of Medicine have solved part of the mystery of how these proteins do their job, a process called DNA mismatch repair (MMR).

“One of the major questions in MMR is how MMR proteins figure out which base in a DNA mispair is the wrong one,” said Ludwig Institute assistant investigator Christopher D. Putnam, an adjunct assistant professor of medicine at UC San Diego. “For example, if guanine (G) is inappropriately in a base-pair with thymine (T), is the G or the T the error? Picking the wrong base results in mutations, not fixes.”

Using Saccharomyces cerevisiae, or baker’s yeast, as their model organism, the researchers, led by Richard D. Kolodner, Ludwig Institute investigator and UC San Diego professor of medicine and cellular and molecular medicine, discovered that newly replicated DNA produces a temporary signal for 10 to 15 minutes after replication which helps identify it as new — and thus a potential subject for MMR.

The actual signal was not identified, but Putnam said it might be tell-tale nicks in single-stranded DNA or certain proteins associated with replication. The scientists are working to pinpoint the precise signal.

The findings, combined with earlier, published work that visualized MMR in a living cell for the first time, more fully explains how eukaryotes eliminate DNA replication errors, which can result in defects and the development of cancers.

“How eukaryotes identify the newly synthesized strand of DNA is a mystery that has persisted for at least 30 years,” said Putnam. “These findings really change our ideas of how MMR works,” said Putnam.

Co-authors include Hans Hombauer and Anjana Srivatsan of the Ludwig Institute for Cancer Research, UC San Diego departments of Medicine and Cellular and Molecular Medicine, Institute of Genomic Medicine and UC San Diego Moores Cancer Center.

Funding for this research came from the National Institutes of Health.

UC San Diego researchers lead international team of scientists in study.

Jonathan Sebat, UC San Diego

An international team of scientists, led by researchers at the University of California, San Diego, School of Medicine, reports that abnormal sequences of DNA known as rare copy number variants, or CNVs, appear to play a significant role in the risk for early onset bipolar disorder.

The findings will be published in the Dec. 22 issue of the journal Neuron.

CNVs are genomic alterations in which there are too few or too many copies of sections of DNA. Researchers have known that spontaneously occurring (de novo) CNVs – genetic mutations not inherited from parents – significantly increase the risk for some neuropsychiatric conditions, such as schizophrenia or the autism spectrum disorders. But their role was unclear in bipolar disorder, previously known as manic depression.

Principal investigator Jonathan Sebat, Ph.D., assistant professor of psychiatry and cellular and molecular medicine at UC San Diego’s Institute of Genomic Medicine, and colleagues, found that de novo CNVs contribute significant genetic risk in about 5 percent of early onset bipolar disorder, which appears in childhood or early adulthood.

In other words, said the study’s first author Dheeraj Malhotra, assistant project scientist in Sebat’s lab, “having a de novo mutation increases the chances of having an earlier onset of disease.”

The cause or causes of bipolar disorder remain unclear. There is a clear genetic component – the disease runs in families – but previous studies that have focused mainly on common inherited variants have met with limited success in identifying key susceptibility genes.

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Interaction between immune response and later infection can mean difference between mild fever and death.

Researchers collecting samples from local children, monitored by Eva Harris (right), as part of the UC Berkeley/Sustainable Sciences Institute Pediatric Dengue Cohort Study in Managua, Nicaragua.

One of the most vexing challenges in the battle against dengue virus, a mosquito-borne virus responsible for 50-100 million infections every year, is that getting infected once can put people at greater risk for a more severe infection down the road.

Now, for the first time, an international team of researchers that includes experts from the University of California, Berkeley, has pulled apart the mechanism behind changing dengue virus genetics and dynamics of host immunity, and they are reporting their findings in today’s (Dec. 21) issue of Science Translational Medicine.

The virus that causes dengue disease is divided into four closely related serotypes (dengue virus 1, 2, 3 and 4), and those serotypes can be further divided into genetic variants, or subtypes.

The researchers showed that a person’s prior immune response to one serotype of dengue virus could influence the interaction with virus subtypes in a subsequent infection. How that interaction plays out could mean the difference between getting a mild fever and going into a fatal circulatory failure from dengue hemorrhagic fever or dengue shock syndrome.

The findings have implications for the efforts to combat a disease that has grown dramatically in recent decades, including the development of a first-ever dengue vaccine.

According to the World Health Organization, dengue disease is now endemic in more than 100 countries around the world, and recent estimates say some 3 billion people — almost half of the world’s population — are at risk.

It was already known that upon a person’s first infection with dengue virus, the immune system reacts normally by creating antibodies to fight the viral invaders. The problem is that those antibodies can then be confused if confronted later with one of the other three types of dengue virus and, as this new study revealed, even different subtypes within the same serotype.

“With the second infection, the antibodies sort of recognize the new type of viruses, but not well enough to clear them from the system,” said study lead author Molly OhAinle, postdoctoral fellow in infectious diseases at UC Berkeley’s School of Public Health. “Instead of neutralizing the viruses, the antibodies bind to them in a way that actually helps them invade the immune system’s other cells and spread.”

The study authors noted that this Trojan horse effect has been shown before, but the new research provides an analysis of the interplay between viral genetics and immune response with unprecedented detail, going beyond the main serotype.

Putting the puzzle pieces together required UC Berkeley’s expertise in immunology and virology, the genome analysis and biostatistical capabilities at the Broad Institute of Harvard University and Massachusetts Institute of Technology, and the epidemiological and clinical field work at Nicaragua’s National Virology Laboratory.

Researchers used data from two independent, Nicaragua-based studies headed by Eva Harris, professor of infectious diseases and vaccinology and director of UC Berkeley’s Center for Global Public Health, and Dr. Angel Balmaseda, director of the National Virology Laboratory in Nicaragua. One was a hospital-based study that examined children admitted to the National Pediatric Reference hospital with dengue between 2005 and 2009. The other was a prospective study that had followed 3,800 children since 2004, with blood samples collected annually.

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Grants will support research on cell mechanics and the genetics of common diseases.

David Segal, UC Davis

The W.M. Keck Foundation has awarded $2 million in grants to the University of California, Davis, for research on cell mechanics and the genetics of common diseases.

Professors Gang-Yu Liu, Department of Chemistry, and Ian Kennedy, Department of Mechanical and Aerospace Engineering, received $1 million to develop a new instrument for measuring the mechanics of single cells and using it to study the toxicity of nanoparticles. Associate professor David Segal, Department of Pharmacology, was awarded $1 million to take a novel approach to identifying genetic changes associated with heart disease.

UC Davis is one of only three institutions to receive grants from the foundation’s medical research program this year, and one of only six institutions to receive grants from the foundation’s science and engineering research program.

Liu and Kennedy will use their grant to develop a microscope that can measure the stiffness and other mechanical properties of individual cells, as well as see activity inside them. The new instrument will combine a confocal microscope, which can focus on layers within a living cell, with an atomic force microscope, which can study surfaces in exquisite detail as well as press a tiny bead against a cell and measure its resistance.

Gang-Yu Liu, UC Davis

“We are very excited to accept this grant and extremely grateful to the Keck Foundation for this and past support,” said Winston Ko, dean of the Division of Mathematical and Physical Sciences in the College of Letters and Science.

The foundation’s total philanthropic support to UC Davis exceeds $7.9 million, including previous major grants to faculty to support work on the Large Synoptic Survey Telescope in Chile and the Keck Center for Active Visualization in Earth Sciences, housed at UC Davis.

“I have every reason to believe that professor Liu’s research will lead to the same level of discovery and innovation,” Ko said.

Liu’s laboratory has already demonstrated the potential of the microscope concept in experiments with nerve cells, which become stiffer when they are affected by the prion proteins related to Alzheimer’s disease. The new instrument will be able to test a wider range of cell types and incorporate other features that make it easier to use with live cells, Liu said.

Liu and Kennedy now plan to use the microscope to test whether early signs of damage to endothelial cells — which line the blood vessels and airways, for example — show up as changes in the cells’ mechanical properties. The experiments will use novel nanoparticles made by Kennedy’s lab, which combine tiny particles of metal oxides — similar to particles that are widespread in the environment, and that are also becoming common in products such as sunscreens — with gold or other elements that allow the particles to be tracked within cells.

The new microscope will help to answer questions that are difficult to address with current technology. Zinc oxides, for example, are used in some sunscreens and also occur naturally in the environment. There is some evidence that they can cause damage to cells, but no clear scientific consensus about how serious the problem is, Kennedy said.

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Childhood disorder called PKD that causes epileptic seizures linked to genetic mutations.

Louis Ptacek, UC San Francisco

A large, international team of researchers led by scientists at the University of California, San Francisco, has identified the gene that causes a rare childhood neurological disorder called PKD/IC, or “paroxysmal kinesigenic dyskinesia with infantile convulsions,” a cause of epilepsy in babies and movement disorders in older children.

The study involved clinics in cities as far flung as Tokyo, New York, London and Istanbul and may improve the ability of doctors to diagnose PKD/IC, and it may shed light on other movement disorders, like Parkinson’s disease.

The culprit behind the disease turns out to be a mysterious gene found in the brain called PRRT2. Nobody knows what this gene does, and it bears little resemblance to anything else in the human genome.

“This is both exciting and a little bit scary,” said Louis Ptacek, M.D., who led the research. Ptacek is the John C. Coleman Distinguished Professor of Neurology at UCSF and a Howard Hughes Medical Institute Investigator.

Discovering the gene that causes PKD/IC will help researchers understand how the disease works. It gives doctors a potential new way of definitively diagnosing the disease by looking for genetic mutations in the gene. The work may also shed light on other conditions that are characterized by movement disorders, including possibly Parkinson’s disease.

“Understanding the underlying biology of this disease is absolutely going to help us understand movement disorders in general,” Ptacek said.

PKD/IC strikes infants with epileptic seizures that generally disappear within a year or two. However, the disease often reemerges later in childhood as a movement disorder in which children suffer sudden, startling, involuntary jerks when they start to move. Even thinking about moving is enough to cause some of these children to jerk involuntarily.

The disease is rare, and Ptacek estimates strikes about one out of every 100,000 people in the United States. At the same time, the disease is classified as “idiopathic” — which is just another way of saying we don’t really understand it, Ptacek said.

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Genetic trigger discovered that makes the nose renew its smell sensors.

Elongated green cells are sensory neurons; cells labeled in red are immature cells

University of California, Berkeley, neuroscientists have discovered a genetic trigger that makes the nose renew its smell sensors, providing hope for new therapies for people who have lost their sense of smell due to trauma or old age.

The gene tells olfactory stem cells ‑ the adult tissue stem cells in the nose ‑ to mature into the sensory neurons that detect odors and relay that information to the brain.

“Anosmia ‑ the absence of smell ‑ is a vastly underappreciated public health problem in our aging population. Many people lose the will to eat, which can lead to malnutrition, because the ability to taste depends on our sense of smell, which often declines with age,” said lead researcher and campus neuroscientist John Ngai.

“One reason may be that as a person ages, the olfactory stem cells age and are less able to replace mature cells, or maybe they are just depleted,” he said. “So, if we had a way to promote active stem cell self-renewal, we might be better able to replace these lost cells and maintain sensory function.”

Gary K. Beauchamp, director of the Monell Chemical Senses Center in Philadelphia, who was not a member of the research team, noted that the olfactory system stands out for its ability to regenerate following injury or certain diseases

“This new paper … presents an elegant analysis of some of the underlying genetic mechanisms regulating this regeneration,” Beauchamp said. “It also provides important insights that should eventually allow clinicians to enhance regeneration, induce it in cases where, for currently unknown reasons, olfactory loss appears permanent, or even prevent functional loss as a person ages.”

The discovery may also help scientists harness olfactory stem cells and stem cells found in other sensory systems more generally, to recover sensory function following injury or degenerative disease, said Ngai, the Coates Family Professor of Neuroscience in UC Berkeley’s Department of Molecular and Cell Biology and director of the Helen Wills Neuroscience Institute and the QB3 Functional Genomics Laboratory.

Ngai, post-doctoral fellow Russell B. Fletcher and their UC Berkeley colleagues report their findings in the Dec. 8 issue of the journal Neuron.

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